Hazardous Reagent Substitution: A Pharmaceutical Perspective
Chapter 7: Development of a Safe, Scalable, Azide-free Synthesis of 1-Aryl-1H-tetrazoles Using Diformylhydrazine
Published:28 Nov 2017
Special Collection: 2017 ebook collection , ECCC Environmental eBooks 1968-2022Series: Green Chemistry
Sivaraj Ramasamy, Thirumalai Lakshminarasimhan, Jayaprakash Karamil, Sabuj Mukherjee, Manjunath Gujjar, 2017. "Development of a Safe, Scalable, Azide-free Synthesis of 1-Aryl-1H-tetrazoles Using Diformylhydrazine", Hazardous Reagent Substitution: A Pharmaceutical Perspective, Rakesh Kumar Sharma, Rakeshwar Bandichhor
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This chapter details the process research and development efforts towards a practical and effective means to prepare 1-(4-chloro-3-fluoro-2-iodophenyl)-1H-tetrazole via reaction of an aryl diazonium salt (derived from the appropriate aniline) with diformylhydrazine. The most commonly employed methods to synthesize 1-aryl-1H-tetrazoles involve the use of azides, which can pose significant safety challenges. The use of diformylhydrazine affords the desired tetrazoles under conditions that are mild, convenient, safe and scalable, and circumvents the need to use azides. The other added advantage of this approach is that the entire sequence of reactions (diazotization of the amine followed by reaction with diformylhydrazine) can be carried out under aqueous conditions, rendering it very attractive from a green chemistry perspective. Several reaction parameters including pH, stoichiometry and order of addition were systematically explored, and our investigations resulted in the definition of optimal conditions for carrying out this transformation. This methodology may be extended to the general synthesis of 1-aryl substituted-1H-tetrazoles on-scale.