Cross-Coupling Reactions of Indium Organometallics with 2,5-Dihalopyrimidines: Synthesis of Hyrtinadine A

Abstract

The palladium-catalyzed cross-coupling reaction of triorganoindium reagents (R3In) with 5-bromo-2-chloropyrimidine proceeds chemoselectively, in good yields, to give 5-substituted-2-chloropyrimidines or 2,5-disubstituted pyrimidines using 40 or 100 mol % of R3In, respectively. Sequential cross-couplings are also performed, in one pot, using two different R3In. This method was used to achieve the first synthesis of the alkaloid hyrtinadine A. The key step was a two-fold cross-coupling reaction between a tri(3-indolyl)indium reagent and 5-bromo-2-chloropyrimidine.

Aerobic oxidative C–H/C–H coupling of azaaromatics with indoles and pyrroles in the presence of TiO2as a photocatalyst

“…3 Several examples are given in Figure 1. Hyrtinadine A is an alkaloid, having 2,5-bis(indolyl) substituted pyrimidine structure, 5 which exhibits cytotoxic activity in vitro against murine leukemia L1210 cells and human epidermoid carcinoma KB cells. Hyrtinadine A is an alkaloid, having 2,5-bis(indolyl) substituted pyrimidine structure, 5 which exhibits cytotoxic activity in vitro against murine leukemia L1210 cells and human epidermoid carcinoma KB cells.…”

Marine Bi-, Bis-, and Trisindole Alkaloids

“…84 Lithium halogen exchange of the 3-bromoindole derivative 153 with the subsequent addition of InCl 3 yielded the indolylindium precursor 154. Palladiumcatalyzed coupling with 5-bromo-2-chloropyrimidine afforded the 2,5-bis(indolyl)pyrimidine 155.…”

“…Demethylation followed by silyl deprotection provided the natural product. 84 A similar one-pot coupling strategy was used by Tasch et al to synthesize 152 (Scheme 1.27). Starting from N-Boc-protected 3-iodo-5-methoxy-indole 156, they used Masuda borylation followed by Suzuki arylation with 5-bromo-2-iodopyrimidine in the presence of cesium carbonate to yield the desired precursor 157.…”

Cross‐Coupling Reactions to sp Carbon Atoms

“…The possibility of a stoichiometry-controlled sequential one-pot cross-coupling to 3,4-dichloromaleimides under Pd catalysis has been demonstrated [362]. A distinct chemoselectivity of triorganoindium reagents has been observed favoring replacement of bromo over chloro functionalities in 2,5-dihalopyrimidines [360]. The chemistry of alkynylindium reagents has recently been extended to metalcatalyzed enantioselective C(sp)-C(sp 3 ) cross-couplings [363].…”