GEWALD Heterocycle synthesis

The few thiophene syntheses reported in which the formation of the heterocycle is realized on an insoluble support (Entries 1-3, Table 15.10) are based on the intramolecular addition of C,H-acidic compounds to nitriles (Thorpe-Ziegler reaction), or on the Gewald thiophene synthesis. The mechanism of these cyclizations is outlined in Figure 15.6. In thiophene preparations performed on solid phase, the required a-(cya-... 

Tinsley, J. M. Gewald Aminothiophene Synthesis. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, pp 193-198. (Review). 

Cyclization reactions effected by intramolecular attack of a heteroatom on a nitrile group provide a useful source of 2-amino heterocycles, e.g. (120) —> (121), and numerous syntheses employ this strategy (vide infra). Thus, the reaction of a,(3-unsaturated nitriles (122) with elemental sulfur in basic media, the Gewald synthesis, provides a most convenient route to 2-aminothiophenes (123), many of which are a useful as intermediates in the preparation of dyestuffs and pharmaceuticals. 

The MCR covered herein has found broad applicability in the synthesis of heterocycles containing Gewald moiety (2-amino-thiophene) (Fig. 12.5), with interesting properties [138] and overall antimicrobial activities, such as phthala-zinediones [139], thienopyridines [140], thienothiadiazines... 

The Knoevenagel condensation also plays a part in a number of prominent heterocycle syntheses including the Knorr pyrrole synthesis/ Hantzsch dihydropyridine synthesis/ Feist-Benary furan synthesis and the Gewald reaction, which is used to make 2-aminothiophenes. 

The importance of this field of heterocyclic chemistry gave impetus to the present study, where the data on synthesis, reactivity and application of variously substituted 2-aminothiophenes are systematized and analyzed. Emphasis is given to the recent studies published, in which the most general approaches to the synthesis of basic 2-aminothiophenes via the Gewald reaction and other target structures were considered. Data of the utilization of 2-aminothiophenes in the synthesis of novel type of fused heterocycles and their application are included. Particular attention is given to studies published in the previous 15-20 years. 

In this chapter we have extended the problems of synthesis of variety of substituted 2-aminothiophenes and their scope and utilization. The title compounds are readily obtainable by the Gewald reaction and its variations widely used since the time of its discoveiy in 1961 until now. These important heterocyclic compounds represent a group of precursors applied in synthesis of pharmaceutical and disperse dyes and in recent times the preparation of conductive polymers using 2-aminothiophenes is highlighted. The scope of our chapter does not include all of the publications on the chemistry of substituted 2-aminothiophenes, but the most interesting studies in the subject areas are considered. 

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