Anilines oxindoles from

GASSMAN Oxmdote Synthesis Synthesis of oxindoles from anilines... 

This reaction was first reported by Hinsberg in 1888. It is the synthesis of N-alkyl-oxindole from IV-alkyl aniline and the glyoxal-bisulfite adduct after hydrolysis by hydrochloric acid. Similarly, the reaction of A -alkyl naphthylamine with glyoxal-bisulfite adduct leads to benzo-oxindole. In contrast, the reaction between primary aryl amines and... 

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. 

G A S S M A N Oxindole Synthesis Synthesis of oxindoles from anilines (see 1st edition)... 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

A convenient modification of the Gassman oxindole synthesis was reported using ethyl (methylsulfinyl)acetate (101) activated by oxalyl chloride to generate the same chlorosulfonium salt 102 normally generated from ethyl (methylthio)acetate 100 and elemental chlorine <96TL4631>. Thus, treatment of the sulfoxide 101 with oxalyl chloride, followed by the addition of the desired aniline, triethylamine, and finally acid cyclization of 103 affords the oxindoles 104. This procedure is particularly convenient for reactions carried out on smaller scales and for anilines that ate susceptible to electrophiUc halogenation. 

Indole synthesis from anilines and glyoxal (Hinsberg), oxindole synthesis from anilines and a-haloacyl halides (Stolle) (see 1st edition). 

Indole-2(3 -one (oxindole), colourless needle-like crystals, mp 127°C, is made from aniline and chloroacetyl chloride as follows [54] ... 

The use of rhodium catalysts to obtain 3-carbo-ethoxyoxindoles from N-(2-diazomalonyl)anilines was explored. <94J0C2447> Rhodium(II) trifluoroacetamide and rhodium(II) perfluorobutanamides were found to be preferable to rhodium carboxylates both in terms of reaction rate and selectivity for oxindole formation. 

The perfluoroalkanamide catalysts favor aromatic insertion over insertion or addition involving the N-substituent. The starting materials can be prepared readily from ethyl 2-diazomalonyl chloride and anilines. The oxindoles were subsequently converted to 0-trialkyl-si lyl and 0-benzoyl indoles. 

The proposed mechanisms for the two main variations of the Gassman oxindole synthesis are shown below. The A -chloroaniline starting material 6 is prepared from an aniline and tert-butyl hypochlorite. 

Applications of the Gassman oxindole synthesis in total synthesis are uncommon. Savall and McWhorter prepared a 6,7-dihydroxyindole derivative, part of the potent antihelmintic compound paraherquamide A, by using a chlorosulfonium ion (15) obtained from ethyl methylthioacetate and sulfuryl chloride.The intermediate oxindole 23 was obtained in 80% crude yield. The starting aniline was obtained in good yield from 2,3-dimethoxybenzoic acid via a modified Curtius rearrangement. Removal of the thiomethyl functionality with Raney nickel gave the final product in 62% yield. 

The synthetic and kinetic regularities of the amino-Claisen rearrangement were studied for the transformation of 2,5-dimethyl-Af-(pent-3-en-2-yl)aniline." The products are obtained via conversion of a binary r-complex formed by the reaction of N-alkenylaniline hydrochloride with the hydrochloride of the solvent (2,5-dimethylaniline). Spirocyclic oxindoles have been prepared from iodoindoles via a sequential intramolecular Ullmann coupling and Claisen rearrangement." Nucleophilic ort/io-propargylation of aryl sulfoxides has been reported to occur by intermolecular delivery of the nucleophile to sulfur followed by an intramolecular relay to carbon in a... 

Acid-catalyzed oxindole formation from aniline and a-chlorocarboxylic acid chloride. 

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