Coupling Reactions of Alkynyl Indoles and CO₂ by Bicyclic Guanidine: Origin of Catalytic Activity?

Abstract

Density functional theory calculations were used to investigate the three possible modes of activation for the coupling of CO with alkynyl indoles in the presence of a guanidine base. The first of these mechanisms, involving electrophilic activation, was originally proposed by Skrydstrup et al. (Angew. Chem. Int. Ed. 2015, 54, 6682). The second mechanism involves the nucleophilic activation of CO . Both of these electrophilic and nucleophilic activation processes involve the formation of a guanidine-CO zwitterion adduct. We have proposed a third mechanism involving the bifunctional activation of the bicyclic guanidine catalyst, allowing for the simultaneous activation of the indole and CO by the catalyst. We demonstrated that a second molecule of catalyst is required to facilitate the final cyclization step. Based on the calculated turnover frequencies, our newly proposed bifunctional activation mechanism is the most plausible pathway for this reaction under these experimental conditions. Furthermore, we have shown that this bifunctional mode of activation is consistent with the experimental results. Thus, this guanidine-catalyzed reaction favors a specific-base catalyzed mechanism rather than the CO activation mechanism. We therefore believe that this bifunctional mechanism for the activation of bicyclic guanidine is typical of most CO coupling reactions.

Transition Metal‐Free CO2 Fixation into New Carbon–Carbon Bonds

“…Hence, the use of 5equivalents LiOtBu (V)u nder 1atm CO 2 in DMF at 100 8Ca ffords 19 a-f in 19-96% yield within 24 h. Notably,t he reaction proceeds smoothly with N-unprotected indoles, whereas N-alkyl indoles do not undergo carboxylation under the optimized conditions. [16] ChemSusChem 2018, 11,3056 -3070 www.chemsuschem.org the negative charge between the nitrogen atom and C3 (21). X = O, S; A= N, C. [17] Scheme2.a) Proposed reaction mechanism and b) observed regioselectivity for the three-component reaction betweena rynes,imines, and CO 2 developed by Yoshida, Kunai and co-workers.…”

Direct Carboxylation of C(sp3)-H and C(sp2)-H Bonds with CO2 by Transition-Metal-Catalyzed and Base-Mediated Reactions

“…of TBD for optimal conversion (9 examples, 53-86% yields). A plausible reaction mechanism was proposed by Skrydstrup (Scheme 54) encompassing the formation of the well characterized TBD-CO2 zwitterionic adduct (129). Interaction of the 2-alkynyl indole with the TBD-CO2 adduct promotes deprotonation of the NH-functionality and subsequent electrophilic attack by CO2 at the 3 position of the indole ring (130).…”

“…Interaction of the 2-alkynyl indole with the TBD-CO2 adduct promotes deprotonation of the NH-functionality and subsequent electrophilic attack by CO2 at the 3 position of the indole ring (130). Re-aromatization of the indole ring by 3,1-hydrogen shift produces the carboxylate (131) which is prone to attack the A plausible reaction mechanism was proposed by Skrydstrup (Scheme 54) encompassing the formation of the well characterized TBD-CO 2 zwitterionic adduct (129). Interaction of the 2-alkynyl indole with the TBD-CO 2 adduct promotes deprotonation of the NH-functionality and subsequent electrophilic attack by CO 2 at the 3 position of the indole ring (130).…”

“…Re-aromatization of the indole ring by 3,1-hydrogen shift produces the carboxylate (131) which is prone to attack the alkynyl-moiety via a 6-endo-dig-cyclization mechanism. Recently, the reaction mechanism proposed by Skrydstrup has been reanalyzed by Wong and co-workers via a DFT study [129] using the energetic span model developed by Shaik and Kozuch [130] to calculate turnover frequencies (TOFs). The DFT analysis suggests that the more favored activation pathway encompasses a bifunctional mechanism in which TBD is able to deprotonate 127 at the nitrogen atom (proton transfer 1, Scheme 54b) engaging, at the same time, hydrogen bond with CO 2 (132).…”

Organic Base-Catalyzed C–S Bond Construction from CO2: A New Route for the Synthesis of Benzothiazolones

“…Methyl-substituted lower reactivity, and the yields of the substituted substrates with neither electron-withdrawing groups nor electron-donating groups were also lower than the model reaction. Based on previous reports and the experimental results [28,33,41,42,45], a probable catalytic cycle was proposed for the reaction of 2-aminothiophenols with CO 2 to benzothiazolones using DBN as a catalyst, as depicted in Scheme 2. Firstly, CO 2 could react with DBN to form the key carbamate Based on previous reports and the experimental results [28,33,41,42,45] …”