Copper Coils as Efficient and Inexpensive Reactors for the Synthesis of Tetrazoles in Flow Chemistry

Copper-coil reactors are used for the synthesis of tetrazoles starting from benzonitriles in continuous flow. The reaction is carried out at high temperatures and residence times, in the presence of sodium azide, making the flow chemistry approach safer than the batch alternatives. Several tetrazoles have been prepared, including a key precursor of sartan drugs.

Sartans are an important family of drugs used to treat hypertension. A common characteristic of most of them is a biphenyl moiety with a tetrazole ring in the ortho position of the phenyl–phenyl bond. This tetrazole is typically synthesized from the respective nitriles through a [3 + 2] azide-nitrile cycloaddition. However, the use of large amounts of azides at high temperatures for extended periods of time is inherently concerning, as serious accidents can occur if safety protocols are not thoroughly developed and implemented. The implementation of these procedures in continuous flow would therefore be beneficial from the safety perspective. In this article, a method is presented for the preparation of tetrazoles from the respective nitriles employing a copper coil as reactor and catalyst. The reaction parameters have been studied and optimized to maximize conversion. A variety of benzonitriles with different ring substituents have been transformed in moderate to good yields and copper leaching has been analyzed, showing that the copper leached is enough to catalyze this reaction. More interestingly, the method has been applied to obtain the tetrazole ring present in a key intermediate used in sartan manufacturing, a highly sterically hindered compound.

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