Pyrazole Pechmann synthesis

Pyrazoles from the 1,3-dipolar cycloaddition of diazo compounds and alkynes. 

3-dipolar cycloaddition between diazoalkanes and alkynes resulting in pyrazole formation is known as the Pechmann pyrazole synthesis.  

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. 

3-dipolar cycloaddition of ethyl propiolate and ethyl diazoacetate was catalyzed by InCb in water to afford pyrazole bis-ester. For secondary diazo compounds, the InCU-catalyzed 1,3-dipolar cycloaddition often gives a mixture of two regioisomers. 

Ethyldiazoacetate (EDAC) has become a commonly utilized 1,3-dipole in the Pechmann pyrazole synthesis. In efforts toward the rational design of growth inhibitors of Mycobacterium tuberculosis, Kozikowski and co-workers utilized this strategy for the synthesis of the pyrazole ester. Treatment of a mixture of alkyne and EDAC under microwave conditions resulted in the preparation of the pyrazole ester as a mixture of H and 2H tautomers. The pyrazole ester proved inactive in the anti-TB assay, thereby proving the importance of an isoxazole moiety for anti-TB activity, as previous work by these authors suggested.  

Finally, a facile and regioselective synthesis of rimonabant was accomplished through an enamine-directed 1,3-dipolar cycloaddition. In the presence of triethylamine, hydrazonoyl iodide was converted into the nitrile imine in situ. The subsequent 1,3-dipolar cycloaddition with the morpholine enamine provided the 1,5-diarylpyrazole, which was transformed into rimonabant. 

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

Other references related to the Pechmann pyrazole synthesis are cited in the literature. 

The Pechmann pyrazole synthesis features a 1,3-dipolar [3 + 2] cycloaddition between a diazoalkane and an alkyne followed by tautomerization, presumably via a 1,5-hydride shift, to give the pyrazole (1). 

Given the somewhat diminished reactivity between some 1,3-dipoles and dipolarophiles, several different approaches have been examined to expedite the Pechmann pyrazole synthesis. The general idea behind the two approaches discussed below is very similar both rely on manipulating the HOMO and LUMO of the reacting partners.The first approach relies on the ability of Lewis acids to lower the energy of the dipolarophile s LUMO,... 

In a number of studies, the Pechmann pyrazole synthesis has found utility in the synthesis of fluorinated heterocycles.As an example, the cyclization between 13 and diazomethane resulted in the efficient preparation of trifluoroalkyl pyrazole 14. As is the case with the majority of isolated pyrazoles, the product 14 is in equilibrium with the other N-H tautomer. 

The Pechmann pyrazole synthesis has also found similar utility for the preparation of perfluoroalkylated heterocyclic phosphonates, as demonstrated by the Shen group. Reaction of EDAC (30) with trifluoromethyl alkynylphosphonate 32 resulted in the formation of regioisomers 33 and 34 in high yield. The two regioisomers, isolated in a ratio of 85 15 (33 34) could be separated by column chromatography. 

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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