Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

Abstract

Two kinds of [3 + 2] cycloaddition intermediates generated from the three-component reactions of 2-bromobenzaldehydes and maleimides with amino esters or amino acids were used for a one-pot N-allylation and intramolecular Heck reactions to form pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines. The multicomponent reaction was combined with one-pot reactions to make a synthetic method with good pot, atom and step economy. MeCN was used as a preferable green solvent for the reactions.

One-pot Double Annulations to Confer Diastereoselective Spirooxindole-pyrrolothiazoles

“…The optimized reaction conditions of stepwise, one-pot and cascade (two-step with one operational step) process for N, S-acetalation and decarboxylative 1,3-dipolar cycloaddition were developed by using two equivalents of 4-bromobenzaldehyde 1a, L-cysteine 2 and olefinic oxindole 4a shown in Table 1. Taking the example by my reported work [54][55][56][57][58][59], we further evaluated the influence of protic solvents such as EtOH, i PrOH and MeOH, which only results in slightly different LC yield (93-95%) of compound 3a and followed by decarboxylative [3+2] cycloaddition with olefinic oxindole 4a under reflux heating, it indicates that the reactions with EtOH and i PrOH afforded the 81% of LC yield for compound 5a slightly better than 78% yield using MeOH as a solvent (Table1, entries 1-4).…”

“…The results indicate that substituent on Ar 2 of the aldehydes could influence the product yield, such as 7c (3-pyridinyl, 43% yield, 4.5:1 dr). In addition, oxindole 4 with different R 1 were employed for the synthesis to give 7f with COMe in the trace amount and no product 7g with Ph, following aliphatic aldehydes to replace aromatic aldehydes, the reaction gave 7h and 7i as complex mixtures [54][55][56][57][58][59]71]. The endo-TS is more favorable than exo-TS for 1,3-dipolar cycloaddition to afford major and minor products.…”

“…The diastereochemistry of non-stabilized azomethine ylides for decarboxylative [3+2] cycloaddition could be identified in reported literature. [54][55][56][57][58][59]71] Through the study of mechanism, it elucidates that the double annulations using L-cysteine undergoes three stages: N, S-acetal I,…”

“…We have reported a series of multicomponent reactions, like Groebke-Blackburn-Bienayme for making BET inhibitors UMB32 and UMB136 [33,34], and Zhang 4-Aminoquinolines synthesis for developing fluorinated analogues of acetylcholinesterase (AChE) inhibitors [35], cascade reactions, such as one-step synthesis of quinolines and quinolin-4-ols involving Histone acetyltransferases (HAT) inhibitors [36,37], as well as one-pot reactions, for example, amino acids(esters)-based [3+2] cycloadditions [38][39][40][41][42][43][44][45][46][47][48] in the synthesis of pyrrolidine-containing systems [49][50][51][52][53][54][55][56][57][58][59].…”

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

“…Zhang developed 4-aminoquinolines for the synthesis of fluorinated analogues of acetylcholin- esterase (AChE) inhibitors [35] in cascade reactions, such as one-step syntheses of quinolines. Quinolin-4-ols involving histone acetyltransferases (HAT) inhibitors [36,37], as well as one-pot reactions were also developed by Zhang using the 4-aminoquinoline synthesis, for example, in amino acids(esters)-based [3 + 2] cycloadditions [38][39][40][41][42][43][44][45][46][47][48] and in the synthesis of pyrrolidine-containing systems [49][50][51][52][53][54][55][56][57][58][59]. Pyrrolothiazole and spirooxindole moieties occupy exclusive positions as valuable source of natural products and therapeutic agents in organic synthesis and drug discovery [60][61][62][63][64][65][66][67][68].…”