Heterocyclic enamines reduction

The reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

The apparently simple procedures of partial dehydrogenation of pyrrolidines and partial hydrogenation of pyrroles afford Zl1-pyr-rolines. However, the reaction is complex and is of little preparative value.97-98 A 1-Pyrrolines may be obtained by isomerization of A 3-pyrrolines.100 From the preparative point of view, partial hydrogenation of quaternary pyridine salts in strongly alkaline media to give 1-alkyl-id 2-piperideines is more important.101 Formation of heterocyclic enamines was observed in the reduction of i -methyl-pyrrolidone with lithium aluminum hydride,102 -alkylpiperidones with sodium in ethanol,103,104 and in the electrolytic reduction of N-methylglutarimide.106... 

Reductions of pyridines, quinolines, isoquinolines and their quaternary salts is a useful approach for the preparation of heterocyclic enamines. 

In contrast, lack of stereoselectivity was found in the reduction of a heterocyclic enamine with NaBH4 (and H2/Pt02), as four isomers were formed. Three of them were isolated130 (Scheme 95). 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

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... 

Imines and enamines under hydroformylation conditions can also be reduced to give saturated amines. With or without additional reduction, these conversions can be used in synthesis of various types of heterocycles. 

Reduction of quinolines in acid solution at a lead cathode or by dissolving zinc leads to attack on the heterocyclic ring with the formation of 4,4-coupled products, together with the tetrahydroquinoline [82,83]. In the case of 2- and 4-methyl substituted quinolines, dimeric products are obtained in 10 90 % yields. In these processes, dimerization of the one-electron addition product is in competition with further reduction to give the 1,4-dihydroquinoline, The latter is an enamine and it... 

The reduction methods of producing enamines from aromatic heterocyclic bases or their derivatives have thus far found only limited application [30]. 

A tautomeric equilibrium between enamine and methylene imine forms has been demonstrated to exist in 2-(3,4-dihydro-3-oxo-2(l//)-quinoxalinylidene)-Al-phenylacetamides and 3,4-dihydro-3-oxo-/V-phenyl-2-quinoxaline acetamides when these are in DMSO solution either in the absence or presence of TFA [95JHC671]. The reduction potentials of some pyrazines and their benzo-fused analogs have been summarized as part of an EPR study of the electron transfer interaction between nitrogen heterocycles and n-B N+BHf [95JOM123]. 

Nitrogen heterocycles more electrophilic than benzene are susceptible to attack by hydride ion from a complex metal hydride anion. In protic solvents the intermediate cyclic enamines can undergo further reduction. The proper choice of reducing agent and reaction conditions thus allows the preparation of many partially reduced nitrogen heterocycles unavailable by other routes. These reduction procedures provide a valuable adjunct to catalytic hydrogenation155 for the syntheses of saturated nitrogen heterocycles. 

A number of syntheses have been devised which lead to heterocyclic derivatives of cholestanes. 4-Aza-5a-sitostane (321 R = H, X = H2) and its N-methyl derivative (321 R = Me, X = H2) have been prepared by way of oxidative opening of ring A of 4-sitosten-3-one to give a 3,5-seco-5-oxo-3-oic acid which was cyclized by reaction with ammonium hydroxide or methylamine to give A5-enamine lactams these upon hydrogenation gave the lactams (321 R = H or Me, X = O) respectively. Hydride reduction completed the route to the required 4-aza-steroids.179... 

The 26 chapters, written by experts from 14 countries, cover a wide spectrum of topics related to the chemistry of enamines, including theory, structural chemistry, spectral properties, formation, reactions and stereochemistry, acidities, rearrangements, oxidation and reduction, as well as other topics. In two chapters, the material related to enamines was meagre. Hence, the chapter on radiation chemistry also deals with compounds with non-conjugated C=C and amino groups, and the chapter on synthesis and uses of isotopically labelled enamines includes enamines in which the nitrogen is part of a heterocyclic system. 

Various accounts report the synthesis of heterocyclic androstane derivatives. 17)8-Acetoxy-4-oxa-androst-2-ene (215) has been prepared in three steps from the hemiacetal (214). Since various 4-aza-steroids exhibit antimicrobial activity, several new 4-aza-androstanes have been prepared. The reduction of ring a enamine lactams, such as 4-aza-androst-5-ene-3,17-dione (216a), under conditions of the Leuckart-Wallace reductive amination, provided 17/ -(iV-methyl-... 

Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 2] cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduction (equation 63). 

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