Enamines by reduction

The preparation of enamines by reduction of aromatic heterocyclic bases and their quaternary salts or of lactams is not the most useful approach (97). The lithium aluminum hydride reduction of N-acyl enamines has been used with both fruitful and unsuccessful results. A series of 3-N-acetyl -d -cholestenes (104) has been prepared by desulfurization of the appropriate thiazolidine (105) (98,99). Lithium aluminum hydride reduction of the... 

Aniline (hen enamine) [62-53-3] is the simplest of the primary aromatic amines. It was first produced ia 1826 by dry distillation of indigo. In 1840 the same oily hquid was obtained by heating indigo with potash, and it was given the name aniline. The stmcture of aniline was estabUshed in 1843 with the demonstration that it could be obtained by reduction of nitrobenzene. 

Androst-4-ene-3,l 1,17-trionehas been converted into several 3,17-dienamine derivatives which, on reduction with LiAlH4 followed by removal of the protecting groups, give 11 jS-hydroxyandrost-4-ene-3,17-dione. An unsaturated 3-ketone has also been protected as an enamine in the LiAlH4 reduction of a 21-ester group a further example is the conversion of 7-methylene-5a-an-drostane-3,17-dione into the 3-pyrrolidine enamine followed by reduction of the 17-ketone by Li[OC(CH3)3]3 AlH. ... 

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

An enamine was obtained in the synthesis of coronaridine (648) by aluminum hydride reduction of a bridged lactam, followed by dehydration on alumina. Additional examples of enamine formation by reduction of enamides (649) and thioenamides (650) were reported. 

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. 

An unexpected reduction of enamines by secondary amines such as pyrrolidine, piperidine, and particularly hexamethyleneimine was discovered in the formation of the norbomanone enamines and extended to hexamethyleneiminocyclopentene (561,562). 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

The spiro compound 206 was prepared in five steps from (S)-l-naphthyl-ethylamine and was composed of a mixture of imine and enamine tautomers. Reduction of the imine function by sodium borohydride occurred on the less hindered si face, leading to the diamine with the R configuration of the newly formed stereo center, then the N-benzyl substituent was removed by hydrogenolysis to give 207 with good overall yield [98] (Scheme 30). 

The oxidation of hexahydroindolo[2,3-a]quinolizin (574) with benzoyl peroxide, followed by reduction and removal of the benzoyl group, gave the cis alcohol (575), while hydroboration-oxidation of the same enamine (574) yielded... 

The present preparation illustrates a general and convenient method for a two-step deoxygenation of carbonyl compounds to olefins. Related procedures comprise the basic decomposition of p-toluenesulfonylhydrazones, the hydride reduction of enol ethers, enol acetates, enamines, the reduction of enol phosphates (and/or enol phosphorodiamidates) by lithium metal in ethylamine (or liquid ammonia),the reduction of enol phosphates by titanium metal... 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

The overall reaction is best viewed as intramolecular oxidative addition of the C(l)—H bond to the Rh(I) center, causing cyclometalation (25), followed by reductive elimination of an enamine from the Rh(III) intermediate accompanied by allylic transposition. Notably, the allylamine ligand in the initial Rh(I) complex as well as the Rh(III) intermediate has an s-trans conformation with respect to the N—C(l) and C(2)—C(3) bonds, allowing the overall suprafacial 1,3-hydrogen shift to produce the is-configured enamine product. 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

The fused tetrahydropyran-2-one (566) is obtained from 2-methylcyclohexanone by Michael addition to methyl prop-2-enoate and reduction of the resulting keto ester (565 Scheme 216) (63JOC34). When the enamine derived from the cyclohexanone reacts with the unsaturated ester, a mixture of keto esters (565) and (567) is formed. The pyranone (568) is formed by reduction of the latter. 

Ab Initio MO calculations of a model complex Rh(PH3)2(NH3)(CH2=CHCH2NH2) were earned out to shed light to the detailed mechanism of Rh(l)-catalyzed isomerization of allylic amines to enamines.5 This study suggests that the square-planar [RhiPHjyNHjXCf CHCHjNHj) complex is transformed to [Rh(PH3)2(NH3)(( )-CH3CH=CHNH2)]+ via intramolecular oxidative addition of the C(l)-H bond to the Rh(I) center, giving a distorted-octahedral Rh(lll) hydride intermediate, followed by reductive elimination accompanied by allylic transposition. 

An intramolecular model for the reductive acyl transfer catalysed by a-keto-acid dehydrogenases relies on the presence of PhHgCl to trap the thiolate generated by reduction of the hpoate disulfide bond by enamine.280 This shows a 10-fold increase in loss of enamine UV-visible absorption over background decomposition attributed by the authors to reductive acyl transfer. However, no reaction products were isolated and... 

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