Synthesis of Isatins

The most frequently used synthesis of isatins is the Sandmeyer procedure, which involves the formation of an isonitrosoacetanilide (3) from an aniline (2), chloral hydrate, and hydroxylamine. The isonitroso- 

Gripenberg, E. Honkanen, and O. Patoharju, Acta. Chem. Scand. 11, 1485 (1957). 

Raileanu and C. D. Nenitzescu, Acad. Repub. Pop. Rom. Stud. Cercet. Chim. 11, 19 (1963). 

Giovannini, P. Portmann, A. Johl, K. Schnyder, B. Knecht, and H. P. Zen-Ruffinen, Helv. Chim. Acta 40, 249 (1957). 

Generally meta-substituted anilines give rise to a mixture of 4- and 6-substituted isatins9,13,19,33-37 although 4-trifluoromethyl,15,33,35,36 4-nitro,13 4-amino,13 4-hydroxy,13 4-carboxy,13 6-methoxy,35 and 6-bromo 4 isatins have been reported without the other isomer. 

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Meth-Cohn has developed an efficient one-pot synthesis of isatins 108 by the sequential treatment of iV-substituted formanilides 107 with oxalyl chloride, Hunig s base, and bromine... 

Synthesis of isatin 109 derivatives readily proceeds from anilide-derived oximes 108 by interaction with sulfuric acid (equation 46) ... 

The method developed by Sandmeyer is the oldest and the most frequently used for the synthesis of isatin. It consists in the reaction of aniline with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate to form an isonitrosoacetanilide, which after isolation, when treated with concentrated sulfuric acid, furnishes isatin in >75% overall yield17. The method applies well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline18, and to some heterocyclic amines, such as 2-aminophenoxathine19 (Scheme 1). 

A more recent method for the synthesis of isatins is based upon the directed ortho-metalation (DoM) of A-pivaloyl- and 7V-(/-butoxycarbonyl (-anilines. The corresponding dianions are treated with diethyl oxalate and the isatins are obtained after deprotection and cyclisation of the intermediate a-ketoesters. This method has the advantage of being regioselective for the synthesis of 4-substituted isatins from me to-substituted anilines where the substituent is a metalation directing group (e.g. OMe) 49 (Scheme 12). 

Recently, a metal-halogen exchange method was described for the synthesis of isatins by lithiation of o/7/ o-bromophenylureas, carbonylation and subsequent intramolecular cyclisation to give the desired products in 71-79% yield51 (Scheme 14). 

These previously discussed methodologies are the most general and/or most commonly employed procedures for the synthesis of isatins. Other methodologies have been employed, but they are less general and some of them lead to the desired product in low yield. 

Heating in orr/zo-dichlorobenzene results in a retro-aldol reaction and the obtention of the N-alkylated isatin. More recently the use of CaH2 in DMF has been reported and this method was used for the synthesis of both mono and bis-iV-alkylisatins. These latter compounds have been previously prepared using dihaloalkanes and NaH in dioxane or DMF or by the use of LiH82 Some of these alkylation methodologies were evaluated for the synthesis of isatins... 

Isatin.— Another compound is also obtained on the oxidation of indigo, viz., isatin. That isatin is related to anthranilic acid and is probably another intermediate product of the breaking down of indigo, lying between indigo and anthranilic acid, may be seen by the following synthesis of isatin from ortho-nitro benzoic acid. 

Pandeya SN, Raja AS, Stables JP. Synthesis of isatin semicarbazones as novel anticonvulsants-Role of hydrogen bonding. J Pharm Pharm Sci 2002 5 266-71. 

Synthesis of isatin. This synthesis originated with Sandmeyer and was further improved by Marvel and Hiers. " The first step, in which aniline is condensed with chloral hydrate and hydroxylamine hydrochloride to form isonitrosoacetanilide (I) is represented schematically as follows ... 

A new method for synthesis of isatins which is based on directed lithiation of t-butoxycarbonanilides... 

This reaction has a general application in the synthesis of isatin derivatives, which could be used as the starting materials for quinolines, acridines and indophenazines etc. 

Isatins are indole derivatives with broad use in synthetic dye production and are intermediates in the synthesis of other heterocyclic molecules/ They also possess a variety of biological activities/ Aksenov et al. reported a one-pot synthesis of isatins using ethyl nitroacetate with substituted benzenes such as anisole (159) in polyphosphoric acid fScheme 5.38)/ The process for isatin formation likely includes a hybrid between the Nef and Vilsmeier reactions of anisole 159 and nitro ester 160 to form the oxime intermediate 161, which then undergoes a Beckmann rearrangement to give the anilide 162. Subsequent intramolecular acylation yields isatin 163. 

From 1913 to 1930, R. Stolle published several manuscripts describing the synthesis of oxindoles from anilines and a-chloroacyl chlorides. His typical substrates were chloroacetanilides or the corresponding MA -diphenylamide. The manuscripts also described the synthesis of isatines (2,3-dioxindoles) from arylamines and oxalyl chloride. The reactions require high temperatures (typically > 150 °C) to complete the cyclization step. 

Indole-2,3-dione (isatin), red crystals, mp 204°C, is formed inter alia (cf p. 146) by the oxidation of indigo. A generally applicable synthesis of isatins 126 is the Sandmeyer synthesis, in which isonitrosoacetanilides 125 (easily accessible from primary arylamines, chloral hydrate, and hydroxylamine hydrochloride) are cyclized in acidic medium [195] ... 

Ilangovan and Satish reported that tertiary amines can also be used for the synthesis of isatins under Cu(0Ac)2-H20, NaOAc, and air system at relatively lower... 

Scheme 8.39 CutOAcjj HjO catalyzed synthesis of isatins from tertiary amines.

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