Nitriles reductive cyclization

Dihydro-4H-benzo[/]pyrrolo[l,2-fl][l,4]diazepin-4-one 220 is a product of reductive cyclizations of ester nitrile 219a (R = COOMe, = CN), while amido... 

Substituted pyrrolidines 46 can be prepared by a one-pot approach via the reductive cyclization of the precursor 45, which is prepared by conjugate addition of the -(alkylideneamino)nitrile 44 to methyl vinyl ketone (Scheme 34) C2005S945, CHEC-III(3.03.7)321>. 

A one-pot approach giving a series of l-(2-naphthyl)methylene- or l-(3,4-dimethoxybenzyl)pyrrolidines 432 has been developed, as illustrated by the reductive cyclization of the four-carbon precursor 433, which was prepared by conjugate addition of the a-(alkylideneamino)nitrile 434 to methyl vinyl ketone (Scheme 55) <2005S945>. 

An intramolecular reductive coupling of ketones with nitriles has been reported for acyclic and monocyclic substrates y9-amino nitriles were isolated from acyclic malononitrile adducts [87]. The Sml2-initiated reductive cyclization of cyclic a-cyanoalkyl-substituted ketones leads to acyloin products in high yields. In this instance further irradiation of the reaction mixtures was performed to afford complete conversion (Scheme 27) [88]. More applications have been collected in several excellent reviews [89-92]. 

Keto nitriles, such as 153, function admirably as substrates in reductive cyclizations [40, 41]. Two product types are obtained, one the simple ketone 155, the other 154, incorporating the a-hydroxy ketone (ketol) functionality that is present in many natural products. Both controlled-potential and constant-current conditions have been utilized. Of the electrodes examined (Ag, Cd, Pb, Zn, C-fiber, and Sn), tin generally proved most effective. Using tin, the controlled potential reduction of 153 in /-PrOH at —2.8 V versus SCE (divided cell, ceramic diaphragm) afforded a 76% yield of ketol 154 accompanied by 2% of ketone 155. As illustrated in Table 5, the preference for ketol formation drops when the transformation is carried out at constant current or without using a diaphragm. 

Other synthetic applications derive from various cyclizations that occur during reduction of the substrates that contain a reactive function at a specific position. These cyclizations proceed through the intermediate imine or amine to the cyclic amine. Various functional units such as olefins, heterocyclic rings, ketones, acids, amides, amines, nitrile, and nitro have been involved. Palladium, Rh, and finely divided Ni (Raney Ni) under more vigorous conditions are commonly used. Reductive cyclization of ketonitrile 1 over Raney Ni gives myosmine 2 along with some nomicotine 3 as overreduced product ... 

If other active groups are present y or S to the reducible nitro group, hydrogenation can result in formation of nitrogen heterocyclic products. Several such cyclizations provide an entry to indoles, such as reductive cyclizations of dinitrostyrene 1 [equation (a)], of o-nitrobenzyl ketone 2 [equation (b)], and of nitro nitrile 3 [equation (c)] , all of them carried out on palladium-on-carbon. 

Reductive cyclization of a nitro-nitrile yields a fused pyrrole ring. 

Intermolecular cyclization of 4-dialkylamino-2-aza-l,3-diene-1,1-dicarbonitriles proceeds on treatment with hydrogen bromide in acetic acid to yield 2-bromo-3-cyanopyrazine <90HCA1210>. Tetraalkyl or -arylpyrazines are synthesized by reductive cyclization of the corresponding nitriles with titanium tetrachloride and zinc in modest to good yields (Equation (18)) <90S70l>. 

Reduction of nitriles has been used to prepare branched primary amines by alkylation of the nitriles followed by reduction of the imine intermediate with lithium-ammonia.6 4-Amino-2-quinolones were produced by the cyclization of N-(a-halogenoacyl)-N-alkyl substituted anthranilonitriles induced by Grignard or organolithium... 

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