The chemistry of indoles. XXXIX. A facile synthetic method for 7-substituted indoles.

Abstract

A simple four-step synthetic method for 7-iodo-, 7-bromo-and 7-chloroindole was established with high overall yield starting from 2,3-dihydroindole. Several 7-substituted indoles carrying a carbon side chain and 7-methoxyindole were also synthesized. Keywordsthallation; 7-substituted indole; regioselective metalation; 7-iodoindole; 7-bromoindole; 7-chloroindole; 7-methoxyindole; methyl 3-(indol-7-yl)acrylate; 4-(indo1-7-y1)-2-methy1-3-buten-2-ol; Heck reaction For one possible approach to the construction of various types of structurally and biologically interesting indole alkaloids having a substituent at the 7-position,2) 7-halogenoindoles are required as common building blocks. However, little work has been done on their syntheses and consequently they are available only through a laborious multistep route) with poor overall yield. In our continuing studies on regioselective functionalization of indoles,4, 5) we have elaborated a facile and regioselective synthetic method for 7-halogenoindoles, as reported in the preliminary communication.6) In this report, we describe in detail these results and the syntheses of various 7-substituted indoles. Regioselective Syntheses of 7-HalogenoindolesIn the previous paper, we reported that the thallation-palladation method4) was a useful synthetic reaction for 4-substituted indoles with high regioselectivity. It was also shown that the regioselectivity was dramatically influenced by introduction of an extra substituent into the 2 or 3 position of the indole nucleus.5) Based on these results, we designed the strategy shown in Chart 1. If a suitable ligand (S) is introduced at the indole (or 2,3-dihydroindole) nitrogen, the S group can coordinate to a metal reagent (metal (M)-leaving group (L)) putting the metal close to the 7-position. Consequently, metallation would occur regioselectively at the carbon-7 making the carbon susceptible to various functionalizations.During examination of the feasibility of the strategy as planned, we soon recognized that thallation of 1-acy1-3-unsubstituted indoles with thallium tris-trifluoroacetate (TTFA) was unsuccessful because the compounds were quite sensitive to acids, and formed polymers.

Preparation of 7-Halo-indoles by Thallation of N-Formylindoline and Their Attempted Use for Synthesis of the Right-Hand Segment of Chloropeptin

“…7-Substituted indoles were already synthesized by Somei et al 8,9) using N-acetyl indoline as a starting material and carrying out the thallation of it as a key reaction, followed by substitution reaction with halogen, removal of the acetyl group, dehydrogenation to afford halogeno indoles. Our procedure for 7-substituted indoles is a modification of the Somei method using N-formylindoline.…”

“…2). Somei et al 8,9) also reported a regioselective synthetic method for 7-halogenoindoles by thallation at the 7-C position with TTFA chelating to an Nacetyl carbonyl group (Fig. 2).…”

“…Alkaline hydrolysis of 6b by 20% NaOH at 80°C for 30 min afforded indoline 7b in 94% yield. Dehydrogenation of 7b was carried out under a stream of oxygen gas in the presence of salcomine 9) as a catalyst to give 7-bromoindole (8b) in 79% yield (total yield from 3: 54%). 7-Chloroindole (8a) was obtained from 4 in a similar manner except for using CuCl 2 at the step of the substitution reaction in 46% total yield from 4.…”

“…In this case, KI was used at the step of the substitution reaction using H 2 O as a solvent and 10% NaOH was used at the step of the removal of the formyl group with ease. Thus the formyl group was removed more easily than an acetyl group (40% NaOH) 9) and it will be removed with much more mild conditions using a weak base such as NaHCO 3 according to the literature. 12) Using the formyl group on thallation will serve to enlarge the utility of its method in compounds having an alkaline-sensitive functional group other than indolines.…”

Synthesis and structure–affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

“…The procedures utilized for the synthesis of indole-3-carboxaldehydes and their halogenated derivatives were those reported previously by Jiang et al13, Johnson et al15, Kalir and Szara22, Noland and Reich23, James and Snyder24, and Somei et al25. Briefly, Phosphorus (V) oxychloride (4.25 g, 0.028 mol) was added drop wise to DMF (6 mL) cooled in an ice bath.…”