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

Chapter 10. Aliphatic Substitution, Nucleophilic and Organometallic

10.H. Reactions

The reactions in this chapter are classified according to the attacking atom of the nucleophile in the order O, S, N, halogen, H, C. For a given nucleophile, reactions are classified by the substrate and leaving group. For the most part, only alkyl substrates are considered, since acyl substrates are considered in Chapter 16. Nucleophilic substitutions at a sulfur atom are treated at the end.

Not all the reactions in this chapter are actually nucleophilic substitutions. In some cases, the mechanisms are not known with enough certainty even to decide whether a nucleophile, an electrophile, or a free radical is attacking. In other cases, conversion of one compound to another can occur by two or even all three of these possibilities, depending on the reagent and reaction conditions. However, one or more of the nucleophilic mechanisms previously discussed do hold for the overwhelming majority of the reactions in this chapter. For the alkylations, the S_N2 is by far the most common mechanism, as long as R is primary or secondary alkyl. For the acylations, the tetrahedral mechanism is the most common.

10.H.i. Oxygen Nucleophiles

A. Attack by OH at an Alkyl Carbon

10-1 Hydrolysis of Alkyl Halides

Hydroxy-de-halogenation

Alkyl halides can be converted to alcohols. Hydroxide ion is usually required, although particularly active substrates (e.g., allylic or benzylic alcohols) can be hydrolyzed by water. Ordinary halides can be hydrolyzed by water,⁵³⁰if the solvent is HMPA or N-methyl-2-pyrrolidinone,⁵³¹ or if the reaction is done in an ionic solvent.⁵³² If the hydrolysis (solvolysis) reaction proceeds via ionization, by an S_N1 type mechanism, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl α-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aq acetonitrile.⁵³³ The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols.

Vinylic halides are unreactive (Sec. 10.F), but they can be hydrolyzed to ketones at room temperature with mercuric trifluoroacetate, or with mercuric acetate in either trifluoroacetic acid or acetic acid containing BF₃ etherate.⁵³⁴Primary bromides and iodides give alcohols when treated with bis(tributyltin)oxide (Bu₃Sn–O–SnBu₃) in the presence of silver salts.⁵³⁵

OS II, 408; III, 434; IV, 128; VI, 142, 1037.

10-2 Hydrolysis of gem-Dihalides

Oxo-de-dihalo-bisubstitution

gem-Dihalides can be hydrolyzed using either acid or basic catalysis to give aldehydes or ketones.⁵³⁶ Formally, the reaction may be regarded as giving R–C(OH)XR′, which is unstable and loses HX to give the carbonyl compound. For aldehydes derived from RCHX₂, strong bases cannot be used, because the product undergoes the aldol reaction (16-34) or the Cannizzaro reaction (19-81). A mixture of calcium carbonate and sodium acetate is effective,⁵³⁷ and heating to 100 °C in DMSO gives good yields.⁵³⁸ A simple method heats a gem-dibromide with pyridine, and subsequent treatment with water gives the aldehyde.⁵³⁹ Heating 1,1-dihaloalkenes (C=CX₂) with zinc and water leads to the corresponding methyl ketone.⁵⁴⁰

OS I, 95; II, 89, 133, 244, 549; III, 538, 788; IV, 110, 423, 807. Also see, OS III, 737.

10-3 Hydrolysis of 1,1,1-Trihalides

Hydroxy,oxo-de-trihalo-tersubstitution

This reaction is similar to 10-2. The utility of the method is limited by the lack of availability of trihalides, although these compounds can be prepared by addition of CCl₄ and similar compounds to double bonds (Reaction 15-38) and by the free radical halogenation of methyl groups on aromatic rings (Reaction 14-1). When the reaction is carried out in the presence of an alcohol, a carboxylic ester can be obtained directly.⁵⁴¹ 1,1-Dichloroalkenes can also be hydrolyzed to carboxylic acids, by treatment with aq H₂SO₄. In general 1,1,1-trifluorides do not undergo this reaction,⁵⁴² although exceptions are known.⁵⁴³

Aryl 1,1,1-trihalomethanes can be converted to acyl halides by treatment with sulfur trioxide.⁵⁴⁴ Hydrolysis of the acid chloride gives the carboxylic acid (Reaction 16-57).

Chloroform is more rapidly hydrolyzed with base than dichloromethane or carbon tetrachloride and gives not only formic acid, but also carbon monoxide.⁵⁴⁵ Hine⁵⁴⁶ showed that the mechanism of chloroform hydrolysis is quite different from that of dichloromethane or carbon tetrachloride, although superficially the three reactions appear similar. The first step is the loss of a proton to give CCl₃⁻, which then loses Cl⁻ to give dichlorocarbene (CCl₂), which is hydrolyzed to formic acid or carbon monoxide.

This is an example of an S_N1cB mechanism (Sec. 10.G.iii, category 1). The other two compounds react by the normal mechanisms. Carbon tetrachloride cannot give up a proton and dichloromethane is not acidic enough.

OS III, 270; V, 93. Also see, OS I, 327.

10-4 Hydrolysis of Alkyl Esters of Inorganic Acids

Hydroxy-de-sulfonyloxy-substitution, and so on

Esters of inorganic acids, including those given above and others, can be hydrolyzed to alcohols. The reactions are most successful when the ester is that of a strong acid, but it can be done for esters of weaker acids by the use of hydroxide ion (a more powerful nucleophile) or acidic conditions (which make the leaving group come off more easily). When vinylic substrates are hydrolyzed, the products are enols, which tautomerize to aldehydes or ketones (Sec. 2.N), as shown.

These reactions are all considered at one place because they are formally similar. Although some of them involve R–O cleavage and are thus nucleophilic substitutions at a saturated carbon, others involve cleavage of the bond between the inorganic atom and oxygen and are thus nucleophilic substitutions at a sulfur, nitrogen, and so on. It is even possible for the same ester to be cleaved at either position, depending on the conditions. Thus benzhydryl p-toluenesulfinate (Ph₂CHOSOC₆H₄CH₃) was found to undergo C–O cleavage in HClO₄ solutions and S–O cleavage in alkaline media.⁵⁴⁷ In general, the weaker the corresponding acid, the less likely is C–O cleavage. Thus, sulfonic acid esters (ROSO₂R′) generally give C–O cleavage,⁵⁴⁸ while nitrous acid esters (RONO) usually give N–O cleavage.⁵⁴⁹ Esters of sulfonic acids that are frequently hydrolyzed are mentioned in Section 10.G.iii. For hydrolysis of sulfonic acid esters (see also, Reaction 16-100).

OS VI, 852. See also, VIII, 50.

10-5 Hydrolysis of Diazoketones

Hydro, hydroxy-de-diazo-bisubstitution

Diazoketones are relatively easy to prepare (see Reaction 16-89). When treated with acid, they add a proton to give α-keto diazonium salts, which are hydrolyzed to the alcohols by the S_N1 or S_N2 mechanism.⁵⁵⁰ Relatively good yields of α-hydroxy ketones can be prepared in this way, since the diazonium ion is somewhat stabilized by the presence of the carbonyl group, which discourages N₂ from leaving because that would result in an unstable α-carbonyl carbocation.

10-6 Hydrolysis of Acetals, Enol Ethers, and Similar Compounds⁵⁵¹

The alkoxyl group (OR) is not a leaving group in these reactions, so these compounds must be converted to the conjugate acids before they can be hydrolyzed. Although 100% sulfuric acid and other concentrated strong acids readily cleave simple ethers,⁵⁵² the only acids used preparatively for this purpose are HBr and HI (Reaction 10-49). However, acetals, ketals, and ortho esters⁵⁵³ are easily cleaved by dilute acids. These compounds are hydrolyzed with greater facility because carbocations of type R₂(RO)C⁺ are greatly stabilized by resonance (Sec. 5.A.ii). The reactions therefore proceed by the S_N1 mechanism,⁵⁵⁴ as shown for acetals:⁵⁵⁵

This mechanism, which is an S_N1cA or A1 mechanism, is the reverse of that for acetal formation by reaction of an aldehyde and an alcohol (Reaction 16-5). Among the facts supporting the mechanism are⁵⁵⁶ (1) The reaction proceeds with specific H₃O⁺ catalysis (see Sec. 8.D). (2) It is faster in D₂O. (3) Optically active ROH are not racemized. (4) Even with tert-butyl alcohol the R–O bond does not cleave, as shown by ¹⁸O labeling.⁵⁵⁷ (5) In the case of acetophenone ketals, the intermediate corresponding to 109 [ArCMe(OR)₂] could be trapped with sulfite ions (SO₃²⁻).⁵⁵⁸ (6) Trapping of this ion did not affect the hydrolysis rate,⁵⁵⁸ so the rate-determining step must come earlier. (7) In the case of 1,1-dialkoxyalkanes, intermediates corresponding to 109 were isolated as stable ions in superacid solution at −75 °C, where their spectra could be studied.⁵⁵⁹ (8) Hydrolysis rates greatly increase in the order CH₂(OR′)₂< RCH(OR′)₂ < R₂C(OR′)₂ < RC(OR′)₃, as would be expected for a carbocation intermediate.⁵⁶⁰ Formation of 109 is usually the rate-determining step (as marked above), but there is evidence that at least in some cases this step is fast, and the rate-determining step is loss of R′OH from the protonated hemiacetal.⁵⁶¹ Rate-determining addition of water to 109 has also been reported.⁵⁶²

While the A1 mechanism shown above operates in most acetal hydrolyses, it has been shown that at least two other mechanisms can take place with suitable substrates.⁵⁶³ In one of these mechanisms, the second and third of the above steps are concerted, so that the mechanism is S_N2cA (or A2). This has been shown, for example, in the hydrolysis of 1,1-diethoxyethane, by isotope effect studies:⁵⁶⁴

In the second mechanism, the first and second steps are concerted. In the case of hydrolysis of 2-(p-nitrophenoxy)tetrahydropyran, general acid catalysis was shown⁵⁶⁵ demonstrating that the substrate is protonated in the rate-determining step (Sec. 8.D). Reactions in which a substrate is protonated in the rate-determining step are called A-S_E2 reactions.⁵⁶⁶ However, if protonation of the substrate were all that happens in the slow step, then the proton in the transition state would be expected to lie closer to the weaker base (Sec. 8.D). Because the substrate is a much weaker base than water, the proton should be largely transferred. Since the Brnsted coefficient was found to be 0.5, the proton was actually transferred only about halfway. This can be explained if the basicity of the substrate is increased by partial breaking of the C–O bond. The conclusion drawn is that steps 1 and 2 are concerted. The hydrolysis of ortho esters in most cases is also subject to general acid catalysis.⁵⁶⁷

The hydrolysis of acetals and ortho esters is governed by the stereoelectronic control factor discussed in Section 16.A.i, category 4,⁵⁶⁸ although the effect can generally be seen only in systems where conformational mobility is limited, especially in cyclic systems. There is evidence for synplanar stereoselection in the acid hydrolysis of acetals.⁵⁶⁹ The mechanism of Lewis acid mediated cleavage of chiral acetals is also known.⁵⁷⁰

Convenient reagents for the hydrolysis of acetals are wet silica gel⁵⁷¹ and Amberlyst-15 (a sulfonic acid based polystyrene cation exchange resin).⁵⁷² Both cyclic and acyclic acetals and ketals can be converted to aldehydes or ketones under nonaqueous conditions by treatment with TESOTf-2,6-lutidine (or 2,4,6-collidine) in dichloromethane followed by treatment with water,⁵⁷³ with Lewis acids e.g., 0.8% In(OTf)₃ in acetone,⁵⁷⁴ ceric ammonium nitrate in aq acetonitrile,⁵⁷⁵ or Bi(OTf)₃•xH₂O.⁵⁷⁶

Although acetals, ketals, and ortho esters are easily hydrolyzed by acids, they are extremely resistant to hydrolysis by bases. An aldehyde or ketone can therefore be protected from attack by a base by conversion to the acetal or ketal (Reaction 16-5), and then can be cleaved with acid. Pyridine–HF has also been used for this conversion.⁵⁷⁷ Thioacetals, thioketals, gem-diamines, and other compounds that contain any two of the groups OR, OCOR, NR₂, NHCOR, SR, and halogen on the same carbon can also be hydrolyzed to aldehydes or ketones, in most cases, by acid treatment. Thioacetals [RCH(SR′)₂] and thioketals [R₂C(SR′)₂] are among those compounds generally resistant to acid hydrolysis.⁵⁷⁸ Because conversion to these compounds (Reaction 16-11) serves as an important method for protection of aldehydes and ketones, many methods have been devised to cleave them to the parent carbonyl compounds. Among reagents⁵⁷⁹ used for this purpose are HgCl₂,⁵⁸⁰ FeCl₂•6 H₂O,⁵⁸¹ cetyltrimethylammonium tribromide in dichloromethane,⁵⁸²m-chloroperoxybenzoic acid, the Dess–Martin periodinane⁵⁸³ (see Reaction 19-03), and sodium nitrite in aqueous acetyl chloride.⁵⁸⁴ Mixed acetals and ketals (RO–C–SR) can be hydrolyzed with most of the reagents mentioned above, including N-bromosuccinimide (NBS) in aq acetone,⁵⁸⁵ and glyoxylic acid on Amberlyst-15 with microwave irradiation.⁵⁸⁶

Enol ethers (vinyl ethers) are readily hydrolyzed by acids; the rate-determining step is protonation of the substrate.⁵⁸⁷ However, protonation does not take place at the oxygen, but at the β carbon,⁵⁸⁸ because that gives rise to the stable carbocation (110).⁵⁸⁹ After that, the mechanism is similar to the A1 mechanism given above for the hydrolysis of acetals.

Among the facts supporting this mechanism, which is an A-S_E2 mechanism because the substrate is protonated in the rate-determining step, are (1) the ¹⁸O labeling shows that in ROCH=CH₂ it is the vinyl–oxygen bond and not the RO bond that cleaves;⁵⁹⁰ (2) the reaction is subject to general acid catalysis;⁵⁹¹ (3) there is a solvent isotope effect when D₂O is used.⁵⁹¹ A method has been developed to determine primary kinetic isotope effects relating to proton transfer in the hydrolysis of enol ethers.⁵⁹² Enantioselective protonation is possible in some cases. Cyclic silyl enol ethers are converted to chiral α-substituted ketones, for example, with high enantioselectivity using a chiral Brnsted acid.⁵⁹³

Enamines are also hydrolyzed by acids (see Reaction 16-2); the mechanism is similar. Ketene dithioacetals [R₂C=C(SR′)₂] also hydrolyze by a similar mechanism, except that the initial protonation step is partially reversible.⁵⁹⁴Furans represent a special case of enol ethers that are cleaved by acid to give 1,4-diones.⁵⁹⁵ Thus oxonium ions are cleaved by water to give an alcohol and an ether:

OS I, 67, 205; II, 302, 305, 323; III, 37, 127, 465, 470, 536, 541, 641, 701, 731, 800; IV, 302, 499, 660, 816, 903; V, 91, 292, 294, 703, 716, 937, 967, 1088; VI, 64, 109, 312, 316, 361, 448, 496, 683, 869, 893, 905, 996; VII, 12, 162, 241, 249, 251, 263, 271, 287, 381, 495; VIII, 19, 155, 241, 353, 373

10-7 Hydrolysis of Epoxides

(3) OC-seco-hydroxy-de-alkoxy substitution

The hydrolysis of epoxides is a convenient method for the preparation of vic-diols. The reaction is catalyzed by acids or bases. A basic reagent will attack the polarized carbon of the epoxide unit to open the ring, whereas an acid-catalyzed reaction leads to a protonated epoxide (an oxonium ion),⁵⁹⁶ which is opened by nucleophilic attack at an adjacent carbon. Among acid catalysts, perchloric acid leads to minimal side reactions,⁵⁹⁷ and 10% Bu₄NHSO₄ in water is effective.⁵⁹⁸ However, water reacts directly with epoxides at 60 °C.⁵⁹⁹ Dimethyl sulfoxide is a superior solvent for the alkaline hydrolysis of epoxides.⁶⁰⁰

Cobalt salen [salen = bis(salicylidene)ethylenediamine] catalysts, in the presence of water, open epoxides with high stereoselectivity.⁶⁰¹ The enzyme epoxide hydrolase opens epoxides with high enantioselectivity.⁶⁰²

OS V, 414.

10.H.ii Attack by or at an Alkyl Carbon

10-8 Alkylation with Alkyl Halides: The Williamson Reaction

Alkoxy-de-halogenation

The Williamson reaction (Williamson ether synthesis), discovered in 1850, is still the best general method for the preparation of unsymmetrical or symmetrical ethers.⁶⁰³ The reaction can also be carried out with aromatic R′, although C-alkylation is sometimes a side reaction (see Sec. 10.G.vii).⁶⁰⁴ The normal method involves treatment of a primary or secondary alkyl halide with alkoxide or aroxide ion prepared from an alcohol or phenol by reaction with a suitable base, although methylation using dimethyl carbonate has been reported.⁶⁰⁵ The solvent is usually an aprotic solvent (THF, ether, etc.,) rather than an alcohol solvent, which typically promotes elimination reactions in the presence of alkoxides (see Chap. 17). It is also possible to mix the halide and alcohol or phenol directly with Cs₂CO₃ in acetonitrile,⁶⁰⁶ or with NaH in the presence of DMF.⁶⁰⁷ The reaction can also be carried out in a dry medium,⁶⁰⁸ neat,⁶⁰⁹ or in solvents using microwave irradiation.⁶¹⁰ Williamson ether synthesis in ionic liquids has also been reported.⁶¹¹ The reaction is not successful for tertiary R (elimination predominates), and low yields are often obtained with secondary R. Monoethers can be formed from diols and alkyl halides.⁶¹² It is possible to selectively alkylate the primary hydroxyl in a diol [HOCH₂CH(OH)R] using a tin complex.⁶¹³

Many other functional groups can be present in the molecule without interference. Ethers with one tertiary group can be prepared by treatment of an alkyl halide or sulfate ester (Reaction 10-10) with a tertiary alkoxide (R′O⁻). Di-tert-butylether was prepared in high yield by direct attack by t-BuOH on reaction with the tert-butyl cation (at −80 °C in SO₂ClF).⁶¹⁴ Di-tert-alkyl ethers in general have proved difficult to make, but they can be prepared in low-to-moderate yields by treatment of a tertiary halide with Ag₂CO₃ or Ag₂O.⁶¹⁵ Alcohols react with Mg(ClO₄)₂ and an excess of Boc (Boc = t-butoxycarbonyl) anhydride (Boc₂O) to give the tert-butyl ether.⁶¹⁶

Active halides (e.g., Ar₃CX) may react directly with the alcohol.⁶¹⁷ Hindered alcohols may react as well.⁶¹⁸ The mechanism for these cases is of course S_N1. tert-Butyl halides can be converted to aryl tert-butyl ethers by treatment with phenols and an amine (e.g., pyridine).⁶¹⁹ Aryl alkyl ethers can be prepared from alkyl halides by treatment with an aryl acetate (instead of a phenol) in the presence of K₂CO₃ and a crown ether.⁶²⁰ The Pd-catalyzed displacement of allylic acetates with aliphatic alcohols has been shown to give the corresponding alkyl allyl ether.⁶²¹ A Rh-catalyst⁶²² Ir catalyst,⁶²³ and an In-Si combined Lewis acid catalyst⁶²⁴ have been used in ether forming reactions. Aryl ethers have been prepared using Mitsunobu conditions (see Reaction 10-17).⁶²⁵

Vinyl ethers have been formed by coupling tetravinyl tin with phenols, in the presence of cupric acetate and oxygen.⁶²⁶ The Pd-catalyzed coupling of vinyl triflates and phenols has also been reported.⁶²⁷

Both aryl alkyl and dialkyl ethers can be efficiently prepared with the use of phase-transfer catalysis (Sec. 10.G.v)⁶²⁸ and with micellar catalysis.⁶²⁹ Symmetrical benzylic ethers have been prepared by reaction of benzylic alcohols with Mg/I₂ followed by triflic anhydride.⁶³⁰

A slight variation of the Williamson ether synthesis has been used for the protection of hydroxy groups⁶³¹ by reaction of their salts with chloromethyl methyl ether.

This protecting group is known as MOM (methoxymethyl) and such compounds are called MOM ethers. The resulting acetals are stable to bases and are easily cleaved with mild acid treatment (Reaction 10-7). Another protecting group, the 2-methoxyethoxymethyl group (the MEM group), is formed in a similar manner. Both MOM and MEM groups can be cleaved with dialkyl- and diarylboron halides (e.g., Me₂BBr).⁶³²

Another common method for the protection of alcohols is conversion to the silyl ether (R–O–SiR'₃). The alcohol is generally treated with a base (e.g., trimethylamine or imidazole) and then with a chlorotrialkylsilane (R₃SiCl), or the analogous bromide.⁶²⁹ There are many variations of this basic procedure. Iodine promotes the reaction, for example.⁶³³ There are also many ways to remove the silyl group to regenerate the alcohol, although fluoride ion, including tetrabutylammonium fluoride in THF, is probably the most common method.⁶²⁹

Most Williamson reactions proceed by the S_N2 mechanism, but there is evidence (see Sec. 10.C) that in some cases the SET mechanism can take place, especially with alkyl iodides.⁶³⁴ Secondary alcohols have been converted to the corresponding methyl ether by reaction with methanol in the presence of ferric nitrate nonahydrate.⁶³⁵

OS I, 75, 205, 258, 296, 435; II, 260; III, 127, 140, 209, 418, 432, 544; IV, 427, 457, 558, 590, 836; V, 251, 258, 266, 403, 424, 684; VI, 301, 361, 395, 683; VII, 34, 386, 435; VIII, 26, 161, 155, 373; 80, 227.

10-9 Epoxide Formation (Internal Williamson Ether Synthesis)

(3) OC-cyclo-Alkoxy-de-halogenation

This is a special case of Reaction 10-8. The base removes the proton from the OH group of a halohydrin (chlorohydrin or bromohydrin), and the resulting alkoxide subsequently attacks in an internal S_N2 reaction.⁶³⁶ Many epoxides have been made in this way.⁶³⁷ The course of the reaction can be influenced by neighboring group effects.⁶³⁸ Enantioselective epoxide-forming reactions are known, using chiral additives (e.g., dihydrocinchonidines).⁶³⁹Epoxidation of alkenes has also been accomplished using HOF–MeCN in a continuous flow system.⁶⁴⁰

Larger cyclic ethers can be prepared, including five-and six-membered rings (tetrahydrofurans and tetrahydropyrans, respectively).⁶⁴¹ Additional treatment with base yields the glycol (Reaction 10-7). Thiiranes can be prepared by the reaction of α-chloro ketones with (EtO)₂P(=O)-SH and NaBH₄-Al₂O₃ with microwave irradiation.⁶⁴²

1,2-Diols can be converted to epoxides by treatment with DMF dimethyl acetal, [(MeO)₂CHNMe₂],⁶⁴³ with diethyl azodicarboxylate (Et₂OCN=NCO₂Et), and Ph₃P,⁶⁴⁴ with a dialkoxytriphenylphosphorane,⁶⁴⁵ or with TsCl⁻Na⁻OHPhCH₂NEt₂⁺ Cl⁻.⁶⁴⁶

OS I, 185, 233; II, 256; III, 835; VI, 560; VII, 164, 356; VIII, 434.

10-10 Alkylation with Inorganic Esters

Alkoxy-de-sulfonyloxy substitution

The reaction of alkyl sulfates with alkoxide ions is quite similar to Reaction 10-8 in mechanism and scope. Other inorganic esters can also be used. Methyl ethers of alcohols and phenols are commonly formed by treatment of alkoxides or aroxides with methyl sulfate. The alcohol or phenol can be methylated directly with dimethyl sulfate under various conditions.⁶⁴⁷ Carboxylic esters sometimes give ethers when treated with alkoxides (B_AL2 mechanism, Reaction 16-59) in a very similar process (see also, Reaction 16-64). A related reaction heated 111 with alumina to give the corresponding benzofuran, (112).⁶⁴⁸ The reaction of aliphatic alcohols and potassium organotrifluoroborate salts also gives ethers.⁶⁴⁹

tert-Butyl ethers (113) can be prepared by treating the compound tert-butyl-2,2,2-trichloroacetimidate with an alcohol or phenol in the presence of boron trifluoride etherate.⁶⁵⁰ Trichloroimidates can be used to prepare other ethers as well.⁶⁵¹tert-Butyl ethers can be cleaved by acid-catalyzed hydrolysis.⁶⁵²

OS I, 58, 537; II, 387, 619; III, 127, 564, 800; IV, 588; VI, 737, 859, VII, 41. Also see, OS V, 431.

10-11 Alkylation with Diazo Compounds

Hydro, alkoxy-de-diazo-bisubstitution

Alcohols react with diazo compounds to form ethers, but diazomethane and diazo ketones are most readily available, giving methyl ethers or α-keto ethers,⁶⁵³ respectively. With diazomethane⁶⁵⁴ the method is expensive and requires great caution, but the conditions are mild and high yields are obtained. Diazomethane is used chiefly to methylate alcohols and phenols that are expensive or available in small amounts. Hydroxy compounds react better as their acidity increases; ordinary alcohols do not react at all unless a catalyst (e.g., HBF₄⁶⁵⁵ or silica gel)⁶⁵⁶ is present. The more acidic phenols react very well in the absence of a catalyst. The reaction of oximes, and ketones that have substantial enolic contributions, give O-alkylation to form, respectively, O-alkyl oximes and enol ethers. The mechanism⁶⁵⁷ is as in Reaction 10-5. Note that O-aryloximes are prepared from oximes and aryl halides, mediated by CuI.⁶⁵⁸

Diazoalkanes can also be converted to ethers by thermal or photochemical cleavage in the presence of an alcohol. These are carbene or carbenoid reactions.⁶⁵⁹ Enantioselective insertion into phenolic O–H bond leads to highly substituted ethers.⁶⁶⁰ Similar intermediates are involved when diazoalkanes react with alcohols in the presence of t-BuOCl to give acetals.⁶⁶¹

OS V, 245. Also see, OS V, 1099.

10-12 Dehydration of Alcohols

Alkoxy-de-hydroxylation

The dehydration of alcohols to form symmetrical ethers⁶⁶² is analogous to Reactions 10-8 and 10-10, but the species from which the leaving group departs is ROH₂⁺ or ROSO₂OH. The former is obtained directly on treatment of alcohols with sulfuric acid and may go, by an S_N1 or S_N2 pathway, directly to the ether if attacked by another molecule of alcohol. On the other hand, it may, again by either an S_N1 or S_N2 route, be attacked by the nucleophile HSO₄⁻, in which case it is converted to ROSO₂OH, which in turn may be attacked by an alcohol molecule to give ROR. Elimination is always a side reaction and, in the case of tertiary alkyl substrates, completely predominates. Good yields of ethers were obtained by heating diarylcarbinols [ArAr′CHOH → (ArAr′CH)₂O] with TsOH in the solid state.⁶⁶³ Acids (e.g., Nafion-H with silyl ethers)⁶⁶⁴ can be used in this transformation, and Lewis acids can be used with alcohols in some cases.⁶⁶⁵

Mixed (unsymmetrical) ethers can be prepared if one group is tertiary alkyl and the other primary or secondary, since the latter group is not likely to compete with the tertiary group in the formation of the carbocation, while a tertiary alcohol is a very poor nucleophile.⁶⁶⁶ If one group is not tertiary, the reaction of a mixture of two alcohols leads to all three possible ethers. Unsymmetrical ethers have been formed by treatment of two different alcohols with MeReO₃⁶⁶⁷ or with BiBr₃.⁶⁶⁸ Unsymmetrical ethers have been prepared under Mitsunobu conditions (Reaction 10-17) with a polymer-supported phosphine and diethyl azadicarboxylate (DEAD).⁶⁶⁹ Symmetrical ethers are formed by heating benzylic alcohols with the polymer poly(3,4-ethylenedioxythiophene) in toluene or heptane (a two-phase system), with no other additives.⁶⁷⁰ Diols can be converted to cyclic ethers,⁶⁷¹ although the reaction is most successful for five-membered rings, but five-, six-, and seven-membered rings have been prepared.⁶⁷² Thus, 1,6-hexanediol gives mostly 2-ethyltetrahydrofuran. This reaction is also important in preparing furfural derivatives from aldoses, with concurrent elimination.

Phenols and primary alcohols form ethers when heated with dicyclohexylcarbodiimide⁶⁷³ (see Reaction 16-63).

OS I, 280; II, 126; IV, 25, 72, 266, 350, 393, 534; V, 539, 1024; VI, 887; VIII, 116. Also see, OS V, 721.

10-13 Transetherification

Hydroxy-de-alkoxylation and Alkoxy-de-hydroxylation

The exchange of one alkoxy group for another is rare for ethers without a reactive R group (e.g., diphenylmethyl),⁶⁷⁴ or by treatment of alkyl aryl ethers with alkoxide ions: ROAr + R′O⁻ → ROR′ + ArO⁻.⁶⁷⁵ 3-(2-Benzyloxyethyl)-3-methyl-oxetane was transformed into 3-benzyloxymethyl-3-methyltetrahydrofuran by an internal transetherification catalyzed by BF₃•OEt₂.⁶⁷⁶

Acetals and ortho esters undergo transetherification readily,⁶⁷⁷ as with the transformation of 114 to 115.⁶⁷⁸ As seen in Reaction 10-6, departure of the leaving group from an acetal gives a particularly stable carbocation. It is also possible to convert a dimethylketal directly to a dithiane by reaction with butane 1,4-dithiol on clay.⁶⁷⁹ These are equilibrium reactions, and most often the equilibrium is shifted by removing the lower-boiling alcohol by distillation. Enol ethers can be prepared by treating an alcohol with an enol ester or a different enol ether, with mercuric acetate as a catalyst,⁶⁸⁰ as shown in the example. N,N-Diethylaminoethylthiol reacts with aryl ethers to give the phenol derivative and the corresponding sulfide in what is effectively a transetherification.⁶⁸¹

1,2-Diketones can be converted to α-keto enol ethers by treatment with an alkoxytrimethylsilane (ROSiMe₃).⁶⁸²

OS VI, 298, 491, 584, 606, 869; VII, 334; VIII, 155, 173. Also see, OS V, 1080, 1096.

10-14 Alcoholysis of Epoxides

(3) OC-seco-alkoxy-de-alkoxylation

This reaction is analogous to 10-7. It may be acid (including Lewis acid⁶⁸³), base, or alumina⁶⁸⁴ catalyzed, and may occur by either an S_N1 or S_N2 mechanism. Catalysts (e.g., mesoporous aluminosilicate,⁶⁸⁵ Cu(BF₄)₂•nH₂O,⁶⁸⁶Al(OTf)₃,⁶⁸⁷ or BiCl₃),⁶⁸⁸ have been used. β-Cyclodextrin has been used to promote the reaction with phenoxides in aqueous media.⁶⁸⁹ Many of the β-hydroxy ethers produced in this way are valuable solvents, [e.g., diethylene glycol and Cellosolve (2-ethoxyethanol)]. Reaction with thiols leads to hydroxy thioethers.⁶⁹⁰ Other nucleophilic oxygen or sulfur species have been shown to open epoxides, including thiols⁶⁹¹ (catalyzed by Sc⁶⁹² or In⁶⁹³). (Phenylseleno)silanes react with epoxides to give β-hydroxy selenides.⁶⁹⁴

Opening an epoxide by an alkoxide moiety can be done intramolecularly, and a new cyclic ether is generated. Ethers of various ring sizes can be produced depending on the length of the tether between the alkoxide unit and the epoxide. Specialized conditions are common, as in the conversion of 116 to 117.⁶⁹⁵ Another variant of this transformation used a Co-salen catalyst.⁶⁹⁶ A specialized version has the alkoxide moiety on the carbon adjacent to the epoxide, leading to the Payne rearrangement where a 2,3-epoxy alcohol is converted to an isomeric one, by treatment with aqueous base, as shown in the example.⁶⁹⁷

The reaction results in inverted configuration at C-2. Of course, the product can also revert to the starting material by the same pathway, so a mixture of epoxy alcohols is generally obtained.

The reaction of alcohols with aziridines leads to β-amino ethers,⁶⁹⁸ and reaction with thiols gives β-amino thioethers.⁶⁹⁹ It has been shown that ring opening of aziridines by phenols is promoted by tributylphosphine.⁷⁰⁰ Aldehydes open aziridines when catalyzed by nucleophilic carbenes.⁷⁰¹ Metal catalysts [e.g., Cu(OTf)₂] mediate the ring opening of N-tosylaziridines by alcohols.⁷⁰² The reaction of N-tosyl aziridines with 10% ceric ammonium nitrate in aq methanol leads to N-tosylamino alcohols,⁷⁰³ and reaction with ethanol and 10% BF₃•OEt₂ gives N-tosyl ethers.⁷⁰⁴ In addition, N-tosylaziridines are opened by acetic acid in the presence of In(OTf)₃ to give N-tosylamino acetates.⁷⁰⁵In the presence of Amberlyst-15, N-Boc (Boc = tert-butoxycarbonyl, –CO₂t-Bu) aziridines react with LiBr to give the corresponding bromo amide.⁷⁰⁶ Aziridines are opened by potassium thiocyanate, catalyzed by LiClO₄.⁷⁰⁷Catalytic enantioselective ring opening of N-acyl aziridines with TMSCN and a Gd catalyst leads to amino-nitriles.⁷⁰⁸aza-Payne rearrangements are known, based on reactions of aziridines rather than epoxides (see above).⁷⁰⁹

10-15 Alkylation with Onium Salts

Alkoxy-de-hydroxylation

Oxonium ions are excellent alkylating agents, and ethers can be conveniently prepared by treating them with alcohols or phenols.⁷¹⁰ Quaternary ammonium salts can sometimes also be used.⁷¹¹

OS VIII, 536.

10-16 Hydroxylation via Silanes

Hydroxy-de-silylalkylation

Alkylsilanes can be oxidized, with the silyl unit converted to a hydroxy unit. This usually requires either an aryl group⁷¹² or another silyl group⁷¹³ attached to silicon. It has been shown that a strained four-membered ring silane (a siletane) also gives the corresponding alcohol upon oxidation.⁷¹⁴ Treatment with a fluorinating agent (e.g., tetrabutylammonium fluoride or CsF) replaces Ar or SiR₃ with F, which is oxidized with hydrogen peroxide or a peroxyacid to give the alcohol. This sequence is often called the Tamao–Fleming oxidation.⁷¹² There are several variations in substrate that allow versatility in the initial incorporation of the silyl unit.⁷¹⁵ Hydroperoxide oxidation of a cyclic silane leads to a diol.⁷¹⁶

C. Attack by OCOR at an Alkyl Carbon

10-17 Alkylation of Carboxylic Acid Salts

Acyloxy-de-halogenation

Sodium salts of carboxylic acids, including hindered acids (e.g., mesitoic), rapidly react with primary and secondary bromides and iodides at room temperature in dipolar aprotic solvents, especially HMPA, to give high yields of carboxylic esters.⁷¹⁷ The mechanism is S_N2. Several bases or basic media have been used to generate the carboxylate salt.⁷¹⁸ Sodium salts are often used, but K, Ag, Cs,⁷¹⁹ and substituted ammonium salts have also been used. An important variation uses phase transfer catalysis,⁷²⁰ and good yields of esters have been obtained from primary, secondary, benzylic, allylic, and phenacyl halides.⁷²¹ Without phase-transfer catalysts and in protic solvents, the reaction is useful only for fairly active R [e.g., benzylic and allylic (S_N1 mechanism)], but not for tertiary alkyl, since elimination occurs instead.⁷²² Solid-state procedures are available. Addition of the dry carboxylate salt and the halide to alumina as a solid support, and microwave irradiation gives the ester in a procedure that is applicable to long-chain primary halides.⁷²³ A similar reaction of hexanoic acid and benzyl bromide on solid benzyltributylammonium chloride gave the ester with microwave irradiation.⁷²⁴ Ionic liquid solvents have been shown to facilitate this alkylation reaction.⁷²⁵

The reaction of an alcohol and a carboxylate anion with diethyl azodicarboxylate (EtOOCN=NCOOEt) and Ph₃P⁷²⁶ is called the Mitsunobu reaction.⁷²⁷ Other azocarboxylates may be used in this reaction, including diisopropyl azodicarboxylate (DIAD), and di-2-methoxyethyl azodicarboxylate (DMEAD).⁷²⁸ Other Mitsunobu catalysts are available,⁷²⁹ including organocatalysts,⁷³⁰ and polymer-supported reagents have been used.⁷³¹ A renewable phosphine ligand has been developed.⁷³² Note that other functional groups, including azides⁷³³ and thiocyanates⁷³⁴ can be generated from alcohols using Mitsunobu conditions. This reaction can also be considered as an S_N2 mechanism. Phenol esters can also be formed.⁷³⁵ Mitsunobu cyclodehydration of 1,2-diols leads to epoxides.⁷³⁶

Lactones can be prepared from halo acids by treatment with base (see Reaction 16-63). This has most often been accomplished with γ and δ lactones, but macrocyclic lactones (e.g., 11-17-members) have also been prepared in this way.⁷³⁷ An interesting variation treated 2-ethylbenzoic acid with hypervalent iodine and then I₂/hν to give the five-membered ring lactone.⁷³⁸

Copper(I) carboxylates give esters with primary (including neopentyl without rearrangement), secondary, and tertiary alkyl, allylic, and vinylic halides.⁷³⁹ A simple S_N mechanism is obviously precluded in this case. Vinylic halides can be converted to vinylic acetates by treatment with sodium acetate if palladium(II) chloride is present.⁷⁴⁰

A carboxylic acid (not the salt) can be the nucleophile if F⁻ is present.⁷⁴¹ Mesylates are readily displaced, for example, by benzoic acid/CsF.⁷⁴² Dihalides have been converted to diesters by this method.⁷⁴¹ A COOH group can be conveniently protected by reaction of its ion with a phenacyl bromide (ArCOCH₂Br).⁷⁴³ The resulting ester is easily cleaved when desired with zinc and acetic acid. Dialkyl carbonates can be prepared without phosgene (see Reaction 16-61) by phase-transfer catalyzed treatment of primary alkyl halides with dry KHCO₃ and K₂CO₃.⁷⁴⁴

Other leaving groups can also be replaced by OCOR. Alkyl chlorosulfites (ROSOCl) and other derivatives of sulfuric, sulfonic, and other inorganic acids can be treated with carboxylate ions to give the corresponding esters. Treatment with oxalyl chloride allows displacement by carboxylate salts.⁷⁴⁵ The use of dimethyl sulfate⁷⁴⁶ or trimethyl phosphate⁷⁴⁷ allows sterically hindered COOH groups to be methylated. The reaction of benzoic acid with aq lithium hydroxide, and then dimethyl sulfate gave methyl benzoate.⁷⁴⁸ Dimethyl carbonate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, see Reaction 17-13) has been used to prepare methyl esters.⁷⁴⁹ With certain substrates, carboxylic acids are strong enough nucleophiles for the reaction. Examples of such substrates are trialkyl phosphites [P(OR)₃]⁷⁵⁰ and acetals of DMF.⁷⁵¹

This is an S_N2 process, since inversion is found at R. Another good leaving group is NTs₂ and ditosylamines react quite well with acetate ion in dipolar aprotic solvents:⁷⁵² RNTs₂ + OAc⁻ → ROAc. Ordinary primary amines have been converted to acetates and benzoates by the Katritzky pyrylium–pyridinium method (Sec. 10.G.iii).⁷⁵³ Quaternary ammonium salts can be cleaved by heating with AcO⁻ in an aprotic solvent.⁷⁵⁴ Oxonium ions can also be used as substrates:⁷⁵⁵ R₃O⁺ + R′COO⁻ → R′COOR + R₂O. The reaction of potassium thioacetate with alkyl halides give dithiocarboxylic esters.⁷⁵⁶

In a variation of this reaction, alkyl halides can be converted to carbamates, by treatment with a secondary amine and K₂CO₃ under phase transfer conditions.⁷⁵⁷ The reaction of alcohols and alkyl halides can lead to carbonates.⁷⁵⁸

OS II, 5; III, 650; IV, 582; V, 580; VI, 273, 576, 698.

10-18 Cleavage of Ethers with Acetic Anhydride or Acid Halides

Acyloxy-de-alkoxylation

Dialkyl ethers can be cleaved by treatment with anhydrous ferric chloride in acetic anhydride,⁷⁵⁹ or with Me₃SiOTf in acetic anhydride.⁷⁶⁰ In this reaction, both R groups are converted to acetates and yields are moderate to high. Ethers can also be cleaved by the mixed, anhydride acetyl tosylate:⁷⁶¹

Epoxides give β-hydroxyalkyl carboxylates when treated with a carboxylic acid or a carboxylate ion and a suitable catalyst.⁷⁶² Tetrahydrofuran was opened to give O-acyl-4-iodo-1-butanol by treatment with acid chlorides and samarium halides⁷⁶³ or BCl₃.⁷⁶⁴ In a highly specialized transformation, the reaction of an epoxide with CO₂ and ZnCl₂ in an ionic liquid leads to a cyclic carbonate.⁷⁶⁵ Epoxides react with CO and CH₃OH in the presence of 10% of 3-hydroxypyridine and 5% of Co₂(CO)₈ to give a β-hydroxy methyl ester.⁷⁶⁶

OS VIII, 13.

10-19 Alkylation of Carboxylic Acids with Diazo Compounds

Hydro, acyloxy-de-diazo-bisubstitution

Carboxylic acids can be converted to esters with diazo compounds in a reaction essentially the same as 10-11. In contrast to alcohols, carboxylic acids undergo the reaction quite well at room temperature, since the reactivity of the reagent increases with acidity. The reaction is used where high yields are important or where the acid is sensitive to higher temperatures. Because of availability, diazomethane (CH₂N₂)⁶⁵⁴ is commonly used to prepare methyl esters, and diazo ketones are common. The mechanism is as shown in Reaction 10-11.

OS V, 797.

D. Other Oxygen Nucleophiles

10-20 Formation of Oxonium Salts

Dialkyloxonio-de-halogenation

Alkyl halides can be alkylated by ethers or ketones to give oxonium salts, if a very weak, negatively charged nucleophile is present to serve as a counterion and a Lewis acid is present to combine with X⁻.⁷⁶⁷ A typical procedure consists of treating the halide with the ether or the ketone in the presence of AgBF₄ or AgSbF₆. The Ag⁺ serves to remove X⁻ and the BF₄⁻ or SbF₆⁻ acts as the counterion. Another method involves treatment of the halide with a complex formed between the oxygen compound and a Lewis acid (e.g., R₂O•BF₃ + RX → R₃O⁺ BF₄⁻), although this method is most satisfactory when the oxygen and halogen atoms are in the same molecule so that a cyclic oxonium ion is obtained. Ethers and oxonium ions also undergo exchange reactions:

OS V, 1080, 1096, 1099; VI, 1019.

10-21 Preparation of Peroxides and Hydroperoxides

Hydroperoxy-de-halogenation

Hydroperoxides can be prepared by treatment of alkyl halides, esters of sulfuric or sulfonic acids, or alcohols with hydrogen peroxide in basic solution, where it is actually HO₂⁻.⁷⁶⁸ Sodium peroxide is similarly used to prepare dialkyl peroxides (2RX + Na₂O₂ → ROOR). Another method, which gives primary, secondary, or tertiary hydroperoxides and peroxides, involves treatment of the halide with H₂O₂ or a peroxide in the presence of silver trifluoroacetate.⁷⁶⁹ Peroxides can also be prepared⁷⁷⁰ by treatment of alkyl bromides or tosylates with potassium superoxide (KO₂) in the presence of crown ethers (though alcohols may be side products⁷⁷¹) and by the reaction between alkyl triflates and germanium or tin peroxide.⁷⁷²

Diacyl peroxides and acyl hydroperoxides can similarly be prepared⁷⁷³ from acyl halides or anhydrides and from carboxylic acids.⁷⁷⁴ Diacyl peroxides can also be prepared by the treatment of carboxylic acids with hydrogen peroxide in the presence of dicyclohexylcarbodiimide,⁷⁷⁵ Sulfuric acid, methanesulfonic acid, or some other dehydrating agent. Mixed alkyl–acyl peroxides (peresters) can be made from acyl halides and hydroperoxides.

OS III, 619, 649; V, 805, 904; VI, 276.

10-22 Preparation of Inorganic Esters

Nitrosooxy-de-hydroxylation, and so on.

The above transformations show a few of the many inorganic esters that can be prepared by the reaction of an alcohol with an inorganic acid or, better, its acid halide or anhydride⁷⁷⁶ These similar reactions are grouped together for convenience, but not all involve nucleophilic substitutions at R. The other possible pathway is nucleophilic substitution at the inorganic central atom, such as the attack of the alcohol oxygen at the electrophilic sulfur atom in 118,⁷⁷⁷or a corresponding S_N2 type process (see Sec. 16.B.v). In such cases, there

is no alkyl-O cleavage. Mono esters of sulfuric acid (alkylsulfuric acids), which are important industrially because their salts are used as detergents, can be prepared by treating alcohols with SO₃, H₂SO₄, ClSO₂OH, or SO₃complexes.⁷⁷⁸ It is possible to prepare a primary sulfonate ester (e.g., tosylate), in the presence of a secondary alcohol unit when tosic acid reacts with a 1,2-diol in the presence of Fe³⁺-Montmorillonite.⁷⁷⁹ Polymer-bound reagents have been used to prepared sulfonate esters.⁷⁸⁰ Phenolic triflates have been prepared using N,N-ditrifylaniline and K₂CO₃ under microwave irradiation.⁷⁸¹ Sulfinic esters are readily prepared from alcohols and sulfinyl chlorides, and in the presence of Cinchona alkaloids the reaction is enantioselective.⁷⁸²

Alkyl nitrites⁷⁸³ can be conveniently prepared by an exchange reaction ROH + R′ONO → RONO + R′OH, where R = t-Bu.⁷⁸⁴ Primary amines can be converted to alkyl nitrates (RNH₂ → RONO₂) by treatment with N₂O₄ at −78 °C in the presence of an excess of amidine base.⁷⁸⁵ Mitsunobu conditions (Reaction 10-17) can be used to prepare phosphate ester or phosphonate esters. The reaction can be done intramolecularly for prepare cyclic phosphonate esters.⁷⁸⁶

Alkyl halides are often used as substrates instead of alcohols. In such cases, the salt of the inorganic acid is usually used and the mechanism is nucleophilic substitution at the carbon atom. An important example is the treatment of alkyl halides with silver nitrate to form alkyl nitrates. This is used as a test for alkyl halides. In some cases, there is competition from the central atom. Thus nitrite ion is an ambident nucleophile that can give nitrites or nitro compounds (see Reaction 10-42).⁷⁸⁷ Dialkyl or aryl alkyl ethers can be cleaved with anhydrous sulfonic acids.⁷⁸⁸

Here R″ may be alkyl or aryl. For dialkyl ethers, the reaction does not end as indicated above, since R′OH is rapidly converted to R′OR′ by the sulfonic acid (Reaction 10-12), which in turn is further cleaved to R′OSO₂R″ so that the product is a mixture of the two sulfonates. For aryl alkyl ethers, cleavage always takes place to give the phenol, which is not converted to the aryl ether under these conditions. Ethers can also be cleaved in a similar manner by mixed anhydrides of sulfonic and carboxylic acids⁷⁸⁹ (prepared as in Reaction 16-68). β-Hydroxyalkyl perchlorates⁷⁹⁰ and sulfonates can be obtained from epoxides.⁷⁹¹ Epoxides and oxetanes give α,ω-dinitrates when treated with N₂O₅.⁷⁹² Aziridines and azetidines react similarly, giving nitramine nitrates (e.g., N-butylazetidine gave NO₂OCH₂CH₂CH₂N(Bu)NO₂).⁷⁹²

Phosphinate esters are prepared by transesterification-type reactions (16-64) from alcohols and other phosphinates.⁷⁹³

OS II, 106, 108, 109, 112, 204, 412; III, 148, 471; IV, 955; V, 839; VIII, 46, 50, 616. Also see, OS II, 111.

10-23 Alcohols from Amines

Hydroxy-de-amination

This transformation is rare. A rather direct method was reported whereby a primary amine reacted with KOH in diethylene glycol at 210 °C.⁷⁹⁴ The reaction of (S)-phenethylamine and the bis-(sulfonyl chloride) of 1,2-benzenesulfonic acid, followed by KNO₂ and 18-crown-6 gave (R)-phenethyl alcohol in 70% yield and 40% enantiomeric excess (ee).⁷⁹⁵

10-24 Alkylation of Oximes⁷⁹⁶

Oximes can be alkylated by alkyl halides or sulfates. N-Alkylation is a side reaction, yielding a nitrone.⁷⁹⁷ The relative yield of oxime ether and nitrone depends on the nature of the reagents, including the configuration of the oxime, and on the reaction conditions.⁷⁹⁸ For example, anti-benzaldoximes give nitrones, while the syn isomers give oxime ethers.⁷⁹⁹

OS III, 172; V, 1031. Also see, OS V, 269; VI, 199.

10.H.iii. Sulfur Nucleophiles

Sulfur compounds⁸⁰⁰ are better nucleophiles than their oxygen analogues (Sec. 10.G.ii), so in most cases these reactions take place faster and more smoothly than the corresponding reactions with oxygen nucleophiles. There is evidence that some of these reactions take place by SET mechanisms.⁸⁰¹

10-25 Attack by SH at an Alkyl Carbon: Formation of Thiols⁸⁰²

Mercapto-de-halogenation

Sodium sulfhydride (NaSH) is a much better reagent for the formation of thiols (mercaptans) from alkyl halides than H₂S and is used much more often. It is easily prepared by bubbling H₂S into an alkaline solution, but hydrosulfide on a supported polymer resin has also been used.⁸⁰³ The reaction is most useful for primary halides. Secondary substrates give much lower yields, and the reaction fails completely for tertiary halides because elimination predominates. Sulfuric and sulfonic esters can be used instead of halides. Thioethers (RSR) are often side products.⁸⁰⁴ The conversion can also be accomplished under neutral conditions by treatment of a primary halide with F⁻ and a tin sulfide (e.g., Ph₃SnSSnPh₃).⁸⁰⁵ An indirect method for the preparation of a thiol is the reaction of an alkyl halide with thiourea to give an isothiuronium salt (119), and subsequent treatment with alkali or a high-molecular-weight amine gives cleavage to the thiol.

Other indirect methods are treatment of the halide with silyl-thiols and KH, followed by treatment with fluoride ion and water,⁸⁰⁶ and hydrolysis of Bunte salts (see Reaction 10-28) is another method.

Thiols have also been prepared from alcohols. One method involves treatment with H₂S and a catalyst (e.g., Al₂O₃),⁸⁰⁷ but this is limited to primary alcohols. Another method involves treatment with Lawesson's reagent (see Reaction 16-10).⁸⁰⁸ Tertiary nitro compounds give thiols (RNO₂ → RSH) when treated with sulfur and sodium sulfide, followed by amalgamated aluminum.⁸⁰⁹

OS III, 363, 440; IV, 401, 491; V, 1046; VIII, 592. Also see, OS II, 345, 411, 573; IV, 232; V, 223; VI, 620.

10-26 Attack by S at an Alkyl Carbon: Formation of Thioethers

Alkylthio-de-halogenation; Alkylthio-de-hydroxylation

Thioethers (sulfides) can be prepared by treatment of alkyl halides with salts of thiols (thiolate anions).⁸¹⁰ The R′ group may be alkyl or aryl and organolithium bases can be used to deprotonate the thiol.⁸¹¹ As in Reaction 10-25, RX cannot be a tertiary halide, and sulfuric and sulfonic esters can be used instead of halides. As in the Williamson Reaction (10-8), yields are often improved by phase-transfer catalysis.⁸¹² Thiols react directly with alkyl halides in the presence of bases (e.g., DBU; see Reaction 17-13)⁸¹³ or CsF.⁸¹⁴ Leaving groups other than chloride can be used, as in the Ru catalyzed reaction of thiols with propargylic carbonates.⁸¹⁵ Vinylic sulfides can be prepared by treating vinylic bromides with PhS⁻ in the presence of a Ni complex,⁸¹⁶ or in the presence of Pd(PPh₃)₄. Alternatively, the Ag salt of an enethiol reacts with iodomethane to give the corresponding methyl vinyl sulfide.⁸¹⁷

In some cases, alcohols can be converted to thioethers by reaction with thiols. Tertiary alcohols react with thiols in the presence of sulfuric acid to give thioethers, and the reaction works best with tertiary substrates.⁸¹⁸ This reaction is analogous to Reaction 10-12. Thiophenol reacts with propargylic alcohols in the presence of a Ru catalyst to give propargylic thioethers.⁸¹⁹ Primary and secondary alcohols can be converted to alkyl aryl sulfides (ROH → RSAr) in high yields by treatment with Bu₃P and an N- (arylthio)succinimide in benzene.⁸²⁰ Iodine catalyzes the allylic alkylation of thiols.⁸²¹ Thioethers (RSR′) can be prepared from an alcohol ROH and a halide R′Cl by treatment with tetramethylthiourea Me₂NC(=S)NMe₂ followed by NaH.⁸²²

Thiolate ions are also useful for the demethylation of certain ethers,⁸²³ esters, amines, and quaternary ammonium salts. Aryl methyl ethers⁸²⁴ can be cleaved by heating with EtS⁻ in the dipolar aprotic solvent DMF: ROAr + EtS⁻→ ArO⁻ + EtSR.⁸²⁵ Allylic sulfides have been prepared by treating allylic carbonates ROCO₂Me (R = an allylic group) with a thiol and a Pd(0) catalyst.⁸²⁶ A good method for the demethylation of quaternary ammonium salts consists of refluxing them with PhS⁻ in 2-butanone to give the amine and methyl phenyl sulfide.⁸²⁷

A methyl group is cleaved more readily than other simple alkyl groups (e.g., ethyl), although loss of these groups competes. Benzylic and allylic groups cleave even more easily, and this is a useful procedure for the cleavage of benzylic and allylic groups from quaternary ammonium salts, even if methyl groups are also present.⁸²⁸

Symmetrical thioethers (R–S–R) can also be prepared by treatment of an alkyl halide (R–X) with sodium sulfide (Na₂S).⁸²⁹ Symmetrical thioethers have also been prepared by the reaction of S(MgBr)₂ with allylic halides_.⁸³⁰ This reaction can be carried out internally, by treatment of sulfide ions with 1,4-, 1,5-, or 1,6-dihalides, to prepare five-, six-, and seven-membered⁸³¹ sulfur-containing heterocyclic rings. Certain larger rings have also been closed in this way.⁸³²

gem-Dihalides can be converted to dithioacetals [RCH(SR′)₂],⁸³³ and acetals have been converted to monothioacetals [R₂C(OR′)(SR²)],⁸³⁴ and to dithioacetals.⁸³⁵ The combination of carbon disulfide and NaBH₄ converted 1,3-dibromopropane to 1,3-dithiane.⁸³⁶

When epoxides are substrates,⁸³⁷ reaction with PhSeSnBu₃/BF₃•OEt₂⁸³⁸ gives the corresponding β-hydroxy selenide in a manner analogous to that mentioned in Reaction 10-25. Reaction of an epoxide with Ph₃SiSH followed by treatment with Bu₄NF gives hydroxy-thiols.⁸³⁹

Epoxides can also be directly converted to episulfides (thiiranes)⁸⁴⁰ by treatment with a phosphine sulfide (e.g., Ph₃PS),⁸⁴¹ with thiourea and titanium tetraisopropoxide⁸⁴² or thiourea and LiBF₄ in acetonitrile,⁸⁴³, with NH₄SCN and TiO (tfa)₂ (tfa = trifluoacetyl),⁸⁴⁴ with (EtO)₂P(=O)H/S/Al₂O₃,⁸⁴⁵ with KSCN and InBr₃,⁸⁴⁶ and with KSCN in ionic liquids (Sec. 9.D.iii).⁸⁴⁷ 2,4,6-Trichloro-1,3,5-triazine catalyzes this conversion under solvent-free conditions.⁸⁴⁸

Selenides (selenoethers) and tellurides can be prepared via RSe⁻ and RTe⁻ species,⁸⁴⁹ and Se and borohydride exchange resin followed by the halide give the selenoether.⁸⁵⁰ The La/I₂ catalyzed reaction of diphenyl diselenide with primary alkyl iodides gave arylalkyl selenides,⁸⁵¹ Indium has been used with alkyl halides.⁸⁵² A Zn mediated synthesis of tertiary alkyl selenides from tertiary alkyl halides is known.⁸⁵³ Diaryl selenides (Ar–Se–Ar′) have been prepared by coupling aryl iodides with tin reagents (ArSeSnR₃) with a Pd catalyst.⁸⁵⁴ α-Seleno aldehydes are prepared by the reaction of an aldehyde with PhSe(N(phthalimide).⁸⁵⁵

OS II, 31, 345, 547, 576; III, 332, 751, 763; IV, 396, 667, 892, 967; V, 562, 780, 1046; VI, 5, 31, 268, 364, 403, 482, 556, 601, 683, 704, 737, 833, 859; VII, 453; VIII, 592. See also, OS VI, 776.

10-27 Formation of Disulfides⁸⁵⁶

Dithio-de-dihalo- aggre -substitution

Disulfides can be prepared by treatment of alkyl halides with disulfide ions and also indirectly by the reaction of Bunte salts (see Reaction 10-28) with acid solutions of iodide, thiocyanate ion, or thiourea,⁸⁵⁷ or by pyrolysis or treatment with hydrogen peroxide. Alkyl halides also give disulfides when heated to reflux with sulfur and NaOH.⁸⁵⁸ Some molybdenum compounds convert alkyl halides to disulfides, including (BnNEt₃)₆Mo₇S₂₄.⁸⁵⁹

There are no OS references, but a similar preparation of a polysulfide may be found in OS IV, 295.

10-28 Formation of Bunte Salts

Sulfonatothio-de-halogenation

Primary and secondary, but not tertiary, alkyl halides are easily converted to Bunte salts (RSSO₃⁻) by treatment with thiosulfate ion.⁸⁶⁰ Bunte salts can be hydrolyzed with acids to give the corresponding thiols⁸⁶¹ or converted to disulfides, tetrasulfides, or pentasulfides.⁸⁶²

OS VI, 235.

10-29 Alkylation of Sulfinic Acid Salts

Alkylsulfonyl-de-halogenation

Alkyl halides or alkyl sulfates, treated with the salts of sulfinic acids, give sulfones.⁸⁶³ A Pd catalyzed reaction with a chiral complexing agent led to sulfones with modest asymmetric induction.⁸⁶⁴ Alkyl sulfinates (R′SO–OR) may be side products.⁸⁶⁵ Sodium tosylsulfinate reacted with allylic acetates in the presence of a Pd catalyst to give the corresponding sulfone.⁸⁶⁶ Sulfonic acids themselves can be used, if DBU (see Reaction 17-13) is present.⁸⁶⁷Sulfonyl halides react with allylic halides in the presence of AlCl₃–Fe⁸⁶⁸ and with benzyl halides in the presence of Sm/HgCl₂.⁸⁶⁹ Sulfones have also been prepared by treatment of alkyl halides with tosylhydrazide.⁸⁷⁰ The copper(II)-catalyzed cross-coupling of organoboronic acids and sulfinate salts leads to sulfones.⁸⁷¹ Vinyl sulfones were prepared from PhSO₂Na and vinyl iodinium salts C=C–I⁺Ph BF₄⁻.⁸⁷²

OS IV, 674; IX, 497. See also, OS VI, 1016.

10-30 Formation of Alkyl Thiocyanates

Thiocyanato-de-halogenation

Alkyl halides⁸⁷³ or sulfuric or sulfonic esters can be heated with sodium or potassium thiocyanate to give alkyl thiocyanates,⁸⁷⁴ although the attack by the analogous cyanate ion (Reaction 10-44) gives exclusive N-alkylation. Primary amines can be converted to thiocyanates by the Katritzky pyrylium–pyridinium method (Sec. 10.G.iii).⁸⁷⁵ Tertiary chlorides are converted to tertiary thiocyanates with Zn(SCN)₂ in pyridine and ultrasound.⁸⁷⁶

OS II, 366.

10.H.iv. Nitrogen Nucleophiles

A. Attack by NH₂, NHR, or NR₂ at an Alkyl Carbon

10-31 Alkylation of Amines

Amino-de-halogenation (alkyl)

The reaction between alkyl halides and ammonia or primary amines is not usually a feasible method for the preparation of primary or secondary amines, since they are stronger bases than ammonia and preferentially attack the substrate. However, the reaction is very useful for the preparation of tertiary amines⁸⁷⁷ and quaternary ammonium salts. If ammonia is the nucleophile,⁸⁷⁸ the three or four alkyl groups on the nitrogen of the product must be identical. If a primary, secondary, or tertiary amine is used, then different alkyl groups can be placed on the same nitrogen atom. The conversion of tertiary amines to quaternary salts is called the Menshutkin reaction.⁸⁷⁹ It is sometimes possible to use this method for the preparation of a primary amine by the use of a large excess of ammonia or a secondary amine by the use of a large excess of primary amine. Metal-catalyzed methods are available to convert primary amines to secondary amines,⁸⁸⁰ and secondary amines can be converted to tertiary amines.⁸⁸¹ Ionic liquids have been used to facilitate amination reactions.⁸⁸² The use of ammonia in methanol with microwave irradiation has also been effective.⁸⁸³ Microwave irradiation has also been used in reactions of aniline with allyl iodides.⁸⁸⁴ Bromides react faster than chlorides, and secondary amines reaction with 3-chloro-1-bromopropane via the bromide, in the presence of Zn and THF.⁸⁸⁵N-Alkylation has been accomplished using alkyl halides in aqueous media.⁸⁸⁶

Bases other than amine can be used. Both sodium carbonate⁸⁸⁷ and lithium hydroxide⁸⁸⁸ have been used. Cesium hydroxide was successfully used as a base in the presence of molecular sieve 4 Å,⁸⁸⁹ and cesium fluoride has been used with benzylic halides.⁸⁹⁰ Potassium carbonate in DMSO has been used for the alkylation of aniline.⁸⁹¹

The limitations of this approach can be seen in the reaction of a saturated solution of ammonia in 90% ethanol with ethyl bromide in a 16:1 molar ratio, which gave 34.2% of the primary amine (at a 1:1 ratio the yield was 11.3%).⁸⁹² α-Halo acids are one type of substrate that give reasonable yields of primary amine (provided a large excess of NH₃ is used) and are subsequently converted to amino acids. N-Chloromethyl lactams also react with amines to give good yields to the N-aminomethyl lactam.⁸⁹³ An indirect method to prepare primary amines from alkyl halides uses Reaction 10-43, followed by reduction of the azide (19-32),⁸⁹⁴ and the Gabriel synthesis (10-41) is effective.

The immediate product in any particular step is the protonated amine, but it rapidly loses a proton to another molecule of ammonia or amine in an equilibrium process, for example,

When a primary or secondary amine must be converted directly to the quaternary salt (exhaustive alkylation), the rate can be increased by the addition of a non-nucleophilic strong base that serves to remove the proton from RR′NH₂⁺ or RR′R²NH⁺ and thus liberates the amine to attack another molecule of RX.⁸⁹⁵

The conjugate bases of ammonia and of primary and secondary amines (NH₂⁻, RNH⁻ R₂N⁻) are generically known as amide bases, and are sometimes used as nucleophiles,⁸⁹⁶ including amide bases generated from organolithium reagents and amines (R₂NLi).⁸⁹⁷ This is in contrast to analogous methods 10-1, 10-8, 10-25, and 10-26. Primary alkyl, allylic, and benzylic bromides, iodides, and tosylates react with sodium bis(trimethylsilyl)amide to give derivatives that are easily hydrolyzed to produce amine salts in high overall yields.⁸⁹⁸ Primary arylamines are easily alkylated, but diaryl- and triarylamines are very poor nucleophiles. However, the reaction has been carried out with diarylamines.⁸⁹⁹ Sulfates or sulfonates can be used instead of halides. N-Alkylation of heterocycles is sometimes problematic, but pyrrole is converted to N-methylpyrrole with KOH, iodomethane in ionic liquids.⁹⁰⁰

The reaction can be carried out intramolecularly to give cyclic amines, with three-, five-, and six-membered (but not four-membered) rings being easily prepared. Thus, 4-chloro-1-aminobutane treated with base gives pyrrolidine, and 2-chloroethylamine gives aziridine⁹⁰¹ (analogous to Reaction 10-9):

Reduction of N-(3-bromopropyl) imines gives a bromoamine in situ, which cyclizes to the aziridine.⁹⁰² Five-membered ring amines (pyrrolidines) can be prepared from alkenyl amines via treatment with N-chlorosuccinimide (NCS) and then Bu₃SnH.⁹⁰³ The Pd catalyzed internal addition of amine to allylic acetates leads to cyclic products via a S_N2′ reaction.⁹⁰⁴ Three-membered cyclic amines (aziridines) can be prepared from chiral conjugated amides via bromination and reaction with an amine.⁹⁰⁵ Four-membered cyclic amines (azetidines) have been prepared from the ditosylate of 1,3-propanediol⁹⁰⁶ and from 1,3-dichloropropane.⁹⁰⁷ This reaction was also used to close five-, six-, and seven-membered rings.

As usual, tertiary substrates do not give the reaction at all, but undergo preferential elimination upon treatment with a basic amine. However, tertiary (but not primary or secondary) halides (e.g., R₃CCl) can be converted to primary amines (R₃CNH₂) by treatment with NCl₃ and AlCl₃⁹⁰⁸ in a reaction related to Reaction 10-39. Ruthenium(II) complexes have been used for the alkylation of aryl amines.⁹⁰⁹

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine⁹¹⁰ followed by cleavage of the resulting salt with ethanolic HCl. The method called the Delépine reaction is most successful for active halides (e.g., allylic and benzylic halides and α-halo ketones).

A convenient way of obtaining secondary amines without contamination by primary or tertiary amines involves treatment of alkyl halides with the sodium or calcium salt of cyanamide (NH₂–CN) to give disubstituted cyanamides, which are then hydrolyzed and decarboxylated to secondary amines. Good yields are obtained when the reaction is carried out under phase-transfer conditions.⁹¹¹ The R group may be primary, secondary, allylic, or benzylic. 1,ω-Dihalides give cyclic secondary amines. Aminoboranes react with sulfonate esters to give a derivative that can be hydrolyzed to a tertiary amine.⁹¹² An aminyl-radical cyclization process was used to prepare cyclic amines.⁹¹³N-Silylalkyl amines are formed from amines by reaction with halotrialkylsilanes and a suitable base.⁹¹⁴ Amines react directly with triarylsilanes in the presence of Yb catalysts.⁹¹⁵

Palladium compounds react with allylic halides, acetates, or carbonate derivatives to generate π-allyl Pd intermediates that react with amines to give an allylic amine (see the reaction below).⁹¹⁶ The same reaction is discussed in Reaction 10-60 with other nucleophiles. Propargylic amines can be prepared by similar methodology.⁹¹⁷ Boronic acid derivatives leads to methylation of aniline derivatives in the presence of cupric acetate.⁹¹⁸ tert-Butylamines can be prepared from isobutylene, HBr, and the amine by heating a sealed tube.⁹¹⁹

Phosphines behave similarly to amines, and compounds, such as R₃P and R₄P⁺ X⁻, can be prepared.⁹²⁰ The reaction between triphenylphosphine and quaternary salts of nitrogen heterocycles in an aprotic solvent is probably the best way of dealkylating the heterocycles, for example,⁹²¹

Other phosphorus compounds can be alkylated. Phosphinate esters, for example, react with a suitable base and then an alkyl halide to give the P-substituted product.⁹²²

OS I, 23, 48, 102, 300, 488; II, 85, 183, 290, 328, 374, 397, 419, 563; III, 50, 148, 254, 256, 495, 504, 523, 705, 753, 774, 813, 848; IV, 84, 98, 383, 433, 466, 582, 585, 980; V, 88, 124, 306, 361, 434, 499, 541, 555, 608, 736, 751, 758, 769, 825, 883, 985, 989, 1018, 1085, 1145; VI, 56, 75, 104, 106, 175, 552, 652, 704, 818, 967; VIII, 9, 152, 231, 358. Also see, OS II, 395; IV, 950; OS V, 121; OS I, 203.

For N-arylation of amines see Reaction 13-5.

10-32 Replacement of a Hydroxy or Alkoxy by an Amino Group

Amino-de-hydroxylation and Amino-de-alkoxylation

Alcohols can be converted to alkyl halides, which then react with amines (Reaction 10-43). Alcohols react with various amine reagents that give products convertible to the amine.⁹²³ The conversion ROH → RNH₂ can be accomplished for primary and secondary alcohols by treatment with hydrazoic acid (HN₃), diisopropyl azodicarboxylate (iPr–OOCN=NCOO–iPr), and excess Ph₃P in THF, followed by water or aq acid.⁹²⁴ This is a type of Mitsunobu Reaction (see 10-17).⁹²⁵ Primary and secondary alcohols (ROH, but not methanol) can be converted to tertiary amines⁹²⁶ Primary amines can be generated directly from primary alcohols and ammonia.⁹²⁷ Formation of R′₂NR required treatment with the secondary amine (R′₂NH) with the (t-BuO)₃Al compound in the presence of Raney nickel.⁹²⁸

Allylic alcohols (ROH) react with amines in the presence of Pt⁹²⁹ or Pd⁹³⁰ complexes, to give allylic amines.⁹³¹ Amines can be N-alkylated by reaction with alcohols, in a sealed tube with microwave irradiation,⁹³² and also by Ru-,⁹³³ Ir-,⁹³⁴ or Au catalyzed⁹³⁵ reactions, or by Ti mediated⁹³⁶ reactions. Copper–aluminum hydrotalcite can also be used to generate amines from alcohols.⁹³⁷ The use of aniline gives secondary amines (PhNHR). Phenols can be converted to aniline derivatives.^938,939 Heating indoles with benzylic alcohols in the presence of Me₃P=CH(CN) gives the N-benzylindole.⁹⁴⁰ Heating an alcohol on γ-Al₂O₃ leads to an amine,⁹⁴¹ as does treatment with the amine, SnCl₂, and Pd(PPh₃)₄.⁹⁴² The Ru catalyzed reaction of amines and diols leads to cyclic amines.⁹⁴³

β-Amino alcohols give aziridines (120) when treated with triphenylphosphine dibromide in the presence of triethylamine.⁹⁴⁴ The fact that inversion takes place at the OH carbon indicates that an S_N2 mechanism is involved, with OPPh₃ as the leaving group.

Alcohols can be converted to amines in an indirect manner.⁹⁴⁵ The alcohols are converted to alkyloxyphosphonium perchlorates, which in DMF successfully monoalkylate not only secondary but also primary amines.⁹⁴⁶

Thus by this means secondary as well as tertiary amines, can be prepared in good yields. Benzylic alcohols can be converted to an azide and then treated with triphenylphosphine to give the amine (Reaction 19-50).⁹⁴⁷

Cyanohydrins can be converted to amines by treatment with ammonia. The use of primary or secondary amines instead of ammonia leads to secondary and tertiary cyanoamines, respectively. It is more common to perform the conversion of an aldehyde or ketone directly to the cyanoamine without isolation of the cyanohydrin (see Reaction 16-52). α-Hydroxy ketones (acyloins and benzoins) behave similarly.⁹⁴⁸

A solution of the sodium salt of N-methylaniline in HMPA can be used to cleave the methyl group from aryl methyl ethers:⁹⁴⁹ ArOMe + PhNMe⁻ → ArO⁻ + PhNMe₂. This reagent also cleaves benzylic groups. In a similar reaction, methyl groups of aryl methyl ethers can be cleaved with lithium diphenylphosphide (Ph₂PLi).⁹⁵⁰ This reaction is specific for methyl ethers and can be carried out in the presence of ethyl ethers with high selectivity. Phenyl allyl ethers react with secondary amines in the presence of a Pd catalyst to give phenol and the tertiary allyl amine.⁹⁵¹

OS II, 29, 231; IV, 91, 283; VI, 567, 788; VII, 501. Also see, OS I, 473; III, 272, 471.

10-33 Transamination

Alkylamino-de-amination

Where the nucleophile is the conjugate base of a primary amine, NH₂ can be a leaving group. The method has been used to prepare secondary amines.⁹⁵² In another process, primary amines are converted to secondary amines in which both R groups are the same (2 RNH₂ → R₂NH + NH₃)⁹⁵³ by refluxing in xylene in the presence of Raney nickel.⁹⁵⁴ Quaternary salts can be dealkylated with ethanolamine.⁹⁵⁵

In this reaction, methyl groups are cleaved in preference to other saturated alkyl groups. A similar reaction takes place between a Mannich base (see Reaction 16-19) and a secondary amine, where the mechanism is elimination–addition (see Sec. 10.F). Transamination has been accomplished using yeast alcohol dehydrogenase.⁹⁵⁶

See also, Reaction 19-5.

OS V, 1018.

10-34 Alkylation of Amines With Diazo Compounds

Hydro, dialkylamino-de-diazo-bisubstitution

The reaction of diazo compounds with amines is similar to Reaction 10-11.⁹⁵⁷ The acidity of amines is not great enough for the reaction to proceed without a catalyst, but BF₃, which converts the amine to the F₃B–NHR′₂ complex, enables the reaction to take place. Cuprous cyanide can also be used as a catalyst.⁹⁵⁸ Ammonia has been used rather than an amine but, as in the case of Reaction 10-31, mixtures of primary, secondary, and tertiary amines are obtained. However, a highly chemoselective reaction of amines in water has been reported.⁹⁵⁹ Primary aliphatic amines give mixtures of secondary and tertiary amines. Secondary amines give successful alkylation. Primary aromatic amines also give the reaction, but diaryl or arylalkylamines react very poorly.

10-35 Reaction of Epoxides with Nitrogen Reagents⁹⁶⁰

(3) OC-seco-Amino-de-alkoxylation

The reaction between epoxides and ammonia⁹⁶¹ (or ammonium hydroxide)⁹⁶² is a general and useful method for the preparation of β-hydroxyamines. With epoxides derived from terminal alkenes, the reaction with ammonia gives largely the primary amine, but secondary and tertiary amine products are possible from the appropriate epoxide. The reaction of 121 with ammonium hydroxide with microwave irradiation, for example,

gave 122.⁹⁶³ Ethanolamines, which are useful solvents, as well as synthetic precursors, are prepared by this reaction. Similar ring-opening occurs with alkyl and aromatic amines.⁹⁶⁴ For another way of accomplishing this conversion, see Reaction 10-40. Ring opening has been accomplished with aniline on silica gel,⁹⁶⁵ and with aromatic amines in the presence of heteropoly acids in water.⁹⁶⁶

Primary and secondary amines give, respectively, secondary and tertiary amines (121). Aniline reacts with epoxides in the presence of aq β-cyclodextrin⁹⁶⁷ in 5 M LiClO₄ in ether,⁹⁶⁸ or in fluoro-alcohol solvents.⁹⁶⁹ Aniline reacts with epoxides in the presence of a VCl₃ catalyst⁹⁷⁰ or a Cu(II) catalyst.⁹⁷¹N-Boc-amine (H₂N–CO₂t-Bu) reacted with epoxides in the presence of a cobalt–salen catalyst to give the amido alcohol.⁹⁷² Solvent-free reactions using a catalytic amount of SnCl₄ are known.⁹⁷³ Other metal-catalyzed ring-opening reactions of epoxides with amines have been reported,⁹⁷⁴ often with high enantioselectivity.

Enantioselective ring-opening reactions typically use a metal catalyst in the presence of a chiral additive. Amines react with epoxides using a catalytic amount of a Nb complex, in the presence of a 1,1-bi-2-naphthol (BINOL) derivative, to give chiral amino alcohols.⁹⁷⁵ Other enantioselective ring-opening reactions include a V–salen-catalyzed reaction,⁹⁷⁶ and a Mg–BINOL complex.⁹⁷⁷

Tetrahydropyrimidones can be used to mediate the addition of indole to epoxides.⁹⁷⁸ Amide bases react differently with epoxides. Lithium 2,2,6,6-tetramethylpiperidide (LTMP), for example, reacted with epoxides, but the product was the corresponding enamine.⁹⁷⁹ This latter reaction follows a very different mechanism. Initial formation of the lithio-epoxide is followed by rearrangement to give the aldehyde,⁹⁸⁰ and subsequent reaction with the amine byproduct of the lithiation leads to the enamine.

An indirect method for generating an amino alcohol (124) is to open an epoxide with azide to give the azido-alcohol (123),⁹⁸¹ and subsequent reduction (Reaction 19-50) gives the amine group.⁹⁸² The cerium ammonium nitrate catalyzed reaction of epoxides and sodium azide, for example, gave the azido alcohol with selectivity for the azide group on the more substituted position.⁹⁸³ Cerium chloride has also been used, giving the azide on the less substituted carbon.⁹⁸⁴ Under Mitsunobu conditions (Reaction 10-17), epoxides are converted to 1,2-diazides with HN₃.⁹⁸⁵ The reaction of trimethylsilyl azide and an epoxide was reported using an ionic solvent.⁹⁸⁶ In the presence of AlCl₃ in water at pH 4, sodium azide reacts with epoxy acids to give the β-azido-α-hydroxycarboxylic acid.⁹⁸⁷ Silylazides can be used as well.⁹⁸⁸

Sodium nitrate (NaNO₂) reacts with epoxides in the presence of MgSO₄ to give the nitro alcohol.⁹⁸⁹ The nitro group can also be reduced to give the amine (Reaction 19-45).⁹⁹⁰

Episulfides (thiiranes), which can be generated in situ in various ways, react similarly to give β-amino thiols,⁹⁹¹ and aziridines react with amines to give 1,2-diamines (Reaction 10-38). Triphenylphosphine similarly reacts with epoxides to give an intermediate that undergoes elimination to give alkenes (see the Wittig Reaction, 16-44).

OS X, 29. See OS VI, 652 for a related reaction.

10-36 Formation of Aziridines from Epoxides

Amino-de-alkoxylation

It is possible to prepare aziridines, which are synthetically important molecules, directly from the corresponding epoxide. Reaction of Ph₃P=NPh with an epoxide in the presence of ZnCl₂ gives the N-phenyl aziridine.⁹⁹²Guanidines have also been used to prepare aziridines from epoxides.⁹⁹³ Tosylamines react with epoxides to give the N-tosylaziridine.⁹⁹⁴

Various methods are available to convert an aminomethyl epoxide to a hydroxymethyl aziridine (125).⁹⁹⁵

10-37 Amination of Oxetanes

(4) OC-homoseco-Amino-de-alkoxylation

Oxetanes are significantly less reactive with nucleophiles due to diminished ring strain. Under certain conditions, however, amines can open oxetanes to give amino alcohols. tert-Butyl amine reacts with oxetanes in the presence of Yb(OTf)₃, for example, to give 3-hydroxy amines.⁹⁹⁶ Lithium tetrafluoroborate has also been used for this purpose.⁹⁹⁷

10-38 Reaction of Aziridines with Nitrogen

(3) NC-seco-Amino-de-aminoalkylation

Just as epoxides can be opened by amines to give hydroxy amines, aziridines can be opened to give diamines.⁹⁹⁸ With bicyclic aziridines, the major product is usually the trans diamine. N-Aryl or N-alkyl aziridines react with amines in the presence of T-Binolate,⁹⁹⁹ Sn(OTf)₂¹⁰⁰⁰ or B(C₆F₅)₃¹⁰⁰¹ to give the diamine. Activated aziridines undergo regioselective ring opening with organoalanes.¹⁰⁰² Amines react with N-tosylaziridines, in the presence of various catalysts or additives to give the corresponding diamine derivative.¹⁰⁰³ This reaction also takes place on activated silica.¹⁰⁰⁴ The reaction of LiNTf₂ and an amine, in the presence of an N-alkyl aziridine gives the diamine.¹⁰⁰⁵

Tosyl-aziridines react with azide ion to generate azido tosylamines,¹⁰⁰⁶ and a clay-catalyzed variation¹⁰⁰⁷ has been reported. Reduction of the azide (Reaction 19-50) gives the diamine. Silylazides (e.g., Me₃SiN₃) also react with aziridine derivatives to give the azido-amine.¹⁰⁰⁸ This latter reaction can be catalyzed by InCl₃.¹⁰⁰⁹

10-39 Amination of Alkanes

Amino-de-hydrogenation or Amination

Alkanes, arylalkanes, and cycloalkanes can be aminated, at tertiary positions only, by treatment with trichloroamine and aluminum chloride at 0–10 °C.¹⁰¹⁰ For example, p-MeC₆H₄CHMe₂ gives p-MeC₆H₄CMe₂NH₂, methylcyclopentane gives 1-amino-1-methylcyclopentane, and adamantane gives 1-aminoadamantane, all in good yields. A Ag catalyzed reaction has also been reported.¹⁰¹¹ There are not many other methods for the preparation of tert-alkyl amines. The mechanism has been rationalized as an S_N1 process with H⁻ as the leaving group:¹⁰¹⁰

Note that under photochemical conditions, ammonia opens cyclopropane derivatives to give the corresponding alkyl amine.¹⁰¹² See also Reaction, 12-12.

OS V, 35.

10-40 Formation of Isonitriles (Isocyanides)

Haloform-isocyanide transformation

There are several methods available for the preparation of isonitriles, otherwise known as isocyanides.¹⁰¹³ Reaction with chloroform under basic conditions is a common test for primary amines, both aliphatic and aromatic, since isonitriles (126) have very strong bad odors. The reaction probably proceeds by an S_N1cB mechanism with dichlorocarbene (127) as an intermediate.

Yields are generally not high,¹⁰¹⁴ but an improved procedure has been reported.¹⁰¹⁵ When secondary amines are involved, the adduct 128 cannot lose two molar equivalents of HCl. Instead it is hydrolyzed to an N,N-disubstituted formamide.¹⁰¹⁶

A completely different way of preparing isocyanides involves the reaction of epoxides or oxetanes with trimethylsilyl cyanide and zinc iodide to give the isocyanide 129.¹⁰¹⁷

The products can be hydrolyzed to protected hydroxy-amines (e.g., 130).

OS VI, 232.

B. Attack by NHCOR

10-41 N-Alkylation or N-Arylation of Amides and Imides

Acylamino-de-halogenation

Amides are very weak nucleophiles,¹⁰¹⁸ far too weak to attack alkyl halides, so they first must be converted to their conjugate bases, the anion. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides.¹⁰¹⁹ Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination and O-Alkylation is at times a side reaction.¹⁰²⁰ Both amides and sulfonamides have been alkylated under phase-transfer conditions.¹⁰²¹ Metal-catalyzed amidations are known, including an Ir(I) catalyzed allylic amidation.¹⁰²²

Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide.¹⁰²³ Other 2-pyrrolidinone derivatives can be alkylated using a similar procedure.¹⁰²⁴N-Cyclopropyl lactams are prepared using a Bi reagent in the presence of cupric acetate.¹⁰²⁵N-Aryl lactams can be prepared using Ph₃Bi and Cu(OAc)₂.¹⁰²⁶N-Arylation of sulfonamides has been reported using a Pd catalyst,¹⁰²⁷ and this method has been applied to an intramolecular arylation leading to bicyclic lactams.¹⁰²⁸

N-Alkenyl amides have been prepared from vinyl iodides and primary amides, using 10% CuI and two molar equivalents of cesium carbonate.¹⁰²⁹ A related Pd catalyzed vinylation of lactams was repeated using vinyl ethers as a substrate.¹⁰³⁰ Oxazolidin-2-ones (a cyclic carbamate) can be N-alkylated using an alkyl halide with KF/Al₂O₃.¹⁰³¹

The Gabriel synthesis¹⁰³² for converting halides to primary amines is based on this reaction. The halide is treated with potassium phthalimide and the resulting product hydrolyzed (Reaction 16-60)

It is obvious that the primary amines formed in this reaction will be uncontaminated by secondary or tertiary amines (unlike Reaction 10-31). The reaction is usually rather slow, but the rate can be conveniently increased by the use of a dipolar aprotic solvent (e.g., DMF)¹⁰³³ or with a crown ether.¹⁰³⁴ Hydrolysis of the phthalimide, whether acid or base catalyzed (acid catalysis is used far more frequently), is also usually very slow, and better procedures are generally used. A common one is the Ing–Manske procedure,¹⁰³⁵ in which the phthalimide is heated with hydrazine in an exchange reaction,¹⁰³⁶ but other methods have been introduced, using Na₂S in aq THF or acetone,¹⁰³⁷ and 40% aq methylamine.¹⁰³⁸ N-Aryl imides can be prepared from ArPb(OAc)₃ and NaH.¹⁰³⁹

An alternative to the Gabriel synthesis, in which alkyl halides can be converted to primary amines in good yields, involves treatment of the halide with the strong base guanidine followed by alkaline hydrolysis.¹⁰⁴⁰ There are several other alternative procedures.¹⁰⁴¹

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide (Ph₃P) and diethyl azodicarboxylate (EtO₂CN=NCO₂Et) at room temperature (the Mitsunobu Reaction, 10-17).¹⁰⁴² A related reaction treats an alcohol with ClCH=NMe₂⁺Cl⁻, followed by potassium phthalimide and treatment with hydrazine give the amine.¹⁰⁴³ Metal-catalyzed syntheses of amides via oxidative coupling of alcohols and amines are known. Variations include the use of a Ru complex,¹⁰⁴⁴ a RuCl₃ catalyzed reaction,¹⁰⁴⁵ an FeCl₃ catalyzed reaction,¹⁰⁴⁶ an Ir complex catalyzed reaction,¹⁰⁴⁷ and an InCl₃ catalyzed coupling of alcohols with ToSMIC (ToSMIC = toluene sulfonyl methyl cyanide).¹⁰⁴⁸

Amides can also be alkylated with diazo compounds, as in Reaction 10-34. Salts of sulfonamides (ArSO₂NH⁻) can be used to attack alkyl halides to prepare N-alkyl sulfonamides (ArSO₂NHR) that can be further alkylated to ArSO₂NRR′. Hydrolysis of the latter is a good method for the preparation of secondary amines. Secondary amines can also be made by crown-ether assisted alkylation of F₃CCONHR (R = alkyl or aryl) and hydrolysis of the resulting F₃CCONRR′.¹⁰⁴⁹

The reaction of a primary amide and benzaldehyde, in the presence of a silane and trifluoroacetic acid, leads to the corresponding N-benzylamide.¹⁰⁵⁰ This transformation is a reductive alkylation (Reaction 16-17). N-Alkynyl amides have been prepared by the copper-catalyzed reaction of 1-bromoalkynes and secondary amides.¹⁰⁵¹ 1-Haloalkynes are typically prepared by base-induced elimination of 1,1-dihaloalkenes¹⁰⁵² or by direct halogenation of an alkyne with sodium or potassium hypohalite, prepared by reaction of the appropriate base with the halogen.¹⁰⁵³

Internal N-alkylation has been used to prepare the highly strained compounds α-lactams.¹⁰⁵⁴

OS I, 119, 203, 271; II, 25, 83, 208; III, 151; IV, 810; V, 1064; VI, 951; VII, 501.

C. Other Nitrogen Nucleophiles

10-42 Formation of Nitro Compounds¹⁰⁵⁵

Nitro-de-halogenation

Sodium nitrite can be used to prepare nitro compounds from primary or secondary alkyl bromides or iodides, but the method is of limited scope. Silver nitrite gives nitro compounds only when RX is a primary bromide or iodide.¹⁰⁵⁶ Nitrite esters are an important side product in all these cases (Reaction 10-22) and become the major product (by an S_N1 mechanism) when secondary or tertiary halides are treated with silver nitrite. Alkyl nitro compounds can be prepared from the alkyl halide via the corresponding azide, by treatment with HOF in acetonitrile.¹⁰⁵⁷

Nitro compounds can be prepared from alcohols using NaNO₂/AcOH/HCl.¹⁰⁵⁸

OS I, 410; IV, 368, 454, 724.

10-43 Formation of Azides

Azido-de-halogenation

Alkyl azides can be prepared by treatment of the appropriate halide with azide ion.¹⁰⁵⁹ Phase-transfer catalysis,¹⁰⁶⁰ ultrasound,¹⁰⁶¹ and the use of reactive clays¹⁰⁶² are important variations. Substrates with leaving groups other than halogen have been used,¹⁰⁶³ including OMs (Ms = methanesulfonyl), OTs (Ts = tosyl),¹⁰⁶⁴ and OAc (Ac = acetyl).¹⁰⁶⁵ There are protocols for the conversion of alcohols to azides¹⁰⁶⁶ Boronic acids are precursors to azides.¹⁰⁶⁷ Aryl azides are prepared from aryl amines by reaction with t-BuONO and moist NaN₃ in t-BuOH.¹⁰⁶⁸

Ring-opening reactions of epoxides with nitrogen nucleophiles were discussed in Reaction 10-35. However, it is appropriate to discuss epoxide-opening reactions involving azides. Epoxides react with NaN₃ (10-35), under various conditions and media, including in ionic liquids.¹⁰⁶⁹ Other reagents include TMSN₃ (TMS = trimethylsilyl) and Ph₄SbOH¹⁰⁷⁰ or SmI₂¹⁰⁷¹ or (i-Bu)₂AlHN₃Li¹⁰⁷² to give β-azido alcohols; these are easily converted to aziridines (131).¹⁰⁷³

This conversion has been used as a key step in the preparation of optically active aziridines from optically active 1,2-diols (prepared by Reaction 15-48).¹⁰⁷⁴ Even hydrogen can be the leaving group. Benzylic hydrogen atoms have been replaced and N₃ and treatment with HN₃ in CHCl₃ in the presence of DDQ (see Reaction 19-01).¹⁰⁷⁵

Tertiary alkyl azides can be prepared by stirring tertiary alkyl chlorides with NaN₃ and ZnCl₂ in CS₂¹⁰⁷⁶ or by treating tertiary alcohols with NaN₃ and CF₃COOH¹⁰⁷⁷ or with HN₃ and TiCl₄¹⁰⁷⁸ or BF₃.¹⁰⁷⁹ Aryl azides can be prepared from aniline and aniline derivatives.¹⁰⁸⁰

Acyl azides, which can be used in the Curtius Reaction (18-14), are generally prepared from acyl halides, anhydrides,¹⁰⁸¹ esters,¹⁰⁸² or other acyl derivatives.¹⁰⁸³ Acyl benzotriazoles are also precursors to acyl azides.¹⁰⁸⁴ Acyl azides also can be prepared from aldehydes using SiCl₄/NaN₃–MnO₂,¹⁰⁸⁵ TMSN₃/CrO₃¹⁰⁸⁶ or the Dess–Martin periodinane (see Reaction 19-03, category 5) with NaN₃.¹⁰⁸⁷

OS III, 846; IV, 715; V, 273, 586; VI, 95, 207, 210, 910; VII, 433; VIII, 116; IX, 220; X, 378. See also, OS VII, 206.

10-44 Formation of Isocyanates and Isothiocyanates

Isocyanato-de-halogenation

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (10-30), but the cyanate ion practically always gives exclusive N-alkylation.⁵⁰⁹ Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide (NaNCNNO₂) and m-chloroperoxybenzoic acid, followed by heating of the initially produced RN(NO₂)CN.¹⁰⁸⁸ When alkyl halides are treated with NCO⁻ in the presence of ethanol, carbamates can be prepared directly (see Reaction 16-8).¹⁰⁸⁹ Acyl halides give the corresponding acyl isocyanates and isothiocyanates.¹⁰⁹⁰ For the formation of isocyanides (isonitriles), see Reaction 10-75. Isonitriles, in the presence of sulfur and a Rh catalyst, are converted to isothiocyanate,¹⁰⁹¹ as are amines.¹⁰⁹²

OS III, 735.

10-45 Formation of Azoxy Compounds

Alkyl- NNO-azoxy-de-halogenation

The reaction between alkyl halides and alkanediazotates (132) gives azoxyalkanes.¹⁰⁹³ The R and R′ groups may be the same or different, but neither may be aryl or tertiary alkyl. The reaction is regioselective; only the isomer shown is obtained.

10.H.v. Halogen Nucleophiles¹⁰⁹⁴

10-46 Halide Exchange

Halo-de-halogenation

Halide exchange, sometimes call the Finkelstein reaction, is an equilibrium process, but it is often possible to shift the equilibrium.¹⁰⁹⁵ The reaction is most often applied to the preparation of iodides and fluorides. Iodides can be prepared from chlorides or bromides by taking advantage of the fact that sodium iodide, but not the bromide or chloride, is soluble in acetone. When an alkyl chloride or bromide is treated with a solution of sodium iodide in acetone, the equilibrium is shifted by the precipitation of sodium chloride or bromide. Since the mechanism is S_N2, the reaction is much more successful for primary halides than for secondary or tertiary halides; sodium iodide in acetone can be used as a test for primary bromides or chlorides. Tertiary chlorides can be converted to iodides by treatment with excess NaI in CS₂, and ZnCl₂ as catalyst.¹⁰⁹⁶ Vinylic bromides give vinylic iodides with retention of configuration when treated with KI and a nickel bromide-zinc catalyst,¹⁰⁹⁷ or with KI and CuI in hot HMPA.¹⁰⁹⁸

Fluorides¹⁰⁹⁹ are prepared by treatment of other alkyl halides with any of a number of fluorinating agents,¹¹⁰⁰ among them anhydrous HF (which is useful only for reactive substrates, e.g., benzylic or allylic), AgF, KF,¹¹⁰¹ HgF₂, Et₃N•2HF,¹¹⁰² 4-Me–C₆H₄IF₂,¹¹⁰³ and Me₃SiF₂Ph⁺.¹¹⁰⁴ The Pd catalyzed conversion of chlorides to fluorides has also been reported.¹¹⁰⁵ The equilibria in these cases are shifted because the alkyl fluoride once formed has little tendency to react, owing to the extremely poor leaving-group ability of fluorine. Phase-transfer catalysis of the exchange reaction is a particularly effective way of preparing both fluorides and iodides.¹¹⁰⁶

Primary alkyl chlorides can be converted to bromides with ethyl bromide, N-methyl-2-pyrrolidinone and a catalytic amount of NaBr,¹¹⁰⁷ with LiBr under phase-transfer conditions,¹¹⁰⁸ and with Bu₄N⁺ Br⁻.¹¹⁰⁹ Primary bromides were converted to chlorides with TMSCl/imidazole in hot DMF.¹¹¹⁰ For secondary and tertiary alkyl chlorides, treatment with excess gaseous HBr and an anhydrous FeBr₃ catalyst in CH₂Cl₂ has given high yields¹¹¹¹ (this procedure is also successful for chloride-to-iodide conversions). Alkyl chlorides or bromides can be prepared from iodides by treatment with HCl or HBr in the presence of HNO₃, making use of the fact that the leaving I⁻ is oxidized to I₂ by the HNO₃.¹¹¹² Primary iodides give the chlorides when treated with PCl₅ in POCl_3.,¹¹¹³ Primary alkyl halides are converted to the corresponding fluoride with tetrabutylammonium fluoride in tert-butanol.¹¹¹⁴ Alkyl fluorides and chlorides are converted to the bromides and iodides (and alkyl fluorides to the chlorides) by heating with the corresponding HX in excess amounts.¹¹¹⁵

OS II, 476; IV, 84, 525; VIII, 486; IX, 502.

10-47 Formation of Alkyl Halides from Esters of Sulfuric and Sulfonic Acids

Halo-de-sulfonyloxy-substitution, and so on

Alkyl sulfates, tosylates, and other esters of sulfuric and sulfonic acids can be converted to alkyl halides with any of the four halide ions.¹¹¹⁶ Neopentyl tosylate, for example, reacts with Cl⁻, Br⁻, or I⁻ without rearrangement in HMPA.¹¹¹⁷ Similarly, allylic tosylates can be converted to chlorides without allylic rearrangement by reaction with LiCl in the same solvent.¹¹¹⁸ Inorganic esters are intermediates in the conversion of alcohols to alkyl halides with SOCl₂, PCl₅, PCl₃, and so on (Reaction 10-48), but those esters are seldom isolated.

OS I, 25; II, 111, 404; IV, 597, 753; V, 545.

10-48 Formation of Alkyl Halides from Alcohols

Halo-de-hydroxylation

Alcohols can be converted to alkyl halides with several reagents,¹¹¹⁹ the most common of which are halogen acids (HX) and inorganic acid halides, (e.g., SOCl₂,¹¹²⁰ PCl₅, PCl₃, and POCl₃).¹¹²¹ When the reagent is HX, the mechanism is S_N1cA or S_N2cA; that is, the leaving group is not , but OH₂ (Sec. 10.G.iii). The leaving group is not with the other reagents either, since in these cases the alcohol is first converted to an inorganic ester (e.g., ROSOCl) with SOCl₂ (Reaction 10-22). The leaving group is therefore or a similar group (Reaction 10-47). These may react by the S_N1 or S_N2 mechanism and, in the case of ROSOCl, by the S_Ni mechanism¹¹²² (Sec. 10.D).

The reagent HBr is usually used for alkyl bromides¹¹²³ and HI for alkyl iodides. These reagents are often generated in situ from the halide ion and an acid (e.g., phosphoric or sulfuric). The use of HI sometimes results in reduction of the alkyl iodide to the alkane (Reaction 19-53) and, if the substrate is unsaturated, can also reduce the double bond.¹¹²⁴ The reaction can be used to prepare primary, secondary, or tertiary halides, but alcohols of the isobutyl or neopentyl type often give large amounts of rearrangement products.¹¹²⁵ Tertiary chlorides are easily made with concentrated HCl, but primary and secondary alcohols react with HCl so slowly that a catalyst, usually zinc chloride, is required.¹¹²⁶ Primary alcohols give good yields of chlorides upon treatment with HCl in HMPA.¹¹²⁷

The inorganic acid chlorides (SOCl₂,¹¹²⁸ PCl₃, etc.) give primary, secondary, or tertiary alkyl chlorides with much less rearrangement than is observed with HCl. Inorganic bromides and iodides, especially PBr₃, have also been used, but they are more expensive and used less often than HBr or HI, although some of them may also be generated in situ (e.g., PBr₃ from phosphorous and bromine). Secondary alcohols always give some rearranged bromides if another secondary position is available, even with PBr₃, PBr₅, or SOBr₂; thus 3-pentanol gives both 2- and 3-bromopentane. Such rearrangement can be avoided by converting the alcohol to a sulfonate and then using Reaction 10-47,¹¹²⁹ or by the use of phase-transfer catalysis.¹¹³⁰ Tertiary alcohols can be converted to the bromide with BBr₃ at 0 °C.¹¹³¹ Iodides have been prepared by simply heating the alcohol with iodine.¹¹³² Trichloroisocyanuric acid (1,3,5-trichlorohexahydrotriazin-2,4,6-trione) and triphenylphosphine converts primary alcohols to the corresponding chloride.¹¹³³ Pivaloyl chloride–DMF has been used to convert alcohols to chlorides.¹¹³⁴ Sodium iodide and Amberlyst-15¹¹³⁵ or tosic acid and KI with microwave irradiation¹¹³⁶ converts primary alcohols to the iodide.

The preparation of alkyl fluorides can be problematic, and specialized reagents are usually required. Hydrogen fluoride does not generally convert alcohols to alkyl fluorides.¹¹³⁷ The most important reagent for this purpose is the commercially available diethylaminosulfur trifluoride (Et₂NSF₃, DAST),¹¹³⁸ which converts primary, secondary, tertiary, allylic, and benzylic alcohols to fluorides in high yields under mild conditions.¹¹³⁹ Fluorides have also been prepared from alcohols by treatment with nonaflyl fluoride,¹¹⁴⁰ tetrabutylammonium difluoride,¹¹⁴¹ CsI/BF₃,¹¹⁴² TMSI/ZnCl₂,¹¹⁴³ and indirectly, by conversion to a sulfate or tosylate, and so on (Reaction 10-47). A mixture of IF₅, NEt₃, and excess KF¹¹⁴⁴ or (Cl₃CO)₂C=O [bis(trichloromethyl)carbonate] and KF (which gives COF₂in situ) with 18-crown-6¹¹⁴⁵ also converts primary alcohols to primary fluorides.

Primary, secondary, and tertiary alcohols can be converted to any of the four halides by treatment with the appropriate NaX, KX, or NH₄X in polyhydrogen fluoride–pyridine solution.¹¹⁴⁶ This method is even successful for neopentyl halides. Ionic liquids can be used for halogenation, and bmim-Cl (1-n-butyl-3-methylimidazolium chloride) generates the chloride directly from the alcohol without any additional reagent.¹¹⁴⁷ Triphenylphosphine and iodine will convert alcohols to iodides in ionic liquids, under solvent-free conditions.¹¹⁴⁸tert-Butyl halides halogenate alcohols in the ionic liquid [pmim]Br with sonication.¹¹⁴⁹

Other reagents¹¹⁵⁰ have also been used, including ZrCl₄/NaI,¹¹⁵¹ Me₃SiCl and BiCl₃,¹¹⁵² or Me₃SiCl and InCl₃¹¹⁵³ or GaCl₃–tartrate,¹¹⁵⁴ or simply Me₃SiCl in DMSO.¹¹⁵⁵ 1,2-Dipyridiniumditribromide ethane is an efficient brominating agent, and simply grinding the reagent and an alcohol in a porcelain mortar at room temperature with no solvent gives the product.¹¹⁵⁶ Other specialized reagents include (RO)₃PRX¹¹⁵⁷ and R₃PX₂¹¹⁵⁸, which give good yields for primary (including neopentyl), secondary, and tertiary halides without rearrangements,¹¹⁵⁹ Similarly, a mixture of PPh₃ and CCl₄¹¹⁶⁰ (or CBr₄¹¹⁶¹) give good results, and PPh₃/Cl₃CCONH₂ is an efficient chlorinating reagent.¹¹⁶² The compound PPh₃–CCl₃CN converts neopentyl alcohol to neopentyl chloride, in 95% yield.¹¹⁶³

The PPh₃–CCl₄ or CBr₄ method converts allylic alcohols¹¹⁶⁴ to the corresponding halides without allylic rearrangements,¹¹⁶⁵ and also cyclopropylcarbinyl alcohols to the halides without ring opening.¹¹⁶⁶ A mixture of triphenylphosphine and iodine converts alcohols to iodides under solvent-free conditions, using microwave irradiation.¹¹⁶⁷ Hexabromoacetone–ethyltribromoacetate is an efficient brominating reagent.¹¹⁶⁸ N-Bromosaccharin and N-iodosaccharin in the presence of PPh₃ gives the corresponding bromide or iodide.¹¹⁶⁹

Allylic and benzylic alcohols can also be converted to bromides or iodides with NaX–BF₃ etherate,¹¹⁷⁰ and to iodides with AlI₃.¹¹⁷¹ A mixture of methanesulfonic acid and NaI also converts benzylic alcohols to benzylic iodides.¹¹⁷² Allylic alcohols are converted to allylic halides in a procedure that uses acetyl halides, but the reaction proceeds with allylic rearrangement.¹¹⁷³ A simple method that is specific for benzylic and allylic alcohols (and does not give allylic rearrangement) involves reaction with NCS or NBS and methyl sulfide.¹¹⁷⁴ A mixture of NBS, Cu(OTf)₂, and diisopropylcarbodiimide converted primary alcohols to the corresponding bromide.¹¹⁷⁵ The use of NCS gave the chloride and N-iodosuccinimide (NIS) gave the iodide under identical conditions. Thiols are converted to alkyl bromides by a similar procedure using PPh₃ and NBS.¹¹⁷⁶

Trialkylsilyl ethers (e.g., ROSiMe₃) are converted to the corresponding iodide with SiO₂–Cl/NaI.¹¹⁷⁷ Hydroxy ketones are converted to the iodide with iodine and iodic acid.¹¹⁷⁸ Propargyilc fluorides can be prepared from allenylsilanes by treatment with Selectfluor.¹¹⁷⁹

OS I, 25, 36, 131, 142, 144, 292, 294, 533; II, 91, 136, 159, 246, 308, 322, 358, 399, 476; III, 11, 227, 370, 446, 698, 793, 841; IV, 106, 169, 323, 333, 576, 681; V, 1, 249, 608; VI, 75, 628, 634, 638, 781, 830, 835; VII, 210, 319, 356; VIII, 451. Also see, OS III, 818; IV, 278, 383, 597.

10-49 Formation of Alkyl Halides from Ethers

Halo-de-alkoxylation

Ethers can be cleaved by heating with concentrated HI or HBr.¹¹⁸⁰ Hydrogen chloride is seldom successful,¹¹⁸¹ and HBr reacts more slowly than HI, but is often a superior reagent, since it causes fewer side reactions. Phase-transfer catalysis has also been used,¹¹⁸² and 47% HBr in ionic liquids has proven effective.¹¹⁸³ Dialkyl ethers and alkyl aryl ethers can be cleaved. In the latter case, the alkyl–oxygen bond is the one broken. As in Reaction 10-48, the actual leaving group is not OR′⁻, but ⁻OHR'. Although alkyl aryl ethers always cleave so as to give an alkyl halide and a phenol, there is no general rule for dialkyl ethers. Often cleavage occurs from both sides, and a mixture of two alcohols and two alkyl halides is obtained. However, methyl ethers are usually cleaved so that methyl iodide or bromide is a product. An excess of HI or HBr converts the alcohol product into alkyl halide, so that dialkyl ethers (but not alkyl aryl ethers) are converted to 2 equiv of alkyl halide. This procedure is often carried out so that a mixture of only two products is obtained instead of four.

O-Benzyl ethers are readily cleaved to the alcohol and the hydrocarbon via hydrogenolysis, and the most common methods are hydrogenation¹¹⁸⁴ or dissolving metal conditions (Na or K in ammonia).¹¹⁸⁵ Heating in anisole with 3% Sc(NTf₂)₃¹¹⁸⁶ or with In metal in aq ethanol¹¹⁸⁷ also cleaves benzyl ethers. Isoprenyl alkyl ethers are cleaved using iodine in dichloromethane,¹¹⁸⁸ and allyl alkyl ethers are cleaved with Lewis acids under various conditions.¹¹⁸⁹The OCH₂CH=CHPh unit of mixed allyl ethers (O–CH₂CH=CH₂ and OCH₂CH=CHPh) can be cleaved selectively under electrolytic conditions.¹¹⁹⁰

Cyclic ethers (usually THF derivatives) can be similarly cleaved (see Reaction 10-50 for epoxides). Treatment of 2-methyltetrahydrofuran with acetyl chloride and ZnCl₂ gave primarily O-acetyl-4-chloro-1-pentanol.¹¹⁹¹ A mixture of Et₂NSiMe₃/2 MeI cleaved THF to give the O-trimethylsilyl ether of 4-iodo-1-butanol.¹¹⁹² Ethers have also been cleaved with Lewis acids [e.g., BF₃, Ce(OTf)₄,¹¹⁹³ SiCl₄/LiI/BF₃,¹¹⁹⁴ BBr₃,¹¹⁹⁵ or AlCl₃].¹¹⁹⁶ In such cases, the departure of the OR is assisted by complex formation with the Lewis acid (see 133). The reagent NaI–BF₃ etherate selectively cleaves ethers in the order benzylic ethers > alkyl methyl ethers > aryl methyl ethers.¹¹⁹⁷

Dialkyl and alkyl aryl ethers are cleaved with Me₃SiI¹¹⁹⁸: ROR′ + Me₃SiI → RI + Me₃SiOR.¹¹⁹⁹ A more convenient and less expensive alternative, which gives the same products, is a mixture of chlorotrimethylsilane and NaI.¹²⁰⁰Triphenyldibromophosphorane (Ph₃PBr₂) cleaves dialkyl ethers to give 2 molar equivalents of alkyl bromide.¹²⁰¹ Alkyl aryl ethers can also be cleaved with LiI to give alkyl iodides and salts of phenols¹²⁰² in a reaction similar to Reaction 10-51. Allyl aryl ethers¹²⁰³ are efficiently cleaved with NaI/Me₃SiCl,¹²⁰⁴ or NbCl₅.¹²⁰⁵ Aryl benzyl ethers are cleaved with BCl₃ using pentamethylbenzene as a non-Lewis basic cation scavenger.¹²⁰⁶ Cleavage in ionic liquids is also known.¹²⁰⁷

A closely related reaction is cleavage of oxonium salts.

For these substrates, HX is not required, and X can be any of the four halide ions.

tert-Butyldimethylsilyl ethers (ROSiMe₂CMe₃) can be converted to bromides (RBr) by treatment with Ph₃PBr₂,¹²⁰⁸ Ph₃P–CBr₄,¹²⁰⁹ BBr₃,¹²¹⁰ and CuBr₂.¹²¹¹ Alcohols are often protected by conversion to this kind of silyl ether.¹²¹²

OS I, 150; II, 571; III, 187, 432, 586, 692, 753, 774, 813; IV, 266, 321; V, 412; VI, 353. See also, OS VIII, 161, 556.

10-50 Formation of Halohydrins from Epoxides

(3)OC-seco -Halo-de-alkoxylation

This is a special case of Reaction 10-49 and is frequently used for the preparation of halohydrins.¹²¹³ In contrast to the situation with open-chain ethers and with larger rings, many epoxides react with all four hydrohalic acids, although with HF¹²¹⁴ the reaction is unsuccessful with simple aliphatic and cycloalkyl epoxides.¹²¹⁵ Hydrogen fluoride does react with more rigid epoxides, such as those in steroid systems. The reaction can be applied to simple epoxides¹²¹⁶ if polyhydrogen fluoride–pyridine is the reagent. The reagent NEt₃•3HF converts epoxides to fluorohydrins with microwave irradiation.¹²¹⁷ Organocatalysts have been used to convert epoxides to fluorohydrins using an acetyl fluoride/fluorous alcohol combination.¹²¹⁸ Chloro-, bromo-, and iodohydrins can also be prepared¹²¹⁹ by treating epoxides with Ph₃P and X₂,¹²²⁰ with 3/NaBr/H₂O,¹²²¹ LiBr on Amberlyst-15 resin,¹²²² ceric ammonium nitrate/KBr,¹²²³ I₂ with a SmI₂ catalyst,¹²²⁴ and LiI on silica gel.¹²²⁵ Epoxides can be converted directly to 1,2-dichloro compounds by treatment with SOCl₂ and pyridine,¹²²⁶ or with Ph₃P and CCl₄.¹²²⁷ These are two-step reactions: a halohydrin is formed first and is then converted by the reagents to the dihalide (Reaction 10-48). As expected, inversion is found at both carbons. Meso epoxides were cleaved enantioselectively with the chiral B-halodiisopinocampheylboranes (see Reaction 15-16), where the halogen was Cl, Br, or I.¹²²⁸ Diatomic iodine gives an iodohydrin with a 2,6-bis[2-(o-aminophenoxy)methyl]-4-bromo-1-methoxybenzene catalyst.¹²²⁹ Epoxides are converted to the corresponding chlorohydrin upon treatment with the ionic liquid [AcMIm]Cl.¹²³⁰

Bicyclic epoxides are usually opened to the trans-halohydrin. Unsymmetrical epoxides are usually opened to give mixtures of regioisomers. In a typical reaction, the halogen is delivered to the less sterically hindered carbon of the epoxide. In the absence of this structural feature, and in the absence of a directing group, relatively equal mixtures of regioisomeric halohydrins are expected. The phenyl is such a group, and in 1-phenyl-2-alkyl epoxides reaction with POCl₃/DMAP (DMAP = 4-dimethylaminopyridine) leads to the chlorohydrin with the chlorine on the carbon bearing the phenyl.¹²³¹ When done in an ionic liquid with Me₃SiCl, styrene epoxide gives 2-chloro-2-phenylethanol.¹²³² The reaction of thionyl chloride and poly(vinylpyrrolidinone) converts epoxides to the corresponding 2-chloro-1-carbinol.¹²³³ Bromine with a phenylhydrazine catalyst, however, converts epoxides to the 1-bromo-2-carbinol.¹²³⁴ An alkenyl group also leads to a halohydrin with the halogen on the carbon bearing the C=C unit.¹²³⁵ Epoxy carboxylic acids are another example. When NaI reacts at pH 4, the major regioisomer is the 2-iodo-3-hydroxy compound, but when InCl₃ is added, the major product is the 3-iodo-2-hydroxy carboxylic acid.¹²³⁶

Acyl chlorides react with ethylene oxide in the presence of NaI to give 2-iodoethyl esters.¹²³⁷

Acyl chlorides react with epoxides in the presence of a Eu(dpm)₃ catalyst¹²³⁸ [dpm = 1,1-bis(diphenylphosphino)methane] or a YCp₂Cl catalyst¹²³⁹ to give chloro esters.

A related reaction with episulfides leads to 2-chlorothio-esters.¹²⁴⁰ Aziridines have been opened with PPh₃ and halogenating agents,¹²⁴¹ and also by MgBr₂ to give 2-haloamides in a related reaction¹²⁴²N-Tosyl aziridines react with KF•2 H₂O to give the 2-fluoro tosylamine product.¹²⁴³ Aziridinium salts are opened by bromide ion.¹²⁴⁴

OS I, 117; VI, 424; IX, 220.

10-51 Cleavage of Carboxylic Esters with Lithium Iodide

Iodo-de-acyloxy-substitution

Carboxylic esters, where R is methyl or ethyl, can be cleaved by heating with lithium iodide in refluxing pyridine or a higher-boiling amine.¹²⁴⁵ The reaction is useful where a molecule is sensitive to acid and base (so that Reaction 16-59 cannot be used) or where it is desired to cleave selectively only one ester group in a molecule containing two or more. For example, refluxing O-acetyloleanolic acid methyl ester with LiI in s-collidine

cleaved only the 17-carbomethoxy group, not the 3-acetyl group.¹²⁴⁶ Esters (RCO₂R′) and lactones can also be cleaved with a mixture of Me₃SiCl and NaI to give R′I and RCO₂H.¹²⁴⁷ The reaction of acetyl chloride and an allylic acetate leads to the allylic chloride.¹²⁴⁸

10-52 Conversion of Diazo Ketones to α-halo Ketones

Hydro, halo-de-diazo bisubstitution

When diazo ketones are treated with HBr or HCl, they give the respective α-halo ketones. Hydrogeniodide does not give the reaction, since it reduces the product to a methyl ketone (Reaction 19-67). α-Fluoro ketones can be prepared by addition of the diazo ketone to polyhydrogen fluoride–pyridine.¹²⁴⁹ This method is also successful for diazoalkanes.

Diazotization of α-amino acids in the above solvent at room temperature gives α-fluoro carboxylic acids.¹²⁵⁰ If this reaction is run in the presence of excess KCl or KBr, the corresponding α-chloro or α-bromo acid is obtained instead.¹²⁵¹

OS III, 119.

10-53 Conversion of Amines to Halides

Halo-de-amination

Primary alkyl amines (RNH₂) can be converted¹²⁵² to alkyl halides by (1) conversion to RNTs₂ (Sec. 10.G.ii) and treatment of this with I⁻ or Br⁻ in DMF,⁴¹⁵ or to N(Ts)–NH₂ derivatives followed by treatment with NBS under photolysis conditions,¹²⁵³ (2) diazotization with tert-butylnitrite and a metal halide (e.g., TiCl₄ in DMF),¹²⁵⁴ or (3) the Katritzky pyrylium–pyridinium method (Sec. 10.G.ii).¹²⁵⁵ Alkyl groups can be cleaved from secondary and tertiary aromatic amines by concentrated HBr in a reaction similar to Reaction 10-49, for example,¹²⁵⁶

Tertiary aliphatic amines are also cleaved by HI, but useful products are seldom obtained. Tertiary amines can be cleaved by reaction with phenyl chloroformate¹²⁵⁷: R₃N + ClCOOPh → RCl + R₂NCOOPh. α-Chloroethyl chloroformate behaves similarly.¹²⁵⁸ Alkyl halides may be formed when quaternary ammonium salts are heated: R₄N⁺ X⁻ → R₃N + RX.¹²⁵⁹

OS VIII, 119. See also, OS I, 428.

10-54 Conversion of Tertiary Amines to Cyanamides: The von Braun Reaction

Bromo-de-dialkylamino substitution

The von Braun reaction involves the cleavage of tertiary amines by cyanogen bromide to give an alkyl bromide and a disubstituted cyanamide, and can be applied to many tertiary amines.¹²⁶⁰ Usually, the R group that cleaves is the one that gives the most reactive halide (e.g., benzyl or allyl). For simple alkyl groups, the smallest are the most readily cleaved. One or two of the groups on the amine may be aryl, but they do not cleave. Cyclic amines have been frequently cleaved by this reaction. Secondary amines also give the reaction, but the results are usually poor.¹²⁶¹

The mechanism consists of two successive nucleophilic substitutions, with the tertiary amine as the first nucleophile and the liberated bromide ion as the second:

The intermediate N-cyanoammonium bromide has been trapped, and its structure confirmed by chemical, analytical, and spectral data.¹²⁶² The BrCN in this reaction has been called a counterattack reagent; that is, a reagent that accomplishes, in one flask, two transformations designed to give the product.¹²⁶³

OS III, 608.

10.H.vi. Carbon Nucleophiles

In any heterolytic reaction in which a new carbon–carbon bond is formed,¹²⁶⁴ one carbon atom attacks as a nucleophile and the other as an electrophile. The classification of a given reaction as nucleophilic or electrophilic is a matter of convention and is usually based on analogy. Although not discussed in this chapter, Reactions 11-8–11-25 and 12-16–12-21 are nucleophilic substitutions with respect to one reactant, but following convention, we classify them with respect to the other. Similarly, all the reactions in this section would be called electrophilic substitution (aromatic or aliphatic) if we were to consider the reagent as the substrate.

In Reactions 10-56–10-65, the nucleophile is a “carbanion” part of an organometallic compound, often a Grignard reagent. There is much that is still not known about the mechanisms of these reactions and many of them are not nucleophilic substitutions at all. In those reactions that are nucleophilic substitutions, the attacking carbon brings a pair of electrons with it to the new C–C bond, whether or not free carbanions are actually involved. The connection of two alkyl or aryl groups is called coupling. Reactions 10-56–10-65 include both symmetrical and unsymmetrical coupling reactions. The latter are also called cross-coupling reactions. Other coupling reactions are considered in later chapters.

10-55 Coupling with Silanes

De-silylalkyl-coupling

Organosilanes (RSiMe₃ or RSiMe₂F, where R can be vinylic, allylic, or alkynyl) couple with vinylic, allylic, and aryl bromides and iodides (R′X), in the presence of certain catalysts, to give RR′ in good yields.¹²⁶⁵ Allylsilanes react with allylic acetates in the presence of iodine.¹²⁶⁶ The transition metal catalyzed coupling of silanes, particularly allyl silanes, is a mild method for incorporating alkyl fragments into a molecule.¹²⁶⁷ Here PhSiMe₂Cl couples to give biphenyl in the presence of CuI and Bu₄NF,¹²⁶⁸ and vinyl silanes react with allylic carbonates and a palladium catalyst to give dienes.¹²⁶⁹ Allylsilanes have been coupled to substrates containing a benzotriazole unit, in the presence of BF₃•etherate.¹²⁷⁰ One variation used a silylmethyltin derivative in a palladium-catalyzed coupling with aryl iodides.¹²⁷¹ Homoallyl silanes coupled to Ph₃BiF₂ in the presence of BF₃•OEt₂ to give the phenyl coupling product.¹²⁷²

α-Silyloxy methoxy derivatives [RCH(OMe)OSiR¹₃], react with allyltrimethylsilane (Me₃SiCH₂CH=CH₂) in the presence of TiX₄ derivatives to give displacement of the OMe group and RCH(OSiR¹₃)CH₂CH=CH₂).¹²⁷³ A tertiary silyloxy group was displaced by allyl in the presence of ZnCl₂.¹²⁷⁴ Allylic acetates react with Me₃SiSiMe₃ and LiCl with a Pd catalyst to give the allyl silane.¹²⁷⁵ The RSiF₃ reagents can also be used in coupling reaction with aryl halides.¹²⁷⁶ Allyl silanes react with epoxides, in the presence of BF₃•OEt₂ to give 2-allyl alcohols.¹²⁷⁷ The reaction of α-bromo lactones and CH₂=CHCH₂Si(SiMe₃)₃ and azoisobutyronitrile (AIBN) leads to the α-allyl lactone.¹²⁷⁸

Silyl epoxides have been prepared from epoxides via reaction with sec-butyllithium and chlorotrimethylsilane.¹²⁷⁹ α-Silyl-N-Boc-amines were prepared in a similar manner from the N-Boc-amine.¹²⁸⁰ Benzyl silanes coupled with allyl silanes to give ArCH₂–R derivatives in the presence of VO(OEt)Cl₂¹²⁸¹ and allyltin compounds couple with allyl silanes in the presence of SnCl₄.¹²⁸² Allyl silanes couple to the α-carbon of amines under photolysis conditions.¹²⁸³

Arylsilanes were prepared by reaction of an aryllithium intermediate with TfOSi(OEt)₃.¹²⁸⁴ In the presence of BF₃•etherate, allyl silane and α-methoxy N-carbobenzoxy (N-Cbz) amines were coupled.¹²⁸⁵ Aryl cyanides have been converted to arylsilanes using a Rh catalyst and Me₃SiSiMe₃.¹²⁸⁶

The reaction of a vinyl iodide with (EtO)₃SiH and a Pd catalyst generated a good yield of the corresponding vinylsilane.¹²⁸⁷

OSCV 10, 531.

10-56 Coupling of Alkyl Halides: The Wurtz Reaction

De-halogen-coupling

The coupling of alkyl halides by treatment with sodium to give a symmetrical product is called the Wurtz reaction. Side reactions (elimination and rearrangement) are so common that the reaction is seldom used. Mixed Wurtz reactions of two alkyl halides are even less feasible because of the number of products obtained. A somewhat more useful reaction (but still not very good) takes place when a mixture of an alkyl and an aryl halide is treated with sodium to give an alkylated aromatic compound (the Wurtz–Fittig reaction).¹²⁸⁸ However, the coupling of two aryl halides with sodium is impractical (but see Reaction 13-11). Other metals have also been used to effect Wurtz reactions,¹²⁸⁹ notably Ag, Zn,¹²⁹⁰ Fe,¹²⁹¹ activated Cu,¹²⁹² In,¹²⁹³ La,¹²⁹⁴ and Mn compounds.¹²⁹⁵ Lithium, under the influence of ultrasound, has been used to couple alkyl, aryl, and benzylic halides.¹²⁹⁶

In a related reaction, Grignard reagents (Reaction 12-38) have been coupled in the presence of trifluorosulfonic anhydride.¹²⁹⁷ Tosylates and other sulfonates and sulfates couple with Grignard reagents,¹²⁹⁸ most often those prepared from aryl or benzylic halides.¹²⁹⁹ Alkyl sulfates and sulfonates generally make better substrates in reactions with Grignard reagents than the corresponding halides (Reaction 10-57). The method is useful for primary and secondary R.

One type of Wurtz reaction that is quite useful is the closing of small rings, especially three-membered rings.¹³⁰⁰ For example, 1,3-dibromopropane can be converted to cyclopropane by Zn and NaI.¹³⁰¹ Two highly strained molecules prepared this way are bicyclobutane¹³⁰² and tetracyclo[3.3.1.1³,⁷.0¹,³]decane.¹³⁰³ Three- and four-membered rings can also be closed in this manner with certain other reagents,¹³⁰⁴ including benzoyl peroxide,¹³⁰⁵t-BuLi,¹³⁰⁶ and lithium amalgam,¹³⁰⁷ as well as electrochemically.¹³⁰⁸ The Pd or Ni catalyzed cross-coupling reaction of a Grignard reagent and an alkyl halide, is often called Kumada coupling.¹³⁰⁹

Vinylic halides can be coupled to give 1,3-butadienes (134) by treatment with activated Cu powder in a reaction analogous to the Ullmann Reaction (13-11).¹³¹⁰ This reaction is stereospecific, with retention of configuration at both carbons. Vinylic halides can also be coupled¹³¹¹ with Zn–NiCl₂,¹³¹² and with n-BuLi in ether in the presence of MnCl₂.¹³¹³ The coupling reaction with vinyltin reagents and vinyl halides occurs with a Pd catalyst.¹³¹⁴

It seems likely that the mechanism of the Wurtz reaction consists of two basic steps. The first is halogen–metal exchange to give an organometallic compound (RX + M → RM), which in many cases can be isolated (Reaction 12-38). Following this, the organometallic compound reacts with a second molecule of alkyl halide (RX + RM → RR). This reaction and its mechanism are considered in Section (Reaction 10-57).

OS III, 157; V, 328, 1058; VI, 133, 153.

A variation of the Wurtz coupling uses other metals to mediate or facilitate the coupling. In certain cases, such variations can be synthetically useful. Because of the presence of the 1,5-diene moiety in many naturally occurring compounds, methods that couple¹³¹⁵ allylic groups¹³¹⁶ are quite important. In one of these methods, allylic halides, tosylates, and acetates can be symmetrically coupled by treatment with nickel carbonyl¹³¹⁷ to give 1,5-dienes.¹³¹⁸The order of halide reactivity is I > Br > Cl. With unsymmetrical allylic substrates, coupling nearly always takes place at the less-substituted end.

The reaction can be performed intramolecularly; large (11–20-membered) rings can be made in good yields (60–80%) by the use of high dilution.¹³¹⁹ The mechanism of coupling likely involves reaction of the allylic compound with Ni(CO)₄ to give one or more π-allyl complexes, one of which may be the η³-complex 135. Loss of CO to give a π-allylnickel bromide (136) and ligand transfer leads to coupling and the final product. In some cases, the η³-complexes (136) can be isolated from the solution and crystallized as stable solids.

Unsymmetrical coupling can be achieved by treating an alkyl halide directly with 136, in a polar aprotic solvent,¹³²⁰ and coupling occurs at the less substituted end. There is evidence that free radicals are involved in such couplings.¹³²¹ Hydroxy or carbonyl groups in the alkyl halide do not interfere. When 136 reacts with an allylic halide, a mixture of three products is obtained because of halogen–metal interchange. For example, allyl bromide treated with 136 prepared from methallyl bromide gave an approximately statistical mixture of 1,5-hexadiene, 2-methyl-1,5-hexadiene, and 2,5-dimethyl-1,5-hexadiene.¹³²² A symmetrical coupling of allylic tosylates used Ni(CO)₄.

Symmetrical coupling of allylic halides occurs by heating with magnesium in ether.¹³²³ The coupling of two different allylic groups has been achieved by treatment of an allylic bromide with an allylic Grignard reagent in THF containing HMPA,¹³²⁴ or with an allylic tin reagent.¹³²⁵ This type of coupling can be achieved with almost no allylic rearrangement in the substrate (and almost complete allylic rearrangement in the reagent) by treatment of allylic halides with lithium allylic boron ate complexes (RCH=CHCH₂B–R²₃Li⁺).¹³²⁶ The reaction between primary and secondary halides and allyltributylstannane provides another method for unsymmetrical coupling RX + CH₂=CHCH₂SnBu₃ → RCH₂CH=CH₂.¹³²⁷

In another method for the coupling of two different allylic groups,¹³²⁸ a carbanion derived from a β,γ-unsaturated thioether couples with an allylic halide to give 137.¹³²⁹ The product (137) contains an SPh group that must be removed (with Li in ethylamine) to give the 1,5-diene. Unlike most of the methods previously discussed, this method has the advantage that the coupling preserves the original positions and configurations of the two double bonds; no allylic rearrangements take place.

Treatment of conjugated ketones with SmI₂ in HMPA gave the coupled diketone via Wurtz-type coupling.¹³³⁰

OS III, 121; IV, 748; VI, 722.

10-57 The Reaction of Alkyl Halides and Sulfonate Esters with Group 1 and 2 Organometallic Reagents¹³³¹

Alkyl-de-halogenation

A variety of Group 1 and 2 organometallic compounds¹³³² couple with alkyl halides.¹³³³ Organosodium and organopotassium compounds are more reactive than Grignard reagents, and couple even with less reactive halides (see below). Coupling of organolithium compounds with alkyl halides¹³³⁴ or aryl halides¹³³⁵ is possible.¹³³⁶ Unactivated aryl halides couple with alkyllithium reagents in THF.¹³³⁷ The reaction of n-butyllithium/TMEDA with a homoallylic alcohol [CH₂=C(Me)CH₂CH₂OH] leads to the allyllithium reagent, and subsequent reaction with an alkyl halide gives the substituted homoallylic alcohol [CH₂=C(CH₂R)CH₂CH₂OH].¹³³⁸ Organolithium reagents exhibit an important side reaction: They react with ether solvents, and their half-life in such solvents is known.¹³³⁹ With highly reactive organolithium reagents, preparing and keeping them long enough for the alkyl halide to be added is sometimes a problem (but usually not with simple primary organolithium reagents). Alkenes can be prepared by the coupling of vinylic lithium compounds with primary halides¹³⁴⁰ or of vinylic halides with alkyllithium reagents in the presence of a Pd or Ru catalyst.¹³⁴¹ α-Lithioepoxides can also be formed, and reaction with an alkyl halide gives the substituted epoxide.¹³⁴² Arylsilanes (e.g., 2-trimethylsilylpyridine) undergo a deprotonation reaction of a silyl methyl group when treated with tert-butyllithium to give the corresponding ArMe₂SiCH₂Li reagent.¹³⁴³ Subsequent reaction with an alkyl halide leads to the substituted silane. Organolithium reagents formed by Li–H exchange in the presence of (–)-sparteine couple with alkyl halides with high asymmetric induction.¹³⁴⁴ Exchange of organotin compounds with organolithium reagents generates a new organolithium, and in one case intramolecular coupling in the presence of (–)-sparteine led to chiral pyrrolidine derivatives.¹³⁴⁵ Propargyl lithium reagents formed in the presence of mercuric salts couple with halides.¹³⁴⁶ Note that 1-lithioalkynes were coupled to alkyl halides in the presence of a palladium catalyst.¹³⁴⁷

Aryllithium reagents are formed by metal–halogen exchange with aryl halides or H–metal exchange with various aromatic compounds, and they react with alkyl halides. The reaction of 138 with n-butyllithium, for example, generated the aryllithium (139), which reacted with iodomethane to give 140.¹³⁴⁸ When an aromatic ring has an attached heteroatom or an heteroatom-containing substituent, reaction with a strong base (e.g., an organolithium reagent) usually leads to an ortho lithiated species.¹³⁴⁹ Subsequent reaction with an electrophilic species gives the ortho substituted product. This phenomenon is known as directed ortho metalation (See 13-17). This selectivity was discovered independently by Gilman and by Wittig in 1939–1940, when anisole was found to give ortho deprotonation in the presence of butyllithium.¹³⁵⁰ Alkylation ortho to a carbonyl is possible, and treatment of the acyl hydrazide [PhC(=O)NHNMe₂] with sec-butyllithium and then iodoethane gave the ortho ethyl derivative.¹³⁵¹ Note that aminonaphthalene derivatives were reacted with tert-butyllithium and aryllithium formation occurred on the ring distal to the amino group, and subsequent reaction with iodomethane gave methylation on that ring.¹³⁵²

In a method for propargylating an alkyl halide without allylic rearrangement, the halide is treated with lithio-1-trimethylsilylpropyne (141), which is a lithium compound protected by an SiMe₃ group.¹³⁵³ Reaction at its 1 position (which gives an allene) takes place only to a small extent, because of steric blockage by the large SiMe₃ group. The SiMe₃ group is easily removed by treatment with Ag⁺ followed by CN⁻. Propargyl derivative 141 is prepared by treating propynyllithium with Me₃SiCl to give MeCCSiMe₃ from which a proton is removed with BuLi. The R group may be primary or allylic.¹³⁵⁴ On the other hand, propargylic halides can be alkylated with essentially complete allylic rearrangement, to give allenes, by treatment with Grignard reagents and metallic salts,¹³⁵⁵ or with dialkylcuprates (R₂Cu).¹³⁵⁶

Grignard reagents are generally unreactive with alkyl halides unless allylic and benzylic reagents and substrates are used.¹³⁵⁷ Grignard reagents have the advantage that they are usually simpler to prepare than the corresponding R'₂CuLi (see Reaction 10-58), but the reaction is much narrower in scope. Grignard reagents couple only with active halides: allylic (though allylic rearrangements are common) and benzylic. They also couple with tertiary alkyl halides, but generally in low or moderate yields.¹³⁵⁸

Allylic halides are more reactive than aliphatic alkyl halides, but Cu salts have been used to facilitate coupling with alkylmagnesium halides.¹³⁵⁹ Indeed, Grignard reagents may react with alkyl halides in the presence of certain metal catalysts,¹³⁶⁰ and stereocontrol is possible in these reactions.¹³⁶¹ These catalysts include Cu(I) compounds (see Reaction 10-58),¹³⁶² Ag compounds,¹³⁶³ Pd¹³⁶⁴ complexes, Co compounds,¹³⁶⁵ Fe compounds,¹³⁶⁶ and an Fe–amine complex was shown to catalyze Grignard coupling reactions.¹³⁶⁷ Iron nanoparticles have also been employed to facilitate this type of coupling.¹³⁶⁸ Alkyl triflates have been used rather than alkyl halides.¹³⁶⁹ Chiral Cu complexes have been used with allylic halides to give rearranged alkylated products, with high enantioselectivity.¹³⁷⁰ A similar reaction was reported using a Grignard reagent and a chiral imidazolium carbene complex.¹³⁷¹ As noted above, Grignard reagents react with allylic substrates, but if there is steric hindrance at the carbon bearing the leaving group, the reaction may proceed by an S_N2' pathway (Sec. 10.E).¹³⁷²

Aryl halides, even when activated, generally do not couple with Grignard reagents, although certain transition metal catalysts do effect this reaction in variable yields,¹³⁷³ including V compounds.¹³⁷⁴ The reaction with Grignard reagents proceeds better when OR can be the leaving group, providing that activating groups are present in the ring. Aryl triflates couple with arylmagnesium halides in the presence of a Pd catalyst,¹³⁷⁵ as do vinyl halides with RMgX with a Pd¹³⁷⁶ or Ni catalyst.¹³⁷⁷ Alkyl halides are coupled to arylmagnesium bromides in the presence of a Co catalyst.¹³⁷⁸ It is also possible to couple alkynylmagnesium halides with aryl iodides in the presence of Pd catalysts.¹³⁷⁹ A silica-supported phosphine–Pd complex was used to couple arylmagnesium halides with aryl iodides.¹³⁸⁰ Aryl Grignard reagents couple with alkyl halides, including neopentyl iodide, in the presence of ZnCl₂ and a Ni catalyst.¹³⁸¹

Vinyl¹³⁸² and aryl halides¹³⁸³ also couple with alkyl Grignard reagents in the presence of a catalytic amount of an Fe catalyst,¹³⁸⁴ as do vinyl triflates with CuI¹³⁸⁵ or vinyl halides with a Co catalyst.¹³⁸⁶ Grignard reagents prepared from primary or secondary¹³⁸⁷ alkyl or aryl halides can be coupled with vinylic or aryl halides (see Reaction 13-9) in high yields in the presence of a Ni(II) catalyst.¹³⁸⁸ When a chiral Ni(II) catalyst is used, optically active hydrocarbons can be prepared from achiral reagents.¹³⁸⁹ The Pd catalyzed coupling of arylmagnesium halides and vinyl bromides has also been reported.¹³⁹⁰

Because Grignard reagents react with the C=O group (Reaction 16-24 and 16-82), they cannot be used to couple with halides containing ketone, CO₂R, or amide functions. Although the coupling of Grignard reagents with ordinary alkyl halides is usually not useful for synthetic purposes, small amounts of symmetrical coupling product are commonly formed while Grignard reagents are being prepared.

For symmetrical coupling of organometallic reagents (2RM → RR), see Reaction 14-24 and 14-25.

Much study has been devoted to the mechanisms of these reactions,¹³⁹¹ but firm conclusions are still lacking, in part because the mechanisms vary depending on the metal, the R group, the catalyst, if any, and the reaction conditions. Two basic pathways can be envisioned: a nucleophilic substitution process (which might be S_N1 or S_N2) and a free radical mechanism. This could be an SET pathway, or some other route that provides radicals. In either case, the two radicals R• and R′• would be in a solvent cage:

It is necessary to postulate the solvent cage because, if the radicals were completely free, the products would be ~ 50% RR′, 25% RR, and 25% R′R′. This is generally not the case; in most of these reactions RR′ is the predominant or exclusive product.¹³⁹² An example where an S_N2 mechanism has been demonstrated (by the finding of inversion of configuration at R) is the reaction between allylic or benzylic lithium reagents with secondary halides.¹³⁹³ The fact that in some of these cases the reaction can be successfully applied to aryl and vinylic substrates indicates that a simple S_N process cannot be the only mechanism. One possibility is that the reagents first undergo an exchange reaction: ArX + RM → RX + ArM, and then a nucleophilic substitution takes place. On the other hand, there is much evidence that many coupling reactions involving organometallic reagents with simple alkyl groups occur by free radical mechanisms. Among the evidence¹³⁹⁴ is the observation of CIDNP in reactions of alkyl halides with simple organolithium reagents¹³⁹⁵ (see Sec. 5.C.i), the detection of free radicals by ESR spectroscopy¹³⁹⁶ (Sec. 5.C.i), and the formation of 2,3-dimethyl-2,3-diphenylbutane when the reaction was carried out in the presence of cumene¹³⁹⁷ (this product is formed when a free radical abstracts a hydrogen from cumene to give PhCMe₂, which dimerizes). Evidence for free radical mechanisms has also been found for the coupling of alkyl halides with simple organosodium compounds (Wurtz),¹³⁹⁸ with Grignard reagents,¹³⁹⁹ and with lithium dialkylcopper reagents (see Reaction 10-58).¹⁴⁰⁰ Free radicals have also been implicated in the metal–ion catalyzed coupling of alkyl and aryl halides with Grignard reagents.¹⁴⁰¹

OS I, 186; III, 121; IV, 748; VI, 407; VII, 77, 172, 326, 485; VIII, 226, 396; IX, 530; X, 332, 396.

10-58 Reaction of Alkyl Halides and Sulfonate Esters with Organocuprates

Alkyl-de-halogenation

The reagents lithium dialkylcopper¹⁴⁰² (known as lithium dialkyl cuprates, also called Gilman reagents)¹⁴⁰³ react with alkyl bromides, chlorides, and iodides in ether or THF to give good yields of the cross-coupling products.¹⁴⁰⁴They are prepared (see Reaction 12-36) by the reaction of an organolithium compound with CuI or CuBr, but other Cu(I) compounds can be used.¹⁴⁰⁵ They are usually generated at temperatures <0 °C due to the thermal instability of any dialkyl cuprate that has a hydrogen atom on a carbon that is β- to the Cu.

The reaction with alkyl halides is of wide scope¹⁴⁰⁶ and R in R₂CuLi may be primary alkyl, allylic, benzylic, aryl, vinylic, or allenic, and may contain keto, CO₂H, CO₂R, or CONR₂ groups.¹⁴⁰⁷ The mechanism of these reactions probably involves formation of a Cu(II) intermediate.¹⁴⁰⁸ Reaction with allylic substrates usually proceeds with high selectivity for the γ-position,¹⁴⁰⁹ in S_N2'-type reactions.¹⁴¹⁰

Inversion of configuration has been shown in the reaction of 2-bromobutane with Ph₂CuLi,¹⁴¹¹ but the same reaction with 2-iodobutane was reported to proceed with racemization.¹⁴¹² The reaction at a vinylic substrate occurs stereospecifically, with retention of configuration.¹⁴¹³ Many gem-dihalides do not react, but when the two halogens are on a carbon α to an aromatic ring¹⁴¹⁴ or on a cyclopropane ring,¹⁴¹⁵ both halogens can be replaced by R (e.g., PhCHCl₂ → PhCHMe₂). However, 1,2-dibromides give exclusive elimination (Reaction 17-22).¹⁴¹⁶ Vinylmagnesium halides, upon addition of a catalytic amount of Li₂CuCl₄, couple to alkyl halide.¹⁴¹⁶

Lithium dialkylcopper reagents couple with alkyl tosylates.¹⁴¹⁷ High yields are obtained with primary tosylates; secondary tosylates give lower yields,¹⁴¹⁸ but aryl tosylates do not react. Vinylic triflates¹⁴¹⁹ couple very well to give alkenes¹⁴²⁰ and they also couple with allylic cuprates, to give 1,4-dienes.¹⁴²¹ Propargylic tosylates couple with vinylic cuprates to give vinylic allenes.¹⁴²²

The R′ in R'₂CuLi may be primary alkyl, vinylic, allylic, or aryl. Thus, in the reaction so far described, the alkyl groups on the organocuprate or the alkyl halide may not be secondary or tertiary alkyl. However, secondary and tertiary alkyl coupling can be achieved (on primary RX) by the use of R'₂CuLi•PBu₂¹⁴²³ (but this procedure introduces problems in the workup) or by the use of PhS(R′)CuLi,¹⁴²⁴ which selectively couples a secondary or tertiary R′ with a primary iodide (RI) to give RR′.¹⁴²⁵ It is possible to prepare mixed cuprates, where one ligand is tightly bound to the copper, allowing the other ligand to be transferred in a coupling reaction. A common example is adds a 2-thienyl group to the cuprate to give R(Th)CuLi, where the R group is transferred in lieu of the thienyl unit.¹⁴²⁶ A lithium neopentyl aryl cuprate selectively transferred from an aryl group to an allylic halide.¹⁴²⁷

Coupling to a secondary alkyl halide (R in RX above = secondary) can be achieved in high yield with the reagents R'₂Cu(CN)Li₂,¹⁴²⁸ where R′ is primary alkyl or vinylic (but not aryl).¹⁴²⁹ This modified reagent is commonly known as a higher order mixed cuprate. The reagents RCu(PPh₂)Li, RCu(NR'₂)Li, and RCu(PR'₂)Li (R′ = cyclohexyl) are more stable than R₂CuLi and can be used at higher temperatures.¹⁴³⁰ These reagents are rather reactive. Unactivated aryl triflates¹⁴³¹ (ArOSO₂CF₃) react to give ArR in good yields when treated with R₂Cu(CN)Li₂,¹⁴³² with R₃Al,¹⁴³³ or with R₃SnR and a Pd complex catalyst.¹⁴³⁴ See Reaction 10-59 for other examples involving Al, Sn, and Pd coupling reactions. Both OTf units in RCH(OTf)₂ can be replaced with Me₂(CN)CuLi₂.¹⁴³⁵ With an allenic substrate, reaction with R(CN)CuLi can give ordinary displacement (with retention of configuration)¹⁴³⁶ or an S_N2′ reaction to produce an alkyne.¹⁴³⁷ In the latter case, a chiral allene (see Sec. 4.C, category 5) gave a chiral alkyne. The structures of these “higher order mixed” cuprates has been called into question¹⁴³⁸ by Bertz,¹⁴³⁹ who suggested the reagent actually existed as R₂CuLi•LiCN in THF. This was contradicted by Lipshutz and James.¹⁴⁴⁰

The fact that R'₂CuLi do not react with ketones provides a method for the alkylation of ketones via the organocuprate coupling with α-haloketones (e.g., 142¹⁴⁴¹; see also, Reactions 10-68 and 10-73). Note that halogen–metal exchange (Reaction 12-39) is a side reaction and can become the main reaction.¹⁴⁴² When α,α′-dibromo ketones are treated with Me₂CuLi in ether at −78 °C and the mixture quenched with methanol, monomethylation takes place¹⁴⁴³(no dimethylation is observed). It has been suggested that the reaction involves cyclization (10-56) to a cyclopropanone followed by nucleophilic attack to give the enolate anion, which is protonated by the methanol. If iodomethane is added instead of methanol, an α,α′-dimethyl ketone is obtained, presumably from S_N2 attack (Reaction 10-68). Primary, secondary, and tertiary monoalkylation can be achieved with a lithium tert-butoxy(alkyl)copper reagent¹⁴⁴⁴instead of Me₂CuLi, one of the few methods for introducing a tertiary alkyl group to a carbonyl group.

When dialkylcopperzinc reagents (R₂CuZnCl) couple with allylic halides, allylic rearrangement occurs (S_N2′) almost completely, and the reaction is diastereoselective if the allylic halide contains a δ alkoxy group.¹⁴⁴⁵ Another type of copper reagent was prepared from RZnI/CuCN, and was shown to couple with alkenyl halides.¹⁴⁴⁶ Diethylzinc in the presence of a catalytic amount of CuBr coupled to allylic chlorides.¹⁴⁴⁷ When treated with organocopper compounds and Lewis acids (e.g., n-BuCu•BF₃), allylic halides give substitution with almost complete allylic rearrangement, independently of the degree of substitution at the two ends of the allylic system.¹⁴⁴⁸

OS IX, 502.

10-59 Reaction of Alkyl Halides and Sulfonate Esters with Other Organometallic Reagents

Alkyl-de-halogenation

In addition of Mg, Li, and Cu, other metals and metal complexes can be used to catalyze or mediate coupling reactions. Organoaluminum compounds couple very well with tertiary (to give products containing a quaternary carbon) and benzylic halides at −78 °C.¹⁴⁴⁹ This reaction can also be applied to allylic, secondary, and some primary halides, but several days standing at room temperature is required (see also, Reaction 10-63). Vinylic aluminum compounds (in the presence of a suitable transition metal catalyst) couple with allylic halides, acetates, and alcohol derivatives to give 1,4-dienes,¹⁴⁵⁰ and with vinylic and benzylic halides to give 1,3-dienes and allylic arenes, respectively.¹⁴⁵¹ Note that alkylboronic acids are coupled in the presence of Ag₂O and a catalytic amount of CrCl₂ to give the symmetrical alkyl derivative.¹⁴⁵²

Products containing a quaternary carbon can also be obtained by treatment of tertiary halides with dialkyl or diaryl zinc reagents in CH₂Cl₂,¹⁴⁵³ with Me₃Si and AlCl₃,¹⁴⁵⁴ or with alkyltitanium reagents (RTiCl₃ and R₂TiCl₂).¹⁴⁵⁵Alkyl or aryl triflates (halides) couple with alkyl or ArZn(halide) reagents in the presence of a Pd catalyst.¹⁴⁵⁶ This organozinc coupling reaction has been done in ionic liquids.¹⁴⁵⁷ Vinyl halides can be coupled with vinyltin reagents in the presence of CuI,¹⁴⁵⁸ and aryl tin compounds couple with vinyl halides¹⁴⁵⁹ or vinyl triflates when a Pd catalyst is present.¹⁴⁶⁰ When the vinyltin reagent is coupled with a vinyl triflate in the presence of a Pd catalyst, the reaction is known as the Stille reaction (Reaction 12-15). In the Stille reaction, vinylic triflates, in the presence of a Pd catalyst and LiCl, couple with organotin compounds (R′SnMe₃), where R′ can be alkyl, allylic, vinylic, or alkynyl.¹⁴⁶¹The reaction has been performed intramolecularly, to prepare large-ring lactones.¹⁴⁶²

The coupling of alkyl or alkenyl halides and an organozinc compound with a Ni complex has come to be known as Negishi coupling.¹⁴⁶³ Several variations have been reported over the years. Arylzinc compounds¹⁴⁶⁴ have been used, and also arylvinyl iodides.¹⁴⁶⁵ The structure of bis(iodozincio)methane in THF solution has been reported.¹⁴⁶⁶ Pyridylzinc compounds have been used in Negishi coupling.¹⁴⁶⁷ Carbonylative cross coupling reactions have been reported.¹⁴⁶⁸ Palladium-catalyzed variations are also known for alkyl or vinyl halides with organozinc compounds.¹⁴⁶⁹ Dialkylzinc compounds can be coupled to alkyl halides in the presence of a nickel catalyst,¹⁴⁷⁰ but with geminal diiodo compounds without a catalyst.¹⁴⁷¹ Asymmetric variations are known using various chiral additives or chiral catalysts,¹⁴⁷² including the example shown for an allylic chloride (DMA = dimethylactamide).¹⁴⁷³ Coupling with propargylic substrates has also been reported.¹⁴⁷⁴

Copper compounds can also be used as catalysts with dialkylzinc reagents.¹⁴⁷⁵ The reaction of aryl halides with Me₄ZnLi₂ and then VO(OEt)Cl₂ leads to the methylated aryl.¹⁴⁷⁶ Isopropylzinc (iPrZn) displaces the iodide in γ-iodo ketones to give the alkyl substitution product, without reaction at the carbonyl.¹⁴⁷⁷ Reactions of organozinc reagents with a carbonyl compound via acyl addition is presented in 16-31 (the Reformatsky reaction). Tertiary halides have also been coupled to allyltin reagents in the presence of AIBN.¹⁴⁷⁸ Alkyl halides can be treated with SmI₂ and then CuBr to give a reactive species that couples with other alkyl halides.¹⁴⁷⁹ Trialkylindium compounds couple to allylic bromides in the presence of Cu(OTf)₂•P(OEt)₃¹⁴⁸⁰ and vinyl indium compounds are coupled to α-halo esters with a BEt₃ catalyst.¹⁴⁸¹ Arylsulfonyl chlorides couple with allyl halides in the presence of bismuth to give allyl-aryls.¹⁴⁸²Vinyl iodides couple with RMnCl with an iron catalyst¹⁴⁸³ and Bu₃MnMgBr reacted with a geminal dibromocyclopropane to give a dialkylated cyclopropane.¹⁴⁸⁴ α-Haloketones are coupled with aryl halides using a Ni catalyst.¹⁴⁸⁵Allylgallium reagents have been coupled to α-bromo esters in the presence of BEt₃/O₂.¹⁴⁸⁶

Arylpalladium salts (ArPdX) prepared from arylmercury compounds and lithium palladium chloride couple with allylic chlorides in moderate yields, although allylic rearrangements can occur.¹⁴⁸⁷ In most cases, better yields are obtained by addition of a Pd complex to the substrate, sometimes in conjunction with another metal, to facilitate coupling. Under these conditions, any arylpalladium species is generated in situ. Allylic, benzylic, vinylic, and aryl halides or triflates (trifluoromethylsulfonates) couple with organotin reagents in a reaction catalyzed by Pd complexes.¹⁴⁸⁸ The advantage of this procedure is that the aryl group may contain nitro, ester, or aldehyde groups, and so on, which cannot be present in a Grignard reagent. Such functional groups as CO₂R, CN, OH, and CHO may be present in either reagent, but the substrate may not bear a β hydrogen on an sp³ carbon, because that results in elimination. Indium metal has been used to mediate the coupling of an allylic halide and an arylpalladium complex.¹⁴⁸⁹ Organoindium compounds were coupled to 1-iodonaphthalene with a Pd catalyst.¹⁴⁹⁰ Aryl halides were also coupled to allylic silanes in the presence of a Pd catalyst.¹⁴⁹¹

Dimethylzinc was coupled to aryl halides with a Pd catalyst,¹⁴⁹² and Reformatsky-type zinc derivatives (see Reaction 16-28) have been coupled to aryl halides using a Pd catalyst and microwave irradiation.¹⁴⁹³ Alkyl halides couple with ArMnCl or RMnCl in the presence of a Pd catalyst.¹⁴⁹⁴ Cobalt-catalyzed coupling reactions are known.¹⁴⁹⁵

In many cases, the organometallic reagent is prepared from the corresponding organolithium reagent (Reaction 10-57), as in the conversion of an aryllithium to an arylzirconium reagent, which was subsequently coupled to an aryl halide in the presence of a Pd catalyst.¹⁴⁹⁶ Vinylzirconium reagents can be coupled to allylic halides in the presence of Cu(I) compounds.¹⁴⁹⁷

Alkylboranes are coupled to alkyl halides in the presence of a Ni catalyst.¹⁴⁹⁸

OS VII, 245; VIII, 295; X, 391.

10-60 Coupling of Organometallic Reagents with Carboxylic Esters

Alkyl-de-acyloxy-substitution

Several organometallic reagents react with allylic esters and carbonates to give the coupling product. Lithium dialkylcopper reagents couple with allylic acetates to give normal coupling products or those resulting from allylic rearrangement, depending on the substrate.¹⁴⁹⁹ A mechanism involving a σ-allylic copper(III) complex has been suggested.¹⁵⁰⁰ Silyl cuprates have also been used, with benzoate esters, to give allyl silanes.¹⁵⁰¹ Interestingly, allylic silanes have been coupled to acetates using B(C₆F₅)₃¹⁵⁰² or BF₃.¹⁵⁰³

Allenes are obtained when propargyl acetates are treated with methylmagnesium iodide.¹⁵⁰⁴ Lithium dialkylcopper reagents give normal coupling products with enol acetates of β-dicarbonyl compounds.¹⁵⁰⁵ It is also possible to carry out the coupling of allylic acetates with Grignard reagents, if catalytic amounts of cuprous salts are present.¹⁵⁰⁶ Yields are better with this method, and regioselectivity can be controlled by the choice of cuprous salts.

Several metal-catalyzed coupling reactions are known. Allylic, benzylic, and cyclopropylmethyl acetates couple with trialkylaluminums,¹⁵⁰⁷ and allylic acetates couple with aryl and vinylic tin reagents, in the presence of a Pd catalyst¹⁵⁰⁸ (see below). Allylic acetates can be symmetrically coupled by treatment with Ni(CO)₄ (Reaction 10-56) or with Zn and a Pd–complex catalyst,¹⁵⁰⁹ or converted to unsymmetrical 1,5-dienes by treatment with an allylic stannane (R₂C=CHCH₂SnR₃) in the presence of a Pd complex.¹⁵¹⁰ Other Ni(0) coupling reactions are known.¹⁵¹¹ Titanium-mediated¹⁵¹² coupling, Ir catalyzed,¹⁵¹³ and Fe catalyzed¹⁵¹⁴ reactions are also known. Aryl halides can be coupled to allylic acetates with CoBr₂/Mn/FeBr₂.¹⁵¹⁵ Allylic phosphonates have been used as substrates for displacement by higher order cuprates¹⁵¹⁶ (see Reaction 10-58) or dialkylzinc reagents.¹⁵¹⁷

A common method is the reaction of η³-π-allyl palladium complexes¹⁵¹⁸ (see Sec 3.C.i) with various nucleophiles,¹⁵¹⁹ where the complex is obtained from allylic esters (acetate is the most common) or allylic carbonates (also see Reaction 10-31). This coupling reaction is often called the Tsuji–Trost reaction.¹⁵²⁰ The mechanism of such π-allyl palladium reactions has been discussed.¹⁵²¹ The structure and nature of the ligands associated with the metal are important to the reaction, particularly with respect to stereoselectivity of a given reaction.¹⁵²² A typical transformation is shown for the reaction of 143 with diethyl malonate, BSA (N,O-bis(trimethylsilyl)acetamide), and potassium acetate, which gives coupling product 144 in the presence of the Pd catalyst.¹⁵²³ This reaction is a variation of the basic transformation reported several years ago by Trost et al.¹⁵²⁴ Enolate anions of active methylene compounds¹⁵²⁵and also sulfone anions¹⁵²⁶ have been used as nucleophiles most of the time. In most reported cases, the R′M species is the anion of an active methylene compound (e.g., sodium, potassium, or lithium dimethylmalonate) or Knoevenagel-type carbanions (see Reaction 16-38) or amino acid surrogates.¹⁵²⁷ Enolate anions (see Reaction 10-68) have also been used.¹⁵²⁸ Other nucleophiles can be used to displace allylic acetates.¹⁵²⁹ The Pd catalyst used, the reaction conditions, and the nature of the organometallic compounds varies widely. Although two allylic coupling products are possible via the π-allyl intermediate, attack at the less substituted position is generally favored. This transformation has been done in ionic liquids¹⁵³⁰ and ionic liquids have been used as additives in catalytic amounts in other solvents.¹⁵³¹ Palladium nanoparticles have been used to catalyze the reaction.¹⁵³² The S_N2′ reactions with allylic substrates have been reported.¹⁵³³ Benzoate esters have been used successfully in lieu of the acetate.¹⁵³⁴ Catalyst metals other than Pd have been used for this reaction with allylic acetates.¹⁵³⁵

The use of chiral ligands¹⁵³⁶ or chiral additives that may act as ligands¹⁵³⁷ lead to asymmetric induction in the coupling product.¹⁵³⁸

As mentioned above, a common variation is to replace the acetate leaving group with a carbonate (–OCO₂R), where methyl carbonate (–OCO₂Me) is most common.¹⁵³⁹ A representative reaction is the transformation of 145 to 146,¹⁵⁴⁰ where the use of a chiral ligand led to modest asymmetric induction. Indeed, as with allylic acetates, chiral ligands and chiral additives lead to asymmetric induction.¹⁵⁴¹ A variety of active methylene compounds can be used as nucleophiles,¹⁵⁴² including enolate anions.¹⁵⁴³ Other nucleophiles can be used to displace allylic carbonates,¹⁵⁴⁴ often in conjunction with chiral ligands to give the product with enantioselectivity. Polymer-supported phosphine ligands have been used successfully,¹⁵⁴⁵ and catalyst systems other than Pd have been used for this reaction with allylic carbonates.¹⁵⁴⁶. Potassium vinyltrifluoroborates (Reaction 10-73) have also been used in Pd catalyzed coupling reactions with allylic acetates.¹⁵⁴⁷

Intramolecular cyclization is possible when the active methylene compound and an allylic acetate or carbonate is incorporated into the same molecule.¹⁵⁴⁸ Propargylic esters have been used in Pd catalyzed coupling reactions, including a reaction with trialkylindium reagents.¹⁵⁴⁹

10-61 Coupling of Organometallic Reagents with Sulfate Esters, Sulfoxides, Sulfones, Nitro, and Acetals

Alkyl-de-sulfonyl and de-sulfonyloxy-substitution, and so on;Alkyl-de-alkoxy-substitution, and so on;Alkyl-de-nitration, and so on

Leaving groups other than halide, esters or carbonate, or sulfonate esters are sometimes used. Sulfates, sulfonates, and epoxides give the expected products. The reactions of sodium sulfonates and alkyl halides in ionic liquids have been reported.¹⁵⁵⁰ The SO₂Ph group of allylic sulfones can be a leaving group if a Pd complex is present.¹⁵⁵¹ The NR₂ group from Mannich bases (e.g., RCOCH₂CH₂NR₂), can also act as a leaving group in this reaction (elimination–addition mechanism, Sec. 10.F). A nitro group can be displaced¹⁵⁵² from α-nitro esters, ketones, nitriles, and α,α-dinitro compounds,¹⁵⁵³ and even from simple tertiary nitro compounds of the form R₃CNO₂¹⁵⁵⁴ or ArR₂CNO₂¹⁵⁵⁵ by salts of nitroalkanes, for example,

These reactions take place by SET mechanisms.¹⁵⁵⁶ However, with α-nitro sulfones it is the sulfone group that is displaced, rather than the nitro group.¹⁵⁵⁷ The SO₂R group of allylic sulfones can be replaced by CHZZ′ (C=CCH₂–SO₂R → C=CCH₂–CHZZ′) if a Mo(CO)₆ catalyst is used.¹⁵⁵⁸

tert-Butylsulfones react with organolithium reagents, in the presence of a catalytic amount of an iron complex, to give coupling.¹⁵⁵⁹ In this case the t-BuSO₂ unit becomes a “leaving group”. A sulfoxide was a “leaving group” in the cyclization of a carboxylic acid that contains a sulfoxide unit at C-4. Treatment with phenyliodonium bis(trifluoroacetate) gave the five-membered ring lactone.¹⁵⁶⁰ Similar displacement of TolSO₂ was observed with tolylsulfones and diethylzinc.¹⁵⁶¹

Phosphonic esters, ROPO(OR)₂, react with allylic Grignard reagents to give the coupling product.¹⁵⁶²

OS I, 471; II, 47, 360; VII, 351; VIII, 97, 471.

10-62 The Bruylants Reaction

Alkyl-de-cyanation

The Bruylants reaction is the reaction of an aminonitrile with a Grignard reagent to give a substituted amine.¹⁵⁶³ This reaction is most often used for the preparation of aliphatic amines via aliphatic Grignard reagents. In a few cases, vinylic Grignard reagents can be used to prepare allylic amines.¹⁵⁶⁴ The use of AgBF₄ to convert amino nitriles to the corresponding iminium ion facilitates the Bruylants reaction with vinylic Grignard reagents.¹⁵⁶⁵Replacement of the cyano group in a tertiary nitrile is also possible.¹⁵⁶⁶

Displacement of a cyano group in α-cyanoketones is possible. Treatment of the α-cyanoketone with SmI₂ followed by addition of an excess of allyl bromide gave the α-allyl ketone derivative.¹⁵⁶⁷ α-Cyano amines react with allyl bromide and then zinc metal to give homoallylic amines after treatment with dilute acetic acid in THF.¹⁵⁶⁸

10-63 Coupling Involving Alcohols

De-hydroxyl-coupling

In some cases, it is possible to couple an alcohol in the presence of an organometallic compound.¹⁵⁶⁹ Allylic alcohols are coupled with alkylmagnesium bromides in the presence of Ti(OiPr)₄, for example.¹⁵⁷⁰ Allylic alcohols can be coupled with arylboronic acids in an ionic liquid solvent and a Rh catalyst.¹⁵⁷¹ The Pd catalyzed reaction of active methylene compounds with allylic alcohols¹⁵⁷² or benzylic alcohols¹⁵⁷³ is also known. The coupling of an alcohol to the α carbon of a ketone (RCOMe + R′OH) to give a β-substituted alcohol [RCH(OH)CH₂R′] is possible in the presence of a Ru catalyst.¹⁵⁷⁴ Alcohols are coupled to allenes in the presence of an Ir catalyst.¹⁵⁷⁵ Allylic carbonates are coupled to allylic alcohols with a Ni catalyst.¹⁵⁷⁶

Allylic or benzylic alcohols can be symmetrically coupled¹⁵⁷⁷ by treatment with methyllithium and titanium trichloride at −78 °C¹⁵⁷⁸ or by refluxing with TiCl₃ and LiAlH₄ (as shown).¹⁵⁷⁹ When the substrate is an allylic alcohol, the reaction is not regiospecific, but a mixture of normal coupling and allylic-rearranged products is found. A free radical mechanism is involved.¹⁵⁸⁰ The TiCl₃–LiAlH₄ reagent can also convert 1,3-diols to cyclopropanes, provided that at least one phenyl group is present.¹⁵⁸¹

Tertiary alcohols (R₃C–OH) react with trimethylaluminum at 80–200 °C to give methylation (R₃C–Me).¹⁵⁸² The presence of side products from elimination and rearrangement, as well as the lack of stereospecificity,¹⁵⁸³ indicate an S_N1 mechanism. The reaction can also be applied to primary and secondary alcohols if these contain an aryl group in the α position. Higher trialkylaluminums are far less suitable, because reduction competes with alkylation [see also, reactions of Me₃Al with ketones (16-24) and with carboxylic acids (16-82)]. The Me₂TiCl₂ compound reacts with tertiary alcohols in the same way.¹⁵⁸⁴ β-Alkylation of secondary alcohols has been reported using alcohol substrates in the presence of an Ir complex.¹⁵⁸⁵

Allylic alcohols couple with a reagent prepared from MeLi, CuI, or R′Li in the presence of (Ph₃PNMePh)⁺ I⁻ to give alkenes (e.g., 147) that are products of allylic rearrangement.¹⁵⁸⁶

The reaction gives good yields with primary, secondary, and tertiary alcohols, and with alkyl and aryllithium reagents.¹⁵⁸⁷ Allylic alcohols also couple with certain Grignard reagents¹⁵⁸⁸ in the presence of a nickel complex to give both normal products and the products of allylic rearrangement.

Allenic alcohols couple with allyl indium reagents at 140 °C to give allylic alcohol products.¹⁵⁸⁹ Similarly, ω-hydroxy lactones couple with organoindium reagents.¹⁵⁹⁰ Phenols react with vinyl boronates and a copper catalyst to give aryl vinyl ethers.¹⁵⁹¹

Alcohols react with allylsilanes, in the presence of an InCl₃¹⁵⁹² or InBr₃¹⁵⁹³ catalyst to give the corresponding coupling product (R₂CHOH → R₂CH–CH₂CH=CH₂). Silyl ethers are also coupled to allylsilanes in the presence of InCl₃.¹⁵⁹⁴ Proparygylic alcohols have been coupled to allylic silanes using an Au catalyst¹⁵⁹⁵ or a Rh catalyst.¹⁵⁹⁶

10-64 Coupling of Organometallic Reagents with Compounds Containing the Ether Linkage¹⁵⁹⁷

Alkyl-de-alkoxy-substitution

Acetals,¹⁵⁹⁸ ketals, and ortho esters¹⁵⁹⁹ react with Grignard reagents to give, respectively, ethers and acetals (or ketals). The latter can be hydrolyzed to aldehydes or ketones (Reaction 10-6). This procedure is a way of converting a halide (R″X, which may be alkyl, aryl, vinylic, or alkynyl) to an aldehyde (R″CHO), increasing the length of the carbon chain by one carbon (see also, Reaction 10-76). The ketone synthesis generally gives lower yields. Acetals, including allylic acetals, also give this reaction with organocopper compounds and BF₃.¹⁶⁰⁰ Dihydropyrans react with Grignard reagents in the presence of a Ni catalyst.¹⁶⁰¹ Acetals also undergo substitution when treated with silyl enol ethers or allylic silanes, with a Lewis acid catalyst,¹⁶⁰² for example,

ω-Ethoxy lactams react with Grignard regents to give ω-substituted lactams.¹⁶⁰³ Tertiary amines can be prepared by the reaction of amino ethers with Grignard reagents,¹⁶⁰⁴ (R₂NCH₂–OR′ + R²MgX → R₂NCH₂–R²) or with lithium dialkylcopper reagents.¹⁶⁰⁵

Ordinary ethers are not cleaved by Grignard reagents (in fact, diethyl ether and THF are the most common solvents for Grignard reagents), although more active organometallic compounds often do cleave them.¹⁶⁰⁶ However, methyl ethers have been replaced with a methyl group (MeMgX + ROMe → R–Me) via a Ni catalyzed coupling reaction with MeMgBr.¹⁶⁰⁷ Oxetanes have been opened with organolithium reagents and BF₃•OEt₂¹⁶⁰⁸ and also with excess Li metal with a biphenyl catalyst.¹⁶⁰⁹ Allylic ethers can be cleaved by Grignard reagents in THF if CuBr is present.¹⁶¹⁰ The reaction can take place either with or without allylic rearrangement.¹⁶¹¹ Propargylic ethers give allenes.¹⁶¹² Vinylic ethers can also be cleaved by Grignard reagents in the presence of a catalyst, in this case, a Ni complex.¹⁶¹³ Silyl enol ethers R₂C=CROSiMe₃ behave similarly.¹⁶¹⁴ Bicyclic benzofurans can be opened by dialkylzinc reagents in the presence of a Pd catalyst.¹⁶¹⁵

Certain acetals and ketals can be dimerized in a reaction similar to Reaction 10-56 by treatment with TiCl₄–LiAlH₄, for example,¹⁶¹⁶

Also see, Reaction 10-65.

OS II, 323; III, 701. Also see, OS V, 431.

10-65 The Reaction of Organometallic Reagents with Epoxides

3(OC)-seco -Alkyl-de-alkoxy-substitution

The reaction between Grignard reagents or organolithium reagents and epoxides is very valuable and is often used to increase the length of a carbon chain by two carbons.¹⁶¹⁷ The Grignard reagent may be aromatic or aliphatic, although tertiary Grignard reagents give low yields. As expected for an S_N2 process, attack is at the less substituted carbon. With allylic Grignard reagents, the addition of a catalytic amount of Yb(OTf)₃ facilitated alkylation.¹⁶¹⁸Organolithium reagents,¹⁶¹⁹ in the presence of chiral additives, lead to the 2-substituted alcohol with good enantioselectivity. Similar reaction with a chiral Schiff base gave the same type of product, with excellent enantioselectivity.¹⁶²⁰

Lithium dialkylcopper reagents also give the reaction,¹⁶²¹ as do higher order cuprates,¹⁶²² often producing higher yields. They have the additional advantage that they do not react with ester, ketone, or carboxyl groups so that the epoxide ring of epoxy esters, ketones, and carboxylic acids can be selectively attacked, often in a regioselective manner.¹⁶²³ The use of BF₃ increases the reactivity of R₂CuLi, enabling it to be used with thermally unstable epoxides.¹⁶²⁴ Lithium diaminocyano cuprates have also been used.¹⁶²⁵

The reaction has also been performed with other organometallic compounds.¹⁶²⁶ Trialkylaluminum reagents open epoxides with delivery of the alkyl group to carbon.¹⁶²⁷ In the presence of a Lewis acid catalyst (e.g., BF₃), alkylation can occur at the more substituted carbon.¹⁶²⁸Friedel–Crafts type alkylation (see Reaction 11-11) is possible when an aromatic compound reacts with an epoxide and AlCl₃.¹⁶²⁹ Epoxides react with allyl bromide in the presence of In metal, with the expected delivery of allyl to the less substituted carbon.¹⁶³⁰ When a substituted epoxide was treated with CO, BF₃•OEt₂, and a Co catalyst, carbonylation occurred and the final product was a β-lactone.¹⁶³¹ Similar β-lactone forming reactions were reported using substituted epoxides, CO, and a metal compound–BF₃ complex.¹⁶³² A double carbonylation reaction was reported in the presence of an Al complex, generating an anhydride.¹⁶³³ Five-membered ring lactams were formed from substituted epoxides using BF₃•OEt₂ followed by treatment with KHF₂.¹⁶³⁴ Ring opening of epoxides with Ti compounds has been shown to be selective for the more substituted carbon.¹⁶³⁵ Epoxides react with Ag salts of alkynes, in the presence of Zr compounds, to give the rearrangement product, a propargylic alcohol.¹⁶³⁶ A Ga/Sm induced ring opening with alkyl halides has been reported.¹⁶³⁷

In the presence of a Sc catalyst, chiral allylic boranes open epoxides at the less substituted position to generate chiral, homoallylic alcohols.¹⁶³⁸

When gem-disubstituted epoxides (148), and sometimes other epoxides, are treated with Grignard reagents, the product may be 149, that is, the new alkyl group may appear on the same carbon as the OH. In such cases, the epoxide is isomerized to an aldehyde or a ketone before reacting with the Grignard reagent. Halohydrins are often side products.

When the substrate is a vinylic epoxide,¹⁶³⁹ Grignard reagents generally give a mixture of the normal product and the product of allylic rearrangement (150).¹⁶⁴⁰ Butyllithium reacted with a gem-difluoroalkylidene epoxide (F₂C=CR–epoxide) and S_N2′ displacement gave alkylation at the difluoro carbon and opened the epoxide.¹⁶⁴¹ The latter often predominates. In the case of R₂CuLi,¹⁶⁴² acyclic substrates give mostly allylic rearrangement (S_N2′).¹⁶³⁹The double bond of the “vinylic” epoxide can be part of an enolate anion. In this case, R₂CuLi give exclusive allylic rearrangement (S_N2′) to 151 after hydrolysis, while Grignard and organolithium reagents opened the epoxide directly (S_N2) to give 152 after hydrolysis.¹⁶⁴³

An organometallic equivalent that opens epoxides is a hydrosilane, for example, Me₃SiH, and CO, catalyzed by dicobalt octacarbonyl:¹⁶⁴⁴ See Reaction 10-55 for other coupling reactions with organosilanes. Silyl enol ethers react with epoxides in a related reaction, but a Lewis acid (e.g., TiCl₄) is required.¹⁶⁴⁵

OS I, 306; VII, 501; VIII, 33, 516; X, 297.

10-66 Reaction of Organometallics with Aziridines

Aziridines have been opened by organometallic reagents to give amines.¹⁶⁴⁶ It is also possible to open aziridines, although they are less reactive than epoxides,¹⁶⁴⁷ with organometallic reagents particularly when there is an N-sulfonyl group (e.g., tosyl, formally making it a sulfonamide). Grignard reagents react with N-tosyl 2-phenylaziridine to give the corresponding N-tosylamine.¹⁶⁴⁸ Organocuprates (10-58) reaction with N-alkylaziridines to give the corresponding amine.¹⁶⁴⁹ In a Friedel–Crafts type reaction (11-11), aziridines react with benzene, in the presence of In(OTf)₃, to give the β-aryl amine.¹⁶⁵⁰

N-Tosyl aziridines have also been opened with enolate anions, which led to a pyrroline derivative,¹⁶⁵¹ and with Me₂S=CHCO₂Et (see Reaction 16-46) to generate a N-tosyl azetidine.¹⁶⁵² Allylic alcohols open N-tosylaziridines with KSF–Montmorillonite clay.¹⁶⁵³ C-Arylation is possible with a Ag(I) catalyst.¹⁶⁵⁴N-Sulfonyl aziridines react with the enolate anions of β-keto esters under phase-transfer conditions.¹⁶⁵⁵N-Tosylaziridines react with InCl₃ to give the chloro N-tosylamine.¹⁶⁵⁶

Aziridines react with nucleophiles other than carbon nucleophiles. In the presence of tetrabutylammonium fluoride (TBAF), trimethylsilyl azide reacts with N-tosylaziridines to give the azido N-tosylamine.¹⁶⁵⁷N-Benzylic aziridines are opened by trimethylsilyl azide in the presence of a Cr catalyst.¹⁶⁵⁸ Acetic anhydride reacts with N-tosylaziridines, in the presence of PBu₃, to give the N-tosylamino acetate.¹⁶⁵⁹ Mediated by Lewis bases, aziridines react with silylated nucleophiles.¹⁶⁶⁰

10-67 Alkylation at a Carbon Bearing an Active Hydrogen

Bis(ethoxycarbonyl)methyl-de-halogenation, and so on

The metal-catalyzed displacement of allylic acetates and carbonates (Reaction 10-60) clearly falls into this category. However, this section will focus on the more general reaction of active methylene compounds with substrates bearing a leaving group, not necessarily allylic substrates or metal catalyzed. When compounds contain two or three strong electron-withdrawing groups on a carbon atom bearing a proton (the so-called α-proton), that proton is more acidic than compounds without such groups (Sec. 5.B.i, category 1). Treatment with a suitable base (a base that has a conjugate acid with a pK_a greater than the α-proton) removes the α-proton and generates the corresponding enolate anion (Reaction 10-68). These enolate anions react as carbon nucleophiles and attack alkyl halides, resulting in their alkylation.¹⁶⁶¹ Both Z and Z′ may be COOR′, CHO, COR′,¹⁶⁶² CONR'₂, COO⁻, CN,¹⁶⁶³ NO₂, SOR′, SO₂R′,¹⁶⁶⁴ SO₂OR′, SO₂NR'₂ or similar groups.¹⁶⁶⁵ Some commonly used bases are sodium ethoxide and potassium tert-butoxide, each in its respective alcohol as solvent. With particularly acidic compounds (e.g., β-diketones–Z, Z′ = COR′), sodium hydroxide in water or aq alcohol or acetone, or even sodium carbonate,¹⁶⁶⁶ is a strong enough base for the reaction. If at least one Z group is COOR′, saponification is a possible side reaction. In addition to the groups listed above, Z may also be phenyl, but if two phenyl groups are on the same carbon, the acidity is less than in the other cases and a stronger base must be used. However, the reaction can be successfully carried out with diphenylmethane with NaNH₂ as the base.¹⁶⁶⁷ If the solvent used in the reaction is acidic enough to protonate either the enolate anion or the base, an equilibrium will be established leading to only small amounts of the enolate anion (thermodynamic conditions). Such protic solvents include water, alcohols, or amines. To avoid this reaction, solvents that do not contain an acidic proton (aprotic solvents) are used, but protic solvents can be used in some cases. The use of polar aprotic solvents (e.g., DMF or DMSO), markedly increases the rate of alkylation¹⁶⁶⁸ but also increases the extent of alkylation at the oxygen rather than the carbon with highly reactive species (e.g., iodomethane, Sec. 10.G.viii). In general, enolate anions, such as those described here, react with alkyl halides via C-alkylation, although trialkylsilyl halides and anhydrides tend to react via O-alkylation. Phase-transfer catalysis has also been used,¹⁶⁶⁹and the use of chiral phase-transfer catalysts led to enantioselectivity in the alkylated product.¹⁶⁷⁰ The reaction is successful for primary and secondary alkyl, allylic (with allylic rearrangement possible), and benzylic RX, but fails for tertiary halides, since these undergo elimination under the reaction conditions (see, however, Reaction 10-67). Various functional groups may be present in RX as long as they are not sensitive to base. Side reactions that may cause problems are the above-mentioned competing O-alkylation, elimination (if the enolate anion is a strong enough base), and dialkylation.

With substrates (e.g., ZCH₂Z′) it is possible to alkylate twice. Initial removal of the proton with a base followed by alkylation of the resulting enolate anion with RX, can be followed by subsequent removal of the proton from ZCHRZ′ and then alkylation with the same or a different RX. An important example of this reaction is the malonic ester synthesis, in which both Z groups are COOEt. The product can be hydrolyzed and decarboxylated (Reaction 12-40) to give a carboxylic acid. An illustration is the preparation of 2-ethylpentanoic acid (153) from malonic ester. A variation of this alkylation sequence employs 1,2-dibromoethane as the alkylating agent, and subsequent treatment with 1, 8-diazabicycl [5.4.0]undec-7-ene (DBU) leads to incorporation of a vinyl group on the α carbon.¹⁶⁷¹ Another variation involved coupling of a dimalonate with an allylic carbonate (see Reaction 10-60), using a polymer-supported Pd catalyst.¹⁶⁷²

It is obvious that many carboxylic acids of the formulas RCH₂CO₂H and RR′CHCO₂H can be synthesized by this method [for some other ways of preparing such acids (see Reactions 10-70–10-73)]. Another important example is the acetoacetic ester synthesis, in which Z is CO₂Et and Z′ is COCH₃. In this case, the product can be decarboxylated with acid or dilute base (Reaction 12-40) to give a ketone (154) or cleaved with concentrated base (Reaction 12-43) to give a carboxylic ester (155) and a salt of acetic acid. This reaction has been done in tert-butanol in the presence of alumina, in vacuo, to give the alkylated keto acid directly from the keto ester.¹⁶⁷³

Another way of preparing ketones involves alkylation¹⁶⁷⁴ of β-keto sulfoxides¹⁶⁷⁵ or sulfones,¹⁶⁷⁶ to give 156.

The sulfoxide group in the product (156) is easily reduced (desulfurized, see Reaction 19-70) to give the ketone in high yields using aluminum amalgam or by electrolysis.¹⁶⁷⁷ β-Keto sulfoxides [e.g., 156 or sulfones (–SO₂–)] are easily prepared (Reaction 16-86). When one group attached to the sulfur atom is chiral, the alkylation proceeds with reasonable enantioselectivity.¹⁶⁷⁸

Other examples of the reaction are the cyanoacetic ester synthesis, in which Z is CO₂Et and Z′ is CN (as in the malonic ester synthesis, the product here can be hydrolyzed and decarboxylated), and the Sorensen method of amino acid synthesis, using N-acetylaminomalonic esters, (EtO₂C)₂CHNHCOCH₃. Hydrolysis and decarboxylation of the product in this case gives an α-amino acid. The amino group is also frequently protected by conversion to a phthalimido group.

The reaction is not limited to Z–CH₂–Z′ compounds. Other compounds have acidic CH hydrogens. Some examples are the methyl hydrogens of α-aminopyridines, the methyl hydrogens of ynamines of the form CH₃CCNR₂¹⁶⁷⁹(the product in this case can be hydrolyzed to an amide RCH₂CH₂CONR₂), the CH₂ hydrogens of cyclopentadiene and its derivatives (Sec. 2.I.ii), hydrogens connected to a triple-bond carbon (Reaction 10-74), and the hydrogen of HCN (Reaction 10-75) can also be removed with a base and the resulting ion alkylated (see also, Reactions 10-68–10-72). α-Imino esters have been used since treatment with a strong base with a titanium catalyst followed by an aldehyde leads to hydroxy amino esters.¹⁶⁸⁰

Alkylation takes place at the most acidic position of a reagent molecule; for example, acetoacetic ester (CH₃COCH₂COOEt) is alkylated at the methylene and not at the methyl group, because the former is more acidic than the latter, and hence gives up its proton to the base. However, if 2 molar equivalents of base are used, then not only is the most acidic proton removed but also the second most acidic. Alkylation of this doubly charged anion (a dianion) occurs at the less acidic position, in this case the second most acidic position¹⁶⁸¹ (see Sec. 10.G.vii). The first and second ion pair acidities of β-diketones has been studied.¹⁶⁸²

When ω,ω′-dihalides are used, ring closures can be effected:¹⁶⁸³

This method has been used to close rings of three (n = 0) to seven members, although five-membered ring closures proceed in highest yields. Another ring-closing method involves internal alkylation.¹⁶⁸⁴

This method has been shown to be applicable to medium rings (10–14 members) without the use of high-dilution techniques.¹⁶⁸⁵

The mechanism of these reactions is usually S_N2 with inversion taking place at a chiral RX, although an SET¹⁶⁸⁶ mechanism may be involved in certain cases,¹⁶⁸⁷ especially where the nucleophile is an α-nitro carbanion¹⁶⁸⁸ and/or the substrate contains a nitro or cyano¹⁶⁸⁹ group. Tertiary alkyl groups can be introduced by an S_N1 mechanism if the ZCH₂Z′ compound (not the enolate anion) is treated with a tertiary carbocation generated in situ from an alcohol or alkyl halide and BF₃ or AlCl₃,¹⁶⁹⁰ or with a tertiary alkyl perchlorate.¹⁶⁹¹

Alkylation α to a nitro group can be achieved with the Katritzky pyrylium–pyridinium reagents.¹⁶⁹² This reaction probably has a free radical mechanism.¹⁶⁹³

OS I, 248, 250; II, 262, 279, 384, 474; III, 213, 219, 397, 405, 495, 705; IV, 10, 55, 288, 291, 623, 641, 962; V, 76, 187, 514, 523, 559, 743, 767, 785, 848, 1013; VI, 223, 320, 361, 482, 503, 587, 781, 991; VII, 339, 411; VIII, 5, 312, 381. See also, OS VIII, 235.

10-68 Alkylation of Ketones, Aldehydes, Nitriles, and Carboxylic Esters

α-Acylalkyl-de-halogenation, and so on

Ketones,¹⁶⁹⁴ nitriles,¹⁶⁹⁵ and carboxylic esters¹⁶⁹⁶ can be alkylated in the α position in a reaction similar to 10-67.¹⁶⁵² The pK_a of the proton α to the carbonyl or CN is in the range of 19–25 depending on the number of substituents (see Table 8.1), and a base that has a conjugate acid with a pK_a greater than that proton must be employed. Note that since only one activating group is present, compared with two activating groups for the substrates in Reaction 10-67, the pK_a of the α-proton is higher (a weaker acid) and a stronger base is required. Reaction of the α-proton with the base generates the key nucleophilic intermediate, an enolate anion (157). The most common bases¹⁶⁹⁷ are lithium diethylamide (Et₂NLi), lithium diisopropylamide[(Me₂CH)₂NLi, LDA],¹⁶⁹⁸ lithium hexamethyldisilazide [LiN(SiMe₃)₂], t-BuOK, NaNH₂, and KH. The base lithium N-isopropyl-N-cyclohexylamide (LICA) is particularly successful for carboxylic esters¹⁶⁹⁹ and nitriles.¹⁷⁰⁰ Enolate anion formation with lithium amides can also be regioselective (see Reaction 12-22).¹⁷⁰¹ Lithium enolate anions exist as aggregates in solution.¹⁷⁰² The mechanism for this deprotonation reaction has been studied,¹⁷⁰³ as has the rate of deprotonation.¹⁷⁰⁴

Solid KOH in Me₂SO has been used to methylate ketones, in high yields.¹⁷⁰⁵ Some of these bases are strong enough to convert the ketone, nitrile, or ester completely to its enolate anion conjugate base; others (especially t-BuOK) convert a significant fraction of the molecules. In the latter case, the aldol reaction (16-34) or Claisen condensation (16-85) may be side reactions, since under the thermodynamic conditions associated with this base both the free molecule and its conjugate base are present at the same time. Both lactones¹⁷⁰⁶ and lactams are similarly alkylated.¹⁷⁰⁷ Protic solvents are generally not suitable because they protonate the base (though of course this is not a problem with a conjugate pair, e.g., t-BuOK in t-BuOH). Some common solvents are DME, THF, DMF, and liquid NH₃. Phase-transfer catalysis has been used to alkylate many nitriles, as well as some esters and ketones.¹⁷⁰⁸ Amino acid surrogates (158, R = N derivative) can be alkylated, often under phase-transfer conditions.¹⁷⁰⁹

Direct alkylation of aldehydes is difficult when bases (e.g., KOH and NaOMe) are used, due to rapid aldol reaction (16-34), but aldehydes bearing only one α hydrogen have been alkylated with allylic and benzylic halides in good yields using the base KH to prepare the potassium enolate,¹⁷¹⁰ or in moderate yields, by the use of a phase-transfer catalyst.¹⁷¹¹ Even the use of amide bases (e.g., lithium diisopropylamide, LDA), lithium hexamethyl disilazide (LHMDS), or lithium tetramethylpiperidide (LTMP) to generate the enolate anion in an aprotic solvent (e.g., ether or THF) cannot completely suppress rapid aldol side reactions.

As in Reaction 10-67, the alkyl halide that reacts with the enolate anion may be primary or secondary. Tertiary halides give elimination. Even primary and secondary halides may give predominant elimination if the enolate anion is a strong enough base (e.g., the enolate anion from Me₃CCOMe).¹⁷¹² Tertiary alkyl groups, as well as other groups that normally give S_N1 reactions, can be introduced if the reaction is performed on a silyl enol ether¹⁷¹³ of a ketone, aldehyde, or ester (see 158) with a Lewis acid catalyst.¹⁷¹⁴ Tertiary alkyl fluorides were coupled to silyl enol ethers with BF₃•etherate.¹⁷¹⁵ Note that tin enolates (C=C–OSnR₃) react with halides in the presence of a Zn catalyst.¹⁷¹⁶ A chiral variation of this latter reaction was reported involving generation of the enolate anion in the presence of Me₃SnCl, a Pd catalyst, and a chiral ligand.¹⁷¹⁷

Metal-catalyzed alkylations that are related to this reaction are known. 1,3-Diketones are benzylated or allylated using Bi catalysts.¹⁷¹⁸ Monoalkylation is possible using Pd catalysts,¹⁷¹⁹ and Pd catalyzed asymmetric allylic alkylation is known¹⁷²⁰ α-Alkylation of ketones with alcohols uses a Ru catalyst,¹⁷²¹ or Ni nanoparticles.¹⁷²² A recyclable Pd catalyst is available.¹⁷²³ Zinc enolate anions have been used in enantioselective Pd catalyzed alkylation reactions.¹⁷²⁴

Silyl enol ethers can be converted to the enolate anion, which can then be alkylated in the usual manner. The reaction of silyl enol ether (159) with KOEt followed by LiBr and a catalytic amount of n-butyllithium with allyl iodide gave 160.¹⁷²⁵ Metal-catalyzed alkylation reactions are known with silyl enol ethers, including an In catalyzed¹⁷²⁶ reaction. An Ir catalyzed regioselective and enantioselective alkylation of silyl enol ethers using allylic carbonates as a substrate has been reported.¹⁷²⁷

The metal-catalyzed (usually Ni) coupling reaction of an alkyl halide or an electrophilic substrate with a silane¹⁷²⁸ is known as Hiyama coupling.¹⁷²⁹ A Ni catalyzed Hiyama cross-coupling with a chiral additive leads to a chiral alkylated ketone.¹⁷³⁰ The nature of the ligand has an important impact on the reaction.¹⁷³¹ There is a Pd catalyzed Hiyama cross-coupling.¹⁷³² Aryl siloxanes have been used in this reaction.¹⁷³³

Enol carbonates react with alkylating agents in the presence of a Pd catalyst. The decarboxylative alkylation of allyl enol carbonates to the corresponding allylcyclohexanone derivatives is known.¹⁷³⁴ An asymmetric version of this reaction has been reported.¹⁷³⁵ The same reaction can be done using enolate anion and allylic acetates with a Pd catalyst.¹⁷³⁶

Vinylic and aryl halides can be used to vinylate or arylate carboxylic esters (but not ketones) by the use of NiBr₂ as a catalyst.¹⁷³⁷ Ketones have been vinylated by treating their enol acetates with vinylic bromides in the presence of a Pd catalyst,¹⁷³⁸ but direct reaction of a ketone, a vinyl halide, sodium tert-butoxide and a Pd catalyst also give the α-vinyl ketone.¹⁷³⁹ Also as in Reaction 10-67, this reaction can be used to close rings.¹⁷⁴⁰ Rings have been closed by treating a dianion of a dialkyl succinate with a 1,ω-dihalide or ditosylate.¹⁷⁴¹ This was applied to the synthesis of three-, four-, five-, and six-membered rings. When the attached groups were chiral (e.g., menthyl) the product was formed with > 90% ee.¹⁷⁴⁰

Efficient enantioselective alkylations are known,¹⁷⁴² including the use a chiral base to form the enolate anion.¹⁷⁴³ Alternatively, a chiral auxiliary can be attached. Many auxiliaries are based on the use of chiral amides¹⁷⁴⁴ or esters.¹⁷⁴⁵ Subsequent formation of the enolate anion allows alkylation to proceed with high enantioselectivity. A subsequent step is required to convert the chiral amide or ester to the corresponding carboxylic acid. Chiral additives can also be used,¹⁷⁴⁶ and the influence of chelating ligands and hydrocarbon cosolvents has been studied for LiN(TMS)₂ mediated enolization reactions.¹⁷⁴⁷ The addition of triethylamine influences the (E/Z) selectivity of the enolate anion.¹⁷⁴⁸ Dynamic kinetic resolution has been used for the asymmetric alkylation of malonate derivatives using allenyl acetates.¹⁷⁴⁹

When the compound to be alkylated is an unsymmetrical ketone, the question arises as to which side will be alkylated (regioselectivity). If a phenyl or a vinylic group is present on one side, alkylation goes predominantly on that side. When only alkyl groups are present, the reaction is generally not regioselective; mixtures are obtained in which sometimes the more alkylated and sometimes the less alkylated side is predominantly alkylated. Which product is found in higher yield depends on the nature of the substrate, the base,¹⁷⁵⁰ the cation, and the solvent. In any case, di- and trisubstitution are frequent¹⁷⁵¹ and it is often difficult to stop with the introduction of just one alkyl group.¹⁷⁵²

Several methods have been developed for ensuring that alkylation takes place regioselectively on the desired side of a ketone.¹⁷⁵³ Among these are the following:

1. Block one side of the ketone by introducing a removable group. Alkylation takes place on the other side; the blocking group is then removed. A common reaction for this purpose is formylation with ethyl formate (Reaction 16-86). This generally blocks the less hindered side. The formyl group is easily removed by alkaline hydrolysis (Reaction 12-43).

2. Introduce an activating group on one side. Alkylation then takes place on that side (Reaction 10-67). The activating group is then removed.

3. Prepare the desired one of the two possible enolate anions.¹⁷⁵⁴ The two ions (e.g., 161 and 162) for

2-heptanone, interconvert rapidly only in the presence of the parent ketone or any stronger acid.¹⁷⁵⁵ In the absence of such acids, it is possible to prepare either 161 or 162 and thus achieve selective alkylation on either side of the ketone.¹⁷⁵⁶ The desired enolate anion can be obtained by treatment of the corresponding enol acetate with 2 equiv of methyllithium in 1,2-dimethoxyethane. Each enol acetate gives the corresponding enolate, for example,

The enol acetates, in turn, can be prepared by treatment of the parent ketone with an appropriate reagent.¹⁷⁴⁵ Such treatment generally gives a mixture of the two enol acetates in which one or the other predominates, depending on the reagent. The mixtures are easily separable.¹⁷⁵⁵ An alternate procedure involves conversion of a silyl enol ether¹⁷⁵⁷ (see Reaction 12-17) or a dialkylboron enol ether¹⁷⁵⁸ (an enol borinate, see Reaction 10-73) to the corresponding enolate anion. If the less hindered enolate anion is desired (e.g., 161), it can be prepared directly from the ketone by treatment with LDA in THF or DME at −78 °C.¹⁷⁵⁹

4. Begin not with the ketone itself, but with an α,β-unsaturated ketone in which the double bond is present on the side where alkylation is desired. Upon treatment with lithium in liquid NH₃, such a ketone is reduced to an enolate anion. When the alkyl halide is added, it must react with the enolate anion on the side where the double bond was.¹⁷⁶⁰ Of course, this method is not actually an alkylation of the ketone, but of the α,β-unsaturated ketone, although the product is the same as if the saturated ketone had been alkylated on the desired side.

Both sides of acetone have been alkylated with different alkyl groups, in one operation, by treatment of the N,N-dimethylhydrazone of acetone with n-BuLi, followed by a primary alkyl, benzylic, or allylic bromide or iodide; then another mole of n-BuLi, a second halide, and finally hydrolysis of the hydrazone.¹⁷⁶¹ Alkylation of an unsymmetrical ketone at the more substituted position was reported using an alkyl bromide, NaOH, and a calix[n]arene catalyst (see Sec. 4.H. category 2 for calixarenes).¹⁷⁶²

Among other methods for the preparation of alkylated ketones are (1) Alkylation of silyl enol ethers using various reagents as noted above, (2) the Stork enamine reaction (Reaction 10-69), (3) the acetoacetic ester synthesis (Reaction 10-67), (4) alkylation of β-keto sulfones or sulfoxides (Reaction 10-67), (5) acylation of CH₃SOCH₂⁻ followed by reductive cleavage (Reaction 16-86), (6) treatment of α-halo ketones with lithium dialkylcopper reagents (Reaction 10-57), and (7) treatment of α-halo ketones with trialkylboranes (Reaction 10-73).

Aldehydes can be indirectly alkylated via an imine derivative of the aldehyde.¹⁷⁶³ The derivative is easily prepared (Reaction 16-13) and the product easily hydrolyzed to the aldehyde (Reaction 16-2). Either or both R groups may be hydrogen, so that mono-, di-, and trisubstituted acetaldehydes can be prepared by this method. The R′ group may be primary alkyl, allylic, or benzylic. Imine alkylation can also be applied to the preparation of substituted amine derivatives. An amino acid surrogate (e.g., Ph₂C=NCH₂CO₂R), when treated with KOH and an alkyl halide gives the C-alkylated product.¹⁷⁶⁴ When a chiral additive is used, good enantioselectivity was observed. This reaction has also been done in the ionic liquid Bmim tetrafluoroborate (see Sec. 9.D.iii).¹⁷⁶⁵ It is possible to alkylate α-amino amides directly.¹⁷⁶⁶

Hydrazones and other compounds with C=N bonds can be similarly alkylated.¹⁷⁴³ The use of chiral amines or hydrazines¹⁷⁶⁷ [followed by hydrolysis (Reaction 16-2) of the alkylated imine] can lead to chiral alkylated ketones in high optical yields¹⁷⁶⁸ (for an example, see Sec. 4.J). Lithiated imines are generated by the treatment of an imine with a suitable base, and reaction with an alkyl halide gives the alkylated imine.¹⁷⁶⁹ α-Magnesio imines also react with alkyl halides.¹⁷⁷⁰

In α,β-unsaturated ketones, nitriles, and esters (e.g., 163), the γ hydrogen assumes the acidity normally held by the position α to the carbonyl group, especially when R is not hydrogen and so cannot compete. This principle, called vinylogy (see Sec. 6.B), operates because the resonance effect is transmitted through the double bond. However, because of the resonance, alkylation at the α position (with allylic rearrangement) competes with alkylation at the γ position and usually predominates.

α-Hydroxynitriles (cyanohydrins), protected by conversion to acetals with ethyl vinyl ether (Reaction 15-5), can be easily alkylated with primary or secondary alkyl or allylic halides.¹⁷⁷¹ The R group can be aryl or a saturated or unsaturated alkyl. Since the cyanohydrins¹⁷⁷² are easily formed from aldehydes (Reaction 16-52) and the product is easily hydrolyzed to a ketone, this is a method for converting an aldehyde (RCHO) to a ketone (RCOR′)¹⁷⁷³ (for other methods, see Reactions 10-71, 16-82, and 18-9).¹⁷⁷⁴ In this procedure, the normal mode of reaction of a carbonyl carbon is reversed. The C atom of an aldehyde molecule is normally electrophilic and is attacked by nucleophiles (Chapter 16), but by conversion to the protected cyanohydrin this carbon atom has been induced to perform as a nucleophile.¹⁷⁷⁵ The German word Umpolung¹⁷⁷⁶ is used to describe this kind of reversal (another example is found in Reaction 10-71). Since the ion 164 serves as a substitute for the unavailable R(C=O)⁻ anion, it is often called a “masked” R(C=O)⁻ ion. This method fails for formaldehyde (R = H), but other masked formaldehydes have proved successful.¹⁷⁷⁷ In an interesting variation of nitrile alkylation, a quaternary bromide [PhC(Br)(Me)CN] reacted with allyl bromide, in the presence of a Grignard reagent, to give the alkylated product [PhC(CN)(Me)CH₂CH=CH₂].¹⁷⁷⁸

A coupling reaction of two ketones to form a 1,4-diketone has been reported, using ZnCl₂/Et₂NH.¹⁷⁷⁹ An interesting allylic substitution at a 3° center involves the reaction of 3° 2-bromonitriles with iPrMgBr and allyl bromide to give the 2-allyl nitrile.¹⁷⁸⁰

α-Alkylation of ketones with primary alcohols is possible using polymer-associated nanoparticulate Pd.¹⁷⁸¹

Protonation of enolate anions is discussed in Reaction 16-34, in connection with the aldol condensation.

OS III, 44, 219, 221, 223, 397; IV, 278, 597, 641, 962; V, 187, 514, 559, 848; VI, 51, 115, 121, 401, 818, 897, 958, 991; VII, 153, 208, 241, 424; VIII, 141, 173, 241, 403, 460, 479, 486; X, 59, 460; 80, 31.

10-69 The Stork Enamine Reaction

α-Acylalkyl-de-halogenation¹⁷⁸²

When enamines are treated with alkyl halides, an alkylation occurs to give an iminium salt via electron transfer from the electron pair on nitrogen, through the C=C to the electrophilic carbon of the alkyl halide.¹⁷⁸³ In effect, an enamine behaves as a “nitrogen enolate anion” and generally reacts as carbon nucleophiles.¹⁷⁸⁴ Hydrolysis of the iminium salt gives a ketone. Since the enamine is normally formed from a ketone (Reaction 16-13), the net result is alkylation of the ketone at the α position. The method, known as the Stork enamine reaction,¹⁷⁸⁵ is an alternative to the ketone alkylation considered in Reaction 10-68, generally giving monoalkylation of the ketone. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. There are metal-catalyzed enamine alkylation reactions, including the use of Ir catalysts.¹⁷⁸⁶ There are reactions that are catalyzed by enamines, including asymmetric reactions.¹⁷⁸⁷

The method is quite useful for particularly active alkyl halides, (e.g., allylic, benzylic, and propargylic halides), and for α-halo ethers and esters. Other primary and secondary halides can show sluggish reactivity. The reaction of enamines with benzotriazole derivatives has been reported.¹⁷⁸⁸ Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (e.g., 2,4-dinitrochlorobenzene; see Chapter 13), to epoxides,¹⁷⁸⁹ and to activated alkenes (e.g., acrylonitrile). The latter is a Michael-type reaction (15-24) with respect to the alkene.

Acylation¹⁷⁹⁰ can be accomplished with acyl halides or with anhydrides. Hydrolysis of the resulting iminium salt leads to a 1,3-diketone. A COOEt group can be introduced by treatment of the enamine with ethyl chloroformate (ClCOOEt;¹⁷⁹¹ a CN group with cyanogen chloride¹⁷⁹² (not cyanogen bromide or iodide, which leads to halogenation of the enamine); a CHO group with the mixed anhydride of formic and acetic acids¹⁷⁹¹ or with DMF and phosgene;¹⁷⁹³ and a C(R)=NR′ group with a nitrilium salt RCN⁺R′.¹⁷⁹⁴ The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an α hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (Reaction 17-14), which adds to the enamine to give a cyclobutanone (Reaction 15-63). This compound can be cleaved in the solution to form the same acylated imine salt (that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.¹⁷⁹⁵

N-Alkylation can be a problem, particularly with enamines derived from aldehydes. An alternative method, which gives good yields of alkylation with primary and secondary halides, is alkylation of enamine salts, which are prepared by treating an imine with ethylmagnesium bromide in THF:¹⁷⁹⁶

The imines are prepared by the reaction of secondary amines with aldehydes or ketones, mainly ketones (16-13). The enamine salt method has also been used to give good yields of mono α alkylation of α,β-unsaturated ketones.¹⁷⁹⁷ Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields.¹⁷⁹⁸ N-Alkylation in this case is presumably prevented by steric hindrance.

When the nitrogen of the substrate contains a chiral R group, both the Stork enamine synthesis and the enamine salt method can be used to perform enantioselective syntheses.¹⁷⁹⁹ The use of S-proline can generate a chiral enamine in situ, thus allowing alkylation to occur, giving alkylated product with good enantioselectivity. The reaction has been done intramolecularly.¹⁸⁰⁰

Conjugate addition (Michael addition) occurs when enamines react with conjugated ketones. This reaction is discussed in Reaction 15-24.

OS V, 533, 869; VI, 242, 496, 526; VII, 473.

10-70 Alkylation of Carboxylic Acid Salts

α-Carboxyalkyl-de-halogenation

Carboxylic acids can be alkylated in the α position by conversion of their salts to dianions, which have resonance contributors,¹⁸⁰¹ by treatment with a strong base (e.g., LDA).¹⁸⁰² The use of Li⁺ as the counterion increases the solubility of the dianionic salt. The reaction has been applied¹⁸⁰³ to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCH₂CO₂H and RR²CHCO₂H.¹⁶⁹⁵ Allkylation occurs at carbon, the more nucleophilic site relative to the carboxylate oxygen anion (see Sec. 10.G.vii). This procedure is an alternative to the malonic ester synthesis (Reaction 10-67) as a means of preparing carboxylic acids and has the advantage that acids of the form RR′R²CCO₂H can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure.¹⁸⁰⁴

OS V, 526; VI, 517; VII, 249. See also, OS VII, 164.

10-71 Alkylation at a Position α to a Heteroatom

2-(2-Alkyl-thio) de-halogenation

The presence of a sulfur atom on a carbon enhances the acidity of a proton on that carbon, and in dithioacetals and dithioketals that proton RSCH₂SR is even more acidic. 1,3-Dithianes can be alkylated¹⁸⁰⁵ if a proton is first removed by treatment with butyllithium in THF.¹⁸⁰⁶ Since 1,3-dithianes can be prepared by treatment of an aldehyde or its acetal (see OS VI, 556) with 1,3-propanedithiol (Reaction 16-11) and can be hydrolyzed (Reaction 10-7), this is a method for the conversion of an aldehyde to a ketone¹⁸⁰⁷ (see also, Reactions 10-68 and 18-9):

This is another example of Umpolung (see Reaction 10-68);¹⁷⁷³ the normally electrophilic carbon of the aldehyde is made to behave as a nucleophile. The reaction can be applied to the unsubstituted dithiane (R = H) and one or two alkyl groups can be introduced, so a wide variety of aldehydes and ketones can be made starting with formaldehyde.¹⁸⁰⁸ The R′ group may be a primary or secondary alkyl or benzylic. Iodides give the best results. The reaction has been used to close rings.¹⁸⁰⁹ A similar synthesis of aldehydes can be performed starting with ethyl ethylthiomethyl sulfoxide (EtSOCH₂SEt).¹⁸¹⁰

Group A may be regarded as a structural equivalent for carbonyl group B, since introduction of A into a molecule is actually an indirect means of introducing B. It is convenient to have a word for units within molecules. Such a word is synthon, introduced by Corey,¹⁸¹¹ which is defined as a structural unit within a molecule that can be formed and/or assembled by known or conceivable synthetic operations. There are many other synthons equivalent to Aand B (e.g., C; by Reactions 19-36 and 19-3) and D (by Reactions 10-2 and 16-23).¹⁸¹²

Carbanions generated from 1,3-dithianes also react with epoxides¹⁸¹³ to give the expected products. Reaction with epoxides leads to intermediates that undergo the Brook rearrangement (Reaction 18-44), which is synthetically useful in what is known as anion relay chemistry.

Another useful application of this reaction stems from the fact that dithianes can be desulfurated with Raney nickel (Reaction 14-27). Aldehydes can therefore be converted to chain-extended hydrocarbons:¹⁸¹⁴

Similar reactions have been carried out with other thioacetals, as well as with compounds containing three thioether groups on a carbon.¹⁸¹⁵

If a stabilizing group other than sulfur is attached to the S–CH₂ unit of a thioether (RSCH₂X, where X is a stabilizing group), formation of the anion and alkylation can be facile. For example, benzylic and allylic thioethers (RSCH₂Ar and RSCH₂CH=CH₂)¹⁸¹⁶ and thioethers of the form RSCH₃ (R = tetrahydrofuranyl or 2-tetrahydropyranyl)¹⁸¹⁷ have been successfully alkylated at the carbon adjacent to the sulfur atom.¹⁸¹⁸ Stabilization by one thioether group has also been used in a method for the homologation of primary halides.¹⁸¹⁹ Thioanisole is treated with BuLi to give the corresponding anion,¹⁸²⁰ which reacts with the halide to give the thioether, which is then refluxed with a mixture of methyl iodide and sodium iodide in DMF to give the alkyl iodide as the final product (via an intermediate sulfonium salt). By this sequence, an alkyl halide (RX) is converted to its homologue RCH₂X by a pathway involving two laboratory steps (see also, Reaction 10-64).

Vinylic sulfides containing an α hydrogen can also be alkylated¹⁸²¹ by alkyl halides or epoxides. This method is for converting an alkyl halide (RX) to an α,β-unsaturated aldehyde, which is the synthetic equivalent of the unknown ⁻HC=CH–CHO ion.¹⁸²² Even simple alkyl aryl sulfides (RCH₂SAr and RR′CHSAr) have been alkylated α to the sulfur.¹⁸²³

Sulfones¹⁸²⁴ and sulfonic esters can also be alkylated in the α position if strong enough bases are used.¹⁸²⁵ Alkylation at the α position of selenoxides allows the formation of alkenes, since selenoxides easily undergo elimination (Reaction 17-12).¹⁸²⁶

Alkylation can also be carried out, in certain compounds, at positions α to other heteroatoms,¹⁸²⁷ for example, at a position α to the nitrogen of tertiary amines.¹⁸²⁸ Alkylation α to the nitrogen of primary or secondary amines is not generally feasible because an NH hydrogen is usually more acidic than a CH hydrogen.

α-Lithiation of N-Boc amines has been accomplished and these react with halides in the presence of a Pd catalyst.¹⁸²⁹ Alkylation α to the nitrogen atom of a carbamate occurs when the carbamate is treated with a Grignard reagentunder electrolysis conditions.¹⁸³⁰ α-Methoxy amides also react with allyl halides and zinc metal to give alkylation via replacement of the OMe unit.¹⁸³¹ It has been accomplished, however, by replacing the NH hydrogens with other (removable) groups.¹⁸³² In one example, a secondary amine is converted to its N-nitroso derivative (Reaction 12-50).¹⁸³³ The N-nitroso product is easily hydrolyzed to the product amine (Reaction 19-51).¹⁸³⁴ Alkylation of secondary and primary amines has also been accomplished with > 10 other protecting groups, involving conversion of amines to amides, carbamates,¹⁸³⁵ formamidines,¹⁸³⁶ and phosphoramides.¹⁸³¹ In the case of formamidines (165), use of a chiral R′ leads to a chiral amine, in high ee, even when R is not chiral.¹⁸³⁷ The reaction of hydrazones with aryl halides, in the presence of a Pd catalyst leads to replacement of H with an aryl group (R'NH–N=CRH → R'NHC=NRR”).¹⁸³⁸

A proton can be removed from an allylic ether by treatment with an alkyllithium at about −70 °C (at higher temperatures the Wittig rearrangement, 18-22, takes place) to give the ion 166, which reacts with alkyl halides

to give the two products shown.¹⁸³⁹ Similar reactions¹⁸⁴⁰ have been reported for allylic¹⁸⁴¹ and vinylic tertiary amines. In the latter case, enamines (167), treated with a strong base, are converted to anions that are then alkylated, generally at C-3.¹⁸⁴² (For direct alkylation of enamines at C-2, see Reaction 10-69.)

It is also possible to alkylate a methyl, ethyl, or other primary group of an aryl ester (ArCO₂R), where Ar is a 2,4,6-trialkylphenyl group.¹⁸⁴³ Since esters can be hydrolyzed to alcohols, this constitutes an indirect alkylation of primary alcohols. Methanol has also been alkylated by converting it to ⁻CH₂O⁻.¹⁸⁴⁴

OS VI, 316, 364, 542, 704, 869; VIII, 573.

10-72 Alkylation of Dihydro-1,3-Oxazine. The Meyers Synthesis of Aldehydes, Ketones, and Carboxylic Acids

A synthesis of aldehydes¹⁸⁴⁵ developed by Meyers et al.¹⁸⁴⁶ begins with the commercially available dihydro-1,3-oxazine derivatives (168; A = H, Ph, or COOEt).¹⁸⁴⁷ Removal of a proton from the indicated carbon in 168 leads to the resonance stabilized and bidentate anion (169). Alkylation occurs regioselectively at carbon using many alkyl bromides and iodides. The R group of RX can be primary or secondary alkyl, allylic, or benzylic and can carry another halogen or a CN group.¹⁸⁴⁸ The alkylated oxazine (170) is then reduced and hydrolyzed to give an aldehyde containing two more carbons than the starting RX. This method thus complements Reaction 10-71, which converts RX to an aldehyde containing one more carbon. Since A can be H, mono- or disubstituted acetaldehydes can be produced by this method.

The ion 169 also reacts with epoxides, to form γ-hydroxy aldehydes after reduction and hydrolysis,¹⁸⁴⁹ and with aldehydes and ketones (Reaction 16-38). Similar aldehyde synthesis has also been carried out with thiazoles¹⁸⁵⁰ and thiazolines¹⁸⁵¹ (five-membered rings containing N and S in the 1 and 3 positions).

The reaction has been extended to the preparation of ketones:¹⁸⁵² Treatment of a dihydro-1,3-oxazine (171) with iodomethane forms the iminium salt (Reaction 10-31) which, when treated with a Grignard reagent or organolithium compound (16-31), produces 172, which can be hydrolyzed to a ketone. The R group can be alkyl, cycloalkyl, aryl, benzylic, and so on, and R′ of the Grignard reagent can be alkyl, aryl, benzylic, or allylic. Note that the heterocycles 168, 170, or 171 do not react directly with Grignard reagents. In another procedure, 2-oxazolines¹⁸⁵³ (173) can be alkylated to give 174,¹⁸⁵⁴ which are easily converted directly to the esters 175 by heating in 5–7% ethanolic sulfuric acid.

2-Oxazolines (173 and 174) are thus synthons for carboxylic acids; this is another indirect method for the α alkylation of a carboxylic acid,¹⁸⁵⁵ representing an alternative to the malonic ester synthesis (10-67) and to Reactions 10-70 and 10-73. The method can be adapted to the preparation of optically active carboxylic acids by the use of a chiral reagent.¹⁸⁵⁶ Note that, unlike 168, 173 can be alkylated even if R is alkyl. However, the C=N bond of 173 and 174cannot be effectively reduced, so that aldehyde synthesis is not feasible here.¹⁸⁵⁷

OS VI, 905.

10-73 Alkylation with Boranes, Boronic Acids, and Boronates

Alkyl-de-halogenation

Trialkylboranes react rapidly and in high yields with α-halo ketones,¹⁸⁵⁸ α-halo esters,¹⁸⁵⁹ α-halo nitriles,¹⁸⁶⁰ and α-halo sulfonyl derivatives (sulfones, sulfonic esters, sulfonamides)¹⁸⁶¹ in the presence of a base to give, respectively, alkylated ketones, esters, nitriles, and sulfonyl derivatives.¹⁸⁶² Potassium tert-butoxide is often a suitable base, but potassium 2,6-di-tert-butylphenoxide at 0 °C in THF gives better results in most cases, possibly because the large bulk of the two tert-butyl groups prevents the base from coordinating with the R₃B.¹⁸⁶³ The trialkylboranes are prepared by treatment of 3 equiv of an alkene with 1 equiv of BH₃ (Reaction 15-16).¹⁸⁶⁴ With appropriate boranes, the R group transferred to α-halo ketones, nitriles, and esters can be vinylic,¹⁸⁶⁵ or (for α-halo ketones and esters) aryl.¹⁸⁶⁶

The reaction can be extended to α,α-dihalo esters¹⁸⁶⁷ and α,α-dihalo nitriles.¹⁸⁶⁸ It is possible to replace just one halogen or both. In the latter case, the two alkyl groups can be the same or different. When dialkylation is applied to dihalo nitriles, the two alkyl groups can be primary or secondary, but with dihalo esters, dialkylation is limited to primary R. Another extension is the reaction of boranes (BR₃) with γ-halo-α,β-unsaturated esters.¹⁸⁶⁹ Alkylation takes place in the γ position, but the double bond migrates out of conjugation with the CO₂Et unit [BrCH₂CH=CHCO₂Et → RCH=CHCH₂CO₂Et]. In this case, however, double-bond migration is an advantage, because nonconjugated β,γ-unsaturated esters are usually much more difficult to prepare than their α,β-unsaturated isomers.

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by H.C. Brown¹⁸⁷⁰ (see also, Reactions 15-16, 15-27, 18-31–18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (via the BR₃) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see Reaction 10-68) or a carboxylic acid (see Reaction 10-70), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (Reaction 10-67).

Although superficially this reaction resembles Reaction 10-57, it is likely that the mechanism is quite different, involving migration of an R group from boron to carbon (see also, Reactions 18-23–18-26). The mechanism is not known with certainty,¹⁸⁷¹ but it may be tentatively shown as (illustrated for an α-halo ketone):

The first step is removal of the acidic proton by the base to give an enolate anion that combines with the borane (Lewis acid–base reaction). An R group then migrates, displacing the halogen leaving group.¹⁸⁷² Another migration follows, this time of BR₂ from carbon to oxygen to give the enol borinate (176),¹⁸⁷³ which is hydrolyzed. Configuration at the alkyl group R is retained.¹⁸⁷⁴

Alkenylboranes (R'₂C=CHBZ₂; Z = various groups) couple in high yields with vinylic,¹⁸⁷⁵ alkynyl, aryl, benzylic, and allylic halides or triflates in the presence of a Pd catalyst and a base to give R'₂C=CHR.¹⁸⁷⁶ 9-Alkyl-9-BBN compounds (Reaction 15-16) also couple with vinylic and aryl halides,¹⁸⁷⁷ as well as with α-halo ketones, nitriles, and esters.¹⁸⁷⁸

The reaction has also been applied to compounds with other leaving groups. Diazo ketones, diazo esters, diazo nitriles, and diazo aldehydes (177)¹⁸⁷⁹ react with trialkylboranes in a similar manner.

The mechanism is probably also similar. In this case, a base is not needed, since the carbon already has an available pair of electrons. The reaction with diazo aldehydes¹⁸⁸⁰ is especially notable, since successful reactions cannot be obtained with α-halo aldehydes.¹⁸⁸¹

Alkyl¹⁸⁸² and aryl¹⁸⁸³ boronic acids [RB(OH)₂] react with allylic acetates to give the alkylated product in the presence of a Pd catalyst.¹⁸⁸⁴ A cyclopropylboronic acid was coupled to an allylic bromide with silver oxide/KOH and a Pd catalyst.¹⁸⁸⁵ Arylboronic acids undergo a coupling reaction with epoxides in the presence of a Pd catalyst.¹⁸⁸⁶ Alkylboronic acids can also be coupled to aromatic compounds in the presence of Cu(OAc)₂ and a Pd catalyst.¹⁸⁸⁷ The Pd catalyzed coupling of vinyl halides and alkylboronic acids,¹⁸⁸⁸ which gives substituted alkenes, is related to the Suzuki coupling (Reaction 13-12). Vinyl zirconium reagents were coupled to alkyl halides with a Pd catalyst.¹⁸⁸⁹Arylation of sp³ C–H positions can be done using arylboronates and a Rh catalyst.¹⁸⁹⁰ In a related but metal-free reaction, activated epoxides and aziridines are opened by borates.¹⁸⁹¹

Potassium aryl- and 1-alkenyltrifluoroborates (ArBF₃K and RBF₃K) are easily prepared from organoboronic acids or esters. In general, the trifluoroborates have greater air stability and greater nucleophilicity¹⁸⁹² when compared to the corresponding organoboranes and organoboronic acid derivatives. Potassium alkyltrifluoroborates undergo the Pd catalyzed coupling reaction with arenediazonium tetrafluoroborates,¹⁸⁹³ diaryliodonium salts,¹⁸⁹⁴ aryl halides,¹⁸⁹⁵ as well as with aryl triflates. An example of the latter reaction converted 178 to diphenylmethane via coupling with phenyl triflate.¹⁸⁹⁶ Alkenyltrifluoroborates can be coupled to aryl halides.¹⁸⁹⁷

where dppf = bis(diphenylphosphino)ferrocene.

OS VI, 919; IX, 107.

10-74 Alkylation at an Alkynyl Carbon

Alkynyl-de-halogenation

The reaction between alkyl halides and acetylide ions is useful, but of limited scope.¹⁸⁹⁸ Only primary halides unbranched in the β-position give good yields, although allylic halides can be used if CuI is present.¹⁸⁹⁹ If acetylene is the reagent, two different groups can be successively attached. Sulfates, sulfonates, and epoxides¹⁹⁰⁰ are sometimes used as substrates. The acetylide ion is often prepared by treatment of an alkyne with a strong base (e.g., NaNH₂). Magnesium acetylides (prepared as in Reaction 12-22) are also frequently used, although they react only with active substrates (e.g., allylic, benzylic, and propargylic halides) and not with primary alkyl halides. Alternatively, the alkyl halide can be treated with a lithium acetylide–ethylenediamine complex.¹⁹⁰¹ If 2 equiv of a very strong base are used, alkylation can be effected at a carbon α to a terminal triple bond: RCH₂CCH + 2BuLi → RCHC(C:⁻ + R′Br → RR′CHCC:⁻.¹⁹⁰² For another method of alkylating at an alkynyl carbon, see Reaction 18-26. An alternative method for generating an alkyne anion treated a trialkylsilyl alkyne with potassium carbonate in methanol, and then methyllithium/LiBr.¹⁹⁰³ In the presence of an alkyl iodide, alkylation at the alkynyl carbon occurred. Terminal alkynes react with alkylzinc reagents in the presence of a Pd catalyst.¹⁹⁰⁴

Other metalated terminal alkynes can be coupled to substrates with a leaving group, and even with other organometallics. In the presence of a Pd catalysts, an alkynyltin reagent reacts with an alkylzinc compound to give the corresponding alkyne.¹⁹⁰⁵ Terminal alkynes react with allylic bromides in the presence of a Ni catalyst.¹⁹⁰⁶ The reaction of a terminal alkyne with Zn(II) compounds allows reaction with silanes to give the 1-silylalkyne.¹⁹⁰⁷ A Re catalyzed C–H insertion reaction is known using terminal alkynes and an active methylene compound.¹⁹⁰⁸ Alkynylzinc compounds undergo Pd catalyzed cross-coupling reactions.¹⁹⁰⁹

1-Haloalkynes react with various substrates in the presence of a metal catalyst. 1-Haloalkynes (e.g., R–CC–X react with ArSnBu₃ and CuI to give R–CC–Ar.¹⁹¹⁰ Organozirconium compounds react in a similar manner.¹⁹¹¹Acetylene reacts with 2 equiv of iodobenzene, in the presence of a Pd catalyst and CuI, to give 1,2-diphenylethyne.¹⁹¹² 1-Trialkylsilyl alkynes react with 1-haloalkynes, in the presence of a CuCl catalyst, to give diynes¹⁹¹³ and with aryl triflates to give 1-aryl alkynes.¹⁹¹⁴ The enolate anion derived from a β-keto ester couples with 1-bromoalkynes to give the corresponding substitution product.¹⁹¹⁵ 1-Bromoalkynes react with nitrogen compounds (e.g., imidazole) in the presence of a Cu catalyst to give the corresponding alkyne.¹⁹¹⁶ 1-Bromoalkynes react with Grignard derived reagents in the presence of an Fe catalyst.¹⁹¹⁷

Alkynes couple with alkyl halides in the presence of SmI₂/Sm,¹⁹¹⁸ or a copper catalyst.¹⁹¹⁹ Alkynes react with hypervalent iodine compounds¹⁹²⁰ and with reactive alkanes (e.g., adamantane) in the presence of AIBN.¹⁹²¹ The reaction of benzylic amines with terminal alkynes, in the presence of copper triflate and tert-butylhydroperoxide, leads to incorporation of the alkyne group α to the nitrogen.¹⁹²² A similar reaction occurs at a methyl group of N,N-dimethylaniline.¹⁹²³ α-Methoxycarbamates (MeO–CHR–NR¹– CO₂R²) react with terminal alkynes and CuBr to give the alkynylamine.¹⁹²⁴ In the presence of GaCl₃, ClCCSiMe₃ reacts with silyl enol ethers to give, after treatment with methanolic acid, an α-ethynyl ketone.¹⁹²⁵

In a related reaction, terminal alkynes react with silanes (R₃SiH) in the presence of an Ir catalyst¹⁹²⁶ or zinc triflate¹⁹²⁷ to give the 1-trialkylsilyl alkyne. Similar products are obtained when terminal alkynes react with N-trialkylsilylamines and ZnCl₂.¹⁹²⁸

OS IV, 117; VI, 273, 564, 595; VIII, 415; IX, 117, 477, 688; 76, 263. Also see, OS IV, 801; VI, 925.

10-75 Preparation of Nitriles

Cyano-de-halogenation

The reaction between cyanide ion and alkyl halides is a convenient method for the preparation of nitriles,¹⁹²⁹ The reaction proceeds by a S_N2 mechanism,¹⁹³⁰ so primary, benzylic, and allylic halides give good yields of nitriles; secondary halides give moderate yields. The reaction fails for tertiary halides, which give elimination under these conditions. Many other groups on the molecule do not interfere. A number of solvents have been used, but the high yields and short reaction times observed with DMSO make it a very good solvent for this reaction.¹⁹³¹ In general, polar aprotic solvents are the best choice. Other ways to obtain high yields under mild conditions are to use a phase-transfer catalyst,¹⁹³² in alternative solvents (e.g., PEG 400 (a polyethylene glycol)],¹⁹³³ or with ultrasound.¹⁹³⁴ This is an important way of increasing the length of a carbon chain by one carbon, since nitriles are easily hydrolyzed to carboxylic acids (Reaction 16-4).

The cyanide ion is an ambident nucleophile (it can react via N or via C) and isonitriles (also called isocyanides, R–NC) may be side products.¹⁹³⁵ If the preparation of isocyanides is desired (see Reaction 10-40), they can be made the main products by the use of reagents with more covalent metal–carbon bonds [e.g., silver or copper(I) cyanide,¹⁹³⁶ Sec. 10.G.vii, category 3]. However, the use of an excess of LiCN in acetone/THF gave the nitrile as the major product.¹⁹³⁷ Tosyl cyanide (TolSO₂CN) has been used in some cases.¹⁹³⁸ A radical cyanation of alkyl iodides has been reported using diethylphosphoryl cyanide¹⁹³⁹ (see Chap. 14).

Vinylic bromides can be converted to vinylic cyanides with CuCN,¹⁹⁴⁰ with KCN, a crown ether, and a Pd complex,¹⁹⁴¹ or with KCN and a Ni(0) catalyst.¹⁹⁴² Halides can be converted to the corresponding nitriles by treatment with trimethylsilyl cyanide in the presence of catalytic amounts of SnCl₄: R₃CCl + Me₃SiCN → R₃CCN.¹⁹⁴³ Primary, secondary, and tertiary alcohols are converted to nitriles in good yields by treatment with NaCN, Me₃SiCl, and a catalytic amount of NaI in DMF–MeCN.¹⁹⁴⁴ Lewis acids have been used in conjunction with NaCN or KCN.¹⁹⁴⁵ α,β-Epoxy amides were opened to the β-cyano-α-hydroxyamide with Et₂AlCN.¹⁹⁴⁶ Cyanohydrins react with alkyl halides in some cases to give the nitrile.¹⁹⁴⁷

Substrates that react with cyanide may contain leaving groups other than halides (e.g., esters of sulfuric and sulfonic acids, sulfates and sulfonates, respectively). Vinylic triflates give vinylic cyanides when treated with LiCN, a crown ether, and a Pd catalyst.¹⁹⁴⁸ Epoxides give β-hydroxy nitriles. The C-2-Selectivity was observed when NaCN and B(OMe)₃ were reacted with a disubstituted epoxide.¹⁹⁴⁹ The use of trimethylsilyl cyanide (Me₃SiCN) and a Lewis acid generates the O-TMS β-hydroxy nitrile, and the use of YbCl₃ and a salen complex gave good enantioselectivity.¹⁹⁵⁰ Tetrabutylammonium cyanide converted a primary alcohol to the corresponding nitrile in the presence of PPh₃/DDQ.¹⁹⁵¹ Alcohols are converted to cyanides by reaction with triphenylphosphine and cyanogen bromide.¹⁹⁵²

Sodium cyanide in HMPA selectively cleaves methyl esters in the presence of ethyl esters:¹⁹⁵³

OS I, 46, 107, 156, 181, 254, 256, 536; II, 292, 376; III, 174, 372, 557; IV, 438, 496, 576; V, 578, 614.

10-76 Direct Conversion of Alkyl Halides to Aldehydes and Ketones

Formyl-de-halogenation

The direct conversion of alkyl bromides to aldehydes, with an increase in the chain length by one carbon, can be accomplished¹⁹⁵⁴ by treatment with sodium tetracarbonylferrate(-2)¹⁹⁵⁵ (Collman's reagent) in the presence of triphenylphosphine and subsequent quenching of 179 with acetic acid. The reagent Na₂Fe(CO)₄ can be prepared by treatment of iron pentacarbonyl [Fe(CO)₅] with sodium amalgam in THF. Good yields are obtained from primary alkyl bromides; secondary bromides give lower yields. The reaction is generally not satisfactory for benzylic bromides, but a good yield of the ketone was obtained using benzyl chloride and aryl iodides.¹⁹⁵⁶ The initial species produced from RX and Na₂Fe(CO)₄ is the ion RFe(CO)₄⁻, which can be isolated;¹⁹⁵⁷ it then reacts with Ph₃P to give 179.¹⁹⁵⁸

The synthesis can be extended to the preparation of ketones in six distinct ways.¹⁹⁵⁹ These include quenching 179 with a second alkyl halide (R′X) rather than acetic acid; omitting PPh₃ with first RX and then adding the second, R′X; treatment with RX in the presence of CO,¹⁹⁵⁵ followed by treatment with R′X′; treatment with an acyl halide followed by treatment with an alkyl halide or an epoxide, gives an α,β-unsaturated ketone.¹⁹⁶⁰ The final variations involve reaction of alkyl halides or tosylates with Na₂Fe(CO)₄ in the presence of ethylene to give alkyl ethyl ketones;¹⁹⁶¹ when 1,4-dihalides are used, five-membered cyclic ketones are prepared.¹⁹⁶²

Yet another approach uses electrolysis conditions with the alkyl chloride, Fe(CO)₅, and a Ni catalyst, which gives the ketone directly, in one step.¹⁹⁶³ In the first stage of methods 1, 2, and 3, primary bromides, iodides, and tosylates and secondary tosylates can be used. The second stage of the first-four methods requires more active substrates (e.g., primary iodides or tosylates or benzylic halides). Method 5 has been applied to primary and secondary substrates.

Other acyl organometallic reagents are known. An acyl zirconium reagent [e.g., RCOZr(Cl)Cp₂] reacted with allylic bromide in the presence of CuI to give the corresponding ketone, but with allylic rearrangement.¹⁹⁶⁴

Symmetrical ketones (R₂CO) can be prepared by treatment of a primary alkyl or benzylic halide with Fe(CO)₅ and a phase-transfer catalyst,¹⁹⁶⁵ or from a halide RX (R = primary alkyl, aryl, allylic, or benzylic) and CO by an electrochemical method involving a nickel complex.¹⁹⁶⁶ Aryl, benzylic, vinylic, and allylic halides have been converted to aldehydes by treatment with CO and Bu₃SnH, with a Pd catalyst.¹⁹⁶⁷ Various other groups do not interfere. Several procedures for the preparation of ketones are catalyzed by Pd complexes. Alkyl aryl ketones are formed in good yields by treatment of a mixture of an aryl iodide, an alkyl iodide, and a Zn–Cu couple with CO (ArI + RI + CO → RCOAr).¹⁹⁶⁸ Vinylic halides react with vinylic tin reagents in the presence of CO to give unsymmetrical divinyl ketones.¹⁹⁶⁹ Aryl, vinylic, and benzylic halides can be converted to methyl ketones (RX → RCOMe) by reaction with (α-ethoxyvinyl)tributyltin [Bu₃SnC(OEt)=CH₂].¹⁹⁷⁰ In addition, SmI₂ can be used to convert alkyl chlorides to ketones, in the presence of 50 atm of CO.¹⁹⁷¹

The conversion of alkyl halides to aldehydes and ketones can also be accomplished indirectly (Reaction 10-71). See also, Reaction 12-33.

OS VI, 807.

10-77 Carbonylation of Alkyl Halides, Alcohols, or Alkanes

Alkoxycarbonyl-de-halogenation

A direct method for preparing a carboxylic acid treats an alkyl halide with NaNO₂ in acetic acid and DMSO.¹⁹⁷² Reaction of an alkyl halide with ClCOCO₂Me and (Bu₃Sn)₂ under photochemical conditions leads to the corresponding methyl ester.¹⁹⁷³

Several methods, all based on carbon monoxide or metal carbonyls, have been developed for converting an alkyl halide to a carboxylic acid or an acid derivative with the chain extended by one carbon.¹⁹⁷⁴ When an alkyl halide is treated with SbCl₅–SO₂ at −70 °C, it dissociates into the corresponding carbocation (Sec. 5.A.ii). If carbon monoxide and an alcohol are present, a carboxylic ester is formed by the following route:¹⁹⁷⁵

This has also been accomplished with concentrated H₂SO₄ saturated with CO.¹⁹⁷⁶ Not surprisingly, only tertiary halides perform satisfactorily; secondary halides give mostly rearrangement products. An analogous reaction takes place with alkanes possessing a tertiary hydrogen, using HF–SbF₅–CO.¹⁹⁷⁷

Carboxylic acids or esters are the products, depending on whether the reaction mixture is solvolyzed with water or an alcohol. Alcohols with more than seven carbons are cleaved into smaller fragments by this procedure.¹⁹⁷⁸Similarly, tertiary alcohols¹⁹⁷⁹ react with H₂SO₄ and CO (which is often generated from HCOOH and the H₂SO₄ in the solution) to give trisubstituted acetic acids in a process called the Koch–Haaf reaction (see also, 15-35).¹⁹⁸⁰ If a primary or secondary alcohol is the substrate, the carbocation initially formed rearranges to a tertiary ion before reacting with the CO. Better results are obtained if trifluoromethanesulfonic acid (F₃CSO₂OH) is used instead of H₂SO₄.¹⁹⁸¹ Iodo alcohols were transformed into lactones under radical conditions (AIBN, allylSnBu₃) and 45 atm of CO.¹⁹⁸²

Another method¹⁹⁸³ for the conversion of alkyl halides to carboxylic esters is treatment of a halide with nickel carbonyl [Ni(CO)₄] in the presence of an alcohol and its conjugate base.¹⁹⁸⁴ When R′ is primary, RX may only be a vinylic or an aryl halide; retention of configuration is observed at a vinylic R. Consequently, a carbocation intermediate is not involved here. When R′ is tertiary, R may be primary alkyl as well as vinylic or aryl. This is thus one of the few methods for preparing esters of tertiary alcohols. Alkyl iodides give the best results, then bromides. In the presence of an amine, an amide can be isolated directly, at least in some instances.

Still another method for the conversion of halides to acid derivatives makes use of Na₂Fe(CO)₄. As described in Reaction 10-76, primary and secondary alkyl halides and tosylates react with this reagent to give the ion RFe(CO)₄⁻or, if CO is present, the ion RCOFe(CO)₄⁻. Treatment of RFe(CO)₄⁻ or RCOFe(CO)₄⁻ with oxygen or sodium hypochlorite gives, after hydrolysis, a carboxylic acid.¹⁹⁸⁵ Alternatively, RFe(CO)₄⁻ or RCOFe(CO)₄⁻ reacts with a halogen (e.g., I₂) in the presence of an alcohol to give a carboxylic ester,¹⁹⁸⁶ or in the presence of a secondary amine or water to give, respectively, the corresponding amide or free acid. Both RFe(CO)₄⁻ and RCOFe(CO)₄⁻, which are prepared from primary R, give high yields. With secondary R, the best results are obtained in the solvent THF by the use of RCOFe(CO)₄⁻ prepared from secondary tosylates. Ester and keto groups may be present in R without being affected. Carboxylic esters (RCO₂R′) have also been prepared by treating primary alkyl halides RX with alkoxides R′O⁻ in the presence of Fe(CO)₅.¹⁹⁸⁷ Here RCOFe(CO)₄⁻ is presumably an intermediate.

Palladium complexes also catalyze the carbonylation of halides.¹⁹⁸⁸ Aryl (see Reaction 13-15),¹⁹⁸⁹ vinylic,¹⁹⁹⁰ benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a Pd complex.¹⁹⁹¹ The Pd catalyzed carbonylation of organoindium compounds in the presence of methanol gives methyl esters.¹⁹⁹² Similar reactivity was reported with vinyl triflates.¹⁹⁹³ α-Halo ketones are converted to β-keto esters with CO, an alcohol, NBu₃ and a palladium catalyst at 110 °C.¹⁹⁹⁴ Use of an amine instead of the alcohol or alkoxide leads to an amide.¹⁹⁹⁵ Reaction with an amine, AIBN, CO, and a tetraalkyltin catalyst also leads to an amide.¹⁹⁹⁶ Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a Co–imine complex.¹⁹⁹⁷ Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions.¹⁹⁹⁸ Allylic O-phosphates were converted to allylic amides with CO and ClTi=NTMS, in the presence of a Pd catalyst.¹⁹⁹⁹ Terminal alkynes were converted to the alkynyl ester using CO, PdBr₂, CuBr₂ in methanol, and sodium bicarbonate.²⁰⁰⁰

Other organometallic reagents can be used to convert alkyl halides to carboxylic acid derivatives. Benzylic halides were converted to carboxylic esters with CO in the presence of a rhodium complex.²⁰⁰¹ Variations introduce the R′ group via an ether (R'₂O),²⁰⁰² or an Al, Ti, or Zr alkoxide.²⁰⁰³ The reaction of an alkene, a primary alcohol, and CO, in the presence of a Rh catalyst, led to carbonylation of the alkene and formation of the corresponding ester.²⁰⁰⁴Vinyl triflates were converted to the conjugated carboxylic acid with CO₂ and a Ni catalyst.²⁰⁰⁵ Reaction with an α,ω-diiodide, Bu₄NF, and Mo(CO)₆ gave the corresponding lactone.²⁰⁰⁶

A number of double carbonylations have been reported. In these reactions, two molecules of CO are incorporated in the product, leading to α-keto acids or their derivatives.²⁰⁰⁷ When the catalyst is a Pd complex, best results are obtained in the formation of α-keto amides.²⁰⁰⁸ The R group is usually aryl or vinylic.²⁰⁰⁹ The formation of α-keto acids²⁰¹⁰ or esters²⁰¹¹ requires more severe conditions. α-Hydroxy acids were obtained from aryl iodides when the reaction was carried out in the presence of an alcohol, which functioned as a reducing agent.²⁰¹² Cobalt catalysts have also been used and require lower CO pressures.²⁰⁰⁷

OS V, 20, 739.

Notes

1. See Hartshorn, S.R. Aliphatic Nucleophilic Substitution, Cambridge University Press, Cambridge, 1973; Katritzky, A.R.; Brycki, B.E. Chem. Soc. Rev. 1990, 19, 83; Richard, J.P. Adv. Carbocation Chem. 1989, 1, 121; Streitwieser, A. Solvolytic Displacement Reactions, McGraw-Hill, NY, 1962.

2. See Sun, L.; Hase, W. L.; Song, K. J. Am. Chem. Soc. 2001, 123, 5753. Nucleophlicity and leaving group ability for frontside and backside attack have been studied. See Bento, A.P.; Bickelhaupt, F.M. J. Org. Chem. 2008, 73,7290.

3. Hasanayn, F.; Streitwieser, A.; Al-Rifai, R. J. Am. Chem. Soc. 2005, 127, 2249. See also Cruickshank, F.R.; Hyde, A.J.; Pugh, D. J. Chem. Ed. 1977, 54, 288.

4. For a theoretical investigation of a kinetic isotope effect, see Matsson, O.; Dybala-Defratyka, A.; Rostkowski, M.; Paneth, P.; Westaway, K.C. J. Org. Chem. 2005, 70, 4022.

5. For a discussion of this type of solvent effect, see Arnaut, L.G.; Formosinho, S.J. Chemistry: European J. 2007, 13, 8018.

6. Cowdrey, W.A.; Hughes, E.D.; Ingold, C.K.; Masterman, S.; Scott, A.D. J. Chem. Soc. 1937, 1252. The idea that the addition of one group and removal of the other are simultaneous was first suggested by Lewis, G.N. in Valence and the Structure of Atoms and Molecules, Chemical Catalog Company, NY, 1923, p. 113. The idea that a one-step substitution leads to inversion was proposed by Olsen, A.R. J. Chem. Phys. 1933, 1, 418.

7. Walden, P. Ber. 1893, 26, 210; 1896, 29, 133; 1899, 32, 1855.

8. For a discussion of these cycles, see Kryger, L.; Rasmussen, S.E. Acta Chem. Scand. 1972, 26, 2349.

9. Phillips, H. J. Chem. Soc. 1923, 123, 44. See Garwood, D.C.; Cram, D.J. J. Am. Chem. Soc. 1970, 92, 4575; Cram, D.J.; Cram, J.M. Fortschr. Chem. Forsch. 1972, 31, 1.

10. See Kenyon, J.; Phillips, H.; Shutt, G.R. J. Chem. Soc. 1935, 1663 and references cited therein.

11. Streitwieser, Jr., A. J. Am. Chem. Soc. 1953, 75, 5014.

12. Speranza, M.; Angelini, G. J. Am. Chem. Soc. 1980, 102, 3115 and references cited therein; Kempf, B.; Hampel, N.; Ofial, A.R.; Mayr, H. Chem. Eur. J. 2003, 9, 2209. See Riveros, J.M.; José, S.M.; Takashima, K. Adv. Phys. Org. Chem. 1985, 21, 197.

13. Li, C.; Ross, P.; Szulejko, J.E.; McMahon, T.B. J. Am. Chem. Soc. 1996, 118, 9360.

14. See Müller, P.; Mareda, J. in Olah, G.A. Cage Hydrocarbons, Wiley, NY, 1990, pp. 189–217; Fort, Jr., R.C.; Schleyer, P.v.R. Adv. Alicyclic Chem. 1966, 1, 283.

15. Doering, W. von E.; Levitz, M.; Sayigh, A.; Sprecher, M.; Whelan, Jr., W.P. J. Am. Chem. Soc. 1953, 75, 1008. Actually, a slow substitution was observed in this case, but not by an S_N2 mechanism.

16. Cope, A.C.; Synerholm, M.E. J. Am. Chem. Soc. 1950, 72, 5228.

17. Hughes, E.D.; Juliusburger, F.; Masterman, S.; Topley, B.; Weiss, J. J. Chem. Soc. 1935, 1525.

18. Tenud, L.; Farooq, S.; Seibl, J.; Eschenmoser, A. Helv. Chim. Acta 1970, 53, 2059. See also, King, J.F.; McGarrity, M.J. J. Chem. Soc., Chem. Commun. 1979, 1140.

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42. Benfey, O.T.; Hughes, E.D.; Ingold, C.K. J. Chem. Soc. 1952, 2488.

43. Bateman, L.C.; Hughes, E.D.; Ingold, C.K. J. Chem. Soc. 1940, 960.

44. In the experiments mentioned, the solvent was actually "70" or "80%" aq acetone. The "80%" aq acetone consists of 4 vol of dry acetone and 1 vol of water.

45. Creary, X.; Wang, Y.-X. J. Org. Chem. 1992, 57, 4761. Also see, Farcasiu, D.; Marino, G.; Harris, J.M.; Hovanes, B.A.; Hsu, C.S. J. Org. Chem. 1994, 59, 154.

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51. For synthetic examples, see Kraus, G.A.; Hon, Y. J. Org. Chem. 1985, 50, 4605.

52. Olah, G.A.; Liang, G.; Wiseman, J.R.; Chong, J.A. J. Am. Chem. Soc. 1972, 74, 4927.

53. Della, E.W.; Pigou, P.E.; Tsanaktsidis, J. J. Chem. Soc., Chem. Commun. 1987, 833.

54. Eaton, P.E.; Yang, C.; Xiong, Y. J. Am. Chem. Soc. 1990, 112, 3225; Moriarty, R.M.; Tuladhar, S.M.; Penmasta, R.; Awasthi, A.K. J. Am. Chem. Soc. 1990, 112, 3228.

55. Hrovat, D.A.; Borden, W.T. J. Am. Chem. Soc. 1990, 112, 3227.

56. Lee, I.; Kim, N.D.; Kim, C.K. Tetrahedron Lett. 1992, 33, 7881.

57. White, E.H.; McGirk, R.H.; Aufdermarsh, Jr., C.A.; Tiwari, H.P.; Todd, M.J. J. Am. Chem. Soc. 1973, 95, 8107; Beak, P.; Harris, B.R. J. Am. Chem. Soc. 1974, 96, 6363.

58. For a review of reactions with the OCOCl leaving group, see Beak, P. Acc. Chem. Res. 1976, 9, 230.

59. See Arnett, E.M.; Molter, K.E. Acc. Chem. Res. 1985, 18, 339.

60. Lee, I.; Lee, Y.S.; Lee, B.-S.; Lee, H.W. J. Chem. Soc. Perkin Trans. 2 1993, 1441.

61. See Beletskaya, I.P. Russ. Chem. Rev. 1975, 44, 1067; Harris, J.M. Prog. Phys. Org. Chem. 1974, 11, 89; Raber, D.J.; Harris, J.M.; Schleyer, P.v.R. in Szwarc, M. Ions and Ion Pairs in Organic Reactions, Vol. 2, Wiley, NY, 1974, pp. 247–374.

62. For an alternative view, See Uggerud, E. J. Org. Chem. 2001, 66, 7084.

63. Proposed by Winstein, S.; Clippinger, E.; Fainberg, A.H.; Heck, R.; Robinson, G.C. J. Am. Chem. Soc. 1956, 78, 328.

64. Marcus, Y.; Hefter, G. Chem. Rev. 2006, 106, 4585.

65. See Kessler, H.; Feigel, M. Acc. Chem. Res. 1982, 15, 2.

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67. Savéant, J.-M. J. Am. Chem. Soc. 2008, 130, 4732.

68. See Richard, J.P.; Toteva, M.M.; Amyes, T.L. Org. Lett. 2001, 3, 2225.

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70. See McManus, S.P.; Safavy, K.K.; Roberts, F.E. J. Org. Chem. 1982, 47, 4388; Kinoshita, T.; Komatsu, K.; Ikai, K.; Kashimura, K.; Tanikawa, S.; Hatanaka, A.; Okamoto, K. J. Chem. Soc. Perkin Trans. 2 1988, 1875; Ronco, G.; Petit, J.; Guyon, R.; Villa, P. Helv. Chim. Acta 1988, 71, 648; Kevill, D.N.; Kyong, J.B.; Weitl, F.L. J. Org. Chem. 1990, 55, 4304.

71. Jia, Z.S.; Ottosson, H.; Zeng, X.; Thibblin, A. J. Org. Chem. 2002, 67, 182.

72. Diaz, A.F.; Lazdins, I.; Winstein, S. J. Am. Chem. Soc. 1968, 90, 1904.

73. Paradisi, C.; Bunnett, J.F. J. Am. Chem. Soc. 1985, 107, 8223; Fujio, M.; Sanematsu, F.; Tsuno, Y.; Sawada, M.; Takai, Y. Tetrahedron Lett. 1988, 29, 93.

74. Goering, H.L.; Hopf, H. J. Am. Chem. Soc. 1971, 93, 1224 and references cited therein.

75. Dietze, P.E.; Wojciechowski, M. J. Am. Chem. Soc. 1990, 112, 5240.

76. Cristol, S.J.; Noreen, A.L.; Nachtigall, G.W. J. Am. Chem. Soc. 1972, 94, 2187.

77. Simon, J.D.; Peters, K.S. J. Am. Chem. Soc. 1982, 104, 6142.

78. Goering, H.L.; Briody, R.G.; Sandrock, G. J. Am. Chem. Soc. 1970, 92, 7401.

79. Goering, H.L.; Briody, R.G.; Levy, J.F. J. Am. Chem. Soc. 1963, 85, 3059.

80. Winstein, S.; Gall, J.S.; Hojo, M.; Smith, S. J. Am. Chem. Soc. 1960, 82, 1010. See also, Shiner, Jr., V.J.; Hartshorn, S.R.; Vogel, P.C. J. Org. Chem. 1973, 38, 3604.

81. Jorgensen, W.L.; Buckner, J.K.; Huston, S.E.; Rossky, P.J. J. Am. Chem. Soc. 1987, 109, 1891.

82. Okamoto, K. Pure Appl. Chem. 1984, 56, 1797. Also see Lee, I.; Kim, H.Y.; Kang, H.K.; Lee, H.W. J. Org. Chem. 1988, 53, 2678; Lee, I.; Kim, H.Y.; Lee, H.W.; Kim, I.C. J. Phys. Org. Chem. 1989, 2, 35.

83. Okamoto, K.; Kinoshita, T.; Shingu, H. Bull. Chem. Soc. Jpn. 1970, 43, 1545.

84. Kinoshita, T.; Ueno, T.; Ikai, K.; Fujiwara, M.; Okamoto, K. Bull. Chem. Soc. Jpn. 1988, 61, 3273; Kinoshita, T.; Komatsu, K.; Ikai, K.; Kashimura, K.; Tanikawa, S.; Hatanaka, A.; Okamoto, K. J. Chem. Soc. Perkin Trans. 21988, 1875.

85. For an essay on borderline mechanisms in general, see Jencks, W.P. Chem. Soc. Rev. 1982, 10, 345.

86. Sneen, R.A.; Felt, G.R.; Dickason, W.C. J. Am. Chem. Soc. 1973, 95, 638 and references cited therein; Sneen, R.A. Acc. Chem. Res. 1973, 6, 46.

87. See Kevill, D.N.; Degenhardt, C.R. J. Am. Chem. Soc. 1979, 101, 1465.

88. See Sneen, R.A.; Felt, G.R.; Dickason, W.C. J. Am. Chem. Soc. 1973, 95, 638 and references cited therein; Sneen, R.A. Acc. Chem. Res. 1973, 6, 46; Blandamer, M.J.; Robertson, R.E.; Scott, J.M.W.; Vrielink, A. J. Am. Chem. Soc. 1980, 102, 2585; Stein, A.R. Can. J. Chem. 1987, 65, 363.

89. See Raber, D.J.; Harris, J.C.; Hall, R.E.; Schleyer, P.v.R. J. Am. Chem. Soc. 1971, 93, 4821; McLennan, D.J. Acc. Chem. Res. 1976, 9, 281; Stein, A.R. J. Org. Chem. 1976, 41, 519; Katritzky, A.R.; Musumarra, G.; Sakizadeh, K. J. Org. Chem. 1981, 46, 3831. For a reply, see Sneen, R.A.; Robbins, H.M. J. Am. Chem. Soc. 1972, 94, 7868. See Klumpp, G.W. Reactivity in Organic Chemistry, Wiley, NY, 1982, pp. 442–450.

90. See Thibblin, A. J. Chem. Soc. Perkin Trans. 2 1987, 1629.

91. Katritzky, A.R.; Sakizadeh, K.; Gabrielsen, B.; le Noble, W.J. J. Am. Chem. Soc. 1984, 106, 1879.

92. Bentley, T.W.; Bowen, C.T.; Morten, D.H.; Schleyer, P.v.R. J. Am. Chem. Soc. 1981, 103, 5466.

93. Also see Laureillard, J.; Casadevall, A.; Casadevall, E. Tetrahedron 1984, 40, 4921; Helv. Chim. Acta 1984, 67, 352. For evidence against the S_N2 (intermediate) mechanism, see Richard, J.P.; Amyes, T.L.; Vontor, T. J. Am. Chem. Soc. 1991, 113, 5871.

94. Amyes, T.L.; Richard, J.P. J. Am. Chem. Soc. 1990, 112, 9507. Also see Richard, J.P.; Rothenberg, M.E.; Jencks, W.P. J. Am. Chem. Soc. 1984, 106, 1361; Richard, J.P.; Jencks, W.P. J. Am. Chem. Soc. 1984, 106, 1373, 1383; Katritzky, A.R.; Brycki, B.E. J. Phys. Org. Chem. 1988, 1, 1; Stein, A.R. Can. J. Chem. 1989, 67, 297.

95. The relationship between electropilicity and rate coefficients is discussed in Aizman, A.; Contreras, R.; Pérez, P. Tetrahedron 2005, 61, 889.

96. See, however, Sneen, R.A.; Larsen, J.W. J. Am. Chem. Soc. 1969, 91, 6031.

97. Weiner, H.; Sneen, R.A. J. Am. Chem. Soc. 1965, 87, 287.

98. According to this scheme, the configuration of the isolated RN₃ should be retained. It was, however, largely inverted, owing to a competing S_N2 reaction where N₃⁻ directly attacks ROBs.

99. See Streitwieser, Jr., A.; Walsh, T.D.; Wolfe, Jr., J.R. J. Am. Chem. Soc. 1965, 87, 3682; Streitwieser, Jr., A.; Walsh, T.D. J. Am. Chem. Soc. 1965, 87, 3686; Beronius, P.; Nilsson, A.; Holmgren, A. Acta Chem. Scand. 1972, 26, 3173. See also, Knier, B.L.; Jencks, W.P. J. Am. Chem. Soc. 1980, 102, 6789.

100. Bank, S.; Noyd, D.A. J. Am. Chem. Soc. 1973, 95, 8203; Ashby, E.C.; Goel, A.B.; Park, W.S. Tetrahedron Lett. 1981, 22, 4209. For discussions of the relationship between S_N2 and SET mechanisms, see Lewis, E.S. J. Am. Chem. Soc. 1989, 111, 7576; Shaik, S.S. Acta Chem. Scand. 1990, 44, 205.

101. See Savéant, J. Adv. Phys. Org. Chem. 1990, 26, 1; Ashby, E.C. Acc. Chem. Res. 1988, 21, 414. See also, Pross, A. Acc. Chem. Res. 1985, 18, 212; Chanon, M. Acc. Chem. Res. 1987, 20, 214. See Rossi, R.A.; Pierini, A.B.; Peñéñory, A.B. Chem. Rev. 2003, 103, 71.

102. Daasbjerg, K.; Lund, T.; Lund, H. Tetrahedron Lett. 1989, 30, 493.

103. See also, Fuhlendorff, R.; Lund, T.; Lund, H.; Pedersen, J.A. Tetrahedron Lett. 1987, 28, 5335.

104. See, for example, Russell, J.A.; Pecoraro, J.M. J. Am. Chem. Soc. 1979, 101, 3331.

105. Santiago, A.N.; Morris, D.G.; Rossi, R.A. J. Chem. Soc., Chem. Commun. 1988, 220.

106. See Newcomb, M.; Curran, D.P. Acc. Chem. Res. 1988, 21, 206; Newcomb, M. Acta Chem. Scand. 1990, 44, 299. For replies to this criticism, see Ashby, E.C. Acc. Chem. Res. 1988, 21, 414; Ashby, E.C.; Pham, T.N.; Amrollah-Madjdabadi, A.A. J. Org. Chem. 1991, 56, 1596.

107. In this book, there is a distinction between the SET and S_RN1 mechanisms. However, many workers use the designation SET to refer to the S_RN1, the chain version of the SET, or both.

108. Nazareno, M.A.; Rossi, R.A. J. Org. Chem. 1996, 61, 1645.

109. Ashby, E.C.; Sun, X.; Duff, J.L. J. Org. Chem. 1994, 59, 1270.

110. Haberfield, P. J. Am. Chem. Soc.1995, 117, 3314.

111. Shaik, S.S. Acta Chem. Scand.1990, 44, 205.

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113. See Capon, B.; McManus, S. Neighboring Group Participation, Vol. 1, Plenum, NY, 1976.

114. See McCortney, B.A.; Jacobson, B.M.; Vreeke, M.; Lewis, E.S. J. Am. Chem. Soc. 1990, 112, 3554.

115. See Page, M.I. Chem. Soc. Rev. 1973, 2, 295.

116. Winstein, S.; Lucas, H.J. J. Am. Chem. Soc. 1939, 61, 1576, 2845.

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130. Haupt, F.C.; Smith, M.R. Tetrahedron Lett. 1974, 4141.

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148. Bly, R.S.; Bly, R.K.; Bedenbaugh, A.O.; Vail, O.R. J. Am. Chem. Soc. 1967, 89, 880.

149. See Peterson, P.E.; Vidrine, D.W. J. Org. Chem. 1979, 44, 891; Rappoport, Z. React. Intermed. (Plenum) 1983, 3, 440.

150. Von Lehman, T.; Macomber, R. J. Am. Chem. Soc. 1975, 97, 1531.

151. Gassman, P.G.; Zeller, J.; Lamb, J.T. Chem. Commun. 1968, 69.

152. See Olah, G.A.; Berrier, A.L.; Arvanaghi, M.; Prakash, G.K.S. J. Am. Chem. Soc. 1981, 103, 1122.

153. Gassman, P.G.; Fentiman, Jr., A.F. J. Am. Chem. Soc. 1969, 91, 1545; 1970, 92, 2549.

154. See Lambert, J.B.; Mark, H.W.; Holcomb, A.G.; Magyar, E.S. Acc. Chem. Res. 1979, 12, 317.

155. Malnar, I.; Juric, S.; Vrcek, V.; Gjuranovic, Z.; Mihalic, Z.; Kronja, O. J. Org. Chem. 2002, 67, 1490.

156. Gassman, P.G.; Hall, J.B. J. Am. Chem. Soc. 1984, 106, 4267.

157. In this section, systems are considered in which at least one carbon separates the cyclopropyl ring from the carbon bearing the leaving group. For a discussion of systems in which the cyclopropyl group is directly attached to the leaving-group carbon, see below, category 4.b.

158. For a review, see Haywood-Farmer, J. Chem. Rev. 1974, 74, 315.

159. Tanida, H.; Tsuji, T.; Irie, T. J. Am. Chem. Soc. 1967, 89, 1953; Battiste, M.A.; Deyrup, C.L.; Pincock, R.E.; Haywood-Farmer, J. J. Am. Chem. Soc. 1967, 89, 1954.

160. For a competitive study of cyclopropyl versus double-bond participation, see Lambert, J.B.; Jovanovich, A.P.; Hamersma, J.W.; Koeng, F.R.; Oliver, S.S. J. Am. Chem. Soc. 1973, 95, 1570.

161. Also see Gassman, P.G.; Creary, X. J. Am. Chem. Soc. 1973, 95, 2729; Takakis, I.M.; Rhodes, Y.E. Tetrahedron Lett. 1983, 24, 4959.

162. Haywood-Farmer, J. Chem. Rev. 1974, 74, 315.

163. Haywood-Farmer, J.; Pincock, R.E. J. Am. Chem. Soc. 1969, 91, 3020. Also see Rhodes, Y.E.; Takino, T. J. Am. Chem. Soc. 1970, 92, 4469; Hanack, M.; Krause, P. Liebigs Ann. Chem. 1972, 760, 17.

164. Gassman, P.G.; Seter, J.; Williams, F.J. J. Am. Chem. Soc. 1971, 93, 1673. See Haywood-Farmer, J.; Pincock, R.E. J. Am. Chem. Soc. 1969, 91, 3020; Chenier, P.J.; Jenson, T.M.; Wulff, W.D. J. Org. Chem. 1982, 47, 770.

165. See Schipper, P.; Driessen, P.B.J.; de Haan, J.W.; Buck, H.M. J. Am. Chem. Soc. 1974, 96, 4706; Ohkata, K.; Doecke, C.W.; Klein, G.; Paquette, L.A. Tetrahedron Lett. 1980, 21, 3253.

166. See Lancelot, L.A.; Cram, D.J.; Schleyer, P.v.R. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 3, Wiley, NY, 1972, pp. 1347–1483.

167. Kevill, D.N.; D'Souza, M.J. J. Chem. Soc. Perkin Trans. 2 1997, 257.

168. Cram, D.J. J. Am. Chem. Soc.1949, 71, 3863; 1952, 74, 2129.

169. Brookhart, M.; Anet, F.A.L.; Cram, D.J.; Winstein, S. J. Am. Chem. Soc. 1966, 88, 5659; Lee, C.C.; Unger, D.; Vassie, S. Can. J. Chem. 1972, 50, 1371.

170. Brown, H.C.; Kim, C.J. J. Am. Chem. Soc. 1971, 93, 5765.

171. Diaz, A.; Winstein, S. J. Am. Chem. Soc. 1969, 91, 4300. See also, Schadt, F.L.; Lancelot, C.J.; Schleyer, P.v.R. J. Am. Chem. Soc. 1978, 100, 228.

172. Nordlander, J.E.; Kelly, W.J. J. Am. Chem. Soc. 1969, 91, 996.

173. Jablonski, R.J.; Snyder, E.I. J. Am. Chem. Soc. 1969, 91, 4445.

174. Thompson, J.A.; Cram, D.J. J. Am. Chem. Soc. 1969, 91, 1778. See also Kingsbury, C.A.; Best, D.C. Bull. Chem. Soc. Jpn. 1972, 45, 3440.

175. Coke, J.L.; McFarlane, F.E.; Mourning, M.C.; Jones, M.G. J. Am. Chem. Soc. 1969, 91, 1154; Jones, M.G.; Coke, J.L. J. Am. Chem. Soc. 1969, 91, 4284. See also, Harris, J.M.; Schadt, F.L.; Schleyer, P.v.R.; Lancelot, C.J. J. Am. Chem. Soc. 1969, 91, 7508.

176. See Ando, T.; Shimizu, N.; Kim, S.; Tsuno, Y.; Yukawa, Y. Tetrahedron Lett. 1973, 117.

177. Lancelot, C.J.; Schleyer, P.v.R. J. Am. Chem. Soc. 1969, 91, 4291, 4296; Lancelot, C.J.; Harper, J.J.; Schleyer, P.v.R. J. Am. Chem. Soc. 1969, 91, 4294; Schleyer, P.v.R.; Lancelot, C.J. J. Am. Chem. Soc. 1969, 91, 4297.

178. Ramsey, B.; Cook Jr., J.A.; Manner, J.A. J. Org. Chem. 1972, 37, 3310.

179. Olah, G.A.; Comisarow, M.B.; Kim, C.J. J. Am. Chem. Soc. 1969, 91, 1458. See, however, Ramsey, B.; Cook, Jr., J.A.; Manner, J.A. J. Org. Chem. 1972, 37, 3310.

180. Olah, G.A.; Spear, R.J.; Forsyth, D.A. J. Am. Chem. Soc. 1976, 98, 6284.

181. See Olah, G.A.; Singh, B.P.; Liang, G. J. Org. Chem. 1984, 49, 2922; Olah, G.A.; Singh, B.P. J. Am. Chem. Soc. 1984, 106, 3265.

182. Mishima, M.; Tsuno, Y.; Fujio, M. Chem. Lett. 1990, 2277.

183. See Tanida, H. Acc. Chem. Res. 1968, 1, 239; Shiner, Jr., V.J.; Seib, R.C. J. Am. Chem. Soc. 1976, 98, 862; Ferber, P.H.; Gream, G.E. Aust. J. Chem. 1981, 34, 2217; Fujio, M.; Goto, M.; Seki, Y.; Mishima, M.; Tsuno, Y.; Sawada, M.; Takai, Y. Bull. Chem. Soc. Jpn. 1987, 60, 1097. For a discussion of evidence obtained from isotope effects, see Scheppele, S.E. Chem. Rev. 1972, 72, 511, p. 522.

184. Jackman, L.M.; Haddon, V.R. J. Am. Chem. Soc. 1974, 96, 5130; Gates, M.; Frank, D.L.; von Felten, W.C. J. Am. Chem. Soc. 1974, 96, 5138; Ando, T.; Yamawaki, J.; Saito, Y. Bull. Chem. Soc. Jpn. 1978, 51, 219.

185. See Olah, G.A. Angew. Chem. Int. Ed. 1973, 12, 173, pp. 192–198.

186. See Olah, G.A.; Prakash, G.K.S.; Williams, R.E. Hypercarbon Chemistry, Wiley, NY, 1987, pp. 157–170; Grob, C.A. Angew. Chem. Int. Ed. 1982, 21, 87; Sargent, G.D. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 3, Wiley, NY, 1972, pp. 1099–1200; Sargent, G.D. Q. Rev. Chem. Soc. 1966, 20, 301; Gream, G.E. Rev. Pure Appl. Chem. 1966, 16, 25. Also see Kirmse, W. Acc. Chem. Res. 1986, 19, 36. See also, Ref. 190.

187. Winstein, S.; Clippinger, E.; Howe, R.; Vogelfanger, E. J. Am. Chem. Soc. 1965, 87, 376.

188. For another view, see Bielmann, R.; Fuso, F.; Grob, C.A. Helv. Chim. Acta 1988, 71, 312; Flury, P.; Grob, C.A.; Wang, G.Y.; Lennartz, H.; Roth, W.R. Helv. Chim. Acta 1988, 71, 1017.

189. See Menger, F.M.; Perinis, M.; Jerkunica, J.M.; Glass, L.E. J. Am. Chem. Soc. 1978, 100, 1503.

190. See Lenoir, D.; Apeloig, Y.; Arad, D.; Schleyer, P.v.R. J. Org. Chem. 1988, 53, 661; Grob, C.A. Acc. Chem. Res. 1983, 16, 426; Brown, H.C. Acc. Chem. Res. 1983, 16, 432; Walling, C. Acc. Chem. Res. 1983, 16, 448. Also see Arnett, E.M.; Hofelich, T.C.; Schriver, G.W. React. Intermed. (Wiley) 1985, 3, 189, pp. 193–202.

191. See Lajunen, M. Acc. Chem. Res. 1985, 18, 254; Apeloig, Y.; Arad, D.; Schleyer, P.v.R. J. Org. Chem. 1988, 53, 661.

192. Also see Werstiuk, N.H.; Dhanoa, D.; Timmins, G. Can. J. Chem. 1983, 61, 2403; Brown, H.C.; Ikegami, S.; Vander Jagt, D.L. J. Org. Chem. 1985, 50, 1165; Nickon, A.; Swartz, T.D.; Sainsbury, D.M.; Toth, B.R. J. Org. Chem. 1986, 51, 3736.

193. The presence of hydride shifts (Reaction 18-01) under solvolysis conditions has complicated the interpretation of the data.

194. Olah, G.A. Acc. Chem. Res. 1976, 9, 41; Saunders, M. Acc. Chem. Res. 1983, 16, 440. See also, Johnson, S.A.; Clark, D.T. J. Am. Chem. Soc. 1988, 110, 4112.

195. See Kramer, G.M.; Scouten, C.G. Adv. Carbocation Chem. 1989, 1, 93. See, however, Olah, G.A.; Prakash, G.K.S.; Farnum, D.G.; Clausen, T.P. J. Org. Chem. 1983, 48, 2146.

196. Myhre, P.C.; Webb, G.G.; Yannoni, C.S. J. Am. Chem. Soc. 1990, 112, 8991.

197. See Lossing, F.P.; Holmes, J.L. J. Am. Chem. Soc. 1984, 106, 6917 and references cited therein.

198. Koch, W.; Liu, B.; DeFrees, D.J.; Sunko, D.E.; Vancik, H. Angew. Chem. Int. Ed. 1990, 29, 183.

199. See, for example, Koch, W.; Liu, B.; DeFrees, D.J. J. Am. Chem. Soc. 1989, 111, 1527.

200. Olah, G.A.; DeMember, J.R.; Lui, C.Y.; White, A.M. J. Am. Chem. Soc. 1969, 91, 3958. See also, Forsyth, D.A.; Panyachotipun, C. J. Chem. Soc., Chem. Commun. 1988, 1564.

201. Olah, G.A. Acc. Chem. Res. 1976, 9, 41. See also, Farnum, D.G.; Wolf, A.D. J. Am. Chem. Soc. 1974, 96, 5166.

202. Nickon, A.; Lin, Y. J. Am. Chem. Soc. 1969, 91, 6861. See also, Montgomery, L.K.; Grendze, M.P.; Huffman, J.C. J. Am. Chem. Soc. 1987, 109, 4749.

203. Fry, A.J.; Farnham, W.B. J. Org. Chem. 1969, 34, 2314.