Ethynyl Benziodoxolones for the Direct Alkynylation of Heterocycles: Structural Requirement, Improved Procedure for Pyrroles, and Insights into the Mechanism

Abstract

This report describes a full study of the gold‐catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3‐ and 6‐position of triisopropylsilylethynyl‐1,2‐benziodoxol‐3(1H)‐one (TIPS‐EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2‐pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a π activation or an oxidative mechanism are most probable for the alkynylation reaction.

Alkynylation with Hypervalent Iodine Reagents

“…This protocol was especially efficient in the case of aryl or silyl substituted alkynes, and could also be used to access bistrifluoro-13 methyl-substituted benziodoxole derivatives. Waser and co-workers showed later that the protocol was highly useful for both, the synthesis of benzene-ring modified analogues and the synthesis of silyl-substituted EBX reagents on larger scale (up to 40 g [103,104]). The synthesis of dimethyl-substituted ethynylbenziodoxole reagents was reported by Waser and co-workers in 2012 where the use of a more reactive lithium acetylide as alkynylation reagent was required in the synthesis (Scheme 2.12, C [103]).…”

“…Waser and co-workers showed later that the protocol was highly useful for both, the synthesis of benzene-ring modified analogues and the synthesis of silyl-substituted EBX reagents on larger scale (up to 40 g [103,104]). The synthesis of dimethyl-substituted ethynylbenziodoxole reagents was reported by Waser and co-workers in 2012 where the use of a more reactive lithium acetylide as alkynylation reagent was required in the synthesis (Scheme 2.12, C [103]). Koser and co-workers already reported in 1993 that cyclic hypervalent iodine reagents bearing a more electron-withdrawing sulfonate group could be also easily accessed from the hydroxy derivative 34 using terminal acetylenes and toluene sulfonic acid as activator (Scheme 2.12, D [105]).…”

“…Due to the high stability of TIPS-EBX 52 many reaction conditions are tolerated, which was important to optimize the alkynylation of other classes of aromatic compounds. For example, pyrroles were best functionalized in the presence of pyridine to avoid decomposition [103]. In this case, selective functionalization of the more electron-rich position was observed, unless it was blocked.…”

“…Furthermore, the formation of gold particles was also observed during the reaction. Initially, two mechanisms were proposed as shown in Scheme 2.19 [103,117]. 1) an oxidative mechanism involving oxidative addition of the reagent on the gold(I) 19 catalyst to give a gold(III) intermediate I, followed by electrophilic auration to give II and final reductive elimination (Scheme 2.19, A) or 2) a -activation mechanism proceeding via coordination of the gold catalyst to give intermediate III followed by nucleophilic addition leading to IV (Scheme 2.19, B).…”

“…In 2015, Nachtsheim and co-workers investigated the directed alkynylation of ortho-vinyl phenols with EBX reagents (Scheme 2.25 [141]). As only moderate yields were obtained using TIPS-EBX 52, the more reactive TIPS-EBX* 60, introduced by Waser and co-workers [103], was used. Apart of its enhanced reactivity, the ortho-methyl group in 60 also blocked pathways leading to C-H activation side products.…”