Indole, cross-dehydrogenative coupling

Li, Z. and Li, C.-J. 2005. CuBr-catalyzed direct indolation of tetrahydroisoquinolines via cross-dehydrogenative coupling between sp3 C-H and sp2 C-H bonds. Journal of the American Chemical Society, 127 6968-69. 

Copper Catalysts Direct oxidative functionalization of tertiary amines is of importance both enzymatically and synthetically. The combination of CuBr—TBHP has proved to be as an efficient system in the oxidative activation of sp3 C—H bonds adjacent to a nitrogen atom [10]. Various types of cross-dehydrogenative coupling (CDC) reactions have been developed, including compounds with activated methylene groups [11], indoles [12], and terminal alkynes (Scheme 11.2) [13]. Because 1,2,3,4-tetrahydroisoquinoline derivatives are important structure motifs of natural... 

Scheme 56 Rh- (a) and Cu-catalyzed (b) cross-dehydrogenative coupling of IH-indoles and 1 H-pyrroles with heteroarenes.

Future efforts in the CDC of arenes will perhaps include enzyme-mediated reactions, since enzymes have low toxicity, high catalytic turnovers, and are able to run in very mild conditions. In 2006, °° dTschia and co-workers used peroxidase enzymes to catalyze the oxidative dimerization of indole derivatives. This technology, albeit low yielding, appears to be an excellent lead to optimize cross-dehydrogenative-coupling. 

The first cross-dehydrogenative intermolecular arylation of a heteroarene with an arene was reported by Fagnou in 2007. N-acetyl-lH-indoles were coupled with simple arenes and selective C3-arylation was obtained (88 89) in the presence of Pd(TFA)2 as catalyst in combination with superstoichiometric Cu(OAc)2 as terminal oxidant (Scheme 40) (2007SCI1172). The N-acetyl group proved to be crucial as no reaction product was achieved with IH-indoles, furthermore N-methyl-lH-indoles gave only self-dimerized products. 

The proposed iminium intermediate in the CDC-type allgmylation implies that other C-H based pronueleophiles, besides terminal allqmes, can also couple with an a-sp C-H bond of a nitrogen in amines via the same process. Thus, we examined eleetron-rieh arenes as one such nucleophile via a cross-dehydrogenative Friedel-Crafts type arylation. Indole derivatives were coupled with N-aryl-THIQs under the CuBr/TBHP system to produce the desired CDC reaction product in good-to-excellent yields (Scheme 1.9). It is worth noting that the reaction was not sensitive to moisture or air, and that the desired product was obtained in reasonable yield even when the reaction was... 

Doi and Mori made excellent use of dihydroindole triflate 189 in Pd-catalyzed cross-coupling reactions. This compound was discussed earlier in the Suzuki section, and it also undergoes Stille couplings as illustrated below [140]. A final dehydrogenation completes the sequence to indoles. 

Silver(I) acetate functions as an oxidant in the dehydrogenative cross-coupling of indoles and pyrroles with arenes. Whereas AgOAc favored C2 arylation for A-protected indoles, Cu(OAc)2 produced an inversion with selectivity, showing preference for C3 arylation (eq 29). Trace amounts of diarylated product were also detected. 

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