Synthesis of 5,6‐carbonyldioxyindole, a melanogenic cyclic carbonate ester of 5,6‐dihydroxyindole

Lutz, Wilson B.; McNamara, C.; Olinger, Max R.; Schmidt, David F.; Doster, Douglas E.; Fiedler, M.

doi:10.1002/jhet.5570210451

Cited by 9 publications

(1 citation statement)

References 20 publications

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“…Of the several strategies that have been devised for the preparation of 4a and its congeners, [6][7][8][9][10][11][12][13][14][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][11][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.…”

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confidence: 99%

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

Novellino¹,

d'Ischia²,

Prota³

1999

Synthesis

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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...

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confidence: 99%

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

Novellino¹,

d'Ischia²,

Prota³

1999

Synthesis

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Cyclization of Vinyl and Aryl Azides into Pyrroles, Indoles, Carbazoles, and Related Fused Pyrroles

Berkowitz

McCombie

2017

Organic Reactions

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This chapter reviews in detail those reactions that form of a new pyrrole ring from vinyl, aryl, and heteroaryl azides via formal C–H insertion processes under thermal, photochemical, and metal‐catalyzed conditions. These reactions proceed via the intermediacy of vinyl or aryl nitrenes (or their metallonitrene equivalents) and generate a wide variety of pyrroles, indoles, carbazoles, and related systems. Methods for the synthesis of the starting azides are summarized, and a comprehensive survey of the cyclization processes is provided.

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1987

Chemistry of Heterocyclic Compounds: A Series of Monographs

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Synthesis of 5,6‐carbonyldioxyindole, a melanogenic cyclic carbonate ester of 5,6‐dihydroxyindole

Cited by 9 publications

References 20 publications

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

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

Cyclization of Vinyl and Aryl Azides into Pyrroles, Indoles, Carbazoles, and Related Fused Pyrroles

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