Two Rearrangement Pathways in the Geminal Acylation of 2‐Methoxyoxazolidines Leading to Substituted 1,4‐Oxazines

Abstract

Lewis acid‐mediated geminal acylation of 2‐methoxyoxazolidines with five‐ or six‐membered acyloins followed by heterocyclization afforded 1,4‐oxazines fused to cyclopentenone or cyclohexenone rings. Overall yields ranged from 30 to 73 %. The position of the carbonyl group in the products depended on whether or not water was present during the ring‐expanding acyl migration step. The route lacking water during the acyl migration step was best conducted in one pot. The addition of water effected cleavage of a silyloxy group in the intermediate during the initial Mukaiyama aldol reaction prior to the acyl migration.

Ring-Opening Cyclization (ROC) of Aziridines with Propargyl Alcohols: Synthesis of 3,4-Dihydro-2H-1,4-oxazines

“…All commercial reagents were used as received. The 1 H NMR (400 and 500 MHz) and 13 C NMR (100 and 125 MHz) data were recorded with CDCl 3 as solvent at room temperature unless specified otherwise. The chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.…”

“…1 H NMR spectra were recorded with tetramethylsilane (δ = 0.00 ppm) as an internal reference. 13 C NMR spectra were recorded with CDCl 3 (δ = 77.0 ppm) as an internal reference. 1 H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), multiplet (m), etc.…”

“…The crude concentrate was purified by flash column chromatography on a silica gel using 5% ethyl acetate in petroleum ether as the eluent to afford the pure product (±)-2phenyl-N-tosyl aziridine (1a) as a white crystalline solid (mp 88−89 °C) in 58% (1383 mg, 5.062 mmol) yield. R f = 0.43 in 20% ethyl acetate in petroleum ether; IR υ max (KBr, cm −1 ) 3036, 2958,1667,1594,1494,1458,1379,1156; 1 H NMR (500 MHz, CDCl 3 ) δ 7.87 (d, 2H, J = 8.6 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.29−7.26 (m, 3H), 7.22−7.20 (m, 2H), 3.77 (dd, 1H, J = 7.4, 4.0 Hz), 2.98 (d, 1H, J = 7.4 Hz), 2.43 (s, 3H), 2.38 (d, 1H, J = 4.6 Hz); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 144. 7, 135.2, 135.1, 129.8, 128.6, 128.4, 128.0, 126.6, 41.1, 36.0, 21.7; HRMS (ESI-TOF) m/z: [M + H] + calcd for C 15 H 16 NO 2 S 274.0897; found 274.0896.…”

“…(±)-4-Methyl-N-(2-phenyl-2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (3aa). The general method A described above was followed when racemic (±)-2-phenyl-Ntosyl aziridine 1a (50 mg, 0.183 mmol, 1.0 equiv) was treated with propargyl alcohol 2a (21 μL, 0.366 mmol, 2.0 equiv) in the presence of Zn(OTf) 2 (7 mg, 0.018 mmol, 10 mol %) in DCM (44 μL) at RT for 20 min to get 3aa as a white crystalline solid, mp 51−53 °C in 84% (51 mg, 0.154 mmol) yield; R f 0.33 in 20% ethyl acetate in petroleum ether; IR υ max (KBr, cm −1 ) 3280, 2923,2853,2120,1597,1493,1452,1326,1158,1072,814; 1 H NMR (500 MHz, CDCl 3 ) δ 7.72 (d, 2H, J = 8.0 Hz), 7.33−7.31 (m, 3H), 7.29 (d, 2H, J = 8.0 Hz), 7.22− 7.20 (m, 2H), 4.97 (d, 1H, J = 8.6 Hz), 4.55 (dd, 1H, J = 9.7, 4.0 Hz), 4.06 (dd, 1H, J = 16.0, 2.9 Hz), 3.81 (dd, 1H, J = 15.5, 2.3 Hz), 3.25−3.20 (m, 1H), 3.06−3.01 (m, 1H), 2.42− 2.41 (m, 4H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 143. 4, 137.3, 136.9, 129.7, 128.8, 128.75, 127.1, 126.8, 79.3, 79.0, 74.9, 55.9, 49.0, 21.5 (±)-5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4oxazine (4aa).…”

“…There are a number of reports for the synthesis of 3,4 - dihydro-2 H -1,4-oxazine derivatives via Lewis acid/base-promoted regioselective 6 -exo-dig cyclization of amino propargyl ethers, N -protected alkynyl amino alcohols, N -protected alkynals/alkynones, epoxy-ynamides, etc. Other approaches for the synthesis of oxazines include the Pd­(II)-catalyzed aerobic oxidative cyclization of 3-aza-5-alkenols, Rh­(II)-catalyzed reaction between 1-tosyl-1,2,3-triazoles and epoxides/glycidols/halohydrins, Lewis-acid-mediated geminal acylation of 2-methoxyoxazolidines with five- or six-membered acyloins followed by heterocyclization, and Ir­(I)-catalyzed intramolecular asymmetric allylic substitution reaction …”