The heterocyclic nitrogen of 6-methylindole was protected using di-tert-butyl dicarbonate and catalytic 4-DMAP to give l-(tert-butoxycarbonyl)-6-methylindole 2 in 86% yield. Irradiation of the protected methylindole 2 in the presence of NBS and dibenzoyl peroxide provided the 6-(bromomethyl) derivative 3 (69% yield).Treatment of the brominated compound with excess AgF then gave 1 -(terf-butoxycarbonyI)-6-(fluoromethyl)indole 4 (30% yield). Conventional methods for removing the BOC protecting group proceeded with concomitant loss of the halomethyl functionality. Flash vacuum thermolysis” (400°C) of a 5-10% (wt/vol) benzene-d6 solution of 1 -(tert-butoxycarbonyl)-6-(fluoromethyl)indole 4 did, however, provide a compound consistent with the desired, 6-(fluoromethyl)indole 1. This molecule proved to be too unstable for further manipulation.
The unstability of compound 1 can be explained as follow:
The synthesis of 6-(difluoromethyl)indole 5 was then examined for the added stability that a second fluorine substituent should lend to this heterocyclic system. Oxidation of 6-(bromomethyl)- 1 -(tert-butoxycarbonyl)indole with DMSO/NaHCO3, generated indole-6-carboxaldehyde in a crude yield of 86%; as indicated, the BOC group was lost under the conditions of this reaction (20 minutes at 150°C). Treatment of the reprotected indole-6-carboxaldehyde 6 with DAST (neat) overnight afforded a 65% yield of the 6-(difluoromethyl) derivative 7. Flash vacuum thermolysis of 7 then gave the deprotected 6- (difluoromethyl)indole 5 in 51% yield after column purificationi
The efficiency of fluoride elimination varies widely in the series of mono-, di-, and trifluoromethyl-substituted indoles. As described, 6- and 7-(fluoromethyl)indole decomposed quite readily. In contrast, there was no indication of fluoride elimination from 6-(trifluoromethyl)indole when treated with 100 mM NaOH at 25°C (i.e., there was no hydrolysis to indole-6-carboxylate); this was monitored by both UV spectroscopy and TLC over a two hour period. A balance in reactivity was demonstrated by 6-(difluoromethyl)indole. This compound was stable to silica gel chromatography and storage as an ethanol solution at -20% for at least one month. Under aqueous conditions, 6-(difluoromethyl)indole hydrolyzed to indole-6-carboxaldehyde 8 (Scheme V) with a rate constant of 0.01 /min (0.2 M potassium phosphate buffer, pH 8.0). Additionally, this process was found to be independent of both pH and buffer concentration within a pH range of 3-12; above pH 13 aldehyde formation was greatly stimulated.
Tetrahedron Letters,Vo1_30,No_45,pp 6117-6120,1989
