Synthesis of Chiral gem-Difluoromethylene Compounds by Enantioselective Ethoxycarbonyldifluoromethylation of MBH Fluorides via Silicon-Assisted C–F Bond Activation

Abstract

The enantioselective ethoxycarbonyldifluoromethylation of Morita−Baylis−Hillman (MBH) fluorides with Me 3 SiCF 2 CO 2 Et under organocatalysis is described. Moderately functionalized chiral gem-difluoromethylene compounds with a stereogenic "C-CF 2 -C*" unit were synthesized in high yields with high enantioselectivities. The initial C−F bond activation is assisted by the silicon atom via a dual S N 2′-S N 2′ stepwise pathway. Dynamic kinetic resolution of the MBH-fluorides explained the high yields and high ee's of the products. The method was extended to the enantioselective introduction of "Het-CF 2 " units.

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silylated Stabilized Carbon Nucleophiles with Allylic Fluorides

“…The configuration of the enantiomer predominantly formed when (DHQD)2PHAL was used as the catalysts was assigned as S based on the analogy with previous reports. [4][5] Similar to the previously reported allylations using allylic fluorides, these reactions also proceed as kinetic resolutions of the starting allylic 6 fluoride. The residual fluorides that could be isolated at the end of the reactions were typically highly enantioenriched.…”

“…In the arena of C-centered nucleophiles, Shibata's pioneering studies have demonstrated that alkynyl, trifluoromethyl and some benzyl silanes can be used as C-centered pronucleophiles in allylic substitutions of allylic fluorides catalyzed by chiral Lewis bases (Scheme 2). [5] We took advantage of the same approach to achieve enantioselective allylation of silylated difluoromethyl phosphonate and for the first time produced bioisosters of allyl phosphates in an enantioselective manner. [6] Unlike nitrogen centered nucleophiles, the C-H acidic precursors of carbanions are not strongly nucleophilic and they thus avoid the problems outlined above.…”

“…Reaction scope for allylic fluoride reflected the scope of the previously reported allylic substitutions with similar substrates. [4][5][6]8] Both electron rich (3b -3d) and electron poor (3e -3h) allylic fluorides gave moderate to excellent yields. When halogenated allylic fluorides (3i -3p) were used, the corresponding products were also obtained in good yields.…”

“…The reactions may proceed via (i) two consecutive SN2' additions involving an ammonium ion, produced by the attack of the Lewis base catalysts on MBH fluoride and the consequent elimination of fluoride, and a short-lived activated anionic nucleophile (Scheme 6a, left), [4] or (ii) via concerted mechanism involving a highly ordered ternary transition state consisting of the fluoride, silyl enol ether and the catalyst proposed by Shibata for the related processes (Scheme 6a, right). [5] Besides these two border scenarios, a silicon-assisted cleavage of the C-F bond has been proposed. [11] The central point appears to be whether or not a free anionic activated nucleophile is produced during the reactions.…”

(Fluoro)alkylation of alkenes promoted by photolysis of alkylzirconocenes

“…To this end, efforts toward the development of efficient methods to access CF 2 -containing molecules have been witnessed over the past decade. 6 However, most of these developed synthesis methods mainly focus on the preparation of difluoroalkylated arenes (ArCF 2 R) with CF 2 at the benzylic position. 6 a ,7…”