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R. J. DEORAZIO ET AL.
solution in Et2O, 7.70 mmol), sec-BuLi (5.90 mL of a 1.3 M solution in cyclohexane,
7.70 mmol), and 1,4-cyclohexanedione mono-ethylene ketal (1.30 g, 8.40 mmol) in
anhydrous THF (10 mL) were added sequentially at 30-min intervals. After the final
addition, the reaction mixture was allowed to warm to room temperature. The
reaction was quenched by the addition of saturated NH4Cl (20 mL). The reaction
mixture was diluted with EtOAc (200 mL), washed with saturated NaCl (100 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by
flash chromatography (silica, 1:1 hexanes=EtOAc to 1:3 hexanes=EtOAc) gave
6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-3H-benzoxazol-2-one (1.16 g, 57%) as a
1
white foam: mp 185–186 ꢁC; H NMR (300 MHz, DMSO-d6): d 11.52 (s, 1H), 7.34
(s, 1H), 7.23 (dd, J ¼ 8, 1 Hz, 1H), 7.02 (d, J ¼ 8 Hz, 1H), 4.98 (s, 1H), 3.88 (s,
4H), 1.99–1.86 (m, 4H), 1.65–1.52 (m, 4H); ESI MS m=z 292 [M þH]þ. Anal. calcd.
for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.55; H, 6.10; N, 4.85.
6-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-3H-benzothiazol-2-one
Following procedure B, bromide 2 was metallated and then condensed with
1,4-cyclohexanedione mono-ethylene ketal. Purification of the crude product by flash
chromatography (silica, 1:1 to 1:2 hexanes=EtOAc) gave the alcohol (1.81 g, 54%) as
a white foam: mp 196–197 ꢁC; 1H NMR (500 MHz, DMSO-d6): d 11.78 (s, 1H), 7.63
(s, 1H), 7.35 (d, J ¼ 8 Hz, 1H), 7.05 (d, J ¼ 8 Hz, 1H), 4.93 (s, 1H), 3.88 (s, 4H),
2.07–1.87 (m, 4H), 1.69–1.47 (m, 4H); ESI MS m=z 308 [MþH]þ. Anal. calcd. for
C15H17NO4S: C, 58.61; H, 5.57; N, 4.56. Found: C, 58.58; H, 5.64; N, 4.54.
6-(1-Benzyl-4-hydroxypiperidin-4-yl)-3H-benzoxazol-2-one
Following procedure B, bromide 1 was metallated and then condensed with
1-benzylpiperidin-4-one. Purification of the crude product by flash chromatography
1
(silica, 4:1 CH2Cl2=MeOH) gave the alcohol (6.31 g, 69%) as an off-white solid: H
NMR (300 MHz, CD3OD): d 7.40–7.25 (m, 7H), 7.02 (d, J ¼ 8 Hz, 1H), 3.62 (s, 2H),
2.80 (d, J ¼ 11 Hz, 2H), 2.58 (dt, J ¼ 12, 2 Hz, 2H), 2.11 (dt, J ¼ 13, 4 Hz, 2H), 1.73
(d, J ¼ 12 Hz, 2H); ESI MS m=z 325 [MþH]þ. Anal. calcd. for C19H20N2O3ꢃ
0.25H2O: C, 69.39; H, 6.28; N, 8.52. Found: C, 69.70; H, 6.17; N, 8.48.
6-(1-Benzyl-3-hydroxypyrrolidin-3-yl)-3H-benzoxazol-2-one
Following procedure B, bromide 1 was metallated and then condensed with
1-benzylpyrrolidin-3-one. Purification of the crude product by flash chromatography
(silica, 4:1 CH2Cl2=MeOH) gave the alcohol (1.80 g, 51%) as a pale brown solid: 1H
NMR (300 MHz, CD3OD): d 7.40–7.22 (m, 7H), 7.02 (d, J ¼ 8 Hz, 1H), 3.77 (br s,
2H), 3.07–2.76 (m, 4H), 2.35–2.25 (m, 1H), 2.19–2.11 (m, 1H); ESI MS m=z 311
[MþH]þ. Anal. calcd. for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.36; H, 5.95; N, 8.95.
REFERENCES
1. (a) Nikam, S. S.; Meltzer, L. NR2B selective NMDA receptor antagonists. Curr. Pharm.
Des. 2002, 8 (10), 845–855. (b) Kornberg, B. E.; Lewthwaite, R. A.; Manning, D.; Nikam,