Reduction of enamines with

Olefins are also the products of hydroboratlon of enamines, followed by treatment of the organoborane products with hot acid (543,544). The reduction of enamines with sodium borohydride and acetic acid (545) and the selective reduction of dienamines with sodium borohydride to give homo-allylic tertiary amines (138-140,225,546,547), has been applied to the synthesis of conessine (548) and other aminosteroid analogs (545,549-552). Further examples of the reduction of imonium salts by sodium borohydride can be found in the reduction of Bischler-Napieralski products, and other cyclic imonium salts (102). 

Greater stereoselectivity for the formation of equatorial amines has been found in the reduction of enamines with formic acid or formamides (553-559). The selective formation of 3-a-amino-5- -steroids by this method and of 3- 3-amino-5- 3-steroids by catalytic reduction (5<50) of the corresponding enamines is of interest. 

Table 10 Reduction of Enamines with Hydride Reagents in Acidic Media... 

Reduction of Enamines. The reduction of enamines with NaBHsCN under acidic conditions proceeds via an iminium ion, similar to that seen in the reduction of imines. Examples, such as the reduction of an enamine-fulvene to the corresponding amine target (eq 45) and the reduction of the enamino-butenolide to the expected lactone (eq 46), are abundant in the current literature. 

An earlier report (126) which assigned the irons configuration to the enamine (175) derived from the cyanamine (176) upon reaction with potassium amide in liquid ammonia has been questioned by Munk and Kim (725). They also have doubts about the structures (177 and 178) proposed for the products obtained by the reduction of acetonitrile with sodium (727). 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

Simple synthesis of ( )-17-epiyohimbol (73) has been reported by Mori et al. (214). yV-Benzyloctahydroindolo[2,3-a]quinolizinone (126), prepared according to the procedure of Novdk and Szdntay (97) was coverted to the corresponding pyrrolidine enamine, which was treated with methyl vinyl ketone to give N-benzylyohimbenone (379). Reduction of 379 with sodium in liquid ammonia... 

An efficient synthesis of ( )-yohimbine has been published by Stork and Guthikonda (222). Reaction of the pyrrolidine enamine of A-methylpiperidone with methyl 3-oxo-4-pentenoate gave 411 in good yield. Reduction of 411 with lithium in liquid ammonia furnished trans-TV-methyldecahydroisoquinolone 412. This building block was transformed in simple reaction steps to secoyohimbane 413 from which ( )-yohimbine could be obtained by oxidative cyclization with... 

Coordination of the aluminum atom of the reducing complex was proposed to take place both to the oxygen atom of the hydroxy group and to the nitrogen atom of the amino group. The asymmetric reduction of enamine perchlorates and ketimines with menthol and bomeol chiral auxiliary reagents (50,51) presumably involves coordination of aluminum to the nitrogen atom of the substrate. 

Vinylamines (enamines) are reduced by alane, mono- and dichloroalane to saturated amines, and hydrogenolyzed to amines and alkenes [710]. Reduction is favored by dichloroalane while hydrogenolysis is favored by alane. Alane, chloroalane and dichloroalane gave the following results with -N-pyrrolidinylcyclohexene V-pyrrolidinylcyclohexane in 13, 15 and 22% yield, and pyrrolidine and cyclohexene in 80, 75 and 75% yields, respectively [710]. Saturated amines were also obtained by treatment of enamines with sodium borohydride [711], with sodium cyanoborohydride [103, 712] (Procedure 22, p. 210) and by heating for 1-2 hours at 50-70° with 87% or 9S% formic acid (yields 37-89%) [320]. 

For a review of the reduction of enamines and indoles with NaBH, and a carboxylic acid, see Gribble Nutaitis Org. Prep. Proced. Int. 1985, 17, 317-384. Enamines can also be reduced by formic acid sec Nilsson Carlson Acta Chem. Scand. Sect. B 1985, 39, 187. 

Asymmetric hydrogenation offers a useful synthetic route to chiral amines. Although the mechanism is unknown, only the (7%/V-acetyl-1 -arvlalkylamine 21 with 95% ee was obtained by the hydrogenation of a mixture of ( )- and (Z)-enamides 20a and 20b using Rh-Me-DuPHOS (XI). The A-acetvl enamines 20a,b are prepared by the reduction of oximes with Fe powder in acetic anhydride [21]. Also the acetamide 23 was obtained from 22 [22]. 

Imines are formed by condensation of aldehydes or ketones with primary amines, but they form with more difficulty than enamines.84,85 A special case of enamine preparation was described with 20-oxo-steroids.86 Treatment of these ketones with a primary amine gives a 20-ketimine, which is acetylated with acetic anhydride, with migration of the double bond and formation of 20-(A-acetylalkylamino)-J17(20)-pregnene (14) reduction of 14 with lithium aluminum hydride affords the enamine. 

The reduction of enamine unit occurs much more rapidly than that of the carbonyl group. Therefore, this reagent can be used to perform reductive amination of aldehydes and ketones, by simply reacting the carbonyl compound with a fourfold excess of the amine. In a similar manner, reductive methylation of amines could be accomplished by addition of formaldehyde to the amine119. 

Treatment of enamines with a,/ -unsaturated esters yields Michael adducts 189, which undergo reductive cyclization with lithium aluminium hydride to tetrahydropyrans 190. Elimination of the secondary amine moiety then affords dihydropyrans 191 (equation 81)102. 

Enamines represent a final class of vinyl-heteroatom derivatives that can be prepared from ketones and subsequently reduced to alkenes (Scheme 47). Since enamine formation is covered in depth elsewhere, this section will deal only with the reduction of enamines to alkenes. 

For a review of the reduction of enamines and indoles with NaBH4 and a carboxylic acid, see Gribble,... 

The structure of (24) was established by the chemical correlation shown in Scheme 3. Reduction of (24) with NaBH4 gave a mixture of (26), O-to-N acyl migration product, and (27) the latter was methylated to (29) which was identical with the product formed from the enamine (28) by oxidative hydroboration. 

Reduction of iminium salts. 1,3-Diamines can be elaborated via reduction of the monoiminium species which arise from condensation of enamines with aldiminium salts. The subsequent reduction is carried out with NaBH, in methanol. Oximes of a-aminocycloalkanones undergo fragmentation and reduction, furnishing co-amino nitriles. A route to substituted ureas involves reductive alkylation, condensation with aldehydes in the presence of MejSiCl followed by treatment with NaBH. The borohydride reduction of P-amino-a,P-unsaturated esters in the presence of isobutanoic acid may also proceed via iminium species. 

The TV-substituted ethylenediamines and propylenediamines can be prepared, according to Goodwin and Lions,1 by the reaction of the diamine with the appropriate aldehyde followed by the reduction of enamine by zinc dust, MBH4 (M = Na, K), or hydrogen with Pt/C catalyst. This method has been employed to obtain pyridyl- and pyrazyl-substituted ligands such as (4)2 or (5),3... 

Table 4.7 Synthesis of esters of a substituted 3 amino acids 40 by reduction of enamines/imines 38/39 with trichlorosilane, catalyzed by Sigamide 35 (Scheme 4.4). ...

The lithium-propylamine reducing system has been found capable of reducing julolidine to a mixture of enamines . Selective reduction of lactams with... 

The use of formic acid for reduction of enamines is so characteristic that this reaction can be used for detection of the enamine group.128,129 Even enamines that are resistant to catalytic hydrogenation with Raney nickel or palladium can be reduced smoothly by formic acid.130... 

These reagents were first used for reduction of enamines. Their most useful propeny is the ability to alkylate amines Unsymmctrical tertiary amines can be obtained from pnmafy amines by a two-step reaction with two different carboxylic acids in combination with NaBIl. ... 

The ability to reduce compounds under acidic conditions is ideal for the reduction of enamines. Protonation of nitrogen gives an iminium salt in acidic media that is then reduced with cyanoborohydride to an amine.Imines can be reduced in acidic media in the presence of many other functional groups, as shown by Cook s reduction of imine 165 to give 166 in 79% yield in a synthesis of substituted tetrahydro-P-carbolines. 2 This reagent is excellent for the reduction of iminium salts at neutral pH as well,l 3 and it is also useful for the reductive alkylation of amines. Dimethylamino derivatives such as 168 can be prepared from the amine (167 in this case) by treatment with formaldehyde and cyanoborohydride, even in the presence... 

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