Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

Abstract

By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing β-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was prepared and characterized. Surprisingly, a well-documented approach to obtain peptide-containing carboxylic acids through acid hydrolysis of the convertible isocyanide moiety in the Ugi bisamides proceeded in an unexpected manner in our case, leading to the formation of derivatives of amides of heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the β-chlorovinyl fragment into a vinyl one is provided.

Keywords: Ugi reaction; convertible isocyanides; multicomponent reaction; post-Ugi transformation; pyrrole derivative.

Scheme 1

The use of α,β-unsaturated aldehydes in the Ugi reaction.

Scheme 2

Comparison of isocyanide conversion conditions.

Figure 1

Azomethines based on ethyl 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylate and 4-[(E)-1-chloro-3-oxoprop-1-enyl]-3,5-dimethyl-1H-pyrrole-2-carboxylate.

Figure 2

Molecular structure of ethyl (Z)-4-(3-(N-(4-bromophenyl)-2-chloroacetamido)-4-(tert-butylamino)-1-chloro-4-oxobut-1-en-1-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (8c) according to the X-ray diffraction study. Non-hydrogen atoms are presented as thermal ellipsoids with 50% probability.

Scheme 3

Hydrolysis of Ugi bisamide 5d in the presence of HCl. Conditions: (A) 5 equiv HCl, MeOH, 80 °C, 3 h; (B) 5 equiv HCl, EtOH, MW 120 °C, 15 min; (C) 5 equiv HCl, MeCN, MW 100 °C, 20 min.

Figure 3

Molecular structure of ethyl (E)-4-(4-(tert-butylamino)-3,4-dioxobut-1-en-1-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (10d) according to X-ray diffraction data. Non-hydrogen atoms are presented as thermal ellipsoids with 50% probability.

Figure 4

Molecular structure of ethyl 4-(3-(N-(4-bromophenyl)-2-chloroacetamido)-4-(tert-butylamino)-4-oxobutanoyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate (12e) according to the X-ray diffraction data. Non-hydrogen atoms are presented as thermal ellipsoids with 50% probability.

Scheme 4

The Ugi-4CR with the participation of p-anisidine and benzyl isocyanide.

Scheme 5

Successful attempt at tandem one-pot coupling of the Ugi-4CR reaction and post-transformation of the corresponding bisamide 8c.

Scheme 6

Plausible transformation sequence of the formation of amides 10 and ketobisamides 12.