Regiocontrolled Synthesis of Pyrrole-2-carboxaldehydes and 3-Pyrrolin-2-ones from Pyrrole Weinreb Amides

Abstract

A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-carboxaldehydes was completed in two steps from acyclic starting materials. A Barton-Zard pyrrole synthesis between N-methoxy-N-methyl-2-isocyanoacetamide and alpha-nitroalkenes or beta-nitroacetates provided N-methoxy-N-methyl pyrrole-2-carboxamides (pyrrole Weinreb amides), which were converted into the corresponding pyrrole-2-carboxaldehydes by treatment with lithium aluminum hydride. A regioselective oxidation of the pyrrole-2-carboxaldehydes gave the corresponding 3,4-disubstituted 3-pyrrolin-2-ones.

Synthesis of Unsymmetrical 3,4-Diaryl-3-pyrrolin-2-ones Utilizing Pyrrole Weinreb Amides

“…19 To a 0 °C stirred solution of 12 (1.5 mmol) and DBU (1.5 mmol) and i -PrOH (1.5 mmol) in inhibitor-free THF 46 (15 mL), a solution of 11 (1.0 mmol) in THF (15 mL) was added dropwise via addition funnel. The yellow solution stirred at 0 °C for 30 min then at rt until analysis by TLC showed complete conversion of the starting material 11 (usually 6-24 h).…”

“…27 We previously adapted the Barton-Zard reaction to prepare pyrrole-2-carboxamides 8 including one example of a 3,4-diarylpyrrole. 19 We synthesized 8a (Ar 3 = Ph; Ar 4 = Ph) by the cyclocondensation of the corresponding nitroalkene 11a with 2-isocyano- N -methoxy- N -methylacetamide ( 12 ). 19 We herein report a significant extension of our methodology to the synthesis of unsymmetrical 3,4-diarylpyrrole-2-carboxamides 8 and to their subsequent conversion to the corresponding 3,4-diaryl-3-pyrrolin-2-ones 10 (Ar 3 ≠Ar 4 ).…”

“…19 We synthesized 8a (Ar 3 = Ph; Ar 4 = Ph) by the cyclocondensation of the corresponding nitroalkene 11a with 2-isocyano- N -methoxy- N -methylacetamide ( 12 ). 19 We herein report a significant extension of our methodology to the synthesis of unsymmetrical 3,4-diarylpyrrole-2-carboxamides 8 and to their subsequent conversion to the corresponding 3,4-diaryl-3-pyrrolin-2-ones 10 (Ar 3 ≠Ar 4 ). This work describes an entirely new approach that varies greatly from previously reported methods to this class of molecules.…”

Five‐Membered Heterocycles: Pyrrole and Related Systems

“…For example, the isocyanide 462, which is available in four steps from Boc-glycine, was converted upon reaction with the b-nitroacetate 463 into the Weinreb amide 464 (Scheme 4.145) [712]. The use of ketene S,S-or S,N-acetals in Barton-Zard reactions provides a route to substituted pyrroles bearing methylthio-or amino groups at C3.…”

A new and general method for the synthesis of tripeptide aldehydes based on the multi-component Ugi reaction

“…Allyl isocyanide (6a) was obtained by the Hofmann method in 65% yield. Isocyanide 6b was synthesized from glycine in five steps applying the method reported by Coffin et al 19 Isocyanide 6c was obtained according to Amato and Marcaccini 20 in two steps from amino acetaldehyde diethyl acetal. 2-Isocyanoethyl acetate (6d) was obtained from 2-aminoethanol by N-formylation, O-acylation, and final dehydration of the formamide group.…”