Bromination of Dimethyl 1-Substituted Indole-2,3-dicarboxylates

Treatment of dimethyl indole-2,3-dicarboxylate with pyridinium hydrobromide perbromide or bromine in the presence of Lewis acid gave dimethyl 5-bromoindole-2,3-dicarboxylate as the sole product.In a similar manner, dimethyl 1-benzyl-and 1-benzenesulfonyl-indole-2,3-dicarboxylates provided a mixture of the corresponding 5-bromoindole and 6-bromoindole derivatives.However, methyl 1-trifluoromethanesulfonylindole-2,3-dicarboxylate gave methyl 6-bromo-1-trifluoromethanesulfonylindole-2,3-dicarboxylate as a major product.Bromoindole alkaloids have been isolated as secondary metabolites of marine organisms, such as sponges, tunicates, and so on, which are promising sources of new biologically active molecules.1 Moreover, a bromo group is a useful functional group, which could be converted to various groups by Heck-type reaction in the presence of a palladium catalyst.We have reported that dimethyl indole-2,3-dicarboxylates and indole-2,3-dicarboxylic anhydrides were useful synthons in the synthesis of pratosine, 2 hippadine, 2 murrayaquinone-A, 3 ellipticine, 4-6 olivacine, 7 and caulersin. 8However, there are many indole alkaloids, having a substituent on the benzene ring of the indole skeleton, especially a bromo group at the 5-and 6-psition of the indole ring. 1,9-11Chae reported that bromination of dimethyl indole-2,3-dicarboxylate (1a) by bromine in the presence of sodium acetate in acetic acid gave dimethyl 5-bromoindole-2,3-dicarboxylate (2a) as the sole product, but the influence of the substituents on the indole nitrogen in bromination of 1a was not examined. 12In this paper, we show bromination of dimethyl 1-substituted indole-2,3-dicarboxylates (1) and enhancement of their utility as a synthon.Reaction of dimethyl indole-2,3-dicarboxylate (1a) with pyridinium hydrobromide perbromide (PHPB)(1 equiv.) in the presence of titanium (IV) chloride, aluminum (III) chloride, or tin (IV) chloride in dichloromethane at room temperature gave dimethyl 5-bromoindole-2,3-dicarboxylate (2a) in 43%, 62%, 60% yield, respectively, as the sole product, but other isomers of monobromoindole derivative were not isolated.(Entries 1-3) Treatment of 1a with PHPB (3 equiv.) in the presence of tin (IV) chloride afforded 2a in 71% yield.(Entry 4) When 1a was reacted with bromine (4 equiv.) in the presence of tin (IV) chloride 2a was afforded in 77% yield, (Entry 5) but a complex mixture was obtained in hot