Enantioselective Synthesis of Bromodifluoromethyl‐containing Oxazolines by Concerted Lewis/Brønsted Base Catalysis with Chiral Bisphosphine Oxide

Abstract

We describe regio‐ and enantioselective bromocyclization of difluoroalkenes catalyzed by chiral bisphosphine oxides. Owing to the simultaneous activation of both the brominating reagent and amide substrate, the desired cyclization reaction proceeds smoothly even at low temperature to provide bromodifluoromethyl‐containing oxazolines with a chiral quaternary center in a highly enantioselective fashion (up to 99% ee). This protocol features the use of commercially available brominating reagents and readily accessible chiral catalysts. The regioselectivity and enantioselectivity are influenced by the catalyst structure, the brominating reagent, and the reaction temperature. Under the optimal conditions, 5‐exo cyclization proceeds preferentially compared with 6‐endo cyclization, depending on the electronic properties of the alkene substrates. A gram‐scale synthesis of chiral oxazoline was achieved with as little as 1 mol % of the catalyst.

Switching Regioselectivity in the Asymmetric Bromocyclization of Difluoroalkenes Catalyzed by a Chiral Bisphosphine Oxide

“…White solid. Spectral data for 4m were consistent with those reported in ref4 1. H NMR (500 MHz, CDCl3) d 7.99-7.97 (m, 2H), 7.69 (dd, J = 9.3, 5.3 Hz, 2H), 7.52 (t, J = 7.0 Hz, 1H), 7.45-7.42 (m, 2H), 7.11-7.06 (m, 2H), 4.60 (dt, J = 18.0, 3.3 Hz, 1H), 4.52 (dt, J = 18.0, 3.8 Hz, 1H).13 C{1H} NMR (125 MHz, CDCl3) d 163.0 (d, J = 249.1 Hz), 150.9, 132.0, 131.1 (d, J = 2.4 Hz), 130.1 (d, J = 8.4 Hz, 2C), 129.9, 128.4 (2C), 127.6 (2C), 120.7 (t, J = 261.7 Hz), 115.6 (d, J = 21.5 Hz, 2C), 56.1, 55.8 (t, J = 26.1 Hz).…”

“…Incorporation of fluorine atom(s) into biologically active molecules has emerged as a key strategy for drug design and lead optimization. 1 In particular, there has been a surge of interest in the difluoromethylene (R 1 -CF2-R 2 ) group owing to its ability to act as a bioisostere for carbonyl, sulfonyl, and ether groups. 2 Indeed, several difluoromethylene-containing drugs, such as lubiprostone, 3 gemcitabine, 4 and vinflunine, 5 have been developed to date (Figure 1).…”

“…84% yield, 3e/4e = 1:7.0, 75% ee. White solid 1. H NMR (500 MHz, CDCl3) d 7.93 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H),6.92 (d, J = 9.0 Hz, 2H), 4.58 (dt, J = protected by copyright.…”

“…oxazine (4i): 91% yield, 3i/4i = 1:>20, 80% ee. Colorless oil 1. H NMR (500 MHz, CDCl3) d 8.00-7.98 (m, 2H), 7.53-7.48 (m, 3H), 7.43 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 4.61 (dt, J = 18.5, 3.3 Hz, 1H), 4.52 (dt, J = 18.5, 3.8 Hz, 1H), 2.39 (s, 3H).…”

“…87% yield, 3k/4k = 1:14, 85% ee. White solid 1. H NMR (500 MHz, CDCl3) d 8.01 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.63-7.58 (m, 4H), 7.53 (t, J = 7.5 Hz, 1H), 7.47-7.43 (m, 4H), 7.38 (t, J = 7.5 Hz, 1H), 4.67 (dt, J = 17.8, 3.1 Hz, 1H), 4.58 (dt, J = 17.8, 3.8 Hz, 1H).13 C{1H} NMR (125 MHz, CDCl3) d 150.9, 142.3, 139.8, 134.0, 131.9, 130.0, 128.9 (2C), 128.4 (4C), 127.9, 127.7 (2C), 127.3 (2C), 127.1 (2C), 120.8 (t, J = 261.6 Hz), 56.5 (t, J = 27.0 Hz), 56.1.…”