Pyrrolidines reductive amination

Extension of the alkyl group on the carbon bearing the amine changes the pharmacologic profile. Reductive amination of 1-phenylbutanone-2 (60) with pyrrolidine in formic acid gives pro-litane (61), a central nervous system stimulant agent with antidepressant properties. 

The reductive amination of hexane-2,5-dione and heptane-2,6-dione with ammonia and primary amines RNH2 (R = PhCH2, Ph2CH, PhMeCH, Ph, 4-MeOC6H4, 2-ClC6H4 and 2,6-Me2CgH3) under the influence of sodium cyanoborohydride or sodium triacetoxyboro-hydride has been studied. The reactions yield respectively pyrrolidines and piperidines as mixtures of cis- and fraws-isomers no cyclic products were obtained when 2-chloroaniline of 2,6-dimethylaniline were employed (equation 57)168. 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

Catalytic hydrogenation of the unstable pyrroles (281a-c), which are prepared by heating the 1,4-diketones (280a-c) with an excess of ammonium carbonate at 120°C, gives 2,5-dialkylpyrrolidines (lOa-c) (cis trans = 85 15, 85% conversion) (Scheme 25) 133). Reductive amination of 1,4-diketones (282b,f,h,i) with ammonium acetate and sodium cyanoborohydride produces 2,5-dialkylpyr-rolidines (10b,f,h,i) identical to natural products in 50-90% yields. Each pyrrolidine is an approximately 1 1 mixture of cis and trans isomers (Scheme 26) 25,138). 

Dialkylpyrrolidines. These compounds can be prepared by reductive amination of 1,4-diketones with sodium cyanoborohydride and ammonium acetate (4, 448-449). 1-Pyrrolines are usually formed also, but they can be reduced to pyrrolidines by NaBH4 in a second step.1... 

The principal component of the secretion of the poison gland of the European thief ant (Solenopsis fugax) is rrarcs-2-n-butyl-5-n-heptylpyrrolidine, identified by mass spectrometry and synthesis.5 The reductive amination of 1,4-diketones with sodium cyanoborohydride and ammonium acetate has yielded various 2,5-dialkyl-pyrrolidines that occur in the poison glands of ants of Monomorium spp.6... 

A similar double-reductive amination of 5-keto-D-fructose provides a route to pyrrolidines (equation I). This reductive amination also shows some stereoselectivity for the glucitol isomer. 

The venomous constituent of the cryptic thief ant, Solenopsis xenovenenum, has been identified as the 3-heptyl-5-methylpyrrolizidine (50) from its mass spectrum and the fact that a related pyrrolidine (51) has been isolated from another species of ant.47 This is the first reported occurrence of a 3,5-dialkyl-pyrrolizidine, and its structure was confirmed by synthesis. Reductive amination of the known triketone (52) with sodium cyanoborohydride and ammonium acetate gave a mixture of four isomers of 3-heptyl-5-methylpyrrolizidine, which were separated by preparative g.l.c. The stereochemistry of the ring-junction of each isomer was established from its i.r. and n.m.r. spectra. 

Reductive amination of keto-steroids, both of the 5a and 5/1 series, was accomplished by pyrrolidine over Pd/C, furnishing the 3/ -amino derivatives, whereas the a,/ -un-saturated analogues gave mixtures of 5a- and 5/ - and 3a- and 3/ -isomers182. 

Bel skii328 succeeded in converting furfural and furfurylidene acetaldehyde into pyrrole at 300° and pyrrolidine homologs at 200°, by reductive amination on Raney nickel, which was followed by rearrangement in the gas phase, in the presence of Pt ... 

Consequently, a dihydroxylated azidodialdehyde was examined next which indeed behaved as anticipated. When generated from the racemic allylic azide 37 [109], FruA catalysis effected a smooth tandem addition to the dialdehyde to provide a diastereoisomerically pure bipyranoid azido C-disaccharide 38, from which the pyrrolidine type aza sugar 39 was highly stereoselectively produced by standard reductive amination [108]. Model considerations suggest a close resemblance of the protonated aza C-disaccharide to transition states of saccha-rase or maltase. Indeed, several of the glycosidases tested were inhibited by 39 at concentrations below 1 mM. 

The N-substituted pyrrolidines (147) can be prepared in generally good yields by reductive amination of succinaldehyde,... 

It is not clear whether secondary amines (excluding such compact pyrrolidine derivatives as proline) could be successfully coupled to 35 using this reaction because of steric constraints inflicted by the neighboring bulky 2,3-0-isopropylidene substituent it was possible, however, to alkylate the secondary amine nitrogen in A-(l-deoxy-2,3 4,5-di-C)-isopropylidene-P-D-fiiictopyranos-l-yl)-peptides by reductive amination of small aldehydes with 36. Of note is the fact that, one of the first conversions of 35 into a ketosamine derivative was carried by Tronchet et a/., who employed hydrogenation over Pd catalyst to perform reductive amination and deprotection simultaneously, resulting in a 92% yield of bis-(l-deoxy-2,3 4,5-di-0-isopIo-pylidene-P-D-finctopyranos-l-yl)amine (37) (Scheme 15). 

The reaction was proposed to occur via an enamine-intermediate, which attacks the aldimines to generate q M-Mannich-type intermediates (Scheme 5.48). Cyclisation to produce the hemiaminal, followed by reductive amination, generates the functionalised pyrrolidine products stereoselectively. 

Scheme 12.3 Pd(0)-catalyzed Alder-ene cycloisomerization-reductive amination sequence to p-amino ethyl alkylidene tetrahydrofurans and pyrrolidines 9.

A short homochiral synthesis of substituted vinyl pyrrolidines by a reductive ring opening-reductive amination sequence, followed by spontaneous displacement of benzoate has been reported (Scheme 9)/ ... 

---