Leimgruber synthesis

Somei et al. have demonstrated the utility of TiCls as the reducing agent in the Batcho-Leimgruber synthesis. The product distribution is sometimes dependent on the... 

Leimgruber synthesis Aminomethylenation of nitrotoluene followed by hydrogenation yield indole. 

The more recent Leimgruber synthesis is illustrated by the aminomethylenation of nitrotoluene 7.19 to give 7.20, followed by hydrogenation to produce indole 7.1. 

Some examples of the Leimgruber synthesis are shown below. 

IIab Bateho-Leimgruber synthesis of indoles from o-nitrotoluenes via 3.06.3.1... 

This method (Batcho-Leimgruber synthesis) is particularly suitable for the synthesis of indoles substituted on the benzene ring but unsubstituted on the pyrrole moiety [49]. 

Indoles are obtained by specific cyclizations (Fischer synthesis, Reissert synthesis, Batcho-Leimgruber synthesis, Nenitzescu synthesis), as are carbazoles from biphenylene or diphenyl-amines and pyrrolidines (Hofmann-Loffler reaction). 

As advanced precursors in aU syntheses, racemic 2-tert-prenylated tryptophan derivatives were synthesised, which had to be oxygenated at C6 of the indole ring. Batcho-Leimgruber synthesis afforded 6-OBoc-indole 200 in four steps from... 

As in the Batcho-Leimgruber synthesis, key intermediates for cyclization are (o-aminophenyl)-substituted enamines, which (like 59) have to be regarded as equivalents of (o-aminobenzyl) compounds 41 proposed by retrosynthesis. 

Baker-Venkataraman rearrangement 338 Balaban synthesis (pyrylium ion) 302 Bamberger-Hughes-Ingold rearrangement 350 Barton-Zard synthesis (pyrrole) 120 Batcho-Leimgruber synthesis (indole) 136 Baylis-Hillman reaction 452 Beirut reaction 254, 500 Bemthsen synthesis... 

The indole nucleus is present in various bioactive molecules and many selective protocols for its construction have been developed. Classical methods for the indole synthesis include the Fischer indole synthesis, the Batcho-Leimgruber synthesis from o-nitrotoluenes and dimethylformamide acetals, the Gassman synthesis from N-haloanilines, the reductive cyclization of o-nitrobenzyl ketones, and the Madelung cyclization of A/ -acyl-o-toluidines [42,43]. 

The Leimgruber-Batcho synthesis is a two-step method which provides indoles that arc substituted only in the benzene ring. The method was initially disclosed in a patent[l] and a representative procedure is available in Organic Syntheses[2]. A review of the reaction is available[3]. The reaction involves... 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The Batcho-Leimgruber indole synthesis involves the condensation of o-nitrotoluene derivatives 1 with formamide acetals 2, followed by reduction of the trans-p-dimethylamino-2-nitrostyrene 3 which results to furnish indole derivatives represented by... 

In 1971, Batcho and Leimgruber introduced a new method for the synthesis of indoles. For example, condensation of o-nitrotoluene (5) with N,N-dimethylformamide dimethyl acetal (6) (DMFDMA) was followed by reduction of the rrans-P-dimethylamino-2-nitrostyrene (7) which resulted to provide the indole (8). ... 

Garcia et al. has extended the Batcho-Leimgruber procedure to the synthesis of 2-substituted indoles. Treatment of 36 with o-fluorobenzoyl chloride 37, followed by in situ hydrolysis and deformylation gave ketone 38. Reduction of nitroarylketone 38 with sodium hydrosulfite then furnished indole 39. Similarly, bromoacetylation of 36 gave an acylenamine which was converted into the phthalimido derivative 40. Hydrolysis and deformylation gave phthalimidoketone 41 which underwent reductive cyclization to furnish indole 42. 

Conversions of 2-oxo groups to bromine have been reported [86H(24)2879 88H(27)1585], The Batcho-Leimgruber indole synthesis... 

Schreiber, J., Leimgruber, W., Pesaro, M., Schudel, R, Eschenmoser, A. (1961) Synthesis of Colchicine. Helvetica Chimica Acta, 44, 540-597. 

Carrera and Sheppard improved upon a Leimgruber-Batcho indole synthesis [24] to prepare 6-bromoindole (20) in excellent overall yield from 4-bromo-2-nitrotoluene [29a], and Rapoport utilized this method to synthesize 4-, 5-, 6-, and 7-bromoindole [29b]. 

Li, J. Cook, J. M. Batcho—Leimgruber Indole Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 104—109. (Review). 

When indoles unsubstituted in the heterocyclic ring are required, the Leimgruber-Batcho synthesis can be used. In its original form the... 

Indoles from p-dialkylamino-o-nitrostyrenes. The Leimgruber Batcho synthesis 7... 

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