Indole synthesis Gassman

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

Van Vranken and colleagues synthesized 2,4-dimethyl-7-chloroindole from 2-chloro-5-methylaniline in 36% yield 

The Gassman indole synthesis involves an one-pot process in which hypohalite, a P-carbonyl sulfide derivative 2, and a base are added sequentially to an aniline or a substituted aniline 1 to provide 3-thioalkoxyindoles 3. Raney nickel-mediated desulfurization of 3 then produces the parent indole 

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

The Gassman indole synthesis provides a single regioisomer when ortho/para substituted anilines are employed, the yields of which are quite good generally. This provides some advantage in the preparation of 7-substituted indoles compared to other methods which normally give low yields, that is, the Fischer indole process.  

The /neta-substituted anilines provide one or two isomeric products depending on the nature of the substituents (vide infra). 

Ishikawa, H. Uno, T. Miyamoto, H. Ueda, H. Tamaoka, H. Tominaga, M. Naka-gawa, K. Chem. Pharm. Bull. 1990, 38, 2459. 

Gassman Indole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 128—131. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 108, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 116, Springer International Publishing Switzerland 2014 

Barluenga, J. Valdes, C. In Modem Heterocyclic Chemistry Alvarez-Builla, J. Vaquero, J. J. Barluenga, J. eds. Wiley-VCH Weinheim, Germany (2011), 7, 377-531. (Review). 

Sulfur-substituted indole synthesis. The sulfur can be easily hydrogenolyzed off. 

---

The Gassman indole synthesis has one serious limitation. Attempts to use anilines with an ortho/para- methoxy moiety failed to indolize. One means to overcome this was synthesis of the corresponding oxindoles followed by reduction to the indoles. ... 

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. 

In the synthesis of an indoloquinolone antibacterial, the Gassman indole synthesis was explored to serve as the central operation. Therefore, difluoroaniline was selectively monobrominated. Although the Fischer indole cyclization for the resulting 2-bromo-4,5-difluoroaniline only gave the indole in poor yield, the Gassman indole synthesis worked well in one pot. Thus, treatment of the aniline with r-butyl hypochlorite was followed by addition of ethylthio-2-propanone and treatment with triethylamine to produce the indole in excellent yield. 

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

This reaction is closely related to the Gassnum Reaction and Gassman Indole Synthesis. 

---