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Synlett 2009(17): 2836-2838  
DOI: 10.1055/s-0029-1217985
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Jonathan Clayden*, James Clayton, Rebecca A. Harvey, Ol’ga Karlubíková
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax: +44(161)2754939; e-Mail: clayden@man.ac.uk;
Further Information

Publication History

Received 10 July 2009
Publication Date:
24 September 2009 (online)

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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

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(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.

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(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.