Orthogonal Synthesis of Densely Functionalized Pyrroles and Thiophenes from the Reactions of Imidazo[1,5-a]pyridine Carbene-Derived Zwitterions with Electron-Deficient Alkynes

Abstract

1-Thiocarbamoyl imidazo[1,5-a]pyridinium inner salts, which were obtained readily from the addition of C,N-substituted heterocyclic carbenes imidazo[1,5-a]pyridine-1-ylidenes to isothiocyanates, are powerful ambident nucleophilic zwitterions. They acted as nitrogen nucleophiles toward ethyl propiolate to produce polyfunctionalized pyrrole derivatives in high yields. When treated with dimethyl acetylenedicarboxylate, they behaved exclusively as sulfur nucleophiles to afford fully substituted thiophenes in excellent yields. This work provides highly efficient orthogonal synthesis of polyfunctionalized pyrroles and thiophenes that were not easily obtained by other chemical means.

Dimethyl Acetylenedicarboxylate: A Versatile Tool in Organic Synthesis

“…to isothiocyanates 623, are powerful ambident nucleophilic zwitterions. When treated with DMAD, they behaved exclusively as sulfur nucleophiles to afford fully substituted thiophenes 625 in excellent yields, providing an efficient orthogonal synthesis of polyfunctionalized thiophenes not easily obtained by other chemical means (Scheme 154) 221. Pan et al222 reported a multicomponent reaction using both N-heterocyclic carbenes and substituted phthalaldehydes.…”

Exploring the nucleophilicity of N,N′‐diamidocarbenes: Heteroallenes and related compounds as coupling reagents

“…These reactions are generally rapid, proceed with complete atom economy, and give high yields of products that are attractive for the synthesis of heteroatom rich compounds . Moreover, such carbene–heteroallene coupling reactions have been used in applications that range from small molecule activation and catalysis to the synthesis of novel polymers and heterocycles …”

“…[18,37] Moreover, such carbene-heteroallene coupling reactions have been used in applications that range from small molecule activation [23,24,38] and catalysis [39][40][41] to the synthesis of novel polymers [25,42] and heterocycles. [19][20][21][22]26,37,[43][44][45][46][47][48][49] Herein, we explore the nucleophilicity of a DAC (i.e., 1; Fig. 1) by evaluating its propensity to couple to various heteroallenes, including azides, isothiocyanates, isocyanates, and ketenes.…”

“…[61] Subsequent efforts were directed toward analyzing the reaction of 1 with isothiocyanates, substrates that typically afford imidothioates when exposed to NHCs. [44][45][46][47][48][49] Stirring a C 6 H 6 solution of 1 with an equimolar amount of 4-nitrophenyl isothiocyanate at room temperature for 1 h ([1] 0 = 0.13 M) resulted in the formation of dihydropyrimidinium imidothioate 3 (Scheme 2), as evidenced by the FT-IR carbonyl stretching frequencies observed at 1769 and 1740 cm À1 and the 1:1 DAC:isothiocyanate stoichiometry gleaned from 1 H NMR spectroscopic analysis of the crude reaction mixture. Pure 3 was isolated in high yield (96%) as a red-orange solid by recrystallizing the crude product from CHCl 3 /pentane, and the structural assignment was verified via single crystal X-ray diffraction (XRD) analysis ( Fig.…”

The multicomponent reaction of imidazo[1,5-a]pyridine carbenes with phthalaldehydes and dimethyl acetylenedicarboxylate: a facile construction of benzo[d]furo[3,2-b]azepines

“…Very recently, we developed a method for the syntheses of highly functionalized pyrroles or thiophenes from the reaction of dipolar adducts, which were derived from imidazo [1,5-a]pyridine-1-ylidenes and isothiocyanates, with different alkynes. 9 We also provided a straightforward approach to fully substituted furans via the threecomponent reactions of imidazo [1,5-a]pyridine-3-ylidenes with aldehydes and DMAD or allenoates. 10 After that, our attention was then turned to the multicomponent reaction comprised of N-heterocyclic carbenes and substituted phthalaldehydes.…”