gem-Difluoroolefination of Diazo Compounds with TMSCF₃ or TMSCF₂Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursors

Abstract

A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.

Palladium‐Catalyzed Defluorinative Coupling of 1‐Aryl‐2,2‐Difluoroalkenes and Boronic Acids: Stereoselective Synthesis of Monofluorostilbenes

“…Difluoroalkenes are ar eadily accessible class of substrates. [13] While avariety of methods exist for their synthesis, perhaps the most notable is through aJ ulia-Kocienski olefination protocol utilizing commercially available difluoromethyl 2-pyridyl sulfone (Husr eagent) and aldehydes or ketones,which we found to be useful for our purposes.…”

Designs and Strategies for the Halo‐Functionalization of Diazo Compounds

“…Similarly, in other work on the gem ‐difluoroolefination of diazo compounds, Hu et al. reported that gem ‐difluoroolefination of diazo compounds 144 could be achieved by the transition‐metal‐free cross‐coupling of two carbene precursors, namely, diazo compounds and Ruppert‐Prakash reagent, TMSCF 3 ( 147 ) or TMSCF 2 Br ( 145 ) …”

Fluoroalkylation of Diazo Compounds with Diverse Rfn Reagents

“…[14] Later, Hu and coworkers again reported a transition-metalfree difluoroolefination protocol for the cross-coupling of diazo compounds (33 and 36) with TMSCF 3 or TMSCF 2 Br (Scheme 5). [15] The use of sodium iodide (NaI), a less basic activator, instead of a fluoride source led to a relatively slower release of difluorocarbene from TMSCF 3 , which was beneficial for the olefination. The reaction proceeded through a direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N 2 , and furnished a variety of 1,1difluoroalkenes (34 and 37), e. g., difluoroacrylates, diaryldifluoroolefins, and arylalkyldifluoroolefins, which showed a broader 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 substrate scope than that of the Cu-catalyzed difluoroolefination.…”

“…Two possible reaction pathways might be involved in this difluoroolefination (Scheme 5), and the direct carbene-carbene cross-coupling is probably less rational (path b) according to the control experiments. [15] Almost at the same time, Wang and coworkers independently disclosed a similar transition-metal-free difluoromethylenation of diaryl diazomethanes and α-diazo esters using TMSCF 2 Br as a difluoromethylene source and tetrabutylammonium bromide (TBAB) as a promoter. [16] The reaction was run under mild conditions and tolerated various functional groups, wherein hydrazones (45) were also readily converted to afford the corresponding 1,1-difluoroolefins (46) in moderate to excellent yields (Scheme 6).…”