March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Chapter 15. Addition to Carbon–Carbon Multiple Bonds

15.C. Reactions

15.C.i. Isomerization of Double and Triple Bonds

15-1 Isomerization

Without a transition metal catalyst, there is usually a rather high-energy barrier for the excited state required for (E/Z) isomerization.¹⁴⁶ The transition metal catalyzed isomerization of an alkene from (E) to (Z) or (Z) to (E) is a well-studied reaction.¹⁴⁷ Among the metals used, Pt is widely used, and rather selective.¹⁴⁸ The Pd catalyzed isomerization of (Z)-alkenes to (E)-alkenes required the presence of Bu₃SnH.¹⁴⁹ However, a 1:1 mixture of cis/trans-styrene derivatives was isomerized to a 90% yield of the trans-styrene derivatives reported using a Pd catalyst.¹⁵⁰ Isomerization of cyclic alkenes is difficult for rings of seven members and less, but cis/trans isomerization of cyclooctene is induced photochemically.¹⁵¹ Radical-induced (E/Z) isomerization is known.¹⁵² Isomerization of the C=C units in dienes is also induced photochemically.¹⁵³

In a different type of reaction, isomerization of alkynes to 1,3-dienes is possible using Rh or Pd catalysts.¹⁵⁴

There are several reagents that lead to isomerization of a double bond to form a new alkene. In general, there is an energetic preference of an α,β- versus β,γ-double bond.¹⁵⁵ Allylic arenes (Ar–CH₂CH=CH₂) have been converted to the corresponding (Z)-1-propenyl arene (Ar–CH=CHMe using an Ru catalyst¹⁵⁶ or a polymer-supported Ir catalyst.¹⁵⁷ In the presence of a Rh catalyst, certain allylic amines are converted to an enamine with high selectivity for the (Z) isomer.¹⁵⁸ Double-bond migration has been observed in sulfide photoirradiation, induced by singlet oxygen.¹⁵⁹ Many of these reactions were discussed in Reaction 12-2.

For conjugated carbonyl compounds that have a hydrogen atom at the γ-position (C-4), it is possible to move a double bond out of conjugation. Photolysis of conjugated esters, at −40 °C in the presence of N,N-dimethylaminoethanol, gave the nonconjugated ester.¹⁶⁰ Heating an N-allylic amide (N–C–C=C) with Fe(CO)₅, neat, gave the enamide (N–C=C–C).¹⁶¹ Conjugated aldehydes have been isomerized using thiourea in DMF.¹⁶²

Double bonds of atoms other than carbon are subject to isomerization. Azobenzenes (Ar–N=N–Ar) exist as (E) and (Z) isomers, and photochemical isomerization is possible.¹⁶³

15.C.ii. Reactions in Which Hydrogen Adds to One Side

A. Halogen on the Other Side

15-2 Addition of Hydrogen Halides

Hydro-halo-addition

Any of the four hydrogen halides can be added to double bonds.¹⁶⁴ Alkenes react as Brnsted–Lowry bases with HI, HBr, and HF¹⁶⁵ at room temperature, but reaction with HCl is more difficult and usually requires heat.²⁴Hydrogen Chloride adds easily in the presence of silica gel. However,¹⁶⁶ HF is difficult to handle, but a convenient method for the addition of HF involves the use of a polyhydrogen fluoride–pyridine solution in THF.¹⁶⁷

The addition of hydrogen halides to simple alkenes, in the absence of peroxides, takes place by an electrophilic mechanism, and the orientation is in accord with Markovnikov's rule.¹⁶⁸ In other words, the π bond of the alkenes donates two electrons to the acidic proton of H–X. The addition follows second-order kinetics.¹⁶⁹ When peroxides are added, the addition of HBr occurs by a free-radical mechanism and the orientation is anti-Markovnikov (Sec. 15.B.i).¹⁷⁰ It must be emphasized that this is true only for HBr. Free radical addition of HF and HI has never been observed, even in the presence of peroxides; free radical addition of HCl has been observed only rarely. In the rare cases where free radical addition of HCl was noted, the orientation was still Markovnikov, presumably because the more stable product was formed.¹⁷¹ Free radical addition of HF, HI, and HCl is energetically unfavorable (see the discussions in Sec. 14.B.i and 14.C.i). It is known that under some conditions anti-Markovnikov addition of HBr takes place even when peroxides have not been added. This happens because the substrate alkenes absorb oxygen from the air, forming small amounts of peroxides (Reaction 14-7). Markovnikov addition can be ensured by rigorous purification of the substrate, but in practice this is not easy to achieve. It is more common to add inhibitors (e.g., phenols or quinones), which suppress the free radical pathway. The presence of free radical precursors (e.g., peroxides) does not inhibit the ionic mechanism, but does inhibit the more rapid radical reaction, which is a chain process. In most cases, it is possible to control the mechanism (and hence the orientation) by adding peroxides to achieve complete free radical addition, or inhibitors to achieve complete electrophilic addition, although there are some cases where the ionic mechanism is fast enough to compete with the free radical mechanism and complete control cannot be attained. Markovnikov addition of HBr, HCl, and HI has also been accomplished, in high yields, by the use of phase transfer catalysis.¹⁷² For alternative methods of adding HBr (or HI) with anti-Markovnikov orientation, see Reaction 12-31.

Alkynes also react as bases with acids (e.g., HX). It is possible to add 1¹⁷³ or 2 equiv of any of the four hydrogen halides to triple bonds. Markovnikov's rule ensures that gem-dihalides and not vic-dihalides are the products of the addition of 2 equiv.

Chlorotrimethylsilane can be added to alkenes to give alkyl chlorides. 1-Hexene reacts with Me₃SiCl in water, for example, to give 2-chlorohexane.¹⁷⁴ Treatment of an alkene with KHF₂ and SiF₄ leads to the alkyl fluoride,¹⁷⁵ and bromotrimethylsilane adds to alkynes to give the vinyl bromide.¹⁷⁶

Brnsted–Lowry acids (e.g., HX) are electrophilic reagents, and many polyhalo or polycyano alkenes do not react with them in the absence of free radical conditions. Vinylcyclopropanes, however, react with opening of the cyclopropane ring to give a homoallylic chloride.¹⁷⁷ When such reactions do occur, however, they take place by a nucleophilic addition mechanism, that is, initial attack is by X⁻. This type of mechanism also occurs with Michael-type substrates (C=C–Z),¹⁷⁸ where the orientation is always such that the halogen goes to the carbon that does not bear the Z, so the product is of the form X–C–CH–Z, even in the presence of free radical initiators.

The reaction has been carried out with conjugated dienes, where both 1,2- and 1,4-addition are possible. Hydrogen iodide adds 1,4 to conjugated dienes in the gas phase by a pericyclic mechanism:¹⁷⁹

In a related reaction, HX can be added to ketenes¹⁸⁰ to give acyl halides:

OS I, 166; II, 137, 336; III, 576; IV, 238, 543; VI, 273; VII, 59; 80, 129.

B. Oxygen on the Other Side

15-3 Hydration of Double bonds

Hydro-hydroxy-addition

Double bonds can be hydrated by treatment with water and an acid catalyst. Sulfuric acid is a common catalyst, but other acids that have relatively non-nucleophilic counterions, such as nitric, perchloric, or more commonly sulfonic acids (p-toluenesulfonic acid, methanesulfonic acid, etc.) can also be used. The mechanism is electrophilic and begins with attack of the π bond on an acidic proton (Sec. 15.A.i). The resulting carbocation is then attacked by negative species (e.g., HSO₄⁻, or a similar counterion in the case of other acids), to give the initial product (32), which can be isolated in some cases. However, such compounds are rather unstable, and

under the conditions of the reaction are usually hydrolyzed to the alcohol (Reaction 10-4). Under some reaction conditions, other nucleophiles are present in the reaction, either from the solvent or from added compounds. In an aqueous medium, water is a competitive nucleophile, and attack by water forms oxonium ion 33. Products, such as 32, are not involved when other nucleophiles react with the carbocation, and the mechanism is exactly (by the principle of microscopic reversibility) the reverse of El elimination of alcohols (Reaction 17-1).¹⁸¹ The initial carbocation occasionally rearranges to a more stable one. For example, hydration of CH₂=CHCH(CH₃)₂ gives CH₃CH₂COH(CH₃)₂. Hydration of simple alkenes leads to alcohols predicted by Markovnikov's rule.

Oxymercuration¹⁸² (addition of oxygen and mercury) of alkenes followed by in situ treatment with sodium borohydride¹⁸³ (Reaction 12-24), gives an alcohol (see example) under mild conditions, in high yields, and without rearrangement products. For example, treatment of 2-methyl-1-butene with mercuric acetate,¹⁸⁴ followed by NaBH₄, gave 2-methyl-2-butanol. Oxymercuration of alkenes has been reported in water, using cyclodextrins as phase-transfer catalysts.¹⁸⁵

This method, which is applicable to mono-, di-, tri-, and tetraalkyl, as well as phenyl-substituted alkenes, gives almost complete Markovnikov addition. Hydroxy, methoxy, acetoxy, halo, and other groups may be present in the substrate, and generally do not cause difficulties.¹⁸⁶ When two double bonds are present in the same molecule, changing the carboxylic acid ligand of the mercuric salt allows oxymercuration of the less-substituted one without affecting the other, with ultrasound.¹⁸⁷ A related reaction treats an alkene with zinc borohydride on silica gel to give a 35:65 mixture of secondary/primary alcohols.¹⁸⁸

With substrates of the type C=C–Z (Z is as defined in Sec.15.A.ii) the product is almost always HO–C–CH–Z and the mechanism is usually nucleophilic,¹⁸⁹ although electrophilic addition gives the same product¹⁹⁰ since a cation CH–C–Z would be destabilized by the positive charges (full or partial) on two adjacent atoms. However, the α-hydroxy compound HC–CH(OH)Z, was obtained by treatment of the substrate with O₂, PhSiH₃, and a manganese-complex catalyst.¹⁹¹ Addition of water to RCH=CZZ′ substrates may result in cleavage of the adduct to give an aldehyde and CH₂ZZ′ (34).¹⁹² The cleavage step is an example of Reaction 12-41.

For another method of anti-Markovnikov hydration, see hydroboration (Reaction 15-16).

Indirect hydration, with anti-Markovnikov orientation, was achieved by treatment of the alkene with a 1:1 mixture of PhCH₂NEt₃⁺ BH₄⁻ and Me₃SiCl, followed by addition of an aqueous solution of K₂CO₃.¹⁹³ Reaction of alkenes with Ti(BH₄)₃, and then aq K₂CO₃ also leads to the anti-Markovnikov alcohol.¹⁹⁴ Alkenes react with PhO₂BH and a Nb catalyst, followed by oxidation with NaOO⁻, to give the alcohol,¹⁹⁵ and Cp₂TiCl₄ can also be used.¹⁹⁶Conjugated alkenes also react with PhSiH₂ and oxygen, with a Mn catalyst, to give an α-hydroxy ketone.¹⁹⁷ Alkenes react with molecular oxygen in the presence of a Co porphyrin catalyst, and reduction with P(OMe)₃ leads to the secondary alcohol.¹⁹⁸ This procedure has also been used to hydrate conjugated dienes,¹⁹⁹ although conjugated dienes are seldom hydrated.

The addition of water to enol ethers causes hydrolysis to aldehydes or ketones (Reaction 10-6). Ketenes add water to give carboxylic acids (R₂C=C=O → R₂CO₂H) in a reaction catalyzed by acids²⁰⁰:

OS IV, 555, 560; VI, 766. Also see, OS V, 818.

15-4 Hydration of Triple Bonds

Dihydro-oxo-biaddition

The hydration of triple bonds is generally carried out with mercuric ion salts (often the sulfate or acetate or even mercuric oxide) as catalysts.²⁰¹ In contrast to oxymercuration of alkenes, the organomercury intermediate from this reaction is unstable and loss of mercury in situ leads to an enol product. The enol tautomerizes to the ketone (see Sec. 2.N.i), so the isolated product is the ketone from either an internal or terminal alkyne (the OH unit will always be on the more substituted carbon via the more stable secondary vinyl carbocation). Only acetylene gives an aldehyde. With alkynes of the form RCCR′ both possible ketone products are usually obtained. The reaction can be conveniently carried out with a catalyst prepared by impregnating mercuric oxide onto Nafion-H (a superacidic perfluorinated resinsulfonic acid; see Sec. 5.A.ii).²⁰² Gold,²⁰³ In,²⁰⁴ and Ru²⁰⁵ catalysts have been used to convert alkynes to the ketone. Gold(I) catalysts have also been used in the hydration of allenes.²⁰⁶ Internal alkynes were treated with 2-aminophenol in refluxing dioxane using a Pd catalyst to produce the corresponding ketone.²⁰⁷ Lactones have been prepared from trimethylsilyl alkenes containing a hydroxyl unit elsewhere in the molecule, when reacted with molecular oxygen, CuCl₂, and a Pd catalyst.²⁰⁸ When a carboxylic acid that contains a double bond in the chain is treated with a strong acid, the intramolecular hydration reaction gives a γ- and/or a δ-lactone, regardless of the original position of the double bond in the chain, since strong acids catalyze double-bond shifts (Reaction 15-1; and see 12-2).²⁰⁹ The double bond always migrates to a position favorable for the reaction, whether this has to be toward or away from the carboxyl group. The use of a chiral Cinchonidine alkaloid additive leads to lactone formation with modest enantioselectivity.²¹⁰

The first step of the mercury-mediated mechanism is formation of a complex (35). It is known that ions like Hg²⁺ form complexes with alkynes (Sec. 3.C.i). Water then attacks in an S_N2 type process to give the intermediate 36, which loses a proton to give 37. Hydrolysis of 37 (an example of Reaction 12-34) gives the enol, which tautomerizes to the product. A spectrum of the enol was detected by flash photolysis when phenylacetylene was hydrated photolytically.²¹¹ Note that another possibility for 35 is a mercury-stabilized carbocation rather than a formal three-membered ring complex. In such a carbocation, the carbocation is stabilized by back-donation from the metal, and nucleophilic attack is more like a S_N1 type process.

Metal-free reactions are known, often using strong acids. Phenyl acetylene was converted to acetophenone [e.g., in water at 100 °C with a catalytic amount of Tf₂NH (trifluoromethanesulfonimide)], which is a very powerful acid.²¹² Simple alkynes can also be converted to ketones by heating with formic acid, without a catalyst.²¹³ Metal-free hydration of terminal alkynes occurs by reacting water, heated with microwave irradiation, to give the corresponding methyl ketone.²¹⁴ 1-Selenoalkynes (e.g., PhSe-CC-Ph) react with tosic acid in dichloromethane to give a seleno ester [PhSeC(=O)SH₂Ph] after treatment with water.²¹⁵ Allenes can be hydrolyzed to ketones using an acid catalyst.²¹⁶

Carboxylic esters, thiol esters, and amides can be made, respectively, by acid-catalyzed hydration of acetylenic ethers, thioethers,²¹⁷ and ynamines, without a mercuric catalyst.²¹⁸

This is ordinary electrophilic addition, with rate-determining protonation as the first step.²¹⁹ Certain other alkynes have also been hydrated to ketones with strong acids in the absence of mercuric salts.²²⁰

Catalysts have been developed for the anti-Markovnikov hydration of alkynes.²²¹ When 1-octyne was heated with water, isopropyl alcohol and a Ru catalyst, for example, the product was octanal.²²² The presence of certain functionality can influence the regioselectivity of hydration.

A Ni catalyzed reaction has been reported between alkynes and allyl phenyl sulfides to give thioallylation.²²³

OS III, 22; IV, 13; V, 1024.

15-5 Addition of Alcohols and Phenols

Hydro-alkoxy-addition

Just as water adds to an alkene via hydration to form an alcohol, alcohols can also add to form an ether. Addition of alcohols and phenols to double bonds is catalyzed by acids or bases. When the reactions are acid catalyzed, the mechanism is electrophilic, where H⁺ of the acid catalyst, is attacked by the π bond. The more stable carbocation is formed and subsequently attacked by a molecule of alcohol to give an oxonium ion (38).

The addition, therefore, follows Markovnikov's rule. Primary alcohols give better results than secondary, and tertiary alcohols are relatively inactive. This method is convenient for the preparation of tertiary ethers by the use of a suitable alkene (e.g., Me₂C=CH₂). Addition of alcohols to allylic systems can proceed with rearrangement, and the use of chiral additive can lead to asymmetric induction.²²⁴ The uncatalyzed addition of alcohols occurs in supercritical alcohols.²²⁵

Metal-catalyzed addition to alkenes is a useful variation. The Pd catalyzed addition of alcohols to aryl alkenes gives the ether.²²⁶ The Au(III)–CuCl₂ catalyzed reaction of alcohols and alkenes gives the ether.²²⁷ Gold(I) catalyzed intermolecular addition of phenols leads to aryl ethers.²²⁸

Alcohols add intramolecularly to alkenes to generate cyclic ethers, and the product often bears a hydroxyl unit,²²⁹ but not always.²³⁰ Cyclization is facilitated by Re,²³¹ Ti,²³² or Pt compounds,²³³ forming functionalized tetrahydrofurans or tetrahydropyans. Intramolecular addition of alcohols to alkenes can be promoted by a Pd catalyst, but migration of the double bond in the final product is sometimes a problem.²³⁴ Furan derivatives are available from alkene–ketones using CuCl₂ and a Pd²³⁵ Cr,²³⁶ Ag(I),²³⁷ or lanthanide catalyst.²³⁸ A gold catalyst was used with conjugated ketones bearing an alkyne substituent to give fused-ring furans.²³⁹ Note that the reaction of an alkene–alcohol and NIS with a chiral Ti catalyst leads to a THF with a pendant iodoalkyl group, with modest enantioselectivity.²⁴⁰

Alcohols add to alkynes under certain conditions to give vinyl ethers. In an excess of alcohol, and in the presence of a Pt²⁴¹ or a Au catalyst,²⁴² internal alkynes are converted to ketals. The alcohol to alkyne addition reaction is quite useful for the preparation of heterocycles. Dihydrofurans,²⁴³ furans,²⁴⁴ benzofurans,²⁴⁵ and pyran derivatives²⁴⁶ have been prepared using this approach. Tetrahydrofurans bearing an exocyclic double bond (vinylidene tetrahydrofurans) were prepared from alkynyl alcohols and a silver carbonate catalyst.²⁴⁷

Allenes that react with alcohols and allenic alcohols have been converted to THF derivatives bearing a vinyl group at the α-position, using diphenyliodonium salts.²⁴⁸ In the presence of allylic bromide and a Pd catalyst, allenic alcohols lead to allylically substituted dihydrofurans.²⁴⁹ The intramolecular Au(I) catalyzed reaction of alcohols and allenes has been reported.²⁵⁰ Intramolecular addition of alcohols to allenes leads to cyclic vinyl ethers.²⁵¹

Functionalized ethers can be formed in the presence of other reagents. In methanol with a R–Se–Br reagent, alkenes are converted to selenoalkyl ethers (MeO–C–C–SeR).²⁵²

Base-catalyzed reactions are known. For those substrates more susceptible to nucleophilic attack, for example, polyhalo alkenes and alkenes of the type C=C–Z, it is better to carry out the reaction in basic solution, where the attacking species is RO⁻.²⁵³ The reactions with C=C–Z are of the Michael type, and OR goes to the side away from the Z.²⁵⁴

Since triple bonds are more susceptible to nucleophilic attack than double bonds, it might be expected that bases would catalyze addition to triple bonds particularly well. This is the case, and enol ethers and acetals can be produced by this reaction.²⁵⁵ Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids.²⁵⁶ One utilization of this reaction

involves the compound dihydropyran (39), which is often used to protect the OH groups of primary and secondary alcohols²⁵⁷ and phenols.²⁵⁸ When the desired reactions are completed, 40 is easily cleaved by treatment with dilute acids (Reaction 10-6). In base-catalyzed addition to triple bonds, the rate falls in going from a primary to a tertiary alcohol, and phenols require more severe conditions.

Photochemical addition of alcohols to certain double-bond compounds (cyclohexenes, cycloheptenes) is possible²⁵⁹ in the presence of a photosensitizer (e.g., benzene). The mechanism is electrophilic and Markovnikov orientation is found. The alkenes react in their first excited triplet states.²⁶⁰

The oxymercuration–demercuration procedure mentioned in Reaction 15-3 can be adapted to the preparation of ethers in what is known as alkoxymercuration–demercuration (Markovnikov orientation), if the reaction is carried out in an alcohol (ROH) solvent.²⁶¹ For example, oxymercuration of 2-methyl-1-butene in ethanol gives EtMe₂COEt.²⁶² Primary alcohols give good yields when mercuric acetate is used, but for secondary and tertiary alcohols, it is necessary to use mercuric trifluoroacetate.²⁶³ However, even this reagent fails where the product would be a ditertiary ether. It is possible to combine the alcohol reactant with another reagent. The reaction of an alkene with iodine and allyl alcohol, in the presence of HgO, gave the vic-iodo ether.²⁶⁴ Alkene-alcohols react with mercuric trifluoroacetate and the aq KBr (with LiBH₄/BEt₃) to give a THF derivative bearing an iodoalkyl substituent [–O–C–CH(I)R].²⁶⁵ Alkynes generally react under the same conditions to give acetals. If the oxymercuration is carried out in the presence of a hydroperoxide instead of an alcohol, the product (after demercuration with NaBH₄) is an alkyl peroxide (peroxy-mercuration).²⁶⁶ This can be done intramolecularly.²⁶⁷

Both alcohols and phenols add to ketenes to give carboxylic esters [R₂C=C=O + ROH → R₂CHCO₂R].²⁶⁸ This has been done intramolecularly (with the ketene end of the molecule generated and used in situ) to form medium- and large-ring lactones.²⁶⁹ In the presence of a strong acid, ketene reacts with aldehydes or ketones (in their enol forms) to give enol acetates. 1,4-Asymmetric induction is possible when chiral alcohols add to ketenes.²⁷⁰

OS III, 371, 774, 813; IV, 184, 558; VI, 916; VII, 66, 160, 304, 334, 381; VIII, 204, 254; IX, 472.

15-6 Addition of Carboxylic Acids to Form Esters

Hydro-acyloxy-addition

Carboxylic esters are produced by the addition of carboxylic acids to alkenes, a reaction that is usually acid catalyzed (by Brnsted–Lowry or Lewis acids²⁷¹) and similar in mechanism to Reaction 15-5. Since Markovnikov's ruleis followed, hard-to-get esters of tertiary alcohols can be prepared from alkenes of the form R₂C=CHR.²⁷² Carboxylic esters have also been prepared by the acyloxymercuration–demercuration of alkenes (similar to the procedures mentioned in Reactions 15-3 and 15-4).²⁷³ Addition of carboxylic acids to alkenes to form esters or lactones is catalyzed by Pd compounds.²⁷⁴ Thallium acetate also promotes this cyclization reaction.²⁷⁵ Diene carboxylic acids have been cyclized using acetic acid and a Pd catalyst to form lactones that have an allylic acetate moiety elsewhere in the molecule.²⁷⁶

Triple bonds can give enol esters²⁷⁷ or acylals when treated with carboxylic acids. Mercuric salts are usually catalysts,²⁷⁸ and vinylmercury compounds (RO₂C–C=C–HgX) are intermediates,²⁷⁹ but Ru complexes have also been used.²⁸⁰ Terminal alkynes (RCCH) react with CO₂, a secondary amine (R′₂NH), and a Ru complex catalyst, to give enol carbamates [RCH=CHOC(=O)NR].²⁸¹ This reaction has also been performed intramolecularly, to produce unsaturated lactones.²⁸² Cyclic unsaturated lactones (internal vinyl esters) have been generated from alkyne-carboxylic acids using a Pd²⁸³ or a Ru catalyst.²⁸⁴ Carboxylic esters can also be obtained by the addition to alkenes of diacyl peroxides.²⁸⁵ These reactions are catalyzed by Cu and are free radical processes.

Allene carboxylic acids have been cyclized to butenolides with copper(II) chloride.²⁸⁶ Allene esters were converted to butenolides by treatment with acetic acid and LiBr.²⁸⁷ Cyclic carbonates can be prepared from allene alcohols using carbon dioxide and a Pd catalyst.²⁸⁸ Carboxylic acids react with ketenes to give anhydrides²⁸⁹ and acetic anhydride is prepared industrially in this manner [CH₂=C=O + MeCO₂H → (MeC=O)₂O].

Sulfonic acids add to alkenes and alkynes. The reaction of an alkyne with p-toluenesulfonic acid and treatment with silica gives the vinyl sulfonate (C=C–OSO₂Tol).²⁹⁰ Cyclic sulfonates can be generated by the reaction of an allylic sulfonate salt (C=C–C–OSO₃⁻) with silver nitrate in acetonitrile containing an excess of bromine and a catalytic amount of water.²⁹¹ Sultones are formed when alkenes react with PhIO and 2 equiv of Me₂SiSO₃Cl.²⁹²

OS III, 853; IV, 261, 417, 444; V, 852, 863; VII, 30, 411. Also see, OS I, 317.

C. Sulfur on the Other Side

15-7 Addition of H₂S and Thiols

Hydro-alkylthio-addition

Hydrogen sulfide (H₂S) and thiols add to alkenes to give alkyl thiols or sulfides by electrophilic, nucleophilic, or free radical mechanisms.²⁹³ In the absence of initiators, the addition to simple alkenes is by an electrophilic mechanism, similar to that in Reaction 15-5, and Markovnikov's rule is followed. However, this reaction is usually very slow and often cannot be done or requires very severe conditions unless a Brnsted–Lowry or Lewis acid catalyst is used. For example, the reaction can be performed in concentrated H₂SO₄²⁹⁴ or with the addition of AlCl₃.²⁹⁵ In the presence of free radical initiators, H₂S and thiols add to double and triple bonds by a free radical mechanism and the orientation is anti-Markovnikov.²⁹⁶ Anti-Markovnikov addition of thiols to vinyl ethers occurs under solvent- and catalyst-free conditions,²⁹⁷ and is promoted by water.²⁹⁸

Additives can influence the regioselectivity. Styrene reacts with thiophenol to give primarily the anti-Markovnikov product, whereas addition of thiophenol in the presence of Montmorillonite K-10 clay gives primarily the Markovnikov addition product.²⁹⁹ The addition of thiophenol to an alkene with a zeolite, however, leads to the anti-Markovnikov sulfide.³⁰⁰ In fact, the orientation can be used as a diagnostic tool to indicate which mechanism is operating. Free radical addition can be done with H₂S, RSH (R may be primary, secondary, or tertiary), ArSH, or RCOSH.³⁰¹ The R group may contain various functional groups. The alkenes may be terminal, internal, contain branching, be cyclic, and have various functional groups including OH, CO₂H, CO₂R, NO₂, RSO₂, and so on. Addition of Ph₃SiSH to terminal alkenes under radical conditions also leads to the primary thiol.³⁰²

Alkynes react with thiols to give vinyl sulfides. With alkynes it is possible to add 1 or 2 molar equivalents of RSH, giving a vinyl sulfide³⁰³ or a dithioketal, respectively. Thiols also add to alkynes with a Pd catalyst to give vinyl sulfides.³⁰⁴ Thiols add to alkenes under photochemical conditions to form thioethers, and the reaction can be done intramolecularly to give cyclic thioethers.³⁰⁵ Thiocarbonates function as thiol surrogates, converting alkenes to alkyl thiols in the presence of TiCl₄ and CuO.³⁰⁶ Sulfonic acids add to alkynes to give vinyl sulfonates in the presence of a Au catalyst.³⁰⁷ A cesium carbonate catalyzed reaction gives the vinyl sulfide with good (Z)-selectivity.³⁰⁸ The Rh⁻³⁰⁹ In⁻,³¹⁰ organoactinide⁻,³¹¹ organozirconium-,³¹² or Pt catalyzed³¹³ reaction of alkynes with thiols gives the corresponding vinyl sulfide. Similar results were obtained under solvent-free conditions using an alumina–KF system.³¹⁴Alternative preparations are available, as in the reaction of a terminal alkyne with Cp₂Zr(H)Cl followed by PhSCl to give the vinyl sulfide with the SPh unit at the less substituted position (PhCH=CHSPh).³¹⁵ The intramolecular addition of a thiol to an ene–yne, with a Pd catalyst, leads to substituted thiophene derivatives.³¹⁶ Alkenes react with diphenyl disulfide in the presence of GaCl₃ to give the product with two phenylthio units (PhS–C–C–SPh).³¹⁷ The reaction of an alkyne with diphenyl disulfide and a Pd catalyst leads to the bis(vinyl) sulfide (PhS–C=C–SPh).³¹⁸

When thiols are added to substrates susceptible to nucleophilic attack, bases catalyze the reaction and the mechanism is nucleophilic. These substrates may be of the Michael type³¹⁹ or may be polyhalo alkenes or alkynes.²⁵⁵ As with the free-radical mechanism, alkynes can give either vinylic thioethers or dithioacetals:

By any mechanism, the initial product of addition of H₂S to a double bond is a thiol, which is capable of adding to a second molecule of alkene, so that sulfides are often produced: C=C → H–C–C–S–C–C–H. As with alcohols, ketenes add thiols to give thiol esters [R₂C=C=O + RSH → R₂CHCOSR].³²⁰

Selenium compounds (RSeH) add in a similar manner to thiols.³²¹ Vinyl selenides can be prepared from alkynes using diphenyl diselenide and sodium borohydride.³²² A Pd(II) catalyzed reaction of PhSeH with alkynes, in pyridine, also gives the corresponding vinyl selenide.³²³

The conjugate addition of thiols to α,β-unsaturated carbonyl derivatives is discussed in Reaction 15-31.

OS III, 458; IV, 669; VIII, 302. See also, OS VIII, 458.

D. Nitrogen or Phosphorus on the Other Side

15-8 Addition of Ammonia and Amines, Phosphines, and Related Compounds³²⁴

Hydro-amino-addition

Hydro-phosphino-addition

Ammonia and primary and secondary amines add to alkenes in some cases.³²⁵ Ammonia and amines are much weaker acids than water, alcohols, and thiols (see Reactions 15-3, 15-5, and 15-7) and since acids turn NH₃ into the weak acid, the ammonium ion (NH₄⁺), this reaction does not occur by an electrophilic mechanism. The reaction tends to give very low yields, if any, with ordinary alkenes, unless extreme conditions are used (e.g., 178–200 °C, 800–1000 atm, and the presence of metallic Na, for the reaction between NH₃ and ethylene³²⁶). There is, however, a proton-catalyzed hydroamination reaction in which aniline derivatives add to alkenes in the presence of anilinium salts, in 20–90% yield depending on the alkene.³²⁷

There are many examples of transition-catalyzed addition of nitrogen compounds to alkenes, alkynes,³²⁸ and so on. Amines can be added to certain nonactivated alkenes using Pd,³²⁹ Rh,³³⁰ In,³³¹ Ti,³³² Fe,³³³ Ta,³³⁴ Au,³³⁵ Y,³³⁶Mo,³³⁷ and various lanthanide catalysts.³³⁸ 1,3-Dienes,³³⁹ and also allenes,³⁴⁰ undergo hydroamination in the presence of an Au catalyst. Complexation with the metal lowers the electron density of the double bond, facilitating nucleophilic attack.³⁴¹ Markovnikov orientation is observed and the addition is anti.³⁴² Aniline reacts with dienes and a Pd catalyst to give allylic amines.³⁴³ Diene amines react with Sm catalysts to give 2-alkenyl pyrrolidines.³⁴⁴ The mechanism of the Au(I) catalyzed hydroamination reaction of alkenes has been studied.³⁴⁵ It is believed to involve a ligand substitution reaction in the active Au species followed by nucleophile attack of the N-nucleophile on the activated double bond, which is followed by proton transfer from the NH₂ group to the unsaturated carbon atom.

Cyclization reactions are useful variations of this reaction. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a Pd³⁴⁶ Rh,³⁴⁷ Sc,³⁴⁸ Sm,³⁴⁹ Ti,³⁵⁰ Zr,³⁵¹ or a Lu catalyst.³⁵² as well as a lanthanide reagent,³⁵³ or a Y reagent.³⁵⁴ An intramolecular Ca mediated reaction of amino alkenes leads to cyclic amines.³⁵⁵ Alkenyl amines give cyclic amines as the major product, in good yield, when treated with n-butyllithium.³⁵⁶ Reaction of a secondary amine with butyllithium generates an amide base, which reacts with alkenes to give alkyl amines,³⁵⁷ and can add intramolecularly to an alkene to form a pyrrolidine.³⁵⁸ Pyrroles can be generated in this manner.³⁵⁹

Other nitrogen compounds, among them hydroxylamine and hydroxylamines,³⁶⁰ hydrazines, and amides (Reaction 15-9), also add to alkenes. Tertiary amines (except those that are too bulky) add to Michael-type substrates (C=C–Z) in a reaction that is catalyzed by acids like HCl or HNO₃ to give the corresponding quaternary ammonium salts (R₃N⁺–C–C–Z).³⁶¹ The tertiary amine can be aliphatic, cycloalkyl, or heterocyclic (including pyridine). The reaction of NaOH with an amine containing two distal alkene units, followed by addition of a neodymium catalyst, leads to a bicyclic amine.³⁶²

Primary amines add to triple bonds³⁶³ to give enamines that have a hydrogen on the nitrogen and (analogously to enols) tautomerize (Sec. 2.N.ii, category 4) to the more stable imines (41).³⁶⁴ The reaction has been done with a Pd,³⁶⁵ a Ti,³⁶⁶ a Ta,³⁶⁷ a Cu,³⁶⁸ or an Au catalyst.³⁶⁹ An intramolecular addition of amines to an alkyne unit in the presence of a Pd catalyst generated heterocyclic or cyclic amine compounds.³⁷⁰ A variation treats an alkynyl imine with CuI to form pyrroles.³⁷¹ N,N-Diphenylhydrazine reacts with diphenyl acetylene and a Ti catalyst to give indole derivatives.³⁷² Treatment of an imine of 2-alkynyl benzaldehyde with iodide gave a functionalized isoquinoline.³⁷³When ammonia is used instead of a primary amine, the corresponding R₂C=NH imine product is not stable enough for isolation, but polymerizes. Ammonia and primary amines (aliphatic and aromatic) add to conjugated diynes to give pyrroles (42).³⁷⁴ Anti-Markovnikov addition of alkynes is possible using a Cu catalyst.³⁷⁵

A related reaction of amines and alkynes, in supercritical CO₂, leads to amides.³⁷⁶

Allenes are reaction partners,³⁷⁷ and amines add to allenes in the presence of a catalytic amount of CuBr,³⁷⁸ Au,³⁷⁹ or Pd compounds.³⁸⁰ Intramolecular reaction of allene amines leads to dihydropyrroles, using a Au catalyst.³⁸¹Cyclic imines can be prepared from allene amines using a Ti catalyst.³⁸²

A NH₂ or NR₂ unit can be added to double bonds (even ordinary double bonds) in an indirect manner by the use of hydroboration (Reaction 15-16) followed by treatment with NH₂Cl or NH₂OSO₂OH (Reaction 12-32). This produces a primary amine with anti-Markovnikov orientation. An indirect way of adding a primary or secondary amine to a double bond consists of aminomercuration to give 43, followed by reduction (see Reaction 15-3 for the analogous oxymercuration–demercuration procedure) to give amine 44.³⁸³ The addition of a secondary amine produces a tertiary amine, while addition of a primary amine gives a secondary amine. The overall orientation follows Markovnikov's rule. For conversion of 43 to other products, see Reaction 15-53.

Phosphines add to alkenes to give alkyl phosphines (45) and to alkynes to give vinyl phosphines. A Pd catalyzed reaction of alkenes and triarylphosphines gives alkyltriarylphosphonium salts.³⁸⁴ Alkenes also react with diarylphosphines and a Ni catalyst to give the alkyl phosphine.³⁸⁵ Silylphosphines (R₃Si–PAr₂) react with alkenes and Bu₄NF to give the anti-Markovnikov allyl phosphine.³⁸⁶ Phosphine oxides can be prepared by the reaction of an aryl substituted alkene and diphenylphosphine oxide, Ph₂P(=O)H.³⁸⁷ Phosphonate esters were similarly prepared from alkenes and diethyl phosphite [(EtO)₂P(=O)H] and an Mn catalyst in a reaction exposed to oxygen.³⁸⁸ Similar addition was observed in the reaction of an alkene with NaH₂PO₂ to give the phosphinate [RCH=CH₂ → RCH₂CH₂PH(=O)ONa].³⁸⁹ Palladium catalysts were used for the preparation of similar compounds from alkenes³⁹⁰ and the reaction of terminal alkynes with dimethyl phosphite and a Ni catalyst gave the Markovnikov vinyl phosphonate ester.³⁹¹

In the presence of an Yb catalyst, diphenylphosphine added to diphenyl acetylene to give the corresponding vinyl phosphine.³⁹² A Pd catalyst was used for the addition of diphenylphosphine to terminal alkynes, giving the anti-Markovnikov vinyl phosphine, but a Ni catalyst led to the Markovnikov vinyl phosphine.³⁹³ A Co catalyst has also been used.³⁹⁴ Diphenylphosphine oxide also reacted with terminal alkynes to give the anti-Markovnikov vinyl phosphine oxide using an Rh catalyst.³⁹⁵ Other phosphites were added to dienes to give an allylic phosphonate ester using a Pd catalyst.³⁹⁶ Diarylphosphines react with vinyl ethers and a Ni catalyst to give α-alkoxy phosphonate esters.³⁹⁷

OS I, 196; III, 91, 93, 244, 258; IV, 146, 205; V, 39, 575, 929; VI, 75, 943; VIII,188, 190, 536; 80, 75. See also, OS VI, 932.

15-9 Addition of Amides

Hydro-amido-addition

Under certain conditions, primary and secondary amides can add directly to alkenes to form N-alkylated amides. Sulfonamides react in a similar manner. Alkenes react with amides and related compounds in the presence of certain transition metals. The Ti catalyzed reaction of alkenyl N-tosylamines gives N-tosyl cyclic amines.³⁹⁸

The reaction can be done intramolecularly. 3-Pentenamide cyclized to 5-methyl-2-pyrrolidinone by treatment with trifluorosulfonic acid.³⁹⁹ N-Benzyl pent-4-ynamide reacted with tetrabutylammonium fluoride to an alkylidene lactam.⁴⁰⁰ Acyl hydrazine derivatives also cyclize in the presence of hypervalent iodine reagents to give lactams.⁴⁰¹ Treatment of triflamide alkenes with triflic acid gives the corresponding N-triflyl cyclic amine.⁴⁰² Intramolecular cyclization of sulfamate esters, catalyzed by a Rh complex, leads to cyclic sulfamates.⁴⁰³

Alkynes and allenes also react with amides. A Ru/In catalyzed addition of sulfonamides to alkynes leads to cyclic N-sulfonyl derivatives.⁴⁰⁴ Palladium-catalyzed reactions give similar results,⁴⁰⁵ and Bi and Hf have been used as catalysts.⁴⁰⁶ Phenylthiomethyl alkynes were converted to N-Boc-N-phenylthio allenes with Boc azide and an iron catalyst.⁴⁰⁷ Enamides are prepared by the Re⁴⁰⁸ or Ru catalyzed⁴⁰⁹ hydroamidation of terminal alkynes with amides. The Pd catalyzed reaction of an allene amide, with iodobenzene, leads to N-sulfonyl aziridines having an allylic group at C-1.⁴¹⁰ Other allene N-tosylamines similarly give N-tosyl tetrahydropyridines.⁴¹¹

N-Bromocarbamates also add to alkenes, in the presence of BF₃·OEt₂ to give a vic-bromo N-Boc amine.⁴¹² When a carbamate was treated with Bu₃SnH, and AIBN, addition to an alkene led to a bicyclic lactam.⁴¹³ Alkenyl amides and carbamates react with transition metal catalysts to form lactams or cyclic carbamates. Similar addition of a tosylamide–alkene, with a Pd catalyst, led to a vinyl N-tosyl pyrrolidine.⁴¹⁴ Both Pd⁴¹⁵ and Au⁴¹⁶ catalyzed cyclization reactions of carbamates are known, and Os compounds have been used.⁴¹⁷ Ionic liquids have been used to catalyze these reactions.⁴¹⁸

Imides can also add to alkenes or alkynes. Phthalimide reacts with an alkene in the presence of a Pd catalyst.⁴¹⁹ Ethyl 2-propynoate reacted with phthalimide, in the presence of a Pd catalyst, to give ethyl 2-phthalimido-2-propenoate.⁴²⁰

Nickel-catalyzed hydrophosphinylation reactions are known, such as the reaction of an alkyne with an alkyl phosphinate to give a vinyl phosphinate ester.⁴²¹ Both H-phosphinates and secondary phosphine oxides add to alkenes in an anti-Markovnikov manner, induced by air in what is likely a radical reaction.⁴²²

15-10 Addition of Hydrazoic Acid

Hydro-azido-addition

Hydrazoic acid (HN₃) can be added to certain Michael-type substrates (Z is as defined in Sec. 15.A.ii) to give β-azido compounds.⁴²³ The reaction apparently fails if R is phenyl. Hydrazoic acid also adds to enol ethers CH₂=CHOR to give CH₃ –CH(OR)N₃, and to silyl enol ethers,⁴²⁴ but it does not add to ordinary alkenes unless a Lewis acid catalyst (e.g., TiCl₄) is used, in which case good yields of azide can be obtained.⁴²⁴ Hydrazoic acid can also be added indirectly to ordinary alkenes by azidomercuration, followed by demercuration,⁴²⁵ analogous to the

similar procedures mentioned in Reactions 15-3, 15-5, 15-6, and 15-8. The method can be applied to terminal alkenes or strained cycloalkenes (e.g., norbornene), but fails for unstrained internal alkenes. A variation is the hydroazidation reaction of alkenes using a Co catalyst and tert-BuOOH to give the alkyl azide.⁴²⁶

E. Hydrogen on Both Sides

15-11 Hydrogenation of Double and Triple Bonds⁴²⁷

Dihydro-addition

Most carbon–carbon double bonds, whether substituted by electron-donating or electron-withdrawing substituents, can be catalytically hydrogenated, usually in quantitative or near-quantitative yields.⁴²⁸ However, a transition metal catalyst is required to break apart H₂ into metal-bound hydrogen atoms before reaction can occur with the alkene. Almost all known alkenes added hydrogen at temperatures between 0 and 275 °C. The catalysts used can be divided into two broad classes, both of which mainly consist of transition metals and their compounds: (1) Catalysts insoluble in the reaction medium (heterogeneous catalysts). Among the most effective are Raney nickel,⁴²⁹ Pd-on-charcoal (perhaps the most common),⁴³⁰ NaBH₄ reduced nickel⁴³¹ (also called nickel boride), Pt metal or its oxide, Rh, Ru, and zinc oxide,⁴³² (2) Catalysts soluble in the reaction medium (homogeneous catalysts).⁴³³ An important example is chlorotris(triphenylphosphine)rhodium [RhCl(Ph₃P)₃,⁴³⁴ 46, Wilkinson's catalyst),⁴³⁵ which catalyzes the hydrogenation of many alkenyl compounds without disturbing such groups as CO₂R, NO₂, CN, or COR present in the same molecule.⁴³⁶ Even unsaturated aldehydes can be reduced to saturated aldehydes,⁴³⁷ although in this case decarbonylation (Reaction 14-32) may be a side reaction. In general, for catalytic hydrogenation many functional groups may be present in the molecule, for example, OH, COOH, NR₂ (including NH₂), and N(R)COR′ (including carbamates),⁴³⁸ CHO, COR, CO₂R, or CN. Vinyl esters can be hydrogenated using homogeneous Rh catalyst.⁴³⁹Some of these groups are also susceptible to catalytic reduction, but it is usually possible to find conditions under which double bonds can be reduced selectively⁴⁴⁰ (see Table 19.2). Controlling the solvent allows catalytic hydrogenation of an alkene in the presence of an aromatic nitro group.⁴⁴¹

Modification of the catalyst includes a polymer bound Ru catalyst,⁴⁴² and a polymer incarcerated Pd catalyst.⁴⁴³ A nanoparticulate Pd catalyst in an ionic liquid has been used for the hydrogenation of alkenes.⁴⁴⁴

Homogeneous catalysts have the advantages of better catalyst reproducibility and better selectivity. Apart from Wilkinson's catalyst (46), chlorotris(triphenylphosphine)hydridoruthenium(II) [(Ph₃P)₃RuClH]⁴⁴⁵ is an important homogeneous catalyst that is specific for terminal double bonds (other double bonds are hydrogenated slowly or not at all). Homogeneous catalysts are also less susceptible to catalyst poisoning.⁴⁴⁶ Heterogeneous catalysts are usually poisoned by small amounts of sulfur, often found in rubber stoppers, or by thiols and sulfides.⁴⁴⁷ Note that heterogeneous catalysts are usually easier to separate from a reaction mixture.

Using soluble, homogeneous catalysts, unfunctionalized alkenes are hydrogenated with good diastereoselectivity and enantioselectivity⁴⁴⁸ using various metal catalysts (e.g., Ir,⁴⁴⁹ Pd,⁴⁵⁰ or Zr,⁴⁵¹ and chiral ligands).⁴⁵² The chiral transition metal catalyst (Rh and Ru are probably the most common) is usually prepared with suitable chiral ligands prior to addition to the reaction. Alternatively, an achiral catalyst (e.g., Wilkinson's catalyst, 46), is simply added along with a chiral ligand. With monophosphine chiral ligands, ⁴⁵³ the phosphorous may be chiral, as in 47 (called R-camp)⁴⁵⁴ or bis(phosphine) 48 (called dipamp),⁴⁵⁵ but pyramidal inversion at elevated temperatures (see Sec. 4.C) limits the utility of such ligands. The alternative is to prepare phosphines that contain a chiral carbon, as in 49 (known as Chiraphos),⁴⁵⁶ but there are many variations of chiral bis(phosphine) ligands.⁴⁵⁷ Chiral poisoning has been used as a strategy for asymmetric catalysis.⁴⁵⁸

Hydrogenations are carried out at room temperature and just above atmospheric pressure, in most cases, but some double bonds are more resistant and require higher temperatures and pressures. The poor reactivity is usually a function of increasing substitution and is presumably caused by steric factors. Trisubstituted double bonds require, say, 25 °C and 100 atm, while tetrasubstituted double bonds may require 275 °C and 1000 atm. Among the double bonds most difficult to hydrogenate or which cannot be hydrogenated at all are those common to two rings, as in steroid 49. Hydrogenations, even at about atmospheric pressure, are often performed in a special hydrogenator, but this is not always necessary. Indeed, placing a hydrogen-filled balloon over the reaction flask is common for small-scale hydrogenations that do not require heat or pressure. The great variety of catalysts available often allows an investigator to find one that is highly selective. For example, the catalyst Pd(salen) encapsulated in zeolites permitted the catalytic hydrogenation of 1-hexene in the presence of cyclohexene.⁴⁵⁹ It has been shown that the pressure of the reaction can influence enantioselectivity in asymmetric catalytic hydrogenations.⁴⁶⁰

Triple bonds can be reduced, either by catalytic hydrogenation or by the other methods mentioned in the following two sections. The comparative reactivity of triple and double bonds depends on the catalyst. With most catalysts (e.g., Pd), triple bonds are hydrogenated more easily, and therefore it is usually possible to add just 1 equiv of hydrogen and reduce a triple to a double bond or to reduce a triple bond without affecting a double bond present in the same molecule.⁴⁶¹ A particularly good catalyst for this purpose is the Lindlar catalyst (Pd–CaCO₂–PbO),⁴⁶² which gives rather lean syn addition, and a (Z)-alkene. An alternative catalyst used for selective hydrogenation to cis-alkenes is the Pd on a barium sulfate (BaSO₄) catalyst, poisoned with quinoline⁴⁶³ (sometimes called the Rosenmund catalyst). Palladium on calcium carbonate in PEG has also been used as a recyclable catalyst system.⁴⁶⁴ Catalytic hydrogenation of alkynes leads to cis-alkenes with a Pd catalyst and DMF/KOH was found to be an efficient transfer-hydrogen source.⁴⁶⁵ Hydrogenation of a CC unit occurs in the presence of other functional groups, including NR₂ including NH₂,⁴⁶⁶ and sulfonyl.⁴⁶⁷

Conjugated dienes can add hydrogen by 1,2- or 1,4-addition. Selective 1,4-addition can be achieved by hydrogenation in the presence of CO, with bis(cyclopentadienyl)chromium as catalyst.⁴⁶⁸ With allenes,⁴⁶⁹ catalytic hydrogenation usually reduces both double bonds. Hydrogenation of functionalized alkenes is possible. The Rh catalyzed hydrogenation of enamines leads to amines,⁴⁷⁰ for example. Hydrogenation of fluorinated alkenes has been reported using an Ir catalyst.⁴⁷¹ The hydrogenation of conjugated alkenes is discussed in Reaction 15-14.

Most catalytic reductions of double or triple bonds, whether heterogeneous or homogeneous, have been shown to be mostly syn, with the hydrogen atoms incorporated from the less-hindered side of the molecule.⁴⁷² This selectivity depends in large part of how well the reactive intermediates are bound to the metal, and isomerization of the double bond is possible. Stereospecificity can be investigated only for tetrasubstituted alkenes (except when the reagent is D₂), which are the hardest to hydrogenate, but the results of these investigations show that the addition is usually 80–100% syn, although some of the anti-addition product is normally also found and in some cases predominates. Catalytic hydrogenation of alkynes is nearly always stereoselective, giving the cis-alkene (usually at least 80%), even when it is thermodynamically less stable. For example, 50 gave 51, even though the steric hindrance is such that a planar molecule is impossible.⁴⁷³ This is

thus a useful method for preparing cis-alkenes.⁴⁷⁴ However, when steric hindrance is too great, the trans-alkene may be formed. One factor that complicates the study of the stereochemistry of heterogeneous catalytic hydrogenation is that exchange of hydrogen atoms takes place, as can be shown by hydrogenation with deuterium.⁴⁷⁵ Thus deuterogenation of ethylene produced all the possible deuterated ethylenes and ethanes (even C₂H₆), as well as HD.⁴⁷⁶ With 2-butene, it was found that double-bond migration, cis–trans isomerization, and even exchange of hydrogen with groups not on the double bond could occur (e.g., C₄H₂D₈ and C₄HD₉ were detected on treatment of cis-2-butene with deuterium and a catalyst).⁴⁷⁷ Indeed, alkanes have been found to exchange with deuterium over a catalyst,⁴⁷⁸ and even without deuterium (e.g., CH₄ + CD₄ → CHD₃ + CH₃D in the gas phase), with a catalyst. All this makes it difficult to investigate the stereochemistry of heterogeneous catalytic hydrogenation.

The mechanism of the heterogeneous catalytic hydrogenation of double bonds is not thoroughly understood because it is a very difficult reaction to study.⁴⁷⁹ Because the reaction is heterogeneous, kinetic data, although easy to obtain (measurement of decreasing hydrogen pressure), are difficult to interpret. Furthermore, there are the difficulties caused by the aforementioned hydrogen exchange. The currently accepted mechanism for the common two-phase reaction was originally proposed in 1934.⁴⁸⁰ According to this, the alkene is adsorbed onto the surface of the metal, although the nature of the actual bonding is unknown,⁴⁸¹ despite many attempts to elucidate it.⁴⁸² In the 1934 work, the metallic site was indicated by an asterisk, but here is used. For steric reasons it is apparent that adsorption of the alkene takes place with its less-hindered side attached to the catalyst surface, probably as an η²complex (Sec. 3.C.i). The fact that addition of hydrogen is generally also from the less-hindered side indicates that the hydrogen too is probably adsorbed on the catalyst surface before it reacts with the alkene. It is likely that as the H₂ molecule is adsorbed on (coordinated to) the metal catalyst, cleavage occurs to give η¹-coordinated hydrogen atoms (Sec. 3.C.i). Note that this model suggests a single metal particle for coordination of the alkene and the hydrogen atoms, but the hydrogen atoms and the alkene could be coordinated to different metal particles. It has been shown that Pt catalyzes homolytic cleavage of hydrogen molecules.⁴⁸³ In the second step, one of the adsorbed (η¹-coordinated) hydrogen atoms becomes attached to a carbon atom, creating in effect, an alkyl radical, which is still bound to the catalyst although only by one bond, probably η¹-coordination. Transfer of a hydrogen atom to carbon opens a site on the metal catalyst for coordination to additional hydrogen atoms. Finally, another hydrogen atom (not necessarily the one originally connected to the first hydrogen) combines with the radical to give the reaction product, freed from the catalyst surface, and the metal catalyst that is now available for coordination of additional hydrogen atoms and/or alkenes. All the various side reactions, including hydrogen exchange and isomerism, can be explained by this type of process.⁴⁸⁴ Although this mechanism is satisfactory as far as it goes,⁴⁸⁵ there are still questions it does not answer, among them questions⁴⁸⁶ that involve the nature of the asterisk, the nature of the bonding, and the differences caused by the differing nature of each catalyst.⁴⁸⁷

Another problem with any study of heterogeneous catalysis is that it occurs at the surface, and different types of metal particles are exposed to the medium and reactants. Maier⁴⁸⁸ suggested the presence of terrace-, step-, and kink-type atoms (in Fig. 15.1)⁴⁸⁸ on the surface of a heterogeneous catalyst. These terms refer to different atom types, characterized by the number of nearest neighbors, which correspond to different transition metal fragments, as well as to different coordination states of that metal.⁴⁸⁹ A terrace-type atom (A in Fig. 15.1) typically has eight or nine neighbors and corresponds to a geometry shown for the ML₅ particle. The step type of atom (B) usually has seven neighbors and can be correlated with the geometry shown for the ML₄ particle. Finally, the kink-type atom (C) has six neighbors and corresponds to geometry shown for the ML₃ particle. In general, as the particle size increases, the relative concentration of terrace atoms will increase, whereas small particle size favors the kink type of surface atoms.

Fig. 15.1 The principal surface and particle sites for heterogeneous catalysts. [Reprinted with permission from Maier, W.F. Angew. Chem. Int. Ed. 1989, 135, Wiley–VCH Verlag GmbH & Co. KGaA, Weinheim. Copyright © 1989by Wiley-VCH Verlag]

The mechanism of homogeneous hydrogenation⁴⁹⁰ catalyzed by RhCl(Ph₃P)₃ (46, Wilkinson's catalyst)⁴⁹¹ involves reaction of the catalyst with hydrogen to form a metal hydride (PPh₃)₂RhH₂Cl (52).⁴⁹² Replacement of a triphenylphosphine ligand with two toms of hydrogen constitutes an oxidative addition. After coordination of the alkene to form 53, transfer of hydrogen to carbon is an insertion process, presumably generating 55, and a second insertion liberates the hydrogenated compound, and Rh species 54, which adds hydrogen by oxidative addition to give 55. In a different study of Pd catalyzed hydrogenations, a palladium hydride species was detected.⁴⁹³Alternatively, replacement of triphenylphosphine can lead to 53, with two hydrogen atoms and a η² alkene complex. If a mixture of H₂ and D₂ is used, the product contains only dideuterated and nondeuterated compounds; no monodeuterated products are found, indicating that (unlike the case of heterogeneous catalysis) H₂ or D₂ has been added to one alkene molecule and that no exchange takes place.⁴⁹¹ Although conversion of 53 to the products takes place in two steps,⁴⁹⁴ the addition of H₂ to the double bond is syn, although bond rotation in 55 can lead to stereochemical mixtures.

The occurrence of hydrogen exchange and double-bond migration in heterogeneous catalytic hydrogenation means that the hydrogenation does not necessarily take place by straightforward addition of two hydrogen atoms at the site of the original double bond. Consequently, this method is not synthetically useful for adding D₂ to a double or triple bond in a regioselective or stereospecific manner. However, this objective can be achieved (with syn addition) by a homogeneous catalytic hydrogenation, which usually adds D₂ without scrambling⁴⁹⁵ or by the use of one of the diimide methods (Reaction 15-12). Deuterium can also be regioselectively added by the hydroboration–reduction procedure previously mentioned.

Reductions of double and triple bonds are found at OS I, 101, 311; II, 191, 491; III, 385, 794; IV, 298, 304, 408; V, 16, 96, 277; VI, 68, 459; VII, 226, 287; VIII, 420. 609; IX, 169, 533.

Catalysts and apparatus for hydrogenation are found at OS I, 61, 463; II, 142; III, 176, 181, 685; V, 880; VI, 1007.

15-12 Other Reductions of Double and Triple Bonds

Although catalytic hydrogenation is the method most often used, double or triple bonds can be reduced by other reagents as well. These include sodium in ethanol, sodium and tert-butyl alcohol in HMPA,⁴⁹⁶ lithium in aliphatic amines⁴⁹⁷ (see also, Reaction 15-13), zinc and acids, and (EtO)₃SiH–Pd(OAc)₂.⁴⁹⁸ Trialkylsilanes (R₃SiH) in conjunction with an acid will reduce double bonds.⁴⁹⁹ When double bonds are reduced by lithium in ammonia or amines, the mechanism is similar to that of the Birch reduction (Reaction 15-13).⁵⁰⁰ The reduction with trifluoroacetic acid and Et₃SiH has an ionic mechanism, with H⁺ coming in from the acid and H⁻ from the silane.²⁸⁹ In accord with this mechanism, the reaction can be applied only to those alkenes that when protonated can form a tertiary carbocation or one stabilized in some other way (e.g., by a OR substitution).⁵⁰¹ It has been shown, by the detection of CIDNP, that reduction of α-methylstyrene by hydridopentacarbonylmanganese(I), [HMn(CO)₅], involves free radical addition.⁵⁰²

Triethylamine reduces alkynes in the presence of a Pd catalyst.⁵⁰³ Samarium iodide in water and a triamine additive led to reduction of alkenes.⁵⁰⁴ Similar reduction was reported using Co₂(CO)₈ and an excess of water in dimethoxyethane.⁵⁰⁵

Another hydrogenation method is called transfer hydrogenation.⁵⁰⁶ In this method, the hydrogen atom comes from another organic molecule, and that molecule is oxidized. A transition metal catalyst, heterogeneous or homogeneous, is frequently employed. A common reducing agent is cyclohexene, which, when a Pd catalyst is used, is oxidized to benzene, losing 2 molar equivalents of hydrogen. Nickel nanoparticles reduce alkenes by transfer hydrogenation using 2-propanol.⁵⁰⁷

Diimide (NH=NH) is a reducing agent for simple alkenes, formed in situ from N₂H₄ from the reaction of a mixture of hydrazine and hydroxylamine.⁵⁰⁸ The rate of this reaction has been studied.⁵⁰⁹ Diimide is also generated from hydrazine using a flavin catalyst in an oxygen atmosphere.⁵¹⁰ Although both the syn and anti forms of diimide are produced, only the syn form reduces the double bond,⁵¹¹ at least in part by a cyclic mechanism:⁵¹²

The addition is stereospecifically syn⁵¹³ and, like catalytic hydrogenation, generally takes place from the less-hindered side of a double bond, although not much discrimination in this respect is observed where the difference in bulk effects is small.⁵¹⁴ Diimide reductions are most successful with symmetrical multiple bonds (C=C, CC, N=N) and are not useful for those inherently polar (CN, C=N, C=O, etc.). Diimide is not stable enough for isolation at ordinary temperatures, although it has been prepared⁵¹⁵ as a yellow solid at −196°C.

An indirect method⁵¹⁶ of double-bond reduction involves formation of an alkylborane from an alkene, followed by hydrolysis of the borane (prepared by Reaction 15-16). Trialkylboranes can be hydrolyzed by heating to reflux with carboxylic acids,⁵¹⁷ while monoalkylboranes (RBH₂) can be hydrolyzed with base.⁵¹⁸ A mild procedure involves treatment of the alkene with 2 molar equivalents of catecholborane, a catalytic amount of MeCONMe₂, followed by reduction of the organoborane with 4 molar equivalents of MeOH and then treatment with air.⁵¹⁹ Triple bonds can be similarly reduced to cis-alkenes.⁵²⁰ Further reduction is also possible. When an alkyne was treated with decaborane and Pd/C in methanol, 2 equiv of hydrogen are transferred to give the alkane.⁵²¹ Reduction of alkenes occurs with tert-butylamine·borane complex in methanol with 10% Pd/C.⁵²² In a related reaction, reduction occurs in situ when an alkene is treated with NaBH₄, NiCl₂·6 H₂O with moist alumina.⁵²³ Hydrogenation with Ni₂B on borohydride-exchange resin (BER) has also been used.⁵²⁴

Metallic hydrides (e.g., lithium aluminum hydride and sodium borohydride) do not typically reduce carbon–carbon double bonds, although in special cases where the double bond is polar, as in 1,1-diarylethenes⁵²⁵ and in enamines,⁵²⁶ reduction can occur. Note that both LiAlH₄ and NaBH₄, as well as NaH, reduce ordinary alkenes and alkynes when complexed with transition metal salts (e.g., FeCl₂ or CoBr₂).⁵²⁷ Lithium aluminum hydride reduces cyclopropenes with a pendant alcohol in the allylic position to the corresponding cyclopropane.⁵²⁸ Transition metals catalyze the reduction of alkenes using NaBH₄. Among the metals used for this purpose are Pd,⁵²⁹ and Ru.⁵³⁰ A mixture of NaBH₄ and BiCl₃ also reduced certain alkenes.⁵³¹ Zinc metal catalyzes the reduction of alkenes in water in the presence of a Rh complex.⁵³²

The fact that ordinary double bonds are inert toward metallic hydrides is quite useful, since it permits reduction of, say, a carbonyl or nitro group, without disturbing a double bond in the same molecule (see Chap 19 for a discussion of selectivity in reduction reactions). Sodium in liquid ammonia also does not reduce ordinary double bonds,⁵³³ although it does reduce alkynes, allenes, conjugated dienes,⁵³⁴ and aromatic rings (Reaction 15-13).

Enantioselective reduction of certain alkenes has also been achieved by reducing with baker's yeast.⁵³⁵

Catalytic hydrogenation of triple bonds and the reaction with Dibal-H (diisobutylaluminum hydride) usually give the cis-alkene (Reaction 15-11). Most of the other methods of triple-bond reduction lead to the more thermodynamically stable trans-alkene. However, this is not the case with the method involving hydrolysis of boranes or with the reductions with activated zinc, hydrazine, or NH₂OSO₃H, which also give the cis products.

Triple bonds can also be selectively reduced to double bonds with Dibal-H,⁵³⁶ with activated zinc (see Reaction 12-38),⁵³⁷ or (internal triple bonds only) with alkali metals (Na, Li) in liquid ammonia or a low-molecular-weight amine.⁵³⁸ Terminal alkynes are not reduced by the Na–NH₃ procedure because they are converted to acetylide ions under these conditions. However, terminal triple bonds can be reduced to double bonds by the addition to the Na–NH₂ solution of (NH₄)₂SO₄, which liberates the free ethynyl group.⁵³⁹ The reaction of a terminal alkyne with lithium naphthalenide and NiCl₂ effectively reduced the alkyne unit.⁵⁴⁰ This reagent is also effective for the reduction of simple alkenes.⁵⁴¹

Alkynes are converted to trans-alkenes with siloxanes [(RO)₃SiH] ⁵⁴² and a Ru catalyst, followed by treatment with AgF, or silanes⁵⁴³ and a Ru catalyst, followed by treatment with CuI and Bu₄NF. Reduction of an alkyne to an alkene can be done via an organometallic, by heating the alkyne with In metal in aq ethanol.⁵⁴⁴ Alkynes are reduced with palladium acetate and sodium ethoxide. In methanol, the product is the alkane, whereas in THF the product is the cis-alkene.⁵⁴⁵

Reduction of just one double bond of an allene, to give an alkene, has been accomplished by treatment with Na–NH₃⁵⁴⁶ or with Dibal-H,⁵⁴⁷ and by hydrogenation with RhCl(PPh₃)₃ as catalyst.⁵⁴⁸

Reductions of double and triple bonds are found at OS III, 586, 742; IV, 136, 302, 887; V, 281, 993; VII, 524; 80, 120.

15-13 Hydrogenation of Aromatic Rings

Aromatic rings can be reduced by catalytic hydrogenation,⁵⁴⁹ but higher temperatures (100–200 °C) are required than for double bonds in alkenes.⁵⁵⁰ Although the reaction is usually carried out with heterogeneous catalysts, homogeneous catalysts have also been used; conditions are much milder with these.⁵⁵¹ Hydrogenations using phase transfer catalysts often proceed under mild conditions.⁵⁵² Hydrogenation in ionic liquids is known,⁵⁵³ and also hydrogenation in supercritical ethane containing water.⁵⁵⁴ Many functional groups (e.g., OH, O⁻, CO₂H, CO₂R, NH₂) do not interfere with the reaction, but some groups may be preferentially reduced. Among these are CH₂OH groups, which undergo hydrogenolysis to CH₃ (Reaction 19-54). Phenols may be reduced to cyclohexanones, presumably through the enol. A computational study of the mechanism of hydrogenation of aromatic compounds has been reported, and it was shown that the barrier for uncatalyzed 1,4-hydrogenation is substantially lower than that for 1,2-hydrogenation, despite similar reaction enthalpies.⁵⁵⁵

It is usually impossible to stop the reduction of benzene rings after only one or two bonds have been reduced, since alkenes are more easily reduced than aromatic rings.⁵⁵⁶ Thus, 1 molar equivalent of benzene, treated with 1 molar equivalent of hydrogen, gives no cyclohexadiene or cyclohexene, but one-third equivalent of cyclohexane and two-thirds equivalent of recovered benzene. This is not true for all aromatic systems. With anthracene, for example, it is easy to stop after only the 9,10-bond has been reduced (Sec. 2.I.i). Hydrogenation of phenol derivatives can lead to conjugated cyclohexenones.⁵⁵⁷ Hydrogenation of toluene in an ionic liquid using a Ru catalyst gave methylcyclohexane.⁵⁵⁸

Heterocyclic compounds are often reduced by hydrogenation.⁵⁵⁹ Furan gives THF, pyrroles⁵⁶⁰ give pyrrolidines, and pyridines⁵⁶¹ give piperidines. The nitrogen-containing ring of quinolines is reduced by hydrogenation using iodine and an Ir catalyst.⁵⁶² Catalytic hydrogenation of the five-membered ring in indole derivatives using a chiral Rh catalyst gave hydroindoles with excellent enantioselectivity.⁵⁶³

When aromatic rings are reduced by Li (or K or Na) in liquid ammonia (such reductions are known as dissolving metal reductions), usually in the presence of an alcohol (often ethyl, isopropyl, or tert-butyl alcohol), 1,4-addition of hydrogen takes place and nonconjugated cyclohexadienes are produced.⁵⁶⁴ This reaction is called the Birch reduction.⁵⁶⁵ Heterocycles (e.g., pyrroles,⁵⁶⁶ furans,⁵⁶⁷ pyridines,⁵⁶⁸ and indolones⁵⁶⁹) can be reduced using Birch reduction. Ammonia obtained commercially often has iron salts as impurities that lower the yield in the Birch reduction. Therefore it is often necessary to distill the ammonia. When substituted aromatic compounds are subjected to the Birch reduction, electron-donating groups (e.g., alkyl or alkoxyl) decrease the rate of the reaction and are generally found on the nonreduced positions of the product. For example, anisole gives 1-methoxy-1,4-cyclohexadiene, not 3-methoxy-1,4-cyclohexadiene. On the other hand, electron-withdrawing groups (e.g., COOH or CONH₂) increase the reaction rate and are found on the reduced positions of the product.⁵⁷⁰ The regioselectivity of the reaction has been examined.⁵⁷¹ The mechanism involves solvated electrons,⁵⁷² which are transferred from the metal to the solvent, and hence to the ring:⁵⁷³

The sodium becomes oxidized to Na⁺ and creates a radical ion (56).⁵⁷⁴ There is a great deal of evidence from ESR spectra for these species.⁵⁷⁵ The radical ion accepts a proton from the alcohol to give a radical, which is reduced to a carbanion by another sodium atom. Finally, 57 accepts another proton. Thus the function of the alcohol is to supply protons, since with most substrates ammonia is not acidic enough for this purpose. In the absence of the alcohol, products arising from dimerization of 56 are frequently obtained. There is evidence⁵⁷⁶ at least with some substrates (e.g., biphenyl) that the radical ion corresponding to 56 is converted to the carbanion corresponding to 56 by a different pathway, in which the order of the steps is reversed: First a second electron is gained to give a dianion,⁵⁷³ which then acquires a proton, producing the intermediate (e.g., 56).

Ordinary alkenes are usually unaffected by Birch-reduction conditions, and double bonds may be present in the molecule if they are not conjugated with the ring. However, phenylated alkenes, internal alkynes (Reaction 15-12),⁵⁷⁷and conjugated alkenes (with C=C or C=O) are reduced under these conditions.

Note that 56 is a resonance hybrid; that is, two additional canonical forms can be written. The question therefore arises: Why does the carbanion pick up a proton at the 6 position to give the 1,4-diene? Why not at the 2 position to give the 1,3-diene?⁵⁷⁸ An answer to this question has been proposed by Hine,⁵⁷⁹ who suggested that this case is an illustration of the operation of the principle of least motion. According to this principle, “those elementary reactions will be favored that involve the least change in atomic position and electronic configuration.”⁵⁷⁸ The principle can be applied to the case at hand in the following manner (simplified): The valence bond bond orders (Sec. 2.A) for the six carbon–carbon bonds (on the assumption that each of the three forms contributes equally) are (going around the ring) 1, 1, 1, 1, 1, and 1. When the carbanion is converted to the diene, these bond orders change as follows:

It can be seen that the two bonds whose bond order is 1 are unchanged in the two products, but for the other four bonds there is a change. If the 1,4-diene is formed, the change is , while formation of the 1,3-diene requires a change of . Since a greater change is required to form the 1,3-diene, the principle of least motion predicts formation of the 1,4-diene. This may not be the only factor, because the ¹³C NMR spectrum of 111shows that the 6 position has a somewhat greater electron density than the 2 position, which presumably would make the former more attractive to a proton.⁵⁸⁰

Reduction of aromatic rings with Li⁵⁸¹ or Ca⁵⁸² in amines (instead of ammonia: called Benkeser reduction) proceeds further and cyclohexenes are obtained. It is thus possible to reduce a benzene ring, by proper choice of reagent, so that one, two, or all three double bonds are reduced.⁵⁸³ Lithium triethylborohydride (LiBEt₃H) has also been used, to reduce pyridine derivatives to piperidine derivatives.⁵⁸⁴

Transition metals and metal compounds can reduce aromatic rings in the proper medium. Indium metal reduces the pyridine ring in quinoline in aq ethanol solution,⁵⁸⁵ as well as the C=C unit in the five-membered ring of indole derivatives.⁵⁸⁶ Samarium iodide (SmI₂) reduces pyridine in aq THF⁵⁸⁷ and phenol in MeOH/KOH.⁵⁸⁸ Ammonium formate and a Pd–C catalyst reduces pyridine N-oxide to piperidine in methanol.⁵⁸⁹ The nitrogen-containing ring of quinolines is reduced with an In catalyst in isopropyl alcohol.⁵⁹⁰

OS I, 99, 499; II, 566; III, 278, 742; IV, 313, 887, 903; V, 398, 400, 467, 591, 670, 743, 989; VI, 371, 395, 461, 731, 852, 856, 996; VII, 249.

15-14 Reduction of the Double or Triple Bonds Conjugated to Carbonyls, Cyano, Nitro, and so on

Reduction of only the C=C bond of conjugated C=C–C=O and C=C–CN systems⁵⁹¹ has been achieved by many reducing agents,⁵⁹² including catalytic hydrogenation with a Rh,⁵⁹³ a Ru,⁵⁹⁴ a Pd,⁵⁹⁵ or an Ir catalyst,⁵⁹⁶ and with Raney nickel alone.⁵⁹⁷ Reagents, such as SmI₂⁵⁹⁸ and catecholborane,⁵⁹⁹ are effective. Conjugated ketones react with 2 equiv of Cp₂TiCl in THF/MeOH to give the corresponding saturated ketone.⁶⁰⁰ Zinc and acetic acid has been used for the conjugate reduction of dihydropyridin-4-ones.⁶⁰¹ Formic acid with a Pd catalyst reduced conjugated carboxylic acids.⁶⁰² A zinc–titanocene protocol has been developed for conjugate reductions.⁶⁰³ Both NaBH₄ in MeOH–THF⁶⁰⁴ and NaCNBH₃ on a zeolite⁶⁰⁵ reduce α,β-unsaturated nitro compounds to nitroalkanes.

In certain cases,⁶⁰⁶ metallic hydride reagents may selectively reduce double bonds that are in conjugation with C=O bonds,⁶⁰⁷ although the C=O bonds are also reduced in many cases, as in the conversion of cyclopentenone to cyclopentanol.⁶⁰⁸ The reagent NaBH₄ has a greater tendency than LiAlH₄ to effect this double reduction, although even with NaBH₄ the product of 1,2-reduction (of the C=O bond) is usually formed in larger amount than the doubly reduced product. The C=C unit proximal to the carbonyl in dienyl amides is selectively reduced with NaBH₄/I₂.⁶⁰⁹ Mixed hydride reducing agents (e.g., NaBH₄–BiCl₃,⁶¹⁰ NaBH₄–InCl₃,⁶¹¹ and Dibal-H–Co(acac)₂)⁶¹² have been used. The InCl₃–NaBH₄ reagent was used to covert conjugated diene ketones (C=C–C=C–C=O) selectively to the nonconjugated alkenyl ketone (C=C–CH₂CH₂–C=O).⁶¹³ Lithium aluminum hydride also reduces the double bonds of allylic alcohols.⁶¹⁴

Transfer hydrogenation can be applied to the reduction of conjugated alkenes. Reduction of the C=C unit of conjugated aldehydes is accomplished with an imidazolidinone catalyst⁶¹⁵ or an amino ester⁶¹⁶ in the presence of a Hantzch ester (e.g., 58). Nitroalkenes are hydrogenated using a thiourea catalyst in the presence of 58.⁶¹⁷ Palladium/carbon with microwave heating is used for the transfer hydrogenation of conjugated carboxylic acids, using 1,4-cyclohexadiene as the hydrogen-transfer agent.⁶¹⁸ Solvent-free transfer hydrogenation is possible using a Ru complex, with formic acid or water⁶¹⁹ as the hydrogen donor.⁶²⁰ Palladium–P(t-Bu)₃ has been used as a mild catalyst for transfer hydrogenation.⁶²¹ Titanium-catalyzed reductions are also known.⁶²²

Silanes reduce the C=C unit in conjugated systems in the presence of Cu species.⁶²³ An asymmetric CuH catalyzed hydrosilation reaction is known.⁶²⁴ Phenylsilane (PhSiH₃) and a Ni catalyst,⁶²⁵ CuCl,⁶²⁶ a Mn catalyst⁶²⁷ or a Mo⁶²⁸ catalyst have been used for hydrosilation reactions. Triphenylsilane was also used for the asymmetric reduction of nitro alkenes (C=C–NO₂).⁶²⁹ Poly(methylhydrosiloxane) with a chiral Cu catalyst gave conjugate reduction of conjugated esters to give the saturated derivative with high enantioselectivity.⁶³⁰ Polymethylhydrosiloxane, in the presence of a Co-catalyst reduces conjugated nitriles.⁶³¹ A β-bromo conjugated lactone was reduced to the β-bromolactone with modest enantioselectivity using an excess of Ph₃SiH and a CuCl catalyst with a chiral ligand.⁶³² Tributyltin hydride, in the presence of MgBr₂·OEt₂ gave 1,4-reduction of conjugated esters.⁶³³

Optically active homogeneous hydrogenation catalysts have been used to achieve the enantioselective hydrogenation⁶³⁴ of many prochiral conjugated substrates.⁶³⁵ For example,⁶³⁶ hydrogenation of 59 with a suitable catalyst gives the (+) or (−) amino ester (depending on which enantiomer of the catalyst is used) with an ee as high as 96%.⁶³⁷ Prochiral substrates that give such high optical yields generally contain functional groups (e.g., a carbonyl group,⁶³⁸ amide groups, cyano groups) or combinations of such groups as in 58.⁶³⁹ The catalyst in such cases⁶⁴⁰ is usually a Ru⁶⁴¹ or Rh complex⁶⁴²with chiral phosphine ligands.⁶⁴³ Good asymmetric induction⁶⁴⁴ has been achieved using chiral Rh complexes with other chiral additives.⁶⁴⁵ Iridium complexes have been used with excellent enantioselectivity.⁶⁴⁶ The role of solvent has been examined.⁶⁴⁷ A pressure-dependent enantioselective hydrogenation has been reported.⁶⁴⁸ Asymmetric catalytic hydrogenation has been reported for conjugated carboxylic acids⁶⁴⁹ and conjugated ketones.⁶⁵⁰ Asymmetric hydrogenation of conjugated carboxylic acids in an ionic liquid is known using a chiral Ru complex⁶⁵¹

See Reaction 19-36 for methods of reducing C=O bonds in the presence of conjugated C=C bonds.

The C=C unit of conjugated aldehydes has been reduced using AlMe₃ with a catalytic amount of CuBr⁶⁵² and with ammonium formate/Pd–C.⁶⁵³ Polymer-supported formate has been used for the 1,4-reduction of conjugated ketones⁶⁵⁴ and for conjugated acids using an Rh catalyst and microwave irradiation.⁶⁵⁵ Isopropyl alcohol and an Ir catalyst gives conjugate reduction of conjugated ketones.⁶⁵⁶ The reaction of conjugated ketones with aluminum chlorides, followed by treatment with water generates the saturated ketone.⁶⁵⁷

Enzymatic reduction of conjugated systems requires the reactivity with certain purified or whole cell enzymes. Baker's yeast reduces conjugated nitro compounds to nitroalkanes⁶⁵⁸ and also the C=C unit of conjugated ketones.⁶⁵⁹Other enzymatic reductions are possible. A reductase from Nicotiana tabacum reduced a conjugated ketone to the saturated ketone, with excellent enantioselectivity.⁶⁶⁰ Enzyme YNAR-I and NADP-H reduces conjugated nitro compounds to nitroalkanes.⁶⁶¹ Conjugated nitro compounds are reduced in the presence of Clostridium sporogenes.⁶⁶²

15-15 Reductive Cleavage of Cyclopropanes

Cyclopropanes can be cleaved by catalytic hydrogenolysis.⁶⁶³ Among the catalysts used have been Ni, Pd, Rh,⁶⁶⁴ and Pt. The reaction can often be run under mild conditions.⁶⁶⁵ Certain cyclopropane rings, especially cyclopropyl ketones and aryl-substituted cyclopropanes,⁶⁶⁶ can be reductively cleaved by an alkali metal (generally Na or Li) in liquid ammonia.⁶⁶⁷ Similar reduction has been accomplished photochemically in the presence of LiClO₄.⁶⁶⁸ This reaction is an excellent way to introduce a gem-dimethyl unit into a molecule. Hydrogenation of the cyclopropane ring in 60, for example, gave the gem-dimethyl unit in 61 using PtO₂ (Adam's catalyst).⁶⁶⁹

F. A Metal on the Other Side

15-16 Hydroboration

When alkenes are treated with borane⁶⁷⁰ in ether solvents, BH₃ adds across the double bond.⁶⁷¹ The alkene reacts as a base with the boron essentially reacting as a Lewis acid. Borane cannot be prepared as a stable pure compound⁶⁷² (it dimerizes to diborane, B₂H₆), but it is commercially available in the form of “ate” complexes with THF, Me₂S,⁶⁷³ phosphines, or tertiary amines. The alkenes can be treated with a solution of one of these complexes. Tetrahydrofuran–BH₃ reacts at 0 °C and is the most convenient to use and R₃N–BH₃ generally require temperatures of ~100 °C. The latter can be prepared as air-stable liquids or solids, while the former can only be used as relatively dilute solutions in THF and are decomposed by moisture in air) or with a mixture of NaBH₄ and BF₃ etherate, which generates borane in situ.⁶⁷⁴ Pyridine–borane can be used for the hydroboration of alkenes at room temperature.⁶⁷⁵With relatively unhindered alkenes, the process cannot be stopped with the addition of one molecule of BH₃ because the resulting RBH₂ adds to another molecule of alkene to give R₂BH, which in turn adds to a third alkene molecule, so that the isolated product is a trialkylborane (R₃B). The reaction can be performed on alkenes with one to four substituents, including cyclic alkenes, but when the alkene is moderately hindered, the product is the dialkylborane (R₂BH) or even the monoalkylborane (RBH₂).⁶⁷⁶ For example, 62 (disiamylborane) and 63 (thexylborane)⁶⁷⁷ have been prepared in this manner. Monoalkylboranes (RBH₂), which can be prepared from hindered alkenes, (as above) and dialkylboranes (R₂BH) also add to alkenes, to give the mixed trialkylboranes (RR′₂B and R₂R′B), respectively. Surprisingly, when methylborane (MeBH₂),⁶⁷⁸ which is not a bulky molecule, adds to alkenes in the solvent THF, the reaction can be stopped with one addition to give dialkylboranes (RMeBH).⁶⁷⁹ Reaction of this with a second alkene produces the trialkylborane (RR′MeB).⁶⁸⁰ Other monoalkylboranes (iPrBH₂, n-BuBH₂, s-BuBH₂, and t-BuBH₂), behave similarly with internal alkenes, but not with alkenes of the type RCH=CH₂.⁶⁸¹

In all cases, the boron goes to the side of the double bond that has more hydrogen atoms (less substituted), whether the substituents are aryl or alkyl.⁶⁸² Technically, this follows Markovnikov's rule, since boron is more positive than hydrogen. The regioselectivity is caused mostly by steric factors, although electronic factors also play a part. Studies of the effect of ring substituents on rates and on the direction of attack in hydroboration of substituted styrenes showed that the reaction with boron and the alkene has electrophilic character.⁶⁸³ When both sides of the double bond are monosubstituted or disubstituted, about equal amounts of each isomer are obtained. However, it is possible in such cases to make the addition regioselective by the use of a large borane molecule. For example, treatment of iPrCH=CHMe with borane gave 57% of product with boron on the methyl-bearing carbon and 43% of the other, while treatment with 62 gave 95% 64 and only 5% of the other isomer.⁶⁸⁴

Another reagent with high regioselectivity is 9-borabicyclo[3.3.1]nonane (9-BBN, 65), which is prepared by hydroboration of 1,5-cyclooctadiene,⁶⁸⁵ and has the advantage that it is stable in air. Borane is quite unselective and attacks all sorts of double bonds. Disiamylborane, 9-BBN, and similar molecules are far more selective and preferentially react at the less-hindered bonds, so it is often possible to hydroborate one double bond in a molecule and leave others unaffected or to hydroborate one alkene in the presence of a less reactive alkene.⁶⁸⁶ For example, 1-pentene can be removed from a mixture of 1- and 2-pentenes, and a cis-alkene can be selectively hydroborated in a mixture of the cis and trans isomers.

For most substrates, the addition in hydroboration is stereospecific and syn, with attack taking place from the less-hindered side.⁶⁸⁷ Note that organoboranes can be analyzed using ¹¹B NMR.⁶⁸⁸ The mechanism⁶⁸⁹ may be a cyclic four-center one:⁶⁹⁰

When the substrate is an allylic alcohol or amine, the addition is generally anti,⁶⁹¹ although the stereoselectivity can be changed to syn by the use of catecholborane and Rh complexes.⁶⁹² Because the mechanism is different, use of this procedure can result in a change in regioselectivity as well (e.g., styrene, PhCH=CH₂, gave PhCH(OH)CH₃).⁶⁹³

Monochloroborane⁶⁹⁴ (BH₂Cl) coordinated with DMS shows greater regioselectivity than BH₃ for terminal alkenes or those of the form R₂C=CHR, and the hydroboration product is a dialkylchloroborane (R₂BCl).⁶⁹⁵ For example, 1-hexene gave 94% of the anti-Markovnikov product (the boron is on the less substituted carbon) with BH₃–THF, but 99.2% with BH₂Cl⁻SMe₂. Treatment of alkenes with dichloroborane–DMS (BHCl₂–SMe₂) in the presence of BF₃⁶⁹⁶ or with BCl₃ and Me₃SiH⁶⁹⁷ gives alkyldichloroboranes (RBCl₂). Extensions of this basic approach are possible with dihalo alkylboranes. The reaction of an alkene with allyl dibromoborane, incorporated an allyl group and the boron on adjacent carbons.⁶⁹⁸

An important use of the hydroboration reaction is oxidation of an organoborane to alcohols with H₂O₂ and NaOH (see Reaction 12-27). The synthetic result is an indirect way of adding H₂O across a double bond in an anti-Markovnikov manner. However, boranes undergo many other reactions as well. Among other things, they react with α-halo carbonyl compounds to give alkylated products (Reaction 10-73), with α,β-unsaturated carbonyl compounds to give Michael-type addition of R and H (Reaction 15-27), with CO to give alcohols and ketones (Reactions 18-23–18-24); they can be reduced with carboxylic acids (Reaction 15-11), or they can be oxidized with chromic acid or pyridinium chlorochromate to give ketones⁶⁹⁹ or aldehydes (from terminal alkenes),⁷⁰⁰ dimerized with silver nitrate and NaOH (Reaction 14-26), isomerized (Reaction 18-11), or converted to amines (Reaction 12-32), halides (Reaction 12-31), or carboxylic acids.⁷⁰¹ They are thus useful intermediates for the preparation of a wide variety of compounds. Intramolecular hydroboration reactions are possible.⁷⁰²

Such functional groups as OR, OH, NH₂, SMe, halogen, and CO₂R may be present in the molecule,⁷⁰³ but not groups that are reducible by borane (e.g., COOH). Hydroboration of enamines with 9-BBN provides an indirect method for reducing an aldehyde or ketone to an alkene, for example,⁷⁰⁴

The presence of certain functional groups has directing effects on hydroboration reactions. Amides direct hydroboration reactions in alkenyl amides, for example.⁷⁰⁵ Intramolecular hydroboration is directed by amine groups in alkenyl amines.⁷⁰⁶ Alkenyl alcohols or ethers also undergo hydroboration, where delivery of boron is directed by the oxygen.⁷⁰⁷

Use of the reagent diisopinocampheylborane (66, prepared by treating optically active α-pinene with BH₃) results in enantioselective hydroboration–oxidation.⁷⁰⁸ Since both (+) and (−) α-pinene are readily available, both enantiomers can be prepared. Alcohols with moderate-to-excellent enantioselectivities have been obtained

in this way.⁷⁰⁹ However, 66 does not give good results with even moderately hindered alkenes; a better reagent for these compounds is isopinocampheylborane⁷¹⁰ although optical yields are lower. Limonylborane,⁷¹¹ 2- and 4-dicaranylboranes,⁷¹² a myrtanylborane,⁷¹³ and dilongifolylborane⁷¹⁴ have also been used. Other new asymmetric boranes have also been developed. The chiral cyclic boranes trans-2,15-dimethylborolanes (67 and 68) also add enantioselectively to alkenes (except alkenes of the form RR′C=CH₂) to give boranes of high optical purity.⁷¹⁵ When chiral boranes are added to trisubstituted alkenes of the form RR′C=CHR″, two new chiral centers are created, and, with 67 or 68, only one of the four possible diastereomers is predominantly produced, in yields >90%.⁷¹⁵ This has been called double-asymmetric synthesis.⁷¹⁶ An alternative asymmetric synthesis of alcohols involves the reaction of catechol borane with an alkene in the presence of a chiral Rh catalyst, giving the alcohol enantioselectivity after the usual oxidation.⁷¹⁷

The double bonds in a conjugated diene are hydroborated separately; that is, there is no 1,4-addition. However, it is not easy to hydroborate just one of a conjugated system, since conjugated double bonds are less reactive than isolated ones. Thexylborane⁶⁷⁷ (63) is particularly useful for achieving the cyclic hydroboration of dienes, conjugated or nonconjugated, as in the formation of 69.⁷¹⁸

Rings of five, six, or seven members can be formed in this way. Similar cyclization can also be accomplished with other monoalkylboranes and, in some instances, with BH₃ itself.⁷¹⁹ One example is the formation of 9-BBN, shown above. Another is conversion of 1,5,9-cyclododecatriene to perhydro-9b-boraphenalene (70).⁷²⁰

Boronate esters are prepared from alkenes. The reaction of an alkene with pyridine iodoborane, followed by treatment with pinacol and NaOH, for example, leads to the pinacol boronate ester.⁷²¹

Triple bonds⁷²² can be monohydroborated to give vinylic boranes, which can be reduced with carboxylic acids to cis-alkenes or oxidized and hydrolyzed to aldehydes or ketones. Terminal alkynes give aldehydes by this method, in contrast to the mercuric or acid-catalyzed addition of water discussed in Reaction 15-4. However, terminal alkynes give vinylic boranes⁷²³ (and hence aldehydes) only when treated with a hindered borane (e.g., 62, 63, or catecholborane, Reaction 12-31 and Sec. 14.A.i),⁷²⁴ or with BHBr₂–SMe₂.⁷²⁵ The reaction between terminal alkynes and BH₃ produces 1,1-dibora compounds, which can be oxidized either to primary alcohols (with NaOH–H₂O₂) or to carboxylic acids (with m-chloroperoxybenzoic acid).⁷²⁶ Double bonds can be hydroborated in the presence of triple bonds if the reagent is 9-BBN.⁷²⁷ On the other hand, dimesitylborane selectively hydroborates triple bonds in the presence of double bonds.⁷²⁸ Furthermore, it is often possible to hydroborate selectively one particular double bond of a nonconjugated diene.⁷²⁹ A triple bond can be hydroborated in the presence of a ketone, and treatment with acetic acid reduces the CC unit to a cis- alkene (see Reaction 15-12).⁷³⁰ When the reagent is catecholborane, hydroboration is catalyzed by Rh complexes,⁷³¹ (e.g., Wilkinson's catalyst, 46,⁷³² by SmI₂,⁷³³ or lanthanide reagents).⁷³⁴Enantioselective hydroboration–oxidation has been achieved by the use of optically active Rh complexes.⁷³⁵

A chain extension variation involved the reaction of styrene with catecholborane and then Me₃SiCHN₂.⁷³⁶ Subsequent oxidation with NaOH/H₂O₂ and the reaction with Bu₄NF gave 3-phenyl-1-propanol.

OS VI, 719, 852, 919, 943; VII, 164, 339, 402, 427; VIII, 532.

15-17 Other Hydrometalation

Hydro-metallo-addition

Metal hydrides of Groups 13 and 14 of the periodic table (e.g., AlH₃, GaH₃), as well as many of their alkyl and aryl derivatives (e.g., R₂AlH and Ar₃SnH) add to double bonds to give organometallic compounds.⁷³⁷ In each case, the alkene reacts with the Lewis acid. The hydroboration reaction (15-16) is the most important example but, as mentioned, other important metals in this reaction are Al,⁷³⁸ Sn,⁷³⁹ and Zr⁷⁴⁰ (a Group 4 metal). Some of these reactions are uncatalyzed, but in other cases various types of catalyst have been used.⁷⁴¹ Hydrozirconation is most commonly carried out with Cp₂ZrHCl (Cp = cyclopentadienyl),⁷⁴² known as Schwartz's reagent. The mechanism with Group 13 hydrides seems to be electrophilic (or four-centered pericyclic with some electrophilic characteristics) while with Group 14 hydrides a mechanism involving free radicals seems more likely. Dialkylmagnesium reagents have been obtained by adding MgH₂ to double bonds.⁷⁴³ With some reagents triple bonds⁷⁴⁴ can add 1 or 2 equiv.⁷⁴⁵ When 2 molar equivalents are added, electrophilic addition generally gives 1,1-dimetallic products (as with hydroboration), while free radical addition usually gives the 1,2-dimetallic products.

OS VII, 456; VIII, 268, 295, 507; 80, 104. See also, OS VIII, 277, 381.

G. Carbon or Silicon on the Other Side

15-18 Addition of Alkanes

Hydro-alkyl-addition

There are two important ways of adding alkanes to alkenes: direct heating, and acid catalysis.⁷⁴⁶ Both give mixtures, and neither is useful for the preparation of relatively pure compounds in reasonable yields. However, both are useful industrially. In the thermal method, the reactants are heated to high temperatures (~500 °C) at high pressures (150–300 atm) without a catalyst. As an example, propane and ethylene gave 55.5% isopentane, 7.3% hexanes, 10.1% heptanes, and 7.4% alkenes.⁷⁴⁷ The mechanism is undoubtedly of a free radical type and can be illustrated by one possible sequence in the reaction between propane and ethylene:

There is kinetic evidence that the initiation takes place primarily by steps like 1, which are called symproportionation steps⁷⁴⁸ (the opposite of disproportionation, see Sec. 5.C.ii).

In the acid-catalysis method, a protonic or Lewis acid is used as the catalyst and the reaction is carried out at temperatures between –30 and 100 °C. This is a Friedel–Crafts process that proceeds via a carbocation mechanism⁷⁴⁹(illustrated for a proton acid catalyst):

Carbocation 72 often rearranges before a hydride is transferred, explaining, for example, why the principal product from the reaction between isobutane and ethylene is 2,3-dimethylbutane. Instead of abstracting a hydride, it is also possible for 71 (or 72) to add to another molar equivalent of alkene, so that not only rearrangement products, but also dimeric and polymeric products, are frequent. If the tri- or tetrasubstituted alkenes are treated with Me₄Si, HCl, and AlCl₃, protonation gives a tertiary carbocation, which reacts with the Me₄Si to give a product that is the result of addition of H and Me to the original alkene.⁷⁵⁰ (For a free radical hydro-methyl addition, see Reaction 15-28.) An intramolecular cyclization of 1-dodecene to cyclododecane was reported using aluminum chloride in an ionic liquid.⁷⁵¹

Alkanes add to alkynes under photolysis conditions to give an alkene.⁷⁵² Tetrahydrofuran adds to alkynes to give the alkene with microwave irradiation.⁷⁵³

The reaction can also be base catalyzed, in which case there is nucleophilic addition and a carbanion mechanism.⁷⁵⁴ Carbanions most often used are those stabilized by one or more α-aryl groups. For example, toluene adds to styrene in the presence of sodium to give 1,3-diphenylpropane:⁷⁵⁵

Conjugated dienes give 1,4-addition.⁷⁵⁶ This reaction has also been performed with salts of carboxylic acids in what amounts to a method of alkylation of carboxylic acids⁷⁵⁷ (see also, Reaction 10-59).

There are transition metal catalyzed addition reactions of alkyl units to alkenes,⁷⁵⁸ often proceeding with metal hydride elimination to form an alkene. An intramolecular cyclization reaction of an N-pyrrolidino amide alkene was reported using an iridium catalyst for addition of the carbon α to nitrogen at the alkene unit.⁷⁵⁹

OS I, 229; IV, 665; VII, 479.

15-19 Addition of Silanes (Hydrosilation)

Silyl-hydro-addition

Although silanes bearing at least one Si–H unit do not generally react with alkenes or alkynes, addition occurs to give the corresponding alkyl or vinyl silane in the presence of transition metal catalysts.⁷⁶⁰ This reaction is known as hydrosilation. The reaction of an alkylsilane and an alkene with a Ru,⁷⁶¹ Rh,⁷⁶² Pd,⁷⁶³ Re,⁷⁶⁴ La,⁷⁶⁵ Y,⁷⁶⁶ Pt⁷⁶⁷ Cu,⁷⁶⁸ or Sm⁷⁶⁹ catalyst leads to addition with high anti-Markovnikov selectivity. Silanes add to dienes with a Pd catalyst, and asymmetric induction is achieved by using a chiral binapthyl additive.⁷⁷⁰ Alkenes react with Li metal and t-Bu₂SiCl₂ to give a three-membered ring silane.⁷⁷¹

Dienes react with zirconium compounds and silanes to produce cyclic compounds in which the silyl group has also added to one C=C unit.⁷⁷² With an Y catalyst, PhSiH₃ reacts with nonconjugated dienes to give cyclic alkenes with a pendant CH₂SiH₂Ph group.⁷⁷³ Rhodium compounds allow silanes to add to enamides to give the α-silylamide.⁷⁷⁴ Formation of silanes via reaction with alkenes can be followed by reaction with fluoride ion and then oxidation to give an alcohol⁷⁷⁵ (see Reaction 10-16; Tamao–Fleming oxidation). A variation of this reaction generated allylic silanes from terminal alkenes and a dianion-type zincate using a Ti catalyst.⁷⁷⁶

In the presence of BEt₃, silanes add to alkenes to give the alkylsilane with anti-Markovnikov selectivity,⁷⁷⁷ or to alkynes to give the corresponding vinyl silane.⁷⁷⁸ Similar selectivity was observed when a silylated zinc reagent was added to a terminal alkyne.⁷⁷⁹ Hydrosilation of alkynes is accomplished using transition metal catalysts (e.g., Ru⁷⁸⁰ Pt,⁷⁸¹ Ti,⁷⁸² or Ir).⁷⁸³ Organocatalyts have been used as well.⁷⁸⁴ Siloxanes [e.g., (RO)₃SiH] add to alkynes with a Ru catalyst to give the corresponding vinyl silane.⁷⁸⁵ The reaction of Cl₂MeSiH and terminal alkynes, in ethanol–triethylamine with a Ru catalyst, to give primarily the Markovnikov vinyl silane.⁷⁸⁶ However, Et₃SiH adds to terminal alkynes with a Rh⁷⁸⁷ or a Pt⁷⁸⁸ catalyst to give the anti-Markovnikov vinyl silane. Using a 0.5 molar equivalent of HfClO₄ with alkynes bearing a dimethylphenylsilyl unit gave a cyclic vinyl silane with transfer of the phenyl group to carbon (see 73).⁷⁸⁹

Silanes add to alkenes under radical conditions (using AIBN) with high anti-Markovnikov selectivity.⁷⁹⁰ An alternative route to alkylsilanes reacted an alkene with Li metal in the presence of 3 equiv of chlorotrimethylsilane, giving bis-1,2-trimethylsilyl compounds after treatment with water.⁷⁹¹ Silanes also add to alkenes to form the anti-Markovnikov alkylsilane (R₃Si–C–C–R′) in the presence of a hyponitrite.⁷⁹²

In a reaction more related to those in Reaction 15-24, vinyl silanes add to conjugated carbonyl compounds in the presence of a Ru catalyst,⁷⁹³ or to acrylonitriles with a Co catalyst.⁷⁹⁴ Silyl phosphines react with conjugated ynones directly to give an enone with an α-trimethylsilyl and a β-phosphine group.⁷⁹⁵ Siloxanes of the type (RO)₃SiH add to the α-carbon of enamines in the presence of a dirhodium catalyst.⁷⁹⁶ The uncatalyzed reaction of trimethylsilyl cyanide and ynamines, however, gave an enamine with a β-trimethylsilyl and an α-cyano group.⁷⁹⁷

bis(Silanes) add to alkylidene malonate derivatives (see Reaction 15-24) in the presence of a Cu catalyst to give β-silyl malonates [RCH(SiR₃)CH(CO₂Me)₂].⁷⁹⁸ Alkylsilane units add using bis(trialkylsilyl)zinc reagents with a CuCN catalyst.⁷⁹⁹ Trimethylsilyl cyanide (Me₃SiCN) adds a cyano group to α,β-unsaturated amines with a specialized Al(salen)-Y catalyst.⁸⁰⁰

15-20 Addition of Alkenes and/or Alkynes to Alkenes and/or Alkynes

Hydro-alkenyl-addition

With certain substrates, alkenes can be dimerized by acid catalysts, so that the product is a dimer that contains one double bond.⁸⁰¹ A catalyst comprised of a combination of Zn and a CoCl₂ accomplished this type of coupling.⁸⁰²One alkene adds to another in the presence of a Ni catalyst.⁸⁰³ α-Alkenes add to dienes in a 1,4-manner in the presence of an Fe catalyst.⁸⁰⁴

This reaction is more often carried out internally, as in the formation of cyclohexene (74). A Pd catalyzed cyclization is known, in which dienes are converted to cyclopentene derivatives (e.g., 75).⁸⁰⁵

Ring-forming reactions are possible. A Ru catalyzed version of this reaction gave the five-membered ring with an exocyclic double bond.⁸⁰⁶ Carbocyclization of an alkene unit to another alkene unit was reported using a Y,⁸⁰⁷ or a Ti catalyst.⁸⁰⁸ In some cases, internal coupling of two alkenes can form larger rings.⁸⁰⁹ Carbocyclization was reported using Pd,⁸¹⁰ Rh,⁸¹¹ Ru,⁸¹² Ir,⁸¹³ or a Zr catalyst.⁸¹⁴ Alkene allene substrates were cyclized to form cyclic products with an exocyclic double bond using a Pd catalyst.⁸¹⁵ An interesting variation adds a silyl enol ether to an alkyne using GaCl₃ to give an unconjugated ketone (O=C–C–C=C).⁸¹⁶ Alkenes and alkynes can also add to each other to give cyclic products in other ways (see Reaction 15-63 and 15-65).

Processes of this kind are important in the biosynthesis of steroids and tetra- and pentacyclic terpenes. For example, squalene 2,3-oxide is converted by enzymatic catalysis to dammaradienol. The squalene → lanosterol biosynthesis, which is a key step in the biosynthesis of cholesterol, is similar. The idea that the biosynthesis of

such compounds involves this type of multiple ring closing was proposed in 1955 and is known as the Stork–Eschenmoser hypothesis.⁸¹⁷ Such reactions can also be carried out in the laboratory, without enzymes.⁸¹⁸ By putting cation-stabilizing groups at positions at which positive charges develop, Johnson and co-workers⁸¹⁹ have been able to close as many as four rings stereoselectively and in high yield, in one operation. An example is formation of 76,⁸²⁰ by what is known as the Johnson polyene cyclization.⁸²¹ Lewis acids can be used to initiate this cyclization,⁸²² including EtAlCl₂ used for the coupling of an alkyne and an alkene.⁸²³ A Pd catalyst has been used for a similar cyclization reaction.⁸²⁴ A radical cyclization approach (Reaction 15-30) to polyene cyclization using a seleno–ester anchor gave a tetracyclic system.⁸²⁵

The addition of alkenes to alkenes⁸²⁶ can also be mediated by bases.⁸²⁷ Coupling reactions can occur using transition metal catalyst systems⁸²⁸ (e.g., alkylaluminum compounds, known as Ziegler catalysts),⁸²⁹ Rh,⁸³⁰ Fe,⁸³¹ or Ni⁸³²catalysts. The 1,4-addition of alkenes to conjugated dienes to give nonconjugated dienes⁸³³ occurs with various transition metal catalysts, as does the dimerization of 1,3-butadienes to octatrienes.⁸³⁴ A

molecule containing two distal conjugated diene units was cyclized to give a bicyclic molecule with an exocyclic double bond using a Pd catalyst.⁸³⁵ A Ni catalyst converted a similar system to a saturated five-membered ring containing an allylic and a vinyl group.⁸³⁶ Ethylene adds to alkenes to form a new alkene in the presence of a Ni⁸³⁷ or a Zr catalyst,⁸³⁸ and to alkynes in the presence of a Ru catalyst⁸³⁹ to form a diene. Allenes add to alkynes to give a diene with a Ti catalyst.⁸⁴⁰

In the presence of cuprous chloride and ammonium chloride, acetylene undergoes self-coupling to give vinylacetylene. Alkynes are coupled to dienes to give enynes in the presence of a Ni catalyst.⁸⁴¹

Another type of alkyne dimerization is the reductive coupling in which two molecules of alkyne, the same or different, give a 1,3-diene, as shown.⁸⁴² In this method, one alkyne is treated with Schwartz's reagent (see Reaction 15-17) to produce a vinylic zirconium intermediate. Addition of MeLi or MeMgBr, followed by the second alkyne, gives another intermediate, which, when treated with aq acid, gives the diene in moderate-to-good yields.⁸⁴³If the second intermediate is treated with I₂ instead of aq acid, the 1,4-diiodo-1,3-diene is obtained, in comparable yield and isomeric purity. The reaction of an alkyne with a Grignard reagent, followed by an Fe complex and then an alkene leads to enynes.⁸⁴⁴ A Rh catalyzed coupling reaction of alkenes and electron-deficient internal alkynes leads to 1,3-dienes.⁸⁴⁵ A combination of Zr and Cr reagents allows the coupling of alkynes to form linear polyenes.⁸⁴⁶Alkynes can also be coupled to allylic silyl ethers with a Ru catalyst to give dienes.⁸⁴⁷ Other alkyne–allylic coupling reactions are known to give dienes.⁸⁴⁸

This reaction can also be done intramolecularly, as in the cyclization of diyne 77 to (E,E)-exocyclic dienes (78) by treatment with a Zr,⁸⁴⁹ Rh,⁸⁵⁰ Ru,⁸⁵¹ Au,⁸⁵² or Pt complex.⁸⁵³ A similar reaction was reported using a Ti catalyst from a diyne amide.⁸⁵⁴ Rings of four, five, and six members were obtained in high yield; seven-membered rings in lower yield. When the reaction is applied to enynes, compounds similar to 78 are formed using various catalysts, but with only one double bond⁸⁵⁵ Larger rings can be formed from the appropriate enyne, including forming cyclohexadiene compounds.⁸⁵⁶ Spirocyclic compounds can be prepared from enynes in this manner using formic acid and a Pd catalyst.⁸⁵⁷

The Rh catalyzed cyclization of 1,6-enynes, triggered by arylboronic acids, leads to rings with an exocyclic alkylidene group.⁸⁵⁸ Alkynes are coupled to give enynes using Ni,⁸⁵⁹ Pd,⁸⁶⁰ Lu,⁸⁶¹ and Ru⁸⁶² catalysts. Similar products are obtained by cross-coupling terminal alkynes with an allene, using a combination of Pd and CuI catalysts.⁸⁶³ The reaction has been carried out internally to convert diynes to large-ring cycloalkynes with an exocyclic double bond.⁸⁶⁴ Diynes have also been cyclized to form cyclic enynes (an endocyclic double bond) using a diruthenium catalyst with ammonium tetrafluoroborate in methanol.⁸⁶⁵ Enynes are similarly cyclized to cyclic alkenes with an endocyclic C=C unit using a dicobalt catalyst.⁸⁶⁶

Enynes can also be converted to cyclic and bicyclic compounds using a Au⁸⁶⁷ Rh,⁸⁶⁸ Fe,⁸⁶⁹ or Pd⁸⁷⁰ catalyst. Enynes having a conjugated alkene unit also undergo this reaction in the presence of ZnBr₂.⁸⁷¹ Using mercury(II) triflate in water, cyclization leads to five-membered rings having an exocyclic double bond, and a pendant alcohol group.⁸⁷² Enynes give cyclic compounds with an endocyclic double bond conjugated to another alkene unit (a conjugated diene) when treated with GaCl₃⁸⁷³ or a Pt catalyst in an ionic liquid.⁸⁷⁴ Allene–alkenes give a similar product with a Pd⁸⁷⁵ or a Ru catalyst,⁸⁷⁶ as do alkyne–allenes with a dirhodium catalyst.⁸⁷⁷

There are many useful variations. Internal coupling of an alkyne with a vinyl halide, using triethylsilane and a Pd catalyst, gave the saturated cyclic compound with two adjacent exocyclic double bonds (a 2,3-disubstituted diene).⁸⁷⁸ Alkynes are added to propargyl acetates using Pd catalyst to give an alkyne–allene.⁸⁷⁹ Alkyne–alkenes were formed by coupling terminal alkynes and allenes in the presence of a Pd catalyst.⁸⁸⁰ An alkyne was coupled internally to give an allene using a Pd catalyst, to give an product that has an exocyclic methylene group and a vinyltin derivative.⁸⁸¹ A similar process occurred with RhCl(PPh₃)₃ to incorporate a vinyl chloride.⁸⁸² Allene–allylic halide systems reacted with phenylboronic acid and a Pd catalyst to give cyclopentane rings with two pendant vinyl groups, one of which contained a phenyl group.⁸⁸³

OS VIII, 190, 381, 505; IX, 310.

15-21 Addition of Organometallics to Double and Triple Bonds Not Conjugated to Carbonyls

Hydro-alkyl-addition

Neither Grignard reagents nor lithium dialkylcopper reagents generally add to ordinary C=C double bonds in the absence of a transition metal catalyst.⁸⁸⁴ Grignard reagents usually add only to double bonds susceptible to nucleophilic attack (e.g., fluoroalkenes and tetracyanoethylene).⁸⁸⁵ However, active Grignard reagents (benzylic, allylic) also add to the double bonds of allylic amines,⁸⁸⁶ and of allylic and homoallylic alcohols,⁸⁸⁷ as well as to the triple bonds of propargyl alcohols and certain other alkynols.⁸⁸⁸ Transition metal complexes facilitate the addition of Grignard reagents to alkenes. Examples include Ti,⁸⁸⁹ Mn,⁸⁹⁰ Zr,⁸⁹¹ Ni,⁸⁹² Fe,⁸⁹³ and Cu compounds.⁸⁹⁴Cyclopropenes are an exception, and an excess of a Grignard reagent will add at low temperatures.⁸⁹⁵ Cyclopropene derivatives also react with CuI and then allyl bromide.⁸⁹⁶

Benzylic alkenes react with silylmethyl Grignard reagents in the presence of oxygen.⁸⁹⁷ It is likely that cyclic intermediates are involved in these cases, in which the Mg coordinates with the heteroatom. Allylic, benzylic, and tertiary alkyl Grignard reagents also add to 1-alkenes and strained internal alkenes (e.g., norbornene), if the reaction is carried out in a hydrocarbon solvent (e.g., pentane) rather than ether, or in the alkene itself as solvent, heated, under pressure if necessary, to 60–130 °C.⁸⁹⁸ Yields are variable.

Intramolecular addition of RMgX to completely unactivated double and triple bonds has been demonstrated.⁸⁹⁹ The reaction of tosylates bearing a remote alkene unit and a Grignard reagent leads to cyclization when a Zr catalyst is used.⁹⁰⁰ The intramolecular addition of a CH₂Br unit to the C=C unit of an allylic ether was accomplished using PhMgBr and a Co catalyst, give a functionalized THF and incorporation of the phenyl group on the C=C unit as well.⁹⁰¹

In a useful variation, vinyl epoxides react with Grignard reagents and CuBr to give an allylic alcohol via reaction at the C=C unit and concomitant opening of the epoxide.⁹⁰² Conjugated dienes react with arylmagnesium halides, Ph₃SiCl, and a Pd catalyst to give a coupling product involving the reaction of 2 equiv of the diene and incorporation of two SiPh₃ units.⁹⁰³ The Cr catalyzed formation of arylmagnesium compounds⁹⁰⁴ and the Rh catalyzed hydroarylation⁹⁰⁵ of alkynes are also known. The Pd catalyzed hydroarylation⁹⁰⁶ of alkynes is possible using arenediazonium salts⁹⁰⁷ as substrates or hydroarylation of 1,3-dienes with boronic acids.⁹⁰⁸

Organolithium reagents (primary, secondary, and tertiary alkyl and in some cases aryl) add to the double and triple bonds of allylic and propargylic alcohols,⁹⁰⁹ (tetramethylethylenediamine is a catalyst) and also to certain other alkenes containing hetero groups (e.g., OR, NR₂, or SR). Mixing an organolithium reagent with transition metal compounds [e.g., CeCl₃⁹¹⁰ or Fe(acac)₃]⁹¹¹ leads to addition of the alkyl group. Cyclopropane derivatives have been formed in this manner.⁹¹² The organolithium reagents can contain heteroatoms (e.g., nitrogen) elsewhere in the molecule, and the organolithium species can be generated from an intermediate organotin derivative.⁹¹³ Organolithium reagents add to the less substituted C=C unit of conjugated dienes.⁹¹⁴ Addition of butyllithium to alkenes has been observed with good enantioselectivity when sparteine was added.⁹¹⁵

The intramolecular addition of RLi and R₂CuLi has been reported.⁹¹⁶ Organolithium reagents containing an alkene⁹¹⁷ or alkyne⁹¹⁸ unit cyclize⁹¹⁹ at low temperatures and quenching with methanol replaces the new C–Li bond with C–H. Tandem cyclization is possible with dienes and enynes to form more than one ring,⁹²⁰ including bicyclic compounds.⁹²¹ Tandem cyclization is possible with alkyne iodides⁹²² or alkynes with a homoallylic CH₂Li unit.⁹²³ The organolithium compound can be generated in situ by reaction of an organotin compound with butyllithium, allowing cyclization to occur upon treatment with an excess of LiCl.⁹²⁴

Unactivated alkenes or alkynes⁹²⁵ react with other organometallic compounds under certain conditions. The Pt catalyzed addition to alkynes leads to functionalized alkenes.⁹²⁶ Phenylboronic acids add to alkynes in the presence of a Co⁹²⁷ or a Pd catalyst.⁹²⁸ Trimethylaluminum reacts with 4-methyl-1-pentene, in the presence of Cl₂ZrCp₂, for example, and subsequent reaction with molecular oxygen leads to (2R),4-dimethyl-1-pentanol in good yield and 74% ee.⁹²⁹ These reagents also add to alkynes.⁹³⁰ Ruthenium catalysts have been used to mediate the addition of allylic alcohols to alkynes.⁹³¹ Samarium iodide (SmI₂) induces cyclization of a halide moiety to an alkyne unit⁹³² or an alkene unit⁹³³ to form cyclized products. Copper complexes can catalyze similar cyclization to alkenes, even when an ester unit is present in the molecule.⁹³⁴ Allyl manganese compounds add to allenes to give nonconjugated dienes.⁹³⁵

Organomanganese reagents add to alkenes.⁹³⁶ Manganese triacetate [Mn(OAc)₃], in the presence of cupric acetate, facilitates intramolecular cyclization of a halide unit to an alkene.⁹³⁷ Alkynes react with In reagents [e.g., (allyl)₃In₂I₃] to form dienes (allyl substituted alkenes from the alkyne).⁹³⁸ Allylic halides add to propargyl alcohols using In metal to form the aryl organometallic in situ.⁹³⁹ Allyltin reagents add to alkynes in a similar manner in the presence of ZrCl₄.⁹⁴⁰ Alkylzinc reagents add to alkynes to give substituted alkenes in the presence of a Pd catalyst.⁹⁴¹ Allylzinc reagents add to alkynes in the presence of a Co catalyst.⁹⁴² A vinyltellurium reagent adds to alkynes in the presence of CuI/PdCl₂.⁹⁴³

Ketones with an α-hydrogen add to alkenes intramolecularly when heated in a sealed tube with CuCl₂ and a Pd catalyst.⁹⁴⁴ A similar reaction was reported using Yb(OTf)₃ and a Pd catalyst⁹⁴⁵ or an In catalyst.⁹⁴⁶ Keto esters add to alkynes using 10% benzoic acid and a Pd catalyst,⁹⁴⁷ or an In catalyst.⁹⁴⁸ 1,3-Diketones add to dienes (1,4-addition) using a Pd catalyst,⁹⁴⁹ a AuCl₃/AgOTf catalyst,⁹⁵⁰ and this addition has been done intramolecularly using 2.4 molar equivalents of CuCl₂ and a Pd catalyst.⁹⁵¹ The intermolecular addition of diesters (e.g., malonates) to alkynes was accomplished in acetic acid and a Pd catalyst under microwave irradiation.⁹⁵² The enolate anion derived from the reaction of a nitrile with potassium tert-butoxide added to the less substituted carbon of the C=C unit of styrene in DMSO.⁹⁵³ Silyl enol ethers add to alkynes using a W catalyst.⁹⁵⁴ Malonate derivatives add to alkenes in the presence of an Al(OR)₃ catalyst.⁹⁵⁵ 1,3-Dicarbonyl compounds add to allenes in the presence of a Pd catalyst.⁹⁵⁶

Aryl iodides add to alkynes using a Pt complex in conjunction with a Pd catalyst.⁹⁵⁷ A Pd catalyst has been used alone for the same purpose,⁹⁵⁸ and the intramolecular addition of a arene to an alkene was accomplished with a Pd⁹⁵⁹or a GaCl₃ catalyst.⁹⁶⁰ Alkyl iodides add intramolecularly to alkenes with a Ti catalyst,⁹⁶¹ or to alkynes using In metal and additives.⁹⁶² The latter cyclization of aryl iodides to alkenes was accomplished with In and I₂⁹⁶³ or with SmI₂.⁹⁶⁴

Aromatic hydrocarbons (e.g., benzene) add to alkenes using a Ru catalyst⁹⁶⁵ a catalytic mixture of AuCl₃/AgSbF₆,⁹⁶⁶ or a Rh catalyst,⁹⁶⁷ and Ru complexes catalyze the addition of heteroaromatic compounds (e.g., pyridine) to alkynes.⁹⁶⁸ Such alkylation reactions are clearly reminiscent of the Friedel–Crafts reaction (11-11). Palladium catalysts can also be used for the addition of aromatic compounds to alkynes,⁹⁶⁹ and Rh catalysts for addition to alkenes (with microwave irradiation).⁹⁷⁰ Note that vinylidene cyclopropanes react with furans and a Pd catalyst to give allylically substituted furans.⁹⁷¹

Arylboronic acids (see Reaction 13-13) add to alkynes to give the substituted alkene using a Rh catalyst.⁹⁷² Allenes react with phenylboronic acid and an aryl iodide, in the presence of a Pd catalyst, to give a substituted alkene.⁹⁷³2-Bromo-1,6-dienes react with phenylboronic acid with a Pd catalyst to give a cyclopentane with an exocyclic double bond and a benzyl substituent.⁹⁷⁴

An indirect addition converts alkynes to an organozinc compound using a Pd catalyst, which then reacts with allylic halides.⁹⁷⁵ Similarly, the reaction of an alkyne with Ti(OiPr)₄/2 iPrMgCl followed by addition of an alkyne leads to a conjugated diene.⁹⁷⁶

OS 81, 121.

15-22 The Addition of Two Alkyl Groups to an Alkyne

Dialkyl-addition

Two different alkyl groups can be added to a terminal alkyne⁹⁷⁷ in one laboratory step by treatment with an alkylcopper–magnesium bromide reagent (called Normant reagents)⁹⁷⁸ and an alkyl iodide in ether–HMPA containing triethylphosphite.⁹⁷⁹ The groups add stereoselectively syn. The reaction, which has been applied to primary⁹⁸⁰ R′ and to primary, allylic, benzylic, vinylic, and α-alkoxyalkyl R′, involves initial addition of an intermediate alkylcopper reagent,⁹⁸¹ followed by a coupling reaction (10-57):

Acetylene itself (R = H) undergoes the reaction with R₂CuLi instead of the Normant reagent.⁹⁸² The use of R′ containing functional groups has been reported.⁹⁸³ If the alkyl iodide is omitted, the vinylic copper intermediate (79) can be converted to a carboxylic acid by the addition of CO₂ (see Reaction 16-30) or to an amide by the addition of an isocyanate, in either case in the presence of HMPA and a catalytic amount of triethyl phosphite.⁹⁸⁴ The use of I₂results in a vinylic iodide.⁹⁸⁵

Similar reactions, in which two alkyl groups are added to a triple bond, have been carried out with trialkylalanes (R₃Al) and zirconium complexes as catalysts.⁹⁸⁶ Internal alkynes undergo bis(allylation) using a Ni catalysts and triallylindium.⁹⁸⁷ Allyl ethers and iodobenzene have also been added using a Zr complex.⁹⁸⁸ Similarly, allyl ethers and allyl chlorides have been added.⁹⁸⁹

Arylboronic acids (see Reaction 13-13) react with alkynes and 1 equiv of an aryl iodide, with a Pd catalyst, to add two aryl groups across the triple bond.⁹⁹⁰

OS VII, 236, 245, 290.

15-23 The Ene Reaction

Hydro-allyl-addition

An interesting addition of RH to a double bond involves the reaction of alkenes with an alkene having an allylic hydrogen (80), and is called the ene reaction or the ene synthesis.⁹⁹¹ The reaction proceeds without a catalyst, but one of the components must be a reactive dienophile (reacts with a diene; see Reaction 15-60 for a definition of this word), such as maleic anhydride, but the other (which supplies the hydrogen) may be a simple alkene (e.g., propene) as long as there is an allylic hydrogen atom. Rather high reaction temperatures (250–450 °C) are common unless the substrates are very activated, but steric acceleration of the uncatalyzed ene reaction is known.⁹⁹² The reaction is compatible with a variety of functional groups that can be appended to the ene and dienophile. N,N-Diallyl amides give an ene cyclization, for example.⁹⁹³ There has been much discussion of the mechanism of this reaction, and both concerted pericyclic (as shown above) and stepwise mechanisms have been suggested. The mechanism of the ene reaction of singlet () oxygen with simple alkenes was found to involve two steps, with no intermediate.⁹⁹⁴ A retro-ene reaction is known with allylic dithiocarbonate.⁹⁹⁵ An intramolecular ene reaction between oxazolones and enol ethers leads to functionalized oxazolones.⁹⁹⁶ The reaction between maleic anhydride and optically active PhCHMeCH=CH₂ gave an optically active product (81),⁹⁹⁷ which is strong evidence for a concerted rather than a stepwise mechanism.⁹⁹⁸ The reaction can be highly stereoselective.⁹⁹⁹

The reaction can be extended to less-reactive enophiles by the use of Lewis acid catalysts, especially alkylaluminum halides.¹⁰⁰⁰ Titanium catalysts,¹⁰⁰¹ Sc,¹⁰⁰² LiClO₄¹⁰⁰³ Y,¹⁰⁰⁴ In,¹⁰⁰⁵ Pd,¹⁰⁰⁶ Co,¹⁰⁰⁷ Ni catalysts,¹⁰⁰⁸ as well as a combination of Ag and Au catalysts¹⁰⁰⁹ have also been used. A magnesium–ene cyclization stereochemically directed by an allylic oxyanionic group has been reported.¹⁰¹⁰ The Lewis acid catalyzed reaction probably has a stepwise mechanism.¹⁰¹¹ An Ir catalyzed ene reaction has been done in an ionic liquid.¹⁰¹² An ene reaction of arynes with alkynes leads to aryl allenes.¹⁰¹³ An aza–ene reaction¹⁰¹⁴ has been used in a synthesis of enantioenriched piperidines, using two different imines as starting materials.¹⁰¹⁵ Ene reactions of imines are sometimes called imino–ene reactions.¹⁰¹⁶

The carbonyl–ene reaction¹⁰¹⁷ is also very useful, and often gives synthetically useful yields of products when catalyzed by Lewis acids.¹⁰¹⁸ Scandium triflate¹⁰¹⁹ and chromium complexes¹⁰²⁰ are useful Lewis acids in this reaction. Asymmetric catalysts¹⁰²¹ for enantioselective carbonyl ene reactions have been reported using chiral Sc catalysts¹⁰²² In,¹⁰²³ or chiral Ni catalysts.¹⁰²⁴ Ketoester ene reactions with silyl enol ethers occurs in the presence of Pd and Ag catalysts.¹⁰²⁵ Carbonyl–ene cyclization has been reported on silica gel at high pressure (15 kbar).¹⁰²⁶ Ene reactions with imines,¹⁰²⁷ nitrile oxides,¹⁰²⁸ as well as nitroso–ene reactions are known.¹⁰²⁹ Vinyl boronates have been prepared via a Ru catalyzed ene reaction.¹⁰³⁰

OS IV, 766; V, 459. See also, OS VIII, 427.

15-24 The Michael Reaction

Hydro-bis(ethoxycarbonyl)methyl-addition, and so on

Compounds containing electron-withdrawing groups (Z is defined in Sec. 15.A.ii as an electron-withdrawing group) add to alkenes of the form C=C–Z in the presence of bases.¹⁰³¹ This is called the Michael reaction and is formally a conjugate addition.¹⁰³² The product formed, RCH₂Z or RCHZZ′, can include aldehydes,¹⁰³³ ketones,¹⁰³⁴ esters,¹⁰³⁵ diesters,¹⁰³⁶ diketones,¹⁰³⁷ keto-esters,¹⁰³⁸ carboxylic acids, dicarboxylic acids,¹⁰³⁹ nitriles,¹⁰⁴⁰ vinyl sulfones,¹⁰⁴¹ nitro compounds (see below),¹⁰⁴² and others of the form ZCH₃, ZCH₂R, ZCHR₂, and ZCHRZ′. ¹⁰⁴³ In the most common examples, a base removes the acidic proton from the substrate adding to C=C–Z and the mechanism is as outlined in Section 15.A.ii. Michael addition is known to be catalyzed by phosphines,¹⁰⁴⁴ as well as other organocatalysts.¹⁰⁴⁵ Catalysts are known that are compatible with an aqueous medium.¹⁰⁴⁶ A double Michaelprocess is possible, where conjugate addition to an alkynyl ketone is followed by an intramolecular Michael reaction to form a functionalized ring.¹⁰⁴⁷ Vinylogous Michael reactions are well known, using a variety of nucleophilic species¹⁰⁴⁸ (see Sec. 6.B for vinylogy). 1,6-Additions are also known.¹⁰⁴⁹ Arylsilanes add to conjugated esters and amides in the presence of a Rh catalyst.¹⁰⁵⁰ Nitro compounds add to conjugated ketones via Michael addition.¹⁰⁵¹Niroalkenes are Michael acceptors¹⁰⁵² for the enolate anions of β-keto esters¹⁰⁵³ or malonate derivatives with a Ni catalyst¹⁰⁵⁴ or an organocatalyst.¹⁰⁵⁵ Other substrates have been added to nitroalkenes via Michael addition.¹⁰⁵⁶Malonate derivatives also add to conjugated ketones,¹⁰⁵⁷ and keto esters add to conjugated esters.¹⁰⁵⁸ Vinyl sulfones undergo Michael addition.¹⁰⁵⁹

It is known that 1,2-addition (to the C=O or CN group) often competes and sometimes predominates (Reaction 16-38).¹⁰⁶⁰ In particular, α,β-unsaturated aldehydes seldom give 1,4-addition.¹⁰⁶¹ The Michael reaction generally gives better yields with fewer side reactions by conversion of the nucleophile to its enolate form (a preformed enolate).¹⁰⁶² Phase-transfer catalysts have been used,¹⁰⁶³ and ionic liquids have been used in conjunction with phase-transfer catalysis.¹⁰⁶⁴ Transition metal compounds Ce,¹⁰⁶⁵ Yb,¹⁰⁶⁶ Bi,¹⁰⁶⁷ Fe,¹⁰⁶⁸ Ni,¹⁰⁶⁹ Cu,¹⁰⁷⁰ La,¹⁰⁷¹ Ru,¹⁰⁷² or Sc¹⁰⁷³ also induce the reaction Conjugate addition has also been promoted by Y-zeolite,¹⁰⁷⁴ and water-promoted Michael additions have also been reported.¹⁰⁷⁵ Acylsilanes, when treated with fluoride ion, add to conjugated amides under certain conditions.¹⁰⁷⁶ Addition to the meta-position of phenolic compounds leads to bicyclic ketones.¹⁰⁷⁷Conjugate addition of nitrones using SmI₂ has been reported.¹⁰⁷⁸ Cyanide ion adds to Michael acceptors, and TMSCN also adds in a Michael reaction.¹⁰⁷⁹

Intramolecular versions of Michael addition are known.¹⁰⁸⁰ The intramolecular Michael addition of an α-chloro ketone enolate anion, formed in situ using DABCO, leads to formation of a bicyclo[4.1.0] diketone.¹⁰⁸¹

An important cyclization procedure involves the acid-catalyzed addition of diene-ketones (e.g., 82), where one conjugated alkene adds to the other conjugated alkene to form cyclopentenones (83). This is called the Nazarov cyclization.¹⁰⁸² While it may be categorized in Reaction 15-20 because one alkene unit adds to another, the addition is formally a Michael addition, and so is placed here. Structural variations are possible that prepare a variety of cyclopentenones. The steric influence of substituents has been discussed,¹⁰⁸³ and the rate-accelerating influence observed in N- and S-heterocycles.¹⁰⁸⁴ Substituents on the C=C units lead to cyclopentenones that bear those substituents. Gold¹⁰⁸⁵ and V catalyzed¹⁰⁸⁶ cyclizations have been reported, as well as a Sc catalyzed cyclization in water.¹⁰⁸⁷ Heating dienones in DME or an ionic liquid has been shown to give the Nazarov product without addition of a Lewis acid.¹⁰⁸⁸ Allenes participate in Nazarov cyclization reactions.¹⁰⁸⁹ A vinylogous Nazarov reaction is involved in the cyclization of cross-conjugated trienes¹⁰⁹⁰ (see Sec. 6.B for vinylogy). The use of a chiral ligand gave the cyclopentenone with modest enantioselectivity.¹⁰⁹¹ Reductive cyclization can also give the nonconjugated five-membered ring.¹⁰⁹² Note that a retro-Nazarov is possible with α-bromocyclopentanones.¹⁰⁹³ In one variation using an Al complex, a cyclohexenone was formed.¹⁰⁹⁴ There is a so-called interrupted Nazarov, in which an amine is trapped after cyclization to give an α-amino conjugated cyclopentenone.¹⁰⁹⁵ Spirocycles have been prepared via a tandem Nazarov–Wagner–Meerwein sequence.¹⁰⁹⁶

In a Michael reaction with suitably different R groups, two new stereogenic centers may be created (see 84). In a diastereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture.¹⁰⁹⁷When either or both of the reaction components have a chiral substituent, the reaction can be enantioselective (only one of the four diastereomers formed predominantly).¹⁰⁹⁸ There are many examples of catalytic enantioselective Michael additions,¹⁰⁹⁹ often by the use of a chiral catalyst¹¹⁰⁰ or by using optically active enamines instead of enolates.¹¹⁰¹ Common chiral catalysts used with carbonyl substrates include Ru,¹¹⁰² Ni,¹¹⁰³ Sr,¹¹⁰⁴ and Al(salen) complexes.¹¹⁰⁵ Chiral organocatalysts¹¹⁰⁶ (e.g., oxazolidinones)¹¹⁰⁷ have been developed and chiral imines have also been used.¹¹⁰⁸ Certain antibodies have been used to facilitate chiral, intramolecular Michael addition reactions.¹¹⁰⁹Enzymes have been used as for asymmetric Michael reactions.¹¹¹⁰ Addition of chiral additives to the reaction (e.g., metal–salen complexes,¹¹¹¹ proline derivatives,¹¹¹² or (−)-sparteine¹¹¹³) lead to product formation with good-to-excellent asymmetric induction. Ultrasound has been used to promote asymmetric Michael reactions.¹¹¹⁴ In reactions of enolate anions, both the enolate anion and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, the (E) enolates gave the syn pair of enantiomers (Sec. 4.G), while (Z) enolates gave the anti pair.¹¹¹⁵

When the substrate contains gem-Z groups, (e.g., 86), bulky groups can be added, if the reaction is carried out under aprotic conditions. For example, addition of enolate 85 to 86 gave 87 in which two adjacent quaternary centers have been formed.¹¹¹⁶

In certain cases, Michael reactions can take place under acidic conditions.¹¹¹⁷ Michael-type addition of radicals to conjugated carbonyl compounds is also known.¹¹¹⁸ Radical addition can be catalyzed by Yb(OTf)₃,¹¹¹⁹ but radicals add under standard conditions as well, even intramolecularly.¹¹²⁰ Electrochemical-initiated Michael additions are known.

Alkynes are reactive, and Michael reactions are sometimes applied to substrates of the type CC–Z, where the coproducts are conjugated systems of the type C=C–Z.¹¹²¹ Terminal alkynes add to conjugated systems.¹¹²² Due to the greater susceptibility of triple bonds to nucleophilic attack, it is even possible for nonactivated alkynes (e.g., acetylene), to be substrates in this reaction.¹¹²³

Silyl enol ethers (e.g., 88) add to α,β-unsaturated ketones and esters when catalyzed¹¹²⁴ by TiCl₄¹¹²⁵ or InCl₃.¹¹²⁶ Aluminum compounds also catalyze this reaction¹¹²⁷ and the reaction has been done in neat tri-n-propylaluminum.¹¹²⁸ A solid-state version of the reaction used alumina·ZnCl₂.¹¹²⁹ Tin-enolates have been used.¹¹³⁰ This reaction has been performed with good diastereoselectivity,¹¹³¹ and silyl enol ethers have been used in conjunction with chiral additives.¹¹³²

The reaction of C=C–Z compounds with enamines (10-69) can also be considered a Michael reaction.

OS I, 272; II, 200; III, 286; IV, 630, 652, 662, 776; V, 486, 1135; VI, 31, 648, 666, 940; VII, 50, 363, 368, 414, 443; VIII, 87, 210, 219, 444, 467; IX, 526. See also, OS VIII, 148.

15-25 1,4-Addition of Organocuprates and Other Organometallic Compounds to Activated Double Bonds

Hydro-alkyl-addition

Lithium dialkylcopper reagents (R₂CuLi reagents,¹¹³³ also known as Gilman reagents, see Reaction 10-57) add to α,β-unsaturated aldehydes¹¹³⁴ and ketones (R′ = H, R, Ar) and other systems of the form CC–C=O¹¹³⁵ to give conjugate addition products¹¹³⁶ in a reaction closely related to the Michael reaction. α,β-Unsaturated esters are less reactive,¹¹³⁷ and the corresponding acids do not react at all. The R group can be primary alkyl, vinylic,¹¹³⁸ or aryl. If Me₃SiCl is present, the reaction takes place much faster and in higher yield; in the example given, the product is the silyl enol ether of 89 (see Reaction 12-17).¹¹³⁹ The use of Me₃SiCl also permits good yields with allylic R groups.¹¹⁴⁰ Conjugated alkynyl-ketones also react via 1,4-addition to give substituted alkenyl-ketones.¹¹⁴¹ Solvent effects are important for the reactivity of organocuprates,¹¹⁴² which influence aggregation and aggregation state of the dialkyl cuprate.¹¹⁴³ Organocuprate reactions have been shown to undergo oscillations in complexation.¹¹⁴⁴

An excess of the cuprate reagent relative to the conjugated substrate is often required. In general, only one of the R groups of R₂CuLi adds to the substrate; the other is wasted with respect to the conjugated substrate. This can be a limitation where the precursor (RLi or RCu, see Reaction 12-36) is expensive or available in limited amounts, particularly if an excess of the reagent is required. The difficulty of group transfer can be overcome by using one of the mixed reagents [R(R′CC)CuLi,¹¹⁴⁵ R(O-t-Bu)CuLi,¹¹⁴⁶ R(PhS)CuLi¹¹⁴⁷ each of which transfers only the R group. Mixed reagents are easily prepared by the reaction of RLi with R′CCCu (R′ = n-Pr or t-Bu), t-BuOCu, or PhSCu, respectively. A further advantage of the mixed reagents is that good yields of addition product are achieved when R is tertiary, so that use of one of them permits the introduction of a tertiary alkyl group. The mixed reagents R(CN)CuLi¹¹⁴⁸ (prepared from RLi and CuCN) and R₂Cu(CN)Li₂¹¹⁴⁹ also selectively transfer the R group.¹¹⁵⁰ With mixed cuprates, one of the ligands may be less prone to transfer than the other, as R(R′Se)Cu(CN)Li₂, leading to selective transfer of the R group.¹¹⁵¹ This less transferable ligand is sometimes referred to as a “dummy ligand”. The selectivity of ligand transfer depends on two factors, thermodynamics of groups (e.g., alkyl or thioalkyl) and kinetic reactivity of groups (e.g., silylalkyl or vinyl).¹¹⁵² The selectivity arises in the Cu(III) intermediate formed by complexation of the cuprate and the unsaturated carbonyl compound.^1150,1153 A Cu(III) complex has been detected using rapid injection NMR.¹¹⁵⁴

Various functional groups (e.g., OH and unconjugated C=O groups) may be present in the substrate when organocuprates are employed.¹¹⁵⁵ There is generally little or no competition from 1,2-addition (to the C=O). However, when R is allylic, 1,4-addition is observed with some substrates and 1,2-addition with others.¹¹⁵⁶ The R₂CuLi group also adds to α,β-unsaturated sulfones,¹¹⁵⁷ but not to simple α,β-unsaturated nitriles.¹¹⁵⁸ Organocopper reagents (RCu) as well as certain R₂CuLi add to α,β-unsaturated and acetylenic sulfoxides.¹¹⁵⁹ The reaction has been carried out¹¹⁶⁰ with α,β-acetylenic ketones,¹¹⁶¹ esters, and nitriles. Conjugate addition to α,β-unsaturated and acetylenic acids and esters, as well as ketones, can be achieved by the use of the coordinated reagents RCu·BF₃ (R = primary).¹¹⁶² Amine units have been transferred using α-lithio amides, CuCN, and various additives, which gave conjugate addition of an amidomethyl unit [–CH₂N(Me)Boc].¹¹⁶³ Other amino-cuprates are known to give conjugate addition reactions.¹¹⁶⁴

Conjugate addition of the cuprate to the α,β-unsaturated ketone leads to an enolate ion (89), as noted above. It is possible for this enolate anion to react with an electrophilic species (tandem vicinal difunctionalization), in some cases at the O and in other cases at the C.¹¹⁶⁵ For example, if an alkyl halide R²X is present (R² = primary alkyl or allylic), the enolate (89) can be alkylated directly to give 90.¹¹⁶⁶ Thus, by this method, both the α and β positions of a ketone are alkylated in one synthetic operation (see also, Reaction 15-22).

As with the Michael reaction (15-24) the 1,4-addition of organometallic compounds has been performed diastereoselectivity¹¹⁶⁷ and enantioselectively.¹¹⁶⁸ The influence of solvent and additives on yield and selectivity has been examined.¹¹⁶⁹ Addition of chiral ligands to the organocuprate conjugate addition reaction leads to alkylation with good-to-excellent enantioselectivity.¹¹⁷⁰ The conjugate addition of dimethyl cuprate in the presence of a chiral ligand (e.g., 91) is an example.¹¹⁷¹ Chiral bis(oxazoline) copper catalysts have been used for the conjugate addition of indoles to α,β-unsaturated esters.¹¹⁷² In the presence of a chiral additive and a Cu catalyst, conjugate addition to trisubstituted cyclohexeneones leads to the formation of stereogenic quaternary centers.¹¹⁷³ Enantioselectivity was improved by the addition of styrene in the conjugate addition reactions of α-halo enones.¹¹⁷⁴ Enantioselectivity is effectively controlled by the choice of ligand and its interaction with the copper compound, where different ligands on the metal may lead to differences in selectivity.¹¹⁷⁵ Chiral templates have also been used with Grignard reagents, directly¹¹⁷⁶ and in the presence of AlMe₂Cl.¹¹⁷⁷

Other organometallic compounds add to conjugated systems. Grignard reagents add to conjugated substrates (e.g., α,β-unsaturated ketones, cyano-ketones,¹¹⁷⁸ esters, and nitriles),¹¹⁷⁹ but 1,2-addition may seriously compete:¹¹⁸⁰The extent of 1,4-addition of Grignard reagents can be increased by the use of a Cu catalyst [e.g., CuCl and Cu(OAc)₂],¹¹⁸¹ forming a magnesium cuprate in situ. Formation of the conjugate addition product is often controlled by steric factors. Thus 92 with phenylmagnesium bromide gives 100% 1,4-addition, while 93 gives 100% 1,2-addition. In general, substitution at the carbonyl group increases 1,4-addition, while substitution at the double bond increases 1,2-addition. In most cases, both products are obtained, but α,β-unsaturated aldehydes nearly always give exclusive 1,2-addition when treated with Grignard reagents. Grignard reagents mixed with CeCl₃ generates a reactive species that gives primarily 1,4-addition.¹¹⁸² It is likely that alkylcopper reagents, formed from RMgX and Cu⁺ (cupric acetate is reduced to cuprous ion by excess RMgX), are the actual reactive species in these cases.¹¹³⁴ Alkylidene malonic ester derivatives [C=C(CO₂R)] increase the facility of 1,4-addition with the two electron-withdrawing groups.¹¹⁸³

A dialkyl copper–magnesium iodide complex (R₂Cu·MgI) has been used for conjugate addition to chiral α,β-unsaturated amides.¹¹⁸⁴ Catalytic enantioselective conjugate addition has been reported with Grignard reagents.¹¹⁸⁵

Organolithium reagents¹¹⁸⁶ generally react with conjugated aldehydes, ketones, and esters by 1,2-addition,¹¹⁸⁷ but 1,4-addition was achieved with esters of the form C=C–CO₂Ar, where Ar was a bulky group (e.g., 2,6-di-tert-butyl-4-methoxyphenyl).¹¹⁸⁸ Alkyllithium reagents can be made to give 1,4-addition with α,β-unsaturated ketones¹¹⁸⁹ and aldehydes,¹¹⁹⁰ if the reactions are conducted in the presence of HMPA.¹¹⁹¹ Among organolithium reagents that have been found to add 1,4 in this manner are 2-lithio-1,3-dithianes (see Reaction 10-71),¹¹⁹² vinyllithium reagents,¹¹⁹³ and α-lithio allylic amides.¹¹⁹⁴ Lithium–halogen exchange (12-22) generates an organolithium species that adds intramolecularly to conjugated esters to give cyclic and bicyclic products.¹¹⁹⁵ A reagent based on RMgX–3 MeLi gave conjugate addition with α,β-unsaturated amides and carboxylic acid derivatives.¹¹⁹⁶ 1,4-Addition of alkyllithium reagents to α,β-unsaturated aldehydes can also be achieved by converting the aldehyde to a benzothiazole derivative (masking the aldehyde function),¹¹⁹⁷ from which the aldehyde group can be regenerated. α,β-Unsaturated nitro compounds undergo conjugate addition with aryllithium reagents, and subsequent treatment with acetic acid gives the α-aryl ketone.¹¹⁹⁸

If the organolithium reagent is complexed, 1,4-addition is more successful. The reaction of an aryllithium reagent with B(OMe)₃, for example, led to a Rh catalyzed conjugate addition with excellent enantioselectivity when a chiral ligand was employed.¹¹⁹⁹ Allylic Te reagents that are treated with lithium diisopropyl amide and then conjugated esters give the 1,4-addition product, which cyclizes to form the corresponding cyclopropane derivative.¹²⁰⁰

Organozinc compounds add to conjugated systems, especially dialkyl zinc compounds (R₂Zn). Many dialkylzinc compounds can be used, including vinylzinc compounds.¹²⁰¹ The use of chiral ligands is effective for conjugate addition of dialkylzinc compounds to α,β-unsaturated ketones, esters, and so on,¹²⁰² including conjugated lactones.¹²⁰³ The addition of a chiral complex to dialkylzinc compounds leads to enantioselective conjugate addition in conjunction with Cu(OTf)₂¹²⁰⁴ CuCN,¹²⁰⁵ or other copper compounds.¹²⁰⁶ Chiral ionic liquids have also been employed.¹²⁰⁷ Diethylzinc adds to conjugated nitro compounds in the presence of a catalytic amount of Cu(OTf)₂ to give the conjugate addition product.¹²⁰⁸ 1,6-Addition of dialkylzinc compounds has been reported, in the presence of a Rh catalyst.¹²⁰⁹ Other transition metal compounds can be used in conjunction with dialkylzinc compounds¹²¹⁰ or with arylzinc halides (ArZnCl).¹²¹¹ Reaction of alkyl iodides with Zn/CuI and ultrasound generates an organometallic that adds to conjugated esters.¹²¹² Diarylzinc compounds (prepared with the aid of ultrasound) in the presence of nickel acetylacetonate, undergo 1,4-addition not only to α,β-unsaturated ketones, but also to α,β-unsaturated aldehydes.¹²¹³ Mixed-alkylzinc compounds also add to conjugated systems.¹²¹⁴ Functionalized allylic groups can be added to terminal alkynes with allylic halides, zinc, and ultrasound, to give 1,4-dienes.¹²¹⁵ Internal alkynes undergo 1,4-addition to conjugated esters using a combination of zinc metal and a Co complex as catalysts.¹²¹⁶

Trialkylalanes (R₃Al) add 1,4 to α,β-unsaturated carbonyl compounds in the presence of nickel acetylacetonate¹²¹⁷ or Cu(OTf)₂.¹²¹⁸ In the presence of aluminum chloride, benzene reacts with conjugated amides to add a phenyl group to C-4.¹²¹⁹ Alkyl halides react via conjugate addition using BEt₃ or AlEt₃.¹²²⁰ Other metals are known to catalyzed conjugate addition of alkyl or aryl groups, including Co.¹²²¹ An In/Cu mediated conjugate addition reaction is known using unactivated alkyl iodides.¹²²²

Terminal alkynes add to conjugated systems when using a Ru,¹²²³ Pd,¹²²⁴ Ni,¹²²⁵ or a Rh catalyst.¹²²⁶ Intramolecular addition of terminal alkynes, in the presence of phenylboronic acid and a Rh catalyst, leads to cyclic compounds.¹²²⁷ Lithium tetraalkylgallium reagents give 1,4-addition.¹²²⁸ Trimethyl(phenyl)tin and a Rh catalyst gives conjugate addition of a methyl group¹²²⁹ and tetraphenyltin and a Pd catalyst adds a phenyl group.¹²³⁰Triphenylbismuth (Ph₃Bi) and a Rh catalyst give conjugate addition of the phenyl group upon exposure to air.¹²³¹ Similar reactivity is observed with a Pd catalyst in aqueous media.¹²³² Allyltin compounds add an allyl group in the presence of a Sc catalyst.¹²³³ Benzylic bromides add to conjugated nitriles using a 2:1 mixture of CrCl₃ and Mn metal.¹²³⁴ Aryl halides add in the presence of NiBr₂.¹²³⁵ Vinyl Zr complexes undergo conjugate addition when using a Rh catalyst.¹²³⁶

In certain cases, Grignard reagents add 1,4 to aromatic systems to give 94 after tautomerization (Sec. 2.N.i) of the initial formed enol.¹²³⁷ Such cyclohexadienes are easily oxidizable to benzenes (often by atmospheric oxygen), so this reaction becomes a method of alkylating and arylating suitably substituted (usually hindered) aryl ketones. A similar reaction has been reported for aromatic nitro compounds where 1,3,5-trinitrobenzene reacts with excess methylmagnesium halide to give 2,4,6-trinitro-1,3,5-trimethylcyclohexane.¹²³⁸

The mechanisms of most of these reactions are not well known. The 1,4-uncatalyzed Grignard reaction has been postulated to proceed by the cyclic mechanism shown, but there is evidence against it.¹²³⁹ The R₂CuLi¹²⁴⁰ and copper-catalyzed Grignard additions may involve a number of mechanisms, since the actual attacking species and substrates are so diverse.¹²⁴¹ A free radical mechanism of some type (perhaps SET) has been suggested¹²⁴² although the fact that retention of configuration at R has been demonstrated in several cases completely rules out a free R^• radical.¹²⁴³ For simple α,β-unsaturated ketones (e.g., 2-cyclohexenone and Me₂CuLi), there is evidence¹²⁴⁴ for this mechanism:

95 is a d, π^∗ complex, with bonding between copper, as a base supplying a pair of d electrons, and the enone as a Lewis acid using the π^∗ orbital of the allylic system.¹²⁴² The NMR spectrum of an intermediate similar to 95 has been reported.¹²⁴⁵

For the addition of organocopper reagents to alkynes and conjugated dienes, see Reaction 15-22.

OS IV, 93; V, 762; VI, 442, 666, 762, 786; VIII, 112, 257, 277, 479; IX, 328, 350, 640.

15-26 The Sakurai Reaction

Allylic silanes (R₂C=CHCH₂SiMe₃) can be added to conjugated systems rather than silyl enol ethers in what is known as the Sakurai reaction.¹²⁴⁶ For example, an allyl group can be added to α,β-unsaturated carboxylic esters, amides and nitriles, with CH₂=CHCH₂SiMe₃ and F⁻ ion (see Reaction 15-47).¹²⁴⁷ This reagent gave better results than lithium diallylcuprate (Reaction 15-25). Catalytic Sakurai reactions are known.¹²⁴⁸ The Pd catalyzed reaction of conjugated ketones with PhSi(OEt)₃ and SbCl₃ and Bu₄NF in acetic acid gave the 1,4-addition product.¹²⁴⁹ A similar reaction was reported using PhSi(OMe)₃ with a Rh catalyst.¹²⁵⁰ Silver fluoride was used to catalyze the reaction with allyl(trimethoxy)silane.¹²⁵¹ In a related reaction, Ph₂SiCl₂, NaF, and a Rh catalyst gives conjugate addition of a phenyl group to α,β-unsaturated ketones.¹²⁵² An interesting Rh catalyzed, conjugate addition of a phenyl group was reported using a siloxane polymer bearing Si–Ph units.¹²⁵³ The Sakurai reaction has been used in multi-component reactions.¹²⁵⁴

15-27 Conjugate Addition of Boranes to Activated Double Bonds

Hydro-alkyl-addition (overall transformation)

Just as trialkylboranes add to simple alkenes (Reaction 15-16), they rapidly add to the double bonds of acrolein, methyl vinyl ketone, and certain related derivatives in THF to give enol borinates (also see Reaction 10-68), which can be hydrolyzed to aldehydes or ketones.¹²⁵⁵ If water is present in the reaction medium from the beginning, the reaction can be run in one laboratory step. Since the boranes can be prepared from alkenes (Reaction 15-16), this reaction provides a means of lengthening a carbon chain by three or four carbons, respectively. Compounds containing a terminal alkyl group [e.g., such as crotonaldehyde (CH₃CH=CHCHO) and 3-penten-2-one], fail to react under these conditions, as does acrylonitrile, but these compounds can be induced to react by the slow and controlled addition of O₂ or by initiation with peroxides or UV light.¹²⁵⁶ A disadvantage is that only one of the

three R groups of R₃B adds to the substrate, so that the other two are wasted. This difficulty is overcome by the use of a β-alkyl borinate (e.g., 96),¹²⁵⁷ which can be prepared as shown. Borinate (96, R = tert-butyl) can be made by treatment of 96 (R = OMe) with t-BuLi. The use of this reagent permits tert-butyl groups to be added. β-1-Alkenyl-9-BBN compounds β-RCH=CR′-9-BBN (prepared by treatment of alkynes with 9-BBN or of RCH=CR′Li with β-methoxy-9-BBN¹²⁵⁸) add to methyl vinyl ketones to give, after hydrolysis, γ,δ-unsaturated ketones,¹²⁵⁹ although β-R-9-BBN, where R = a saturated group, are not useful here, because the R group of these reagents does not preferentially add to the substrate.¹²⁵³ Transition metals catalyze the addition of trialkylboranes to conjugated systems (e.g., the addition of allylboranes in the presence of a Ni catalyst).¹²⁶⁰ The Ni catalyzed addition was enhanced by the addition of methanol.¹²⁶¹

The corresponding β-1-alkynyl-9-BBN compounds also give the reaction.¹²⁶² Since the product 97 is an α,β-unsaturated ketone, it can be made to react with another BR₃, the same or different, to produce a wide variety of ketones (98).

Vinyl boranes add to conjugated ketones in the presence of a Rh catalyst (with high asymmetric induction in the presence of BINAP).¹²⁶³ Alkynyl-boranes also add to conjugated ketones, in the presence of BF₃.¹²⁶⁴

Other boron reagents add to conjugated carbonyl compounds.¹²⁶⁵ Tetraphenylborates add to conjugated alkynes in the presence of a Pd catalyst in a reaction known as hydrophenylation.¹²⁶⁶ Alkynyl boronate esters (Reaction 12-28) give conjugate addition¹²⁶⁷ in the presence of boron trifluoride etherate,¹²⁶⁸ as do arylboronic acids (Reaction 12-28) with a Rh,¹²⁶⁹ Pd,¹²⁷⁰ or a Bi catalyst.¹²⁷¹ Diethylzinc has also been used.¹²⁷² Aryl boronic acids add to the double bond of vinyl sulfones in the presence of a Rh catalyst.¹²⁷³ Vinylboronic acids add directly to conjugated ketones.¹²⁷⁴ An Ir catalyzed 1,6-addition of arylboronic acids is known.¹²⁷⁵ Conjugated alkynes undergo conjugate addition with arylboronic acids in the presence of a Cu catalyst.¹²⁷⁶ Organocatalysts have also been used for the conjugate addition of arylboronic acids to conjugated systems.¹²⁷⁷ Potassium vinyltrifluoroborates (see Reactions 10-59, 13-10, and 13-13) give 1,4-addition with a Rh catalyst,¹²⁷⁸ as do aryltrifluoroborates.¹²⁷⁹ The Rh catalyzed addition of vinyl tetrafluoroborates has been reported.¹²⁸⁰

In the presence of a Rh catalyst, LiBPh(OMe)₃ gave conjugate addition of the phenyl group to α,β-unsaturated esters.¹²⁸¹ The fact that these reactions are catalyzed by free radical initiators and inhibited by galvinoxyl¹²⁸² (a free radical inhibitor) indicates that free-radical mechanisms are involved.

15-28 Radical Addition to Activated Double Bonds

Hydro-alkyl-addition

In a reaction similar to 15-25, alkyl groups can be added to alkenes activated by such groups as COR′, CO₂R′, CN, and even Ph.¹²⁸³ This is a radical addition reaction.¹²⁸⁴ In the method illustrated above, the R group comes from an alkyl halide (R = primary, secondary, or tertiary alkyl; X = Br or I) and the hydrogen from the tin hydride (H atom transfer agents). The reaction of tert-butyl bromide, Bu₃SnH and AIBN (Sec. 14.A.i), for example, adds a tert-butyl group to a conjugated ester via 1,4-addition.¹²⁸⁵ An alkene is converted to an alkylborane with catecholborane (Reaction 12-28) and when treated with a conjugated ketone and O₂, radical conjugate addition leads to the β-substituted ketone.¹²⁸⁶ The Bu₃SnH can also be generated in situ, from R₃SnX and NaBH₄. Like Reaction 15-27, these additions have free radical mechanisms. The reaction has been used for free radical cyclizations of the type discussed in Reaction 15-30.¹²⁸⁷ Such cyclizations normally give predominant formation of five-membered rings, but large rings (11–20 members) have also been synthesized by this reaction.¹²⁸⁸

A BEt₃ (see Sec. 14.A.i) initiated reaction of conjugated amides with an alkyl iodide, in the presence of Bu₃SnH and O₂, leads to conjugate addition of the alkyl group.¹²⁸⁹ Enantioselective radical addition has been reported.¹²⁹⁰

Conjugate addition is possible using photolysis. The photoinduced 1,4-addition of indoles to enones proceeds when irradiated at 350 nm.¹²⁹¹

OS VII, 105.

15-29 Radical Addition to Unactivated Double Bonds¹²⁹²

Alkyl-hydro-addition

Radical addition to alkenes is usually difficult, except when addition occurs to conjugated carbonyl compounds (Reaction 15-24). An important exception involves radicals bearing a heteroatom α to the carbon bearing the radical center. Such radicals are much more stable and can add to alkenes, usually with anti-Markovnikov orientation, as in the radical induced addition of HBr to alkenes (Reaction 15-2).¹²⁹³

Examples of this type of reaction include the use of alcohol-, ester-,¹²⁹⁴ amino-, and aldehyde-stabilized radicals.⁴⁸³ The alkyl group of alkyl iodides adds to alkenes with BEt₃/O₂ as the initiator and in the presence of a tetraalkylammonium hypophosphite.¹²⁹⁵ The radical generated from (EtO)₂POCH₂Br adds to alkenes to generate a new phosphonate ester.¹²⁹⁶ α-Bromo esters add to alkenes in the presence of BEt₃/air to give a γ-bromo ester.¹²⁹⁷ α-Bromo amides add the Br and the acyl carbon to an alkene using Yb(OTf)₃ with BEt₃/O₂ as the radical initiator.¹²⁹⁸ α-Iodo amides add to alkenes using a water-soluble azobis initiator (see Sec. 14.A.i) to give the iodo ester, which cyclizes under the reaction conditions to give a lactone.¹²⁹⁹ β-Keto dithiocarbonates [RC(=O)–C–SC(=S)OEt] generate the radical in the presence of a peroxide and add to alkenes.¹³⁰⁰ 2-Fluoropyridyl derivatives of allylic alcohols react with xanthates in the presence of lauroyl peroxide to give alkenes.¹³⁰¹ Malonate derivatives add to alkenes in the presence of a mixture of Mn/Co catalyst, in oxygenated acetic acid.¹³⁰²

Other radicals can add to alkenes, and the rate constant for the addition of methyl radicals to alkenes has been studied.¹³⁰³ The rate of radical additions to alkenes in general has also been studied.¹³⁰⁴ The kinetic and thermodynamic control of a radical addition regiochemistry has also been studied.¹³⁰⁵ Alkynes are generally less reactive than alkenes in radical coupling reactions.¹³⁰⁶ Nonradical nucleophiles usually react faster with alkynes than with alkenes, however.¹³⁰⁷

15-30 Radical Cyclization¹³⁰⁸

Alkyl-hydro-addition

ω-Haloalkenes generate radicals upon treatment with radical initiator reagents (e.g., AIBN) or under photolysis conditions,¹³⁰⁹ and the radical carbon adds to the alkene to form cyclic compounds.¹³¹⁰ This intramolecular addition of a radical to an alkene is called radical cyclization. In a typical example, haloalkene (101) reacts with the radical produced by AIBN to give radical 100. The radical can add to the more substituted carbon to give 102 via a 5-exo-trig reaction (Sec. 6.E).¹³¹¹ If the radical adds to the less substituted carbon, 103 is formed via a 6-endo-trig reaction.¹³¹² In both cases, the product is another radical, which must be converted to an unreactive product. This is generally accomplished by adding a hydrogen-transfer agent¹³¹³ [e.g., tributyltin hydride (Bu₃SnH)], which reacts with 102 to form methylcyclopentane and Bu₃Sn^•, or with 103 to give cyclohexane. The Bu₃Sn^• formed in both cases usually dimerizes to form Bu₃SnSnBu₃. Cyclization can compete with hydrogen transfer¹³¹⁴ from Bu₃SnH to 100 to give 99, the reduction product. Atom-transfer cyclization is possible with other atoms (e.g., halogen), catalyzed by InCl₃¹³¹⁵ or CuBr.¹³¹⁶ Tin-free radical cyclizations are known using peroxyacids.¹³¹⁷

In general, formation of the five-membered ring dominates the cyclization, but if addition to the C=C unit is relatively slow, the reduction product is formed preferentially. Radical rearrangements can also diminish the yield of the desired product.¹³¹⁸ Given a choice between a larger and a smaller ring, radical cyclization generally gives the smaller ring,¹³¹⁹ but not always.¹³²⁰ Formation of other size rings is possible of course. A 4-exo-trig radical cyclization has been studied,¹³²¹ selectivity in a 7-endo versus 6-exo cyclization,¹³²² and also an 8-endo-trig reaction.¹³²³ In radical cyclization to form large rings, 1,5- and 1,9-hydrogen atom abstractions can pose a problem¹³²⁴ Ring expansion during radical cyclization is possible when the terminal intermediate is a cyclobutylcarbinyl radical.¹³²⁵

The mechanism of this reaction has been discussed.¹³²⁶ Cyclization via 5-endo-dig transition states require reorientation of the radical orbital needed to reach the in-plane acetylene π orbital in the bond-forming step, with accompanying loss of conjugative stabilization, and an increase in the activation energy. Therefore, many 5-endo cyclizations undergo H abstraction or equilibration with an isomeric radical.¹³²⁷

In cases where hydrogen atom transfer gives primarily reduced products, one solution to promote cyclization generates the radical by photochemical cleavage of Bu₃Sn–SnBu₃ and the resulting carbon radical can cyclize (see Reaction 15-46).¹³²⁸ A halogen atom transfer agent (e.g., iodoethane) is used rather than a hydrogen-transfer agent, so the final product is an alkyl iodide.

A mixture of a Grignard reagent and CoCl₂ has been used to initiate aryl radical cyclizations.¹³²⁹ Titanium(III)-mediated radical cyclizations are known,¹³³⁰ and SmI₂ mediated reactions are possible in the presence of a Ni catalyst.¹³³¹ Organoborane-mediated radical cyclizations are known (see Sec. 14.A.i).¹³³² The influence of the halogen atom on radical cyclization has been studied.¹³³³

Both phenylthio¹³³⁴ and phenylseleno groups¹³³⁵ can be used as “leaving groups” for radical cyclization, where S or Se atom transfer leads to formation of the radical. A seleno ester (R₂N–CH₂C(–O)SeMe) has also been used with (Me₃Si)₃SiH (tristrimethylsilylane, TTMSS) and AIBN to generate R₂NCH₂^•.¹³³⁶ O-Phosphonate esters have also served as the leaving group.¹³³⁷ N-(2-bromophenylbenzyl)methylamino have been used as leaving groups for formation of a radical.¹³³⁸

Radical cyclization reaction often proceeds with high diastereoselectivity¹³³⁹ and high asymmetric induction when chiral precursors are used. Internal alkynes are good substrates for radical cyclization,¹³⁴⁰ but terminal alkynes tend to give mixtures of exo/endo-dig products (Sec. 6.E).¹³⁴¹ Radical cyclization has been used to transfer asymmetry from transient atropisomers to form lactams.¹³⁴²

Radical cyclization is compatible with the presence of other functional groups, and heterocyclic rings may be formed via radical cyclization.¹³⁴³ Aryl radicals participate in radical cyclization reactions when the aromatic ring has an alkene or alkyne substituent. o-Iodo aryl allyl ethers cyclize to benzofuran derivatives, for example, when treated with AIBN, aq H₃PO₂ and NaHCO₃ in ethanol.¹³⁴⁴ Cyclization of vinyl radicals¹³⁴⁵ and allenyl radicals¹³⁴⁶ are also well known. Treatment of XCH₂CON(R)–C(R¹)=CH₂ derivatives (X = Cl, Br, I) with Ph₃SnH and AIBN led to formation of a lactam via radical cyclization.¹³⁴⁷ Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam,¹³⁴⁸ and there are other examples of radical cyclization with molecules containing a lactam unit¹³⁴⁹ or an amide unit.¹³⁵⁰ β-Lactams can be produced by radical cyclization, using Mn(OAc)₃.¹³⁵¹ Radical cyclization occurs with enamines as well.¹³⁵² Radical cyclization occurs with oximes to form the corresponding heterocyclic ring.¹³⁵³ Phenylseleno N-allylamines led to cyclic amines.¹³⁵⁴ ω-Iodo acrylate esters cyclize to form lactones,¹³⁵⁵ and allylic acetoxy compounds of the type C=C–C–O₂C–CH₂I cyclize in a similar manner to give lactones.¹³⁵⁶ Iodolactonization (see Reaction 15-41) occurs under standard radical cyclization conditions using allylic acetoxy compounds¹³⁵⁷ and HGaCl₂/BEt₃ has been used to initiate the radical process.¹³⁵⁸ α-Bromo mixed acetals give α-alkoxy THF derivatives¹³⁵⁹ and α-iodoacetals cyclize to give similar products.¹³⁶⁰ The reaction of an o-alkynyl aryl isonitrile with AIBN and 2.2 equiv of Bu₃SnH gave an indole via 5-exo-dig cyclization.¹³⁶¹ Indole derivatives have also been prepared from o-iodoaniline derivatives, using AIBN and TTMSS.¹³⁶² Samarium(II) has been used to initial 5-exo-trig ketyl-alkene coupling, and the mechanism of the reaction has been examined.¹³⁶³

Acyl radicals can be generated and they cyclize in the usual manner.¹³⁶⁴ Molecular orbital calculations have shown that acyl, as well as silyl radicals, simultaneously use SOMO–LUMO (SOMO = singly occupied molecular orbital and LUMO = lowest unoccupied molecular orbital) and LUMO–HOMO interactions in reactions with alkenes.¹³⁶⁵ A polyene-cyclization reaction generated four rings, initiating the sequence by treatment of a phenylseleno ester with Bu₃SnH/AIBN to form the acyl radical, which added to the first alkene unit.¹³⁶⁶ The newly formed carbon radical added to the next alkene, and so on. Acyl radicals generated from Ts(R)NCOSePh derivatives cyclize to form lactams.¹³⁶⁷

Radical cyclization of iodo aldehydes or ketones, at the carbon of the carbonyl, is effectively an acyl addition reaction (16-24 and 16-25). This cyclization is often reversible, and there are many fewer examples of addition to an alkene or alkyne. In one example, a δ-iodo aldehyde was treated with BEt₃/O₂ to initiate formation of the radical, and in the presence of Bu₃SnH cyclization gave a cyclopentanol.¹³⁶⁸ The reaction of an aldehyde-alkene with AIBN, 0.5 PhSiH₃ and 0.1 Bu₃SnH generated a radical from the alkene, which cyclized at the aldehyde to give cyclopentanol derivatives.¹³⁶⁹ An aldehyde–O-methyloxime generated a radical adjacent to nitrogen under standard conditions, which cyclized at the carbonyl to give a cyclic α-hydroxy N-methoxyamine.¹³⁷⁰ Alternatively, an α-bromoacetal–O-methyl oxime cyclized at the C=NOMe unit under electrolytic conditions in the presence of cobaloxime.¹³⁷¹Alkynyl-imines are cyclized to the imino carbon to form alkylidene lactams under radical conditions in the presence of CO.¹³⁷²

The attacking radical in radical cyclization reactions is not limited to a carbon, and a number of heterocycles can be prepared.¹³⁷³ Amidyl radicals are known and give cyclization reactions.¹³⁷⁴ Aminyl radical cyclizations have been reported.¹³⁷⁵ N-Chloroamine-alkenes give an aminyl radical when treated with TiCl₃·BF₃, and cyclization gave a pyrrolidine derivative with a pendant chloromethyl group.¹³⁷⁶ N-(S-substituted) amines give similar results using AIBN/Bu₃SnH.¹³⁷⁷ Oxime-alkenes cyclize to imines when treated with PhSSPh and TEMPO (Sec. 5.C.i).¹³⁷⁸ An oxygen radical can be generated under photochemical conditions, and they add to alkenes in a normal manner.¹³⁷⁹Note that radical substitution occurs, and reaction of Ph₃SnH/AIBN and an O-amidyl compound having a phosphonate ester elsewhere in the molecule gave cyclization to a THF derivative.¹³⁸⁰

15-31 Conjugate Addition with Heteroatom Nucleophiles

Heteroatom nucleophiles add to conjugated systems to give Michael-type products. Conjugated carbonyl compounds react via conjugate addition with amines to give β-amino derivatives (See Reaction 15-31)¹³⁸¹ Conjugate addition of nitrogen-containing compounds is often called the aza-Michael reaction.¹³⁸² Amines add to conjugated systems in the presence of In,¹³⁸³ Pd,¹³⁸⁴ Sm,¹³⁸⁵ Bi,¹³⁸⁶ Cu,¹³⁸⁷ Ce,¹³⁸⁸ La,¹³⁸⁹ or Yb compounds¹³⁹⁰ to give β-amino derivatives. This reaction can be initiated photochemically¹³⁹¹ or with microwave irradiation.¹³⁹² Aniline derivatives add to conjugated aldehydes in the presence of a catalytic amount of DBU,¹³⁹³ and indeed, DBU promotes the aza-Michael reaction.¹³⁹⁴ Lithium amides add to conjugated esters to give the β-amino ester.¹³⁹⁵ Amidocuprates add to conjugated systems to give β-nitrogen compounds, and a β-silyl group has an activating effect of the amidocuprate.¹³⁹⁶ A solvent-free conjugate addition of amines occurs on alumina in the presence of a Ce catalyst.¹³⁹⁷ Boric acid has been used as a catalyst of aza-Michael reactions in water.¹³⁹⁸ An intramolecular addition of an amine unit to a conjugated ketone in the presence of a Pd catalyst, or photochemically, led to cyclic amines.¹³⁹⁹ Amines add to conjugated thiolactams.¹⁴⁰⁰

There are asymmetric versions of the aza-Michael reaction,¹⁴⁰¹ and high enantioselectivity is possible using an organocatalyst.¹⁴⁰² Chiral catalysts lead to enantioselective reactions.¹⁴⁰³ Chiral additives (e.g., chiral Cinchona alkaloids¹⁴⁰⁴ or chiral naphthol derivatives)¹⁴⁰⁵ have also been used. Chiral imines add in a highly stereoselective manner.¹⁴⁰⁶ Chiral catalysts have been used for the conjugated addition of carbamates.¹⁴⁰⁷ Indoles add to nitro alkenes in the presence of an organocatalyst.¹⁴⁰⁸ Other N-heterocycles add with good enantioselectivity in the presence of an organocatalyst.¹⁴⁰⁹

Lactams have been shown to add to conjugated esters in the presence of Si(OEt)₄ and CsF.¹⁴¹⁰ Phthalimide adds to alkylidene malononitriles via 1,4-addition with a Pd catalyst, and the resulting anion can be alkylated with an added allylic halide.¹⁴¹¹ Alkylidene amido-amides, C=C(NHAc)CONHR, react with secondary amines in water to give the β-amino amido amide.¹⁴¹² Amines also add in a conjugate manner to alkynyl phosphonate esters, CC–PO(OEt)₂, using a CuI catalyst.¹⁴¹³ Hydroxylamines add to conjugated nitro compounds to give 2-nitro hydroxylamines.¹⁴¹⁴ N,O-Trimethylsilyl hydroxylamines add to conjugated esters, via nitrogen, using a Cu catalyst.¹⁴¹⁵Trimethylsilyl azide with acetic acid reacts with conjugated ketones to give the β-azido ketone.¹⁴¹⁶ Sodium azide adds to conjugated ketones in aq acetic acid and 20% PBu₃.¹⁴¹⁷ An interesting variation involves a double Michael addition of amido amines, amido alcohols or amido thiols to conjugated alkynes, forming pyrrolidine, oxazolidine, or thiazolidine derivatives.¹⁴¹⁸

The nitrogen of carbamates adds to conjugated ketones with a Pt,¹⁴¹⁹ Pd,¹⁴²⁰ Cu,¹⁴²¹ or with a bis(triflamide) organocatalyst.¹⁴²² The amine moiety of a carbamate adds to conjugated ketones with a polymer-supported acid catalyst,¹⁴²³ or with BF₃·OEt₂.¹⁴²⁴ The reaction of ammonium formate with 1,4-diphenylbut-2-en-1,4-dione, in PEG-200 and a Pd catalyst under microwave irradiation, gave 2,5-diphenylpyrrole.¹⁴²⁵

Phosphines react similarly to amines under certain conditions. Conjugate addition of R₂PH and a Ni catalyst give conjugate addition to α,β-unsaturated nitriles.¹⁴²⁶ A Pd catalyzed addition of diarylphosphines proceeds with good enantioselectivity to give chiral phosphines.¹⁴²⁷ Phosphites add to nitroalkenes in the presence of a chiral organocatalyst to give the corresponding nitro phosphite compound.¹⁴²⁸

Alcohols add to conjugated ketones with a PMe₃ catalyst to give the β-alkoxy ketone.¹⁴²⁹ This reaction is called an oxy-Michael reaction.¹⁴³⁰ Alcohol addition is catalyzed by N-heterocyclic carbenes¹⁴³¹ and other organocatalysts,¹⁴³² often with enantioselectivity.¹⁴³³ The conjugate addition of peroxide anions (HOO⁻ and ROO⁻) to α,β-unsaturated carbonyl compounds is discussed in Reaction 15-48. An intramolecular variation is known that produces dihydropyrones.¹⁴³⁴

Thiophenol and butyllithium (lithium phenylthiolate) adds to conjugated esters.¹⁴³⁵ Similar addition is observed with selenium compounds (RSeLi).¹⁴³⁶ Thiols react with conjugated amides via 1,4-addition with the addition of 10% Hf(OTf)₄ or other lanthanide triflates¹⁴³⁷ or to conjugated ketones in ionic solvents.¹⁴³⁸ Alkyl thiols add to conjugated carbonyl compounds with high enantioselectivity using an organocatalyst.¹⁴³⁹ Iron(III)-catalyzed addition of thiols occurs under solvent-free conditions.¹⁴⁴⁰ Thiols add without a catalyst in water¹⁴⁴¹ in PEG,¹⁴⁴² or in ionic liquids.¹⁴⁴³ Thiol addition is also catalyzed by iodine under solvent-free conditions.¹⁴⁴⁴ Ceric ammonium nitrate promotes the conjugate addition of thiols.¹⁴⁴⁵ Thioaryl moieties can be added in the presence of Yb¹⁴⁴⁶ or a catalytic amount of (DHQD)₂PYR (a dihydroquinidine, see Reaction 15-48).¹⁴⁴⁷ Thioalkyl units (e.g., BuS–) add to conjugated ketones using BuS–SnBu and In–I.¹⁴⁴⁸ Addition of conjugated lactones is possible to produce β-arylthiolated lactones.¹⁴⁴⁹ Dithiocarbamates are prepared by the reaction of an amine, CS₂, and a conjugated carbonyl compound.¹⁴⁵⁰ α,β-Unsaturated sulfones undergo conjugate addition of a cyano group using Et₂AlCN.¹⁴⁵¹

15-32 Acylation of Activated Double Bonds and of Triple Bonds

Hydro-acyl-addition

Under some conditions, acid derivatives add directly to activated double bonds. Acetic anhydride, Mg metal, and Me₃SiCl react with conjugated esters to give a γ-keto ester.¹⁴⁵² Similar reaction with vinyl phosphonate esters leads to a γ-keto phosphonate ester.¹⁴⁵³ Thioesters undergo conjugate addition to α,β-unsaturated ketones in the presence of SmI₂.¹⁴⁵⁴ Using DBU and a thioimidazolium salt, acyl silanes, Ar(C=O)SiMe₃, add in a similar manner.¹⁴⁵⁵ Under microwave irradiation, aldehydes add to conjugated ketones using DBU/Al₂O₃ and a thiazolium salt.¹⁴⁵⁶ The conjugate addition of acyl zirconium complexes in the presence of BF₃·OEt₂ is catalyzed by palladium acetate.¹⁴⁵⁷

An acyl group can be introduced into the 4 position of an α,β-unsaturated ketone by treatment with an organolithium compound and nickel carbonyl¹⁴⁵⁸ to give a 1,4-diketone (104). The R group may be aryl or primary alkyl. The reaction can also be applied to alkynes, which need not be activated, in which case 2 molar equivalents add and the product is also a 1,4-diketone (e.g., R′CCH → RCOCHR′CH₂COR).¹⁴⁵⁹ In a different procedure, α,β-unsaturated ketones and aldehydes are acylated by treatment at −110°C with R₂(CN)CuLi₂ and CO. This method is successful for R = primary, secondary, and tertiary alkyl.¹⁴⁶⁰ For secondary and tertiary groups, R(CN)CuLi, which does not waste an R group, can be used instead.¹⁴⁶¹

The reaction of an aldehyde and cyanide ion (See Reaction 16-52) in a polar aprotic solvent (e.g., DMF or DMSO) leads to a cyanohydrin, which generates a diketone via loss of HCN.¹⁴⁶² This method has been applied to α,β-unsaturated ketones, esters, and nitriles to give the corresponding 1,4-diketones, γ-keto esters, and γ-keto nitriles, respectively (see also, Reaction 16-55). The initial product of this reaction is ion 105, which is a synthon for the unavailable R⁻C=O anion (see Reaction 10-68). It is a masked R⁻C=O anion that upon reaction with the conjugated carbonyl gives 104 after loss of HCN from the cyanohydrin addition product. Other masked carbanions that have been used in this reaction are the RC⁻(CN)NR ion,¹⁴⁶³ the EtSCRSOEt ion,¹⁴⁶⁴ the CH₂=C⁻OEt ion,¹⁴⁶⁵ CH₂=C(OEt)Cu₂Li,¹⁴⁶⁶ CH₂=CMe(SiMe₃),¹⁴⁶⁶ and the RC⁻(OCHMeOEt)CN ion.¹⁴⁶⁷ In the last case, best results are obtained when R is a vinylic group. Anions of 1,3-dithianes (Reaction 10-71) do not give 1,4-addition to these substrates (except in the presence of HMPA, see Reaction 15-25), but add 1,2 to the C=O group instead (Reaction 16-38).

Interestingly, acylation occurs at the α-position of an enone when and α,β-unsaturated ketone is treated with an acid chloride and Et₂Zn in the presence of a Rh catalyst.¹⁴⁶⁸

In another procedure, acyl radicals derived from phenyl selenoesters (ArCOSePh) (by treatment with Bu₃SnH) add to α,β-unsaturated esters and nitriles to give γ-keto esters and γ-keto nitriles, respectively.¹⁴⁶⁹

OS VI, 866; VIII, 620.

15-33 Addition of Alcohols, Amines, Carboxylic Esters, Aldehydes, and so on

Hydro-acyl-addition, and so on

Formates, primary and secondary alcohols, amines, ethers, alkyl halides, compounds of the type Z–CH₂–Z′, and a few other compounds add to double bonds in the presence of free radical initiators.¹⁴⁷⁰ This is formally the addition of RH to a double bond, but the “R” is not just any carbon, but one connected to an oxygen or a nitrogen, a halogen, or to two Z groups (defined as in Sec. 15.A.ii). Formates and formamides¹⁴⁷¹ add similarly:

Alcohols, ethers, amines, and alkyl halides add as follows (shown for alcohols):

The ZCH₂Z′ compounds react at the carbon bearing the active hydrogen¹⁴⁷²:

Similar additions have been successfully carried out with carboxylic acids, anhydrides,¹⁴⁷³ acyl halides, carboxylic esters, nitriles, and other types of compounds.¹⁴⁷⁴

Similar reactions have been carried out on acetylene.¹⁴⁷⁵ In an interesting variation, thiocarbonates add to alkynes in the presence of a Pd catalyst to give a β-phenylthio α,β-unsaturated ester.¹⁴⁷⁶ Aldehydes add to alkynes in the presence of a Rh catalyst to give conjugated ketones.¹⁴⁷⁷ In a cyclic version of the addition of aldehydes, 4-pentenal was converted to cyclopentanone with a Rh complex catalyst.¹⁴⁷⁸ An intramolecular acyl addition to an alkyne was reported using silyl ketones, acetic acid, and a Rh catalyst.¹⁴⁷⁹ Formamides add to alkynes in the presence of a Pd catalyst to form conjugated amides.¹⁴⁸⁰

OS IV, 430; V, 93; VI, 587, 615.

15-34 Addition of Aldehydes

Alkyl-carbonyl-addition

In the presence of metal catalysts (e.g., Rh¹⁴⁸¹ or Yb¹⁴⁸²), aldehydes can add directly to alkenes to form ketones. Additives play an important role in such reactions.¹⁴⁸³ The reaction of ω-alkenyl aldehydes with a Rh catalyst leads to cyclic ketones,¹⁴⁸⁴ with high enantioselectivity if chiral ligands are employed. A carbene organocatalyst was used for an enantioselective intramolecular reaction.¹⁴⁸⁵ β,γ-Unsaturated ketones are prepared by the Rh catalyzed addition of aldehydes to dienes.¹⁴⁸⁶ The addition of aldehydes to activated double bonds, mediated by a catalytic amount of thiazolium salt in the presence of a weak base, is called the Stetter reaction,¹⁴⁸⁷ An internal addition of an alkynyl aldehyde, catalyzed by a Rh complex, led to a cyclopentenone derivative.¹⁴⁸⁸ These reactions are not successful when the alkene contains electron-withdrawing groups (e.g., halo or carbonyl groups). A free radical initiator is required,¹⁴⁸⁹ usually peroxides or UV light. The mechanism is illustrated for aldehydes, but is similar for the other compounds:

In the presence of BF₃ and a Ag salt, aldehydes add to alkynes to give the corresponding conjugated ketone.¹⁴⁹⁰ Polymers are often side products. Photochemical addition of aldehyde to conjugated C=C units can be efficient when a triplet sensitizer (Sec. 7.A.vi, category 5, e.g., benzophenone) is used.¹⁴⁹¹

A variation that is more of an acyl addition (Reaction 16-25) involves the reaction of an allylic alcohol with benzaldehyde. With a Ru catalyst and in an ionic liquid, the C=C unit reacts with the aldehyde, with concomitant oxidation of the allylic alcohol unit, to give a β-hydroxy ketone, PhCHO + C=C–CH(OH)R → PhCH(OH)–CH(Me)COR.¹⁴⁹² In another variation, formate esters add to alkenes using a Ru catalyst to give an alkyl ester via a formylation process.¹⁴⁹³

15-35 Hydrocarboxylation

Hydro-carboxy-addition

The acid-catalyzed hydrocarboxylation of alkenes (the Koch reaction) can be performed in a number of ways.¹⁴⁹⁴ In one method, the alkene is treated with CO and water at 100–350°C and 500–1000-atm pressure with a mineral acid catalyst. However, the reaction can also be performed under milder conditions. If the alkene is first treated with CO and catalyst and then water added, the reaction can be accomplished at 0–50°C and 1–100 atm. If formic acid is used as the source of both the CO and the water, the reaction can be carried out at room temperature and atmospheric pressure.¹⁴⁹⁵ The formic acid procedure is called the Koch–Haaf reaction (the Koch–Haaf reaction can also be applied to alcohols, see Reaction 10-77). Nearly all alkenes can be hydrocarboxylated by one of these procedures. However, conjugated dienes are polymerized under these conditions. Hydrocarboxylation can also be accomplished under mild conditions (160°C and 50 atm) by the use of nickel carbonyl as catalyst. Acid catalysts are used along with the nickel carbonyl, but basic catalysts can also be employed.¹⁴⁹⁶ The Ni(CO)₄ catalyzed oxidative carbonylation with CO and H₂O as a nucleophile is often called Reppe carbonylation.¹⁴⁹⁷ The toxic nature of nickel tetracarbonyl has led to development of other catalysts.¹⁴⁹⁸ Indeed, variations in the reaction procedure include the use of Pd,¹⁴⁹⁹Pt,¹⁵⁰⁰ and Rh¹⁵⁰¹ catalysts. This reaction converts alkenes, alkynes, and dienes and is tolerant of a wide variety of functional groups. When the additive is alcohol or acid, saturated or unsaturated acids, esters, or anhydrides are produced (see Reaction 15-36). The transition metal catalyzed carbonylation has been done enantioselectively, with moderate-to-high optical yields, by the use of an optically active palladium-complex catalyst.¹⁵⁰² Alkenes also react with Fe(CO)₅ and CO to give carboxylic acids.¹⁵⁰³ Electrochemical carboxylation procedures have been developed, including the conversion of alkenes to 1,4-butanedicarboxylic acids.¹⁵⁰⁴ A reductive carboxylation of alkenes with CO and cesium carbonate has been reported.¹⁵⁰⁵

When applied to triple bonds, hydrocarboxylation gives α,β-unsaturated acids under very mild conditions. Triple bonds give unsaturated acids and saturated dicarboxylic acids when treated with CO₂ and an electrically reduced Ni complex catalyst.¹⁵⁰⁶ Alkynes also react with NaHFe(CO)₄, followed by CuCl₂·2 H₂O, to give alkenyl acid derivatives.¹⁵⁰⁷ A related reaction with CO and Pd catalysts in the presence of SnCl₂ leads to conjugated acid derivatives.¹⁵⁰⁸ Terminal alkynes react with CO₂ and Ni(cod)₂ (cod = 1,5-cycloctadiene), and subsequent treatment with DBU gives the α,β-unsaturated carboxylic acid.¹⁵⁰⁹

When acid catalysts are employed, in the absence of nickel carbonyl, the mechanism¹⁵¹⁰ involves initial attack on a proton, followed by attack by CO on the resulting carbocation to give an acyl cation, and subsequent reaction with water gives the product 107. Markovnikov's rule is followed, and carbon skeleton rearrangements and double-bond isomerizations (prior to attack by CO) are frequent.

For the transition metal catalyzed reactions, the nickel carbonyl reaction has been well studied and the addition is syn for both alkenes and alkynes.¹⁵¹¹ The following is the accepted mechanism:¹⁵¹¹

Step 3 is an electrophilic substitution. The principal step of the mechanism, step 4, is a rearrangement.

An indirect method for hydrocarboxylation involves the reaction of an alkene with a borate [(RO)₂BH] and a Rh catalyst. Subsequent reaction with LiCHCl₂, and then NaClO₂, gives the Markovnikov carboxylic acid (RC=C → RC(CO₂H)CH₃.¹⁵¹² When a chiral ligand is used, the reaction proceeds with good enantioselectivity.

15-36 Carbonylation, Alkoxycarbonylation, and Aminocarbonylation of Double and Triple Bonds

Alkyl, Alkoxy, or Amino-carbonyl-addition

In the presence of certain metal catalysts, alkenes and alkynes can be carbonylated or converted to give an amide or an ester.¹⁵¹³ There are several variations. The reaction of an alkyl iodide and a conjugated ester with CO, (Me₃Si)₃SiH, and AIBN in supercritical CO₂ (Sec. 9.D.ii) gave a γ-keto ester.¹⁵¹⁴ Terminal alkynes react with CO and methanol in the presence of CuCl₂ and PdCl₂ to give a β-chloro-α,β-unsaturated methyl ester.¹⁵¹⁵ Conjugated dienes react with thiophenol, CO and Pd(OAc)₂ to give the β,γ-unsaturated thioester.¹⁵¹⁶ Allene reacts with CO, CH₃OH, and a Ru catalyst to give methacrylic acid.¹⁵¹⁷ Alkynes react with thiophenol and CO with a Pd¹⁵¹⁸ or Pt¹⁵¹⁹catalyst to give a conjugated thioester. Terminal alkynes react with CO and CH₃OH, using a combination of a palladium(II) halide and a copper(II) halide, to give a conjugated diester, MeO₂C–C=C–CO₂Me.¹⁵²⁰ A similar reaction with alkenes using a combination of a Pd and a Mo catalyst led to a saturated diester (MeO₂C–C–C–CO₂Me).¹⁵²¹ Alkenes were converted to the dimethyl ester of 1,4-butanedioic acid derivatives with CO/O₂ and a combination of PdCl₂ and CuCl catalysts.¹⁵²² Note that alkenes primarily are converted to the anti-Markovnikov ester upon treatment with arylmethyl formate esters (ArCH₂OCHO) and a Ru catalyst.¹⁵²³ Terminal alkynes react with tosyl azide, water, and a catalytic amount of CuI to give an N-tosyl amide.¹⁵²⁴

A bicyclic ketone was generated when 1,2-diphenylethyne was heated with carbon monoxide, methanol and a dirhodium catalyst.¹⁵²⁵ 2-Iodostyrene reacted at 100 °C with CO and a Pd catalyst to give the bicyclic ketone 1-indanone.¹⁵²⁶ Another variation reacted a conjugated allene–alkene with 5 atm of CO and a Rh catalyst to give a bicyclic ketone.¹⁵²⁷ An intermolecular version of this reaction is known using a Co catalyst, giving a cyclopentenone¹⁵²⁸ in a reaction related to the Pauson–Khand reaction (see below). The reaction of a conjugated diene having a distal alkene unit and CO with a Rh catalyst led to a bicyclic conjugated ketone.¹⁵²⁹ When a Stille coupling (Reaction 12-15) is done in a CO atmosphere, conjugated ketones of the type C=C–CO–C=C are formed,¹⁵³⁰ suitable for a Nazarov cyclization (Reaction 15-20). Alkynes were converted to cyclobutenones using Fe₃(CO)₁₂to form an initial complex, followed by reaction with copper(II) chloride.¹⁵³¹ An interesting variation treated cyclohexene with 5 molar equivalents of Oxone and a RuCl₃ catalyst to give 2-hydroxycyclohexanone.¹⁵³²

The reaction of dienes, diynes, or enynes with transition metals¹⁵³³ (usually Co)¹⁵³⁴ forms organometallic coordination complexes. Rhodium,¹⁵³⁵ Ti,¹⁵³⁶ Mo,¹⁵³⁷ and W¹⁵³⁸ complexes have been used for this reaction. In the presence of CO, the metal complexes derived primarily from enynes (alkene–alkynes) generate cyclopentenone derivatives in what is known as the Pauson–Khand reaction.¹⁵³⁹ This reaction involves (1) formation of a hexacarbonyldicobalt–alkyne complex and (2) decomposition of the complex in the presence of an alkene.¹⁵⁴⁰ A typical example is the preparation of 108.¹⁵⁴¹ Cyclopentenones can be prepared by an intermolecular reaction of a vinyl silane and an alkyne using CO and a Ru catalyst.¹⁵⁴² Carbonylation of an alkene–diene using a Rh catalyst leads to cyclization to an α-vinyl cyclopentanone.¹⁵⁴³ An yne–diene can also be used for the Pauson–Khand reaction.¹⁵⁴⁴

The reaction can be promoted photochemically¹⁵⁴⁵ and the rate is enhanced by the presence of primary amines.¹⁵⁴⁶ Coordinating ligands also accelerate the reaction,¹⁵⁴⁷ polymer-supported promoters have been developed¹⁵⁴⁸ and there are many possible variations in reaction conditions.¹⁵⁴⁹ The Pauson–Khand reaction has been done under heterogeneous reaction conditions,¹⁵⁵⁰ with Co nanoparticles,¹⁵⁵¹ and in water.¹⁵⁵² A dendritic Co catalyst has been used.¹⁵⁵³ Ultrasound promoted¹⁵⁵⁴ and microwave promoted¹⁵⁵⁵ reactions have been developed. Polycyclic compounds (tricyclic and higher) are prepared in a relatively straightforward manner using this reaction.¹⁵⁵⁶ Asymmetric Pauson–Khand reactions are known.¹⁵⁵⁷

The Pauson–Khand reaction is compatible with other groups or heteroatoms elsewhere in the molecule. These include ethers and aryl halides,¹⁵⁵⁸ esters,¹⁵⁵⁹ amides,¹⁵⁶⁰ alcohols,¹⁵⁶¹ diols,¹⁵⁶² and an indole unit.¹⁵⁶³ A silicon-tethered Pauson–Khand reaction is known.¹⁵⁶⁴ Allenes are reaction partners in the Pauson–Khand reaction.¹⁵⁶⁵ This type of reaction can be extended to form six-membered rings using a Ru catalyst.¹⁵⁶⁶ A double-Pauson–Khand process was reported.¹⁵⁶⁷ In some cases, an aldehyde can serve as the source of the carbonyl for carbonylation.¹⁵⁶⁸

The accepted mechanism was proposed by Magnus and Principe,¹⁵⁶⁹ shown for the formation of 109,¹⁵⁷⁰ and supported by Krafft's work.¹⁵⁷¹ It has been shown that CO is lost from the Pauson–Khand complex prior to alkene coordination and insertion.¹⁵⁷² Calculations concluded that the LUMO of the coordinated alkene plays a crucial role in alkene reactivity by determining the degree of back-donation in the complex.¹⁵⁷³

Other carbonylation methods are available. Carbonylation occurs with conjugated ketones to give 1.4-diketones, using phenylboronic acid (see Reaction 13-12), CO and a Rh catalyst.¹⁵⁷⁴ A noncarbonylation route treated a conjugated diene with an excess of tert-butyllithium, and quenching with CO₂ led to a cyclopentadienone.¹⁵⁷⁵ When quenched with CO rather than CO₂, a nonconjugated cyclopentenone was formed.¹⁵⁷⁶ Note that a carbonylation reaction with CO, a diyne, and an Ir¹⁵⁷⁷ or a Co catalyst¹⁵⁷⁸ provided similar molecules.

With any method, if the alkene contains a functional group (e.g., OH, NH₂, or CONH₂), the corresponding lactone (Reaction 16-63),¹⁵⁷⁹ lactam (Reaction 16-74), or cyclic imide may be the product.¹⁵⁸⁰ Titanium,¹⁵⁸¹ Pd,¹⁵⁸²Ru,¹⁵⁸³ and Rh¹⁵⁸⁴ catalysts have been used to generate lactones. Allenic alcohols are converted to butenolides with 10 atm of CO and a Ru catalyst.¹⁵⁸⁵ Larger ring conjugated lactones can also be formed by this route using the appropriate allenic alcohol.¹⁵⁸⁶ Propargylic alcohols lead to β-lactones¹⁵⁸⁷ or to butenolides with CO/H₂O and a Rh catalyst.¹⁵⁸⁸ Allenic tosyl-amides are converted to N-tosyl α,β-unsaturated pyrrolidinones using 20 atm of CO and a Ru catalyst.¹⁵⁸⁹ Conjugated imines are converted to similar products with CO, ethylene, and a Ru catalyst.¹⁵⁹⁰ Propargyl alcohols generate lactones when treated with a chromium pentacarbonyl carbene complex.¹⁵⁹¹ Amines add to allenes, in the presence of CO and a Pd catalyst, to form conjugated amides.¹⁵⁹²

The reaction of a secondary amine, CO, a terminal alkyne, and t-BuMe₂SiH with a Rh catalyst led to a conjugated amide bearing the silyl group of the C=C unit.¹⁵⁹³ Reaction of a molecule containing an amine and an alkene unit was carboxylated with CO in the presence of a Pd catalyst to give a lactam.¹⁵⁹⁴ A similar reaction with a molecule containing an amine and an alkyne also generated a lactam, in the presence of CO and a Rh catalyst.¹⁵⁹⁵ An intramolecular carbonylation reaction of a conjugated imine, with CO, ethylene and a Ru catalyst, led to a highly substituted β,γ-unsaturated lactam.¹⁵⁹⁶

15-37 Hydroformylation

Hydro-formyl-addition

Alkenes can be hydroformylated¹⁵⁹⁷ by treatment with CO and hydrogen over a catalyst, usually a Co carbonyl (see below for a description of the mechanism) or a Rh complex,¹⁵⁹⁸ but other transition metal compounds have also been used. Cobalt catalysts are less active than the Rh type, and catalysts of other metals are generally less active.¹⁵⁹⁹ Commercially, this is called the oxo process, but it can be carried out in the laboratory in an ordinary hydrogenation apparatus. The order of reactivity is straight-chain terminal alkenes > straight-chain internal alkenes > branched-chain alkenes. With terminal alkenes, for example, the aldehyde unit is formed on both the primary and secondary carbon, but proper choice of catalyst and additive leads to selectivity for the secondary¹⁶⁰⁰ or primary product.¹⁶⁰¹ Alkylidenecyclopropane derivatives undergo hydroformylation to give aldehydes with a quaternary center.¹⁶⁰²

Good yields for hydroformylation have been reported using Rh catalysts in the presence of certain other additives.¹⁶⁰³ Among the side reactions are the aldol Reaction (16-34), acetal formation, the Tischenko Reaction (19-82), and polymerization. In one case using a Rh catalyst, 2-octene gave nonanal, presumably via a η³-allyl complex (Sec. 3.C).¹⁶⁰⁴ Conjugated dienes give dialdehydes when Rh catalysts are used¹⁶⁰⁵ but saturated monoaldehydes (the second double bond is reduced) with cobalt carbonyls. Both 1,4- and 1,5-dienes may give cyclic ketones.¹⁶⁰⁶

Hydroformylation of triple bonds proceeds very slowly, and few examples have been reported.¹⁶⁰⁷ However, in the presence of a Rh catalyst, the triple bond of a conjugated enyne is formylated.¹⁶⁰⁸ The Rh catalyzed reaction can be regioselective.¹⁶⁰⁹ Many functional groups (e.g., OH, CHO, CO₂R,¹⁶¹⁰ CN), can be present in the molecule, although halogens usually interfere. Stereoselective syn addition has been reported,¹⁶¹¹ and also stereoselective anti addition.¹⁶¹²

Asymmetric hydroformylation of alkenes has been accomplished with a chiral catalyst,¹⁶¹³ and in the presence of chiral additives.¹⁶¹⁴ The choice of ligand is important in such reactions.¹⁶¹⁵ Cyclization to prolinal derivatives has been reported with allylic amines.¹⁶¹⁶

When dicobalt octacarbonyl [Co(CO)₄]₂ is the catalyst, the species that actually adds to the double bond is tricarbonylhydrocobalt [HCo(CO)₃].¹⁶¹⁷ Carbonylation [RCo(CO)₃ + CO → RCo(CO)₄] takes place followed by a rearrangement and a reduction of the C–Co bond, similar to steps 4 and 5 of the nickel carbonyl mechanism shown in Reaction 15-35. The reducing agent in the reduction step is tetracarbonylhydrocobalt [HCo(CO)₄],¹⁶¹⁸ or, under some conditions, H₂.¹⁶¹⁹ When HCo(CO)₄ was the agent used to hydroformylate styrene, the observation of CIDNP (Sec. 5.C.i) indicated that the mechanism is different, and involves free radicals.¹⁶²⁰ Key intermediates have been detected in the Co catalyzed hydroformylation reaction.¹⁶²¹ Alcohols can be obtained by allowing the reduction to continue after all the CO is used up. It has been shown¹⁶²² that the formation of alcohols is a second step, occurring after the formation of aldehydes, and that HCo(CO)₃ is the reducing agent.

OS VI, 338.

15-38 Addition of HCN

Hydro-cyano-addition

Ordinary alkenes do not react with HCN, but polyhalo alkenes and alkenes of the form C=C–Z add HCN to give nitriles.¹⁶²³ The reaction is therefore a nucleophilic addition and is base catalyzed. Hydrogen cyanide can be added to ordinary alkenes in the presence of dicobalt octacarbonyl¹⁶²⁴ or certain other transition metal compounds.¹⁶²⁵ When Z is COR or, more especially, CHO, 1,2-addition (Reaction 16-53) is an important competing reaction and may be the only reaction. An acid-catalyzed hydrocyanation is also known.¹⁶²⁶ Triple bonds react very well when catalyzed by an aqueous solution of CuCl, NH₄Cl, and HCl or by Ni or Pd compounds.¹⁶²⁷ The HCN can be generated in situ from acetone cyanohydrin (see Reaction 16-52), avoiding the use of the poisonous HCN.¹⁶²⁸ Alkenes react with HCN via this procedure to give a nitrile in the presence of a Ni complex.¹⁶²⁹

One or 2 molar equivalents of HCN can be added to a triple bond, since the initial product is a Michael-type substrate. Acrylonitrile is commercially prepared this way, by the addition of HCN to acetylene. Alkylaluminum cyanides (e.g., Et₂AlCN), or mixtures of HCN and trialkylalanes (R₃Al) are especially good reagents for conjugate addition of HCN¹⁶³⁰ to α,β-unsaturated ketones and α,β-unsaturated acyl halides. An indirect method for the addition of HCN to ordinary alkenes uses an isocyanide (RNC) and Schwartz's reagent (see Reaction 15-17); this method gives anti-Markovnikov addition.¹⁶³¹ tert-Butyl isocyanide and TiCl₄ have been used to add HCN to C=C–Z alkenes.¹⁶³² Pretreatment with NaI/Me₃SiCl followed by CuCN converts alkynes to vinyl nitriles.¹⁶³³

When an alkene is treated with Me₃SiCN and AgClO₄, followed by aq NaHCO₃, the product is the isonitrile (RNC) formed with Markovnikov selectivity.¹⁶³⁴ Enantioselective cyanation using TMSCN and HCN, and a Gd catalyst, leads to β-cyano amides.¹⁶³⁵

OS I, 451; II, 498; III, 615; IV, 392, 393, 804; V, 239, 572; VI, 14.

For addition of ArH, see Reaction 11-12 (Friedel–Crafts alkylation).

15.C.iii Reactions in Which Hydrogen Adds to Neither Side

Some of these reactions are cycloadditions (Reactions 15-50, 15-62, 15-54, and 15-57–15-66). In such cases, addition to the multiple bond closes a ring:

A. Halogen on One or Both Sides

15-39 Halogenation of Double and Triple Bonds (Addition of Halogen, Halogen)

Dihalo-addition

Most double bonds are easily halogenated¹⁶³⁶ with bromine, chlorine, or inter-halogen compounds.¹⁶³⁷ Substitution can compete with addition in some cases.¹⁶³⁸ Iodination has also been accomplished, but the reaction is slower.¹⁶³⁹ Under free radical conditions, iodination proceeds more easily.¹⁶⁴⁰ However, vic-diiodides are generally unstable and tend to revert to iodine and the alkene.

The mechanism is usually electrophilic (see Sec. 15.A.i), involving formation of an halonium ion (Reaction 110),¹⁶⁴¹ followed by nucleophilic ring opening to give the vic-dihalide. Nucleophilic attack occurs with selectivity for the less substituted carbon. When free radical initiators (or UV light) are present, addition can occur by a free radical mechanism.¹⁶⁴² Once Br^• or Cl^• radicals are formed, however, substitution may compete (Reactions 14-1 and 14-3). This is especially important when the alkene has allylic or benzylic hydrogen atoms. Under free radical conditions (UV light) bromine or chlorine adds to a benzene substituent to give, respectively, hexabromo- and hexachlorocyclohexane. These are mixtures of stereoisomers (see Sec. 4.K.ii).¹⁶⁴³

Under ordinary conditions fluorine itself is too reactive to give simple addition, and mixtures are obtained.¹⁶⁴⁴ However, F₂ has been successfully added to certain double bonds in an inert solvent at low temperatures (−78 °C), usually by diluting the F₂ gas with Ar or N₂.¹⁶⁴⁵ Addition of fluorine has also been accomplished with other reagents (e.g., p-Tol-IF₂/Et₃N·5 HF),¹⁶⁴⁶ and a mixture of PbO₂ and SF₄.¹⁶⁴⁷ The Au catalyzed reaction of Et₃N–HF with alkynes gives vinyl fluorides.¹⁶⁴⁸

The reaction with bromine is very rapid and is easily carried out at room temperature,¹⁶⁴⁹ although the reaction is reversible under some conditions.¹⁶⁵⁰ In the case of bromine, an alkene·Br₂ complex has been detected in at least one case.¹⁶⁵¹ Bromine is often used as a qualitative or quantitative test for unsaturation¹⁶⁵² because the vast majority of double bonds can be successfully brominated. Even when functions (aldehyde, ketone, amine, etc.) are present in the molecule, they do not interfere, since the reaction with double bonds is faster. Bromination has been carried out in an ionic liquid.¹⁶⁵³

Several reagents other than chlorine gas add Cl₂ to double bonds, among them Me₃SiCl⁻MnO₂,¹⁶⁵⁴ BnNEt₃MnO₄/Me₃SiCl,¹⁶⁵⁵ and KMnO₄–oxalyl chloride.¹⁶⁵⁶ A convenient reagent for the addition of Br₂ to a double bond on a small scale is the commercially available pyridinium bromide perbromide (C₅H₅NH⁺ Br₃⁻).¹⁶⁵⁷ Potassium bromide with ceric ammonium nitrate, in water/dichloromethane, gives the dibromide.¹⁶⁵⁸ A combination of KBr and Selectfluor also give the dibromide.¹⁶⁵⁹ A combination of CuBr₂ in aq THF and a chiral ligand led to the dibromide with good enantioselectivity.¹⁶⁶⁰ Either Br₂ or Cl₂ can also be added using CuBr₂ or CuCl₂ in the presence of acetonitrile, methanol, or triphenylphosphine.¹⁶⁶¹ Alkenes are brominated using KBr and diacetoxyiodobenzene.¹⁶⁶² Note that theoretical and experimental studies have shown that in nonpolar solvents the bromination of acetylene via a covalent tribromide adduct is strongly favored over the textbook mechanism via a bridged bromonium ion.

Mixed halogenations have also been achieved, and the order of activity for some of the reagents is BrCl > ICl¹⁶⁶³ > Br₂ > IBr > I₂.¹⁶⁶⁴ Mixtures of Br₂ and Cl₂ have been used to give bromochlorination,¹⁶⁶⁵ as has tetrabutylammonium dichlorobromate (Bu₄NBrCl₂).¹⁶⁶⁶ Iodochlorination has been achieved with KICl₂,¹⁶⁶⁷ CuCl₂, and either I₂, HI, or CdI₂; iodofluorination¹⁶⁶⁸ with mixtures of AgF and I₂;¹⁶⁶⁹ and mixtures of N-bromo amides in anhydrous HF give bromofluorination.¹⁶⁷⁰ Bromo-, iodo-, and chlorofluorination have also been achieved by treatment of the substrate with a solution of Br₂, I₂, or an N-halo amide in polyhydrogen fluoride–pyridine;¹⁶⁷¹ while addition of I along with Br, Cl, or F has been accomplished with the reagent bis(pyridine)iodo(I) tetrafluoroborate [I(Py)₂BF₄] and Br⁻, Cl⁻, or F⁻, respectively.¹⁶⁷² This reaction, which is also successful for triple bonds,¹⁶⁷³ can be extended to addition of I and other nucleophiles (e.g., NCO, OH, OAc, and NO₂).¹⁶⁷³

Conjugated systems give both 1,2- and 1,4-addition.¹⁶⁴⁴ Triple bonds add bromine, although generally more slowly than double bonds (see Sec. 15.B.i). Molecules that contain both double and triple bonds are preferentially attacked at the double bond. Addition of 2 molar equivalents of bromine to triple bonds gives tetrabromo products. There is evidence that the addition of the first molar equivalent of bromine to a triple bond may take place by a nucleophilic mechanism.¹⁶⁷⁴ Molecular diiodine on Al₂O₃ adds to triple bonds to give good yields of 1,2-diiodoalkenes.¹⁶⁷⁵ Interestingly, 1,1-diiodo alkenes are prepared from an alkynyltin compound, via initial treatment with Cp₂Zr(H)Cl, and then 2.15 equiv of iodine.¹⁶⁷⁶ A mixture of NaBO₃ and NaBr adds two bromine atoms across a triple bond.¹⁶⁷⁷ With allenes it is easy to stop the reaction after only 1 equiv has added, to give X–C–CX=C.¹⁶⁷⁸Addition of halogen to ketenes gives α-halo acyl halides, but the yields are not good.

OS I, 205, 521; II, 171, 177, 270, 408; III, 105, 123, 127, 209, 350, 526, 531, 731, 785; IV, 130, 195, 748, 851, 969; V, 136, 370, 403, 467; VI, 210, 422, 675, 862, 954; IX, 117; 76, 159.

15-40 Addition of Hypohalous Acids and Hypohalites (Addition of Halogen, Oxygen)

Hydroxy-chloro-addition, and so on.¹⁶⁷⁹

Alkoxy-chloro-addition, and so on

Hypohalous acids (HOCl, HOBr, and HOI) react with alkenes¹⁶⁸⁰ to produce halohydrins.¹⁶⁸¹ Both HOBr and HOCl can be generated in situ by the reaction between water and Br₂ or Cl₂, respectively. The compound HOI, generated from I₂ and H₂O, also adds to double bonds, if the reaction is carried out in tetramethylene sulfone–CHCl₃¹⁶⁸² or if an oxidizing agent (e.g., HIO₃) is present.¹⁶⁸³ Iodine and cerium sulfate in aq acetonitrile generates iodohydrins,¹⁶⁸⁴ as do iodine and ammonium acetate in acetic acid,¹⁶⁸⁵ or NaIO₄ with sodium bisulfite.¹⁶⁸⁶

The HOBr can also be conveniently added by the use of a reagent consisting of an N-bromo amide (e.g., NBS or N-bromoacetamide) and a small amount of water in a solvent (e.g., DMSO or dioxane).¹⁶⁸⁷ N-Iodosuccinimide in aq dimethoxyethane leads to the iodohydrin.¹⁶⁸⁸ An especially powerful reagent for HOCl addition is tert-butyl hydroperoxide (or di-tert-butyl peroxide) along with TiCl₄.¹⁶⁸⁹ Chlorohydrins can be conveniently prepared by treatment of the alkene with Chloramine T (TsNCl⁻ Na⁺)¹⁶⁹⁰ in acetone–water.¹⁶⁹¹ The compound HOI can be added by treatment of alkenes with periodic acid and NaHSO₃.¹⁶⁹² There are Se catalyzed iodohydrin forming reactions.¹⁶⁹³ The reaction of an alkene with polymeric (SnO)_n, and then HCl with Me₃SiOOSiMe₃, leads to the chlorohydrin.¹⁶⁹⁴ Hypervalent iodine compounds react with an alkene and iodine in aqueous media to give the iodohydrin.¹⁶⁹⁵Halohydrins are produced in ionic liquids.¹⁶⁹⁶ N-Bromo and N-iodosaccharin have been used to prepare the corresponding halohydrins.¹⁶⁹⁷

The compound HOF has also been added, but this reagent is difficult to prepare in a pure state and explosions have occurred.¹⁶⁹⁸

The mechanism of HOX addition is electrophilic, with initial attack by the alkene on the positive halogen end of the HOX dipole. Following Markovnikov's rule, the positive halogen goes to the side of the double bond that has more hydrogen atoms (forming a more stable carbocation). This carbocation (or bromonium or iodonium ion in the absence of an aqueous solvent) reacts with or H₂O to give the product. If the substrate is treated with Br₂ or Cl₂ (or another source of positive halogen, e.g., NBS) in an alcohol or a carboxylic acid solvent, it is possible to obtain, directly C–C–C–OR or X–C–C–OCOR, respectively (see also, Reaction 15-48).¹⁶⁹⁹ Even the weak nucleophile CF₃SO₂O⁻ can participate in the second step. The addition of Cl₂ or Br₂ to alkenes in the presence of this ion resulted in the formation of some β-haloalkyl triflates.¹⁷⁰⁰ There is evidence that the mechanism with Cl₂ and H₂O is different from that with HOCl.¹⁷⁰¹ Both HOCl and HOBr can be added to triple bonds to give dihalo carbonyl compounds (–CX₂–CO–).

Alcohols and halogens react with alkenes to form halo ethers. When a homoallylic alcohol is treated with bromine, cyclization occurs to give a 3-bromotetrahydrofuran derivative.¹⁷⁰² tert-Butyl hypochlorite (Me₃COCl), hypobromite, and hypoiodite¹⁷⁰³ add to double bonds to give halogenated tert-butyl ethers (X–C–C–OCMe₃). This is a convenient method for the preparation of tertiary ethers. Iodine and ethanol convert some alkenes to iodo-ethers.¹⁷⁰⁴ Iodine, alcohol, and a Ce(OTf)₂ catalyst also generates the iodo-ether.¹⁷⁰⁵ When Me₃COCl or Me₃COBr is added to alkenes in the presence of excess ROH, the ether X–C–C–OR is produced.¹⁷⁰⁶ Vinylic ethers give β-halo acetals.¹⁷⁰⁷ Chlorine acetate [solutions of which are prepared by treating Cl₂ with Hg(OAc)₂ in an appropriate solvent] adds to alkenes to give acetoxy chlorides.¹⁷⁰⁸ Acetoxy fluorides have been obtained by treatment of alkenes with CH₃COOF.¹⁷⁰⁹

For a method of iodoacetyl addition, see Reaction 15-48.

OS I, 158; IV, 130, 157; VI, 184, 361, 560; VII, 164; VIII, 5, 9.

15-41 Halolactonization and Halolactamization

Halo-alkoxylation

Halo esters can be formed by addition of halogen atoms and ester groups to an alkene. Alkene carboxylic acids give a tandem reaction of formation of a halonium ion followed by intramolecular displacement of the carboxylic group to give a halo lactone. This tandem addition of X and OCOR is called halolactonization.¹⁷¹⁰

The most common version of this reaction is known as iodolactonization,¹⁷¹¹ and a typical example is the conversion of 111 to 112.¹⁷¹² Bromo lactones and, to a lesser extent, chloro lactones have also been prepared. In general, addition of the halogen to an alkenyl acid, as shown, leads to the halo-lactone. Other reagents include I⁺(collidine)₂PF₆⁻,¹⁷¹³ KI/sodium persulfate.¹⁷¹⁴ The Tl¹⁷¹⁵ and Y¹⁷¹⁶ reagents, along with the halogen, have also been used. An enantioselective 5-endo-halolactonization procedure has been reported using systems, such as iodobis(collidine) hexafluorophosphate or AgSbF₆, followed by iodine.¹⁷¹⁷ When done in the presence of a chiral Ti reagent, I₂, and CuO, lactones are formed with good enantioselectivity.¹⁷¹⁸ Iodine monochloride (ICl) has been used, with formation of a quaternary center at the oxygen-bearing carbon of the lactone.¹⁷¹⁹ Organocatalysts have also been used to mediate asymmetric halolactonization reactions.¹⁷²⁰ Enantioselective iodolactonization occurs with pentenoic acid derivatives in the presence of a chiral Co(salen) complex.¹⁷²¹

In the case of γ,δ-unsaturated acids, five-membered rings (γ-lactones) are predominantly formed (as shown above; note that Markovnikov's rule is followed), but six-membered and even four-membered lactones have also been made by this procedure. There is a gem-dimethyl effect that favors formation of 7–11 membered ring lactones by this procedure.¹⁷²²

Formation of halo-lactams (Reaction 15-43) by a procedure similar to halolactonization is difficult, but the problems have been overcome. Formation of a triflate from 113 followed by treatment with iodine leads to the iodolactam (114).¹⁷²³ A related cyclization of N-sulfonyl-amino alkenes and NBS gave the bromo-lactam,¹⁷²⁴ and a dichloro-N,N-bis(allylamide) was converted to a dichloro-lactam with FeCl₂.¹⁷²⁵ Note that lactone formation is possible from unsaturated amides

OS IX, 516

15-42 Addition of Sulfur Compounds (Addition of Halogen, Sulfur)

Alkylsulfonyl-chloro-addition, and so on¹⁷²⁶

Sulfonyl halides add to double bonds to give β-halo sulfones, in the presence of free radical initiators or UV light. A particularly good catalyst is cuprous chloride.¹⁷²⁷ In the presence of TsCl, AIBN and a Ru catalyst, β-chloro sulfones are generated from alkenes.¹⁷²⁸ A combination of the anion ArSO₂Na, NaI, and ceric ammonium nitrate converts alkenes to vinyl sulfones.¹⁷²⁹ Triple bonds behave similarly, to give β-halo-α,β-unsaturated sulfones.¹⁷³⁰ In a similar reaction, sulfenyl chlorides, (RSCl) give β-halo thioethers.¹⁷³¹ The latter may be free radical or electrophilic additions, depending on conditions. The addition of MeS and Cl has also been accomplished by treating the alkene with Me₃SiCl and Me₂SO.¹⁷³² The use of Me₃SiBr and Me₂SO does not give this result; dibromides (Reaction 15-39) are formed instead.

β-Iodothiocyanates can be prepared from alkenes by treatment with I₂ and isothiocyanatotributylstannane (Bu₃SnNCS).¹⁷³³ Bromothiocyanation can be accomplished with Br₂ and thallium(I) thiocyanate.¹⁷³⁴ Lead(II) thiocyanate reacts with terminal alkynes in the presence of PhICl₂ to give the bis(thiocyanato) alkene [ArC(SCN)–CHSCN].¹⁷³⁵ Such compounds were also prepared from alkenes using KSCN and FeCl₃¹⁷³⁶ or iodine thiocyanate.¹⁷³⁷ β-Halo disulfides, formed by addition of arenethiosulfenyl chlorides to double-bond compounds, are easily converted to thiiranes by treatment with sodium amide or sodium sulfide.¹⁷³⁸

OS VIII, 212. See also, OS VII, 251.

15-43 Addition of Halogen and a Nitrogen Group (Addition of Halogen, Nitrogen)

Dialkylamino-chloro-addition

The groups R₂N and Cl can be added directly to alkenes, allenes, conjugated dienes, and alkynes, by treatment with dialkyl-N-chloroamines and acids.¹⁷³⁹ N-Halo amides (RCONHX) add RCONH and X to double bonds under the influence of UV light or chromous chloride.¹⁷⁴⁰ N-Bromoamides add to alkenes in the presence of a transition metal catalyst (e.g., SnCl₄) to give the corresponding β-bromo amide.¹⁷⁴¹ The reaction of TsNCl₂ and a ZnCl₂ catalyst gave the chloro tosylamine.¹⁷⁴² Aminochlorination of alkenes occurs in a CO₂ promoted reaction with Chloramine-T (TolSO₂N⁻–Cl).¹⁷⁴³ These are free radical additions, with initial attack by the R₂NH^•+ radical ion.¹⁷⁴⁴ Amines add to allenes in the presence of a Pd catalyst.¹⁷⁴⁵ A mixture of N-(2-nosyl)NCl₂ and sodium N-(2-nosyl)NH⁻ with a CuOTf catalyst reacted with conjugated esters to give the vicinal (E)-3-chloro-2-amino ester.¹⁷⁴⁶ A variation of this latter reaction was done in an ionic liquid.¹⁷⁴⁷

15-44 Addition of NOX and NO₂X (Addition of Halogen, Nitrogen)

Nitroso-chloro-addition

There are three possible products when NOCl is added to alkenes, a β-halo nitroso compound, an oxime, or a β-halo nitro compound.¹⁷⁴⁸ The initial product is always the β-halo nitroso compound,¹⁷⁴⁹ but these are stable only if the carbon bearing the nitrogen has no hydrogen. If it has, the nitroso compound tautomerizes to the oxime, H–C–N=O → C=N–OH. With some alkenes, the initial β-halo nitroso compound is oxidized by the NOCl to a β-halo nitro compound.¹⁷⁵⁰ Many functional groups may be present without interference (e.g., CO₂H, CO₂R, CN, OR). The mechanism in most cases is probably simple electrophilic addition, and the addition is usually anti, although syn addition has been reported in some cases.¹⁷⁵¹ Markovnikov's rule is followed, the positive NO going to the carbon that has more hydrogen atoms.

Nitryl chloride (NO₂Cl) also adds to alkenes, to give β-halo nitro compounds, but this is a free radical process. The NO₂ goes to the less-substituted carbon.¹⁷⁵² Nitryl chloride also adds to triple bonds to give the expected 1-nitro-2-chloro alkenes.¹⁷⁵³ The compound FNO₂ can be added to alkenes¹⁷⁵⁴ by treatment with HF in HNO₃¹⁷⁵⁵ or by addition of the alkene to a solution of nitronium tetrafluoroborate (NO₂⁺ BF₄⁻; see Reaction 11-2) in 70% polyhydrogen fluoride–pyridine solution¹⁷⁵⁶ (see also, Reaction 15-37).

OS IV, 711; V, 266, 863.

15-45 Addition of XN₃ (Addition of Halogen, Nitrogen)

Azido-iodo-addition

The addition of iodine azide to double bonds gives β-iodo azides.¹⁷⁵⁷ The reagent can be prepared in situ from KI–NaN₃ in the presence of Oxone–wet alumina.¹⁷⁵⁸ The addition is stereospecific and anti, suggesting that the mechanism involves a cyclic iodonium ion intermediate.¹⁷⁵⁹ The reaction has been performed on many double-bond compounds, including allenes¹⁷⁶⁰ and α,β-unsaturated ketones. Similar reactions can be performed with BrN₃¹⁷⁶¹and ClN₃. 1,4-Addition has been found with acyclic conjugated dienes.¹⁷⁶² In the case of BrN₃, both electrophilic and free radical mechanisms are important,¹⁷⁶³ while with ClN₃ the additions are chiefly free radical.¹⁷⁶⁴ Iodine monoazide (IN₃) also adds to triple bonds to give β-iodo-α,β-unsaturated azides.¹⁷⁶⁵

β-Iodo azides can be reduced to aziridines (115) with LiAlH₄¹⁷⁶⁶ or converted to N-alkyl- or N-arylaziridines (116) by treatment with an alkyl- or aryldichloroborane followed by a base.¹⁷⁶⁷ In both cases the azide is first reduced to the corresponding amine (primary or secondary, respectively) and ring closure (Reaction 10-31) follows. With Chloramine T (TsNCl⁻ Na⁺) and 10% of pyridinium bromide perbromide, however, the reaction with alkenes give an N-tosyl aziridine directly.¹⁷⁶⁸

OS VI, 893.

15-46 Addition of Alkyl Halides (Addition of Halogen, Carbon)

Alkyl-halo-addition¹¹³⁵

Alkyl halides can be added to alkenes in the presence of a Friedel–Crafts catalyst, most often AlCl₃.¹⁷⁶⁹ The yields are best for tertiary R. Secondary R can also be used, but primary R give rearrangement products (as with Reaction 11-11). The reactive species is the carbocation formed from the alkyl halide and the catalyst (see Reaction 11-11).¹⁷⁷⁰ The reaction with an alkene follows Markovnikov's rule, and generates the more stable carbocation from the alkene after reaction with the carbocation. Methyl and ethyl halides, which cannot rearrange to a more stable secondary or tertiary carbocation, give no reaction at all. Substitution is a side reaction, arising from loss of hydrogen from the carbocation (117). Conjugated dienes give 1,4-addition.¹⁷⁷¹ Triple bonds also undergo the reaction, to give vinylic halides.¹⁷⁷²

Simple polyhalo alkanes (e.g., CCl₄, BrCCl₃, ICF₃ and related molecules) add to alkenes in good yield.¹⁷⁷³ These are free radical additions and require initiation, for example,¹⁷⁷⁴ by peroxides, metal halides (e.g., FeCl₂, CuCl),¹⁷⁷⁵Ru catalysts,¹⁷⁷⁶ or UV light. The initial reaction generates the more stable radical intermediate, as in most free radical reactions with alkenes:

Polyhalo alkanes add to halogenated alkenes in the presence of AlCl₃ by an electrophilic mechanism. This has been called the Prins reaction (not to be confused with the other Prins Reaction, 16-54).¹⁷⁷⁷

α-Iodolactones add to alkenes in the presence of BEt₃/O₂ to give the addition product.¹⁷⁷⁸ Other α-iodoesters add under similar conditions to give the lactone.¹⁷⁷⁹ Iodoesters also add to alkenes in the presence of BEt₃ to give iodo-esters that have not cyclized.¹⁷⁸⁰

A variant of the free radical addition method has been used for ring closure (see Reaction 15-30).

For another method of adding R and I to a triple bond, see Reaction 15-23.

OS II, 312; IV, 727; V, 1076; VI, 21; VII, 290.

15-47 Addition of Acyl Halides (Addition of Halogen, Carbon)

Acyl-halo-addition

Acyl halides add to many alkenes using Friedel–Crafts catalysts, although polymerization is a problem. The reaction has been applied to straight-chain, branched, and cyclic alkenes, but to very few containing functional groups, other than halogen.¹⁷⁸¹ The mechanism is similar to that of Reaction 15-46, and, as in that case, substitution competes (Reaction 12-16). Increasing temperature favors substitution,¹⁷⁸² but good yields of addition products can be achieved if the temperature is kept under 0°C. The reaction usually fails with conjugated dienes, since polymerization predominates.¹⁷⁸³ Iodo acetates have been formed from alkenes using iodine and Pb(OAc)₂ in acetic acid.¹⁷⁸⁴Rhodium-catalyzed variations are known.¹⁷⁸⁵ The reaction can be performed on triple-bond compounds, producing compounds of the form RCO–C=C–Cl.¹⁷⁸⁶ A formyl group and a halogen can be added to triple bonds by treatment with N,N-disubstituted formamides and POCl₃ (Vilsmeier conditions, Reaction 11-18).¹⁷⁸⁷ Chloroformates add to allenes in the presence of a Rh catalyst to give a β-chloro, β,γ-unsaturated ester.¹⁷⁸⁸

OS IV, 186; VI, 883; VIII, 254.

B. Oxygen, Nitrogen, or Sulfur on One or Both Sides

15-48 Dihydroxylation and Dialkoxylation (Addition of Oxygen, Oxygen)

Dihydroxy-addition, Dialkoxy-addition

There are many reagents that add two OH groups to a double bond (dihydroxylation).¹⁷⁸⁹ The most common are OsO₄,¹⁷⁹⁰ first used by Criegee in 1936,¹⁷⁹¹ and alkaline KMnO₄.¹⁷⁹² Both give syn addition from the less-hindered side of the double bond. Less substituted double bonds are oxidized more rapidly than more substituted alkenes.¹⁷⁹³ Permanganate adds to alkenes to form an intermediate manganate ester (Reaction 118), which is decomposed under alkaline conditions. Transition state structures and the energetics of the permanganate oxidation of alkenes has been studied using molecular mechanics.¹⁷⁹⁴ Bases catalyze the decomposition of 118 by coordinating with the ester. Note that there are alternative Mn complexes that may be used for cis-dihydroxylation of alkenes.¹⁷⁹⁵ Osmium tetroxide adds rather slowly but almost quantitatively to form a cyclic osmate ester (e.g., 119) as an intermediate,¹⁷⁹⁶which may be isolated in some cases, but is usually decomposed in solution with sodium sulfite (Na₂SO₃) in ethanol or other reagents.¹⁷⁹⁷

The chief drawbacks to the use of OsO₄ are the facts that it is expensive and toxic, but the reaction is made catalytic in OsO₄ by using N-methylmorpholine-N-oxide (NMO),¹⁷⁹⁸ tert-butyl hydroperoxide in alkaline solution,¹⁷⁹⁹H₂O₂,¹⁸⁰⁰ peroxyacid,¹⁸⁰¹ K₃Fe(CN)₆,¹⁸⁰² and non-heme iron catalysts.¹⁸⁰³ Polymer-bound OsO₄,¹⁸⁰⁴ and encapsulated OsO₄ have been shown to give the diol in the presence of NMO,¹⁸⁰⁵ as well as OsO₄²⁻ on an ion exchange resin.¹⁸⁰⁶ Dihydroxylation has also been reported in ionic liquids.¹⁸⁰⁷ Other metals have been used to catalyze dihydroxylation, including Fe¹⁸⁰⁸ or Ru catalyzed¹⁸⁰⁹ reactions with H₂O₂. A catalytic amount of K₂OsO₄ with a Cinchona alkaloid on a ordered inorganic support, in the presence of K₃Fe(CN)₆, gives the cis-diol.¹⁸¹⁰

The end product of the reaction is a 1,2-diol. Potassium permanganate is a strong oxidizing agent and can oxidize the glycol product¹⁸¹¹ (see Reaction 19-7 and 19-10). In acidic and neutral solution, it always does so; hence glycols must be prepared with alkaline¹⁸¹² permanganate, but the conditions must be mild. Even so, yields are seldom >50%, although they can be improved with phase-transfer catalysis¹⁸¹³ or increased stirring.¹⁸¹⁴ The use of ultrasound with permanganate has resulted in good yields of the diol.¹⁸¹⁵ This reaction is the basis of the Baeyer test for the presence of double bonds. The oxidation is compatible with a number of functional groups, including trichloroacetamides.¹⁸¹⁶

Anti-hydroxylation can be achieved by treatment with H₂O₂ and formic acid. In this case, epoxidation (Reaction 15-50) occurs first, followed by an S_N2 reaction, which results in overall anti addition:

The same result can be achieved in one step with m-chloroperoxybenzoic acid and water.¹⁸¹⁷ Overall anti addition can also be achieved by the method of Prévost (the Prévost reaction). In this method, the alkene is treated with iodine and silver benzoate in a 1:2 molar ratio. The initial addition is anti and results in a β-halo benzoate, as shown. These can be isolated, and this represents a method of addition of IOCOPh. However, under normal reaction conditions, the iodine is replaced by a second PhCOO group. This is a nucleophilic substitution reaction via the neighboring-group mechanism (Sec. 10.C), so the groups are still anti:

Hydrolysis of the ester does not change the configuration. The Woodward modification of the Prévost reaction is similar, but results in overall syn hydroxylation.¹⁸¹⁸ In this procedure, the alkene is treated with iodine and silver acetate in a 1:1 molar ratio in acetic acid containing water. Here again, the initial product is a β-halo ester; the addition is anti and a nucleophilic replacement of the iodine occurs. However, in the presence of water, neighboring-group participation is prevented or greatly decreased by solvation of the ester function, and the mechanism is the normal S_N2 process,¹⁸¹⁹ so the monoacetate is syn and hydrolysis gives the diol as the product, with overall syn addition. Although the Woodward method results in overall syn addition, the product may be different from that with OsO₄ or KMnO₄, since the overall syn process is from the more hindered side of the alkene.¹⁸²⁰ Both the Prévostand the Woodward methods¹⁸²¹ have been carried out in high yields with thallium(I) acetate and thallium(I) benzoate instead of the silver carboxylates.¹⁸²² Note that cyclic sulfates can be prepared from alkenes by reaction with PhIO and SO₃·DMF.¹⁸²³ Diacetates have been prepared from alkenes using a Cu catalyzed reaction with PhI(OAc)₂ as the oxidizing agent.¹⁸²⁴ A similar Pd/Cu catalyzed reaction is known using O₂ as the oxidant.¹⁸²⁵

Dialkoxylation reactions are possible. The reaction of an aryl alkene with CH₃OH, O₂, and a Pd catalyst leads to the dimethoxy compound (see Reaction 120), with moderate enantioselectivity if a chiral ligand is used.¹⁸²⁶Dihydroxylation to alkenes of the form RCH=CH₂ has been made enantioselective, and addition to RCH=CHR′ both diastereoselective¹⁸²⁷ and enantioselective,¹⁸²⁸ using chiral additives or chiral catalysts¹⁸²⁹ (e.g., 121 or 122, derivatives of the naturally occurring quinine and quinuclidine),¹⁸³⁰ along with OsO₄, in what is called

Sharpless asymmetric dihydroxylation.¹⁸³¹ Other chiral ligands¹⁸³² have also been used, as well as polymer¹⁸³³ and silica-bound¹⁸³⁴ Cinchona alkaloids. These amines bind to the OsO₄ in situ as chiral ligands, causing it to add asymmetrically.¹⁸³⁵ This has been done both with the stoichiometric and with the catalytic method.¹⁸³⁶ The catalytic method has been extended to conjugated ketones¹⁸³⁷ and to conjugated dienes, which give tetrahydroxy products diastereoselectively.¹⁸³⁸ Asymmetric dihydroxylation has also been reported with chiral alkenes.¹⁸³⁹ Ligands 121 and 122 not only cause enantioselective addition, but also accelerate the reaction, so that they may be useful even where enantioselective addition is not required.¹⁸⁴⁰ Although 121 and 122 are not enantiomers, they give enantioselective addition to a given alkene in the opposite sense; for example, styrene predominantly gave the (R) diol with 121, and the (S) diol with 122.¹⁸⁴¹ Note that ionic liquids have been used in asymmetric dihydroxylation.¹⁸⁴²

Two phthalazine derivatives,¹⁸⁴³ (DHQD)₂PHAL (123) and (DHQ)₂PHAL (124) are used in conjunction with an Os reagent to improve the efficiency and ease of use, and are commercial available as AD-mix-β (using 123) and AD-mix-α (using 124). Catalyst 123 is prepared from dihydroquinidine (DHQD) and 1,4-dichlorophthalazine (PHAL), and 124 is prepared from dihydroquinine (DHQ) and PHAL. The actual oxidation using AD-mix α or β- uses 124 or 123, respectively, mixed with potassium osmate [K₂OsO₂(OH)₆], powdered K₃Fe(CN)₆, and powdered K₂CO₃ in an aqueous solvent mixture.¹⁸⁴³ One study showed that osymylation does not always occur preferentially on the most electron-rich double bond. There are examples of the less-rich double bond reacting preferentially, and such preferences may be amplified using AD type reagents, which adds significant steric hindrance to the overall system.¹⁸⁴⁴

These additives have been used in conjunction with microencapsulated OsO₄,¹⁸⁴⁵ and polymer bound 123 has been used.¹⁸⁴⁶ An asymmetric dihydroxylation was reported catalyzed by ionic polymer-supported OsO₄.¹⁸⁴⁷ A catalytic amount of flavin has been used.¹⁸⁴⁸ Both 123¹⁸⁴⁹ and 124¹⁸⁵⁰ have been used to generate diols with high enantioselectivity. Oxidation of a terminal alkene with AD-mix and then oxidation with TEMPO/NaOCl/NaOCl₂leads to α-hydroxyl carboxylic acids with high enantioselectivity.¹⁸⁵¹

Enantioselective and diastereoselective addition have also been achieved by using preformed derivatives of OsO₄, already containing chiral ligands,¹⁸⁵² and by the use of OsO₄ on alkenes that have a chiral group elsewhere in the molecule.¹⁸⁵³ A Rh catalyzed diboration of alkenes in the presence of a chiral ligand, leads to the corresponding diol with good enantioselectivity after oxidation.¹⁸⁵⁴

Alkenes can also be oxidized with metallic acetates [e.g., lead tetraacetate¹⁸⁵⁵ or thallium(III) acetate]¹⁸⁵⁶ to give bis(acetates) of glycols.¹⁸⁵⁷ Oxidizing agents (e.g., benzoquinone, MnO₂, or O₂), along with palladium acetate, have been used to convert conjugated dienes to 1,4-diacetoxy-2-alkenes (1,4-addition).¹⁸⁵⁸

1,2-Diols are also generated from terminal alkynes by two sequential reactions with a Pt catalyst and then a Pd catalyst, both with HSiCl₃, and a final oxidation with H₂O₂–KF.¹⁸⁵⁹ The dihydroxylation of a vinyl ether, derived from an alkyne, leads to α-hydroxy aldehydes.¹⁸⁶⁰ Dihydroxylation of alkenes has been reported using a lipase and hydrogen peroxide, under microwave irradiation.¹⁸⁶¹ A Pd catalyzed diacetoxylation is also known.¹⁸⁶²

1,2-Dithiols can be prepared from alkenes by largely indirect methods.¹⁸⁶³

OS II, 307; III, 217; IV, 317; V, 647; VI, 196, 342, 348; IX, 251, 383.

15-49 Dihydroxylation of Aromatic Rings

Dihydroxy-addition

One π bond of an aromatic ring can be converted to a cyclohexadiene 1,2-diol by reaction with enzymes associated with P. putida.¹⁸⁶⁴ A variety of substituted aromatic compounds can be oxidized, including bromobenzene, chlorobenzene,¹⁸⁶⁵ and toluene.¹⁸⁶⁶ In these latter cases, introduction of the hydroxyl groups generates a chiral molecule that can be used as a template for asymmetric syntheses.¹⁸⁶⁷

OS X, 217.

15-50 Epoxidation (Addition of Oxygen, Oxygen)

epi-Oxy-addition

Alkenes are converted to epoxides (oxiranes) by reaction with many peroxyacids.¹⁸⁶⁸ The reaction, called the Prilezhaev reaction, has wide utility.¹⁸⁶⁹ The most common is probably m-chloroperoxybenzoic acid, but peroxyacetic and peroxybenzoic are available, and trifluoroperoxyacetic acid¹⁸⁷⁰ and 3,5-dinitroperoxybenzoic acid¹⁸⁷¹ are particularly reactive. The limiting factor concerning choice of the peroxyacid is usually whether or not it is commercially available because an in-lab preparation is potentially rather dangerous. Magnesium monoperoxyphthalate (MMPP)¹⁸⁷² is commercially available, and has been shown to be a good substitute for m-chloroperoxybenzoic acid in a number of reactions. Alkyl, aryl, hydroxyl, ester, and other groups may be present, but not amino groups since they are oxidized by the reagent. The presence of electron-donating groups increases the rate, and the reaction is particularly rapid with tetraalkyl alkenes. Conditions are mild and yields are high. Transition metal catalysts can facilitate epoxidation of alkenes at low temperatures or with alkenes that may otherwise react sluggishly.¹⁸⁷³

The one-step mechanism involving a transition state (e.g., 125)¹⁸⁷⁴ was proposed by Bartlett.¹⁸⁷⁵ Evidence for this concerted mechanism is as follows¹⁸⁷⁶: (1) The reaction is second order. If ionization were the rate-determining step, it would be first order in peroxyacid. (2) The reaction readily takes place in nonpolar solvents, where formation of ions is inhibited.¹⁸⁷⁷ (3) Measurements of the effect on the reaction rate of changes in the substrate structure show that there is no carbocation character in the transition state.¹⁸⁷⁸ (4) The addition is stereospecific (i.e., a trans-alkene gives a trans-epoxide and a cis-alkene gives a cis-epoxide) even in cases where electron-donating substituents would stabilize a hypothetical carbocation intermediate.¹⁸⁷⁹ However, where there is an OH group in the allylic or homoallylic position, the stereospecificity diminishes or disappears, with both cis and trans isomers giving predominantly and exclusively the product where the incoming oxygen is syn to the OH group. This probably indicates a transition state in which there is hydrogen bonding between the OH group and the peroxyacid.¹⁸⁸⁰

In general, peroxides (HOOH¹⁸⁸¹ and ROOH) are poor reagents for epoxidation of simple alkenes since OH and OR are poor leaving groups in the concerted mechanism shown above.¹⁸⁸² Transition metal catalysts¹⁸⁸³ have been used with alkyl hydroperoxides,¹⁸⁸⁴ however. Epoxidation occurs with Fe,¹⁸⁸⁵ and with Ti¹⁸⁸⁶ or V catalysts.¹⁸⁸⁷ In the presence of some other reagents,¹⁸⁸⁸ peroxides give good yields of the epoxide. These coreagents include DCC,¹⁸⁸⁹ magnesium aluminates,¹⁸⁹⁰ metalloporphyrins,¹⁸⁹¹ hydrotalcite¹⁸⁹² with microwave irradiation,¹⁸⁹³ and arsines in fluorous solvents.¹⁸⁹⁴ The catalyst MeReO₃¹⁸⁹⁵ has been used for epoxidation using sodium percarbonate and pyrazole,¹⁸⁹⁶ or hydrogen peroxide,¹⁸⁹⁷ or urea–H₂O₂.¹⁸⁹⁸

Epoxidation has been done in ionic liquids using 10% H₂O₂ with MnSO₄¹⁸⁹⁹ or an Fe catalyst.¹⁹⁰⁰ Hypervalent iodine compounds [e.g., PhI(OAc)₂], in conjunction with a Ru catalyst in aqueous media, converts alkenes to epoxides.¹⁹⁰¹ This reagent has been used in an ionic liquid with a Mn catalyst.¹⁹⁰² Sodium chlorite (NaClO₂) in water gives epoxidation from alkenes.¹⁹⁰³ Microwave assisted epoxidations are known using H₂O₂.¹⁹⁰⁴ Epoxidation of vinyl ethers has been studied.¹⁹⁰⁵

Several homogeneous and heterogeneous asymmetric epoxidation protocols have been developed.¹⁹⁰⁶ Enzymatic epoxidation¹⁹⁰⁷ and epoxidation with catalytic antibodies¹⁹⁰⁸ have been reported. Organocatalysts (e.g., chiral iminium salts) have been used.¹⁹⁰⁹ Asymmetric Weitz–Scheffer epoxidation¹⁹¹⁰ (epoxidation of electron-deficient alkenes using H₂O₂ in a strong alkaline solution) is common. Cinchona-derived phase-transfer catalysts, initially used by Wynberg, are now common.¹⁹¹¹ Enantioselectivities can be significantly improved by changes of the catalyst structure, as well as the type of oxidant.¹⁹¹² A Yb–BINOL complex, with t-BuOOH led to epoxidation of conjugated ketones with high asymmetric induction,¹⁹¹³ as did a mixture of NaOCl and a Cinchona alkaloid.¹⁹¹⁴ Treatment with aq NaOCl¹⁹¹⁵ or with an alkyl hydroperoxide¹⁹¹⁶ and a chiral phase-transfer agent leads to chiral nonracemic epoxy-ketones. Epoxides can also be prepared by treating alkenes with oxygen or with an alkyl peroxide¹⁹¹⁷ catalyzed by a complex of a transition metal (e.g., V, Mo, Ti, La,¹⁹¹⁸ Y,¹⁹¹⁹ or Co).¹⁹²⁰ The use of chiral additive leads to enantioselective epoxidation,¹⁹²¹ and organocatalysts have been used as well.¹⁹²² Chiral hydroperoxides have been used for enantioselective epoxidation.¹⁹²³

Other epoxidation methods are available. Dioxiranes,¹⁹²⁴ (e.g., dimethyl dioxirane, 126),¹⁹²⁵ either isolated or generated in situ,¹⁹²⁶ are important epoxidation reagents. With dimethyloxirane, C–H insertion reactions can occur preferentially.¹⁹²⁷ The reaction with alkenes is rapid, mild, safe, and a variety of methods have been developed using an oxidant as a coreagent. Substituent effects in such reactions have been studied¹⁹²⁸ and also substrate variations.¹⁹²⁹ The most commonly used coreagent is probably potassium peroxomonosulfate (KHSO₅). Oxone (2KHSO₅·KHSO₄·K₂SO₄) is a common source of KHSO₅. Oxone reacts with ketones¹⁹³⁰ and sodium bicarbonate to convert an alkene to an epoxide. Oxone converts alkenes to epoxides in the presence of certain additives (e.g., N,N-dialkylalloxans).¹⁹³¹ Oxone, with hydrogen peroxide or a similar oxidant, can be used with chiral ketones¹⁹³² or aldehydes to convert alkenes to chiral, nonracemic epoxides.¹⁹³³ This reaction probably converts alkenes to epoxides with good enantioselectivity by in situ generation of dioxirane.¹⁹³⁴ Chiral dioxiranes have reportedly given nonracemic epoxides.¹⁹³⁵ This transformation with chiral carbohydrates is sometimes called Shi epoxidation.¹⁹³⁶ Epoxidation does not occur in good yields with these reagents in most other solvents, and it is suggested that the active agent that generates dioxirane is peroxyimidic acid [MeC(=NH)OOH].¹⁹³⁷ Note that benzaldehyde with Chloramine-M¹⁹³⁸ will convert alkenes to epoxides.¹⁹³⁹

Oxone oxidizes iminium salts to an oxaziridinium intermediate (127), which can transfer oxygen to an alkene to form an epoxide and regenerate the iminium salt.¹⁹⁴⁰ This variation has been applied to asymmetric¹⁹⁴¹ epoxidations using chiral iminium salt precursors.¹⁹⁴² Other asymmetric epoxidation reactions of alkenes use chiral ketones and iminium salts with an organocatalyst.¹⁹⁴³ Direct epoxidation of alkenes has been done using oxaziridinium salts.¹⁹⁴⁴

Although cis–trans isomerization of epoxides is not formally associated with this section, it is a potential issue in the conversion of an alkene to an epoxide. There are several catalysts for this process.¹⁹⁴⁵

It would be useful if triple bonds could be similarly epoxidized to give oxirenes (see oxirene, above), but they are not stable compounds.¹⁹⁴⁶ Two oxirenes have been trapped in solid argon matrices at very low temperatures, but they decayed upon warming to 35 K.¹⁹⁴⁷ Oxirenes probably form in the reaction,¹⁹⁴⁸ but react further before they can be isolated. Note that oxirenes bear the same relationship to cyclobutadiene that furan does to benzene and may therefore be expected to be antiaromatic (Sec. 2.B and 2.K.ii).

Conjugated dienes can be epoxidized (1,2-addition), although the reaction is slower than for corresponding alkenes, but α,β-unsaturated ketones do not generally give epoxides when treated with peroxyacids.¹⁹⁴⁹ The epoxidation of α,β-unsaturated ketones with H₂O₂ under basic conditions is known as the Waits–Scheffer epoxidation, discovered in 1921.¹⁹⁵⁰ This fundamental reaction has been extended to α,β-unsaturated ketones (including quinones), aldehydes, and sulfones.¹⁹⁵¹ This is a nucleophilic addition by a Michael-type mechanism, involving attack by HO₂⁻¹⁹⁵²: This reaction is another example of 1,4-addition of a heteroatom-containing species, as discussed in Reaction 15-31.

α,β-Unsaturated compounds can be epoxidized alkyl hydroperoxides and a base,¹⁹⁵³ or with H₂O₂ and a base¹⁹⁵⁴or heteropoly acids.¹⁹⁵⁵ The reaction has been done with LiOH and polymer-bound quaternary ammonium salts.¹⁹⁵⁶

Another important asymmetric epoxidation of a conjugated system is the reaction of alkenes with polyleucine,¹⁹⁵⁷ DBU, and urea–H₂O₂, giving an epoxy–carbonyl compound with good enantioselectivity.¹⁹⁵⁸ The hydroperoxide anion epoxidation of conjugated carbonyl compounds with a polyamino acid (e.g., poly-l-alanine or poly-l-leucine is known as the Juliá–Colonna epoxidation.¹⁹⁵⁹ Epoxidation of conjugated ketones to give nonracemic epoxy-ketones was done with aq NaOCl and a Cinchona alkaloid derivative as catalyst.¹⁹⁶⁰ A triphasic phase-transfer catalysis protocol has also been developed.¹⁹⁶¹ β-Peptides have been used as catalysts in this reaction.¹⁹⁶²

When a carbonyl group is elsewhere in the molecule, but not conjugated with the double bond, the Baeyer–Villiger Reaction (18-19) may compete. Allenes¹⁹⁶³ are converted by peroxyacids to allene oxides¹⁹⁶⁴ or spiro dioxides, both of which species can in certain cases be isolated,¹⁹⁶⁵ but more often are unstable under the reaction conditions and react further to give other products.¹⁹⁶⁶

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves,¹⁹⁶⁷ or with peroxyacids.¹⁹⁶⁸ The addition of an appropriate chiral ligand to the metal-catalyzed hydroperoxide epoxidation of allylic alcohols leads to high enantioselectivity. This important modification is known as the Sharpless asymmetric epoxidation,¹⁹⁶⁹ where allylic alcohols are converted to optically active epoxides with excellent enantioselectivity by treatment with t-BuOOH, titanium tetraisopropoxide, and optically active diethyl tartrate.¹⁹⁷⁰ The Ti(OCHMe₂)₄ and diethyl tartrate can be present in catalytic amounts (15–10 mol%) if molecular sieves are present.¹⁹⁷¹ Polymer-supported catalysts have also been reported.¹⁹⁷² The use of a tartrate–PEG reagent (PEG₃₅₀ or PEG₇₅₀) allows generation of both enantiomers.¹⁹⁷³ Both (+) and (−) diethyl tartrate are readily available, so either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, including substrates where the double bond is mono-, di, tri-, and tetrasubstituted,¹⁹⁷⁴ and is highly useful in natural product synthesis. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound¹⁹⁷⁵ formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the t-BuOOH.¹⁹⁷⁶

Ordinary alkenes (without an allylic OH group) do not give optically active alcohols by the Sharpless protocol because binding to the catalyst is necessary for enantioselectivity. Homoallylic alcohols have been converted to the epoxide, however, using a V catalyst in the presence of a chiral bis(hydroxyamide).¹⁹⁷⁷ Simple alkenes can be epoxidized enantioselectively with sodium hypochlorite (NaOCl, commercial bleach) and an optically active manganese complex catalyst.¹⁹⁷⁸ Apart from the commonly used NaOCl, urea–H₂O₂ has been used.¹⁹⁷⁹

The use of a manganese–salen complex¹⁹⁸⁰ with various oxidizing agents, in what is called the Jacobsen–Katsuki reaction.¹⁹⁸¹ Simple alkenes can be epoxidized with high enantioselectivity.¹⁹⁸² In addition to Mn, Cr–salen,¹⁹⁸³ Ti–salen,¹⁹⁸⁴ and Ru–salen complexes¹⁹⁸⁵ have been used for epoxidation.¹⁹⁸⁶ Note that salen ligands are based on salen. The mechanism of this reaction has been examined.¹⁹⁸⁷ Radical intermediates have been suggested for this reaction,¹⁹⁸⁸ A polymer-bound Mn(III)–salen complex, in conjunction with NaOCl, has been used for asymmetric epoxidation,¹⁹⁸⁹ and manganese porphyrin complexes have also been used.¹⁹⁹⁰ Cobalt complexes give similar results.¹⁹⁹¹ A related epoxidation reaction used an iron complex with molecular oxygen and isopropanal.¹⁹⁹² Nonracemic epoxides can be prepared from racemic epoxides with (salen) cobalt(II) catalysts following a modified procedure for kinetic resolution.¹⁹⁹³

In a different type of reaction, alkenes are photooxygenated (with singlet O₂, see Reaction 14-7) in the presence of a Ti, V, or Mo complex to give epoxy alcohols (e.g., 128), formally derived from allylic hydroxylation followed by epoxidation.¹⁹⁹⁴ In other cases, modification of the procedure gives simple epoxidation.¹⁹⁹⁵ Alkenes react with aldehydes and oxygen, with Pd-on-silica¹⁹⁹⁶ or a Ru catalyst,¹⁹⁹⁷ to give the epoxide.

Thiiranes can be prepared directly from alkenes using specialized reagents.¹⁹⁹⁸ Thiourea with a tin catalyst gives the thiirane, for example.¹⁹⁹⁹ Interestingly, internal alkynes were converted to 1,2-dichorothiiranes by reaction with S₂Cl₂ (sulfur monochloride).²⁰⁰⁰ Note that epoxides are converted to thiiranes with ammonium thiocyanate and a cerium complex.²⁰⁰¹ A trans-thiiration reaction occurs with a Mo catalyst, in which an alkene reacts with styrene thiirane to give the new thiirane.²⁰⁰²

OS I, 494; IV, 552, 860; V, 191, 414, 467, 1007; VI, 39, 320, 679, 862; VII, 121, 126, 461; VIII, 546; IX, 288; X, 29; 80, 9.

15-51 Hydroxysulfenylation (Addition of Oxygen, Sulfur)

Hydroxy-arylthio-addition (overall transformation)

Both hydroxy and an arylthio group are added to a double bond by treatment with an aryl disulfide and lead tetraacetate in the presence of trifluoroacetic acid.²⁰⁰³ Manganese and copper acetates have been used instead of Pb(OAc)₄.²⁰⁰⁴ Addition of the groups OH and RSO has been achieved by treatment of alkenes with O₂ and a thiol (RSH).²⁰⁰⁵ Addition to RS groups to give vic-dithiols was observed by treatment of the alkene with a disulfide (RSSR) and BF₃–etherate.²⁰⁰⁶ This reaction has been carried out intramolecularly.²⁰⁰⁷ In a similar manner, the reaction of alkenes with ceric ammonium nitrate and diphenyl diselenide in methanol leads to vicinally substituted phenylselenyl methyl ethers.²⁰⁰⁸ Dimethyl diselenide adds to alkenes to form vicinal bis(methylselenyl) compounds, in the presence of tin tetrachloride.²⁰⁰⁹

Halo-ethers can be formed by the reaction of alkenyl alcohols with various reagents. Hept-6-en-1-ol reacts with (collidine)₂I⁺PF₆⁻, for example, to form 2-iodomethyl-1-oxacycloheptane.²⁰¹⁰

15-52 Oxyamination (Addition of Oxygen, Nitrogen)

Tosylamino-hydroxy-addition

N-Tosylated β-hydroxy alkylamines, which can be easily hydrolyzed to β-hydroxyamines²⁰¹¹, can be prepared²⁰¹² by treatment of alkenes with the trihydrate of Chloramine-T (N-chloro-p-toluenesulfonamide sodium salt)¹⁶⁹⁰ and a catalytic amount of OsO₄.²⁰¹³ In some cases, yields can be improved by the use of phase-transfer catalysis.²⁰¹⁴ The reaction has been carried out enantioselectively.²⁰¹⁵ Alkenes can be converted to amido alcohols enantioselectivity by modification of this basic scheme. The Sharpless asymmetric aminohydroxylation employs a catalyst consisting of Cinchona alkaloid derived ligands and an osmium species in combination with a stoichiometric nitrogen source that also functions as the oxidant.²⁰¹⁶ The Cu catalyzed reaction of an alkene with a N-sulfone oxaziridine leads to an oxazolidine.²⁰¹⁷ N-Chlorosulfonyl isocyanate has been used to prepare 1,2-amino alcohols.²⁰¹⁸ The Cu catalyzed hydroxyamination of alkenes was reported using Boc-hydroxylamine.²⁰¹⁹

The reaction of a carbamate with (DHQ)₂PHAL (124) and the osmium compound, with NaOH and tert-butyl hypochlorite, leads to a diastereomeric mixture of amido alcohols 129 and 130, each formed with high enantioselectivity.²⁰²⁰ An enantioselective aminohydroxylation of acrylamides has been reported.²⁰²¹

In general, the nitrogen adds to the less sterically hindered carbon of the alkene to give the major product. N-Bromoamides, in the presence of a catalytic amount of (DHQ)₂PHAL and LiOH converts conjugated esters to β-amido-α-hydroxy esters with good enantioselectivity.²⁰²² Another oxyamination reaction involves treatment of a Pd complex of the alkene with a secondary or primary amine, followed by lead tetraacetate or another oxidant.²⁰²³

The organolanthanide-catalyzed alkene hydroamination has been reported.²⁰²⁴ With this approach, amino alkenes (not enamines) can be cyclized to form cyclic amines,²⁰²⁵ and amino alkynes lead to cyclic imine.²⁰²⁶ The use of synthesized C-1²⁰²⁷ and C-2 symmetric²⁰²⁸ chiral organolanthanide complexes give the amino alcohol with good enantioselectivity.

β-Amino alcohols can be prepared by treatment of an alkene with a reagent prepared from HgO and HBF₄ along with aniline to give an aminomercurial compound (PhHN–C–C–HgBF₄, aminomercuration; see Reaction 15-7), which is hydrolyzed to PhHN–C–C–OH.²⁰²⁹ The use of an alcohol instead of water gives the corresponding amino ether. β-Azido alcohols are prepared by the reaction of an alkene with Me₃SiOOSiMe₃, Me₃SiN₃, and 20% (Cl₂SnO)_n, followed by treatment with aqueous acetic acid.²⁰³⁰

OS VII, 223, 375.

15-53 Diamination (Addition of Nitrogen, Nitrogen)

Di(alkylarylamino)-addition

Primary (R = H) and secondary aromatic amines react with alkenes in the presence of thallium(III) acetate to give vic-diamines in good yields.²⁰³¹ The reaction is not successful for primary aliphatic amines. In another procedure, alkenes can be diaminated by treatment with the Os compounds R₃NOsO (R = t-Bu) and R₂NOsO₂,²⁰³² analogous to the Os compound mentioned at Reaction 15-52.²⁰³³ The Pd promoted method of Reaction 15-52 has also been extended to diamination.²⁰³⁴ Alkenes can also be diaminated²⁰³⁵ indirectly by treatment of the aminomercurial compound mentioned in Reaction 15-52 with a primary or secondary aromatic amine.²⁰³⁶ The reaction of an alkene with N-arylsulfonyl dichloroamines (ArSO₂NCl₂) followed by reaction with aq Na₂SO₃, gives the anti-vic-diacetamde.²⁰³⁷ The Pd catalyzed addition of saccharin and H(NTs)₂ with an alkene, in the presence of a hypervalent iodine oxidant leads to a precursor that can be converted to a 1,2-diamine.²⁰³⁸

Two azido groups can be added to double bonds by treatment with sodium azide and iodosobenzene in acetic acid, C=C + NaN₃ + PhIO → N₃–C–C–N₃.²⁰³⁹

Dienes react with ureas in the presence of a Pd catalyst, to give an oxazolidinone.²⁰⁴⁰ A Pd catalyzed reaction of dienes with di-tert-butyldiaziridinone also leads to an oxazolidinone.²⁰⁴¹

Alkynes react with the bis(tosylate) of ethylenediamine, in the presence of a CuI catalyst, to give a dihydropiperazine.²⁰⁴²

15-54 Formation of Aziridines (Addition of Nitrogen, Nitrogen)

epi-Arylimino-addition, and so on

Aziridines can be prepared directly from double-bond compounds by photolysis or thermolysis of a mixture of the substrate and an azide.²⁰⁴³ The reaction has been carried out with R = aryl, cyano, EtOOC, and RSO₂, as well as other groups. The reaction can take place by at least two pathways.

In one pathway, a 1,3-dipolar addition (Reaction 15-58) takes place to give a triazoline, which can be isolated, followed thermal by extrusion of nitrogen (Reaction 17-34). Evidence for the nitrene pathway is most compelling for R = acyl groups. In the other, the azide is converted to a nitrene, which adds to the double bond in a manner analogous to that of carbene addition (Reaction 15-64). Sulfonyloxy amines (e.g., ArSO₂ONHCO₂Et) form an aziridine when treated with CaO in the presence of a conjugated carbonyl compound.²⁰⁴⁴ In the presence of Cu,²⁰⁴⁵ Co,²⁰⁴⁶ or Rh complexes,²⁰⁴⁷ ethyl diazoacetate adds to imines to give aziridines. Diazirenes (Sec. 5.D.ii) with n-butyllithium converted conjugated amides to the α,β-aziridino amide.²⁰⁴⁸ Calcium oxide has also been used to generate the nitrene,²⁰⁴⁹ including nitrene precursors that have an attached chiral ester.²⁰⁵⁰ Other specialized reagents have also been used.²⁰⁵¹ As discussed in Section 5.E, singlet nitrenes add stereospecifically while triplet nitrenes do not. Aminonitrenes (R₂NN:) have been shown to add to alkenes²⁰⁵² to give N-substituted aziridines and to triple bonds to give 1-azirines, which arise from rearrangement of the initially formed 2-azirines.²⁰⁵³ N-Aminophthalimide generates a nitrene in the presence of a Pd catalyst, giving an N-phthalimido aziridine upon reaction with electron-deficient alkenes.²⁰⁵⁴ Alkyl azides add to conjugated alkenes in the presence of an acid.²⁰⁵⁵ Intramolecular aziridination reactions are known (e.g., the Pd catalyzed addition of N-tosyloxycarbamates to alkenes to form the bicyclic oxaziridinone).²⁰⁵⁶ Tosylamines react with alkenes in the presence of a Rh catalyst²⁰⁵⁷ or with iodine/PhI(OAc)₂.²⁰⁵⁸ Trichloroethylsulfamate esters react with PhI(OAc)₂ and a Rh catalyst to give the corresponding N-sulfonyl aziridine.²⁰⁵⁹

Like oxirenes (see Reaction 15-50), 2-azirines are unstable. 1-Azirines can be reduced to give chiral aziridines.²⁰⁶⁰

An alternative preparation of aziridines reacts an alkene with iodine and Chloramine-T, generating the corresponding N-tosyl aziridine.²⁰⁶¹ Chloramine T and NBS also give the N-tosyl aziridine,²⁰⁶² and Bromamine-T (TsNBr⁻Na⁺) or TsNIK and have also been used in a similar manner,^2063,2064 Diazoalkanes react with imines to give aziridines.²⁰⁶⁵ Another useful reagent is NsN=IPh, which reacts with alkenes in the presence of Rh compounds²⁰⁶⁶ or Cu complexes²⁰⁶⁷ to give N-Ns aziridines. Other sulfonamide reagents can be used,²⁰⁶⁸ including PhI=NTs.²⁰⁶⁹ Enantioselective aziridination is possible using this reaction with chiral ligands.²⁰⁷⁰ This reagent has been used in ionic liquids with a Cu catalyst.²⁰⁷¹ Palladium catalyzes such reactions²⁰⁷² and we can also use methyl trioxorhenium (MeReO₃).²⁰⁷³ Manganese(salen) catalysts have also been used with this reagent.²⁰⁷⁴ A nitrido Mn(salen) complex was used with ditosyl anhydride, converting a conjugated diene to an allylic N-tosylaziridine.²⁰⁷⁵ Arylsulfonamides react with alkenes via the nitrene using an Au²⁰⁷⁶ or a Cu catalyst.²⁰⁷⁷

Organocatalysts have been used for the enantioselective aziridination of the C=C unit in conjugated aldehydes.²⁰⁷⁸

Nitrenes can add to aromatic rings to give ring-expansion products analogous to those mentioned in Reaction 15-62.²⁰⁷⁹

OS VI, 56.

15-55 Aminosulfenylation (Addition of Nitrogen, Sulfur)

Arylamino-arylthio-addition

An amino and an arylthio group can be added to a double bond by treatment with a sulfenanilide (PhSNHAr) in the presence of BF₃–etherate.²⁰⁸⁰ The addition is anti, and the mechanism probably involves a thiiranium ion.²⁰⁸¹ In another aminosulfenylation procedure, the substrate is treated with dimethyl(methylthio)sulfonium fluoroborate (MeSSMe₂ BF₄⁻) and ammonia or an amine,²⁰⁸² the latter acting as a nucleophile. This reaction was extended to other nucleophiles:²⁰⁸³ N₃⁻,²⁰⁸⁴ NO₂⁻, CN⁻, , and to give MeS–C–C–A, where A = N₃, NO₂, CN, OH, and OAc, respectively. An RS (R = alkyl or aryl) and an NHCOMe group have been added in an electrochemical procedure.²⁰⁸⁵

15-56 Acylacyloxylation and Acylamidation (Addition of Oxygen, Carbon, or Nitrogen, Carbon)

Acyl-acyloxy-addition

An acyl and an acyloxy group can be added to a double bond by treatment with an acyl fluoroborate and acetic anhydride.²⁰⁸⁶ As expected, the addition follows Markovnikov's rule, with the electrophile Ac⁺ going to the carbon with more hydrogen atoms. In an analogous reaction, an acyl and an amido group can be added to give 131, if a nitrile is used in place of the anhydride. Similarly, halo-acetoxylation is known.²⁰⁸⁷ This reaction has also been carried out on triple bonds, to give the unsaturated analogues of 131 (syn addition).²⁰⁸⁸

15-57 The Conversion of Alkenes or Alkynes to Lactones (Addition of Oxygen, Carbon)

This reaction is clearly related to forming esters and lactones by reaction of carboxylic acids with alkenes (Reaction 15-6), but the Mn reagent leads to differences. Alkenes react with manganese(III) acetate to give γ-lactones.²⁰⁸⁹The mechanism is probably free radical, involving addition of ^•CH₂COOH to the double bond. Ultrasound improves the efficiency of the reaction.²⁰⁹⁰ In a related reaction, cyclohexene reacted with MeO₂CCH₂CO₂K and Mn(OAc)₃to give an α-carbomethoxy bicyclic lactone.²⁰⁹¹ The use of dimethyl malonate and ultrasound in this reaction gave the same type of product.²⁰⁹² Lactone formation has also been accomplished by treatment of alkenes with α-bromo carboxylic acids in the presence of benzoyl peroxide as catalyst,²⁰⁹³ and with alkylidene Cr(CO)₅ complexes.²⁰⁹⁴ Alkenes can also be converted to γ-lactones by indirect routes.²⁰⁹⁵ Chromium carbene complexes add to alkenes to give β-lactones using ultrasound.²⁰⁹⁶

Cyclic dienes react with β-keto esters, in the presence of a Ga²⁰⁹⁷ catalyst and water, to give an α-acyl bicyclic lactone.

Alkenyl acids cyclize to the corresponding lactone upon treatment with sodium hypochlorite and a Lewis acid.²⁰⁹⁸ Alkynyl acids cyclize upon treatment with PIFA [phenyliodine(III)-bis(trifluoroacetate)] to give ω-acyl lactones.²⁰⁹⁹ A variation of this reaction also employs a diselenide.²¹⁰⁰ Treatment of alkynyl acids with a Au catalyst²¹⁰¹ leads to an alkylidene lactone.

An intramolecular variation of this reaction is known, involving amides, which generate a lactam.²¹⁰²

OS VII, 400.

Note that the related halolacctonization reaction, including iodolactonization, is discussed in Reaction 15-41.

For addition of aldehydes and ketones, see the Prins reaction (16-54), and Reactions 16-95 and 16-96.

15.C.iv. Cycloaddition Reactions

15-58 1,3-Dipolar Addition (Addition of Oxygen, Nitrogen, Carbon)

There are a large group of reactions ([3 + 2]-cycloadditions) in which five-membered heterocyclic compounds are prepared by addition of 1,3-dipolar compounds to double bonds. This reaction is quite useful in the synthesis of alkaloids,²¹⁰³ including asymmetric syntheses.²¹⁰⁴ These dipolar compounds have a sequence of three atoms a–b–c, of which a has a sextet of electrons in the outer shell and c has an octet with at least one unshared pair (see Table 15.3).²¹⁰⁵ The reaction can then be formulated as shown to generate 132. Note that the initial reaction of potassium permanganate (Reaction 15-48) occurs by [3 + 2]-cycloaddition to give a manganate ester (119).²¹⁰⁶ [3 + 2]-Cycloaddition occurs with other metal oxides.²¹⁰⁷ Hydrazones have also been reported to give [3 + 2]-cycloadditions.²¹⁰⁸

Table 15.3 Some Common 1,3-Dipolar Compounds.

1,3-Dipoles of the type shown in Table 15.3 have an atom with six electrons in the outer shell, which is usually unstable. Such compounds will delocalize the change to alleviate this electronic arrangement (they are resonance stabilized). 1,3-Dipolar compounds can be divided into two main types:

1. Those in which the dipolar canonical form has a double bond on the sextet atom and the other canonical form has a triple bond on that atom:

If the discussion is limited to the first row of the periodic table, b can only be nitrogen, c can be carbon or nitrogen, and a can be carbon, oxygen, or nitrogen; hence there are six types. Among these are azides (a = b = c = N) and diazoalkanes.

2. Those in which the dipolar canonical form has a single bond on the sextet atom and the other form has a double bond:

Here b can be nitrogen or oxygen, and a and c can be nitrogen, oxygen, or carbon, but there are only 12 types, since, for example, N–N–C is only another form of C–N–N. Examples are shown in Table 15.3.

Of the 18 systems, some of which are unstable and must be generated in situ,²¹¹⁷ the reaction has been accomplished for at least 15, but not in all cases with a carbon–carbon double bond (the reaction also can be carried out with other double bonds²¹¹⁸). Not all alkenes undergo 1,3-dipolar addition equally well. The reaction is most successful for those that are good dienophiles in the Diels–Alder Reaction (15-60).

The addition is stereospecific and syn, and the mechanism is probably a one-step concerted process,²¹¹⁹ as illustrated above,²¹²⁰ largely controlled by Frontier Molecular Orbital considerations.²¹²¹ Reactivity has been shown to correlate with the energy required to distort 1,3-dipole and dipolarophiles to the transition state.²¹²² In-plane aromaticity has been invoked for these dipolar cycloadditions.²¹²³ As expected for this type of mechanism, the rates do not vary much with changes in solvent,²¹²⁴ although rate acceleration has been observed in ionic liquids.²¹²⁵ Nitrile oxide cycloadditions have also been done in supercritical carbon dioxide.²¹²⁶ There are no simple rules covering orientation in 1,3-dipolar additions. The regioselectivity has been explained by MO treatments,²¹²⁷ where overlap of the largest orbital coefficients of the atoms forming the new bonds leads to the major regioisomer. When the 1,3-dipolar compound is a thiocarbonyl ylid (R₂C=S⁺–CH₂⁻) the addition has been shown to be nonstereospecific with certain substrates, but stereospecific with others, indicating a nonsynchronous mechanism in these cases, and in fact, a diionic intermediate (see mechanism c in Reaction 15-63, category 4) has been trapped in one such case.²¹²⁸ In a theoretical study of the 1,3-dipolar cycloadditions (diazomethane and ethene; fulminic acid [H–CN–O] and ethyne),²¹²⁹ calculations based on valence bond descriptions suggest that many concerted 1,3-dipolar cycloaddition reactions follow an electronic heterolytic mechanism where the movement of well-identifiable orbital pairs is retained along the entire reaction path from reactants to product.²¹³⁰

An antibody-catalyzed [3 + 2]-cycloaddition has been reported.²¹³¹ Metal-assisted dipolar additions are also known.²¹³² In a different metal-mediated reaction, alkenyl Fischer carbene complexes react with alkynes, in the presence of a Ni catalyst, to give cyclopentenones.²¹³³ Fischer carbene complexes take the form R₂C=M(CO)_x,²¹³⁴ and the metals include those of low oxidation state, and Fe, Mo, Cr, or W. Ligands include π-electron acceptors and π-donor substituents on methylene groups (e.g., alkoxy and amino groups).

Many of the cycloadducts formed from the dipoles in Table 15.3 are unstable, which lead to other products. The reaction of alkyl azides with alkenes generates triazolines (Reaction 15-54), which extrude nitrogen (NN) upon heating or photolysis to give an aziridine.²¹³⁵ With a transition metal catalyst, alkyl azides add to alkynes to give triazoles.²¹³⁶ Retro [3 + 2]-cycloaddition reactions are also known.²¹³⁷ Cycloaddition of azides to allenes leads to pyrrolidines.²¹³⁸

[3 + 2]-Cycloaddition reactions occur intramolecularly to generate bicyclic and polycyclic compounds.²¹³⁹ The intramolecular cycloaddition of azomethine imines give bicyclic pyrazolidines, for example.²¹⁴⁰ When diazoalkanes (including diazo acetates, e.g., ethyl diazoacetate, N₂CHCO₂Et) react with an alkene and a Cr catalyst the initially formed product is a five-membered ring, a pyrazoline.²¹⁴¹ Pyrazolines are generally unstable and extrusion of nitrogen leads to a cyclopropane.²¹⁴² Rhodium-catalyzed cycloaddition using chiral ligands leads to formation of cyclopropanes with good enantioselectivity.²¹⁴³

There are many cases where the [3 + 2]-cycloaddition leads to cycloadducts with high enantioselectivity.²¹⁴⁴ Cycloaddition of diazo esters with a Co catalyst having a chiral ligand leads to cyclopropane derivatives with good enantioselectivity.²¹⁴⁵ Cycloaddition of nitrones and pyrazolinones with a Cu catalyst and a chiral ligand leads to pyrrolidine derivatives with good enantioselectivity.²¹⁴⁶ In the presence of a Ni catalyst and a chiral ligand, nitrones react with activated cyclopropanes to give a tetrahydro-1,2-oxazine, with high enantioselectivity.²¹⁴⁷ Nitrones react with conjugated carbonyl compounds, with a transition metal catalyst (e.g., a Ti complex) to give an 1,2-oxazoline.²¹⁴⁸

Conjugated dienes generally give exclusive 1,2-addition, although 1,4-addition (a 3 + 4 cycloaddition) has been reported.²¹⁴⁹ Carbon–carbon triple bonds can also undergo 1,3-dipolar addition.²¹⁵⁰ For example, azides react to give triazoles, (133).

The 1,3-dipolar reagent can in some cases be generated by the in situ opening of a suitable three-membered ring system. For example, aziridines open to give a zwitterion (e.g., 134), which can add to activated double bonds to give pyrrolidines.²¹⁵¹

Aziridines also add to CC triple bonds, as well as to other unsaturated linkages, including C=O, C=N, and CN.²¹⁵² In some of these reactions, it is a C–N bond of the aziridine that opens rather than the C–C bond.

For other [3 + 2]-cycloadditions, see Reaction 15-59.

OS V, 957, 1124; VI, 592, 670; VIII, 231. Also see, OS IV, 380.

C. Carbon on Both Sides

Reactions 15-58–15-64 are cycloaddition reactions.²¹⁵³

15-59 All-Carbon [3 + 2]-Cycloadditions²¹⁵⁴

Several methods have been reported for the formation of cyclopentanes by [3 + 2]-cycloadditions.²¹⁵⁵ Heating conjugated ketones with trialkylphosphines generates an intermediate that adds to conjugated alkynes.²¹⁵⁶ One type involves reagents that produce intermediates 135 or 136.²¹⁵⁷ A synthetically useful example²¹⁵⁸ uses 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate (139), which is commercially available, and a Pd or other transition metal catalyst to generate 135 or 136, which adds to double bonds to give cyclopentanes

with an exocyclic double bond. The reaction occurs with 139 to generate trimethylenemethane in situ, which reacts with alkenes to give methylenecyclopentane derivatives.²¹⁵⁹ A similar reaction occurs with imines to give methylene pyrrolidines.²¹⁶⁰ The Pd catalyzed reaction with CO₂ leads to butenolides.²¹⁶¹

Note that 136 also reacts with N-tosyl aziridines, with 20% n-butyllithium and 10% of Pd(OAc)₂, to give a vinylidene piperidine derivative.²¹⁶² Similar or identical intermediates generated from bicyclic azo compounds 137 (see Reaction 17-34) or methylenecyclopropane (138)²¹⁶³ also add to activated double bonds. With suitable substrates the addition can be enantioselective.²¹⁶⁴

In a different type of procedure, [3 + 2]-cycloadditions are performed with allylic anions. Such reactions are called 1,3-anionic cycloadditions.²¹⁶⁵ For example, α-methylstyrene adds to stilbene on treatment with the strong base LDA.²¹⁶⁶

The mechanism can be outlined as:

In the case above, 140 is protonated in the last step by the acid HA, but if the acid is omitted and a suitable nucleofuge is present, it may leave, resulting in a cyclopentene.²¹⁶⁷ In these cases, the reagent is an allylic anion, but similar [3 + 2]-cycloadditions involving allylic cations have also been reported.²¹⁶⁸

OS VIII,173, 347.

15-60 The Diels–Alder Reaction

(4 + 2) cyclo- Ethylene-1/4/addition or (4 + 2)cyclo-[Bu t-2-ene-1,4-diyl]-1/2/addition, and so on

In the prototype Diels–Alder reaction, the double bond of an alkene adds 1,4- to a conjugated diene (a [4 + 2]-cycloaddition),²¹⁶⁹ so the product is always a cyclohexene. The cycloaddition is not limited to alkenes or to dienes (see Reaction 15-61), but the substrate that reacts with the diene is called a dienophile. The reaction is of very broad scope²¹⁷⁰ and reactivity of dienes and dienophiles can be predicted based on analysis of the HOMOs²¹⁷¹ and LUMOs of these species (FMO theory).²¹⁷² Ethylene and simple alkenes make poor dienophiles, unless high temperatures and/or pressures are used. Most dienophiles are of the form –C=C–Z or Z–C=C–Z′, where Z and Z′ are electron-withdrawing groups²¹⁷³ (e.g., CHO, COR,²¹⁷⁴ CO₂H, CO₂R, COCl, COAr, CN,²¹⁷⁵ NO₂,²¹⁷⁶ Ar, CH₂OH, CH₂Cl, CH₂NH₂, CH₂CN, CH₂CO₂H, halogen, PO(OEt)₂,²¹⁷⁷ or C=C). In the last case, the dienophile is itself a diene.²¹⁷⁸

The low reactivity of simple alkenes can be overcome by incorporating an electron-withdrawing group to facilitate the cycloaddition, as indicated above. Electron-withdrawing groups may be incorporated to facilitate the Diels–Alder reaction and then removed after cycloaddition. An example is phenyl vinyl sulfone (PhSO₂CH=CH₂),²¹⁷⁹ and the PhSO₂ group can be easily removed with Na–Hg after the ring-closure reaction. Similarly, phenyl vinyl sulfoxide (PhSOCH=CH₂) can be used as a synthon for acetylene.²¹⁸⁰ In this case, PhSOH is lost from the sulfoxide product (Reaction 17-12).

Electron-donating substituents in the diene accelerate the reaction; electron-withdrawing groups retard it.²¹⁸¹ For the dienophile, it is just the reverse: donating groups decrease the rate, and withdrawing groups increase it. The s-cis (cisoid) conformation is required for the cycloaddition,²¹⁸² and acyclic dienes are conformationally mobile so the s-cis conformation will be available.²¹⁸³ Cyclic dienes, in which the s-cis conformation is built in, usually react faster than the corresponding open-chain compounds, which have to achieve the s-cis conformation by rotation.²¹⁸⁴ Dienes can be open-chain, inner-ring (e.g., 141), outer-ring²¹⁸⁵ (e.g., 142), across rings (e.g., 143), or inner–outer (e.g., 145), except that they may not be frozen into a s-trans (transoid) conformation (see category 3). They need no special activating groups, and nearly all conjugated dienes undergo the reaction with suitable dienophiles.²¹⁸⁶

While Diels–Alder reactions generally require no catalyst, Lewis acids are effective catalysts,²¹⁸⁷ particularly those in which Z in the dienophile is a C=O or C=N group.²¹⁸⁸ Chemoselectivity is related to the choice of Lewis acid or Brnsted–Lowry acid catalyst.²¹⁸⁹ A Lewis acid catalyst usually increases both the regioselectivity of the reaction (in the sense given above) and the extent of endo addition,²¹⁹⁰ and, in the case of enantioselective reactions, the extent of enantioselectivity. Copper catalysts have been used.²¹⁹¹ Brnsted acids have also been used to accelerate the rate of the Diels–Alder reaction.²¹⁹² Diels–Alder reactions have been done in ionic liquids (see Sec. 9.D.iii).²¹⁹³Lanthanum triflate [La(OTf)₃] has been reported as a reusable catalyst²¹⁹⁴ and Me₃SiNTf₂ has been used as a green Lewis acid catalyst.²¹⁹⁵ Cationic Diels–Alder catalysts have been developed (e.g., oxazaborolidine catalysts).²¹⁹⁶Some Diels–Alder reactions can also be catalyzed by the addition of a stable cation radical,²¹⁹⁷ for example, tris(4-bromophenyl)aminium hexachloroantimonate (Ar₃N^•+ SbCl₆⁻).²¹⁹⁸ Zirconocene-catalyzed cationic Diels–Alder reactions are known.²¹⁹⁹ Certain antibodies have been developed that catalyze Diels–Alder reactions.²²⁰⁰ Photochemically induced Diels–Alder reactions are also known.²²⁰¹

A number of other methods have been reported for the acceleration of Diels–Alder reactions,²²⁰² including the use of microwave irradiation,²²⁰³ ultrasound,²²⁰⁴ absorption of the reactants on chromatographic absorbents,²²⁰⁵ via encapsulation techniques,²²⁰⁶ and the use of an ultracentrifuge²²⁰⁷ (one of several ways to achieve reaction at high pressures).²²⁰⁸ Solid-state Diels–Alder reactions are known.²²⁰⁹ One of the most common methods is to use water as a solvent or a cosolvent (a hydrophobic effect).²²¹⁰ Catalysts have been developed for aq Diels–Alder reactions²²¹¹ that are suitable for ionic Diels–Alder reactions.²²¹² There are cases of hydrogen-bonding acceleration.²²¹³ The influence of the hydrophobicity of reactants on the reaction has been examined,²²¹⁴ as has micellular effects.²²¹⁵ Another alternative reaction medium is the use of 5M LiClO₄ in Et₂O as solvent.²²¹⁶ An alternative to lithium perchlorate in ether is lithium triflate in acetonitrile.²²¹⁷ The addition of HPO₄⁻ to an aq ethanol solution has also been shown to give a small rate enhancement.²²¹⁸ This appears to be the only case where an anion is responsible for a rate enhancement. The retro-Diels–Alder reaction has also been done in water.²²¹⁹

Note that Diels–Alder reactions have been done with supercritical carbon monoxide²²²⁰ and with supercritical water²²²¹ as solvents. Diels–Alder reactions on solid supports also have been reported,²²²² and zeolites have been used in conjunction with catalytic agents.²²²³ Alumina has been used to promote Diels–Alder reactions.²²²⁴ Diels–Alder reactions can be done in ionic liquids,²²²⁵ including asymmetric Diels–Alder reactions.²²²⁶ Note that the rate of Diels–Alder reactions is faster in water than in ionic liquids.²²²⁷

When an unsymmetrical diene adds to an unsymmetrical dienophile, regioisomeric products (not counting stereoisomers) are possible. Rearrangements have been encountered in some cases.²²²⁸ In simple cases, 1-substituted dienes give cyclohexenes with a 1,2- and a 1,3- substitution pattern. 2-Substituted dienes lead to 1,4- and 1,3-disubstituted products.

Although mixtures are often obtained, one usually predominates (the one shown lowed major above), but selectivity depends on the nature of the substituents on both diene and alkene. This regioselectivity, in which the “ortho” or “para” product is favored over the “meta”, has been explained by molecular orbital considerations.²²²⁹ When X = NO₂, regioselectivity to give the “ortho” or “para” product was very high at room temperature. This method, combined with subsequent removal of the NO₂ (see Reaction 19-67), has been used to perform regioselective Diels–Alder reactions.²²³⁰ Competing reactions are polymerization of the diene or dienophile, or both, and [1,2]-cycloaddition (15-63).

The stereochemistry of the Diels–Alder reaction can be considered from several aspects:²²³¹

1. With respect to the dienophile, the addition is stereospecifically syn, with very few exceptions.²²³² This means that groups that are cis in the alkene will be cis in the cyclohexene ring (A–B and C–D) and groups that are trans in the alkene will be trans in the cyclohexene ring (A–D and C–B).

2. With respect to 1,4-disubstituted dienes, fewer cases have been investigated, but here too the reaction is stereospecific and syn. Thus, trans,trans-1,4-diphenylbutadiene gives cis-1,4-diphenylcyclohexene derivatives. This selectivity is predicted by disrotatory motion of the substituent in the transition state²²³³ of the reaction (see 18-27).

3. The diene must be in the s-cis conformation. If it is frozen into the s-trans conformation, as in 144, the reaction does not take place. The diene either must be frozen into the s-cis conformation or must be able to achieve it during the reaction.

4. There are two possible ways in which addition can occur to a cyclic diene, if the dienophile is not symmetrical: say a monosubstituted alkene. The substituent on the dienophile (usually an electron-withdrawing substituent) may approach under the ring (endo addition), or away from the ring (exo addition):

Most of the time, the addition is predominantly endo; that is, the more bulky side of the alkene is under the ring, and this is probably true for open-chain dienes also.²²³⁴ However, exceptions are known, and in many cases mixtures of exo and endo addition products are found.²²³⁵ An imidazolidone catalyst was used to give a 1:1.3 mixture favoring the exo isomer in a reaction of conjugated aldehydes and cyclopentadiene.²²³⁶ Secondary orbital interactions.²²³⁷ have been invoked, but this approach has been called into question.²²³⁸ There has been a direct evaluation of such interactions, however.²²³⁹ It has been argued that facial selectivity is not due to torsional angle decompression.²²⁴⁰ The endo/exo ratio can be influenced by the nature of the solvent.²²⁴¹

5. As seen previously, the Diels–Alder reaction can be both stereoselective and regioselective.²²⁴² In some cases, the Diels–Alder reaction can be made enantioselective,²²⁴³ as described above. Solvent effects are important in such reactions.²²⁴⁴ The role of reactant polarity on the course of the reaction has been examined.²²⁴⁵ Most enantioselective Diels–Alder reactions have used a chiral dienophile (e.g., 145) and an achiral diene,²²⁴⁶ along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two

faces²²⁴⁷ of 145 takes place at different rates, and 146 and 147 are formed in different amounts.²²⁴⁸ An achiral compound can be converted to a chiral compound by a chemical reaction with a compound that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between the molecule of interest and chiral compound (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels–Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst.²²⁴⁹ Many chiral catalysts have been developed.²²⁵⁰ In many cases, asymmetric Lewis acids form a chiral complex with the dienophile.²²⁵¹ Chiral organocatalysts are increasingly important.²²⁵²

Triple bond compounds (–CC–Z or Z–CC–Z′) may be dienophiles,²²⁵³ generating nonconjugated cyclohexadienes (148). This reaction can be catalyzed by transition metal compounds.²²⁵⁴ Aromatic rings can be generated by cycloaddition of aryl alkynes.²²⁵⁵ Allenes react as dienophiles, but without activating groups are very poor dienophiles.²²⁵⁶ Ketenes, however, do not undergo Diels–Alder reactions.²²⁵⁷

Many interesting compounds can be prepared by the Diels–Alder reaction,²²⁵⁸ some of which would be hard to make in any other way. Some aromatic compounds can behave as dienes,²²⁵⁹ but benzene is very unreactive toward dienophiles,²²⁶⁰ and very few dienophiles (one of them is benzyne) have been reported to give Diels–Alder adducts with it.²²⁶¹ Benzynes (e.g., 149), although not isolable, act as dienophiles and can be trapped with dienes.²²⁶² The interesting compound triptycene can be prepared by a Diels–Alder reaction between benzyne and anthracene.²²⁶³ Naphthalene and phenanthrene are poor reaction partners, although naphthalene has given Diels–Alder addition at high pressures.²²⁶⁴ Anthracene and other compounds with at least three linear benzene rings give Diels–Alder reactions readily.

For both all-carbon and hetero systems, the “diene” can be a conjugated enyne. If the geometry of the molecule is suitable, the diene can even be nonconjugated, for example,²²⁶⁵

This last reaction is known as the homo-Diels–Alder reaction. A similar reaction has been reported with alkynes, using a mixture of a Co complex, ZnI₂, and tetrabutylammonium borohydride.²²⁶⁶

Intramolecular versions of the Diels–Alder reaction are well known,²²⁶⁷and this is a powerful method for the synthesis of mono- and polycyclic compounds.²²⁶⁸ There are many examples and variations, including Lewis acid catalysis.²²⁶⁹ The origin of cis/trans stereoselectivity has been examined using density functional theory.²²⁷⁰

Internal Diels–Alder reactions can be viewed as linking the diene and alkene by a tether, usually of carbon atoms. Dienophile twisting and substituent effects influence the rate of cycloaddition.²²⁷¹ If the tether is replaced by functional groups that allow the selectivity inherent to the intramolecular cycloaddition, but can be cleaved afterward, a powerful modification is available. Indeed, such tethered cycloaddition reactions are increasingly common. After cycloaddition, the tether can be cleaved to give a functionalized cyclohexene derivative. Such tethered reactions allow enhancement of stereoselectivity²²⁷² and sometimes reactivity, relative to an untethered reaction, giving an indirect method for enhancing those parameters. Tethers or linkages include C–O–SiR₂–C²²⁷³ or a C–O–SiR₂–O–C,²²⁷⁴ or hydroxamides.²²⁷⁵ The nature of the tether plays a role in cis/trans selectivity for the intramolecular reaction.²²⁷⁶ Transient tethers can be used, as in the reaction of a diene having an allylic alcohol unit in a reaction with allyl alcohol, with AlMe₃ to give the cycloadduct with good selectivity.²²⁷⁷

The Diels–Alder reaction is usually reversible, although the retro reaction typically occurs at significantly higher temperatures than the forward reaction. However, the reaction is reversible²²⁷⁸ and this fact has been used. A convenient substitute for butadiene in the Diels–Alder reaction is the compound 3-sulfolene, since the latter is a solid, which is easy to handle while the former is a gas.²²⁷⁹ Butadiene is generated in situ by a reverse Diels–Alder reaction (see 17-20).

There are, broadly speaking, three possible mechanisms that have been considered for the uncatalyzed Diels–Alder reaction.²²⁸⁰ In mechanism a, there is a cyclic six-centered transition state and no intermediate. The reaction is concerted and occurs in one step. In mechanism b, one end of the diene fastens to one end of the dienophile first to give a diradical, and then, in a second step, the other ends become fastened.²²⁸¹ A diradical formed in this manner must be a singlet; that is, the two unpaired electrons must have opposite spins, by an argument similar to that outlined in Section 5.C.i. The third mechanism (c, not shown) is similar to mechanism b, but the initial bond and the subsequent bond are formed by movements of electron pairs and the intermediate is a diion. Electrophilicity–nucleophilicity indices have been analyzed to understand the mechanism of polar Diels–Alder reactions.²²⁸² There have been many mechanistic investigations of the Diels–Alder reaction. The bulk of the evidence suggests that most Diels–Alder reactions take place by the one-step cyclic mechanism a,²²⁸³ although it is possible that a diradical²²⁸⁴ or even a diion²²⁸⁵ mechanism may be taking place in some cases. Radical cation Diels–Alder reactions have been considered.²²⁸⁶ The main evidence in support of mechanism a is as follows: (1) the reaction is stereospecific in both the diene and dienophile. A completely free diradical or diion probably would not be able to retain its configuration. (2) In general, the rates of Diels–Alder reactions depend very little on the nature of the solvent. This would rule out a diion intermediate because polar solvents increase the rates of reactions that develop charges in the transition state. (3) It was shown that, in the decomposition of 150, the isotope effect k_I/k_II was equal to 1.00 within experimental error.²²⁸⁷ If bond x were

to break before bond y, there should surely be a secondary isotope effect. This result strongly indicates that the bond breaking of x and y is simultaneous. This is the reverse of a Diels–Alder reaction, and by the principle of microscopic reversibility, the mechanism of the forward reaction should involve simultaneous formation of bonds x and y. Subsequently, a similar experiment was carried out on the forward reaction²²⁸⁸ and the result was the same. There is other evidence for mechanism a.²²⁸⁹ However, the fact that the mechanism is concerted does not necessarily mean that it is synchronous.²²⁹⁰ In the transition state of a synchronous reaction both new σ bonds would be formed to the same extent, but a Diels–Alder reaction with nonsymmetrical components might very well be nonsynchronous;²²⁹¹ that is, it could have a transition state in which one bond has been formed to a greater degree than the other.^2291,2292 A biradical mechanism has been proposed for some Diels–Alder reactions.²²⁹³

In another aspect of the mechanism, the effects of electron-donating and electron-withdrawing substituents (see above) indicate that the diene behaves as a nucleophile and the dienophile as an electrophile. However, this can be reversed. Perchlorocyclopentadiene reacts better with cyclopentene than with maleic anhydride and not at all with tetracyanoethylene, although the latter is normally the most reactive dienophile known. This diene is said to be the electrophile in its Diels–Alder reactions.²²⁹⁴ Reactions of this type are said to proceed with inverse electron demand.²²⁹⁵ It is known that alkynylboronates participate in inverse electron demand cyclization.²²⁹⁶

The Diels–Alder reaction generally takes place rapidly and conveniently. In sharp contrast, the apparently similar dimerization of alkenes to cyclobutanes (Reaction 15-63) gives very poor results in most cases, except when photochemically induced. Woodward and Hoffmann²²⁹⁷ showed that these contrasting results can be explained by the principle of conservation of orbital symmetry, which predicts that certain reactions are allowed and others are forbidden. The orbital-symmetry rules (also called the Woodward–Hoffmann rules)²²⁹⁸ apply only to concerted reactions (e.g., mechanism a) and are based on the principle that reactions take place in such a way as to maintain maximum bonding throughout the course of the reaction. In a separate work, Fukui used MO arguments to explain these reactions. There are several ways of applying the orbital-symmetry principle to cycloaddition reactions, three of which are used more frequently than others.²²⁹⁹ Of these three, two will be discussed: the FMO and the Möbius–Hückel method. The third, called the correlation-diagram method,²³⁰⁰ is less convenient to apply than the other two.

The Frontier-Orbital Method²³⁰¹

As applied to cycloaddition reactions, the rule is that reactions are allowed only when all overlaps between the HOMO of one reactant and the LUMO of the other are such that a positive lobe overlaps only with another positive lobe and a negative lobe only with another negative lobe.²³⁰² Recall that monoalkenes have two π molecular orbitals (Sec. 1.D) and that conjugated dienes have four (Sec. 2.C), as shown in Fig. 15.2. A concerted cyclization of two monoalkenes (a [2 + 2] reaction) is not allowed because it would require that a positive lobe overlap with a negative lobe (Fig. 15.3). On the other hand, the Diels–Alder reaction (a [4 + 2] reaction) is allowed, when considered from either direction (Fig. 15.4).

Fig. 15.2 Schematic drawings of the π orbitals of an isolated C=C bond and a conjugated diene

Fig. 15.3 Overlap of orbitals in a thermal [2 + 2]-cycloaddition

Fig. 15.4 Two ways for orbitals to overlap in a thermal [4 + 2]-cycloaddition

These considerations are reversed when the ring closures are photochemically induced, since in such cases an electron is promoted to a vacant orbital before the reaction occurs. Obviously, the [2 + 2] reaction is now allowed (Fig. 15.5) and the [4 + 2]-reaction is disallowed. The reverse reactions follow the same rules, by the principle of microscopic reversibility. In fact, Diels–Alder adducts are usually cleaved quite readily, while cyclobutanes, despite the additional strain, require more strenuous conditions.

Fig. 15.5 Overlap of orbitals in a photochemical [2 + 2]-cycloaddition

The Möbius–Hückel Method²³⁰³

In this method, the orbital symmetry rules are related to the Hückel aromaticity rule discussed in Chapter 2.²³⁰⁴ Hückel's rule, which states that a cyclic system of electrons is aromatic (hence, stable) when it consists of 4n + 2 electrons, applies of course to molecules in their ground states. In applying the orbital symmetry principle, we are not concerned with ground states, but with transition states. In the present method, do not examine the molecular orbitals themselves, but rather the p orbitals before they overlap to form the molecular orbitals. Such a set of p orbitals is called a basis set (Fig. 15.6). In investigating the possibility of a concerted reaction, the basis sets are put into the position they would occupy in the transition state. Figure 15.7 shows this for both the [2 + 2] and the [4 + 2] ring closures, looking for sign inversions. In Fig. 15.7, there are no sign inversions in either case. That is, the dashed line connects only lobes with a minus sign. Systems with zero or an even number of sign inversions are called Hückel systems. Because they have no sign inversions, both of these systems are Hückel systems. Systems with an odd number of sign inversions are called Möbius systems (because of the similarity to the Möbius strip, which is a mathematical surface, shown in Fig. 15.8).²³⁰⁵ Möbius systems do not enter into either of these reactions, but an example of such a system is shown in Reaction 18.-28, B. Double-twist Möbius aromaticity has been invoked in the Diels–Alder transition state for the reaction of a 5,6-di-tert-butyl substituted decapentaene.²³⁰⁶

Fig. 15.6 Some basis sets

Fig. 15.7 Transition states illustrating Hückel–Möbius rules for cycloaddition reactions

Fig. 15.8 A Möbius strip. Such a strip is easily constructed by twisting a thin strip of paper 180° and fastening the ends together

The rule may then be stated: A thermal pericyclic reaction involving a Hückel system is allowed only if the total number of electrons is 4n + 2. A thermal pericyclic reaction involving a Möbius system is allowed only if the total number of electrons is 4n. For photochemical reactions, these rules are reversed. Since both the [4 + 2]- and [2 + 2]-cycloadditions are Hückel systems, the Möbius–Hückel method predicts that the [4 + 2]-reaction, with 6 electrons, is thermally allowed, but the [2 + 2]-reaction is not. One the other hand, the [2 + 2] -reaction is allowed photochemically, while the [4 + 2]-reaction is forbidden.

Note that both the [2 + 2] and [4 + 2] transition states are Hückel systems no matter what basis sets were chosen. For example, Fig. 15.9 shows other basis sets we might have chosen. In every case there will be zero or an even number of sign inversions.

Fig. 15.9 Transition states of {2 + 2] - and [4 + 2]-cyclizations involving other basis sets

Thus, the FMO and Hückel–Möbius methods (and the correlation-diagram method as well) lead to the same conclusions: Thermal [4 + 2]-cycloadditions and photochemical [2 + 2]-cycloadditions (and the reverse ring openings) are allowed, while photochemical [4 + 2]- and thermal [2 + 2]-ring closings (and openings) are forbidden.

Application of the same procedures to other ring closures shows that [4 + 4]- and [2 + 6]-ring closures and openings require photochemical induction while the [4 + 6]- and [2 + 8]-reactions can take place only thermally (see Reaction 15-53). In general, cycloaddition reactions allowed thermally are those with 4n + 2 electrons, while those allowed photochemically have 4n electrons.

It must be emphasized once again that the rules apply only to cycloaddition reactions that take place by cyclic mechanisms, which is where two σ bonds are formed (or broken) at about the same time.²³⁰⁷ The rule does not apply to cases where one bond is clearly formed (or broken) before the other. It must further be emphasized that the fact that the thermal Diels–Alder reaction (mechanism a) is allowed by the principle of conservation of orbital symmetry does not constitute proof that any given Diels–Alder reaction proceeds by this mechanism. The principle merely says the mechanism is allowed, not that it must go by this pathway. However, the principle does say that thermal [2 + 2]-cycloadditions in which the molecules assume a face-to-face geometry cannot²³⁰⁸ take place by a cyclic mechanism because their activation energies would be too high (however, see below). In Reaction 15-62 it will be seen that such reactions largely occur by two-step mechanisms. Similarly, [4 + 2]-photochemical cycloadditions are also known, but the fact that they are not stereospecific indicates that they also take place by the two-step diradical mechanism (mechanism b).²³⁰⁹

In all of the above discussions, it has been assumed that a given molecule forms both the new σ bonds from the same face of the π system. This manner of bond formation, called suprafacial, is certainly most reasonable and almost always takes place. The subscript s is used to designate this geometry, and a normal Diels–Alder reaction would be called a [_π2_s + _π4_s]-cycloaddition (the subscript π indicates that π electrons are involved in the cycloaddition). However, there is another approach in which the newly forming bonds of the diene lie on opposite faces of the π system, that is, they point in opposite directions. This type of orientation of the newly formed bonds is called antarafacial, and the reaction would be a [_π2_s + _π4_s]-cycloaddition (a stands for antarafacial). The FMO method shows that this reaction (and consequently the reverse ring-opening reactions) are thermally forbidden and photochemically allowed. Thus in order for a [_π2_s + _π4_a] reaction to proceed, overlap between the highest-occupied π orbital of the alkene and the lowest-unoccupied π orbital of the diene would have to occur as shown in Fig. 15.10, with a + lobe overlapping a −lobe. Since like signs are no

longer overlapping, the thermal reaction is now forbidden. Similarly, thermal [[_π4_s + _π2_a] and [_π2_s + _π4_a]-cyclizations are forbidden, while thermal [π4a + π2a]- and [_π2_s + _π2_a]-cyclizations are allowed. These considerations are reversed for the corresponding photochemical processes. Of course, an antarafacial approach is highly unlikely in a [4 + 2]-cyclization,²³¹⁰ but larger ring closures could take place by such a pathway, and [2 + 2] -thermal cyclizations, where the [[_π2_s + _π2_s]-pathway is forbidden, can also do so in certain cases (see Reaction 15-63). Whether a given cycloaddition is allowed or forbidden depends on the geometry of approach of the two molecules involved.

Fig. 15.10 Overlap of orbitals in an antarafacial thermal [4 + 2]-cycloaddition

Symmetry considerations have also been advanced to explain predominant endo addition.²³¹¹ In the case of [4 + 2]-addition of butadiene to acrolein, the approach can be exo or endo. It can be seen (Fig. 15.11) that whether the HOMO of the diene overlaps with the LUMO of acrolein or vice versa, the endo orientation is stabilized by additional secondary overlap of orbitals²³¹² of like sign (dashed lines between heavy dots). Addition from the exo direction has no such stabilization since the sign of the orbitals do not match. Evidence for secondary orbital overlap as the cause of predominant endo orientation, at least in some cases, is that [4 + 6]-cycloaddition is predicted by similar considerations to proceed with predominant exo orientation, and that is what is found.²³¹³ However, this explanation does not account for endo orientation in cases where the dienophile does not possess additional π orbitals, and a number of alternative explanations have been offered.²³¹⁴

Fig. 15.11 Overlap of orbitals in [4 + 2]-cycloaddition of 1,3-butadiene with acrolein

OS II, 102; III, 310, 807; IV, 238, 738, 890, 964; V, 414, 424, 604, 985, 1037; VI, 82, 196, 422, 427, 445, 454; VII, 4, 312, 485; VIII, 31, 38, 298, 353, 444, 597; IX, 186, 722; 75, 201; 81, 171. For a reverse Diels–Alder reaction, see OS VII, 339.

15-61 Heteroatom Diels–Alder Reactions

Alkenes, alkynes, and dienes are not the only units that can participate in Diels–Alder reactions. Other double- and triple-bond compounds can be dienophiles and they give rise to heterocyclic compounds.²³¹⁵ Among these are NC–, –N=C–,²³¹⁶ iminium salts,²³¹⁷ –N=N–, O=N–,²³¹⁸ and –C=O compounds,²³¹⁹ and even molecular oxygen (Reaction 15-62). Several catalysts can be used, depending on the nature of the heteroatoms incorporated into the alkene or diene.²³²⁰ Intramolecular cycloaddition with a diene–imine substrate leads to pyrrolidines.²³²¹

Aldehydes react with suitably functionalized dienes (e.g., 151), known as Danishefsky's diene,²³²² and the reaction usually requires a Lewis acid catalyst (e.g., lanthanide compounds).²³²³ The Diels–Alder reaction of aldehydes with dienes can be catalyzed by many transition metal compounds, including Co²³²⁴ and In²³²⁵ catalysts. Aldehydes react using a chiral Ti²³²⁶ or a Zr²³²⁷ catalyst to give the dihydropyran with good enantioselectivity. Copper(I) catalysts have been used as well.²³²⁸ Note that the reaction of Danishefsky's diene with an imine,²³²⁹ formed in situ by reaction of an aryl aldehyde and an aniline derivative, proceeds without a Lewis acid.²³³⁰ Ketones also react with suitably functionalized dienes.²³³¹ Indium trichloride (InCl₃) is a good catalyst for imino-Diels–Alder reactions.²³³² Hetero-Diels–Alder reactions involving carbonyls have been done in water.²³³³ Ultrasound has been used to promote the Diels–Alder reactions of 1-azadienes.²³³⁴ Polymer-supported dienes have been used.²³³⁵

Hetero-Diels–Alder reactions that proceed with good-to-excellent asymmetric induction are well known.²³³⁶ Asymmetric Diels–Alder reactions of carbonyl compounds are well known.²³³⁷ Chiral 1-aza-dienes have been developed as substrates, for example.²³³⁸ Azadienes also react with chiral dienophiles.²³³⁹ Chiral catalysts have been developed.²³⁴⁰

Dienes related to 151 are known, and their reactivity has been examined. Amino-substituted dienes undergo what is known as hydrogen-bonding catalyzed reactions.²³⁴¹ Imines react with other substrates (e.g., allenes), to give tetrahydropyridine derivatives, with good enantioselectivity in the presence of a chiral ligand.²³⁴² Azo compounds (–N=N–) react as dienophiles in the presence of an Ag catalyst.²³⁴³ Iminium ions undergo Diels–Alder cycloaddition.²³⁴⁴

Azadienes undergo Diels–Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives.²³⁴⁵ Aza-Diels–Alder reactions have been done in ionic liquids.²³⁴⁶ Similarly, acyl iminium salts (C=N(R)–C=O) react with alkenes via cycloaddition.²³⁴⁷ N-Vinyl lactim ethers undergo Diels–Alder reactions with a limited set of dienophiles.²³⁴⁸ Brnsted acids can catalyze inverse electron demand aza-Diels–Alder reactions.²³⁴⁹

Thioketones react with dienes to give Diels–Alder cycloadducts.²³⁵⁰ The carbonyl group of lactams has also been shown to be a dienophile.²³⁵¹ Certain heterocyclic aromatic rings (among them furans)²³⁵² can also behave as dienes in the Diels–Alder reaction. Some hetero dienes that give the reaction are –C=C–C=O, O=C–C=O, and N=C–C=N.²³⁵² Nitroso compounds of the type t-BuO₂C-N=O react with dienes to give the corresponding 2-azadihydropyran.²³⁵³ Conjugated aldehydes react with vinyl ethers, with a chiral Cr catalyst, in an inverse electron demand cycloaddition that give a dihydropyran with good enantioselectivity.²³⁵⁴ Vinyl sulfilimines have been used in chiral Diels–Alder reactions.²³⁵⁵

OS IV, 311; V, 60, 96; 80, 133. See also, OS VII, 326.

15-62 Photooxidation of Dienes (Addition of Oxygen, Oxygen)

[4 + 2] OC,OC-cyclo-Peroxy-1/4/addition

Conjugated dienes react with oxygen under the influence of light to give cyclic peroxides (152).²³⁵⁶ The reaction has mostly²³⁵⁷ been applied to cyclic dienes.²³⁵⁸ Cycloaddition of furan has been reported using singlet oxygen.²³⁵⁹The scope extends to certain aromatic compounds (e.g., phenanthrene).²³⁶⁰ Besides those dienes and aromatic rings that can be photooxidized directly, there is a larger group that gives the reaction in the presence of a photosensitizer (see Sec. 7.A.vi, category 5; e.g., eosin, a red xanthene dye). Among these is α-terpinene, which is converted to ascaridole:

As in Reaction 14-7, it is not the ground-state oxygen (the triplet), that reacts, but the excited singlet state,^2361,2362 so the reaction is actually a Diels–Alder reaction (see Reaction 15-60) with singlet oxygen as dienophile:²³⁶³

Like Reaction 15-60, this reaction is reversible.

As previously discussed, the reaction of singlet oxygen with double-bond compounds gives hydroperoxides (Reaction 14-7), but singlet oxygen can also react with double bonds in another way to give a dioxetane intermediate²³⁶⁴(Reaction 153), which usually cleaves to aldehydes or ketones,²³⁶⁵ but has been isolated.²³⁶⁶ Both the six-membered cyclic peroxides²³⁶⁷ and the four-membered 205²³⁶⁸ have been formed from oxygenation reactions that do not involve singlet oxygen. If cyclic peroxides (e.g., 205) are desired, better reagents²³⁶⁹ are triphenyl phosphite ozonide [(PhO)₃PO₃] and triethylsilyl hydrotrioxide [(Et₃SiOOOH)], but yields are not high.²³⁷⁰

15-63 [2 + 2]-Cycloadditions

[2 + 2]cyclo-Ethylene-1/2/addition

Two alkene molecules react under thermal conditions to give cyclobutane derivatives in what is known as a [2 + 2]-cycloaddition. The cycloaddition occurs when the alkenes are the same or different, but the reaction is not general for all alkenes.²³⁷¹ Certain transition metal complexes can catalyze the cycloaddition.²³⁷² Benzynes undergo cycloaddition to give biphenylene derivatives (154),²³⁷³ activated alkenes (e.g., styrene, acrylonitrile, butadiene), and certain methylenecyclopropanes.²³⁷⁴ Alkenes react with alkynes²³⁷⁵ or with activated alkynes, with a Ru catalyst, to give cyclobutenes.²³⁷⁶ Dimerization of allenes leads to bis(alkylidene) cyclobutanes.²³⁷⁷ Substituted ketenes can dimerize to give cyclobutenone derivatives, although ketene itself dimerizes in a different manner, to give an unsaturated β-lactone (Reaction 16-95).²³⁷⁸

Intramolecular [2 + 2]-cycloadditions are common in which a diene is converted to a bicyclic compound with a four-membered ring fused to another ring. Transition metal catalyzed reactions have been reported, including the use of Fe complexes.²³⁷⁹ Heating N-vinyl imines, where the vinyl moiety is a silyl enol, gives β-lactams.²³⁸⁰ Apart from photochemical initiation of such reactions (see below), intramolecular cycloaddition of two conjugated ketone units, in the presence of PhMeSiH₂ and catalyzed by Co compounds, leads to the bicyclic compound with two ketone substituents.²³⁸¹ In a variation of this reaction, a diyne was treated with Ti(OiPr)₄/2 iPrMgCl to generate a bicyclic cyclobutene with two vinylidene units.²³⁸²

Ketenes react with many alkenes to give cyclobutanone derivatives²³⁸³ and intermolecular cycloadditions are well known.²³⁸⁴ A typical reaction of dimethylketene and ethene gives 2,2-dimethylcyclobutanone, as shown.²³⁸⁵Ketenes react with imines via [2 + 2]-cycloaddition to produce β-lactams.²³⁸⁶ Cycloaddition of an imine with a conjugated ester in the presence of Et₃MeSiH and an Ir catalyst also gives a β-lactam.²³⁸⁷ See Reaction 19-66 for a discussion of reactions that give β-lactams.

Different alkenes combine as follows:

1. F₂C=CX₂ (X = F or Cl), especially F₂C=CF₂, form cyclobutanes with many alkenes. Compounds of this type even react with conjugated dienes to give four-membered rings rather than undergoing normal Diels–Alder reactions.²³⁸⁸

2. Allenes²³⁸⁹ and ketenes²³⁹⁰ react with activated alkenes and alkynes. Ketenes give 1,2-addition, even with conjugated dienes.²³⁹¹ Ketenes also add to unactivated alkenes if sufficiently long reaction times are used.²³⁹² Allenes and ketenes also add to each other.²³⁹³

3. Enamines²³⁹⁴ form four-membered rings with Michael-type alkenes²³⁹⁵ and ketenes.²³⁹⁶ In both cases, only enamines from aldehydes give stable four-membered rings:

Generating the ketene in situ from an acyl halide and a tertiary amine is a convenient way to carry out the reaction of enamines with ketenes.

4. Alkenes with electron-withdrawing groups may form cyclobutanes with alkenes containing electron-donating groups.²³⁹⁷ The enamine reactions, mentioned above, are examples of this, but it has also been accomplished with tetracyanoethylene and similar molecules, which give substituted cyclobutanes when treated with alkenes of the form C=C–A, where A may be OR,²³⁹⁸ SR (enol and thioenol ethers),²³⁹⁹ cyclopropyl,²⁴⁰⁰ or certain aryl groups.²⁴⁰¹

Enantioselective [2 + 2]-cycloaddition reactions are known. Chiral organocatalysts lead to chiral cyclobutane derivatives.²⁴⁰²

Solvents are not necessary for [2 + 2]-cycloadditions. They can be carried out at 100–225 °C under pressure, although the reactions in Group 4 occur under milder conditions. However, the choice of solvent can control the distribution of products in photochemical [2 + 2]-cycloaddition.²⁴⁰³

It has been found that certain [2 + 2]-cycloadditions that do not occur thermally can be made to take place without photochemical initiation using certain catalysts, usually transition metal compounds.²⁴⁰⁴ Among the catalysts used are Lewis acids²⁴⁰⁵ and phosphine–Ni complexes.²⁴⁰⁶ The role of the catalyst is not certain and may be different in each case. One possibility is that the presence of the catalyst causes a forbidden reaction to become allowed, through coordination of the catalyst to the π or s bonds of the substrate.²⁴⁰⁷ In such a case, the reaction would of course be a concerted [2_s + 2_s] process.²⁴⁰⁸ However, the available evidence is more consistent with nonconcerted mechanisms involving metal–carbon σ-bonded intermediates, at least in most cases.²⁴⁰⁹ For example, such an intermediate was isolated in the dimerization of norbornadiene, catalyzed by Ir complexes.²⁴¹⁰ Photochemical²⁴¹¹ [_π2 + _s2]-cycloadditions have also been reported. Visible light mediates cycloaddition in the presence of a Rh catalyst.²⁴¹² Some reverse cyclobutane ring openings can also be catalytically induced (Reaction 18-38).

Thermal cycloadditions leading to four-membered rings can also take place between a cyclopropane ring and an alkene or alkyne²⁴¹³ bearing electron-withdrawing groups.²⁴¹⁴ These reactions are [_π2 + _s2]-cycloadditions. Ordinary cyclopropanes do not undergo the reaction, but it has been accomplished with strained systems (e.g., bicyclo[1.1.0]butanes²⁴¹⁵ and bicyclo[2.1.0]pentanes). For example, bicyclo[2.1.0]pentane reacts with maleonitrile (or fumaronitrile) to give all three isomers of 2,3-dicyanonorbornane, as well as four other products.²⁴¹⁶ The lack of stereospecificity and the negligible effect of solvent on the rate indicate a diradical mechanism.

If dienes are involved in the reaction, the Diels–Alder reaction may compete, although most alkenes react with a diene either entirely by 1,2- or entirely by 1,4-addition. Three mechanisms have been proposed for [2 + 2]-cycloaddition.²⁴¹⁷