On the mechanism of the Au(I)‐mediated addition of alkynes to anthranils to furnish 7‐acylindoles

Abstract

Indole is a very common structural motif in alkaloids with a remarkable history in pharma industry. In the continuous search for more direct and efficient access to these valuable structures, a new and rather elegant approach was found by Jin and coworkers, which involved a gold(I)‐mediated addition of alkynes onto anthralins. This approach selectively furnishes 7‐acylindoles in a rather expeditious way, and it has been shown to be compatible with a large range of decorated reactants, both at the alkyne side and at the anthralin side. We studied the mechanism of this reaction with a set of different alkynes, including disubstituted ones, to establish similarities and differences between them and to aid in the elucidation of key steps in the reaction pathway. The observed regioselectivity seems to be connected to the irreversible formation of a key α‐imino gold carbene intermediate, common to all reaction profiles, through the initial regioselective nucleophilic attack of the anthranil N atom onto the alkyne fragment.

Formation and Intramolecular Capture of α-Imino Gold Carbenoids in the Au(I)-Catalyzed [3 + 2] Reaction of Anthranils, 1,2,4-Oxadiazoles, and 4,5-Dihydro-1,2,4-Oxadiazoles with Ynamides

“…The full profile for the substituted ynamide can be found in Scheme 3, and it compares well with that obtained earlier for the terminal ynamide [50], with regioselectivity still strongly favoring the attack on C1 compared to C2 of the gold-activated ynamide by 12.3 kcal/mol compared to the 14.8 kcal/mol observed for the terminal ynamide. The key chemical steps are the same, and the overall energy barriers are quite similar and follow the general description provided above, which involves five stages (alkyne activation, nucleophilic attack, N-O bond cleavage, cyclization, and deauration).…”

“…We assumed that the general mechanism for the three protocols could be analogous, according to the similarities in the structures of the three nucleophiles, and that the key feature in this reactivity is the oxime fragment embedded in the heterocyclic moiety [47][48][49]. With that assumption in mind, and driven by our recent exploration of anthranil chemistry [50], we anticipated a reaction pathway for the oxadiazoles involving (Scheme 2): (1) Au(I) activation of the alkyne, (2) nucleophilic attack by the oxime nitrogen onto the activated alkyne, (3) N-O cleavage and formation of the key α-imino gold carbene intermediate, (4) cyclization of the α-imino gold carbene intermediate via an intramolecular nucleophilic attack, and (5) deauration leading to the final heterocycle. As a continuation of our efforts to gain a deeper insight into the intricacies of goldmediated transformations [3,[33][34][35][36][37][38][39][40][41][42][43][44][45] and particularly reaction mechanisms including gold carbenes [13,[16][17][18][19][20][21][22]46], here we carried out a thorough investigation of the reaction mechanism of the Au(I)-catalyzed [3 + 2] reaction of the mild nitrogen nucleophiles anthranil, 1,2,4-oxadiazole, and 4,5-dihydro-1,2,4-oxadiazole with ynamides.…”

“…We assumed that the general mechanism for the three protocols could be analogous, according to the similarities in the structures of the three nucleophiles, and that the key feature in this reactivity is the oxime fragment embedded in the heterocyclic moiety [47][48][49]. With that assumption in mind, and driven by our recent exploration of anthranil chemistry [50], we anticipated a reaction pathway for the oxadiazoles involving (Scheme 2): ( 1 As a continuation of our efforts to gain a deeper insight into the intricacies of goldmediated transformations [3,33,[34][35][36][37][38][39][40][41][42][43][44][45] and particularly reaction mechanisms including gold carbenes [13,[16][17][18][19][20][21][22]46], here we carried out a thorough investigation of the reaction mechanism of the Au(I)-catalyzed [3 + 2] reaction of the mild nitrogen nucleophiles anthranil, 1,2,4-oxadiazole, and 4,5-dihydro-1,2,4-oxadiazole with ynamides. We paid particular attention to the formation of the α-imino gold carbene intermediate, the regioselectivity of these reactions which can afford 7-acyl-2-amino-indoles substituted at 2-, or/and 3-position, and 4-aminoimidazoles, respectively, as well as to the difference in reactivity between aromatic and non-aromatic substrates (oxadiazole vs. dihydrooxadiazole).…”

“…We assumed that the general mechanism for the three protocols could be analogous, according to the similarities in the structures of the three nucleophiles, and that the key feature in this reactivity is the oxime fragment embedded in the heterocyclic moiety [47][48][49]. With that assumption in mind, and driven by our recent exploration of anthranil chemistry [50], we anticipated a reaction pathway for the oxadiazoles involving (Scheme 2): (1) Au(I) activation of the alkyne, (2) nucleophilic attack by the oxime nitrogen onto the activated alkyne, (3) N-O cleavage and formation of the key α-imino gold carbene intermediate, (4) cyclization of the α-imino gold carbene intermediate via an intramolecular nucleophilic attack, and (5) deauration leading to the final heterocycle.…”

Comprehensive Overview of Homogeneous Gold-Catalyzed Transformations of π-Systems for Application Scientists

“…We investigated [43] the reaction of anthranils 7b with ynamides 7a as well as apolar alkynes (terminal or central) using DFT calculations. When the alkyne was terminal, the reaction afforded selectively the 2-substituted 7-acyl-indole 7c compared with the 3-substituted 7-acyl-indole indole 7n (Scheme 7).…”