Reaction of a monosubstituted, 1,3-disubstituted, or tetrasubstituted allene with various indoles catalyzed by a 1:1 mixture of a gold(I) N-heterocyclic carbene complex and AgOTf at room temperature leads to hydroarylation with formation of 3-allyl-indoles in modest to good yield.
The conditions optimized for the catalytic intermolecular hydroalkoxylation and hydroamination of allenes proved effective for the intermolecular hydroarylation without further optimization [,]. Typically 1.5 equivalents of allene relative to indole were employed in these gold(I)-catalyzed hydroarylation reactions to offset any loss of allene under reaction conditions, although a number of reactions proceeded to completion with only 1.05 equivalents of allene. As an example of gold(I)-catalyzed hydroarylation, reaction of 1,2-dimethylindole with dimethyl 2,3-butadienylmalonate (2; 1.05 equiv) catalyzed by a 1:1 mixture of (1)AuCl and AgOTf (5 mol %) at room temperature for 48 h led to isolation of (E)-3-allylic indole 3 in 82% yield as a single regio- and stereoisomer ().
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1,3-Disubstituted allenes 4-7 also underwent gold(I)-catalyzed hydroarylation to form the corresponding (E)-3-allylic indoles 8-11 in 48-89% yield with excellent diastereoselectivity (). In the case of differentially disubstituted allenes, the regioselectivity of hydroarylation was affected by both the electronic and steric nature of the allenyl substituents. As examples, hydroarylation of ethyl 5-cyclohexyl-3,4-pentadienoate (5) formed 9 with exclusive attack of indole at the more electron-rich cyclohexyl-bound allenyl carbon atom (), whereas hydroarylation of 4-methyl-1-phenyl-1,2-pentadiene (6) formed 10 with exclusive attack of indole at the less sterically encumbered phenyl-bound allenyl carbon atom (). In comparison, 1-phenyl-1,2-butadiene (7) underwent hydroarylation to form a 1:1.2 mixture of regioisomeric 3-allylic indoles 11a and 11b in good yield (). Although 1,1-disubstituted and trisubstituted allenes failed to undergo efficient gold(I)-catalyzed hydroarylation, the tetrasubsituted allene 2,4-dimethyl-2,3-pentadiene (12) underwent gold(I)-catalyzed hydroarylation with 1,2-dimethylindole to form the 3-(1,1,3-trimethyl-2-butenyl) indole derivative 13 in 56% yield ().
The mechanism of gold(I)-catalyzed allene hydroarylation likely mirrors that of the related hydroalkoxylation and hydroamination processes [,]. Halide abstraction from (1)AuCl with AgOTf generates the active catalyst (1)AuOTf  that presumably undergoes displacement of the triflate ligand with allene to generate an equilibrating mixture of gold π-allene complexes I and Ia (). Outer-sphere attack of the indole on the gold allene complex I in which gold is positioned cis to the proximal alkyl group would form iminium ion II . Deprotonation of II followed by protonolysis of the Au–C bond of neutral gold vinyl species III would release the alkylated indole and regenerate the cationic gold NHC complex.
1,2-Dimethylindole was initially targeted as a nucleophile for the hydroarylation of allenes owing to the enhanced nucleophilicity of N-alkylindoles relative to N-unsubstituted indoles and because substitution at the indole C2 carbon precludes the formation of multiple addition products . Nevertheless, indoles that lacked substitution at the N1 and/or C2 position or that possessed an electron-withdrawing group at the C5 position underwent efficient gold(I)-catalyzed hydroarylation, albeit at higher catalyst loading (). For example, treatment of 1-methylindole with allene 2 (1.05 equiv) catalyzed by a 1:1 mixture of (1)AuCl and AgOTf (10 mol %) at room temperature for 24 h led to isolation of (E)-3-allylic indole 14 in 61% yield as a single regio- and stereoisomer (). Similarly, gold(I)-catalyzed reaction of allene 2 with 2-methylindole, 5-methylindole, or 5-chloro-1,2-dimethylindole at room temperature for 48 h led to isolation of (E)-3-allylic indoles 15-17 in 53-77% yield as single isomers ().
In summary, we have developed a gold(I)-catalyzed protocol for the hydroarylation of monosubstituted, 1,3-disubstituted, and tetrasubstituted allenes with indoles at room temperature. We continue to work toward the elucidation of the mechanisms of gold(I)-catalyzed hydrofunctionalization and toward the development of more effective allene hydroarylation processes.