Acetylene Pechmann pyrazole synthesis

PECHMANN PYRAZOLE SYNTHESIS. Formation of pyrazoles from acetylenes and diazomethane. The analogous addition of diazoacetic esters to the triple bond yields pyrazolecarboxylic acid derivatives. 

The original reaction discovered by Pechmann involved the cycloaddition of diazomethane and acetylene. Although a better understanding of the reaction has led to the common use of more electron-deficient alkynes, diazomethane continues to be synthetically useful. A recent elegant example of the use of diazomethane as the 1,3-dipole was demonstrated in the preparation of 2,3-benzodiazepine derivatives as potential non-competitive AMPA antagonists. " Beginning with the alkyne, the pyrazole moiety could be incorporated into the benzodiazepine structure, using the Pechmann pyrazole synthesis, to produce the 2,3-benzodiazepines. 

The use of ethyldiazoacetate in the Pechmann pyrazole synthesis has been adapted for use on solid support. Treatment of solid-supported acetylenic sulfone 35 with an excess of EDAC, followed by cleavage from the solid support, provided 36 as a single regioisomer. Notably, when the reaction was done in solution phase with 37, the isomers 38 and 39 were isolated in a 4 1 ratio. 

A common dipolarophile for the Pechmann pyrazole synthesis is dimethyl acetylene dicarboxylate (DMAD, 41), a highly electron-deficient alkyne. Spring and co-workers used the 1,3-dipolar cycloaddition between DMAD and a fluorous-tagged diazoacetate (40) as part of studies aimed at production of structurally diverse scaffolds. As expected, the reaction proceeded efficiently to produce 42 in high yield. 

Although unintended, it was found that the a-diazobenzamide 49 readily participates in the Pechmann pyrazole synthesis with dimethyl acetylene dicarboxylate (41). While studying the reactivity of carbenes generated at the benzylic position of 49, the use of Cu(acac)2 did not effectively catalyze the decomposition of the diazo functionality, thereby allowing the Pechmann pyrazole synthesis to proceed efficiently upon treatment with dimethyl acetylene dicarboxylate. 

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