Expedient Synthesis of 5,6-Dihydroxyindole and Derivatives via an Improved Zn(II)-Assisted 2,β-Dinitrostyrene Approach

Abstract

A facile 3-step synthesis of 5,6-dihydroxyindole (4a) is reported, featuring the Zn(II)-controlled regioselective nitration of 3,4-dihydroxynitrostyrene (2) with tetranitromethane at pH 8.0, and the reductive cyclization of the resulting 4,5-dihydroxy-2,b-dinitrostyrene (3a) with Na 2 S 2 O 4 /Zn(II) at pH 4. The latter procedure was successfully extended to the conversion of the 2,b-dinitrostyrenes 3b and 3c to 5,6-dibenzyloxyindole (4b) and 5,6-diacetoxyindole (4c) in good-to-high yields. 5,6-Dihydroxyindole (4a) and its congeners currently represent an attractive synthetic focus because of their central role in mammalian melanin pigmentation 1 and their increasing exploitation as active ingredients in innovative dermocosmetic formulations. 2 Additional impetus for studies of 5,6-dihydroxyindoles has stemmed from the recent recognition of their outstanding free radical scavenging and (photo)protective capabilities, 3 warranting ranking among the most potent endogenous antioxidants. 4 To fully exploit the expanding range of opportunities offered by 4a and its derivatives, e.g. 5,6-dibenzyloxyindole (4b) and 5,6-diacetoxyindole (4c), requires access to synthetic methodology capable of circumventing difficulties posed by the marked instability of 4a and its derivatives to acids, alkali and oxidants, 5 which hampers chromatography, crystallization and other purification procedures, and accounts for extensive polymerization during preparation and workup.Of the several strategies that have been devised for the preparation of 4a and its congeners, 6-15 the most convenient ones hinge on the classical 2,b-dinitrostyrene approach exemplified by the popular Benigni and Minnis 8 scheme. In spite of substantial modifications and refinements 10-12,14 available, 2,b-dinitrostyrene-based routes to 5,6-dihydroxyindole derivatives still suffer from a number of drawbacks, including tedious and cumbersome protection/deprotection steps, lengthy synthetic sequences (up to 2 days), poorly reproducible cyclization yields, and need for product purification, e.g. by HPLC or column chromatography, which discourage application to routine laboratory preparations. In this paper we report the realization of a straightforward 3-step synthesis of 4a (Scheme 1) in which protection-deprotection steps have been circumvented for the first time through expedient use of catalysts and careful selection of reaction conditions. The novel methodology capitalizes on the Zn(II)-assisted regioselective nitration of 3,4-dihydroxy-b-nitrostyrene (2) and features an improved procedure for the reductive cyclization of 4,5-dihydroxy-2,b-dinitrostyrene (3a), which has been conveniently extended to the syntheses of 4c and 4b from the appropriate 2,b-dinitrostyrene precursors. Scheme 1The first intermediate in the process, the nitrostyrene 2, was readily prepared in excellent yield by Henry condensation of 3,4-dihydroxybenzaldehyde (1) with nitromethane. Regioselective nitration of 2 to 3a, however, was anticipated to be difficult because of the presence of the se...

5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin

“…The former approach is exemplified by the classical o,βdinitrostyrene-based synthesis of 1 [12] (Scheme 5), as well as by a number of variants proposed in the 1980s [42,43] and the 1990s. [44] Scheme 5. The o,β-dinitrostyrene route to 5,6-dihydroxyindoles.…”

Design of Potent IGF1‐R Inhibitors Related to Bis‐azaindoles

“…Metal lithium exchange with nBuLi followed by formylation with Dimethylformamide (DMF) afforded the 6‐formyl derivative which was nitrated at position 5 with cupric nitrate trihydrate (21). Condensation with nitro methane under classic Henry conditions (22,23) followed by a modified procedure reported by Novellino (24) gave the hydroxylated nitrostyrene which upon heating with sodium acetate in acetic anhydride gave the nitrostyrene intermediate L as a mixture of isomers. Silica gel‐assisted reductive cyclization (25) of this unstable intermediate, with iron in acetic acid, provided the desired 4‐azaindole M .…”

Silica-Supported Polyphosphoric Acid in the Synthesis of 4-Substituted Tetrahydroisoquinoline Derivatives

“…Due to the uniqueness of the structure and potential medicinal properties of the 4-arylisoquinoline derivatives [ 2 , 3 , 4 , 5 ], many synthetic routes for these compounds [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] and especially cherylline have been reported. The Amaryllidaceae [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ] have been one of the most studied families of plants because of their alkaloids composition. In 1970, Brossi et al [ 1 ] isolated from Crinum powelli an alkaloid with a 4-aryl-1,2,3,4-tetrahydroisoquinoline structure named cherylline.…”