A One-Pot Synthesis of 2-Aryl-4,5-anti-diphenyloxazolines

Abstract

A one-pot procedure for the synthesis of oxazolines was developed. An amino alcohol was coupled with benzoyl chlorides in the presence of triethylamine to produce a β-hydroxyamide. Direct treatment with methanesulfonyl chloride forms oxazolines in good yields.

Key words

oxazoline - arenes - heterocycle substitutions - auxiliary

References and Notes

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13

(4R,5R)-2,4,5-Triphenyloxazoline (4a): Benzoyl chloride (0.59 mL, 1.1 equiv) was added dropwise over a period of 5 min to a stirred solution of the amine [(1R,2S)-2-amino-1,2-diphenylethanol, 1 g, 1.0 equiv] in CH₂Cl₂ (100 mL) and Et₃N (2.6mL, 4 equiv) at 0 ˚C under a nitrogen atmosphere. The solution was stirred for 16 h. The white suspension was cooled to 0 ˚C and methanesulfonyl chloride (0.54 mL, 1.5 equiv) was added dropwise over 5 min (the solution clarified as the oxazoline formed). The reaction was monitored by TLC and quenched with excess aqueous NH₄Cl after all the amide had been consumed. The solution was partitioned between CH₂Cl₂ and aqueous NH₄Cl and extracted with CH₂Cl₂. The organic layers were washed with aqueous sodium hydrogen carbonate and brine. The solution was dried with MgSO₄ and concentrated under reduced pressure, leaving approximately 5 mL solvent to load the crude reaction mixture onto silica gel. Purification using flash chromatography (10% EtOAc in petroleum ether) gave oxazoline 4a in 71% yield. Mp 116 ˚C (EtOAc-Petrol) (Lit.^¹5 93-95 ˚C, Et₂O); [α]_D ^²² +17.6 (c 1, CHCl₃); 1H NMR (CDCl₃, 300 MHz): δ = 8.07 (d, J = 8 Hz, 2 H, CH C-2, C-6), 7.32 (m, 13 H, Ar), 5.35 (d, J = 8 Hz, CH-5′), 5.17 (d,
J = 8 Hz, 1 H, CH-4′); 13C NMR (CDCl₃, 75.5 MHz): δ = 164.1, 141.9, 140.5, 131.8, 128.9, 128.9, 128.7, 128.5, 128.4, 127.8, 127.4, 126.7, 125.8, 89.0, 78.0.

14

(4R,5R)-2-(4′-Methoxy-3′-triisopropylsilyloxymethyl)-phenyl-4,5-diphenyloxazoline (4h): 4-Methoxy-3-(triiso-propylsilyloxymethyl)benzoic acid (0.45 g, 1.3 mmol) was stirred in thionyl chloride-CH₂Cl₂ (1:1 mL) until IR indicated complete conversion into the acyl chloride. The solvent and thionyl chloride was removed under reduced pressure. The crude benzoyl chloride (1.3 mmol) in CH₂Cl₂ (2 mL) was then added dropwise to a stirred solution of the (1R,2S)-2-amino-1,2-diphenylethanol (0.277 g, 1.3 mmol) in CH₂Cl₂ (15 mL) and Et₃N (0.725 mL, 5.2 mmol) at 0 ˚C under nitrogen. The reaction mixture was warmed to r.t. and stirred until TLC indicated the reaction was complete. Methane sulfonyl chloride (0.151 mL, 1.95 mmol) was added and the solution was stirred until no amide remained by TLC. Saturated NH₄Cl (5 mL) was added and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL), the combined organic extracts were dried (NaSO₄) and the solvent was removed under reduced pressure to give the crude oxazoline. Purification by flash column chromatography (Petrol-EtOAc, 8:2) gave oxazoline 4h (0.49 g, 67%) as a yellow gum. R _f = 0.73 (Petrol-EtOAc, 2:1); [α]_D ^¹9.5 -48.2 (c 1.025, CDCl₃); MS (ES⁺): m/z (%) = 516.3 (100) [MH⁺]; HRMS: m/z [MH⁺] calcd for C₃₂H₄₂O₃NSi: 516.2928; found: 516.2931; IR:(film): 2945, 2865, 1647, 1497, 1259 cm^-¹; ^¹H NMR (CDCl₃, 500 MHz): δ = 8.25 (s, 1 H, C-2), 7.96 (dd, J = 2, 9 Hz, 1 H, C-5), 6.79 (d, J = 9 Hz, 1 H, C-4), 7.31-7.17 (m, 10 H, ArH), 5.31 (d, J = 7 Hz, 1 H, CH-5′), 5.1 (d, J = 7 Hz, 1 H, CH-4′), 4.78 (s, 2 H, ArCH ₂), 3.76 (s, 3 H, OCH ₃), 1.07 [m, 21 H, Si(i-Pr)₃]; ^¹³C NMR (CDCl₃, 75 MHz): δ = 163.3, 157.8, 141.5, 139.9, 129.2, 127.8, 127.1, 126.6, 126.6, 125.8, 124.4, 118.8, 108.4, 87.5, 77.9, 59.2, 54.4, 17.0, 16.7, 13.0, 11.5, 11.3, 11.1, 10.7.