Direct Regioselective [3 + 2] Cycloaddition Reactions of Masked Difluorodiazoethane with Electron-Deficient Alkynes and Alkenes: Synthesis of Difluoromethyl-Substituted Pyrazoles

Abstract

Phenylsulfone difluorodiazoethane (PhSOCFCHN), an easy-to-prepare and bench-stable masked CF-building block, has been developed. The synthetic utility of this reagent is demonstrated by a direct regioselective [3 + 2] cycloaddition with electron-deficient alkynes and alkenes. This protocol enables facile construction of an array of difluoromethyl-substituted pyrazoles in good to high yields under mild reaction conditions.

Difluorodiazoethane (CF2HCHN2): A New Reagent for the Introduction of the Difluoromethyl Group

“…It should be noted that under these conditions, typicalc yclopropanation catalysts, such as FeTPPCl or Co(salen) complexes,g ave only unsatisfac-tory results, which might be attributed to the conditions that are required for the synthesis of CF 2 HCHN 2 (Scheme 12). [40] Recently,H ua nd co-workersr eported the application of difluoromethyl carbene in the Cu I -catalyzed synthesiso ff luoroalkyl-substitutedi soxazoles (46)(47)(48). Lewis acidic ZnBr 2 or ZnCl 2 were required to obtain high yields of isoxazoles.…”

“…The sulfone masking group could be readilyr emoved under basic conditions in ao ne-pot procedure. [47]…”

Difluoroacetaldehyde N‐Triftosylhydrazone (DFHZ‐Tfs) as a Bench‐Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane

“…Later, the group of Han and Chen described an ex situ generation of CF 2 HCHN 2 by using the double‐chamber system . In 2018, the Ma group developed an alternative masked CF 2 HCHN 2 reagent, phenylsulfone difluorodiazoethane (PhSO 2 CF 2 CHN 2 ) . On the other hand, since the first discovery of CHOCHN 2 in 1966 by Kaplan and Meloy, two protocols have been reported for its preparation: 1) acylation of diazomethane with either formyl fluoride or acetic formic anhydride (Figure b, left side); 2) by heating excess p ‐toluenesulfonyl azide with β‐ N ‐methylanilinoacrolein .…”

Difluoroacetaldehyde N‐Triftosylhydrazone (DFHZ‐Tfs) as a Bench‐Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane

“…Later, the group of Han and Chen described an ex situ generation of CF 2 HCHN 2 by using the double‐chamber system . In 2018, the Ma group developed an alternative masked CF 2 HCHN 2 reagent, phenylsulfone difluorodiazoethane (PhSO 2 CF 2 CHN 2 ) . On the other hand, since the first discovery of CHOCHN 2 in 1966 by Kaplan and Meloy, two protocols have been reported for its preparation: 1) acylation of diazomethane with either formyl fluoride or acetic formic anhydride (Figure b, left side); 2) by heating excess p ‐toluenesulfonyl azide with β‐ N ‐methylanilinoacrolein .…”