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

Chapter 12. Aliphatic, Alkenyl, and Alkynyl Substitution, Electrophilic and Organometallic

12.C. Reactions

The reactions in this chapter are arranged in order of leaving group: hydrogen, metals, halogen, and carbon. Electrophilic substitutions at a nitrogen atom are treated last.

12.C.i. Hydrogen as Leaving Group

A. Hydrogen as the Electrophile

12-1 Hydrogen Exchange

Deuterio-de-hydrogenation or Deuteriation

Hydrogen exchange can be accomplished by treatment with acids or bases. As with Reaction 11-1, the exchange reaction is mostly used to study mechanistic questions (e.g., relative acidities), but it can be used synthetically to prepare deuterated or tritiated molecules. When ordinary strong acids (e.g., H₂SO₄) are used, only fairly acidic protons on carbon can exchange (e.g., acetylenic and allylic). However, primary, secondary, and tertiary hydrogen atoms of alkanes can be exchanged by treatment with superacids (Sec. 5.A.ii).⁴⁸ The order of hydrogen reactivity is tertiary > secondary > primary. Where C–C bonds are present, they may be cleaved also (Reaction 12-47). The mechanism of the exchange (illustrated for methane) has been formulated as involving attack of H⁺ on the C–H bond to give the pentavalent methanonium ion, which loses

H₂ to give a tervalent carbocation.⁴⁹ The methanonium ion (CH₅⁺) has a three-center, two-electron bond.⁵⁰ It is not known whether the methanonium ion is a transition state or a true intermediate, but an ion (CH₅⁺) has been detected in the mass spectrum.⁵¹ The IR spectrum of the ethanonium ion (C₂H₇⁺) has been measured in the gas phase.⁵² Note that the two electrons in the three-center, two-electron bond can move in three directions, in accord with the threefold symmetry of such a structure. The electrons can move to unite the two hydrogen atoms, leaving the CH₃⁺ free (the forward reaction), or they can unite the CH₃ with either of the two hydrogen atoms, leaving the other hydrogen as a free H⁺ ion (the reverse reaction). Actually, the methyl cation is not stable under these conditions. It can go back to CH₄ by the route shown (leading to H⁺ exchange), or it can react with additional CH₄ molecules (Reaction 12-20) to eventually yield the tert-butyl cation, which is stable in these superacid solutions. Hydride ion can also be removed from alkanes (producing tervalent carbocations) by treatment with pure SbF₅ in the absence of any source of H⁺.⁵³ Complete or almost complete perdeuteriation of cyclic alkenes has been achieved by treatment with dilute DCl/D₂O in sealed Pyrex tubes at 165–280 °C.⁵⁴

Exchange with bases involves an S_E1 mechanism.

Of course, such exchange is most successful for relatively acidic protons (e.g., those α to a carbonyl group), but even weakly acidic protons can exchange with bases if the bases are strong enough (see Sec. 5.B.i).

Alkanes and cycloalkanes, of both low and high molecular weight, can be fully perdeuterated treatment with D₂ gas and a catalyst (e.g., Rh, Pt, or Pd).⁵⁵

OS VI, 432.

12-2 Migration of Double Bonds

3/Hydro-de-hydrogenation

The double bonds of many unsaturated compounds may be isomerized⁵⁶ upon treatment with strong bases.⁵⁷ In many cases, equilibrium mixtures are obtained and the thermodynamically most stable isomer predominates.⁵⁸ If the new double bond can be in conjugation with one already present or with an aromatic ring, the conjugated compound is favored.⁵⁹ If the choice is between an exocyclic and an endocyclic double bond (particularly with six-membered rings), endocyclic is usually preferred. In the absence of such considerations, Zaitsev's rule (Sec. 17.B) applies and the double bond goes to the carbon with the fewest hydrogen atoms. All these considerations lead to predictions that terminal alkenes can be isomerized to internal ones, nonconjugated alkenes to conjugated, exo six-membered ring alkenes to endo, and so on, and not the other way around.

The term prototropic rearrangement is sometimes used as an example of electrophilic substitution with accompanying allylic rearrangement. The mechanism involves abstraction by a base to give a resonance-stabilized carbanion, and reaction with a proton is at the position that will give the more stable alkene:⁶⁰

This mechanism is exactly analogous to the allylic-rearrangement mechanism for nucleophilic substitution (Sec. 10.D). Ultraviolet spectra of allylbenzene and 1-propenylbenzene in solutions containing NH₂⁺ are identical, showing that the same carbanion is present in both cases, as required by this mechanism.⁶¹ The acid BH⁺ protonates the position that will give the more stable product, although the ratio of the two possible products can vary with the identity of BH⁺.⁶² It has been shown that base-catalyzed double-bond shifts are partially intramolecular, at least in some cases.⁶³ The intramolecular nature has been ascribed to a conducted tour mechanism (Sec. 12.A.iii) in which the base leads the proton from one carbanionic site to the other (13 → 14).⁶⁴

Double-bond rearrangements can also take place on treatment with acids. Both proton and Lewis⁶⁵ acids can be used. The mechanism in the case of proton acids is the reverse of the previous one; first a proton is gained, giving a carbocation and then another is lost:

As in the case of the base-catalyzed reaction, the thermodynamically most stable alkene is the one predominantly formed. However, the acid-catalyzed reaction is much less synthetically useful because carbocations give rise to many side products. If the substrate has several possible locations for a double bond, mixtures of all possible isomers are usually obtained. Isomerization of 1-decene, for example, gives a mixture that contains not only 1-decene and cis-and trans-2-decene, but also the cis and trans isomers of 3-, 4-, and 5-decene as well as branched alkenes resulting from rearrangement of carbocations. It is true that the most stable alkenes predominate, but many of them have stabilities that are close together.

Double-bond isomerization can take place in other ways. Nucleophilic allylic rearrangements were discussed in Chapter 10 (Sec. 10.E). Electrocyclic and sigmatropic rearrangements are treated at Reactions 18-27 to 18-35. Double-bond migrations have also been accomplished photochemically,⁶⁶ and by means of metallic ion (most often complex ions containing Pt, Rh, or Ru) or metal carbonyl catalysts.⁶⁷ With metal compounds there are at least two possible mechanisms. One of these, which requires external hydrogen, is called the metal hydride addition–elimination mechanism:

The other mechanism, called the π-allyl complex mechanism, does not require external hydrogen and proceeds by hydrogen abstraction to form the η³-π-allyl complex 15 (see Sec. 3.C.i, category 1 and Reaction 10-60). Another difference between the two mechanisms is that the former involves 1,2- and the latter 1,3-shifts. The isomerization of 1-butene Rh catalyzed reaction is an example that takes place by the metal hydride mechanism,⁶⁸ while an example of the π-allyl complex mechanism is found in the Fe₃(CO)₁₂ catalyzed isomerization of 3-ethyl-1-pentene.⁶⁹ A Pd catalyst was used to convert alkynones (RCOCCCH₂CH₂R′) to 2,4-alkadien-1-ones (RCOCH=CHCH=CHCHR′).⁷⁰ The reaction of an en-yne with HSiCl₃ and a Pd catalyst generated an allene with moderate enantioselectivity (see Sec. 4.C, category 5 for chiral allenes).⁷¹

The metal-catalysis method has been used for the preparation of simple enols, by isomerization of allylic alcohols, for example.⁷² Some enols are stable enough for isolation (see Sec. 4.Q.iv), but slowly tautomerize to the aldehyde or ketone, with half-lives ranging from 40 to 50 min to several days.⁷²

No matter which of the electrophilic methods of double-bond shifting is employed, the thermodynamically most stable alkene is usually formed in the largest amount, although a few anomalies are known. An indirect method of double-bond isomerization is known, leading to migration in the other direction. This involves conversion of the alkene to a borane (Reaction 15-16), rearrangement of the borane (Reaction 18-11), oxidation and hydrolysis of the newly formed borane to the alcohol (17) (see Reaction 12-31), and dehydration of the alcohol (Reaction 17-1) to the alkene. The reaction is driven by the fact that with heating the addition of borane is reversible, and the equilibrium favors formation of the less sterically hindered borane, 16 in this case.

Since the migration reaction is always toward the end of a chain, terminal alkenes can be produced from internal ones, so the migration is often opposite to that with the other methods. Alternatively, the rearranged borane can be converted directly to the alkene by heating with an alkene of molecular weight higher than that of the product (Reaction 17-15). Photochemical isomerization can also lead to the thermodynamically less stable isomer.⁷³

See Reaction 15-1 for related reactions in which double bonds migrate or isomerize.

Triple bonds can also migrate in the presence of bases,⁷⁴ but through an allene intermediate:⁷⁵ In general, strong bases (e.g., NaNH₂) convert internal alkynes to terminal alkynes (a particularly good base for this purpose is potassium 3-aminopropylamide, NH₂CH₂CH₂CH₂NHK⁷⁶), because the equilibrium is shifted by formation of the acetylide ion. With weaker bases (e.g., NaOH), which are not strong enough to remove the acetylenic proton, the internal alkynes are favored because of their greater thermodynamic stability. In some cases, the reaction can be stopped at the allene stage.⁷⁷ The reaction then becomes a method for the preparation of allenes.⁷⁸ The reaction of propargylic alcohols with tosylhydrazine (PPh₃) and DEAD also generates allenes.⁷⁹ In a related reaction, base induced isomerization of propargylic alcohols leads to conjugated ketones in some cases.⁸⁰ Acid-catalyzed migration of triple bonds (with allene intermediates) can be accomplished if very strong acids (e.g., HF–PF₅) are used.⁸¹ If the mechanism is the same as that for double bonds, vinyl cations are intermediates.

OS II, 140; III, 207; IV, 189, 192, 195, 234, 398, 683; VI, 68, 87, 815, 925; VII, 249; VIII, 146, 196, 251, 396, 553; X, 156, 165; 81, 147

12-3 Keto–Enol Tautomerization

3/ O-Hydro-de-hydrogenation

The tautomeric equilibrium between enols and ketones or aldehydes (keto–enol tautomerism) is a form of prototropy,⁸² but is not normally a preparative reaction. For some ketones, however, both forms can be prepared (see Sec. 2.N.i, category 3 for a discussion of this and other types of tautomerism). Keto–enol tautomerism occurs in systems containing one or more carbonyl groups linked to sp³ carbons bearing one or more hydrogen atoms. The keto is generally more stable than the enol tautomer for neutral systems, and for most ketones and aldehydes only the keto form is detectable under ordinary conditions. The availability of additional intramolecular stabilization through hydrogen bonding or complete electron delocalization (as in phenol), may cause the enol tautomer to be favored.

Keto–enol tautomerism is usally a slow process, but it can be catalyzed by a trace of acid or base.⁸³ In this equilibrium, the heteroatom is the basic site and the proton is the acidic site. For tautomerism in general (see Sec. 2.N.i),⁸⁴the presence of an acid or a base is not necessary to initiate the isomerization since each tautomeric substance possesses amphiprotic properties.⁸⁴ Polar protic solvents (e.g., water or alcohol) may participate in the proton transfer by forming a cyclic or a linear complex with the tautomers.⁸⁵ Whether the complex formed is cyclic or linear depends on the conformation and configuration of the tautomers. In a strongly polar aprotic solvent and in the presence of an acid or a base, the tautomeric molecule may lose or gain a proton and form the corresponding mesomeric anion or cation, which, in turn, may gain or lose a proton, respectively, and yield a new tautomeric form.⁸⁶ The structural features of the carbonyl compound influences the equilibrium.⁸⁷ Differing conjugative stabilization by CH-π orbital overlap does not directly influence stereoselectivity, and steric effects are generally not large enough to cause the several kilocalorie per mole (kcal mol⁻¹) energy difference seen between transition structures unless there is exceptional crowding.⁸⁸ Note that sterically stabilized enols are known,⁸⁹ including arylacetaldehydes.⁹⁰ Torsional strain involving vicinal bonds does contribute significantly to stereoselectivity in enolate formation.⁸⁸

The acid base catalyzed mechanisms are identical to those in Reaction 12-2.⁹¹

Acid catalyzed

Base catalyzed⁹²

For each catalyst, the mechanism for one direction is the exact reverse of the other, by the principle of microscopic reversibility.⁹³ As expected from mechanisms in which the C–H bond is broken in the rate-determining step, substrates of the type RCD₂COR show deuterium isotope effects (of ~5) in both the basic-⁹⁴ and the acid⁹⁵-catalyzed processes. The keto–enol/enolate anion equilibrium has been studied in terms of the influence of β-oxygen⁹⁶ or β-nitrogen⁹⁷ substituents. The stereochemistry of enol protonation can be controlled by varying the proximal group and by changing the acidity of the medium.⁹⁸

The base induced reaction generates an enolate anion rather than an enol, and the formation of and reactions of enolate anions are discussed further in Reactions 10-60, 10-67, 16-24, and 16-34. Note that ring strain plays no significant role on the rate of base-catalyzed enolization.⁹⁹ In certain cases (e.g., benzofuranones), base-induced enolate anion formation may give a transition state in which aromaticity can play a role. One study showed that aromatic stabilization of the transition state is ahead of proton transfer, and aromaticity appears to lower the intrinsic barrier to this reaction.¹⁰⁰ Enolizable hydrogen atoms can be replaced by deuterium (and by ) by passage of a sample through a deuterated (or containing) gas-chromatography column.¹⁰¹

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. When enol ethers or esters are hydrolyzed, the initially formed enols immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to a stereogenic carbon α to a carbonyl group (as in 19) is treated with acid or base, racemization results.¹⁰² If there is another stereogenic center in the molecule, the less stable diastereomer can be converted to the more stable one in this manner. For example, cis-decalone can be equilibrated to the trans isomer. Isotopic exchange can similarly be accomplished at the α position of an aldehyde or ketone. In cyclic compounds, cis- to trans- isomerization can occur via the enol.¹⁰³ The role of additives (e.g., ZnCl₂) on the stereogenic enolization reactions using chiral cases has been discussed.¹⁰⁴

If a full equivalent of base per equivalent of ketone is used, the enolate ion (18) is formed and can be isolated¹⁰⁵ (see, e.g., the alkylation reaction in Reaction 10-68).¹⁰⁶ Enantioselective enolate anion protonation reactions have been studied.¹⁰⁷ Enolate protonation is discussed in section Reaction 16-34. For the acid-catalyzed process, exchange or equilibration is accomplished only if the carbonyl compound is completely converted to the enol and then back, but in the base-catalyzed process exchange or equilibration can take place if only the first step (conversion to the enolate ion) takes place. The difference is usually academic. Aggregation behavior of stereoselective enolizations mediated by Mg and Ca bis(amides) have been studied.¹⁰⁸

In the case of the ketone (20), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (21).¹⁰⁹ This happened because 21 reacted with one enantiomer of 20 faster than with the other (an example of kinetic resolution). The enolate (22) must remain coordinated with the chiral amine, and it is the amine that reprotonate 22, not an added proton donor.

There are many enol–keto interconversions and acidification reactions of enolate ions to the keto forms listed in Organic Syntheses. No attempt is made to list them here.

B. Halogen Electrophiles

Halogenation of unactivated hydrocarbons is discussed in Reaction 14-1.

12-4 Halogenation of Aldehydes and Ketones

Halogenation or Halo-de-hydrogenation

Aldehydes and ketones can be halogenated in the α position with bromine, chlorine, or iodine,¹¹⁰ although the reaction is less successful with fluorine.¹¹¹ Sulfuryl chloride,¹¹² Me₃SiCl–Me₂SO,¹¹³ and NCS¹¹⁴ have been used as reagents for chlorination. α-Chloroaldehydes are formed with Cl₂ and a catalytic amount of tetraethylammonium chloride.¹¹⁵ Bromination methods include NBS (see Reaction 14-3),¹¹⁶ Me₃SiBr–DMSO,¹¹⁷ tetrabutylammonium tribromide,¹¹⁸ in situ generated ZnBr₂ in water,¹¹⁹ and bromine•dioxane on silica with microwave irradiation.¹²⁰ α-Chlorination¹²¹ and also bromination¹²² have been reported in ionic liquids. Enantioselective chlorination¹²³ and bromination¹²⁴ methods are known, including methods that use enolate anions as intermediates.¹²⁵ Organocatalyzed asymmetric α-halogenation methods are known that can be applied to incorporation of virtually any halogen.¹²⁶ β-Keto esters and 1,3-diketones are α-brominated using bromodimethylsulfonium bromide.¹²⁷ 1,3-Diketones, β-ketoesters, and malonates are chlorinated using sodium hypochlorite or brominated using sodium hypobromite.¹²⁸

Iodination has been accomplished by the direct reaction of ketones with molecular iodine,¹²⁹ with I₂-cerium(IV) ammonium nitrate,¹³⁰ NCS/NaI,¹³¹ ICl/NaI/FeCl₃,¹³² and with iodine using 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) in methanol.¹³³ Methyl ketones react with NIS and tosic acid with microwave irradiation without solvent to give the α-iodoketone.¹³⁴ An asymmetric iodination of aldehydes used NIS, with a catalytic amount of benzoic acid and a chiral biaryl amine.¹³⁵

Although less prevalent than those noted above, several methods have been reported for the preparation of α-fluoro aldehydes and ketones,¹³⁶ including enantioselective fluorination protocols.¹³⁷ Organocatalytic α-fluorination is known for aldehydes and ketones.¹³⁸ Selectfluor, [F–TEDA–BF₄. 1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] has been used for the monofluorination of ketones,¹³⁹ as has a mixture of KI–KIO₃–H₂SO₄.¹⁴⁰ Active compounds (e.g., β-keto esters and β-diketones) have been fluorinated with an N-fluoro-N-alkylsulfonamide¹⁴¹ (this can result in enantioselective fluorination, if an optically active N-fluorosulfonamide is used¹⁴²), with F₂/N₂–HCO₂H,¹⁴³ and with NF₃O/Bu₄NOH.¹⁴⁴ Acetyl hypofluorite fluorinates simple ketones in the form of their lithium enolate anions.¹⁴⁵ Aldehydes have been α-fluorinated using N-fluorobenzenesulfonimide as an electrophilic source of fluorine and an imidazolidinone as an organocatalyst.¹⁴⁶ The enantioselective α-fluorination of oxindoles has been reported using N-fluorobenzenesulfonimide, a Pd catalyst, and a chiral ligand,¹⁴⁷ and also with an organocatalyst.¹⁴⁸

For unsymmetrical ketones, the preferred position of halogenation is usually the more substituted: a CH group, then a CH₂ group, and then CH₃¹⁴⁹; however, mixtures are frequent. With aldehydes the aldehydic hydrogen is sometimes replaced, but only when there is no α-hydrogen and the reaction is generally not very useful (see Reaction 14-4). It is also possible to prepare di- and polyhalides. When basic catalysts are used, one α position of a ketone is completely halogenated before the other is attacked, and the reaction cannot be stopped until all the hydrogen atoms of the first carbon have been replaced (see below). If one of the groups is methyl, the haloform reaction (12-44) takes place. With acid catalysts, it is usually possible to stop the reaction after only one halogen has been incorporated, although a second halogen can be introduced by the use of excess reagent. In chlorination, the second halogen generally appears on the same side as the first,¹⁵⁰ while in bromination the α,α′-dibromo product is found.¹⁵¹ Actually, with both halogens it is the α,α-dihalo ketone that is formed first, but in the case of bromination this compound isomerizes under the reaction conditions to the α,α′-isomer.¹⁵⁰ α,α′-Dichloro ketones are formed by reaction of a methyl ketone with an excess of CuCl₂ and LiCl in DMF¹⁵² or with HCl and H₂O₂ in methanol.¹⁵³ Aryl methyl ketones can be dibrominated in high yields with benzyltrimethylammonium tribromide.¹⁵⁴ Active methylene compounds are chlorinated with NCS and Mg(ClO₄)₂.¹⁵⁵ Similar chlorination in the presence of a chiral copper catalyst led to α-chlorination with modest enantioselectivity.¹⁵⁶

It is not the aldehyde or ketone itself that is halogenated, but the corresponding enol or enolate ion. The purpose of the catalyst is to provide a small amount of enol or enolate (Reaction 12-3). The reaction is often done without addition of acid or base, but traces of acid or base are always present, and these are enough to catalyze formation of the enol or enolate. With acid catalysis the mechanism is

The first step, as seen in Reaction 12-3, actually consists of two steps. The second step is very similar to the first step in electrophilic addition to double bonds (Sec. 15.A.i). There is a great deal of evidence for this mechanism: (1) the rate is first order in substrate; (2) bromine does not appear in the rate expression at all,¹⁵⁷ a fact consistent with a rate-determining first step;¹⁵⁸ (3) the reaction rate is the same for bromination, chlorination, and iodination under the same conditions;¹⁵⁹ (4) the reaction shows an isotope effect; and (5) the rate of the step 2–step 3 sequence has been independently measured (by starting with the enol) and found to be very fast.¹⁶⁰

With basic catalysts the mechanism may be the same as that given above (since bases also catalyze formation of the enol), or the reaction may go directly through the enolate ion without formation of the enol:

It is difficult to distinguish the two possibilities. It was mentioned above that in the base-catalyzed reaction, if the substrate has two or three α halogens on the same side of the C=O group, it is not possible to stop the reaction after just one halogen atom has entered. The reason is that the electron-withdrawing field effect of the first halogen increases the acidity of the remaining hydrogen atoms; that is, a CHX group is more acidic than a CH₂ group, so that the initially formed halo ketone is converted to enolate ion (and hence halogenated) more rapidly than the original substrate. Other halogenating agents can be used in this reaction.

Regioselectivity in the halogenation of unsymmetrical ketones can be attained by treatment of the appropriate enol borinate of the ketone with NBS or NCS.¹⁶¹ The desired halo ketone is formed in high yield. The appropriate lithium enolate can be brominated at a low temperature¹⁶² (see Reaction 10-68, category 4 for the regioselective formation of enolate ions). α-Halo aldehydes have been prepared in good yield by treatment of silyl enol ethers (R₂C=CHOSiMe₃) with Br₂ or Cl₂,¹⁶³ with sulfuryl chloride (SO₂Cl₂),¹⁶⁴ or with I₂ and silver acetate.¹⁶⁵ Silyl enol ethers generate α-chloroketones with good enantioselectivity using ZrCl₄ in conjunction with an α,α-dichloromalonate ester.¹⁶⁶ Silyl enol ethers can also be fluorinated, with XeF₂¹⁶⁷ or with 5% F₂ in N₂ at −78 °C in FCCl₃.¹⁶⁸ Enol acetates have been regioselectively iodinated with I₂ and either Th(I) acetate¹⁶⁹ or Cu(II) acetate.¹⁷⁰

α,β-Unsaturated ketones can be converted to α-halo-α,β-unsaturated ketones by treatment with phenylselenium bromide or chloride,¹⁷¹ and to α-halo-β,γ-unsaturated ketones by two-phase treatment with HOCl.¹⁷² Conjugated ketones were converted to the α-bromo conjugated ketone (a vinyl bromide) using the Dess–Martin periodinane (see Reaction 19-3, category 5) and tetraethylammonium bromide.¹⁷³

OS I, 127; II, 87, 88, 244, 480; III, 188, 343, 538; IV, 110, 162, 590; V, 514; VI, 175, 193, 368, 401, 512, 520, 711, 991; VII, 271; VIII, 286. See also, OS VI, 1033; VIII, 192.

12-5 Halogenation of Carboxylic Acids and Acyl Halides

Halogenation or Halo-de-hydrogenation

The α hydrogen atoms of carboxylic acids are replaced by bromine or chlorine using a phosphorus halide as catalyst.¹⁷⁴ The reaction, known as the Hell–Volhard–Zelinskii reaction, is not applicable to iodine or fluorine. When there are two α hydrogen atoms, one or both may be replaced, although it is often hard to stop with just one. The reaction actually takes place on the acyl halide formed initially from the carboxylic acid and the halogenating reagent. This means that each molecule of acid is α halogenated while it is in the acyl halide stage. The acids alone are inactive, except for those with relatively high enol content (e.g., malonic acid). Less than one full molar equivalent of catalyst (per molar equivalent of substrate) is required, because of the exchange reaction between carboxylic acids and acyl halides (see Reaction 16-79). The halogen from the catalyst is not transferred to the α position. For example, the use of Cl₂ and PBr₃ results in α-chlorination, not bromination. As expected from the foregoing, acyl halides undergo a halogenation without a catalyst. An enantioselective α-halogenation was reported to give chiral α-haloesters via an alkaloid-catalyzed reaction of acyl halides with perhaloquinone-derived reagents.¹⁷⁵ So do anhydrides and many compounds that enolize easily (e.g., malonic ester and aliphatic nitro compounds). The mechanism is usually regarded as proceeding through the enol as in Reaction 12-4.¹⁷⁶ If chlorosulfuric acid (ClSO₂OH) is used as a catalyst, carboxylic acids can be α-iodinated,¹⁷⁷ as well as chlorinated or brominated.¹⁷⁸ N-Bromosuccinimide in a mixture of sulfuric acid–trifluoroacetic acid can monobrominate simple carboxylic acids.¹⁷⁹

A number of other methods exist for the α halogenation of carboxylic acids or their derivatives.¹⁸⁰ Under electrolytic conditions with NaCl, malonates are converted to 2-chloro malonates.¹⁸¹ Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl.¹⁸² The latter is an ionic, not a free radical halogenation (see Reaction 14-3). Direct iodination of carboxylic acids has been achieved with I₂-Cu(II) acetate in HOAc.¹⁸³ Acyl chlorides can be α iodinated with I₂ and a trace of HI.¹⁸⁴ Carboxylic acids, esters, and amides have been α-fluorinated at −78 °C with F₂ diluted in N₂.¹⁸⁵ Amides have been α-iodinated using iodine and s-collidine.¹⁸⁶

OS I, 115, 245; II, 74, 93; III, 347, 381, 495, 523, 623, 705, 848; IV, 254, 348, 398, 608, 616; V, 255; VI, 90, 190, 403; IX, 526. Also see, OS IV, 877; VI, 427.

12-6 Halogenation of Sulfoxides and Sulfones

Halogenation or Halo-de-hydrogenation

Sulfoxides can be chlorinated in the α position¹⁸⁷ by treatment with Cl₂¹⁸⁸ or NCS,¹⁸⁹ in the presence of pyridine. These methods involve basic conditions. The reaction can also be accomplished in the absence of base with SO₂Cl₂in CH₂Cl₂,¹⁹⁰ or with TsNCl₂.¹⁹¹ The bromination of sulfoxides with bromine¹⁹² and with NBS–bromine¹⁹³ have also been reported. Sulfones have been chlorinated by treatment of their conjugate bases (RSO₂C⁻HR′) with various reagents, among them SO₂Cl₂, CCl₄,¹⁹⁴ or NCS.¹⁹⁵ The α-fluorination of sulfoxides was reported via treatment with diethylaminosulfur trifluoride (Et₂NSF₃, DAST) to give an α-fluoro thioether, usually in high yield. Oxidation of this compound with m-chloroperoxybenzoic acid gave the sulfoxide.¹⁹⁶

C. Nitrogen Electrophiles

12-7 Aliphatic Diazonium Coupling

Arylhydrazono-de-dihydro-bisubstitution

If a C–H unit is acidic enough, that carbon couples with diazonium salts in the presence of a base (via the enolate anion), most often aq sodium acetate.¹⁹⁷ The reaction is commonly carried out on compounds of the form Z–CH₂–Z′, where Z and Z′ are as defined in Section 16-38 (e.g., β-keto esters, β-keto amides, malonic ester).

The mechanism is probably of the simple S_E1 type:

Aliphatic azo compounds in which the carbon containing the azo group is attached to a hydrogen are unstable and tautomerize to the isomeric hydrazones (23), which are the products of the reaction.

When the reaction is carried out on a compound of the form Z–CHR–Z′, the azo compound does not have a hydrogen that can lead to tautomerism, and at least one Z is acyl or carboxyl, this group usually cleaves:

so the product in this case is also the hydrazone, and not the azo compound. In fact, compounds of the type 24 are seldom isolable from the reaction, although this has been accomplished.¹⁹⁸ The cleavage step shown is an example of Reaction 12-43 and, when a carboxyl group cleaves, of Reaction 12-40. The overall process in this case is called the Japp–Klingemann reaction¹⁹⁹ and involves conversion of a ketone (25) or a carboxylic acid (26) to a hydrazone (27). When an acyl and a carboxyl group are both present, the leaving group order has been reported to be MeCO > COOH > PhCO.²⁰⁰ When there is no acyl or carboxyl group present, the aliphatic azo compound is stable.

OS III, 660; IV, 633.

12-8 Nitrosation at a Carbon Bearing an Active Hydrogen

Carbons adjacent to a Z group (as defined in Reaction 10-67) can be nitrosated with nitrous acid or alkyl nitrites.²⁰¹ The initial product is the C-nitroso compound, but these are stable only when there is no hydrogen that can undergo tautomerism. When there is, the product is the more stable oxime. The situation is analogous to that with azo compounds and hydrazones (Reaction 12-7). The mechanism is similar to that in Reaction 12-7:²⁰² R–H → R⁻ + ⁺N=O → R–N=O. The reactive species is either NO⁺ or a carrier of it. When the substrate is a simple ketone, the mechanism goes through the enol (as in halogenation Reaction 12-4):

Evidence is that the reaction, in the presence of X⁻ (Br⁻, Cl⁻, or SCN⁻) was first order in ketone and in H⁺, but zero order in HNO₂ and X⁻.²⁰³ Furthermore, the rate of the nitrosation was about the same as that for enolization of the same ketones. The species NOX is formed by HONO + X⁻ + H⁺ → HOX + H₂O. In the cases of F₃CCOCH₂COCF₃ and malononitrile, the nitrosation went entirely through the enolate ion rather than the enol.²⁰⁴

As in the Japp–Klingemann reaction, when Z is an acyl or carboxyl group (in the case of R₂CH–Z), it can be cleaved. Since oximes and nitroso compounds can be reduced to primary amines, this reaction often provides a route to amino acids. As in the case of Reaction 12-4, the silyl enol ether of a ketone can be used instead of the ketone itself.²⁰⁵ Good yields of α-oximinoketones (28) can be obtained by treating ketones with tert-butyl thionitrate.²⁰⁶

Imines can be prepared in a similar manner by treatment of an active hydrogen compound with a nitroso compound:

Alkanes can be nitrosated photochemically, by treatment with NOCl and UV light.²⁰⁷ For nitration at an activated carbon, see Reaction 12-9. Trialkyltin enol ethers (C=C–O–SnR₃) react with PhNO to give α-(N-hydroxylamino)ketones.²⁰⁸

OS II, 202, 204, 223, 363; III, 191, 513; V, 32, 373; VI, 199, 840. Also see, OS V, 650.

12-9 Nitration of Alkanes

Nitration or Nitro-de-hydrogenation

Nitration of alkanes²⁰⁹ can be carried out in the gas phase at ~400 °C or in the liquid phase. The reaction is not practical for the production of pure products for any alkane except methane. For other alkanes, not only does the reaction produce mixtures of the mono-, di-, and polynitrated alkanes at every combination of positions, but extensive chain cleavage occurs.²¹⁰ A free radical mechanism is involved.²¹¹

Activated positions (e.g., ZCH₂Z′ compounds) can be nitrated by fuming nitric acid in acetic acid, by acetyl nitrate and an acid catalyst,²¹² or by alkyl nitrates under alkaline conditions.²¹³ In the latter case, it is the carbanionic form of the substrate that is actually nitrated. The conjugate base of the nitro compound is isolated under these alkaline conditions, but yields are not high. Of course, the mechanism in this case is not of the free radical type, but is electrophilic substitution with respect to the carbon (similar to the mechanisms of Reactions 12-7 and 12-8). Positions activated by only one electron-withdrawing group (e.g., α positions of simple ketones, nitriles, sulfones, or N,N-dialkyl amides) can be nitrated with alkyl nitrates if a very strong base (e.g., t-BuOK or NaNH₂,) is present to convert the substrate to the carbanionic form.²¹⁴

Electrophilic nitration of alkanes has been performed with nitronium salts (e.g., NO₂⁺ PF₆⁻ and with HNO₃–H₂SO₄ mixtures), but mixtures of nitration and cleavage products are obtained and yields are generally low.²¹⁵ The reaction of alkanes with nitric acid and N-hydroxysuccinimide (NHS), however, gave moderate-to-good yields of the corresponding nitroalkane.²¹⁶ Similar nitration was accomplished with NO₂, NHS and air.²¹⁷ Aliphatic nitro compounds can be a nitrated [R₂C-NO₂ → R₂C(NO₂)₂] by treatment of their conjugate bases RCNO₂ with NO₂⁻ and K₃Fe(CN)₆.²¹⁸

OS I, 390; II, 440, 512.

12-10 Direct Formation of Diazo Compounds

Diazo-de-dihydro-bisubstitution

Compounds containing a CH₂ bonded to two Z groups (active methylene compounds, with Z as defined in Reaction 10-67) can be converted to diazo compounds on treatment with tosyl azide in the presence of a base.²¹⁹ The use of phase-transfer catalysis increases the convenience of the method.²²⁰ Sulfonyl azides also give the reaction.²²¹ The diazo-transfer reaction can also be applied to other reactive positions (e.g., the 5 position of cyclopentadiene).²²²The mechanism is probably as follows:

A diazo group can be introduced adjacent to a single carbonyl group indirectly by first converting the ketone to an α-formyl ketone (Reaction 16-85) and then treating it with tosyl azide. As in the similar cases of Reactions 12-7and 12-8, the formyl group is cleaved during the reaction.²²³

OS V, 179; VI, 389, 414.

12-11 Conversion of Amides to α-Azido Amides

Azidation or Azido-de-hydrogenation

In Reaction 12-10, treatment of Z–CH₂–Z′ with tosyl azide gave the α-diazo compound via diazo transfer. When this reaction is performed on a compound with a single Z group (e.g., an amide), formation of the azide becomes a competing process via the enolate anion.²²⁴ Factors favoring azide formation rather than diazo transfer include K⁺ as the enolate counterion rather than Na⁺ or Li⁺ and the use of 2,4,6-triisopropylbenzenesulfonyl azide rather than TsN₃. When the reaction was applied to amides with a chiral R′ (e.g., the oxazolidinone derivative 29), it was highly stereoselective, and the product could be converted to an optically active amino acid.²²⁴

12-12 Direct Amination at an Activated Position

Alkyamino-de-hydrogenation, and so on

Alkenes can be aminated²²⁵ in the allylic position by treatment with solutions of imido selenium compounds (R–N=Se=N–R).²²⁶ The reaction, which is similar to the allylic oxidation of alkenes with SeO₂ (see Reaction 19-14), has been performed with R = t-Bu and R = Ts. The imido sulfur compound TsN=S=NTs has also been used,²²⁷ as well as PhNHOH–FeCl₂/FeCl₃.²²⁸ Benzylic positions can be aminated with t-BuOOCONHTs in the presence of a catalytic amount of Cu(OTf)₂.²²⁹ Enantioselective allylic amination has been reported using organocatalyts.²³⁰ A Rh catalyzed amination of benzylic positions has also been reported.²³¹

Tertiary alkyl hydrogen can be replaced in some cases via C–H nitrogen insertion. The reaction of sulfamate ester (30) with PhI(OAc)₂, MgO, and a dinuclear Rh carboxylate catalyst, for example, generated oxathiazinane (31).²³²This transformation is a formal oxidation, and primary carbamates have been similarly converted to oxazolidin-2-ones.²³³

Amination of 1,3-dicarbonyl compounds can be done using functionalized dimides and an appropriate catalyst, generating the corresponding hydrazone. Enantioselective amination using this method has been reported, using a chiral guanidine catalyst.²³⁴

See also, Reaction 10-39.

12-13 Insertion by Nitrenes

CH-[Acylimino]-insertion, and so on

Carbonylnitrenes (:NCOW, W = R′, Ar, or OR′) are very reactive species (Sec. 5.E) and insert into the C–H bonds of alkanes to give amides (W = R′ or Ar) or carbamates (W = OR′).²³⁵ The nitrenes are generated as discussed in Section 5.E. The order of reactivity among alkane C–H bonds is tertiary > secondary > primary.²³⁶ Nitrenes are much more selective (and less reactive) in this reaction than carbenes (Reaction 12-17).²³⁷ It is likely that only singlet and not triplet nitrenes insert.²³⁸ Retention of configuration is found at a stereogenic carbon.²³⁹ The mechanism is presumably similar to the simple one-step mechanism for insertion of carbenes (Reaction 12-21). Other nitrenes [e.g., cyanonitrene (NCN)²⁴⁰ and arylnitrenes (NAr)²⁴¹] can also insert into C–H bonds, but alkylnitrenes usually undergo rearrangement before they can react with the alkane. The Au(III) catalyzed insertion of nitrenes into aromatic and benzylic C–H groups has been reported.²⁴² N-Carbamoyl nitrenes undergo insertion reactions that often lead to mixtures of products, but exceptions are known,²⁴³ chiefly in cyclizations.²⁴⁴ For example, heating of 2-(2-methylbutyl)phenyl azide gave ~60% 2-ethyl-2-methylindoline (32).²³⁹ Enantioselective nitrene insertion reactions are known.²⁴⁵

D. Sulfur Electrophiles

12-14 Sulfenylation, Sulfonation, and Selenylation of Ketones and Carboxylic Esters

Alkylthio-de-hydrogenation, and so on

Sulfonation or Sulfo-de-hydrogenation

Ketones, carboxylic esters (including lactones),²⁴⁶ and amides (including lactams)²⁴⁷ can be sulfenylated²⁴⁸ in the α position by conversion to the enolate anion (see Sec. 8.F, part 7), and subsequent treatment with a disulfide.²⁴⁹The reaction, shown above for ketones, involves nucleophilic substitution at sulfur. α-Phenylseleno ketones [RCH(SePh)COR′] and α-phenylseleno esters [RCH(SePh)COOR′] can be similarly prepared²⁵⁰ by treatment of the corresponding enolate anions with PhSeBr,²⁵¹ PhSeSePh,²⁵² or benzeneseleninic anhydride [PhSe(O)OSe(O)Ph].²⁵³ Another method for the introduction of a phenylseleno group into the α position of a ketone involves simple treatment of an ethyl acetate solution of the ketone with PhSeCl (but not PhSeBr) at room temperature.²⁵⁴ This procedure is also successful for aldehydes but not for carboxylic esters. N-Phenylselenophthalimide has been used to convert ketones²⁵⁵ and aldehydes²⁵⁶ to the α- PhSe derivative. Silyl enol ethers are converted to α-alklylthio and α-arylthio ketones via a sulfenylation method, driven by aromatization of an added quinone mono-O,S-acetal in the presence of Me₃SiOTf.²⁵⁷

The α-seleno and α-sulfenyl carbonyl compounds prepared by this reaction can be converted to α,β-unsaturated carbonyl compounds (Reaction 17-12). The sulfenylation reaction has also been used²⁵⁸ as a key step in a sequence for moving the position of a carbonyl group to an adjacent carbon.²⁵⁹

Aldehydes, ketones, and carboxylic acids containing α hydrogen atoms can be sulfonated with sulfur trioxide.²⁶⁰ The mechanism is presumably similar to that of Reaction 12-4. Sulfonation has also been accomplished at vinylic hydrogen.

OS VI, 23, 109; VIII, 550. OS IV, 846, 862.

E. Carbon Reagents

12-15 Alkylation and Alkenylation of Alkenes

Alkylation or Alkyl-de-oxysulfonation (de-halogenation), Arylation or Aryl-de-oxysulfonation (de-halogenation), and so on

Vinyl triflates (C=C–OSO₂CF₃) react with vinyl tin derivatives in the presence of Pd catalysts to form dienes, in what is known as Stille coupling.²⁶¹ Phosphine or bis(phosphine) ligands are most commonly used with the Pd catalyst,²⁶² but other ligands have been used,²⁶³ including triphenylarsine.²⁶⁴ Vinyl triflates can be prepared from the enolate anion by reaction with N-phenyl triflimide.²⁶⁵ Vinyltin compounds are generally prepared by the reaction of an alkyne with an trialkyltin halide (see Reactions 15-17 and 15-21).²⁶⁶ Stille cross-coupling reactions are an important variation of the basic reaction,²⁶⁷ including cross-coupling reactions of unactivated secondary halides and monoorganotin reagents.²⁶⁸ Stille reactions are compatible with many functional groups. Vinyl halides can be used,²⁶⁹ and allenic tin compounds have been used.²⁷⁰ Intramolecular reactions are possible.²⁷¹ Stille coupling has been done using microwave irradiation,²⁷² in fluorous solvents,²⁷³ and in supercritical carbon dioxide (see Sec. 9.D.ii).²⁷⁴ Stille coupling using alkynes as a substrate are known.²⁷⁵

This reaction is highly stereoselective, and proceeds with a retention of geometry of the C=C units, and are usually regiospecific with respect to the newly formed C–C σ-bond. Cine substitution is known with this reaction, and its mechanism has been studied.²⁷⁶ Using ArSnCl₃ derivatives, Stille coupling can be done in aq KOH.²⁷⁷

Aryl halides,²⁷⁸ heteroaryl halides,²⁷⁹ and heteroaryl triflates²⁸⁰ can be coupled to vinyltin reagents²⁸¹ using a Pd catalyst. A Mo catalyzed variation is known.²⁸² A Cu catalyzed cross coupling variation²⁸³ has been reported in ionic liquids.²⁸⁴ Vinyl halides can be coupled to alkenes to form dienes.²⁸⁵ The reaction of dihydrofurans with vinyl triflates and a Pd catalyst leads to a nonconjugated diene,²⁸⁶ illustrating that the product is formed by an elimination step, as with the Heck reaction (13-10), and double-bond migration can occur resulting in allylic rearrangement.

The accepted mechanism for the Stille reaction involves a catalytic cycle²⁸⁷ in which an oxidative addition²⁸⁸ and a reductive elimination step²⁸⁹ are fast, relative to Sn/Pd transmetalation (the rate-determining step).²⁹⁰ It appears that the greater the coordinating ability of the unsaturated species is important, and a coordinated solvent molecule is likely involved in the electrophilic substitution at tin. Another mechanism has been proposed, in which oxidative addition of the vinyl triflate to the ligated Pd gives a cis-Pd complex that isomerizes rapidly to a trans-Pd complex, which then reacts with the organotin compound following an S_E2 (cyclic) mechanism, with release of a ligand.²⁹¹This pathway gives a bridged intermediate, and subsequent elimination of XSnBu₃ yields a three-coordinate species cis-Pd complex, which readily gives the coupling product.²⁹¹ Most of the major intermediates have been intercepted, isolated, and characterized using electrospray ionization mass spectrometry.²⁹²

Cyclopropylboronic acids (Reaction 12-28) couple with vinylic halides²⁹³ or vinyl triflates²⁹⁴ to give vinylcyclopropanes, using a Pd catalyst. Vinyl borates (Reaction 12-28) were coupled to vinyl triflates using a Pd catalyst.²⁹⁵Vinyltrifluoroborates can be coupled to allylic chlorides using microwave irradiation²⁹⁶ and vinyl halides react with vinyltrifluoroborates to give dienes with high stereoselectivity.²⁹⁷ Stille coupling to enols has been reported.²⁹⁸ The coupling of vinyl silanes to give the symmetrically conjugated diene using CuCl and air has also been reported.²⁹⁹

Other methods are available to give Stille-like products. 1-Lithioalkynes were coupled to vinyl tellurium compounds (C=C–TeBu) using a Ni³⁰⁰ or a Pd catalyst³⁰¹ to give a conjugated en-yne. 2-Alkynes (R–CC–Me) react with HgCl₂, n-butyllithium, and ZnBr₂, sequentially, and then with vinyl iodides and a Pd catalyst to give the nonconjugated en-yne.³⁰² Alkynyl groups can be coupled to vinyl groups to give ene-ynes, via reaction of silver alkynes (Ag–CC–R) with vinyl triflates and a Pd catalyst.³⁰³ In the presence of CuI and a Pd catalyst, vinyl triflates³⁰⁴ or vinyl halides³⁰⁵ couple to terminal alkynes. Alkynyl zinc reagents (R–CC–ZnBr) can be coupled to vinyl halides with a Pd catalyst to give the conjugated en-yne.³⁰⁶

Alkyl groups can be coupled to a vinyl unit to give substituted alkenes. The reaction of vinyl iodides and EtZnBr, with a Pd catalyst, gave the ethylated alkene (C=C–Et).³⁰⁷ Aliphatic alkyl bromides reacted with vinyltin compounds to give the alkylated alkene using a Pd catalyst.³⁰⁸ Allylic tosylates were coupled to conjugated alkenes to give a non-conjugated diene using a Pd catalyst.³⁰⁹ An internal coupling reaction was reported in which an alkenyl enamide (33) reacted with Ag₃PO₄ and a chiral palladium catalyst to give 34 enantioselectively.³¹⁰

For the related coupling reaction of alkenes and aryl compounds (arylation of alkenes), see Reaction 13-10.

12-16 Acylation at an Aliphatic Carbon

Acylation or Acyl-de-hydrogenation

Alkenes can be acylated with an acyl halide and a Lewis acid catalyst in what is essentially a Friedel–Crafts Reaction (11-17) at an aliphatic carbon.³¹¹ The product can arise by two paths. The initial attack is by the π bond of the alkene unit on the acyl cation (RCO⁺; or on the acyl halide free or complexed; see Reaction 11-17) to give a carbocation, (35).

Ion 35 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone. The mechanism is similar to the tetrahedral mechanism in Section 16.A.i, but with the charges reversed. If it combines with chloride, the product is a β-halo ketone, which can be isolated, so that the result is addition to the double bond (see Reaction 15-47). On the other hand, the β-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition–elimination mechanism. In the case of unsymmetrical alkenes, the more stable alkene is formed (the more highly substituted and/or conjugated alkene, following Markovnikov's rule, see Sec. 15.B.ii). Anhydrides and carboxylic acids (the latter with a proton acid e.g., anhydrous HF, H₂SO₄, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts, double-bond migrations are occasionally encountered so that, for example, when 1-methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene.³¹²

Conjugated dienes can be acylated by treatment with acyl- or alkylcobalt tetracarbonyls, followed by base-catalyzed cleavage of the resulting π-allyl carbonyl derivatives³¹³ (π-allyl metal complexes were discussed in Sec. 3.C.i. The reaction is very general. With unsymmetrical dienes, the acyl group generally substitutes most readily at a cis double bond, next at a terminal alkenyl group, and least readily at a trans double bond. The most useful bases are strongly basic, hindered amines (e.g., dicyclohexylethylamine). Acylation of vinylic ethers has been accomplished with aromatic acyl chlorides, a base, and a Pd catalyst: ROCH=CH₂ → ROCH=CHCOAr.³¹⁴

Formylation of alkenes can be accomplished with N-disubstituted formamides and POCl₃.³¹⁵ This is an aliphatic Vilsmeier reaction (see Reaction 11-18). Vilsmeier formylation can also be performed on the α position of acetals and ketals, so that hydrolysis of the products gives keto aldehydes or dialdehydes:³¹⁶ A variation heated a 1,1-dibromoalkene with a secondary amine in aq DMF to give the corresponding amide.³¹⁷

Acetylation of acetals or ketals can be accomplished with acetic anhydride and BF₃–etherate.³¹⁸ The mechanism with acetals or ketals also involves attack at an alkenyl carbon, since enol ethers are intermediates.³¹⁸ Ketones can be formylated in the α position by treatment with CO and a strong base.³¹⁹

OS IV, 555, 560; VI, 744. Also see, OS VI, 28.

12-17 Conversion of Enolates to Silyl Enol Ethers, Silyl Enol Esters, and Silyl Enol Sulfonate Esters

3/O-Trimethylsilyl-de-hydrogenation

Silyl enol ethers,³²⁰ important reagents with a number of synthetic uses (see, e.g., Reactions 10-68, 12-4, 15-24, 15-64, and 16-36), can be prepared by base treatment of a ketone (converting it to its enolate anion) followed by addition of a trialkylchlorosilane. Other silylating agents have also been used.³²¹ Both strong bases (e.g., LDA), and weaker bases (Et₃N) have been used for this purpose.³²² In some cases, the base and the silylating agent can be present at the same time.³²³ Enolate anions prepared in other ways (e.g., as shown in Reaction 10-58) also give the reaction.³²⁴ The reaction can be applied to aldehydes by the use of the base KH in 1,2-dimethoxyethane.³²⁵ A particularly mild method for conversion of ketones or aldehydes to silyl enol ethers uses Me₃SiI and the base hexamethyldisilazane [(Me₃Si)₂NH.]³²⁶ Cyclic ketones can be converted to silyl enol ethers in the presence of acyclic ketones, by treatment with Me₃SiBr, tetraphenylstibonium bromide (Ph₄SbBr), and an aziridine.³²⁷ bis(Trimethylsilyl)acetamide is an effective reagent for the conversion of ketones to the silyl enol ether, typically giving the thermodynamic product (see below).³²⁸ Silyl enol ethers have also been prepared by the direct reaction of a ketone and a silane (R₃SiH) with a Pt catalyst.³²⁹

For substituted ketones, (E) and (Z) isomers are usually formed. For 36, the enol is (Z) when R¹ is the priority group, but (E) when R² is the priority group. In some cases, it is possible to control the selectivity to favor more of one isomer than the other. Treatment of 2-methyl-3-pentanone with LDA (THF, -78 °C), for example, gave a 60:40 mixture of the (Z) and (E) enolates.³³⁰ The base used to generate an enolate anion, the solvent and temperature, the conjugate acid of the base used, and the nature of the carbonyl substrate will all play a role in the selectivity. In general, equilibrating (thermodynamic) conditions [protic solvents (e.g., ethanol, water, or ammonia), a base generating a conjugate acid stronger than the starting ketone, more ionic counterions (e.g., K or Na), higher temperatures and longer reaction times] are expected to give more of the (E)-isomer. Conversely, kinetic conditions [aprotic solvents (e.g., ether or THF), a base generating a conjugate acid weaker than the starting ketone, more covalent counterions (e.g., Li, lower temperatures), and relatively short reaction times] usually give more of the (Z)-isomer. It is not always easy to predict the ratio, however. Either isomer is possible from aldehydes using the proper Rh catalyst.³³¹

Magnesium diisopropylamide has been used to prepare kinetic silyl enol ethers in virtual quantitative yield.³³² Reaction with Me₃SiCl/KI in DMF gives primarily the thermodynamic silyl enol ether.³³³

An interesting synthesis of silyl enol ethers involves chain extension of an aldehyde. Aldehydes are converted to the silyl enol ether of a ketone upon reaction with lithium (trimethylsilyl)diazomethane and then a dirhodium catalyst.³³⁴ For example, initial reaction of lithium(trimethylsilyl)diazomethane [LTMSD, prepared in situ by reaction of butyllithium with (trimethylsilyl)diazomethane] to the aldehyde (e.g., 37) gave the alkoxide addition product. Protonation and then capture by a transition metal catalyst, and a 1,2-hydride migration gave the silyl enol ether, (38). Silyl enol ethers can be prepared from acyloin derivatives (see Reaction 19-78).³³⁵

Enol acetates are generally prepared by the reaction of an enolate anion with a suitable acylating reagent.³³⁶ Enolate anions react with acyl halides and with anhydrides to give the acylated product. Both C- and O-acylation are possible, but in general O-acylation predominates.³³⁷ Note that the extent of O- versus C-acylation is very dependent on the local environment and electronic effects within the enolate anion.³³⁸ O-Benzoate enols are formed in good yield from aldehydes or 1,3-diketones in the presence of CuBr and tert-butylhydroperoxide.³³⁹ Silyl sulfonate esters can be prepared by similar methods, using sulfonic acid anhydrides rather than carboxylic anhydrides. A polymer-supported triflating agent was used to prepare silyl enol triflate from ketones, in the presence of diisopropylethylamine.³⁴⁰

When a silyl enol ether is the trimethylsilyl derivative (Me₃Si–O-C=C), treatment with methyllithium will regenerate the lithium enolate anion and the volatile trimethylsilane (Me₃SiH).³⁴¹

OS VI, 327, 445; VII, 282, 312, 424, 512; VIII, 1, 286, 460; IX, 573. See also, OS VII, 66, 266. For the conversion of ketones to vinylic triflates,³⁴² see OS VIII, 97, 126.

12-18 Conversion of Aldehydes to β-Keto Esters or Ketones

Alkoxycarbonylalkylation or Alkoxycarbonylalkyl-de-hydrogenation

β-Keto esters have been prepared in moderate to high yields by treatment of aldehydes with diethyl diazoacetate in the presence of a catalytic amount of a Lewis acid (e.g., SnCl₂, BF₃, or GeCl₂).³⁴³ The reaction was successful for both aliphatic and aromatic aldehydes, but the former react more rapidly than the latter, and the difference is great enough to allow selective reactivity. In a similar process, aldehydes react with certain carbanions stabilized by boron, in the presence of (F₃CCO)₂O or NCS, to give ketones.³⁴⁴

Ketones can be prepared from aryl aldehydes (ArCHO) by treatment with a Rh complex [(Ph₃P)₂Rh(CO)Ar′], whereby the Ar group is transferred to the aldehyde, producing the ketone (Ar–CO–Ar′).³⁴⁵ In another Rh catalyzed reaction, aryl aldehydes (ArCHO) react with Me₃SnAr′ to give the diaryl ketone (Ar–CO–Ar′).³⁴⁶

Acylation of aryl halides with aldehydes gives arylketones in the presence of a Pd catalyst.³⁴⁷

12-19 Cyanation or Cyano-de-hydrogenation

There are several reactions in which a C–H unit is replaced by C–CN. In virtually all cases, the hydrogen being replaced is on a carbon α to a heteroatom or functional group. There are several examples.

Introduction of a cyano group α to the carbonyl group of a ketone can be accomplished by prior formation of the enolate anion with LDA in THF and addition of this solution to p-TsCN at −78 °C.³⁴⁸ The products are formed in moderate to high yields but the reaction is not applicable to methyl ketones. Treatment of TMSCH₂N(Me)C=Nt-Bu with sec-butyllithium and R₂C=O, followed by iodomethane and NaOMe leads to the nitrile (R₂CH–CN).³⁴⁹

Cyanation has been shown to occur α to a nitrogen, specifically in N,N-dimethylaniline derivatives. Treatment with a catalytic amount of RuCl₃ in the presence of oxygen and NaCN leads to the corresponding cyanomethylamine.³⁵⁰ Conversion of tertiary amines to the α-cyanoamine has been reported in the presence of FeCl₂ and t-BuOOH.³⁵¹

In a different kind of reaction, nitro compounds are α-cyanated by treatment with ⁻CN and K₃Fe(CN)₆.³⁵² The mechanism probably involves ion radicals. In still another reaction, secondary amines are converted to α-cyanoamines by treatment with phenylseleninic anhydride and NaCN or Me₃SiCN.^353,354

Another specialized reaction converts the methyl group of arenes (e.g., toluene) into a cyano group: toluene → benzonitrile, for example.³⁵⁵

12-20 Alkylation of Alkanes

Alkylation or Alkyl-de-hydrogenation

Alkanes can be alkylated by treatment with solutions of stable carbocations³⁵⁶ (Sec. 5.A.ii), but the availability of such carbocations is limited and mixtures are usually obtained. In a typical experiment, the treatment of propane with isopropyl fluoroantimonate (Me₂HC⁺ SbF₆⁻) gave 26% 2,3-dimethylbutane, 28% 2-methylpentane, 14% 3-methylpentane, and 32% n-hexane, as well as some butanes, pentanes (formed by Reaction 12-47), and higher alkanes. Mixtures arise in part because intermolecular hydrogen exchange (RH + R′⁺ → R⁺ + R′H) is much faster than alkylation, so that alkylation products are also derived from the new alkanes and carbocations formed in the exchange reaction. Furthermore, the carbocations present are subject to rearrangement (Chapter 18), giving rise to new carbocations. Products result from all the hydrocarbons and carbocations present in the system. As expected from their relative stabilities, secondary alkyl cations alkylate alkanes more readily than tertiary alkyl cations (the tert-butyl cation does not alkylate methane or ethane). Stable primary alkyl cations are not available, but alkylation has been achieved with complexes formed between CH₃F or C₂H₅F and SbF₅.³⁵⁷ The mechanism of alkylation can be formulated (similar to that shown in hydrogen exchange with superacids, Reaction 12-1) as

It is by means of successive reactions of this sort that simple alkanes like methane and ethane give tert-butyl cations in superacid solutions (Sec. 5.A.ii).³⁵⁸

Intramolecular insertion has been reported. The positively charged carbon of the carbocation (40), generated from the diazonium salt of the triptycene compound (39), reacted with the CH₃ group in close proximity with it.³⁵⁹

12-21 Insertion by Carbenes

CH-Methylene-insertion

The highly reactive species methylene (:CH₂) inserts into C–H bonds,³⁶⁰ both aliphatic and aromatic,³⁶¹ although with aromatic compounds subsequent ring expansion is also possible (see Reaction 15-64). This is effectively a homologation reaction.³⁶² The methylene insertion reaction has limited utility because of its nonselectivity (see Sec. 5.D.i). The insertion reaction of carbenes has been used for synthetic purposes.³⁶³

The carbenes can be generated in any of the ways mentioned in Chapter 5 (Sec. 5.D.ii). Alkylcarbenes usually rearrange rather than give insertion (Sec. 5.D.ii, category 4), but, when this is impossible, intramolecular insertion³⁶⁴ is found rather than intermolecular.³⁶⁵ Methylene (:CH₂) generated by photolysis of diazomethane (CH₂N₂) in the liquid phase is indiscriminate (totally nonselective) in its reactivity (Sec. 5.D.ii, category 2). Methylene (:CH₂) generated in other ways and monoalkyl and dialkyl carbenes are less reactive and insert in the order tertiary > secondary > primary.³⁶⁶ Carbene insertion with certain allylic systems can proceed with rearrangement of the double bond.³⁶⁷ Carbenes have been generated using ultrasound.³⁶⁸ Halocarbenes (:CCl₂,:CBr₂, etc.) insert much less readily, although a number of instances have been reported.³⁶⁹

Insertion at an allylic carbon of alkenes has been reported.³⁷⁰ Dirhodium catalyzed insertion into H–C^sp2 bonds is known,³⁷¹ and also H–C^sp bonds.³⁷² Note that cyclopropanation may compete with C–H insertion with electron-rich highly substituted alkenes.³⁷³ Palladacycles formed by C–H insertion reactions with biphenylene have been intercepted.³⁷⁴ Such species have been impicated in the Heck reaction (Reaction 13-10). Insertion of diazoalkane and diazocarbonyl compounds can be catalyzed by copper compounds³⁷⁵ and silver compounds³⁷⁶ as well. Insertion into the α-C–H bond of an aldehyde gives an α-substituted aldehyde.³⁷⁷ Intramolecular insertion at the α carbon of a ketone by a diazoketone, using TiCl₄, gives a bicyclic 1,3-diketone.³⁷⁸ The reaction in which aldehydes are converted to methyl ketones, RCHO + CH₂N₂ → RCOCH₃, while apparently similar, does not involve a free carbene intermediate and is considered in Reaction 18-9. Note that aryl ketenes react with Me₃SiCHN₂ and then silica to give 2-indanone derivatives.³⁷⁹ A three component coupling reaction of vinyl iodides, secondary amines, and diazo(trimethylsilyl)methane gives allylic amines.³⁸⁰ A gold-catalyzed reaction is known that uses alkynes as an α-diazo ketone equivalent.³⁸¹

Insertion into the O–H bond of alcohols, to produce ethers, has been reported using a diazocarbonyl compound and an In(OTf)₃ catalyst.³⁸² The Cu catalyzed insertion of a diazo ester into an oxetane gives the ring-expanded THF derivative.³⁸³ Insertion is also possible with other ethers, including silyl ethers.³⁸⁴ Metal-catalyzed silylene insertion into allylic ethers leads to allylic silanes.³⁸⁵ Similar insertion at the α carbon of an ether leads to cyclic ethers, with high enantioselectivity when a chiral ligand is used with a Rh catalyst.³⁸⁶

The insertion of the diazocarbonyl unit into the C–H bond of an α-diazo amide gives the lactam shown in the reaction.³⁸⁷ Insertion into a 2-pyrrolidinone derivative using Me₃SiCH₂N₂ followed by AgCO₂Ph with ultrasound gave the ring-expanded 2-piperidone derivative.³⁸⁸ Intramolecular insertion reactions are well known,³⁸⁹ and tolerate a variety of functional groups.³⁹⁰

The metal carbene insertion reaction, in contrast to the methylene insertion reaction can be highly selective³⁹¹ and useful in synthesis.³⁹² There are numerous examples, usually requiring a transition metal catalyst.³⁹³ The catalyst typically converts a diazoalkane or diazocarbonyl compound to the metal carbene in situ, allowing the subsequent insertion reaction. Intermolecular reactions are known, including diazoalkane insertion reaction with a dirhodium catalyst.³⁹⁴ When chiral ligands are present good enantioselectivity is observed in the insertion product.³⁹⁵

The mechanism³⁹⁶ of the insertion reaction is not known with certainty, but there seem to be at least two possible pathways.

1. A simple one-step process involving a three-center cyclic transition state:

The most convincing evidence for this mechanism is that in the reaction between isobutene-1 and carbene the product 2-methyl-1-butene was labeled only in the 1 position.³⁹⁷ This rules out a free radical or a carbocation or carbanion intermediate. If 41 (or a corresponding ion) were an intermediate, resonance would ensure that some carbene attacked at the 1 position:

Other evidence is that retention of configuration, which is predicted by this mechanism, has been found in a number of instances.³⁹⁸ An ylid intermediate was trapped in the reaction of :CH₂ with allyl alcohol.³⁹⁹

2. A free radical process in which the carbene directly abstracts a hydrogen from the substrate to generate a pair of free radicals:

One fact supporting this mechanism is that among the products obtained (beside butane and isobutane) on treatment of propane with CH₂ (generated by photolysis of diazomethane and ketene) were propene and ethane,⁴⁰⁰which could arise, respectively, by

and

That this mechanism can take place under suitable conditions has been demonstrated by isotopic labeling⁴⁰¹ and by other means.⁴⁰² However, the formation of disproportionation and dimerization products does not always mean that the free radical abstraction process takes place. In some cases, these products arise in a different manner.⁴⁰³ The product of the reaction between a carbene and a molecule may have excess energy (see Sec. 5.D.ii). Therefore it is possible for the substrate and the carbene to react by mechanism 1 (the direct-insertion process) and for the excess energy to cause the compound thus formed to cleave to free radicals. When this pathway is in operation, the free radicals are formed after the actual insertion reaction.

The mechanism of cyclopropylcarbene reactions has also been discussed.⁴⁰⁴

It has been suggested⁴⁰⁵ that singlet carbenes insert by the one-step direct-insertion process and triplets (which, being free radicals, are more likely to abstract hydrogen) by the free radical process. In support of this suggestion, CIDNP signals⁴⁰⁶ (Sec. 5.C.i) were observed in the ethylbenzene produced from toluene and triplet CH₂, but not from the same reaction with singlet CH₂.⁴⁰⁷ Carbenoids (e.g., compounds of the form R₂CMCl, see Reaction 12-39) can insert into a C–H bond by a different mechanism, similar to pathway 2, but involving abstraction of a hydride ion rather than a hydrogen atom.⁴⁰⁸

For the similar insertion reaction of nitrenes, see Reaction 12-13.

OS VII, 200.

F. Metal Electrophiles

12-22 Metalation with Organometallic Compounds

Metalation or Metalo-de-hydrogenation

Many organic compounds can be metalated by treatment with an organometallic compound.⁴⁰⁹ Since the reaction involves a proton transfer, the equilibrium lies on the side of the weaker acid.⁴¹⁰ For example, fluorene reacts with n-butyllithium to give butane and 9-fluorenyllithium. Since aromatic hydrocarbons are usually stronger acids than aliphatic ones, R is most often aryl. The most common reagent is probably butyllithium.⁴¹¹ Reductive lithiation is an important method for the preparation of organolithium reagents.⁴¹² Normally, only active aromatic rings react with butyllithium. Benzene itself reacts very slowly and in low yield, although benzene can be metalated by butyllithium either in the presence of tert-BuOK⁴¹³ or by n-butyllithium that is coordinated with various diamines.⁴¹⁴ Metalation of aliphatic RH is most successful when the carbanions are stabilized by resonance (allylic, benzylic, propargylic,⁴¹⁵ etc.) or when the negative charge is at an sp carbon (at triple bonds). Trimethylsilylmethyl potassium (Me₃SiCH₂K)⁴¹⁶ and also a combination of an organolithium compound with a bulky alkoxide (LICKOR superbase)⁴¹⁷ are very good reagents for allylic metalation. The former is also useful for benzylic positions. A combination of BuLi, t-BuOK, and tetramethylethylenediamine has been used to convert ethylene to vinylpotassium.⁴¹⁸The reaction can be used to determine relative acidities of very weak acids by allowing two R–H compounds to compete for the same R′M and to determine which proton in a molecule is the most acidic.⁴¹⁹

Note that organolithium compounds are aggregated species and can form hetero-aggregates containing different organic groups.⁴²⁰ N-Lithio-N-(trialkylsilyl)allylamines are deprotonated in ether solvents at the cis-vinylic position to give 3,N-dilithio-N-(trialkylsilyl)allylamines.⁴²¹

In general, the reaction can be performed only with organometallics of active metals (e.g., Li, Na, and K), but Grignard reagents abstract protons from a sufficiently acidic C–H bond, as in R–CC–H → R–CC–MgX. This is the best method for the preparation of alkynyl Grignard reagents.⁴²² Lewis acids have been used to promote α-lithiation of amines.⁴²³ Triethylgallium has been used to generate enolate anions from ketones.⁴²⁴

When a heteroatom (e.g., N, O, S,⁴²⁵ or a halogen),⁴²⁶ is present in a molecule containing an aromatic ring or a double bond, lithiation is usually quite regioselective.⁴²⁷ It has been shown that fluorine is more effective for stabilization of carbanions when compared to the heavier halogens.⁴²⁸ In such compounds, the lithium usually bonds with the sp² carbon closest to the heteroatom, probably because the attacking species coordinates with the heteroatom.⁴²⁹ This type of reaction with compounds such as anisole are often called directed metalations.⁴³⁰ In the case of aromatic rings, this means attack at the ortho position,⁴³¹ but this is considered in Reaction 13-17.

Ref. ⁴³²

In the case of γ,δ-unsaturated disubstituted amides (42), the lithium does not go to the closest position, but in this case too the regiochemistry is controlled by coordination to the oxygen.⁴³³ Cyclopropyllithium reagents are rather stable.⁴³⁴

The mechanism involves an attack by R′⁻ (or a polar R′) on the hydrogen⁴³⁵ (an acid–base reaction) Evidence is that resonance effects of substituents in R seem to make little difference. When R is aryl, OMe and CF₃ both direct ortho, while isopropyl directs meta and para (mostly meta).⁴³⁶ These results are exactly what would be expected from pure field effects, with no contribution from resonance effects, which implies that attack occurs at the hydrogen and not at R. Other evidence for the involvement of H in the rate-determining step is that there are large isotope effects.⁴³⁷ The nature of R′ also has an effect on the rate. In the reaction between triphenylmethane and R′Li, the rate decreased in the order R′ = allyl > Bu > Ph > vinyl > Me, although this order changed with changing concentration of R′Li, because of varying degrees of aggregation of the R′Li.⁴³⁸ With respect to the reagent, this reaction is a special case of Reaction 12-24.

Enantioselective reactions are known. The preparation of chlorodeuteriomethylithium proceeds with inversion from the corresponding enantiopure stannyl derivative.⁴³⁹ Although highly reactive chemically, it is configurationally stable at temperatures up to −78 °C. Enantioselective catalytic deprotonation with chiral ligands has been used for the deprotonation of N-Boc amines to give chiral α-trimethylsilyl derivatives.⁴⁴⁰ A barrier to enantiomerization has been observed for unstablized, chelated, and dipole-stabilized organolithium compounds. Studies of lithiopyrrolidines show free energies for enantiomerization in the range of 19–22 kcal mol⁻¹ (79.5–92.1 kJ mol⁻¹) at 0 °C.⁴⁴¹

A closely related reaction is formation of nitrogen ylids⁴⁴² from quaternary ammonium salts (see Reaction 17-8):

Phosphonium salts undergo a similar reaction (see Reaction 16-44).

OS II, 198; III, 413, 757; IV, 792; V, 751; VI, 436, 478, 737, 979; VII, 172, 334, 456, 524; VIII, 19, 391, 396, 606.

12-23 Metalation with Metals and Strong Bases

Metalation or Metalo-de-hydrogenation

Organic compounds can be metalated at suitably acidic positions by active metals and by strong bases.⁴⁴³ The reaction has been used to study the acidities of very weak acids (see Sec. 5.B.i). The conversion of terminal alkynes to acetylide ions is one important application.⁴⁴⁴ A gold-catalyst conversion of trimethylsilyl substituted esters and carbonates to the corresponding enolate anion has been reported⁴⁴⁵. Synthetically, an important use of the method is to convert aldehydes and ketones,⁴⁴⁶ carboxylic esters, and similar compounds to their enolate forms,⁴⁴⁷ for example, for use in nucleophilic substitutions (Reactions 10-67, 10-68, and 13-14) and in additions to multiple bonds (Reactions 15-24 and 16-53). Note that the reaction of carbonyl compounds with lithium dialkylamides leads to the corresponding enolate anion. This reaction was discussed in Reaction 10-68, in connection with the alkylation reaction of enolate anions.

OS I, 70, 161, 490; IV, 473; VI, 468, 542, 611, 683, 709; VII, 229, 339. Conversions of ketones or esters to enolates are not listed.

12.C.ii. Metals as Leaving Groups

A. Hydrogen as the Electrophile

12-24 Replacement of Metals by Hydrogen

Hydro-de-metalation or Demetalation

Organometallic compounds, including enolate anions, react with acids in reactions that replace the metal with hydrogen.⁴⁴⁸ The R group may be aryl (see Reaction 11-41). The reaction is often used to introduce deuterium or tritium into susceptible positions. For Grignard reagents, water is usually a strong enough acid, but stronger acids are also used. An important method for the reduction of alkyl halides consists of the process RX → RMgX → RH.

The organometallic compounds that are hydrolyzed by water are the ones high in the electromotive series: Na, K, Li, Zn, and so on. Enantioselective protonation of lithium enolates⁴⁴⁹ and cyclopropyllithium compounds⁴⁵⁰ have been reported. When the metal is less active, stronger acids are required. For example, R₂Zn compounds react explosively with water, R₂Cd slowly, and R₂Hg not at all, although the latter can be cleaved with concentrated HCl. However, this general statement has many exceptions, some hard to explain. For example, BR₃ compounds are completely inert to water, and GaR₃ at room temperature cleave just one R group, but AlR₃ reacts violently with water. However, BR₃ can be converted to RH with carboxylic acids.⁴⁵¹ For less active metals, it is often possible to cleave just one R group from a multivalent metal. For example,

Organometallic compounds of less active metals and metalloids (e.g., Si,⁴⁵² Sb, and Bi), are quite inert to water. Organomercury compounds (RHgX or R₂Hg) can be reduced to RH by H₂, NaBH₄, or other reducing agents.⁴⁵³ The reduction with NaBH₄ takes place by a free radical mechanism.⁴⁵⁴ Alkyl-Si bonds are cleaved by H₂SO₄ [e.g., HOOCCH₂CH₂SiMe₃ → 2CH₂ + (HOOCCH₂CH₂SiMe₃)₂O].⁴⁵⁵

When the hydrogen of the HA is attached to carbon, this reaction is the same as 12-22.

This section does not list the many hydrolyses of Na or K enolates, and so on found in Organic Syntheses. The hydrolysis of a Grignard reagent to give an alkane is found at OS II, 478; the reduction of a vinylic tin compound at OS VIII, 381; and the reduction of an alkynylsilane at OS VIII, 281.

B. Oxygen Electrophiles

12-25 The Reaction between Organometallic Reagents and Oxygen⁴⁵⁶

Hydroperoxy-de-metalation; Hydroxy-de-metalation

Oxygen reacts with Grignard reagents to give either hydroperoxides⁴⁵⁷ or alcohols. The reaction can be used to convert alkyl halides to alcohols without side reactions. With aryl Grignard reagents, yields are lower and only phenols are obtained, not hydroperoxides. Because of this reaction, oxygen should be excluded when Grignard reagents are prepared and used in various reactions.

Most other organometallic compounds also react with oxygen. Trialkylboranes and alkyldichloroboranes (RBCl₂) can be conveniently converted to hydroperoxides by treatment with oxygen followed by hydrolysis.⁴⁵⁸ Dilithiated carboxylic acids (see Reaction 10-70) react with oxygen to give (after hydrolysis) α-hydroxy carboxylic acids.⁴⁵⁹ There is evidence that the reaction between Grignard reagents and oxygen involves a free radical mechanism.⁴⁶⁰

OS V, 918. See also, OS VIII, 315.

12-26 Reaction between Organometallic Reagents and Peroxides

tert-Butoxy-de-metalation

A convenient method of preparation of tert-butyl ethers consists of treating Grignard reagents with tert-butyl acyl peroxides.⁴⁶¹ Both alkyl and aryl Grignard reagents can be used. The application of this reaction to Grignard reagents prepared from cyclopropyl halides permits cyclopropyl halides to be converted to tert-butyl ethers of cyclopropanols,⁴⁶² which can then be easily hydrolyzed to the cyclopropanols. The direct conversion of cyclopropyl halides to cyclopropanols by Reaction 10-1 is not generally feasible, because cyclopropyl halides do not generally undergo nucleophilic substitutions without ring opening.

Vinyllithium reagents (43) react with silyl peroxides to give high yields of silyl enol ethers with retention of configuration.⁴⁶³ Since the preparation of 43 from vinylic halides (Reaction 12-39) also proceeds with retention, the overall procedure is a method for the stereospecific conversion of a vinylic halide to a silyl enol ether. Dialky ethers have been prepared from organotrifluoroborates and acetals⁴⁶⁴.

OS V, 642, 924.

12-27 Oxidation of Trialkylboranes to Borates

The reaction of alkenes with borane, monoalkyl, and dialkylboranes leads to a new organoborane (see Reaction 15-16). Treatment of organoboranes with alkaline H₂O₂ oxidizes trialkylboranes to esters of boric acid.⁴⁶⁵ This reaction does not affect double or triple bonds, aldehydes, ketones, halides, or nitriles that may be present elsewhere in the molecule. There is no rearrangement of the R group itself, and this reaction is a step in the hydroboration method of converting alkenes to alcohols (Reaction 15-16). The mechanism has been formulated as involving initial formation of an ate complex when the hydroperoxide anion attacks the electrophilic boron atom. Subsequent rearrangement from boron to oxygen,⁴⁶⁵ as shown, leads to the B–O–R unit.

Similar migration of the other two R groups and hydrolysis of the B–O bonds leads to the alcohol and boric acid. Retention of configuration is observed in R. Boranes can also be oxidized to borates in good yields with oxygen,⁴⁶⁶with sodium perborate (NaBO₃)⁴⁶⁷ and with trimethylamine oxide, either anhydrous⁴⁶⁸ or in the form of the dihydrate.⁴⁶⁹ The reaction with oxygen is free radical in nature.⁴⁷⁰

OS V, 918; VI, 719, 852, 919.

12-28 Preparation of Borates and Boronic Acids

Alkylboronic and arylboronic acids [RB(OH)₂, and ArB(OH)₂], respectively, are increasingly important in organic chemistry. The Pd catalyzed coupling reaction of aryl halides and aryl triflates with arylboronic acids (the Suzuki–Miyaura reaction, 13-12) is probably the most notable example. A simple synthesis involves the reaction of a Grignard reagent (e.g., phenylmagnesium bromide) with an alkyl borate to give phenylboronic acid.⁴⁷¹ Alkylboronic acids are similarly prepared.⁴⁷² Note that boronic acids are subject to cyclic trimerization with loss of water to form boroxines. Tetrahydroxydiboron has been used to prepare allylboronic acids, as well as potassium trifluoro(allyl)borates.⁴⁷³

Trimethylborate [B(OMe)₃] can be used in place of tri-n-butyl borate.⁴⁷⁴ Newer methods involve the Pd mediated borylation of alcohols with bis(pinacolato)diboron⁴⁷⁵ or pinacolborane,⁴⁷⁶ but deprotection of the boronate esters can be a problem. Diolboranes (e.g., catecholborane 44)⁴⁷⁷ are prepared by the reaction of a diol with borane. Cedranediolborane (45, prepared from the cedrane-8,9-diol⁴⁷⁸ by treatment with borane•dimethyl sulfide) can be coupled to aryl iodides with a palladium catalyst, and generates the free boronic acid by treatment with diethanolamine and then aq acid.⁴⁷⁹ Boronate esters are often prepared as a means to purify the organoboron species, but some of these esters are hydrolytically unstable and difficult to deal with upon completion of the reaction.⁴⁸⁰

Alkeneboronic esters and acids are also readily available, as in the addition of vinylmagnesium chloride⁴⁸¹ to trimethyl borate below −50 °C, followed by hydrolysis.⁴⁸² A nonaqueous workup procedure has been reported for the preparation of arylboronic esters [ArB(OR′₂)].⁴⁸³ Uncontrollable polymerization or oxidation of much of the boronic acid occurred during the final stages of the isolation procedure, but could be avoided by in situ conversion to the dibutyl ester by adding the crude product to 1-butanol. The Sm(III) catalyzed hydroboration of olefins with catecholborane is a good synthesis of boronate esters.⁴⁸⁴

Trialkyl borates (sometimes called orthoborates) can be prepared by heating the appropriate alcohol with boron trichloride in a sealed tube, but the procedure works well only for relatively simple alkyl groups.⁴⁸⁵ Heating alcohols with boron trioxide (B₂O₃) in an autoclave at 110–170 °C give the trialkyl borate.⁴⁸⁶ Boric acid can be used for the preparation of orthoborates⁴⁸⁷ by heating with alcohols in the presence of either hydrogen chloride or concentrated sulfuric acid. Removal of water as an azeotrope with excess alcohol improves the yield,⁴⁸⁸ and good yields can be obtained. for trialkyl borates⁴⁸⁹ and even for triphenyl borate.⁴⁹⁰ This method is unsuccessful for those borates whose parent alcohols do not form azeotropes with water and for the tertiary alkyl borates,⁴⁸⁹ impure samples are usually obtained.⁴⁹¹

Potassium organotrifluoroborates (RBF₃K) are readily prepared by the addition of inexpensive KHF₂ to a variety of organoboron intermediates.⁴⁹² They are monomeric, crystalline solids that are readily isolated and indefinitely stable in the air. These reagents can be used in several of the applications where boronic acids or esters are used (Reactions 13-10–13-13).⁴⁹³ Note that vinylboronic acid and even vinylboronate esters are unstable to polymerization,⁴⁹⁴ whereas the analogous vinyltrifluoroborate is readily synthesized and completely stable.⁴⁹⁵

OS 13, 16; 81, 134.

12-29 Oxygenation of Organometallic Reagents and Other Substrates to O-Esters and Related Compounds

In some cases, it is possible to oxygenate a nonaromatic carbon atom using various reagents, where the product is an O- ester rather than an alcohol. In one example, a vinyl iodonium salt was heated with DMF to produce the corresponding formate ester.⁴⁹⁶

C. Sulfur Electrophiles

12-30 Conversion of Organometallic Reagents to Sulfur Compounds

Thiols and sulfides are occasionally prepared by treatment of Grignard reagents with sulfur.⁴⁹⁷ Analogous reactions are known for selenium and tellurium compounds. Grignard reagents and other organometallic compounds⁴⁹⁸react with sulfuryl chloride to give sulfonyl chlorides,⁴⁹⁹ with esters of sulfinic acids to give (stereospecifically) sulfoxides,⁵⁰⁰ with disulfides to give sulfides,⁵⁰¹ and with SO₂ to give sulfinic acid salts,⁵⁰² which can be hydrolyzed to sulfinic acids or treated with halogens to give sulfonyl halides.⁵⁰³

OS III, 771; IV, 667; VI, 533, 979.

D. Halogen Electrophiles

12-31 Halo-de-metalation

Grignard reagents react with halogens to give alkyl halides. The reaction is useful for the preparation of iodo compounds from the corresponding chloro or bromo compounds. The reaction is not useful for preparing chlorides, since the reagents RMgBr and RMgI react with Cl₂ to give mostly RBr and RI, respectively.⁵⁰⁴

Most organometallic compounds, both alkyl and aryl, also react with halogens to give alkyl or aryl halides.⁵⁰⁵ The reaction can be used to convert acetylide ions to 1-haloalkynes.⁵⁰⁶ Vinyliodonium tetrafluoroborates were converted to vinyl fluorides by heating.⁵⁰⁷ Similarly, vinyl trifluoroborates were converted to the vinyl iodide with NaI and chloramine-T in aq THF.⁵⁰⁸ The reaction of an alkene with CuO·BF₄, iodine and triethylsilane gave the 2-iodoalkane.⁵⁰⁹ Vinylzirconate reagents react with I₂ to give the corresponding vinyl iodide.⁵¹⁰

Enolate anions can be converted to the corresponding vinyl phosphate, and subsequent reaction with triphenylphosphine dihalide leads to the vinyl halide.⁵¹¹

Trialkylboranes react rapidly with I₂⁵¹² or Br₂⁵¹³ in the presence of NaOMe in methanol, or with FeCl₃ or other reagents⁵¹⁴ to give alkyl iodides, bromides, or chlorides, respectively. Combined with the hydroboration reaction (Reaction 15-16), this is an indirect way of adding HBr, HI, or HCl to a double bond to give products with an anti-Markovnikov orientation (see Reaction 15-1). Trialkylboranes can also be converted to alkyl iodides by treatment with allyl iodide and air in a free radical process.⁵¹⁵ trans-1-Alkenylboronic acids (47), prepared by hydroboration of terminal alkynes with catecholborane to give 46⁵¹⁶ (Reaction 15-16), followed by hydrolysis, react with I₂ in the presence of NaOH at 0 °C in ethereal solvents to give trans-vinylic iodides.⁵¹⁷

Treatment with ICl also gives the vinyl iodide.⁵¹⁸ This is an indirect way of accomplishing the anti-Markovnikov addition of HI to a terminal triple bond. The reaction cannot be applied to alkenylboronic acids prepared from internal alkynes. However, alkenylboronic acids prepared from both internal and terminal alkynes react with Br₂ (2 molar equivalents of Br₂ must be used) followed by base to give the corresponding vinylic bromide, but in this case with inversion of configuration; so the product is the cis-vinylic bromide.⁵¹⁹ Alkenylboronic acids also give vinylic bromides and iodides when treated with a mild oxidizing agent and NaBr or NaI, respectively.⁵²⁰ Treatment of 47(prepared from terminal alkynes) with Cl₂ gave vinylic chlorides with inversion.⁵²¹ Vinylic boranes can be converted to the corresponding vinylic halide by treatment with NCS or NBS.⁵²² Vinylic halides can also be prepared from vinylic silanes⁵²³ and from vinylic copper reagents. The latter react with I₂ to give iodides,⁵²⁴ and with NCS or NBS at −45 °C to give chlorides or bromides.⁵²⁵ The reaction of an aryl alkyne with HInCl₂/BEt₃ and then iodine leads to a (Z)-vinyl iodide with respect to the aryl group and the iodine atom.⁵²⁶ Boronic acids can be fluorinated in a reaction mediated by Ag(I) triflate.⁵²⁷

For the reaction of lithium enolate anions of esters with I₂ or CX₄, see Reaction 12-5.

The conversion of terminal alkynes to 1-iodo-1-alkynes was reported using NaI under electrochemical conditions.⁵²⁸ 1-Bromo-1-alkynes were converted to the 1-iodo-1-alkyne with CuI.⁵²⁹ 1-Trialkyldisilylalkynes were converted to the corresponding 1-bromoalkyne via reaction with NBS and AgF.⁵³⁰ Terminal alkynes react with (diacetoxyiodo)benzene, KI, and CuI to give 1-iodo-alkynes.⁵³¹ Trichloroisocyanuric acid has been used to convert terminal alkynes to 1-chloroalkynes.⁵³²

It is unlikely that a single mechanism suffices to cover all conversions of organometallic compounds to alkyl halides.⁵³³ In a number of cases, the reaction has been shown to involve inversion of configuration (see Sec. 12.A.i), indicating an S_E2 (back) mechanism, while in other cases retention of configuration has been shown,⁵³⁴ implicating an S_E2 (front) or S_Ei mechanism. In still other cases, complete loss of configuration as well as other evidence demonstrated the presence of a free radical mechanism.^534,535

OS I, 125, 325, 326; III, 774, 813; V, 921; VI, 709; VII, 290; VIII, 586; IX, 573. Also see, OS II, 150.

E. Nitrogen Electrophiles

12-32 The Conversion of Organometallic Compounds to Amines

Amino-de-metalation

There are several methods for conversion of alkyl- or aryllithium compounds to primary amines.⁵³⁶ The two most important are treatment with hydroxylamine derivatives and with certain azides.⁵³⁷ In the first of these methods, treatment of RLi with methoxyamine and MeLi in ether at −78 °C gives RNH₂.⁵³⁸ Grignard reagents from aliphatic halides give lower yields. The reaction can be extended to give secondary amines by the use of N-substituted methoxyamines (CH₃ONHR′).⁵³⁹ There is evidence⁵⁴⁰ that the mechanism involves the direct displacement of OCH₃ by R on an intermediate CH₂ONR′⁻ (CH₂ONR′⁻ Li⁺ + RLi → CH₃OLi + RNR′⁻ Li⁺). Tosyl azide (TsN₃) is a highly useful azide.⁵⁴¹ The initial product is usually RN₃, but this is easily reduced to the amine (Reaction 19-51). With some azides (e.g., azidomethyl phenyl sulfide, PhSCH₂N₃), the group attached to the N₃ is a poor leaving group, so the initial product is a triazene (in this case ArNHN=NCH₂SPh from ArMgX), which can be hydrolyzed to the amine.⁵⁴²

Organoboranes react with a mixture of aq NH₃ and NaOCl to produce primary amines.⁵⁴³ It is likely that the actual reagent is chloramine (NH₂Cl). Chloramine itself,⁵⁴⁴ hydroxylamine-O-sulfonic acid in diglyme,⁵⁴⁵ and trimethylsilyl azide⁵⁴⁶ also give the reaction. Since the boranes can be prepared by the hydroboration of alkenes (Reaction 15-16), this is an indirect method for the addition of NH₃ to a double bond with anti-Markovnikovorientation. Secondary amines can be prepared⁵⁴⁷ by the treatment of alkyl- or aryldichloroboranes or dialkylchloroboranes with alkyl or aryl azides.

The use of an optically active R∗BCl₂ gave secondary amines of essentially 100% optical purity.⁵⁴⁸ Aryllead triacetates [ArPb(OAc)₃] give secondary amines (ArNHAr′) when treated with primary aromatic amines Ar′NH₂ and Cu(OAc)₂.⁵⁴⁹

Secondary amines have been converted to tertiary amines by treatment with lithium dialkylcuprate reagents: R₂CuLi + NHR → RNR′₂.⁵⁵⁰ The reaction was also used to convert primary amines to secondary, but yields were lower.⁵⁵¹

Terminal alkynes reacted with chlorodiphenylphosphine (Ph₃PCl) and a Ni catalyst to give the 1-diphenylphosphino alkyne (R-CC-PPh₂).⁵⁵² Alkynyl halides can be used for a similar reaction. Treatment of methyl carbamates with KHMDS and CuI, followed by 2 equiv of 1-bromophenylacetylene gave the N-substituted alkyne, Ph-CC-N(CO₂Me)R.⁵⁵³

Metal-catalyzed amination reactions are increasingly important in organic methodology. In a typical reaction, an amine is coupled to an alkyl, vinyl, or aryl halide (or with a different leaving group) in the presence of a transition metal, usually Pd. Presumably, the amination occurs via reaction with a transient organometallic species. Amination of aromatic compounds via this approach is discussed in section Reaction 13-5. Aliphatic and vinyl substrates are treated here. In one example, a vinyl triflate is converted to an enamine via reaction with pyrrole in the presence of a Pd catalyst.⁵⁵⁴

OS VI, 943.

F. Carbon Electrophiles

12-33 The Conversion of Organometallic Compounds to Ketones, Aldehydes, Carboxylic Esters, or Amides

Acyl-de-metalation, and so on

Symmetrical ketones⁵⁵⁵ can be prepared in good yields by the reaction of organomercuric halides⁵⁵⁶ with dicobalt octacarbonyl in THF,⁵⁵⁷ or with nickel carbonyl in DMF or certain other solvents.⁵⁵⁸ The R group may be aryl or alkyl. However, when R is alkyl, rearrangements may intervene in the CO₂(CO)₈ reaction, although the Ni(CO)₄ reaction seems to be free from such rearrangements.⁵⁵⁹ Divinylic ketones (useful in the Nazarov cyclization, 15-20) have been prepared in high yields by treatment of vinylic mercuric halides with CO and a Rh catalyst.⁵⁵⁹ In a more general synthesis of unsymmetrical ketones, tetraalkyltin compounds (R₄Sn) are treated with a halide R′X (R′ = aryl, vinylic, benzylic), CO, and a Pd complex catalyst.⁵⁶⁰ Similar reactions use Grignard reagents, Fe(CO)₅, and an alkyl halide.⁵⁶¹

Grignard reagents react with formic acid to give good yields of aldehydes. Two molar equivalents of RMgX are used; the first converts HCO₂H to HCOO⁻, which reacts with the second equivalent to give RCHO.⁵⁶² Alkyllithium reagents and Grignard reagents react with CO to give symmetrical ketones.⁵⁶³ An interesting variation reacts CO₂ with an organolithium, which is then treated with a different organolithium reagent to give the unsymmetrical ketone.⁵⁶⁴ α,β-Unsaturated aldehydes can be prepared by treatment of vinylic silanes with dichloromethyl methyl ether and TiCl₄ at −90 °C.⁵⁶⁵

α,β-Unsaturated esters can be prepared by treating boronic esters (27) with CO, PdCl₂, and NaOAc in MeOH.⁵⁶⁶ The synthesis of α,β-unsaturated esters has also been accomplished by treatment of vinylic mercuric chlorides with CO at atmospheric pressure and a Pd catalyst in an alcohol as solvent, for example,⁵⁶⁷

Alkyl and aryl Grignard reagents can be converted to carboxylic esters with Fe(CO)₅ instead of CO.⁵⁶⁸

Amides have been prepared by the treatment of trialkyl or triarylboranes with CO and an imine, in the presence of catalytic amounts of cobalt carbonyl⁵⁶⁹:

In another method for the conversion RM → RCONR, Grignard reagents and organolithium compounds are treated with a formamide (HCONR′₂) to give the intermediate RCH(OM)NR′₂, which is not isolated, but treated with PhCHO or Ph₂CO to give the product RCONR′₂.⁵⁷⁰

Direct conversion of a hydrocarbon to an aldehyde (R–H → R–CHO) was reported by treatment of the hydrocarbon with GaCl₃ and CO.⁵⁷¹

For carbonylation reactions of aryl halides, see Reaction 13-15.

See also, Reactions 10-76, 15-32, and 18-23–18-24.

OS VIII, 97.

12-34 Cyano-de-metalation

Vinylic copper reagents react with ClCN to give vinyl cyanides, although BrCN and ICN give the vinylic halide instead.⁵⁷² Vinylic cyanides have also been prepared by the reaction between vinylic lithium compounds and phenyl cyanate (PhOCN).⁵⁷³ Alkyl nitriles (RCN) have been prepared, in varying yields, by treatment of sodium trialkylcyanoborates with NaCN and lead tetraacetate.⁵⁷⁴ Vinyl bromides reacted with KCN, in the presence of a Ni complex and Zn metal to give the vinyl nitrile.⁵⁷⁵ Vinyl triflates react with LiCN, in the presence of a Pd catalyst, to give the vinyl nitrile.⁵⁷⁶

For other electrophilic substitutions of the type RM → RC, which are discussed under nucleophilic substitutions in Chapter 10, see also, Reactions 16-81–16-85 and 16-99.

OS IX, 548

G. Metal Electrophiles

12-35 Transmetalation with a Metal

Metalo-de-metalation

Many organometallic compounds are best prepared by this reaction, which involves replacement of a metal in an organometallic compound by another metal. The RM′ compound can be successfully prepared only when M′ is above M in the electromotive series, unless some other way is found to shift the equilibrium. That is, RM is usually an unreactive compound and M′ is a metal more active than M. Most often, RM is R₂Hg, since mercury alkyls⁵⁵⁶are easy to prepare and mercury is far down in the electromotive series.⁵⁷⁷ Alkyls of Li, Na, K, Be, Mg, Al, Ga, Zn, Cd, Te, Sn, and so on, have been prepared this way. An important advantage of this method over Reaction 12-38 is that it ensures that the organometallic compound will be prepared free of any possible halide. This method can be used for the isolation of solid sodium and potassium alkyls.⁵⁷⁸ If the metals lie too close together in the series, it may not be possible to shift the equilibrium. For example, alkylbismuth compounds cannot be prepared in this way from alkylmercury compounds.

OS V, 1116.

12-36 Transmetalation with a Metal Halide

Metalo-de-metalation

In contrast to Reaction 12-35, the reaction between an organometallic compound and a metal halide is successful only when M′ is below M in the electromotive series.⁵⁷⁹ The two reactions considered together therefore constitute a powerful tool for preparing all kinds of organometallic compounds. In this reaction, the most common substrates are Grignard reagents and organolithium compounds.⁵⁸⁰

The MgX of Grignard reagents⁵⁸¹ can migrate to terminal positions in the presence of small amounts of TiCl₄.⁵⁸² The proposed mechanism consists of metal exchange (Reaction 12-36), elimination–addition, and metal exchange:

The addition step is similar to Reactions 15-16 or 15-17 and follows Markovnikov's rule, so the positive titanium goes to the terminal carbon.

Among others, alkyls of Be, Zn,⁵⁸³ Cd, Hg, Al, Sn, Pb, Co, Pt, and Au have been prepared by treatment of Grignard reagents with the appropriate halide.⁵⁸⁴ The reaction has been used to prepare alkyls of almost all nontransition metals and even of some transition metals. Alkyls of metalloids and of nonmetals, including Si, B,⁵⁸⁵ Ge, P, As, Sb, and Bi, can also be prepared in this manner.⁵⁸⁶ Except for alkali-metal alkyls and Grignard reagents, the reaction between RM and M′X is the most common method for the preparation of organometallic compounds.⁵⁸⁷ In the presence of Ir,⁵⁸⁸ or Pd catalysts,⁵⁸⁹ aromatic compunds react with boranes to give the corresponding arylborane.

Lithium dialkylcopper reagents are prepared from 2 molar equivalents of RLi with 1 molar equivalent of a cuprous halide in ether at low temperatures:⁵⁹⁰ The formation of organocuprates of this type are discussed in more detail in Reaction 10-58, in connection with the coupling reaction of organocuprates with alkyl halides.

Another way is to dissolve an alkylcopper compound in an alkyllithium solution. Higher order cuprates can also be prepared, as well as “non-ate” copper reagents.⁵⁹¹

Metallocenes (48, see Sec. 2.I.ii) are usually made by this method. Among others, metallocenes of Sc, Ti, V, Cr, Mn, Fe, Co, and Ni have been prepared in this manner.⁵⁹²

In a related reaction, sulfurated boranes (R₂B–SSiR′₂) react with Grignard reagents (e.g., methylmagneisum bromide) to give the β-alkyl borane (e.g., R₂B–Me) upon heating in vacuo.⁵⁹³

OS I, 231, 550; III, 601; IV, 258, 473, 881; V, 211, 496, 727, 918, 1001; VI, 776, 875, 1033; VII, 236, 290, 524; VIII, 23, 57, 268, 474, 586, 606, 609. Also see, OS IV, 476

12-37 Transmetalation with an Organometallic Compound

Metalo-de-metalation

This type of metallic exchange is used much less often than Reactions 12-35 and 12-36. It is an equilibrium reaction and is useful only if the equilibrium lies in the desired direction. Usually the goal is to prepare a lithium compound that is not prepared easily in other ways,⁵⁹⁴ for example, a vinylic or an allylic lithium, most commonly from an organotin substrate. Examples are the preparation of vinyllithium from phenyllithium and tetravinyltin and the formation of α-dialkylamino organolithium compounds from the corresponding organotin compounds⁵⁹⁵

The reaction has also been used to prepare 1,3-dilithiopropanes⁵⁹⁶ and 1,1-dilithiomethylenecyclohexane⁵⁹⁷ from the corresponding mercury compounds. In general, the equilibrium lies in the direction in which the more electropositive metal is bonded to that alkyl or aryl group that is the more stable carbanion (Sec. 5.B.i). The reaction proceeds with retention of configuration;⁵⁹⁸ an S_Ei mechanism is likely.⁵⁹⁹

“Higher order” cuprates⁶⁰⁰ (see Reaction 10-58) have been produced by this reaction starting with a vinylic tin compound:⁶⁰¹

These compounds are not isolated, but used directly in situ for conjugate addition reactions (Reaction 15-25). Another method for the preparation of such reagents (but with Zn instead of Li) allows them to be made from α-acetoxy halides:⁶⁰²

OS V, 452; VI, 815; VIII, 97.

12.C.iii. Halogen as Leaving Group

The reduction of alkyl halides can proceed by an electrophilic substitution mechanism, but it is considered in Chapter 19 (Reaction 19-53).

12-38 Metalo-de-halogenation

Alkyl halides react directly with certain metals to give organometallic compounds.⁶⁰³ The most common metal is Mg, and of course this is by far the most common method for the preparation of Grignard reagents.⁶⁰⁴ The Grignard reaction with aldehydes or ketones is discussed in Reaction 16-24. The order of halide activity is I > Br > Cl. This reaction can be applied to many alkyl halides primary, secondary, and tertiary and to aryl halides, although aryl chlorides require the use of THF or another higher-boiling solvent instead of the usual ether, or special entrainment methods.⁶⁰⁵ Aryl iodides and bromides can be treated in the usual manner. Allylic Grignard reagents can also be prepared in the usual manner (or in THF),⁶⁰⁶ although in the presence of excess halide these may give Wurtz-type coupling products (see Reaction 10-56).⁶⁰⁷ Like aryl chlorides, vinylic halides require higher-boiling solvents (see OS IV, 258). A good procedure for benzylic and allylic halides is to use magnesium anthracene (prepared from Mg and anthracene in THF)⁶⁰⁸ instead of ordinary magnesium,⁶⁰⁹ although activated magnesium turnings have also been used.⁶¹⁰ Alkynyl Grignard reagents are generally prepared by the method in Reaction 12-22.

Dihalides⁶¹¹ can be converted to Grignard reagents if the halogens are different and are at least three carbons apart. If the halogens are the same, it is possible to obtain dimagnesium compounds [e.g., BrMg(CH₂)₄MgBr].⁶¹² 1,2-Dihalides give elimination⁶¹³ rather than Grignard reagent formation (Reaction 17-22), and the reaction is seldom successful with 1,1-dihalides, although the preparation of gem-disubstituted compounds [e.g., CH₂(MgBr)₂], has been accomplished with these substrates.⁶¹⁴ α-Halo Grignard reagents and α-halolithium reagents can be prepared by the method given in Reaction 12-39.⁶¹⁵ Alkylmagnesium fluorides can be prepared by refluxing alkyl fluorides with Mg in the presence of appropriate catalysts (e.g., I₂ or EtBr) in THF for several days.⁶¹⁶ Nitrogen-containing Grignard reagents have been prepared.⁶¹⁷

The presence of other functional groups in the halide usually affects the preparation of the Grignard reagent. Groups that contain active hydrogen (defined as any hydrogen that will react with a Grignard reagent, e.g., OH, NH₂, and CO₂H), can be present in the molecule, but only if they are converted to the salt form (O⁻, NH⁻, COO⁻, respectively). Groups that react with Grignard reagents (e.g., C=O, CN, NO₂, CO₂R) inhibit Grignard formation entirely. In general, the only functional groups that may be present in the halide molecule without any interference at all are double and triple bonds (except terminal triple bonds) and OR and NR₂ groups. However, β-halo ethers generally give β elimination when treated with Mg (see Reaction 17-24), and Grignard reagents from α-halo ethers⁶¹⁸ can only be formed in THF or dimethoxymethane at a low temperature, for example,⁶¹⁹ because such reagents immediately undergo α elimination (see Reaction 12-39) at room temperature in ether solution.

Because Grignard reagents react with water (Reaction 12-24) and with oxygen (Reaction 12-25), it is generally best to prepare them in an anhydrous nitrogen atmosphere. Grignard reagents are generally neither isolated nor stored; solutions of Grignard reagents are used directly for the required synthesis. Grignard reagents can also be prepared in benzene or toluene, if a tertiary amine is added to complex with the RMgX.⁶²⁰ This method eliminates the need for an ether solvent. With certain primary alkyl halides it is even possible to prepare alkylmagnesium compounds in hydrocarbon solvents in the absence of an organic base.⁶²¹ It is also possible to obtain Grignard reagents in powdered form, by complexing them with the chelating agent tris(3,6-dioxaheptyl)amine [N(CH₂CH₂OCH₂CH₂OCH₃)₃].⁶²²

Next to the formation of Grignard reagents, the most important application of this reaction is the conversion of alkyl and aryl halides to organolithium compounds,⁶²³ but it has also been carried out with many other metals (e.g., Na, Be, Zn, Hg, As, Sb, and Sn). With Na, the Wurtz Reaction (10-56) is an important side reaction. In some cases, where the reaction between a halide and a metal is too slow, an alloy of the metal with K or Na can be used instead. The most important example is the preparation of tetraethyl-lead from ethyl bromide and a Pb–Na alloy.

The efficiency of the reaction can often be improved by use of the metal in its powdered⁶²⁴ or vapor⁶²⁵ form. These techniques have permitted the preparation of some organometallic compounds that cannot be prepared by the standard procedures. Among the metals produced in an activated form are Mg,⁶²⁶ Ca,⁶²⁷ Zn,⁶²⁸ Al, Sn, Cd,⁶²⁹ Ni, Fe, Ti, Cu,⁶³⁰ Pd, and Pt.⁶³¹

The mechanism of Grignard reagent formation involves free radicals,⁶³² and there is much evidence for this, from CIDNP⁶³³ (Sec. 5.C.i) and from stereochemical, rate, and product studies.⁶³⁴ Further evidence is that free radicals have been trapped,⁶³⁵ and that experiments that studied the intrinsic reactivity of MeBr on a magnesium single-crystal surface showed that Grignard reagent formation does not take place by a single-step insertion mechanism.⁶³⁶ The following SET mechanism has been proposed:⁶³³

Other evidence has been offered to support a SET initiated radical process for the second step of this mechanism.⁶³⁷ The species R–X√⁻ and Mg√⁺ are radical ions.⁶³⁸ The subscript “s” is meant to indicate that the species so marked are bound to the surface of the magnesium. It is known that this is a surface reaction.⁶³⁹ It has been suggested that some of the R√ radicals diffuse from the magnesium surface into the solution and then return to the surface to react with the XMg√. There is evidence both for⁶⁴⁰ and against⁶⁴¹ this suggestion. Another proposal is that the fourth step is not the one shown here, but that the R√ is reduced by Mg⁺ to the carbanion R⁻, which combines with MgX⁺ to give RMgX.⁶⁴²

There are too many preparations of Grignard reagents in Organic Syntheses for us to list here. Chiral Grignard reagents are rare, since they are configurationally unstable in most cases. However, a few chiral Grignard reagentsare known.⁶⁴³ Use of the reaction to prepare other organometallic compounds can be found in OS I, 228; II, 184, 517, 607; III, 413, 757; VI, 240; VII, 346; VIII, 505. The preparation of unsolvated butylmagnesium bromide is described at OS V, 1141. The preparation of highly reactive (powdered) magnesium is given at OS VI, 845.

12-39 Replacement of a Halogen by a Metal from an Organometallic Compound

Metalo-de-halogenation

The exchange reaction between halides and organometallic compounds occurs most readily when M is Li and X is Br or I,⁶⁴⁴ although it has been shown to occur with Mg.⁶⁴⁵ The R′ group is usually, although not always, alkyl, and often butyl; R is usually aromatic.⁶⁴⁶ Alkyl halides are generally not reactive enough, while allylic and benzylic halides usually give Wurtz coupling. Of course, the R that becomes bonded to the halogen is the one for which RH is the weaker acid. Despite the preponderance of reactions with bromides and iodides, it is noted that the reaction of 1-fluorooctane with 4–10 equiv of Li powder and 2–4 equiv of DTBB (4,4′-di-tert-butylbiphenyl) in THP (THP=tetrahydropyran) at 0 °C for 5 min, was shown to give a solution of the corresponding 1-octyllithium.⁶⁴⁷ Vinylic halides react with retention of configuration.⁶⁴⁸ The reaction can be used to prepare α-halo organolithium and α-halo organomagnesium compounds⁶⁴⁹ Carbon tetrachloride reacts with butyllithium to give lithiotrichloromethane (Cl₃C–Li), for example.⁶⁵⁰ Such compounds can also be prepared by hydrogen–metal exchange, for example,⁶⁵¹

This is an example of Reaction 12-22. However, these α-halo organometallic compounds are stable (and configurationally stable as well⁶⁵²) only at low temperatures (ca. -100 °C) and only in THF or mixtures of THF and other solvents (e.g., HMPA). At ordinary temperatures, they lose MX (α elimination) to give carbenes, which then react further, or carbenoid reactions. The α-chloro-α-magnesio sulfones [ArSO₂CH(Cl)MgBr] are exceptions, being stable in solution at room temperature and even under reflux.⁶⁵³ Compounds in which a halogen and a transition metal are on the same carbon can be more stable than the ones with lithium.⁶⁵⁴

There is evidence that the mechanism⁶⁵⁵ of the reaction of alkyllithium compounds with alkyl and aryl iodides involves free radicals.⁶⁵⁶

Among the evidence is the fact that coupling and disproportionation products are obtained from R√ and R′√ and the observation of CIDNP.^656,657 However, in the degenerate exchange between PhI and PhLi the ate complex Ph₂I⁻ Li⁺has been shown to be an intermediate,⁶⁵⁸ and there is other evidence that radicals are not involved in all instances of this reaction.⁶⁵⁹

In a completely different kind of process, alkyl halides can be converted to certain organometallic compounds by treatment with organometalate ions, for example,

Most of the evidence is in accord with a free radical mechanism involving electron transfer, although an S_N2 mechanism can compete under some conditions.⁶⁶⁰ Electrochemically genrated zinc has been used to prepare organozinc bomide from the corresponding alkyl halide.⁶⁶¹

OS VI, 82; VII, 271, 326, 495; VIII, 430. See also, OS VII, 512; VIII, 479.

12.C.iv. Carbon Leaving Groups

In these reactions (12-40–12-48), a carbon–carbon bond cleaves. The substrate is the side that retains the electron pair; hence the reactions are considered electrophilic substitutions. The incoming group is hydrogen in all but one (Reaction 12-42) of the cases. The reactions in groups A and B are sometimes called anionic cleavages,⁶⁶² although they do not always occur by mechanisms involving free carbanions (S_E1). When they do, the reactions are facilitated by increasing stability of the carbanion.

A. Carbonyl-Forming Cleavages

These reactions follow the pattern:

The leaving group is stabilized because the electron deficiency at its carbon is satisfied by a pair of electrons from the oxygen. With respect to the leaving group the reaction is elimination to form a C=O bond. Retrograde aldol reactions (16-34) and cleavage of cyanohydrins (16-52) belong to this classification but are treated in Chapter 16 under their more important reverse reactions. Other eliminations to form C=O bonds are discussed in Reaction 17-32.

12-40 Decarboxylation of Aliphatic Acids

Hydro-de-carboxylation

Many carboxylic acids can be successfully decarboxylated, either as the free acid or in the salt form, but not simple aliphatic acids.⁶⁶³ An exception is acetic acid, which as the acetate, heated with base, gives good yields of methane. Malonic acid derivatives are the most common substrates for decarboxylation, giving the corresponding mono-carboxylic acid. Decarboxylation of 2-substituted malonic acids has been reported using microwave irradiation.⁶⁶⁴ Aliphatic acids that do undergo successful decarboxylation have certain functional groups or double or triple bonds in the α or β position. Some of these are shown in Table 12.2.

Table 12.2 Some Acids That Undergo Decarboxylation Fairly Readily^a

Acid Type

Decarboxylation Product

a. Others are described in the text.

For decarboxylation of aromatic acids, see Reaction 11-35. Decarboxylation of an α-cyano acid can give a nitrile or a carboxylic acid, since the cyano group may or may not be hydrolyzed in the course of the reaction. In addition to the compounds listed in Table 12.2, decarboxylation can be carried out on α,β-unsaturated⁶⁶⁵ and α,β-acetylenic acids. Glycidic acids give aldehydes on decarboxylation. The following mechanism has been suggested:⁶⁶⁶

The direct product is an enol that tautomerizes to the aldehyde.⁶⁶⁷ This is the usual last step in the Darzens Reaction (16-40).

Decarboxylations can be regarded as reversal of the addition of carbanions to carbon dioxide (Reaction 16-82), but free carbanions are not always involved.⁶⁶⁸ When the carboxylate ion is decarboxylated, the mechanism can be either S_E1 or S_E2. In the case of the S_E1 mechanism, the reaction is of course aided by the presence of electron-withdrawing groups, which stabilize the carbanion.⁶⁶⁹ Decarboxylation of carboxylate ions can be accelerated by the addition of a suitable crown ether, which in effect removes the metallic ion.⁶⁷⁰ The reaction without the metallic ion has also been performed in the gas phase.⁶⁷¹ Some acids can also be decarboxylated directly and, in most of these cases, there is a cyclic, six-center mechanism:

Here too there is an enol that tautomerizes to the product. The mechanism is illustrated for the case of β-keto acids,⁶⁷² but it is likely that malonic, α-cyano, α-nitro, and β,γ-unsaturated acids⁶⁷³ behave similarly, since similar six-membered transition states can be written for them. Some α,β-unsaturated acids are also decarboxylated by this mechanism by isomerizing to the β,γ-isomers before they actually decarboxylate.⁶⁷⁴ Evidence is that 49 and similar bicyclic β-keto acids resist decarboxylation.⁶⁷⁵ In such compounds, the six-membered cyclic transition state cannot form for steric reasons,⁶⁷⁶ and if it could, formation of the intermediate enol would violate Bredt's rule (Sec. 4.Q.iii).

Some carboxylic acids that cannot form a six-membered transition state can still be decarboxylated, and these presumably react through an S_E1 or S_E2 mechanism.⁶⁷⁷ Further evidence for the cyclic mechanism is that the reaction rate varies very little with a change from a nonpolar to a polar solvent (even from benzene to water⁶⁷⁸), and is not subject to acid catalysis.⁶⁷⁹ The rate of decarboxylation of a β,γ-unsaturated acid was increased ~10⁵–10⁶ times by introduction of a β-methoxy group, indicating that the cyclic transition state has dipolar character.⁶⁸⁰ Rate constants for decarboxylation reactions have been calculated using no barrier theory.⁶⁸¹

β-Keto acids⁶⁸² are easily decarboxylated, but such acids are usually prepared from β-keto esters, and the esters are easily decarboxylated themselves on hydrolysis without isolation of the acids.⁶⁸³ This decarboxylation of β-keto esters involving cleavage on the carboxyl side of the substituted methylene group (arrow) is carried out under acidic, neutral, or slightly basic conditions to yield a ketone. When strongly basic conditions are used, cleavage occurs on the other side of the CR₂ group (Reaction 12-43). β-Keto esters can be decarbalkoxylated without passing through the free-acid stage by treatment with boric anhydride (B₂O₃) at 150 °C.⁶⁸⁴ The alkyl portion of the ester (R′) is converted to an alkene or, if it lacks a β hydrogen, to an ether (R′OR′). Another method for the decarbalkoxylation of β-keto esters, malonic esters, and α-cyano esters consists of heating the substrate in wet DMSO containing NaCl, Na₃PO₄, or some other simple salt.⁶⁸⁵ In this method too, the free acid is probably not an intermediate, but here the alkyl portion of the substrate is converted to the corresponding alcohol. α-Amino acids have been decarboxylated by treatment with a catalytic amount of 2-cyclohexenone.⁶⁸⁶ Amino acids are decarboxylated by sequential treatment with NBS at pH 5 followed by NaBH₄ and NiCl₂.⁶⁸⁷ Certain decarboxylations can also be accomplished photochemically.⁶⁸⁸ See also, the decarbonylation of acyl halides, mentioned in Reaction 14-32. In some cases, decarboxylations can give organometallic compounds: RCOOM → RM + CO₂.⁶⁸⁹ The Cu catalyzed decarboxylation of 2-alkynoic acids to terminal alkynes has been reported.⁶⁹⁰

Decarboxylative alkylation and arylation reactions are known. In the presence of a Ru catalyst and a B-phenyl borinate, decarboxylation of proline esters leads to 2-phenylpyrrolidine derivatives.⁶⁹¹ In the presence of a Pd catalyst, esters undergo decarboxylation with coupling between the alkyl groups on the carbonyl and the ester oxygen to give the corresponding hydrocarbon fragment.⁶⁹²

Some of the decarboxylations listed in Organic Syntheses are performed with concomitant ester or nitrile hydrolysis and others are simple decarboxylations.

With ester or nitrile hydrolysis: OS I, 290, 451, 523; II, 200, 391; III, 281, 286, 313, 326, 510, 513, 591; IV, 55, 93, 176, 441, 664, 708, 790, 804; V, 76, 288, 572, 687, 989; VI, 615, 781, 873, 932; VII, 50, 210, 319; VIII, 263.

Simple decarboxylations: OS I, 351, 401, 440, 473, 475; II, 21, 61, 93, 229, 302, 333, 368, 416, 474, 512, 523; III, 213, 425, 495, 705, 733, 783; IV, 234, 254, 278, 337, 555, 560, 597, 630, 731, 857; V, 251, 585; VI, 271, 965; VII, 249, 359; VIII, 235, 444, 536; 75, 195. Also see, OS IV, 633.

12-41 Cleavage of Alkoxides

Hydro-de-(α-oxidoalkyl)-substitution

Alkoxides of tertiary alcohols can be cleaved in a reaction that is essentially the reverse of addition of carbanions to ketones (Reaction 16-24).⁶⁹³ The reaction is unsuccessful when the R groups are simple unbranched alkyl groups (e.g., the alkoxide of triethylcarbinol). Cleavage is accomplished with branched alkoxides (e.g., the alkoxides of diisopropylneopentylcarbinol or tri-tert-butylcarbinol).⁶⁹⁴ Allylic,⁶⁹⁵ benzylic,⁶⁹⁶ and aryl groups also cleave (e.g., the alkoxide of triphenylcarbinol gives benzene and benzophenone). Studies in the gas phase show that the cleavage is a simple one, giving the carbanion and ketone directly in one step.⁶⁹⁷ However, with some substrates in solution, substantial amounts of dimer R–R have been found, indicating a radical pathway.⁶⁹⁸ Hindered alcohols (not the alkoxides) also lose one R group by cleavage, also by a radical pathway.⁶⁹⁹ The so-called retro-aldol (see Reaction 16-34) is another example.

The reaction has been used for extensive mechanistic studies (see Sec. 12.A.ii).

OS VI, 268.

12-42 Replacement of a Carboxyl Group by an Acyl Group

Acyl-de-carboxylation

When an α-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH₂ becomes acylated. This is called the Dakin–West reaction.⁷⁰⁰ The mechanism involves formation of an oxazolone.⁷⁰¹ The reaction sometimes takes place on carboxylic acids even when an a amino group is not present. A number of N-substituted amino acids [RCH(NHR′)COOH] give the corresponding N-alkylated products.

OS IV, 5; V, 27.

B. Acyl Cleavages

In these reactions (12-43–2-46), a carbonyl group is attacked by a hydroxide ion (or an amide ion), giving an intermediate that undergoes cleavage to a carboxylic acid (or an amide). With respect to the leaving group, this is nucleophilic substitution at a carbonyl group and the mechanism is the tetrahedral one discussed in Section 16.A.i.

With respect to R this is of course electrophilic substitution. The mechanism is usually S_E1.

12-43 Basic Cleavage of β-Keto Esters and β-Diketones

Hydro-de-acylation

When β-keto esters are treated with concentrated base, cleavage occurs, but on the keto side of the CR₂ group (arrow) in contrast to the acid cleavage mentioned in Reaction 12-40. The products are a carboxylic ester and the salt of an acid. However, the utility of the reaction is somewhat limited by the fact that decarboxylation is a side reaction, even under basic conditions. β-Diketones behave similarly to give a ketone and the salt of a carboxylic acid. With both β-keto esters and β-diketones, can be used instead of , in which case the ethyl esters of the corresponding acids are obtained instead of the salts. In the case of β-keto esters, this is the reverse of Claisen condensation(Reaction 16-85). The related cleavage of cyclic α-cyano ketones, in an intramolecular fashion, has been used in a synthesis of macrocyclic lactones (e.g., 50).⁷⁰²

Activated F⁻ (from KF and a crown ether) has been used as the base to cleave an α-cyano ketone.⁷⁰³ Treatment with ceric ammonium nitrate led to cleavage of β-diketones to give a carboxylic acid.⁷⁰⁴

OS II, 266, 531; III, 379; IV, 415, 957; V, 179, 187, 277, 533, 747, 767.

12-44 Haloform Reaction

In the haloform reaction, methyl ketones (and the only methyl aldehyde, acetaldehyde) are cleaved with halogen and a base.⁷⁰⁵ The halogen can be bromine, chlorine, or iodine. What takes place is actually a combination of two reactions. The first is an example of Reaction 12-4, in which, under the basic conditions employed, the methyl group is trihalogenated. Then the resulting trihalo ketone is attacked by hydroxide ion to give tetrahedral intermediate (51).⁷⁰⁶ The X₃C⁻ group is a sufficiently good leaving group (not HX₂C⁻ or H₂XC⁻) that a carboxylic acid is formed, which quickly reacts with the carbanion to give the final products. Primary or secondary methylcarbinols also give the reaction, because they are oxidized to the carbonyl compounds under the conditions employed.

As with Reaction 12-4, the rate-determining step is the preliminary enolization of the methyl ketone.⁷⁰⁷ A side reaction is α halogenation of the non-methyl R group. Sometimes these groups are also cleaved.⁷⁰⁸ The reaction cannot be applied to F₂, but ketones of the form RCOCF₃ (R = alkyl or aryl) give fluoroform and RCOO⁻ when treated with base.⁷⁰⁹ Rate constants for cleavage of X₃CCOPh (X = F, Cl, Br) were found to be in the ratio 1 : 5.3 × 10¹⁰ : 2.2 × 10¹³, showing that an F₃C⁻ group cleaves much more slowly than the others.⁷¹⁰ In the past, the haloform reaction was used as a test for methylcarbinols and methyl ketones. Iodine was most often used as the test reagent, since iodoform (HCI₃) is an easily identifiable yellow solid. The reaction can be used for synthetic purposes. Methyl ketones (RCOCH₃) can be converted directly to methyl esters (RCO₂CH₃) by an electrochemical reaction.⁷¹¹Trifluoromethyl ketones have been converted to ethyl esters via treatment with NaH in aq DMF followed by reaction with bromoethane.⁷¹²

OS I, 526; II, 428; III, 302; IV, 345; V, 8. Also see, OS VI, 618.

12-45 Cleavage of Nonenolizable Ketones

Hydro-de-acylation

Ordinary ketones are generally much more difficult to cleave than trihalo ketones or β-diketones. However, nonenolizable ketones can be cleaved by treatment with a 10:3 mixture of t-BuOK–H₂O in an aprotic solvent [e.g., ether, DMSO, 1,2-dimethoxyethane (glyme),⁷¹³ or with solid t-BuOK in the absence of a solvent].⁷¹⁴ When the reaction is applied to monosubstituted diaryl ketones, that aryl group preferentially cleaves that comes off as the more stable carbanion, except that aryl groups substituted in the ortho position are more readily cleaved than otherwise because of the steric effect (relief of strain).^714,715 In certain cases, cyclic ketones can be cleaved by base treatment, even if they are enolizable.⁷¹⁶

OS VI, 625. See also, OS VII, 297.

12-46 The Haller–Bauer Reaction

Hydro-de-acylation

Cleavage of ketones with sodium amide is called the Haller–Bauer reaction.⁷¹⁷ As with Reaction 12-45, which is exactly analogous, the reaction is usually applied only to non-enolizable ketones, most often to ketones of the form ArCOCR₃, where the products R₃CCONH₂ (after hydrolysis) are not easily attainable by other methods. However, many other ketones have been used, although benzophenone is virtually unaffected. It has been shown that the configuration of optically active alkyl groups (R) is retained.⁷¹⁸ The NH₂ loses its proton from the tetrahedral intermediate (52) before the R group is cleaved.⁷¹⁹

An extension of this cleavage process involves the reaction of α-nitro ketones (O=C–CHRNO₂) with a primary amine, neat, to give the corresponding amide, O=C–NHR′.⁷²⁰

OS V, 384, 1074.

C. Other Cleavages

12-47 The Cleavage of Alkanes

Hydro-de- tert- butylation, and so on

The C–C bonds of alkanes can be cleaved by treatment with superacids (Sec. 5.A.ii). For example, neopentane in FSO₃H–SbF₅ can cleave to give methane and the tert-butyl cation. The C–H cleavage (see Reaction 12-1) is a competing reaction and, for example, neopentane can give H₂ and the tert-pentyl carbocation (formed by rearrangement of the initially formed neopentyl cation) by this pathway. In general, the order of reactivity is tertiary C–H > C–C > secondary C–H primary C–H, although steric factors cause a shift in favor of C–C cleavage in such a hindered compound as tri-tert-butylmethane. The mechanism is similar to that shown in Reactions 12-1 and 12-20 and involves attack by H⁺ on the C–C bond to give a pentavalent cation.

Catalytic hydrogenation seldom breaks unactivated C–C bonds (i.e., R–R′ + H₂ → RH + R′H), but methyl and ethyl groups have been cleaved from substituted adamantanes by hydrogenation with a Ni-Al₂O₃ catalyst at ~250 °C.⁷²¹ Certain C–C bonds have been cleaved by alkali metals.⁷²²

The C–C bond of 2-allyl-2-arylmalonate derivatives was cleaved, with loss of the allylic group to give the 2-arylmalonate, by treatment with a Ni catalyst.⁷²³

12-48 Decyanation or Hydro-de-cyanation

The cyano group of alkyl nitriles can be removed⁷²⁴ by treatment with metallic Na, either in liquid ammonia,⁷²⁵ or together with tris(acetylacetonato)iron(III) [Fe(acac)₃]⁷²⁶ or, with lower yields, titanocene. The two procedures are complementary. Although both can be used to decyanate many kinds of nitriles, the Na–NH₃ method gives high yields with R groups (e.g., trityl, benzyl, phenyl, and tertiary alkyl), but lower yields (~35–50%) when R = primary or secondary alkyl. On the other hand, primary and secondary alkyl nitriles are decyanated in high yields by the Na–Fe(acac)₃ procedure. Sodium in liquid ammonia is known to be a source of solvated electrons, and the reaction may proceed through the free radical R√ that would then be reduced to the carbanion R⁻, which by abstraction of a proton from the solvent, would give RH. The mechanism with Fe(acac)₃ is presumably different. Another procedure,⁷²⁷which is successful for R = primary, secondary, or tertiary, involves the use of potassium metal and the crown ether dicyclohexano-18-crown-6 in toluene.⁷²⁸

α-Amino and α-amido nitriles RCH(CN)NR′₂ and RCH(CN)NHCOR′ can be decyanated in high yield by treatment with NaBH₄.⁷²⁹

12.C.v. Electrophilic Substitution at Nitrogen

In most of the reactions in this section, an electrophile bonds with the unshared pair of a nitrogen atom. The electrophile may be a free positive ion or a positive species attached to a carrier that breaks off in the course of the attack or shortly after:

Further reaction of 53 depends on the nature of Y and of the other groups attached to the nitrogen.

12-49 The Conversion of Hydrazines to Azides

Hydrazine-azide transformation

Monosubstituted hydrazines treated with nitrous acid give azides in a reaction exactly analogous to the formation of aliphatic diazo compounds mentioned in Reaction 13-19. Among other reagents used for this conversion have been N₂O₄⁷³⁰ and nitrosyl tetrafluoroborate (NOBF₄).⁷³¹

OS III, 710; IV, 819; V, 157.

12-50 N-Nitrosation

N-Nitroso-de-hydrogenation

When secondary amines are treated with nitrous acid (typically formed from sodium nitrite and a mineral acid),⁷³² N-nitroso compounds (also called nitrosamines) are formed.⁷³³ The reaction can be accomplished with dialkyl-, diaryl-, or alkylarylamines, and even with mono-N-substituted amides: RCONHR′ + HONO → RCON(NO)R′.⁷³⁴ Tertiary amines have also been N-nitrosated, but in these cases one group cleaves, so that the product is the nitroso derivative of a secondary amine.⁷³⁵ The group that cleaves appears as an aldehyde or ketone product. Other reagents have also been used (e.g., NOCl), which is useful for amines or amides that are not soluble in an acidic aqueous solution or where the N-nitroso compounds are highly reactive. N-Nitroso compounds can be prepared in basic solution by treatment of secondary amines with gaseous N₂O₃, N₂O₄,⁷³⁶ or alkyl nitrites,⁷³⁷ and, in aqueous or organic solvents, by treatment with BrCH₂NO₂.⁷³⁸ Secondary amines are converted to the N-nitroso compound with H₅IO₆ on wet silica.⁷³⁹

The mechanism of nitrosation is essentially the same as in Reaction 13-19 up to the point where 54 is formed. Since this species cannot lose a proton, it is stable and the reaction ends there. The attacking entity can be any of those mentioned in Reaction 13-19. The following has been suggested as the mechanism for the reaction with tertiary amines:⁷⁴⁰

The evidence for this mechanism includes the facts that nitrous oxide is a product (formed by 2HNO → H₂O + N₂O) and that quinuclidine, where the nitrogen is at a bridgehead and cannot give elimination, does not react. Tertiary amines have also been converted to nitrosamines with nitric acid in Ac₂O⁷⁴¹ and with N₂O₄.⁷⁴²

Amines and amides can be N-nitrated⁷⁴³ with nitric acid,⁷⁴⁴ or NO₂⁺,⁷⁴⁵ and aromatic amines can be converted to triazenes with diazonium salts. Aliphatic primary amines can also be converted to triazenes if the diazonium salts contain electron-withdrawing groups.⁷⁴⁶ C-Nitrosation is discussed at Reactions 11-3 and 12-8.

OS I, 177, 399, 417; II, 163, 211, 290, 460, 461, 462, 464 (Also see, V, 842); III, 106, 244; IV, 718, 780, 943; V, 336, 650, 797, 839, 962; VI, 542, 981. Also see, OS III, 711.

12-51 Conversion of Nitroso Compounds to Azoxy Compounds

In a reaction similar to 13-24, azoxy compounds can be prepared by the condensation of a nitroso compound with a hydroxylamine.⁷⁴⁷ The position of the oxygen in the final product is determined by the nature of the R groups, not by which R groups came from which starting compound. Both R and R′ can be alkyl or aryl, but when two different aryl groups are involved, mixtures of azoxy compounds (ArNONAr, ArNONAr′, and Ar′NONAr′) are obtained⁷⁴⁸ and the unsymmetrical product (ArNONAr′) is likely to be formed in the smallest amount. This behavior is probably caused by an equilibration between the starting compounds prior to the actual reaction (ArNO + Ar′NHOH → Ar′NO + ArNHOH).⁷⁴⁹ The mechanism⁷⁵⁰ has been investigated in the presence of base. Under these conditions both reactants are converted to radical anions, which couple:

These radical anions have been detected by ESR.⁷⁵¹ This mechanism is consistent with the following result: When nitrosobenzene and phenylhydroxylamine are coupled, and labeling show that the two nitrogen atoms and the two oxygen atoms become equivalent.⁷⁵² Unsymmetrical azoxy compounds can be prepared⁷⁵³ by combination of a nitroso compound with an N,N-dibromoamine. Symmetrical and unsymmetrical azo and azoxy compounds are produced when aromatic nitro compounds react with aryliminodimagnesium reagents [ArN(MgBr)₂].⁷⁵⁴

12-52 N-Halogenation

N-Halo-de-hydrogenation

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halogen product is seldom isolated but usually rearranges (see Reaction 18-13); however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagents NBS and NCS are made in this manner. N-Halogenation has also been accomplished with other reagents (e.g., sodium bromite, NaBrO₂),⁷⁵⁵ benzyltrimethylammonium tribromide (PhCH₂NMe₃⁺Br₃⁻),⁷⁵⁶ NaCl with Oxone,⁷⁵⁷ and NCS.⁷⁵⁸ Sodium hypohalite in the presence of tert-butanol and acetic acid is an efficient method for the preparation of N-haloamines.⁷⁵⁹ Amides are N-chlorinated with trichloroisocyanuric acid.⁷⁶⁰ The mechanisms of these reactions⁷⁶¹ involve attack by a positive halogen and are probably similar to those of Reactions 13-19 and 12-50.⁷⁶² N-Fluorination can be accomplished by direct treatment of amines⁷⁶³ or amides⁷⁶⁴ with F₂. Fluorination of N-alkyl-N-fluoroamides [RRN(F)COR′] results in cleavage to N,N-difluoroamines (RNF₂).^764,765 Trichloroisocyanuric acid converts primary amines to the N,N-dichloroamine.⁷⁶⁶

OS III, 159; IV, 104, 157; V, 208, 663, 909; VI, 968; VII, 223; VIII, 167, 427.

12-53 The Reaction of Amines With Carbon Monoxide or Carbon Dioxide

N-Formylation or N-Formyl-de-hydrogenation, and so on

Three types of product can be obtained from the reaction of amines with CO, depending on the catalyst. (1) Both primary and secondary amines react with CO in the presence of various catalysts [e.g., Cu(CN)₂, Me₃N-H₂Se, and Rh or Ru complexes] to give N-substituted and N,N-disubstituted formamides, respectively.⁷⁶⁷ Primary aromatic amines react with ammonium formate to give the formamide.⁷⁶⁸ Tertiary amines react with CO and a Pd catalyst to give an amide.⁷⁶⁹ (2) Symmetrically substituted ureas can be prepared by treatment of a primary amine (or ammonia) with CO⁷⁷⁰ in the presence of Se⁷⁷¹ or S.⁷⁷² The R source can be alkyl or aryl. The same thing can be done with secondary amines, using Pd(OAc)₂–I₂–K₂CO₃.⁷⁷³ Primary aromatic amines react with β-keto esters and a Mo–ZrO₂ catalyst to give the symmetrical urea.⁷⁷⁴ Treatment of a secondary amine with nitrobenzene, selenium and carbon monoxide leads to the unsymmetrical urea.⁷⁷⁵ (3) When PdCl₂ is the catalyst, primary amines yield isocyanates.⁷⁷⁶ Isocyanates can also be obtained by treatment of CO with azides: RN₃ + CO → RNCO,⁷⁷⁷ or with an aromatic nitroso or nitro compound and a Rh complex catalyst.⁷⁷⁸ Primary amines react with di-tert-butyltricarbonate to give the isocyanate.⁷⁷⁹

Lactams are converted to the corresponding N-chloro lactam with Ca(OCl)₂ with moist alumina in dichloromethane.⁷⁸⁰ Ring-expanded lactams are obtained from cyclic amines via a similar reaction⁷⁸¹ (see also, Reaction 16-22). Intramolecular carbonylation of amines also leads to lactams.⁷⁸²

A fourth type of product, a carbamate (RNHCOOR′), can be obtained from primary or secondary amines, if these are treated with CO, O₂, and an alcohol (R′OH) in the presence of a catalyst.⁷⁸³ Primary amines react with dimethyl carbonate in supercritical CO₂ (see Sec. 9.D.ii) to give a carbamate.⁷⁸⁴ Carbamates can also be obtained from nitroso compounds, by treatment with CO, R′OH, Pd(OAc)₂, and Cu(OAc)₂,⁷⁸⁵ and from nitro compounds.⁷⁸⁶ When allylic amines (R₂C=CHRCHRNR′₂) are treated with CO and a Pd–phosphine catalyst, the CO inserts to produce the β,γ-unsaturated amides (R₂C=CHRCHRCONR′₂) in good yields.⁷⁸⁷ Silyloxy carbamates (RNHCO₂SiR′₃) can be prepared by the reaction of a primary amine with carbon dioxide and triethylamine, followed by reaction with triisopropylsilyl triflate and tetrabutylammonium fluoride.⁷⁸⁸

Carbon dioxide reacts with amines (ArNH₂) and alkyl halides, under electrolysis conditions, to give the corresponding carbamate (ArNHCO₂Et).⁷⁸⁹ Secondary amines react with all halides and an onium salt in supercritical CO₂(see Sec. 9.D.ii) to give the carbamate.⁷⁹⁰ N-Phenylthioamines react with CO and a palladium catalyst to give a thiocarbamate (ArSCO₂NR′₂).⁷⁹¹ Urea derivatives were obtained from amines, CO₂, and an antimony catalyst.⁷⁹²

Aziridines can be converted to cyclic carbamates (oxazolidinones) by heating with carbon dioxide and a chromium–salen catalyst.⁷⁹³ The reaction of aziridines with LiI, and then CO₂ also generates oxazolidinones.⁷⁹⁴

Notes

1. See Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, 5 Vols., Wiley, NY, 1984–1990; Haiduc, I.; Zuckerman, J.J. Basic Organometallic Chemistry, Walter de Gruyter, NY, 1985; Negishi, E. Organometallics in Organic Synthesis, Wiley, NY, 1980; Aylett, B.J. Organometallic Compounds, 4th ed., Vol. 1, pt. 2; Chapman and Hall, NY, 1979; Maslowsky, Jr., E. Chem. Soc. Rev. 1980, 9, 25, and in Tsutsui, M. Characterization of Organometallic Compounds, Wiley, NY, 1969–1971, the articles by Cartledge, F.K.; Gilman, H. pt. 1, pp. 1–33, and by Reichle, W.T. pt. 2, pp. 653–826.

2. See Abraham, M.H. Comprehensive Chemical Kinetics, Bamford, C.H.; Tipper, C.F.H. Eds., Vol. 12, Elsevier, NY, 1973; Reutov, O.A.; Beletskaya, I.P. Reaction Mechanisms of Organometallic Compounds, North-Holland Publishing Company, Amsterdam, The Netherlands, 1968; Abraham, M.H.; Grellier, P.L. in Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 2, Wiley, NY, pp. 25–149; Reutov, O.A. Pure Appl. Chem. 1978, 50, 717; Tetrahedron 1978, 34, 2827.

3. Gawley, R.E. Tetrahedron Lett. 1999, 40, 4297.

4. Buckle, M.J.C.; Fleming, I.; Gil, S. Tetrahedron Lett. 1992, 33, 4479.

5. The names for these mechanisms vary throughout the literature. For example, the S_Ei mechanism has also been called the S_E2, the S_E2 (closed), and the S_E2 (cyclic) mechanism. The original designations, S_E1, S_E2, and so on, were devised by the Hughes–Ingold school.

6. It has been contended that the S_Ei mechanism violates the principle of conservation of orbital symmetry (sec Reaction 15-60, A), and that the S_E2 (back) mechanism partially violates it: Slack, D.A.; Baird, M.C. J. Am. Chem. Soc. 1976, 98, 5539.

7. See Flood, T.C. Top. Stereochem. 1981, 12, 37. See also, Jensen, F.R.; Davis, D.D. J. Am. Chem. Soc. 1971, 93, 4048.

8. Winstein, S.; Traylor, T.G.; Garner, C.S. J. Am. Chem. Soc. 1955, 77, 3741.

9. Schöllkopf, U. Angew. Chem. 1960, 72, 147. See Fort, Jr., R.C.; Schleyer, P.v.R. Adv. Alicyclic Chem. 1966, 1, 283, pp. 353–370.

10. Hughes, E.D.; Volger, H.C. J. Chem. Soc. 1961, 2359.

11. Jensen, F.R. J. Am. Chem. Soc. 1960, 82, 2469; Ingold, C.K. Helv. Chim. Acta 1964, 47, 1191.

12. Jensen, F.R.; Davis, D.D. J. Am. Chem. Soc. 1971, 93, 4048. See Fukuto, J.M.; Jensen, F.R. Acc. Chem. Res. 1983, 16, 177.

13. See Magnuso, R.H.; Halpern, J.; Levitin, I.Ya.; Vol'pin, M.E. J. Chem. Soc. Chem. Commun. 1978, 44.

14. See Rahm, A.; Pereyre, M. J. Am. Chem. Soc. 1977, 99, 1672; McGahey, L.F.; Jensen, F.R. J. Am. Chem. Soc. 1979, 101, 4397; Olszowy, H.A.; Kitching, W. Organometallics 1984, 3, 1676. Also see Rahm, A.; Grimeau, J.; Pereyre, M. J. Organomet. Chem. 1985, 286, 305.

15. See Bergbreiter, D.E.; Rainville, D.P. J. Organomet. Chem. 1976, 121, 19.

16. See Sokolov, V.I. Chirality and Optical Activity in Organometallic Compounds, Gordon and Breach, NY, 1990.

17. See Jensen, F.R.; Whipple, L.D.; Wedegaertner, D.K.; Landgrebe, J.A. J. Am. Chem. Soc. 1959, 81, 1262; Charman, H.B.; Hughes, E.D.; Ingold, C.K. J. Chem. Soc. 1959, 2523, 2530.

18. This was done first by Walborsky, H.M.; Young, A.E. J. Am. Chem. Soc. 1964, 86, 3288.

19. Jensen, F.R.; Nakamaye, K.L. J. Am. Chem. Soc. 1966, 88, 3437.

20. Abraham, M.H.; Johnston, G.F. J. Chem. Soc. A, 1970, 188.

21. See Abraham, M.H.; Dorrell, F.J. J. Chem. Soc. Perkin Trans. 2 1973, 444.

22. Fukuto, J.M.; Newman, D.A.; Jensen, F.R. Organometallics 1987, 6, 415.

23. Abraham, M.H.; Hill, J.A. J. Organomet. Chem. 1967, 7, 11.

24. Abraham, M.H. Comprehensive Chemical Kinetics, Bamford, C.H.; Tipper, C.F.H., Eds., Vol. 12, Elsevier, NY, 1973, p. 15.

25. Fukuzumi, S.; Kochi, J.K. J. Am. Chem. Soc. 1980, 102, 2141, 7290.

26. Hsu, S.K.; Ingold, C.K.; Wilson, C.L. J. Chem. Soc. 1938, 78.

27. Wilson, C.L. J. Chem. Soc. 1936, 1550.

28. See Hoffman, T.D.; Cram, D.J. J. Am. Chem. Soc. 1969, 91, 1009. For a discussion, see Cram, D.J. Fundamentals of Carbanion Chemistry, Academic Press, NY, 1965, pp. 138–158.

29. See Roitman, J.N.; Cram, D.J. J. Am. Chem. Soc. 1971, 93, 2225, 2231 and references cited therein; Cram, J.M.; Cram, D.J. Intra-Sci. Chem. Rep. 1973, 7(3), 1; Cram, D.J. Fundamentals of Carbanion Chemistry, Academic Press, NY, 1965, pp. 85–105.

30. Cram, D.J.; Ford, W.T.; Gosser, L. J. Am. Chem. Soc. 1968, 90, 2598; Ford, W.T.; Cram, D.J. J. Am. Chem. Soc. 1968, 90, 2606, 2612. See also, Buchholz, S.; Harms, K.; Massa, W.; Boche, G. Angew. Chem. Int. Ed. 1989, 28,73.

31. Almy, J.; Hoffman, D.H.; Chu, K.C.; Cram, D.J. J. Am. Chem. Soc. 1973, 95, 1185.

32. Dreiding, A.S.; Pratt, R.J. J. Am. Chem. Soc. 1954, 76, 1902. See also, Walborsky, H.M.; Turner, L.M. J. Am. Chem. Soc. 1972, 94, 2273.

33. See Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1.

34. Sleezer, P.D.; Winstein, S.; Young, W.G. J. Am. Chem. Soc. 1963, 85, 1890. See also, Kashin, A.N.; Bakunin, V.N.; Khutoryanskii, V.A.; Beletskaya, I.P.; Reutov, O.A. J. Organomet. Chem. 1979, 171, 309.

35. Matassa, V.G.; Jenkins, P.R.; Kümin, A.; Damm, L.; Schreiber, J.; Felix, D.; Zass, E.; Eschenmoser, A. Isr. J. Chem. 1989, 29, 321.

36. Young, D.; Kitching, W. J. Org. Chem. 1983, 48, 614; Tetrahedron Lett. 1983, 24, 5793.

37. Kashin, A.N.; Bakunin, V.N.; Beletskaya, I.P.; Reutov, O.A. J. Org. Chem. USSR 1982, 18, 1973. See also, Wickham, G.; Young, D.; Kitching, W. Organometallics 1988, 7, 1187.

38. See Abraham, M.H. Comprehensive Chemical Kinetics, Bamford, C.H.; Tipper, C.F.H., Eds., Vol. 12, Elsevier, NY, 1973, pp. 211–241.

39. Also see Isaacs, N.S.; Laila, A.H. Tetrahedron Lett. 1984, 25, 2407.

40. See Abraham, M.H.; Broadhurst, A.T.; Clark, I.D.; Koenigsberger, R.U.; Dadjour, D.F. J. Organomet. Chem. 1981, 209, 37.

41. Sayre, L.M.; Jensen, F.R. J. Am. Chem. Soc. 1979, 101, 6001.

42. Also see Nugent, W.A.; Kochi, J.K. J. Am. Chem. Soc. 1976, 98, 5979.

43. Reutov, O.A. J. Organomet. Chem. 1983, 250, 145. See also, Butin, K.P.; Magdesieva, T.V. J. Organomet. Chem. 1985, 292, 47.

44. Richard, J.P. J. Org. Chem. 1992, 57, 625.

45. See Reutov, O.A. Bull. Acad. Sci. USSR Div. Chem. Sci. 1980, 29, 1461. See also, Dembech, P.; Eaborn, C.; Seconi, G. J. Chem. Soc. Chem. Commun. 1985, 1289.

46. See Kitching, W. Rev. Pure Appl. Chem. 1969, 19, 1.

47. See Petrosyan, V.S. J. Organomet. Chem. 1983, 250, 157.

48. See Olah, G.A.; Prakash, G.K.S.; Sommer, J. Superacids, Wiley, NY, 1985, pp. 244–249; Olah, G.A. Angew. Chem. Int. Ed. 1973, 12, 173.

49. See McMurry, J.E.; Lectka, T. J. Am. Chem. Soc. 1990, 112, 869; Culmann, J.; Sommer, J. J. Am. Chem. Soc. 1990, 112, 4057.

50. See Olah, G.A.; Prakash, G.K.S.; Williams, R.E.; Field, L.D.; Wade, K. Hypercarbon Chemistry, Wiley, NY, 1987.

51. See Sefcik, M.D.; Henis, J.M.S.; Gaspar, P.P. J. Chem. Phys. 1974, 61, 4321.

52. Yeh, L.I.; Pric, J.M.; Lee, Y.T. J. Am. Chem. Soc. 1989, 111, 5597.

53. Lukas, J.; Kramer, P.A.; Kouwenhoven, A.P. Recl. Trav. Chim. Pays-Bas 1973, 92, 44.

54. Werstiuk, N.H.; Timmins, G. Can. J. Chem. 1985, 63, 530; 1986, 64, 1564.

55. See Atkinson, J.G.; Luke, M.O.; Stuart, R.S. Can. J. Chem. 1967, 45, 1511.

56. For a list of methods used to shift double and triple bonds, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 220–226, 567–568.

57. See Pines, H.; Stalick, W.M. Base-Catalyzed Reactions of Hydrocarbons and Related Compounds, Academic Press, NY, 1977, pp. 25–123; DeWolfe, R.H. in Bamford, C.H.; Tipper, C.F.H. Comprehensive Chemical Kinetics, Vol. 9, Elsevier, NY, 1973, pp. 437–449; Hubert, A.J.; Reimlinger, H. 1970, 405; Mackenzie, K. in The Chemistry of Alkenes, Vol. 1, Patai, S., pp. 416–436, Vol. 2, Zabicky, J., pp. 132–148; Wiley, NY, 1964, 1970; Broaddus, C.D. Acc. Chem. Res. 1968, 1, 231.

58. See Hine, J.; Skoglund, M.J. J. Org. Chem. 1982, 47, 4766. See also, Hine, J.; Linden, S. J. Org. Chem. 1983, 48, 584.

59. For a review of conversions of β,γ enones to α,β enones, see Pollack, R.M.; Bounds, P.L.; Bevins, C.L. in Patai, S.; Rappoport, Z. The Chemistry of Enones, pt. 1, Wiley, NY, 1989, pp. 559–597.

60. See Pollack, R.M.; Mack, J.P.G.; Eldin, S. J. Am. Chem. Soc. 1987, 109, 5048.

61. Rabinovich, E.A.; Astaf'ev, I.V.; Shatenshtein, A.I. J. Gen. Chem. USSR 1962, 32, 746.

62. Hünig, S.; Klaunzer, N.; Schlund, R. Angew. Chem. Int. Ed. 1987, 26, 1281.

63. See Cram, D.J.; Uyeda, R.T. J. Am. Chem. Soc. 1964, 86, 5466; Ohlsson, L.; Wold, S.; Bergson, G. Ark. Kemi., 1968, 29, 351.

64. Hussénius, A.; Matsson, O.; Bergson, G. J. Chem. Soc. Perkin Trans. 2 1989, 851.

65. See Cameron G.S.; Stimson, V.R. Aust. J. Chem. 1977, 30, 923.

66. Schönberg, A. Preparative Organic Photochemistry, Springer, NY, 1968, pp. 22–24.

67. See Rodriguez, J.; Brun, P.; Waegell, B. Bull. Soc. Chim. Fr. 1989, 799–823; Otsuka, S.; Tani, K. in Morrison, J.D. Asymmetric Synthesis Vol. 5, Academic Press, NY, 1985, pp. 171–191 (enantioselective); Colquhoun, H.M.; Holton, J.; Thompson, D.J.; Twigg, M.V. New Pathways for Organic Synthesis, Plenum, NY, 1984, pp. 173–193; Khan, M.M.T.; Martell, A.E. Homogeneous Catalysis by Metal Complexes, Academic Press, NY, 1974, pp. 9–37; Heck, R.F. Organotransition Metal Chemistry, Academic Press, NY, 1974, pp. 76–82; Jira, R.; Freiesleben, W. Organomet. React. 1972, 3, 1, pp. 133–149.

68. Cramer, R. J. Am. Chem. Soc. 1966, 88, 2272.

69. Casey, C.P.; Cyr, C.R. J. Am. Chem. Soc. 1973, 95, 2248.

70. Trost, B.M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110, 2301.

71. Han, J.W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915.

72. Bergens, S.H.; Bosnich, B. J. Am. Chem. Soc. 1991, 113, 958.

73. See Duhaime, R.M.; Lombardo, D.A.; Skinner, I.A.; Weedon, A.C. J. Org. Chem. 1985, 50, 873.

74. See Pines, H.; Stalick, W.M. Base-Catalyzed Reactions of Hydrocarbons and Related Compounds, Academic Press, NY, 1977, pp. 124–204; Théron F.; Verny, M.; Vessière, R. in Patai, S. The Chemistry of Carbon–Carbon Triple Bond, pt. 1, Wiley, NY, 1978, pp. 381–445; Bushby, R.J. Q. Rev. Chem. Soc. 1970, 24, 585; Iwai, I. Mech. Mol. Migr. 1969, 2, 73.

75. See Huntsman, W.D. in Patai, S. The Chemistry of Ketenes, Allenes, and Related Compounds, pt. 2, Wiley, NY, 1980, pp. 521–667.

76. Macaulay, S.R. J. Org. Chem. 1980, 45, 734; Abrams, S.R. Can. J. Chem. 1984, 62, 1333.

77. See Oku, M.; Arai, S.; Katayama, K.; Shioiri, T. Synlett 2000, 493.

78. See Cunico, R.F.; Zaporowski, L.F.; Rogers, M. J. Org. Chem. 1999, 64, 9307.

79. Myers, A.G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. See Moghaddam, F.M.; Emami, R. Synth. Commun. 1997, 27, 4073 for the formation of alkoxy allenes from propargyl ethers.

80. Sonye, J.P.; Koide, K. J. Org. Chem. 2006, 71, 6254.

81. Barry, B.J.; Beale, W.J.; Carr, M.D.; Hei, S.; Reid, I. J. Chem. Soc. Chem. Commun. 1973, 177.

82. Patai, S. The Chemistry of the Carbonyl Group, Wiley, London, 1966; Rappoport, Z. The Chemistry of Enols, Wiley, NY, 1990; Rappoport, Z.; Frey, J.; Sigalov, M.; Rochlin, E. Pure Appl. Chem. 1997, 69, 1933; Fontana, A.; De Maria, P.; Siani, G.; Pierini, M.; Cerritelli, S.; Ballini, R. Eur. J. Org. Chem. 2000, 1641; Iglesias, E. Curr. Org. Chem. 2004, 8, 1.

83. See Jones, J.R. The Ionisation of Carbon Acids, Academic Press, London, 1973; Toullec, J. Adv. Phys. Org. Chem. 1982, 18, 1; Chiang, Y.; Kresge, A.J.; Santaballa, J.A.; Wirz, J. J. Am. Chem. Soc. 1988, 110, 5506.

84. See Raczynska, E.D.; Kosinska, W.; Osmialowski, B.; Gawinecki, R. Chem. Rev. 2005, 105, 3561 for a general discussion of tautomerism. Also see Rappoport, Z. The Chemistry of Enols, Wiley, NY, 1990; Zabicky, J. The Chemistry of Amides, Wiley, London, 1970; Boyer, J.H. The Chemistry of the Nitro and Nitroso Groups, Interscience Publishers, NY, 1969; Patai, S. The Chemistry of Amino, Nitroso, Nitro Compounds and their Derivatives, Wiley, NY, 1982; Patai, S. The Chemistry of Amino, Nitroso, Nitro and Related Groups, Supplement F2, Wiley, Chichester, 1996; Cook, A.G. Enamines, 2nd ed., Marcel Dekker, NY, 1998.

85. Gorb, L.; Leszczynski, J. J. Am. Chem. Soc. 1998, 120, 5024; Guo, J. X.; Ho, J. J. J. Phys. Chem. A 1999, 103, 6433.

86. Briegleb, G.; Strohmeier, W. Angew. Chem. 1952, 64, 409; Baddar, F. G.; Iskander, Z. J. Chem. Soc. 1954, 203.

87. Hegarty, A.F.; Dowling, J.P.; Eustace, S.J.; McGarraghy, M. J. Am. Chem. Soc. 1998, 120, 2290.

88. Behnam, S.M.; Behnam, S.E.; Ando, K.; Green, N.S.; Houk, K.N. J. Org. Chem. 2000, 65, 8970.

89. Miller, A.R. J. Org. Chem., 1976, 41,3599.

90. Fuson, R.C.; Tan, T.-L. J. Am. Chem. Soc. 1948, 70, 602.

91. See Keeffe, J.R.; Kresge, A.J. in Rappoport, Z. The Chemistry of Enols, Wiley, NY, 1990, pp. 399–480; Toullec, J. Adv. Phys. Org. Chem. 1982, 18, 1. Also see Bell, R.P. The Proton in Chemistry, 2nd ed., Cornell Univ. Press, Ithaca, NY, 1973, pp. 171–181; Shelly, K.P.; Venimadhavan, S.; Nagarajan, K.; Stewart, R. Can. J. Chem. 1989, 67, 1274. Also see Pollack, R.M. Tetrahedron 1989, 45, 4913.

92. Another mechanism for base-catalyzed enolization has been reported when the base is a tertiary amine: See Bruice, P.Y. J. Am. Chem. Soc. 1990, 112, 7361 and references cited therein.

93. For a proposed concerrted mechanism, see Capon, B.; Siddhanta, A.K.; Zucco, C. J. Org. Chem. 1985, 50, 3580. For evidence against it, see Chiang, Y.; Hojatti, M.; Keeffe, J.R.; Kresge, A.J.; Schepp, N.P.; Wirz, J. 1987, 109,4000 and references cited therein.

94. Xie, L.; Saunders, Jr., W.H. J. Am. Chem. Soc. 1991, 113, 3123.

95. Lienhard, G.E.; Wang, T. J. Am. Chem. Soc. 1969, 91, 1146. See also, Toullec, J.; Dubois, J.E. J. Am. Chem. Soc. 1974, 96, 3524.

96. Chiang, Y.; Kresge, A.J.; Meng, Q.; More O'Ferrall, R.A.; Zhu, Y. J. Am. Chem. Soc. 2001, 123, 11562.

97. Chiang, Y.; Griesbeck, A.G.; Heckroth, H.; Hellrung, B.; Kresge, A.J.; Meng, Q.; O'Donoghue, A.C.; Richard, J.P.; Wirz, J. J. Am. Chem. Soc. 2001, 123, 8979.

98. Zimmerman, H.E.; Cheng, J. J. Org. Chem. 2006, 71, 873.

99. Cantlin, R.J.; Drake, J.; Nagorski, R.W. Org. Lett. 2002, 4, 2433.

100. Bernasconi, C.F.; Pérez-Lorenzo, M. J. Am. Chem. Soc. 2007, 129, 2704.

101. Senn, M.; Richter, W.J.; Burlingame, A.L. J. Am. Chem. Soc. 1965, 87, 680; Richter, W.J.; Senn, M.; Burlingame, A.L. Tetrahedron Lett. 1965, 1235.

102. For an exception, see Guthrie, R.D.; Nicolas, E.C. J. Am. Chem. Soc. 1981, 103, 4637.

103. Dechoux, L.; Doris, E. Tetrahedron Lett. 1994, 35, 2017.

104. Coggins, P.; Gaur, S.; Simpkins, N.S. Tetrahedron Lett. 1995, 36, 1545.

105. See Wen, J.Q.; Grutzner, J.B. J. Org. Chem. 1986, 51, 4220.

106. See d'Angelo, J. Tetrahedron 1976, 32, 2979. Also see Fruchart, J.-S.; Lippens, G.; Kuhn, C.; Gran-Masse, H.; Melnyk, O. J. Org. Chem. 2002, 67, 526.

107. Vedejs, E.; Kruger, A.W.; Suna, E. J. Org. Chem. 1999, 64, 7863.

108. He, X.; Allan, J.F.; Noll, B.C.; Kennedy, A.R.; Henderson, K.W. J. Am. Chem. Soc. 2005, 127, 6920.

109. Eleveld, M.B.; Hogeveen, H. Tetrahedron Lett. 1986, 27, 631. See also, Cain, C.M.; Cousins, R.P.C.; Coumbarides, G.; Simpkins, N.S. Tetrahedron 1990, 46, 523.

110. See House, H.O. Modern Synthetic Reactions, 2nd ed., W.A. Benjamin, NY, 1972, pp. 459–478; De Kimpe, N.; Verhé, R. The Chemistry of α-Haloketones, α-Haloaldehydes, and α-Haloimines, Wiley, NY, 1988. For lists of reagents, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp.709–719.

111. See Rozen, S.; Filler, R. Tetrahedron 1985, 41, 1111; German, L.; Zemskov, S. New Fluorinating Agents in Organic Chemistry; Springer, NY, 1989.

112. Tabushi, I.; Kitaguchi, H. in Pizey, J.S. Synthetic Reagents, Vol. 4; Wiley, NY, 1981, pp. 336–396.

113. Fraser, R.R.; Kong, F. Synth. Commun. 1988, 18, 1071.

114. See Mei, Y.; Bentley, P.A.; Du, J. Tetrahedron Lett. 2008, 49, 3802. Alse see Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64, 5191.

115. Bellesia, F.; DeBuyck, L.; Ghelfi, F.; Pagnoni, U.M.; Parson, A.F.; Pinetti, A. Synthesis 2003, 2173.

116. Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem. Commun. 2004, 470. See Guha, S.K.; Wu, B.; Kim, B.S.; Baik, W.; Koo, S. Tetrahedron Lett. 2006, 47, 291; Arbuj, S.S.; Waghmode, S.B.; Ramaswamy, A.V. Tetrahedron Lett. 2007, 48, 1411. See also Sreedhar, B.; Reddy, P.S.; Madhavi, M. Synth. Commun. 2007, 37, 4149.

117. Bellesia, F.; Ghelfi, F.; Grandi, R.; Pagnoni, U.M. J. Chem. Res. (S) 1986, 428.

118. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. Bull. Chem. Soc. Jpn. 1987, 60, 1159.

119. Juneja, S.K. Choudhary, D.; Paul, S.; Gupta, R. Synth. Commun. 2006, 36, 2877.

120. Paul, S.; Gupta, V.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2003, 44, 439.

121. Lee, J.C.; Park, H.J. Synth. Commun. 2006, 36, 777.

122. Pingali, S.R.K.; Madhav, M.; Jursic, B.S. Tetrahedron Lett. 2010, 51, 1383.

123. Brochu, M.P.; Brown, S.P.; MacMillan, D.W.C. J. Am. Chem. Soc. 2004, 126, 4108; Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jorgensen, K.A. J. Am. Chem. Soc. 2004, 126, 4790. See Wang, L.; Cai, C.; Curran, D.P.; Zhang, W. Synlett 2010, 433.

124. See Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jrgensen, K.A. Chem. Commun. 2005, 4821.

125. See France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org. Chem. 2005, 475.

126. See Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005.

127. Khan, A.T.; Ali, Md.A.; Goswami, P.; Choudhury, L.H. J. Org. Chem. 2006, 71, 8961.

128. Meketa, M.L.; Mahajan, Y.R.; Weinreb, S.M. Tetrahedron Lett. 2005, 46, 4749.

129. Rao, M.L.N.; Jadhav, D.N. Tetrahedron Lett. 2006, 47, 6883. Also see Yadav, J.S.; Kondaji, G.; Reddy, M.S.R.; Srihari, P. Tetrahedron Lett. 2008, 49, 3810.

130. Horiuchi, C.A.; Kiji, S. Bull. Chem. Soc. Jpn. 1997, 70, 421. For another reagent, see Sket, B.; Zupet, P.; Zupan, M.; Dolenc, D. Bull. Chem. Soc. Jpn. 1989, 62, 3406.

131. Yamamoto, T.; Toyota, K.; Morita, N. Tetrahedron Lett. 2010, 51, 1364.

132. Mohanakrishnan, A.K.; Prakash, C.; Ramesh, N. Tetrahedron 2006, 62, 3242.

133. Jereb, M.; Stavber, S.; Zupan, M. Tetrahedron 2003, 59, 5935.

134. Lee, J.C.; Bae, Y.H. Synlett 2003, 507.

135. Kano, T.; Ueda, M.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 3728.

136. Davis, F.A.; Kasu, P.V.N. Org. Prep. Proceed. Int. 1999, 31, 125.

137. See Pihko, P.M. Angew. Chem. Int. Ed. 2006, 45, 544.

138. Enders, D.; Hüttl, M.R.M. Synlett 2005, 991.

139. See Loghmani-Khouzani, H.; Poorheravi, M.R.; Sadeghi, M.M.M.; Caggiano, L.; Jackson, R.F.W. Tetrahedron 2008, 64, 7419.

140. Okamoto, T.; Kakinami, T.; Nishimura, T.; Hermawan, I.; Kajigaeshi, S. Bull. Chem. Soc. Jpn. 1992, 65, 1731.

141. Barnette, W.E. J. Am. Chem. Soc. 1984, 106, 452; Ma, J.-A. For an example with asymmetric induction, see Cahard, D. Tetrahedron Asymm 2004, 15, 1007.

142. Differding, E.; Lang, R.W. Tetrahedron 1988, 29, 6087.

143. Chambers, R.D.; Greenhall, M.P.; Hutchinson, J. J. Chem. Soc. Chem. Commun. 1995, 21.

144. Gupta, O.D.; Shreeve, J.M. Tetrahedron Lett. 2003, 44, 2799.

145. Rozen, S.; Brand, M. Synthesis 1985, 665. For another reagent, see Davis, F.A.; Han, W. Tetrahedron Lett. 1991, 32, 1631.

146. Beeson, T.D.; MacMillan, D.W.C. J. Am. Chem. Soc. 2005, 127, 8826.

147. Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164.

148. Steiner, D.D.; Mase, N.; Barbas III, C.F. Angew. Chem. Int. Ed. 2005, 44, 3706.

149. For chlorination this is reversed if the solvent is methanol: Gallucci, R.R.; Going, R. J. Org. Chem. 1981, 46, 2532.

150. Rappe, C. Ark. Kemi 1965, 24, 321. But see also, Teo, K.E.; Warnhoff, E.W. J. Am. Chem. Soc. 1973, 95, 2728.

151. Garbisch Jr., E.W. J. Org. Chem. 1965, 30, 2109.

152. Nobrega, J.A.; Goncalves, S.M.C.; Reppe, C. Synth. Commun. 2002, 32, 3711.

153. Terent'ev, A.O.; Khodykin, S.V.; Troitskii, N.A.; Ogibin, Y.N.; Nikishin, G.I. Synthesis 2004, 2845.

154. Kajigaeshi, S.; Kakinami, T.; Tokiyama, H.; Hirakawa, T.; Okamoto, T. Bull. Chem. Soc. Jpn. 1987, 60, 2667.

155. Yang, D.; Yan, Y.-L.; Lui, B. J. Org. Chem. 2002, 67, 7429.

156. Marigo, M.; Kumaragurubaran, N.; Jrgensen, K.A. Chem. Eur. J. 2004, 10, 2133.

157. See Tapuhi, E.; Jencks, W.P. J. Am. Chem. Soc. 1982, 104, 5758. Also see Pinkus, A.G.; Gopalan, R. J. Am. Chem. Soc. 1984, 106, 2630; Pinkus, A.G.; Gopalan, R. Tetrahedron 1986, 42, 3411.

158. See, however, Deno, N.C.; Fishbein, R. J. Am. Chem. Soc. 1973, 95, 7445.

159. Bell, R.P.; Yates, K. J. Chem. Soc. 1962, 1927.

160. Hochstrasser, R.; Kresge, A.J.; Schepp, N.P.; Wirz, J. J. Am. Chem. Soc. 1988, 110, 7875.

161. Hooz, J.; Bridson, J.N. Can. J. Chem. 1972, 50, 2387.

162. Stotter, P.L.; Hill, K.A. J. Org. Chem. 1973, 38, 2576.

163. Blanco, L.; Amice, P.; Conia, J.M. Synthesis 1976, 194.

164. Olah, G.A.; Ohannesian, L.; Arvanaghi, M.; Prakash, G.K.S. J. Org. Chem. 1984, 49, 2032.

165. Rubottom, G.M.; Mott, R.C. J. Org. Chem. 1979, 44, 1731.

166. Zhang, Y.; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038.

167. Tsushima, T.; Kawada, K.; Tsuji, T. Tetrahedron Lett. 1982, 23, 1165.

168. Purrington, S.T.; Bumgardner, C.L.; Lazaridis, N.V.; Singh, P. J. Org. Chem. 1987, 52, 4307.

169. Cambie, R.C.; Hayward, R.C.; Jurlina, J.L.; Rutledge, P.S.; Woodgate, P.D. J. Chem. Soc. Perkin Trans. 1 1978, 126.

170. Horiuchi, C.A.; Satoh, J.Y. Synthesis 1981, 312.

171. Ley, S.V.; Whittle, A.J. Tetrahedron Lett. 1981, 22, 3301.

172. Hegde, S.G.; Wolinsky, J. Tetrahedron Lett. 1981, 22, 5019.

173. Fache, F.; Piva, O. Synlett 2002, 2035.

174. See Harwood, H.J. Chem. Rev. 1962, 62, 99, pp. 102-103.

175. Wack, H.; Taggi, A.E.; Hafez, A.M.; Drury III, W.J.; Lectka, T. J. Am. Chem. Soc. 2001, 123, 1531. See also, France, S.; Wack, H.; Taggi, A.E.; Hafez, A.M.; Wagerle, Ty.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245.

176. See, however, Kwart, H.; Scalzi, F.V. J. Am. Chem. Soc. 1964, 86, 5496.

177. Ogata, Y.; Watanabe, S. J. Org. Chem. 1979, 44, 2768; 1980, 45, 2831.

178. Ogata, Y.; Adachi, K. J. Org. Chem. 1982, 47, 1182.

179. Zhang, L.H.; Duan, J.; Xu, Y.; Dolbier, Jr., W.R. Tetrahedron Lett. 1998, 39, 9621.

180. For a list of reagents, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 730–738.

181. Okimoto, M.; Takahashi, Y. Synthesis 2002, 2215.

182. Harpp, D.N.; Bao, L.Q.; Black, C.J.; Gleason, J.G.; Smith, R.A. J. Org. Chem. 1975, 40, 3420.

183. Horiuchi, C.A.; Satoh, J.Y. Chem. Lett. 1984, 1509.

184. Rathke, M.W.; Lindert, A. Tetrahedron Lett. 1971, 3995.

185. Purrington, S.T.; Woodard, D.L. J. Org. Chem. 1990, 55, 3423.

186. Kitagawa, O.; Hanano, T.; Hirata, T.; Inoue, T.; Taguchi, T. Tetrahedron Lett. 1992, 33, 1299.

187. For a review, see Venier, C.G.; Barager, III, H.J. Org. Prep. Proced. Int. 1974, 6, 77, pp. 81–84.

188. Tsuchihashi, G.; Iriuchijima, S. Bull. Chem. Soc. Jpn. 1970, 43, 2271.

189. Ogura, K.; Imaizumi, J.; Iida, H.; Tsuchihashi, G. Chem. Lett. 1980, 1587.

190. Tin, K.; Durst, T. Tetrahedron Lett. 1970, 4643.

191. Kim, Y.H.; Lim, S.C.; Kim, H.R.; Yoon, D.C. Chem. Lett. 1990, 79.

192. Cinquini, M.; Colonna, S. J. Chem. Soc. Perkin Trans. 11972, 1883. See also, Cinquini, M.; Colonna, S. Synthesis1972, 259.

193. Iriuchijima, S.; Tsuchihashi, G. Synthesis 1970, 588.

194. Regis, R.R.; Doweyko, A.M. Tetrahedron Lett. 1982, 23, 2539.

195. Paquette, L.A.; Houser, R.W. J. Org. Chem. 1971, 36, 1015.

196. McCarthy, J.R.; Pee, N.P.; LeTourneau, M.E.; Inbasekaran, M. J. Am. Chem. Soc. 1985, 107, 735. See also, Umemoto, T.; Tomizawa, G. Bull. Chem. Soc. Jpn. 1986, 59, 3625.

197. See Parmerter, S.M. Org. React. 1959, 10, 1.

198. See Yao, H.C.; Resnick, P. J. Am. Chem. Soc. 1962, 84, 3514.

199. For a review, see Phillips, R.R. Org. React. 1959, 10, 143.

200. Neplyuev, V.M.; Bazarova, I.M.; Lozinskii, M.O. J. Org. Chem. USSR 1989, 25, 2011. This paper also includes a sequence of leaving group ability for other Z groups.

201. For a review, see Williams, D.L.H. Nitrosation, Cambridge Univ. Press, Cambridge, 1988, pp. 1–45.

202. For a review, see Williams, D.L.H. Adv. Phys. Org. Chem. 1983, 19, 381. See also, Williams, D.L.H. Nitrosation, Cambridge Univ. Press, Cambridge, 1988.

203. Leis, J.R.; Peña, M.E.; Williams, D.L.H.; Mawson, S.D. J. Chem. Soc. Perkin Trans. 2 1988, 157.

204. Iglesias, E.; Williams, D.L.H. J. Chem. Soc. Perkin Trans. 2 1989, 343; Crookes, M.J.; Roy, P.; Williams, D.L.H. J. Chem. Soc. Perkin Trans. 2 1989, 1015. See also, Graham, A.; Williams, D.L.H. J. Chem. Soc. Chem. Commun. 1991, 407.

205. Rasmussen, J.K.; Hassner, A. J. Org. Chem. 1974, 39, 2558.

206. Kim, Y.H.; Park, Y.J.; Kim, K. Tetrahedron Lett. 1989, 30, 2833.

207. See Pape, M. Fortschr. Chem. Forsch. 1967, 7, 559.

208. Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579.

209. See Olah, G.A.; Malhotra, R.; Narang, S.C. Nitration, VCH, NY, 1989, pp. 219–295; Ogata, Y. in Trahanovsky, W.S. Oxidation in Organic Chemisry, part C, Academic Press, NY, 1978, pp. 295–342; Ballod, A.P.; Shtern, V.Ya. Russ. Chem. Rev. 1976, 45, 721.

210. See Matasa, C.; Hass, H.B. Can. J. Chem. 1971, 49, 1284.

211. Titov, A.I. Tetrahedron 1963, 19, 557.

212. Sifniades, S. J. Org. Chem. 1975, 40, 3562.

213. See Larson, H.O. in Feuer, H. The Chemistry of the Nitro and Nitroso Groups, Vol. 1, Wiley, NY, 1969, pp. 310–316.

214. See Feuer, H.; Van Buren, II, W.D.; Grutzner, J.B. J. Org. Chem. 1978, 43, 4676.

215. Olah, G.A.; Lin, H.C. J. Am. Chem. Soc. 1973, 93, 1259. See also, Bach, R.D.; Holubka, J.W.; Badger, R.C.; Rajan, S. J. Am. Chem. Soc. 1979, 101, 4416.

216. Isozaki, S.; Nishiwaki, Y.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2001, 1352.

217. Nishiwaki, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2002, 67, 5663.

218. Garver, L.C.; Grakauskas, V.; Baum, K. J. Org. Chem. 1985, 50, 1699.

219. See Regitz, M.; Maas, G. Diazo Compounds, Academic Press, NY, 1986, pp. 326–435; Regitz, M. Synthesis 1972, 351. See also, Koskinen, A.M.P.; Muñoz, L. J. Chem. Soc. Chem. Commun. 1990, 652.

220. Ledon, H. Synthesis 1974, 347, Org. Synth. VI, 414; Also see Ghosh, S.; Datta, I. Synth. Commun. 1991, 21, 191.

221. Taber, D.F.; Ruckle, Jr., R.E.; Hennessy, M.J. J. Org. Chem. 1986, 51, 4077; Baum, J.S.; Shook, D.A.; Davies, H.M.L.; Smith, H.D. Synth. Commun. 1987, 17, 1709.

222. Doering, W. von E.; DePuy, C.H. J. Am. Chem. Soc. 1953, 75, 5955.

223. See also Danheiser, R.L.; Miller, R.F.; Brisbois, R.G.; Park, S.Z. J. Org. Chem. 1990, 55, 1959.

224. Evans, D.A.; Britton, T.C. J. Am. Chem. Soc. 1987, 109, 6881, and references cited therein.

225. See Sheradsky, T. in Patai, S. The Chemistry of Functional Groups, Supplement F, pt. 1, Wiley, NY, 1982, pp. 395–416.

226. Sharpless, K.B.; Hori, T.; Truesdale, L.K.; Dietrich, C.O. J. Am. Chem. Soc. 1976, 98, 269; Kresze, G.; Münsterer, H. J. Org. Chem. 1983, 48, 3561. For a review, see Cheikh, R.B.; Chaabouni, R.; Laurent, A.; Mison, P.; Nafti, A. Synthesis 1983, 685, pp. 691–696.

227. Sharpless, K.B.; Hori, T. J. Org. Chem. 1979, 41, 176. For other reagents, see Tsushima, S.; Yamada, Y.; Onami, T.; Oshima, K.; Chaney, M.O.; Jones, N.D.; Swartzendruber, J.K. Bull. Chem. Soc. Jpn. 1989, 62, 1167.

228. Srivastava, R.S.; Nicholas, K.M. Tetrahedron Lett. 1994, 35, 8739.

229. Kohmura, Y.; Kawasaki, K.; Katsuki, T. Synlett, 1997, 1456.

230. Poulsen, T.B.; Alemparte, C.; Jrgensen, K.A. J. Am. Chem. Soc. 2005, 127, 11614.

231. Fiori, J.W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562.

232. Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.Soc. 2001, 123, 6935.

233. Espino, C.G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598.

234. Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044.

235. See Lwowski, W. in Lwowski, W. Nitrenes, Wiley, NY, 1970, pp. 199–207.

236. See Maslak, P. J. Am. Chem. Soc. 1989, 111, 8201.

237. See Alewood, P.F.; Kazmaier, P.M.; Rauk, A. J. Am. Chem. Soc. 1973, 95, 5466.

238. See Inagaki, M.; Shingaki, T.; Nagai, T. Chem. Lett. 1981, 1419.

239. Smolinsky, G.; Feuer, B.I. J. Am. Chem. Soc. 1964, 86, 3085.

240. See Anastassiou, A.G.; Shepelavy, J.N.; Simmons, H.E.; Marsh, F.D. in Lwowski, W. Nitrenes, Wiley, NY, 1970, pp. 305–344.

241. See Scriven, E.F.V. Azides and Nitrenes, Academic Press, NY, 1984, pp. 95–204.

242. Li, Z.; Capretto, D.A.; Rahaman, R.O.; He, C. J. Am. Chem. Soc. 2007, 129, 12058.

243. See also, Meinwald, J.; Aue, D.H. Tetrahedron Lett. 1967, 2317.

244. For a list of examples, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 1148–1149.

245. See Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.

246. See Trost, B.M. Pure Appl. Chem. 1975, 43, 563, pp. 572–578; Caine, D. in Augustine, R.L. Carbon–Carbon Bond Formation, Vol. 1, Marcel Dekker, NY, 1979, pp. 278–282.

247. Gassman, P.G.; Balchunis, R.J. J. Org. Chem. 1977, 42, 3236.

248. See Sandrinelli, F.; Fontaine, G.; Perrio, S.; Beslin, P. J. Org. Chem. 2004, 69, 6916.

249. For another reagent, see Scholz, D. Synthesis 1983, 944.

250. See Back, T.G. in Liotta, D.C. Organoselenium Chemistry, Wiley, NY, 1987, pp. 1–125; Paulmier, C. Selenium Reagents and Intermediates in Organic Synthesis, Pergamon, Elmsford, NY, 1986, pp. 95–98.

251. Brocksom, T.J.; Petragnani, N.; Rodrigues, R. J. Org. Chem. 1974, 39, 2114. See also, Liotta, D. Acc. Chem. Res. 1984, 17, 28.

252. Grieco, P.A.; Miyashita, M. J. Org. Chem. 1974, 39, 120. See Miyoshi, N.; Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1982, 23, 4813.

253. Barton, D.H.R.; Morzycki, J.W.; Motherwell, W.B.; Ley, S.V. J. Chem. Soc. Chem. Commun. 1981, 1044.

254. Sharpless, K.B.; Lauer, R.F.; Teranishi, A.Y. J. Am. Chem. Soc. 1973, 95, 6137.

255. Cossy, J.; Furet, N. Tetrahedron Lett. 1993, 34, 7755.

256. Wang, W.; Wang, K.; Li, H. Org. Lett. 2004, 6, 2817.

257. Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.; Anilkumar, G.; Matsumoto, K.; Kita, Y. J. Org. Chem., 2001, 66, 2434.

258. Trost, B.M.; Hiroi, K.; Kurozumi, S. J. Am. Chem. Soc. 1975, 97, 438.

259. See OS VI, 23, 109; 68, 8. See also Morris, D.G. Chem. Soc. Rev. 1982, 11, 397; Kane, V.V.; Singh, V.; Martin, A.; Doyle, D.L. Tetrahedron 1983, 39, 345.

260. See Gilbert, E.E. Sulfonation and Related Reactions, Wiley, NY, 1965, pp. 33–61.

261. Scott, W.J.; Crisp, G.T.; Stille, J.K. J. Am. Chem. Soc. 1984, 106, 4630. See Roth, G.P.; Farina, V.; Liebeskind, L.S.; Peña-Cabrera, E. Tetrahedron Lett. 1995, 36, 2191 for an optimized version of this reaction. Also see Echavarren, A.M. Angew. Chem. Int. Ed. 2005, 44, 3962; Reiser, O. Angew. Chem. Int. Ed. 2006, 45, 2838.

262. See Zhou, W.-J.; Wang, K.-H.; Wang, J.-X. J. Org. Chem. 2009, 74, 5599.

263. Gajare, A.S.; Jensen, R.S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Synlett 2005, 144. For a ligand free reaction, see Yabe, Y.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron 2010, 66, 8654.

264. Lau, K.C.Y.; Chiu, P. Tetrahedron Lett. 2007, 48, 1813.

265. McMurry, J.E.; Scott, W.J. Tetrahedron Lett. 1983, 24, 979.

266. See Maleczka Jr., R.E.; Lavis, J.M.; Clark, D.H.; Gallagher, W.P. Org. Lett. 2000, 2, 3655.

267. Farina, V.; Krishnamurthy, V.; Scott, W.J. Org. React. 1997, 50, 1; Li, J.-H.; Liang, Y.; Wang, D.-P.; Liu, W.-J.; Xie, Y.-X.; Yin, D.-L. J. Org. Chem. 2005, 70, 2832.

268. Powell, D.A.; Maki, T.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 510.

269. Johnson, C.R.; Adams, J.P.; Braun, M.P.; Senanayake, C.B.W. Tetrahedron Lett. 1992, 33, 919.

270. Badone, D.; Cardamone, R.; Guzzi, U. Tetrahedron Lett. 1994, 35, 5477.

271. Segorbe, M.M.; Adrio, J.; Carretero, J.C. Tetrahedron Lett. 2000, 41, 1983.

272. Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D.P. J. Org. Chem. 1997, 62, 5583.

273. Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D.P.; Hallberg, A. J. Org. Chem. 1999, 64, 4539.

274. Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999, 99, 475.

275. Shi, Y.; Peterson, S.M.; Haberaecker III, W.W.; Blum, S.A. J. Am. Chem. Soc. 2008, 130, 2168.

276. Farina, V.; Hossain, M.A. Tetrahedron Lett. 1996, 37, 6997.

277. Rai, R.; Aubrecht, K.B.; Collum, D.B. Tetrahedron Lett. 1995, 36, 3111.

278. Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 1999, 38, 2411.

279. Clapham, B.; Sutherland, A.J. J. Org. Chem. 2001, 66, 9033.

280. Schaus, J.V.; Panek, J.S. Org. Lett. 2000, 2, 469.

281. See Rousset, S.; Abarbri, M.; Thibonnet, J.; Duchêne, A.; Parrain, J.-L. Org. Lett. 1999, 1, 701. Also see Minière, S.; Cintrat, J.-C. J. Org. Chem. 2001, 66, 7385.

282. Lindh, J.; Fardost, A.; Almeida, M.; Nilsson, P. Tetrahedron Lett. 2010, 51, 2470; Sävmarker, J.; Lindh, J.; Nilsson, P. Tetrahedron Lett. 2010, 51, 6886.

283. Mee, S.P.H.; Lee, V.; Baldwin, J.E. Chemistry: European J. 2005, 11, 3294.

284. Li, J.-H.; Tang, B.-X.; Tao, L.-M.; Xie, Y.-X.; Liang, Y.; Zhang, M.-B. J. Org. Chem. 2006, 71, 7488.

285. Voigt, K.; Schick, U.; Meyer, F.E.; de Meijere, A. Synlett 1994, 189.

286. Gilbertson, S.R.; Fu, Z.; Xie, D. Tetrahedron Lett. 2001, 42, 365.

287. Scott, W.J.; Stille, J.K. J. Am. Chem. Soc. 1986, 108, 3033; Stille, J.K. Angew. Chem., Int. Ed. 1986, 25, 508; Farina, V. in Abel, E.W.; Stone, F.G.A.; Wilkinson, G. Comprehensive Organometallic Chemistry II, Vol. 12, Pergamon, Oxford, U.K., 1995, Chapter 3.4.; Brown, J.M.; Cooley, N.A. Chem. Rev. 1988, 88, 1031.

288. Amatore, C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993, 115, 9531 and references cited therein.

289. Ozawa, F.; Fujimori, M.; Yamamoto, T.; Yamamoto, A. Organometallics 1986, 5, 2144; Tatsumi, K.; Hoffmann, R.; Moravski, A.; Stille, J.K. J. Am. Chem. Soc. 1981, 103, 4182; Loar, M.K.; Stille, J.K. J. Am. Chem. Soc.1981, 103, 4174.

290. Deacon, G.B.; Gatehouse, B.M.; Nelson-Reed, K.T. J. Organomet. Chem. 1989, 359, 267.

291. Casado, A.L.; Espinet, P.; Gallego, A.M. J. Am. Chem. Soc. 2000, 122, 11771.

292. Santos, L.S.; Rosso, G.B.; Pilli, R.A.; Eberlin, M.N. J. Org. Chem. 2007, 72, 5809.

293. Zhou, S.-m.; Deng, M.-z. Tetrahedron Lett. 2000, 41, 3951.

294. Yao, M.-L.; Deng, M.-Z. J. Org. Chem. 2000, 65, 5034; Yao, M.-L.; Deng, M.-Z. Tetrahedron Lett. 2000, 41, 9083.

295. Occhiato, E.G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001, 66, 2459.

296. Kabalka, G.W.; Dadush, E.; Al-Masum, M. Tetrahedron Lett. 2006, 47, 7459.

297. Molander, G.A.; Felix, L.A. J. Org. Chem. 2005, 70, 3950.

298. Fu, X.; Zhang, S.; Yin, J.; McAllister, T.L.; Jiang, S.A.; Tann, C.-H.; Thiruvengadam, T.K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573. See Vallin, K.S.A.; Larhed, M.; Johansson, K.; Hallberg, A. J. Org. Chem. 2000, 65, 4537.

299. Nishihara, Y.; Ikegashira, K.; Toriyama, F.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 985.

300. Raminelli, C.; Gargalak Jr., J.; Silveira, C.C.; Comasseto, J.V. Tetrahedron Lett. 2004, 45, 4927; Silveira, C.C.; Braga, A.L.; Vieira, A.S.; Zeni, G. J. Org. Chem. 2003, 68, 662.

301. Zeni, G.; Comasseto, J.V. Tetrahedron Lett. 1999, 40, 4619.

302. Ma, S.; Zhang, A.; Yu, Y.; Xia, W. J. Org. Chem. 2000, 65, 2287.

303. Dillinger, S.; Bertus, P.; Pale, P. Org. Lett. 2001, 3, 1661. See Halbes, U.; Bertus, P.; Pale, P. Tetrahedron Lett. 2001, 42, 8641; Bertus, P.; Halbes, U.; Pale, P. Eur. J. Org. Chem. 2001, 4391.

304. Braga, A.L.; Emmerich, D.J.; Silveira, C.C.; Martins, T.L.C.; Rodrigues, O.E.D. Synlett 2001, 369.

305. Lee, J.-H.; Park, J.-S.; Cho, C.-G. Org. Lett. 2002, 4, 1171. Also see Bates, C.G.; Saejueng, P.; Venkataraman, D. Org. Lett. 2004, 6, 1441.

306. Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org. Lett. 2003, 5, 1597.

307. Abarbri, M.; Parrain, J.-L.; Kitamura, M.; Noyori, R.; Duchêne, A. J. Org. Chem. 2000, 65, 7475.

308. Menzel, K.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 3718.

309. Tsukada, N.; Sato, T.; Inoue, Y. Chem. Commun. 2003, 2404.

310. Kiewel, K.; Tallant, M.; Sulikowski, G.A. Tetrahedron Lett. 2001, 42, 6621.

311. See Groves, E.E. Chem. Soc. Rev. 1972, 1, 73; Satchell, D.P.N.; Satchell, R.S. in Patai, S. The Chemistry of the Carbonyl Group, Vol. 1, Wiley, NY, 1966, pp. 259–266, 270–273; Nenitzescu, C.D.; Balaban, A.T. in Olah, G.A. Friedel–Crafts and Related Reactions, Vol. 3, Wiley, NY, 1964, pp. 1033–1152.

312. Deno, N.C.; Chafetz, H. J. Am. Chem. Soc. 1952, 74, 3940. For other examples, see Grignon-Dubois, M.; Cazaux, M. Bull. Soc. Chim. Fr. 1986, 332.

313. See Heck, R.F. in Wender, I.; Pino, P. Organic Syntheses via Metal Carbonyls, Vol. 1, Wiley, NY, 1968, pp. 388–397.

314. Andersson, C.; Hallberg, A. J. Org. Chem. 1988, 53, 4257.

315. See Burn, D. Chem. Ind. (London) 1973, 870; Satchell, D.P.N.; Satchell, R.S. in Patai, S. The Chemistry of the Carbonyl Group, Vol. 1, Wiley, NY, 1966, pp. 281–282.

316. Youssefyeh, R.D. Tetrahedron Lett. 1964, 2161.

317. Shen, W.; Kunzer, A. Org. Lett. 2002, 4, 1315.

318. Youssefyeh, R.D. J. Am. Chem. Soc. 1963, 85, 3901.

319. See van der Zeeuw, A.J.; Gersmann, H.R. Recl. Trav. Chim. Pays-Bas 1965, 84, 1535.

320. See Poirier, J. Org. Prep. Proced. Int. 1988, 20, 319; Brownbridge, P. Synthesis 1983, 1, 85; Colvin, E.W. Silicon Reagents in Organic Synthesis, Academic Press, NY, 1988; Colvin, E.W. in Hartley, C.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 4, Wiley, NY, pp. 539–621; Ager, D.J. Chem. Soc. Rev. 1982, 11, 493.

321. See Mizhiritskii, M.D.; Yuzhelevskii, Yu.A. Russ. Chem. Rev. 1987, 56, 355. For a list, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 1488–1491.

322. Di-tert-butylmagnesium has also been used. See Kerr, W.J.; Watson, A.J.B.; Hayes, D. Synlett 2008, 1386.

323. Corey, E.J.; Gross, A.W. Tetrahedron Lett. 1984, 25, 495. Also see Lipshutz, B.H.; Wood, M.R.; Lindsley, C.W. Tetrahedron Lett. 1995, 36, 4385.

324. See Cahiez, G.; Figadère, B.; Cléry, P. Tetrahedron Lett. 1994, 35, 6295.

325. Ladjama, D.; Riehl, J.J. Synthesis 1979, 504. See Orban, J.; Turner, J.V.; Twitchin, B. Tetrahedron Lett. 1984, 25, 5099.

326. Miller, R.D.; McKean, D.R. Synth. Commun. 1982, 12, 319. See also, Ahmad, S.; Khan, M.A.; Iqbal, J. Synth. Commun. 1988, 18, 1679.

327. Fujiwara, M.; Baba, A.; Matsuda, H. Chem. Lett. 1989, 1247.

328. Smietana, M.; Mioskowski, C. Org. Lett. 2001, 3, 1037. See also, Tanabe, Y.; Misaki, T.; Kurihara, M.; Iida, A.; Nishii, Y. Chem. Commun. 2002, 1628.

329. Ozawa, F.; Yamamoto, S.; Kayagishi, S.; Hiraoka, M.; Ideda, S.; Minami, T.; Ito, S.; Yoshifuji, M. Chem. Lett. 2001, 972. See Blackwell, J.M.; Morrison, D.J.; Piers, W.E. Tetahedron 2002, 58, 8247; Mori, A.; Kato, T. Synlett2002, 1167.

330. Heathcock, C.H.; Buse, C.T.; Kleschick, W.A.; Pirrung, M.A.; Sohn, J.E.; Lampe, J. J. Org. Chem. 1980, 45, 1066.

331. Vitale, M.; Lecourt, T.; Sheldon, C.G.; Aggarwal, V.K. J. Am. Chem. Soc. 2006, 128, 2524.

332. Lessène, G.; Tripoli, R.; Cazeau, P.; Biran, C.; Bordeau, M. Tetrahedron Lett. 1999, 40, 4037. Also see Patonay, T.; Hajdu, C.; Jeko, J.; Lévai, A.; Micskei, K.; Zucchi, C. Tetrahedron Lett. 1999, 40, 1373.

333. Lin, J.-M.; Liu, B.-S. Synth. Commun. 1997, 27, 739.

334. Aggarwal, V.K.; Sheldon, C.G.; Macdonald, G.J.; Martin, W.P. J. Am. Chem. Soc. 2002, 124, 10300.

335. Robertson, B.D.; Hartel, A.M. Tetrahedron Lett. 2008, 49, 2088.

336. For the synthesis of enol acetates, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, 1484–1485.

337. See Krapcho, A.P.; Diamanti, J.; Cayen, C.; Bingham, R. Org. Synth. Coll. Vol. V 1973, 198.

338. See Honda, T.; Namiki, H.; Kudoh, M.; Watanabe, N.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2000, 41, 5927.

339. Yoo, W.-J.; Li, C.-J. J. Org. Chem. 2006, 71, 6266.

340. Wentworth, A.D.; Wentworth, Jr., P.; Mansoor, U.F.; Janda, K.D. Org. Lett. 2000, 2, 477.

341. House, H.O.; Czuba, L.J.; Gall, M.; Olmstead, H.D. J. Org. Chem. 1969, 34, 2324.

342. Comins, D.L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.

343. Holmquist, C.R.; Roskamp, E.J. J. Org. Chem. 1989, 54, 3258.

344. Pelter, A.; Smith, K.; Elgendy, S.; Rowlands, M. Tetrahedron Lett. 1989, 30, 5643.

345. Krug, C.; Hartwig, J.F. J. Am. Chem. Soc. 2002, 124, 1674.

346. Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004, 126, 15356.

347. Ruan, J.; Saidi, O.; Iggo, J.A.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 10510.

348. Kahne, D.; Collum, D.B. Tetrahedron Lett. 1981, 22, 5011.

349. Santiago, B.; Meyers, A.I. Tetrahedron Lett. 1993, 34, 5839.

350. North, M. Angew. Chem. Int. Ed. 2004, 43, 4126.

351. Han, W.; Ofial, A.R. Chem. Commun. 2009, 5024.

352. Kornblum, N.; Singh, N.K.; Kelly, W.J. J. Org. Chem. 1983, 48, 332.

353. Barton, D.H.R.; Billion, A.; Boivin, J. Tetrahedron Lett. 1985, 26, 1229.

354. Lemaire, M.; Doussot, J.; Guy, A. Chem. Lett. 1988, 1581. See also, Hayashi, Y.; Mukaiyama, T. Chem. Lett. 1987, 1811.

355. Zhou, W.; Zhang, L.; Jiao, N. Angew. Chem. Int. Ed 2009, 48, 7094.

356. Olah, G.A.; Mo, Y.K.; Olah, J.A. J. Am. Chem. Soc. 1973, 95, 4939. See Olah, G.A.; Farooq, O.; Prakash, G.K.S. in Hill, C.L. Activation and Functionalization of Alkanes, Wiley, NY, 1989, pp. 27–78; Ref. 48; Fabre, P.; Devynck, J.; Trémillon, B. Chem. Rev. 1982, 82, 591. See also, Olah, G.A.; Prakash, G.K.S.; Williams, R.E.; Field, L.D.; Wade, K. Hypercarbon Chemistry, Wiley, NY, 1987.

357. Olah, G.A.; DeMember, J.R.; Shen, J. J. Am. Chem. Soc. 1973, 95, 4952. See also, Sommer, J.; Muller, M.; Laali, K. Nouv. J. Chem. 1982, 6, 3.

358. For example, see Hogeveen, H.; Roobeek, C.F. Recl. Trav. Chim. Pays-Bas 1972, 91, 137.

359. Yamamoto, G.; Oki, M. Chem. Lett. 1987, 1163.

360. First reported by Meerwein, H.; Rathjen, H.; Werner, H. Ber. 1942, 75, 1610. See Doyle, M.P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704; Bethell, D. in McManus, S.P. Organic Reactive Intermediates, Academic Press, NY, 1973, pp. 92–101; Kirmse, W. Carbene Chemistry, 2nd ed., Academic Press, NY, 1971, pp. 209–266.

361. Terao, T.; Shida, S. Bull. Chem. Soc. Jpn. 1964, 37, 687. See also, Moss, R.A.; Fedé, J.-M.; Yan, S. J. Am. Chem. Soc. 2000, 122, 9878.

362. See Marek, I. Tetrahedron 2002, 58, 9463.

363. See Paquette, L.A.; Kobayashi, T.; Gallucci, J.C. J. Am. Chem. Soc. 1988, 110, 1305; Doyle, M.P.; Bagheri, V.; Pearson, M.M.; Edwards, J.D. Tetrahedron Lett. 1989, 30, 7001.

364. Friedman, L.; Berger, J.G. J. Am. Chem. Soc. 1961, 83, 492, 500. See Padwa, A.; Krumpe, K.E. Tetrahedron 1992, 48, 5385.

365. See Burke, S.D.; Grieco, P.A. Org. React. 1979, 26, 361.

366. Doering, W. von E.; Knox, L.H. J. Am. Chem. Soc. 1961, 83, 1989.

367. Carter, D.S.; Van Vranken, D.L. Org. Lett. 2000, 2, 1303; Doyle, M.P.; McKervey, M.A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides, Wiley, NY, 1998.

368. Bertram, A.K.; Liu, M.T.H. J. Chem. Soc. Chem. Commun. 1993, 467.

369. See Steinbeck, K. Tetrahedron Lett. 1978, 1103; Boev, V.I. J. Org. Chem. USSR 1981, 17, 1190.

370. Davies, H.M.L.; Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587.

371. Gibe, R.; Kerr, M.A. J. Org. Chem. 2002, 67, 6247.

372. Arduengo, III, A.J.; Calabrese, J.C.; Davidson, F.; Dias, H.V.R.; Goerlich, J.R.; Krafczyk, R.; Marshall, W.J.; Tamm, M.; Schmutzler, R. Helv. Chim. Acta. 1999, 82, 2348.

373. Ventura, D.L.; Li, Z.; Coleman, M.G.; Davies, H.M.L. Tetrahedron 2009, 65, 3052.

374. Masselot, D.; Charmant, J.P.H.; Gallagher, T. J. Am. Chem. Soc. 2006, 128, 694.

375. See Caballero, A.; Díaz-Requejo, M.M.; Belderraín, T.R.; Nicasio, M.C.; Trofimenko, S.; Pérez, P.J. J. Am. Chem. Soc. 2003, 125, 1446.

376. Dias, H.V.R.; Browning, R.G.; Polach, S.A.; Diyabalanage, H.V.K.; Lovely, C.J. J. Am. Chem. Soc. 2003, 125, 9270.

377. Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008,130, 2434.

378. Wee, A.G.H.; Duncan, S.C. J. Org. Chem. 2005, 70, 8372.

379. Dalton, A.M.; Zhang, Y.; Davie, C.P.; Danheiser, R.L. Org. Lett. 2002, 4, 2465.

380. Devine, S.K.J.; Van Vranken, D.L. Org. Lett. 2007, 9, 2047.

381. Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258.

382. Matusamy, S.; Arulananda, S.; Babu, A.; Gunanathan, C. Tetrahedron Lett. 200243, 3133.

383. Lo, M.M.-C.; Fu, G.C. Tetrahedron 2001, 57, 2621.

384. Davies, H.M.L.; Hedley, S.J.; Brooks R.; Bohall, B.R. J. Org. Chem. 2005, 70, 10737.

385. Bourque, L.E.; Cleary, P.A.; Woerpel, K.A. J. Am. Chem. Soc. 2007, 129, 12602.

386. Davies, H.M.L.; Grazini, M.V.A.; Aouad, E. Org. Lett. 2001, 3, 1475.

387. Doyle, M.P.; Protopopova, M.N.; Winchester, W.R.; Daniel, K.L. Tetrahedron Lett. 1992, 33, 7819. See also, Clark, J.S.; Hodgson, P.B.; Goldsmith, M.D.; Street, L.J. J. Chem. Soc., Perkin Trans. 1 2001, 3312.

388. Coutts, I.G.C.; Saint, R.E.; Saint, S.L.; Chambers-Asman, D.M. Synthesis 2001, 247.

389. See Shi, W.; Zhang, B.; Zhang, J.; Liu, B.; Zhang, S.; Wang, J. Org. Lett. 2005, 7, 3103.

390. See Doyle, M.P.; Kalinin, A.V. Synlett, 1995, 1075; Watanabe, N.; Ohtake, Y.; Hashimoto, S.; Shiro, M.; Ikegami, S. Tetrahedron Lett. 1995, 36, 1491; Maruoka, K.; Concepcion, A.B.; Yamamoto, H. J. Org. Chem. 1994, 59, 4725.

391. See Sulikowski, G.A.; Cha, K.L.; Sulikowski, M.M. Tetrahedron Asymmetry, 1998, 9, 3145.

392. Ye, T.; McKervey, M.A. Chem. Rev. 1994, 94, 1091.

393. Doyle, M.P. Pure Appl. Chem. 1998, 70, 1123. See Taber, D.F.; Malcolm, S.C. J. Org. Chem. 1998, 63, 3717 for a discussion of transition state geometry in rhodium mediated C–H insertion.

394. Davies, H.M.L.; Jin, Q. Org. Lett. 2004, 6, 1769; Davies, H.M.L.; Loe, ∅. Synthesis 2004, 2595.

395. See Davies, H.M.L.; Beckwith, R.E.J. Chem. Rev. 2003, 103, 2861. See also Davies, H.M.L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176; Suematsu, H.; Katsuki, T. J. Am. Chem. Soc. 2009, 131, 14218.

396. See Bethell, D. Adv. Phys. Org. Chem. 1969, 7, 153, pp. 190–194.

397. Doering, W. von E.; Prinzbach, H. Tetrahedron 1959, 6, 24.

398. See Seyferth, D.; Cheng, Y.M. J. Am. Chem. Soc. 1971, 93, 4072.

399. Sobery, W.; DeLucca, J.P. Tetrahedron Lett. 1995, 36, 3315.

400. Frey, H.M. Proc. Chem. Soc. 1959, 318.

401. McNesby, J.R.; Kelly, R.V. Int. J. Chem. Kinet. 1971, 3, 293.

402. Ring, D.F.; Rabinovitch, B.S. J. Am. Chem. Soc. 1966, 88, 4285; Can J. Chem. 1968, 46, 2435.

403. Bell, J.A. Prog. Phys. Org. Chem. 1964, 2, 1, pp. 30–43.

404. Cummins, J.M.; Porter, T.A.; Jones, Jr., M. J. Am. Chem. Soc. 1998, 120, 6473.

405. Richardson, D.B.; Simmons, M.C.; Dvoretzky, I. J. Am. Chem. Soc. 1961, 83, 1934.

406. See Roth, H.D. Acc. Chem. Res. 1977, 10, 85.

407. Roth, H.D. J. Am. Chem. Soc. 1972, 94, 1761. See also, Bethell, D.; McDonald, K. J. Chem. Soc. Perkin Trans. 2 1977, 671.

408. See Oku, A.; Yamaura, Y.; Harada, T. J. Org. Chem. 1986, 51, 3730; Ritter, R.H.; Cohen, T. J. Am. Chem. Soc. 1986, 108, 3718.

409. See Wardell, J.L. in Zuckerman, J.J. Inorganic Reactions and Methods, Vol. 11, VCH, NY, 1988, pp. 44–107; Wardell, J.L. in Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 4, Wiley, NY, pp. 1–157, pp. 27–71; Narasimhan, M.S.; Mali, R.S. Synthesis 1983, 957; Biellmann, J.F.; Ducep, J. Org. React. 1982, 27, 1; Gschwend, H.W.; Rodriguez, H.R. Org. React. 1979, 26, 1; Mallan, J.M.; Bebb, R.L. Chem. Rev. 1969, 69, 693.

410. See Saá, J.M.; Martorell, G.; Frontera, A. J. Org. Chem. 1996, 61, 5194.

411. See Durst, T. in Buncel, E.; Durst, T. Comprehensive Carbanion Chemistry, Vol. 5, pt. B, Elsevier, NY, 1984, pp. 239–291, pp. 265–279. For an article on the safe handling of RLi compounds, see Anderson, R. Chem. Ind. (London) 1984, 205.

412. Ivanov, R.; Marek, I.; Cohen, T. Tetrahedron Lett. 2010, 51, 174.

413. Schlosser, M. J. Organomet. Chem. 1967, 8, 9. See also, Schlosser, M.; Katsoulos, G.; Takagishi, S. Synlett, 1990, 747.

414. Rausch, M.D.; Ciappenelli, D.J. J. Organomet. Chem. 1967, 10, 127.

415. See Klein, J. Tetrahedron 1983, 39, 2733; Klein, J. in Patai, S. The Chemistry of the Carbon–Carbon Triple Bond, pt. 1, Wiley, NY, 1978, pp. 343–379.

416. Hartmann, J.; Schlosser, M. Helv. Chim. Acta 1976, 59, 453.

417. Schlosser, M. Pure Appl. Chem. 1988, 60, 1627. For sodium analogues, see Schlosser, M.; Hartmann, J.; Stähle, M.; Kramar, J.; Walde, A.; Mordini, A. Chimia, 1986, 40, 306.

418. Brandsma, L.; Verkruijsse, H.D.; Schade, C.; Schleyer, P.v.R. J. Chem. Soc. Chem. Commun. 1986, 260.

419. See Shirley, D.A.; Hendrix, J.P. J. Organomet. Chem. 1968, 11, 217.

420. Gossage, R.A.; Jastrzebski, J.T.B.H.; van Koten, G. Angew. Chem. Int. Ed. 2005, 44, 1448.

421. Jacobson, M.A.; Keresztes, I.; Williard, P.G. J. Am. Chem. Soc. 2005, 127, 4965. For a computational study of mixed aggregates of chloromethyllithium and lithium dialkylamides, see Pratt, L.M.; Lê, L.T.; Truong, T.N. J. Org. Chem. 2005, 70, 8298. Also see Gupta, L.; Hoepker, A.C.; Singh, K.J.; Collum, D.B. J. Org. Chem. 2009, 74, 2231 for a LiCl catalyzed reaction.

422. See Blagoev, B.; Ivanov, D. Synthesis 1970, 615.

423. Kessar, S.V.; Singh, P.; Singh, K.N.; Venugopalan, P.; Kaur, A.; Bharatam, P.V.; Sharma, A.K. J. Am. Chem. Soc. 2007, 129, 4506.

424. Nishimura, Y.; Miyake, Y.; Amemiya, R.; Yamaguchi, M. Org. Lett. 2006, 8, 5077.

425. See Figuly, G.D.; Loop, C.K.; Martin, J.C. J. Am. Chem. Soc. 1989, 111, 654; Block, E.; Eswarakrishnan, V.; Gernon, M.; Ofori-Okai, G.; Saha, C.; Tang, K.; Zubieta, J. J. Am. Chem. Soc. 1989, 111, 658; Smith, K.; Lindsay, C.M.; Pritchard, G.J. J. Am. Chem. Soc. 1989, 111, 665.

426. See Gilday, J.P.; Negri, J.T.; Widdowson, D.A. Tetrahedron 1989, 45, 4605.

427. See Katritzky, A.R.; Lam, J.N.; Sengupta, S. Prog. Heterocycl. Chem. 1989, 1, 1.

428. Bickelhaupt, F.M.; Hermann, H.L.; Boche, G. Angew. Chem. Int. Ed. 2006, 45, 823.

429. See Beak, P.; Meyers, A.I. Acc. Chem. Res. 1986, 19, 356; Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306; Narasimhan, N.S.; Mali, R.S. Top. Curr. Chem. 1987, 138, 63; Reuman, M.; Meyers, A.I. Tetrahedron 1985, 41, 837.

430. Slocum, D.W.; Coffey, D.S.; Siegel, A.; Grimes, P. Tetrahedron Lett. 1994, 35, 389.

431. See Snieckus, V. Chem. Rev. 1990, 90, 879; Pure Appl. Chem. 1990, 62, 2047. For a discussion of the mechanism, see Bauer, W.; Schleyer, P. v.R. J. Am. Chem. Soc. 1989, 111, 7191.

432. Baldwin, J.E.; Höfle, G.A.; Lever Jr., O.W. J. Am. Chem. Soc. 1974, 96, 7125.

433. Beak, P.; Hunter, J.E.; Jun, Y.M.; Wallin, A.P. J. Am. Chem. Soc. 1987, 109, 5403. See also, Stork, G.; Polt, R.L.; Li, Y.; Houk, K.N. J. Am. Chem. Soc. 1988, 110, 8360; Barluenga, J.; Foubelo, F.; Fañanas, F.J.; Yus, M. J. Chem. Res. (S) 1989, 200.

434. Peñafiel, I.; Pastor, I.M.; Yus, M. Tetrahedron 2010, 66, 2928.

435. Benkeser, R.A.; Trevillyan, E.A.; Hooz, J. J. Am. Chem. Soc. 1962, 84, 4971.

436. Bryce-Smith, D. J. Chem. Soc. 1963, 5983; Benkeser, R.A.; Hooz, J.; Liston, T.V.; Trevillyan, E.A. J. Am. Chem. Soc. 1963, 85, 3984.

437. Pocker, Y.; Exner, J.H. J. Am. Chem. Soc. 1968, 90, 6764.

438. West, P.; Waack, R.; Purmort, J.I. J. Am. Chem. Soc. 1970, 92, 840.

439. Kapeller, D.C.; Hammerschmidt, F. J. Am. Chem. Soc. 2008, 130, 2329.

440. McGrath, M.J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378.

441. Ashweek, J.; Brandt, P.; Coldham, I.; Dufour, S.; Gawley, R.E.; Hæffner, F.; Klein, R.; Sanchez-Jimenezy, G. J. Am. Chem. Soc. 2005, 127, 449.

442. Zugravescu, I.; Petrovanu, M. Nitrogen–Ylid Chemistry, McGraw Hill, NY, 1976, pp. 251–283; Wittig, G.; Rieber, M. Ann. 1949, 562, 177; Wittig, G.; Polster, R. Ann. 1956, 599, 1.

443. See Durst, T. in Buncel, E.; Durst, T. Comprehensive Carbanion Chemistry, Vol. 5, pt. B, Elsevier, NY, 1984, pp. 239–291; Wardell, J.L. Ref. 388; Wakefield, B.J. Organolithium Methods, Academic Press, NY, 1988, pp. 32–44.

444. See Ziegenbein, W. in Viehe, H.G. Acetylenes, Marcel Dekker, NY, 1969, pp. 170–185. For an improved method, see Fisch, A.; Coisne, J.M.; Figeys, H.P. Synthesis 1982, 211.

445. Wang, S.; Zhang, L. Org. Lett. 2006, 8, 4585.

446. Hegarty, A.F.; Dowling, J.P.; Eustace, S.J.; McGarraghy, M. J. Am. Chem. Soc. 1998, 120, 2290.

447. See Caine, D. in Augustine, R.L. Carbon–Carbon Bond Formation, Vol. 1, Marcel Dekker, NY, 1979, pp. 95–145, 284–291.

448. See Abraham, M.H.; Grellier, P.L. in Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 2, Wiley, NY, pp. 25–149, pp. 105–136; Abraham, M.H. Comprehensive Chemical Kinetics, Bamford, C.H.; Tipper, C.F.H. Eds., Vol. 12, Elsevier, NY, 1973, pp. 107–134; Schlosser, M. Angew. Chem. Int. Ed. 1964, 3, 287, 362; Newer Methods Prep. Org. Chem. 1968, 5, 238.

449. Mitsuhashi, K.; Ito, R.; Arai, T.; Yanagisawa, A. Org. Lett. 2006, 8, 1721.

450. Walborsky, H.M.; Ollman, J.; Hamdouchi, C.; Topolski, M. Tetrahedron Lett. 1992, 33, 761.

451. Pelter, A.; Smith, K.; Brown, H.C. Borane Reagents, Academic Press, NY, 1988, see pp. 242–244.

452. See Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57, pp. 89–97, 194–243.

453. See Makarova, L.G. Organomet. React. 1970, 1, 119, see pp. 251–270, 275–300.

454. See Barluenga, J.; Yus, M. Chem. Rev. 1988, 88, 487.

455. Sommer, L.H.; Marans, N.S.; Goldberg, G.M.; Rockett, J.; Pioch, R.P. J. Am. Chem. Soc. 1951, 73, 882. See also, Abraham, M.H.; Grellier, P.L. in Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 2, Wiley, NY, p. 117.

456. See Brilkina, T.G.; Shushunov, V.A. Reactions of Organometallic Compounds with Oxygen and Peroxides, CRC Press, Boca Raton, FL, 1969; Wardell, J.L.; Paterson, E.S. in Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 2, Wiley, NY, 1985, see pp. 219–338, pp. 311–316.

457. See Harada, T.; Kutsuwa, E. J. Org. Chem. 2003, 68, 6716.

458. Brown, H.C.; Midland, M.M. Tetrahedron 1987, 43, 4059.

459. Adam, W.; Cueto, O. J. Org. Chem. 1977, 42, 38.

460. Garst, J.F.; Smith, C.D.; Farrar, A.C. J. Am. Chem. Soc. 1972, 94, 7707. See Davies, A.G. J. Organomet. Chem. 1980, 200, 87.

461. Lawesson, S.; Frisell, C.; Denney, D.B.; Denney, D.Z. Tetrahedron 1963, 19, 1229. See Brilkina, T.G.; Shushunov, V.A. Reactions of Organometallic Compounds with Oxygen and Peroxides, CRC Press, Boca Raton, FL, 1969; Razuvaev, G.A.; Shushunov, V.A.; Dodonov, V.A.; Brilkina, T.G. in Swern, D. Organic Peroxides, Vol. 3, Wiley, NY, 1972, pp. 141–270.

462. Longone, D.T.; Miller, A.H. Tetrahedron Lett. 1967, 4941.

463. Davis, F.A.; Lal, G.S.; Wei, J. Tetrahedron Lett. 1988, 29, 4269.

464. Mitchell, T.A.; Bode, J.W. J. Am. Chem. Soc. 2009, 131, 18057.

465. See Pelter, A.; Smith, K.; Brown, H.C. Borane Reagents, Aademic Press, NY, 1988, pp. 244–249; Brown, H.C. Boranes in Organic Chemistry, Cornell University Press, Ithaca, NY, 1972, pp. 321–325. See also, Brown, H.C.; Snyder, C.; Subba Rao, B.C.; Zweifel, G. Tetrahedron 1986, 42, 5505.

466. Brown, H.C.; Midland, M.M.; Kabalka, G.W. Tetrahedron 1986, 42, 5523.

467. Kabalka, G.W.; Shoup, T.M.; Goudgaon, N.M. J. Org. Chem. 1989, 54, 5930.

468. Köster, R.; Arora, S.; Binger, P. Angew. Chem. Int. Ed. 1969, 8, 205.

469. Kabalka, G.W.; Slayden, S.W. J. Organomet. Chem. 1977, 125, 273.

470. Midland, M.M.; Brown, H.C. J. Am. Chem. Soc. 1971, 93, 1506.

471. Bean, F.R.; Johnson, J.R. J. Am. Chem Soc. 1932, 54, 4415; Lappert, M.F. Chem. Rev. 1956, 56, 959.

472. Khotinsky, E.; Melamed, M. Chem. Ber. 1909, 42, 3090.

473. Sebelius, S.; Olsson, V.J.; Szabó, K.J. J. Am. Chem. Soc. 2005, 127, 10478.

474. Soloway, A.H. J. Am. Chem. Soc. 1959, 81, 3017.

475. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.

476. Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65, 164; Song, Y.L. Synlett 2000, 1210.

477. Kanth, J.V.B.; Periasamy, M.; Brown, H.C. Org. Process Res. Dev. 2000, 4, 550.

478. Song, Y.; Ding, Z.; Wang, Q.; Tao, F. Synth. Commun. 1998, 28, 3757.

479. Song, Y.-L.; Morin, C. Synlett 2001, 266.

480. Lightfoot, A.P.; Maw, G.; Thirsk, C.; Twiddle, S.J.R.; Whiting, A. Tetrahedron Lett. 2003, 44, 7645.

481. Ramsden, H.E.; Leebrick, J.R.; Rosenberg, S.D.; Miller, E.H.; Walburn, J.J.; Balint, A.E.; Cserr, R. J. Org, Chem., 1957, 22, 1602.

482. Matteson, D.S. Acc. Chem. Res. 1970, 3, 186; Matteson, D.S. Progr. Boron Chem. 1970, 3, 117.

483. Wong, K.-T.; Chien, Y.-Y.; Liao, Y.-L.; Lin, C.-C.; Chou, M.-Y.; Leung, M.-K. J. Org. Chem. 2002, 67, 1041.

484. Evans, D.A.; Muci, A.R.; Stuermer, R. J. Org. Chem., 1993, 58, 5307.

485. Councler, C. Ber. 1876, 9, 485; 1877, 10, 1655; 1878, 11, 1106.

486. Schiff, H. Ann. Suppl. 1867, 6, 158; Councler, C. J. Prakt. Chem. 1871, 16, 371.

487. Cohn, G. Pharm. Zentr. 1911, 62, 479.

488. Bannister, W.J. U.S. Patent 1,668,797 (Chem. Abstr. 1928, 22:2172).

489. Haider, S.Z.; Khundhar, M.H.; Siddiqulah, Md. J. Appl. Chem. 1954, 4, 93.

490. Colclough, T.; Gerrard, W.; Lappert, M.F. J. Chem. Soc. 1955, 907.

491. Ahmad, T.; Khundkar, M.H. Chem. Ind. 1954, 248.

492. Vedejs, E.; Fields, S.C.; Hayashi, R.; Hitchcock, S.R.; Powell, D.R.; Schrimpf, M.R. J. Am. Chem. Soc. 1999, 121, 2460.

493. Molander, G.A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302; Molander, G.A.; Yun, C.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534; Molander, G.A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148.

494. Matteson, D. S. J. Am. Chem. Soc. 1960, 82, 4228.

495. Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950.

496. Ochiai, M.; Yamamoto, S.; Sato, K. Chem. Commun. 1999, 1363.

497. See Wardell, J.L.; Paterson, E.S. in Hartley, F.R.; Patai, S. The Chemistry of the Metal–Carbon Bond, Vol. 2, Wiley, NY, 1985, pp. 316–323; Wardell, J.L. in Patai, S. The Chemistry of the Thiol Group, pt. 1, Wiley, NY, 1974, pp. 211–215; Wakefield, B.J. Organolithium Methods, Academic Press, NY, 1988, pp. 135–142.

498. Larock, R.C. Organomercury Compounds in Organic Synthesis, Springer, NY, 1985, pp. 210–216.

499. Bhattacharya, S.N.; Eaborn, C.; Walton, D.R.M. J. Chem. Soc. C 1968, 1265. For similar reactions with organolithiums, see Hamada, T.; Yonemitsu, O. Synthesis 1986, 852.

500. Harpp, D.N.; Vines, S.M.; Montillier, J.P.; Chan, T.H. J. Org. Chem. 1976, 41, 3987.

501. See Negishi, E. Organometallics in Organic Synthesis, Wiley, NY, 1980, pp. 243–247.

502. See Kitching, W.; Fong, C.W. Organomet. Chem. Rev. Sect. A 1970, 5, 281.

503. Asinger, F.; Laue, P.; Fell, B.; Gubelt, C. Chem. Ber. 1967, 100, 1696.

504. Zakharkin, L.I.; Gavrilenko, V.V.; Paley, B.A. J. Organomet. Chem. 1970, 21, 269.