Regioselectivity for the Rh(I)‐catalyzed Annulation of 1,2,3‐Thiadiazoles with Alkynes: Experimental and Computational Analysis Reveal the Surprising Role of the Alkyne Substituent

Abstract

The Rh(I)‐catalyzed denitrogenative annulation reactions of 1,2,3‐thiadiazoles are a new direct approach to synthesizing densely functionalized heterocycles. The synthesis of multisubstituted thiophenes is possible using this methodology, however the difficulty to predict which regioisomer will form is a current limitation. In this current work, systematic computational and experimental studies were performed addressing how the terminal alkyne substituent effects regioselectivity. Our data revealed that the electronic and steric properties of the alkyne substituent effects regioselectivity, including whether the group is aryl or alkyl. The insight gained from our study has allowed the development of a framework for predicting regioselectivity for the Rh(I)‐catalyzed denitrogenative transannulation of 1,2,3‐thiadiazoles with terminal alkynes.

Catalytic Enantioselective (3+2) Annulations of Nucleophilic Thioacyl Rh(I)-Carbenes with Achmatowicz Rearrangement Products

“…HRMS inspection of the crude reaction mixture revealed an obvious molecular peak at m / z = 981.1591. which, as we suggest, points to an α-thioacyl Rh­(I)-carbene species resonating between structures A1 and B1 . Such a suggested structural proposal is based on the mechanistic insights by Bao’s, Keaveney’s, and our groups …”

“…Since 2016, Gevorgyan’s, Lee’s, and our groups have established 1,2,3-thiadiazoles as practical 1,3-dipole precursors under Rh(I)/bisphosphine catalysis and developed several useful transannulations for synthesizing achiral or racemic thiacycles. Previous computational and experimental studies suggested that the key intermediates be 1-thia-2-rhodacyclo-butenes ( A ), , which were proposed to resonate with α-thioacyl Rh(I)-carbene form ( B ) (Scheme C). − Although the reactions of terminal alkenes and highly strained bicyclic alkenes had been reported by Lee’s and our groups, respectively, the envisioned reactions with ARPs are still confronted with the following dilemmas: (1) only one asymmetric transformation of 1,2,3-thiadiazoles was reported by us with poor to moderate enantioselectivity. The parameters responsible for excellent enantiocontrol are still unclear.…”

Recent Advances in the Denitrogenative Annulation Reactions of 1,2,3‐Thiadiazoles

“…This study reinforces the susceptibility of the regiochemical outcome of the Rh(I)-catalyzed denitrogenative transannulation between 1,2,3-thiadiazoles and terminal alkynes to reaction conditions, and the impact of coupling partners and substituents. [36] This understanding enables more rational regioisomer synthesis, and reveals the need for alternative catalytic systems beyond Rh(I) for selective regioisomer synthesis.…”

“…To increase our understanding of how each factor influences the regioselectivity of the Rh(I)-catalyzed transannulation between 1,2,3-thiadiazoles and terminal alkynes, and to create a framework for a priori prediction of regiochemical outcome, our group used a combination of computational and experimental studies to examine how the steric and electronic properties of the substituent on the terminal alkyne influence regioselectivity (Scheme 17b). [36] It was shown that the introduction of an electron-donating group on the aryl alkyne yielded a mixture of regioisomers, slightly favoring formation of the 2,3,4-substituted isomer 116 (however isomer 117 was still the major product), as formation of the 2,3,5-substituted isomer 117 is less likely as it involves a reversible migratory insertion step. In contrast, inclusion of an electron-withdrawing group or steric bulk in the aryl substituent significantly enhanced selectivity for the 2,3,5substituted thiophene 117.…”

“…The terminal alkyne substituent effects on the regioselectivity of the Rh(I)catalyzed transannulation between 1,2,3-thiadiazole 115 and terminal alkynes. [36] Scheme 18. a) Rh(I)-Catalyzed transannulation of 1,2,3-thiadiazoles 118 with acrylonitrile derivatives. [37] inactive, however, norbornene 125 e with high ring strain (19.2 kcal mol À 1 ) exhibited high reactivity resulting in the desired product 126 e in almost quantitative yield (Scheme 19b).…”