A Modular Synthesis of Polysubstituted Indolizines

Abstract

The N‐alkylation of pyridines with cyanohydrin triflates or α‐halonitriles furnishes 1‐(1‐cyanoalkyl)pyridinium salts that can react with nitroolefins under basic conditions to furnish polysubstituted indolizines. Overall, the indolizine core can be constructed from a pyridine, two aldehydes, and a nitroalkane, and no undesired functional groups remain in the products. When bromoacetonitrile was used for the N‐alkylation, indolizine‐3‐carbonitriles were obtained instead. The pyridine component may be replaced by other azines, giving rise to related heterocyclic systems.

Two‐Step Synthesis of 2‐Aminoindolizines from 2‐Alkylpyridines

“…Recently we developed a modular approach to the synthesis of polysubstituted indolizines18 from 1‐(1‐cyanoalkyl)pyridinium salts and nitroalkenes by a formal dipolar cycloaddition reaction, but this reaction does not allow the introduction of strongly electron‐donating substituents. When several pyridinium substrates were screened in this procedure, α‐picolinium salts were found to produce much lower yields of the corresponding indolizines.…”

“…Pyridinium salt 3b and cyanohydrin triflates 2b – d were prepared according to our previously reported procedures 18…”

“…1‐Cyanopentyl Trifluoromethanesulfonate (2a): 18 The title compound was prepared according to the general procedure described above from 2‐hydroxyhexanenitrile (4.30 g, 38.0 mmol). The product 2a (7.30 g, 29.8 mmol, 78 %) was isolated as a light‐yellow liquid.…”

“…General Procedure for the Preparation of Pyridinium Salts 3a–l: 18 A cyanohydrin triflate (1.0 equiv.) was added to a solution of 1 or other heterocycle in diethyl ether (1.0 M ) at room temp., and the reaction mixture was stirred overnight or for 48 h. The products were collected by filtration and washed with the appropriate solvents.…”

Heterocycles from α‐Aminonitriles

“…[40] Nitroolefins 38 are another class of suitable reaction partners for deprotonated a-(alkylideneamino)nitriles and can, for example, be employed for the synthesis of tetrasubstituted pyrroles (Scheme 11). [45] Scheme 9. [41] Similar cyclizations such as the Barton-Zard reaction, the Montforts synthesis, or van Leusen's pyrrole synthesis are limited to the introduction of two or three substituents, at least one of which needs to be electronwithdrawing.…”