Synthesis of N‐Nitroso CHF₂‐Pyrazolines and Their Transformation into CHF₂‐Isoxazolines and ‐Pyrazoles

Abstract

N‐Nitroso CHF2‐pyrazolines were synthesized from in situ generated difluoromethyldiazomethane (CF2HCHN2), tert‐butyl isonitrite (tBuONO), and alkenes. The synthesis of representative CHF2‐pyrazoles and CHF2‐oxazolines was also performed.

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

“…Moreover, it is worth mentioning that only one equivalent of Ps-DFA was employed in these cycloaddition reactions. This is a distinct advantage compared with previously reported CF 2 HCHN 2 chemistry in which the diazo compound was often requisite for more than two equivalents. , …”

“…Despite considerable effort, these protocols often encounter formation of regioisomeric mixtures with respect to substituents incorporated at the 3- and 5-positions of the pyrazole ring. To overcome these limitations, Mykhailiuk reported the in situ generation of difluorodiazoethane (CF 2 HCHN 2 ) and its [3 + 2] cycloaddition with alkynes to provide 3-CF 2 H pyrazoles (Scheme a) . Subsequently, both the groups of Koenigs and Jamison have developed elegant methods to prepare CF 2 H-pyrazoles with CF 2 HCHN 2 by the utilization of continuous-flow technology (Scheme a) .…”

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

“…For example, upon heating, they underwent eliminationo fn itrogen to form CHF 2 -isoxazolines 26 (Scheme 7). [30] Han, Chen, and co-workersf urther investigated this one-pot protocoli n[ 3 + +2]-cycloaddition reactions of CF 2 HCHN 2 (2)a nd 3-ylideneoxindoles to provide spirocyclic CHF 2 -substituted pyrazolines (27,28). The authors conducted this transformation in different solvents, and demonstrated the compatibility of the in situ preparation of CF 2 HCHN 2 with dichloromethane, chloroform, and acetonitrile.…”

“…Substituted N ‐nitroso pyrazolines were shown to be valuable reactive heterocycles. For example, upon heating, they underwent elimination of nitrogen to form CHF 2 ‐isoxazolines 26 (Scheme ) …”

Ex Situ Generation of Difluorodiazoethane (CF2HCHN2): Application in the Regioselective Synthesis of CF2H-Containing Pyrazoles

“…Afterward, Koenigs and Jamison further investigated this transformation in a continuous-flow protocol. Except for alkynes, electron-withdrawing olefins could also be used as coupling partners to finish a [3 + 2] process with CF 2 HCHN 2 , affording the corresponding pyrazolines. ,, In 2016, Koenigs developed Rh­(II)-catalyzed one-step synthesis of difluoromethyl cyclopropanes from CF 2 HCHN 2 and aryl olefins in moderate yields . In our recent studies, we found that different kinds of CF 2 H-containing spirooxindoles and pyrazolo­[1,5- c ]­quinazolines could be easily synthesized from isatin-derived 3-ylideneoxindoles with in situ generated CF 2 HCHN 2 .…”