Enamines reductions, sodium cyanoborohydride

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]. 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

Lhommet and co-workers synthesized (- )-436 by the route shown in Scheme 66 [422). Wittig-Homer reaction between the 2,5-rrans -disubstituted pyrrolidine aldehyde 509, made from (S)-pyroglutamic acid [423), and the protected keto-phosphonate 510 introduced all the skeletal carbon atoms of the target. Simultaneous hydrogenation and //-deprotection of enone 511 gave the aminoketone 512, which spontaneously formed the bicyclic enamine 513 in 98% yield when exposed to trifluoroacetic acid—apparently the first time that such an intermediate has actually been isolated en route to indolizidines. Reduction with sodium cyanoborohydride in acidic medium acid produced a diastereomeric mixture (92 8) of (- )-436 and (+ )-437. The former was isolated in 84% yield after chromatography on silica gel. The overall yield of this 15-step sequence was 8% based on (S)-pyroglutamic acid. 

Evidence for the intermediacy of the enamine (138) and the immonium ion (140) derives from the condensation reaction in which potassium cyanide replaced sodium cyanoborohydride the immonium ion (140) was thus trapped by reaction with nucleophilic cyanide ion, with formation of 21-cyanotetrahydroalstonine (141a) and 21-cyanoakuammigine (141b). Both cyano-compounds suffered slow reduction to the parent alkaloid by sodium borohydride, and were re-converted (by silver acetate) into the precursor immonium ions (140), which could be rapidly reduced (NaBH4) to the alkaloids. Scheme 17 illustrates some, but not by any means all, of the numerous interconversions involved in these biomimetic experiments. 

As with reductive aminations and imine reductions that employ sodium cyanoborohydride, a significant number of enamine reductions now are reported to afford products stereoselectively. Two representative examples include a reduction and subsequent transformation of a bicyclic enamine (eq 47) and the reduction of a highly functionalized enamine (eq 48) In both instances the... 

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