Indole synthesis Batcho-Leimgruber

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).  

There are no detailed reports on the mechanism of the Batcho-Leimgruber process. The mechanism proposed here is based on similar types of reactions reported in the literature.  

Several types of substituted formamide acetals have been utilized in the Batcho-Leimgruber reaction, including N,N-dimethylformamide dimethyl and diethyl acetals, N- 

The condensation reaction can be facilitated by addition of an amine, such as 

There are no detailed reports on the mechanism of the Bateho-Leimgruber process, but it is proposed below. In the presence of the base, o-nitrotoluene is coupled with iV.A dimethylformamide dimethyl acetal [DMFDMA, Me2NCH(OMe)2] to offer the dimethylamino imine. Hydrogenation then reduces the nitro group to aniline. When workup with an acid, cyclization and re-aromatization then delivered the indole. 

The Gassman indole synthesis involves a one-pot process in which a hypohalite, a P-carbonyl sulfide derivative, and a base are added sequentially to an aniline or a substituted aniline to provide 3-thioalkoxyindoles. The sulfur can be readily removed by hydrogenolysis or Raney nickel. 

The mechanism of the Gassman indole synthesis bears some resemblance to that of the Fischer indole reaction. An Sn2 displacement of the TV-chlorinated aniline with the a-keto sulfide gives rise to a sulfonium ion. After deprotonation, a [2,3]-sigmatropic rearrangement (Sommelet-Hauser rearrangement) takes place where the weak N-S bond is broken and a strong C-C bond is formed. Similar to the Fischer indole reaction, the resulting imine was transformed into indole after re-aromatization and cyclization. 

A total synthesis of (+)-paspalicine and (+)-paspalinine took advantage of the Gassman indole synthesis. The thiomethyl ketone was treated with A-chloroaniline (prepared by mixing aniline with t-butyl hypochlorite) to afford the azasulfonium salt, which was transformed into anilinylsulfide upon treatment with triethylamine. Desulfurization with Raney nickel was followed by the acid-catalyzed cyclization to give the hexacyclic indole intermediate. 

Leimgruber, W. Batcho, A. D. Third International Congress of Heterocyclic Chemistry. Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at Hoffmann-La Roche in Nutley, NJ, USA. 

Sundberg, R. J. The Chemistry of Indoles, Academic Press New York London, 1970. (Review). 

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). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 14, Springer-Verlag Berlin Heidelberg 2009 

Condensation of o-nitiotoluene derivatives with fonnamide acetals, followed by reduction of the rr wt5-p-dimethylamino-2-nitn)styiene to furnish indole derivatives. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 17, Springer International Publishing Switzerland 2014 

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

The Batcho-Leimgruber indole synthesis is probably the most important and widely used method for the preparation of lH-2,3-unsubstituted indoles. In an attempt to extend the utility of the process to the preparation of 3-substituted indoles, functionalisation of the specific intermediate enamine 1 was explored. Treatment of 1 with ethyl chloroformate in refluxing chloroform in the presence of AT,JV-diethylaniline failed to give the expected ester. Instead, a product was obtained the spectral data for which suggested that it was a dienamine. The same product could be obtained in 52% yield simply by treatment of 1 with half an equivalent of TsOH in toluene at 90°C, and catalytic hydrogenation of this dienamine gave 2 in 58% yield. 

A few type la reductive cycUzations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of orfho-nitrostyrenes to 2-substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of p-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to iV-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided Al-hydroxyindole 93 via hydroxylamine intermediate 91. 

Other references related to the Batcho-Leimgruber indole synthesis are cited in the literature. 

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