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Synlett 2009(19): 3171-3174  
DOI: 10.1055/s-0029-1218353
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot, Three-Component Synthesis of Chiral 4-Alkylidene-2-oxazolidin­ones

Naoto Kojima*, Shogo Nishijima, Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0879, Japan
Fax: +81(6)68798214; e-Mail: t-tanaka@phs.osaka-u.ac.jp;
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Publication History

Received 1 September 2009
Publication Date:
11 November 2009 (online)

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Abstract

A one-pot convenient access to chiral 2-oxazolidinones is described. Diethylzinc-mediated asymmetric alkynylation of aldehydes with propiolates in the presence of β-sulfonamide alcohol as the chiral ligand, followed by treatment with isocyanates, yielded chiral 4-alkylidene-2-oxazolidinones.

Key words

oxazolidinone - heterocycle - multicomponent reaction - asymmetric synthesis - alkyne

    References and Notes

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10

The absolute configuration of 2-oxazolidinone 1a was assumed based on propargyl alcohol 2 whose absolute configuration was determined by the modified Mosher method.

11

The stereochemistry of the alkene moiety was assigned by nuclear Overhauser effect (NOE) experiment. Irradiation of the alkenyl proton caused an increment of the area intensity of the aromatic proton at the meta position of the tosyl group.

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General Procedure for One-Pot, Three-Component Synthesis of Chiral 2-Oxazolidinones (Table 1, Entry 1)
Ethyl propiolate (0.304 mL, 3.00 mmol) was added to a stirred mixture of (S)-2-(methanesulfonylamino)-1,1-diethyl-3-phenyl-1-propanol (108 mg, 0.300 mmol), DME (0.105 mL, 1.00 mmol), and Et2Zn (1.0 M in n-hexane,
3.00 mL, 3.00 mmol) in toluene (6 mL) at r.t. under Ar atmosphere. After 12 h at the same temperature, Ti(Oi-Pr)4 (0.089 mL, 0.300 mmol) was added and the reaction mixture stirred for 0.5 h. To the resulting solution was added cyclohexanecarbaldehyde (0.121 mL, 1.00 mmol) in one portion. After 2 h, tosyl isocyanate (0.490 mL, 3.20 mmol) was added to the mixture. After 12 h, the reaction was quenched with sat. NH4Cl, and the mixture was extracted with EtOAc. The combined organic layers were washed with sat. NH4Cl, H2O, and brine, dried, and the solvent was evaporated. Purification by column chromatography over silica gel with n-hexane-Et2O (19:1) as eluent yielded
(R,E)-ethyl 2-(5-cyclohexyl-2-oxo-3-tosyloxazolidin-4-ylidene)acetate (1a, 316 mg, 77%, 80% ee) as a colorless amorphous solid.

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Characterization Data of Selected Compounds
( R , E )-Ethyl 2-(5-Cyclohexyl-2-oxo-3-tosyloxazolidin-4-ylidene)acetate (1a)
Colorless amorphous solid; [α]D ²6 +148.9 (c 1.00, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 0.83-0.91 (m, 1 H), 1.01-1.16 (m, 2 H), 1.22-1.39 (m, 4 H), 1.32 (t, J = 7.3 Hz, 3 H), 1.53-1.61 (m, 1 H), 1.73-1.75 (m, 2 H), 2.01-2.11 (m, 1 H), 2.47 (s, 3 H), 4.19 (q, J = 7.3 Hz, 2H), 5.54 (s, 1 H), 6.45 (s, 1 H), 7.39 (d, J = 7.9 Hz, 2 H), 7.98 (d, J = 7.9 Hz, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.2, 21.8, 23.8, 25.5, 25.6, 26.0, 29.2, 41.7, 60.6, 83.2, 98.3, 128.4 (2 C), 129.9 (2 C), 133.7, 146.8, 149.9, 150.6, 165.7. IR (KBr): 1805, 1709, 1647 cm-¹. MS (EI): m/z (%) = 407 (1.1) [M]+, 362 (10.6) [M - OEt]+, 325 (100) [M + H - C6H11]+, 252 (17.2) [M - Ts]+. HRMS (EI): m/z [M]+ calcd for C20H25O6NS: 407.1403; found: 407.1405. HPLC column: DAICEL CHIRALPAK® IC (250 ¥ 4.6 mm), n-hexane-i-PrOH (91:9), 5 mL/min, t R = 35.2 min for 1a and t R = 33.1 min for enantio-1a.
( R , E )-Ethyl 2-[5-Cyclohexyl-3-(4-fluorophenyl)-2-oxooxazolidin-4-ylidene]acetate (1d)
Colorless needles; [α]D ²5 +139.8 (c 1.00, CHCl3); mp 160-161 ˚C (n-hexane-EtOAc). ¹H NMR (500 MHz, CDCl3): δ = 1.14-1.39 (m, 4 H), 1.25 (t, J = 7.3 Hz, 3 H), 1.52-1.60 (m, 2 H), 1.67-1.70 (m, 1 H), 1.82-1.93 (m, 3 H), 2.26-2.34 (m, 1 H), 4.11 (dq, J = 11.0, 7.3 Hz, 1 H), 4.16 (dq, J = 11.0, 7.3 Hz, 1 H), 4.99 (d, J = 1.8 Hz, 1 H), 5.70 (t, J = 1.8 Hz, 1 H), 7.17-7.29 (m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.1, 24.0, 25.65, 25.71, 26.1, 29.6, 41.1, 60.1, 84.0, 91.0, 117.1 [d, ² J(C,F) = 23.0 Hz, 2 C], 128.6 [d, 4 J(C,F) = 3.1 Hz], 129.2 [d, ³ J(C,F) = 8.7 Hz, 2 C], 155.0, 157.0, 162.6 [d, ¹ J(C,F) = 249.7 Hz], 166.1. IR (KBr): 1792, 1701, 1645 cm-¹. MS (EI): m/z (%) = 347 (17.6) [M]+, 302 (4.3) [M - OEt]+, 265 (100.0) [M + H - C6H11]+. HRMS (EI): m/z [M]+ calcd for C19H22NO4F: 347.1533; found: 347.1556. HPLC column: DAICEL CHIRALPAK® IC (250 ¥ 4.6 mm), n-hexane-i-PrOH (91:9), 5 mL/min, t R = 22.0 min for 1d and t R = 24.1 min for enantio-1d.
( R , E )-Ethyl 2-[5-(2-Bromophenyl)-2-oxo-3-tosyloxazolidin-4-ylidene]acetate (1h)
Colorless plates; mp 175-176 ˚C (n-hexane-EtOAc); [α]D ²³ +204.8 (c 1.00, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 1.12 (t, J = 7.3 Hz, 3 H), 2.50 (s, 3 H), 3.98 (dq, J = 11.0, 7.3 Hz, 1 H), 4.02 (dq, J = 11.0, 7.3 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 7.08-7.11 (m, 1 H), 7.22-7.25 (m, 2 H), 7.43 (d, J = 8.5 Hz, 2 H), 7.60-7.63 (m, 1 H), 8.05 (d, J = 8.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 13.9, 21.8, 60.7, 80.1, 100.2, 124.8, 127.6, 127.9, 128.5 (2 C), 130.1 (2 C), 131.1, 133.4 (2 C), 134.6, 147.08, 147.13, 149.7, 164.7. IR (KBr): 1809, 1714, 1655 cm-¹. MS (EI):
m/z (%) = 479 (3.6) [M]+, 400 (19.8) [M - Br]+, 371 (6.2)
[M - Br - Et]+, 324 (18.4) [M + H - Br - C6H5]+, 278 (26.7) [M - Br - C6H5 - OEt]+, 91 (100). HRMS (FAB): m/z [M + H]+ calcd for C20H19BrNO6S: 480.0116; found: 480.0103. HPLC column: DAICEL CHIRALPAK® IC (250 ¥ 4.6 mm), n-hexane-CH2Cl2 (30:70), 1 mL/min, t R = 41.7 min for 1h and t R = 44.8 min for enantio-1h.

15

In the case of the use of phenyl isocyanate (Table  [¹] , entry 5), the slight decrease in optical purity was observed throughout the one-pot reaction, indicating isomerization of
(E)-alkenylzinc 3b into alkenylzinc 3a via enol 5.