September 2012
A Facile Solvent‐Free Synthesis of Chiral Oxazolidinone Derivatives Catalyzed by MgI2
1145
Etherate: An Approach to Enantiopure Synthesis of Linezolid
Scheme 1. An approach to synthesis of linezolid 1.
5‐Chloromethyl‐3‐(2‐methyl‐phenyl)‐oxazolidin‐2‐one
(4b). Yellowish solid, mp 56.8–57.8°C; ir: 2967, CO 1731, 1493
Hz, 1H), 4.13 (t, J = 9.0 Hz, 1H), 4.85–4.90 (m, 1H), 7.41–7.44
(m, 2H), 7.46–7.49 (m, 2H) ppm; Anal. Calcd. for
C10H9BrClNO2: C, 41.34; H, 3.12; N, 4.82. Found: C, 41.47; H,
3.21; N, 4.74.
5‐Phenoxymethyl‐3‐phenyl‐oxazolidin‐2‐one (4i) [18]. White
solid; mp 139.0–139.7°C (lit, 139°C); ir: 3062, CO 1739, 1599,
1502, 1445 cm−1; 1H nmr: δ 4.08 (dd, J = 6.0, 9.0 Hz, 1H),
4.19–4.25 (m, 3H), 4.97–5.01 (m, 1H), 6.91–6.92 (m, 2H), 7.00
(t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.29–7.32 (m, 2H),
7.38–7.41 (m, 2H), 7.57–7.59 (m, 2H) ppm.
1
cm−1; H nmr: δ 2.32 (s, 3H), 3.77 (dd, J = 3.5, 11.5 Hz, 1H),
3.81–3.86 (m, 2H), 4.06 (t, J = 9.0 Hz, 1H), 4.90–4.94
(m, 1H), 7.22–7.29 (m, 4H) ppm. Anal. Calcd. for C11H12ClNO2:
C, 58.54; H, 5.36; N, 6.21. Found: C, 58.65; H, 5.45; N, 6.32.
5‐Chloromethyl‐3‐(2,3‐dimethyl‐phenyl)‐oxazolidin‐2‐one
(4c). White solid. mp 121.7–122.3°C; ir: 2945, CO 1735,
1477 cm−1 1H nmr: δ 2.19 (s, 3H), 2.30 (s, 3H), 3.75–3.82
;
(m, 1H), 3.83 (dd, J = 2.0, 6.0 Hz, 2H), 4.03 (t, J = 9.0 Hz, 1H),
4.89–4.94 (m, 1H), 7.09 (dd, J = 2.5, 6.5 Hz, 1H), 7.12–7.16
(m, 2H) ppm. Anal. Calcd. for C12H14ClNO2: C, 60.13; H, 5.89;
N, 5.84. Found: C, 60.26; H, 5.98; N, 5.68.
5‐Phenoxymethyl‐3‐(5‐chloro‐2‐methyl‐phenyl)‐oxazolidin‐
2‐one (4j) [19]. White solid; mp 126.5–127.5°C; ir: CO 1745,
1594, 1512, 1455 cm−1; 1H nmr: δ 2.33 (s, 3H), 4.03 (dd,
J = 6.0, 9.0 Hz, 1H), 4.14–4.23 (m, 3H), 4.95 (dd, J = 4.5, 9.0
Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 7.18
(d, J = 8.5 Hz, 2H), 7.29 (dd, J = 7.5, 8.0 Hz, 2H), 7.44 (d,
J = 8.5 Hz, 2H) ppm.
5‐Phenoxymethyl‐3‐(2,3,4‐trifluoro‐phenyl)‐oxazolidin‐2‐
one (4k). White solid; mp 104.8–105.5°C; ir: CO 1736, 1610,
1507, 1442 cm−1; 1H nmr: δ 4.05 (dd, J = 6.0, 9.0 Hz, 1H),
4.19–4.23 (m, 2H), 4.27 (dd, J = 4.5, 11.5 Hz, 1H), 5.03 (dd,
J = 4.5, 9.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.00–7.05 (m, 2H),
7.31 (t, J = 8.0 Hz, 3H) ppm; Anal. Calcd. for C16H12F3NO3: C,
59.45; H, 3.74; N, 4.33. Found: C, 59.56; H, 3.67; N, 4.45.
Procedure for 8 from 7. To a stirred solution of (R)‐
epichlorohydrin (923 mg, 10.0 mmol) and 3‐fluoro‐4‐
morpholinyl‐phenyl isocyanate 7 (1.11 g, 5 mmol) was added
MgI2 etherate (1.5 mmol) at room temperature. After addition,
the reaction mixture was allowed to warm to 65°C and
continued to be stirred for 3.0 h. The resulting reaction mixture
was quenched with saturated Na2SO3 aqueous solution.
Extractive workup with EtOAc and flash chromatographic
purification of the crude product on silica gel gave the
compound 8 (941 mg) in 97% yield.
5‐(Chloromethyl)‐3‐(3‐fluoro‐morpholin‐4‐yl‐phenyl)
oxazolidin‐2‐one (8). This compound was obtained as white
solid; mp 117.3–118.3°C; 1H nmr: δ 3.06 (t, J = 5.0 Hz,
4H), 3.73–3.81 (m, 2H), 3.87 (t, J = 5.0 Hz, 4H), 3.91
(dd, J = 6.0, 9.0 Hz, 1H), 4.12 (t, J = 9.0 Hz, 1H),
4.84–4.89 (m, 1H), 6.94 (t, J = 9.0 Hz, 1H), 7.14 (dd, J = 2.0,
9.0 Hz, 1H), 7.44 (dd, J = 2.5, 14.5 Hz, 1H); ms: m/z 314
([M]+, 100), 316 ([M+2]+, 33), 256 (67), 177 (52), 149 (51);
HRMS (EI) calcd for C14H16ClFN2O3: 314.0833, found for
[M]+: 314.0816.
5‐Chloromethyl‐3‐(4‐methyl‐phenyl)‐oxazolidin‐2‐one
(4d) [16]. White solid; mp 100.1–101.1°C; ir: 2970, CO 1736,
1
1542 cm−1; H nmr: δ 2.33 (s, 3H), 3.72–3.80 (m, 2H), 3.94 (dd,
J = 6.0, 9.0 Hz, 1H), 4.15(t, J = 9.0 Hz, 1H), 4.83–4.87 (m, 1H),
7.19 (d, J = 8.0 Hz, 2H), 7.40–7.42 (m, 2H) ppm. Anal. Calcd.
for C11H12ClNO2: C, 58.54; H, 5.36; N, 6.21. Found: C, 58.65;
H, 5.48; N, 6.37.
5‐Chloromethyl‐3‐(2,6‐diisopropyl‐phenyl)‐oxazolidin‐
2‐one (4e). White solid; mp 90.2–91.3°C; ir: 3068, CO 1739,
1
1641, 1548, 1463 cm−1; H nmr: δ 1.24–1.28 (m, 12H), 2.93–2.98
(m, 1H), 3.01–3.07 (m, 1H), 3.76–3.86 (m, 3H), 3.90 (t, J = 9.0
Hz, 1H), 4.95–5.00 (m, 1H), 7.20–7.22 (m, 2H), 7.36 (t, J = 8.0
Hz, 1H) ppm; Anal. Calcd. for C16H22ClNO2: C, 64.97; H, 7.50;
N, 4.74. Found: C, 65.11; H, 7.62; N, 4.88.
5‐Chloromethyl‐3‐(5‐chloro‐2‐methyl‐phenyl)‐oxazolidin‐
2‐one (4f). White solid; mp 108.6–109.5 °C; ir: 2961, CO 1748,
1580, 1487 cm−1; 1H nmr: δ 2.25 (s, 3H), 3.72 (dd, J = 3.5, 12.0
Hz, 1H), 3.77 (dd, J = 6.0, 9.0 Hz, 1H), 3.82 (dd, J = 5.0, 12.0
Hz, 1H), 4.00 (t, J = 9.0 Hz, 1 H), 4.89–4.94 (m, 1 H), 7.19 (dd,
J = 8.5, 9.5 Hz, 2H), 7.23 (s, 1H) ppm; Anal. Calcd. for
C11H11Cl2NO2: C, 50.79; H, 4.26; N, 5.38. Found: C, 50.90; H,
4.37; N, 5.54.
5‐Chloromethyl‐3‐(4‐nitro‐phenyl)‐oxazolidin‐2‐one (4g)
[17].
Yellowish solid; mp 141.0–141.9 °C; ir: 2959, CO
1
1759, 1597, 1519, 1473, 1431 cm−1; H nmr: δ 3.82–3.84 (m,
2H), 4.05 (dd, J = 6.0, 9.0 Hz, 1H), 4.26 (t, J = 9.0 Hz, 1H),
4.96–5.01 (m, 1H), 7.75 (dd, J = 2.0, 7.0 Hz, 2H), 8.28 (dd, J = 2.0,
7.0 Hz, 2H) ppm.
5‐Chloromethyl‐3‐(4‐bromo‐phenyl)‐oxazolidin‐2‐one
(4h). White solid; mp 90.6–91.6°C; ir: 2960, CO 1738, 1591,
1
1490 cm−1; H nmr: δ 3.74–3.80 (m, 2H), 3.91 (dd, J = 6.0, 9.0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet