Indole synthesis Reissert

The Reissert indole synthesis involves base-catalyzed condensation of an o-nitrotoluene derivative with an ethyl oxalate, which is followed by reductive cy-clization to an indole-2-carboxylic acid derivative. 

Reissert Indole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 154-158. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 216, Springer-Verlag Berlin Heidelberg 2009 

Suzuki, H. Gyoutoku, H. Yokoo, H. Shinba, M. Sato, Y. Yamada, H. Murakami, Y.SynlettlfSm, 1196-1198. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 231, Springer International Publishing Switzerland 2014 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

In contrast to the facile condensation of o-nitrotoluene with diethyl oxalate, other a-alky] nitrobenzenes are sluggish to react with diethyl oxalate or fail to react at all. It has been suggested that this is due both to steric and electronic factors effected by the alky] group, which destabilizes the methylene group in regard to formation of the carbanion.  

Butin et al. reported that the indole derivative 29 was prepared by treatment of 2-tosylaminobenzylfuran 25 with ethanolic HCl in 78% yield. The furan ring served as the origin of a carbonyl group in this modification of the Reissert procedure.  

For example, potassium ethoxide in dry ether is a stronger base than sodium ethoxide in ethanol, and iron powder in acetic acid/ethanol, iron filings in hydrochloric add, zinc dust in acetic acid, and sodium dithionite have all been employed for the reduction step [4]. 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John WQey Sons, Ltd. 

Stoll and colleagues prepared 4-, 5-, and 6-hydroxy-tryptamines from the corresponding hydroxyindoles, which were synthesized via a Reissert protocol [10], Plieninger s group used this method to access 4- and 6-bromoindoles [11], and Bergmann and Pelchowicz realized both 5- and 6-fluoroindoles from the respective o-nitrophenylpyruvic acids [12], In addition to these 

This chapter has focused solely on the classic Reissert reductive cychzation of o-nitrophenylpyruvic acids (and pyruvates) to indoles. The myriad other reductive cycliza-tions of nitro carbonyl compounds to give indoles are relegated to subsequent chapters. 

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The classic Reissert indole synthesis, involving the reducdve cyclization of o-ni-trophenylpymvic acid, has been used for synthesis of 2-ethoxycarbonyl-4-alkoxymethylindo-les The modified Reissert reacdon, involving the reducdve cyclizadon of an o-rdtrophenyl acetoaldehyde, has been adapted to solid-phase synthesis... 

Amino groups in compounds of type (23, Z=NH) are frequently derived from nitro groups. In the Reissert indole synthesis, o-nitrotoluene undergoes Claisen condensation with oxalic ester to yield the pyruvic ester (24). When this is reduced with Zn-AcOH the corresponding amino derivative spontaneously cyclizes to the 2-ethoxycarbonylindole (25) (63OS(43)40). 

Weinreb s synthesis4 has two OMe groups where the ortho-quinone will be and puts in the pyrrole last. The idea was to use a Reissert indole synthesis where reduction of the nitro group in 42 would lead to condensation with the ketone. 

The mechanism of the formation of 4-nitroindole parallels the Reissert indole synthesis and is discussed in references 2 and 3. 

Reissert indole synthesis. Condensation of an o-nitrotoluene with oxalic ester, reduction to the amine, and cyclization to the indole. 

This reaction is related to the Reissert Indole Synthesis. 

This reaction is closely related to the Reissert Indole Synthesis, which consists of a decarboxylation in the final step. ... 

Displayed below is the reaction route for the Reissert indole synthesis from c>-nitrotoluene and dimethyl oxalate, where the hydrolysis of methyl indole-2-carboxylate could be omitted, depending on the reaction conditions. 

Other references related to the Reissert indole synthesis are cited in the literature. ... 

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