Metal-free synthesis of α,α-difluorocyclopentanone derivatives via regioselective difluorocyclopropanation/VCP rearrangement of silyl dienol ethers

Abstract

Silyl dienol ethers underwent chemoselective difluorocyclopropanation under mild conditions with difluorocarbene, which was generated from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) using 1,8-bis(dimethylamino)naphthalene (proton sponge) as a catalyst. Successive vinylcyclopropane/cyclopentene (VCP) rearrangements readily proceeded to provide biologically promising 5,5-difluorocyclopent-1-en-1-yl silyl ethers in a one-pot operation without the use of metal catalysts.

Difluorocarbene in Cycloadditions and Annulations for the Synthesis of gem‐Difluorocarbocycles and gem‐Difluoroheterocycles

“…The tandem [2 + 1] cycloaddition of t-butyldimethylsiloxydienes 17 with TFDA and subsequent ring expansion of generated t-butyldimethylsiloxy vinyl gem-difluorocyclopropanes 18 were also achieved under the catalysis of proton sponge N,N,N',N'-tetramethylnaphthalene-1,8-diamine in pxylene, affording 1-t-butyldimethylsiloxy-5,5-difluorocyclopentenes 19 in similar yields as those under the catalysis of nickelpincer-type NHC ligand complex (Scheme 5). [20] This method is a metal-free synthetic route, showing the similar efficiency as that in the previous nickel-catalyzed reaction. [19] The reaction of α-alkylidene-β-dicarbonyl compounds 22 and bromodifluoromethyl(trimethyl)silane (TMSCF 2 Br) generated 2-acyl-5,5-difluorocyclopent-1-en-1-ols 23 directly in the presence of tetrabutylammonium bromide (Bu 4 NBr, TBAB) in toluene.…”

“…The tandem [2+1] cycloaddition of t ‐butyldimethylsiloxydienes 17 with TFDA and subsequent ring expansion of generated t ‐butyldimethylsiloxy vinyl gem ‐difluorocyclopropanes 18 were also achieved under the catalysis of proton sponge N,N,N’,N’ ‐tetramethylnaphthalene‐1,8‐diamine in p ‐xylene, affording 1‐ t ‐butyldimethylsiloxy‐5,5‐difluorocyclopentenes 19 in similar yields as those under the catalysis of nickel‐pincer‐type NHC ligand complex (Scheme 5). [20] This method is a metal‐free synthetic route, showing the similar efficiency as that in the previous nickel‐catalyzed reaction [19] …”

“…The vinyl difluorocyclopropanes 25 undergo a ring expansion to generate 2-acyl-5,5-difluoro-1-trimethylsiloxycyclopentenes 26, which react with HBr to give rise to final products 2-acyl-5,5-difluorocyclopent-1-en-1-ols 23 and TMSBr. Under similar conditions, (E)-4-phenylbut-3-en-2-one ( 27) generated 2,2difluoro-4-phenylcyclopentan-1-one (20) in 92 % NMR yield (Scheme 6). [21] The results indicate that α-alkylidene-βdicarbonyl compounds 22 generate 2-acyl-5,5-difluorocyclopent-1-en-1-ols 23, while α,β-unsaturated enones such as 27 give 2,2-difluorocyclopentanones, for example 20.…”

“…The reactions are TMSCF 2 Br-self-assisted domino reactions. Differently from previous methods with trialkylsiloxydiene as starting materials, [19,20] in this reaction, trialkylsiloxydienes generated in situ, exhibiting good advantages.…”

Generation of difluorocarbenes and introduction of fluorinated one carbon units into carbonyl and related compounds

“…Thus, upon treatment with difluorocarbene generated from TFDA and a proton sponge catalyst, silyl ethers 21 prepared from α,β-unsaturated ketones underwent difluorocyclopropanation, which proceeded selectively on the electron-rich alkene moiety to afford the corresponding difluoro(vinyl)cyclopropanes 22 . 42 The obtained cyclopropanes 22 were heated to 140 °C without isolation, affording difluorinated five-membered silyl enol ethers 23 via vinylcyclopropane–cyclopentene (VCP) rearrangement, 43,44 which was accelerated and directed by the enhanced strain of the difluorocyclopropane ring. Thus regioselective bond cleavage occurred to afford the products, where the carbon alignment was altered from the starting silyl dienol ethers 21 (abnormal [4+1] cycloaddition, –CF 2 – introduction).…”