Directed Lithiation of 1-(tert-Butoxycarbonyl)indolines. A Convenient Route to 7-Substituted Indolines

Abstract

I-(tert-Butoxycarbonyl)indolines were regioselectively lithiated at 7-position with s-BuLi-TMEDA in ether or THF at -78 "C.The lithiated species were reacted with a range of elecmphiles to give 7-substituted indoline derivatives.Regioselective functionalization of the indole nucleus is important for the synthesis of biologically active indole natural products.'The selective functionalization at 3-and 2-positions is easily accomplished via electrophilic substitution2 and lithiation3 strategies, respectively.However, due to profound reactivity of the pynole moiety, the direct functionalization of the benzenoid ring is difficult.Therefore, in order to functionalize benzenoid ring, the indole-indoline synthetic interconversion4 is often employed.In this approach, indoles are tentatively reduced to indolines (2,3-dihydroindoles) and, after functionalization of the aromatic ring, indoles are regenerated by oxidation.By using this methodology, Somei er 01.5 developed a procedure for 7-selective functionalization6 of indole.They employed the chelation-controlled C-7 thallation of 1-acetylindoline as a key reaction.Since the thallated intermediate is convertible to a variety of 7-substituted indolines, this method seems to be highly useful.However, utilization of the toxic thallium reagent is not favorable.Recently, Beak and Lee7 reported on the alithiation of N-tert-butoxycarbonyl secondary amines.They mentioned, however, in the case of I-(tertbutoxycarbonyl)-1,2,3,4-tetrahydroquinoline, lithiation occurred at 8-position of the aromatic ring.We applied this directed lithiation to the I-(tert-hutoxycarbony1)indoline system in order to establish a new general mute to 7-functionalized indolines.