A unique copper-catalyzed cross-coupling reaction by hydrogen (H₂) removal for the stereoselective synthesis of 3-phosphoindoles

Abstract

The first Cu(i)-catalyzed cross-coupling reaction by hydrogen (H2) removal for the stereoselective synthesis of 3-phosphoindoles is reported. Going beyond the oxidative dehydrogenative coupling reactions reported recently, this reaction completely omits the oxidant and base, producing hydrogen (H2) as the only byproduct.

Phosphorylation of C–H bonds of aromatic compounds using metals and metal complexes

“…N-Unsubstituted ethyl indole-2-carboxylate also reacts efficiently, the corresponding products being obtained in high yields (131b,f). 245 Steric effects have no appreciable influence: good yields of the products were observed for the substrates having a Me group in position 4, 5, 6 or 7 (phosphonates 131h ± k). Studying the electronic effects showed that electron-donating groups improve the reactivity of substrates compared to electron-withdrawing ones.…”

“…3-Phosphoindoles represent novel second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs), demonstrating an excellent potency in vitro agaist wild-type and NNRTI-resistant type of HIV-1. 252 ± 256 In the primary study, 245 Yang and co-workers chose ethyl N-methylindole-2-carboxylate (133a) and phosphine oxide Ph 2 P(O)H (92) as model substrates. A broad screening for catalysts, solvents and temperatures was performed.…”

“…It is noteworthy that the reaction may be successfully scaled-up with the high product yields being retained. 245 A special attention was given to the stereoselective synthesis of chiral 3-phosphoindoles. The progress of this stereoselective method is of critical importance for examination of the asymmetric functionalization of C7H-bonds and development of therapeutics against HIV-1.…”

“…The progress of this stereoselective method is of critical importance for examination of the asymmetric functionalization of C7H-bonds and development of therapeutics against HIV-1. 245 The use of (1R,2S,5R)7(7)-menthol as a reactant in this reaction afforded a chiral (1S,2S,5R)7(7)-menthyl phenylphosphinate (134), which was used in the synthesis of chiral 3-phosphoindoles 132a ± s (Scheme 47). The authors identified a wide range of indole derivatives which turned out to be effective substrates in the reaction under consideration.…”

“…The authors identified a wide range of indole derivatives which turned out to be effective substrates in the reaction under consideration. 245 Chiral 3-phosphoindoles bearing electron-donating or electron-withdrawing substituents in the aromatic ring may be obtained in good yields and with high stereoselectivity. Also, N-unsubstituted indoles with different substituents in position 2 proved to be active substrates and demonstrated stability of the functional groups.…”