A Three-Component Catalyst-Free Approach to Regioselective Synthesis of Dual Highly Functionalized Fused Pyrrole Derivatives in Water–Ethanol Media: Thermodynamics versus Kinetics

Abstract

A three-component catalyst-free protocol for the regioselective synthesis of dual highly functionalized fused pyrroles has been developed from a cascade [3 + 2] cyclization of heterocyclic ketene aminals (HKAs) 1 with arylglyoxal monohydrates 2 and cyclohexane-1,3-diones 3 in water–ethanol media. The kinetically controlled products 4 could be synthesized within 1 h but would irreversibly transform to thermodynamically controlled products 5 over an additional 5 h. At the same time, the transformative synthesis of 5a from 4a by controlling the oxygen or nitrogen proved the proposed mechanism. Furthermore, the DFT calculation also corroborated that the stability of products 5 are a 100,000 times more thermodynamically stable than products 4. Finally, the origin of the greater stability of 5 could be explained by the reduced density gradient (RDG) analysis, which hinted that the crucial factors are the formation of a new intramolecular hydrogen bond and the release of the steric effect of the crowded rings. In conclusion, this novel synthetic strategy offers an alternative method using thermodynamic or kinetic control for regioselective construction of biologically meaningful fused pyrrole architectures from a concise, rapid, and environmentally friendly vision.

Recent advances in the synthesis of pyrroles via multicomponent reactions using arylglyoxals

“…70 Chen and coworkers have reported the multicomponent synthesis of N-bridgehead-fused pyrroles 98 and 99 by reaction of arylglyoxals 4, cyclohexane-1,3-diones 31, and heterocyclic ketene aminals 97 under two different reflux conditions in high yield (Scheme 40). 112 Scheme 40. Chen's synthesis of N-bridgehead fused pyrroles.…”

Synthesis of fused hydroxy dihydropyrroles and unexpected dihydropyrazine and dihydroquinoxaline derivatives based on heterocyclic ketene aminals

“…[19] Multi-component domino reactions (MCRs) for total synthesis of natural products or natural-like structures have been powerful tools for the synthesis of numerous complex molecules in modern organic chemistry. [36][37][38] To investigate the scope and limitations of this method and expand the diversity of the fused pyrrole library, another β-dicarbonyl compounds were used in this domino reaction. [24] HKAs have been used as bisnucleophiles to build fused heterocycles, because both the α-carbon and the secondary amino group can react with electrophiles.…”

A Convenient Synthesis of 3,7′-Bisindole Derivatives

“…Heterocyclic ketene aminals (HKAs) are versatile building blocks used to construct a variety of fused heterocyclic compounds [31,32,33], such as quinolones [34,35], pyridines [36,37,38,39,40,41,42], pyrroles [43,44,45,46,47], spirooxindoles [48,49], etc. In recent years, we have developed some protocols to synthesize different substituted indole derivatives based on HKA building blocks [50,51,52] (Figure 2).…”