Synthesis of Bicyclo[2.2.2]octenones from 2-Methoxyphenols
1
1231, 1048 cm-1; H NMR (400 MHz, CDCl3) δ 1.18 (s, 3H),
(s, 3H), 2.14 (s, 3H), 2.33 (ddd, J ) 12.8, 10.2, 3.2 Hz, 1H),
3.04 (ddd, J ) 10.2, 6.8, 1.6 Hz, 1H), 3.28 (dd, J ) 3.2, 3.2 Hz,
1H), 3.30 (s, 3H), 3.36 (s, 3H), 3.38 (d, J ) 1.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.1, 25.2, 28.1, 46.7, 48.9, 50.2,
50.5, 56.1, 94.2, 118.0, 132.8, 198.8, 205.4; MS (70 eV) m/z (rel
intensity) 290 (63), 288 (M+ - CO, 68), 287 (15), 285 (12), 259
(18), 257 (19), 247 (53), 245 (56), 177 (33), 91 (15), 75 (100);
HRMS (EI) calcd for C13H17O479Br 316.0310, found 316.0305;
HRMS (EI) calcd for C13H17O481Br 318.0290, found 318.0438.
Anal. Calcd for C13H17O4Br: C, 49.23; H, 5.40; Found: C, 49.12;
H, 5.41.
1.19 (s, 3H), 1.94 (dd, J ) 13.5, 2.8 Hz, 1H), 2.36 (dd, J )
13.5, 3.2 Hz, 1H), 3.25 (ddd, J ) 3.2, 2.8, 2.8 Hz, 1H), 3.34 (s,
3H), 3.38 (s, 3H), 3.66 (s, 3H), 5.96 (d, J ) 2.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.4, 21.2, 36.0, 48.2, 48.8, 49.7,
50.5, 52.1, 58.0, 93.8, 122.6, 132.2, 174.9, 200.2; MS (70 eV)
m/z (rel intensity) 320 (98), 318 (M+ - CO, 100), 303 (7), 289
(19), 287 (21), 261 (52), 259 (60), 239 (59), 105 (43), 75 (42);
HRMS (EI) calcd for C13H19O479Br (M+ - CO) 318.0467, found
318.0431; HRMS (EI) calcd for C13H19O481Br 320.0447, found
320.0446. Anal. Calcd for C14H19O5Br: C, 48.43; H, 5.52.
Found: C, 48.42; H, 5.47.
(1S*,4R*,7S*)-7-Acetyl-5-br om o-3,3-d im eth oxy-1-m eth -
ylbicyclo[2.2.2]oct-5-en e-2-on e (26c). Following the general
procedure (Method C), MOB 22 generated in situ from phenol
18 was reacted with MVK and the crude product was purified
by column chromatography (EtOAc/hexanes 4:7) to give 26c
(83% yield) as a colorless solid. Mp 104-104.5 °C (from
hexanes); IR (film) 1725, 1712, 1613, 1223, 1053 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.23 (s, 3H), 1.69 (ddd, J ) 12.8, 6.8, 2.7
Hz, 1H), 2.13 (s, 3H), 2.37 (ddd, J ) 12.8, 9.7, 3.4 Hz, 1H),
2.85 (dd, J ) 9.7, 6.8 Hz, 1H), 3.33 (m, 4H), 3.37 (s, 3H), 6.01
(d, J ) 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.1, 27.8,
30.8, 48.8, 50.1, 50.6, 50.7, 53.4, 93.8, 122.2, 130.5, 199.4, 206.7;
MS (EI, 70 eV) m/z (rel intensity) 290 (33), 288 (M+ - CO,
35), 259 (13), 257 (13), 247 (100), 245 (82), 209 (13), 165 (16),
91 (36), 75 (33), 65 (15); HRMS (EI) calcd for C13H17O479Br (M+)
316.0310, found 316.0334; HRMS (EI) calcd for C13H17O481Br
318.0290, found 318.0293. Anal. Calcd for C13H17O4Br: C,
49.23; H, 5.40. Found: C, 49.05; H, 5.43.
Meth yl (1R*,2S*,4S*)-6-Br om o-8,8-d im eth oxy-5-(1,3-d i-
oxola n -2-yl)-7-oxob icyclo[2.2.2]oct -5-en e-2-ca r b oxyla t e
(28a ). Following the general procedure (Method D), MOB 24
generated in situ from phenol 20 was reacted with MA and
the crude product was crystallized from EtOAc-hexanes to
give pure 28a (94% yield) as a colorless solid. Mp 106-108 °C
(from EtOAc-hexanes); IR (film) 1735, 1714, 1642, 1450, 1202,
1
1060 cm-1; H NMR (300 MHz, CDCl3) δ 1.83 (ddd, J ) 13.2,
6.1, 2.9 Hz, 1H), 2.33 (ddd, J ) 13.2, 9.9, 2.0 Hz, 1H), 3.11
(ddd, J ) 2.0, 6.1, 9.9 Hz, 1H), 3.33 (s, 3H), 3.34 (s, 3H), 3.44
(dd, J ) 2.9, 2.9 Hz, 1H), 3.72 (s, 3H), 3.75 (d, J ) 2.0 Hz,
1H), 3.90-4.20 (m, 4H), 5.60 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 25.6, 39.4, 39.8, 49.8, 50.1, 52.3, 60.0, 65.1, 65.3, 93.2,
100.7, 116.1, 140.9, 172.1, 197.6; MS (70 eV) m/z (rel intensity)
392 (M+ + 2, 2), 390 (M+, 2), 364 (10), 362 (10), 332 (30), 299
(8), 287 (10), 251 (52), 229 (12), 199 (10), 179 (8), 149 (8), 103
(100), 73 (32), 59 (10); HRMS (EI) calcd for C15H19O779Br (M+)
390.0314, found 390.0318; HRMS (EI) calcd for C15H19O781Br
392.0294, found 392.0294. Anal. Calcd for C15H19O7Br: C,
46.05; H, 4.90. Found: C, 45.95; H, 4.90.
Meth yl (1R*,2S*,4R*)-5-Br om o-8,8-d im eth oxy-6-m eth -
yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (27a ). Fol-
lowing the general procedure (Method C), MOB 23 generated
in situ from phenol 19 was reacted with MA and the residue
was subjected to column chromatography (EtOAc/hexanes 1:3)
to give 27a (72% yield) as a colorless liquid. IR (film) 1740,
Meth yl (1R*,2S*,4S*)-6-Br om o-8,8-d im eth oxy-5-(1,3-d i-
oxola n -2-yl)-2-m eth yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r -
boxyla te (28b). Following the general procedure (Method D),
MOB 24 generated in situ from phenol 20 was reacted with
MMA and the crude product was crystallized from EtOAc-
hexanes to furnish pure 28b (95% yield) as a colorless solid.
Mp 140-142 °C (from EtOAc-hexanes); IR (film) 1741, 1730,
1713, 1646, 1266, 1059 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.87 (s, 3H), 1.92 (ddd, J ) 13.2, 6.0, 3.0 Hz, 1H), 2.32 (ddd, J
) 13.2, 10.0, 3.0 Hz, 1H), 3.11 (ddd, J ) 10.0, 6.0, 1.6 Hz, 1H),
3.27 (dd, J ) 3.0, 3.0 Hz, 1H), 3.30 (s, 3H), 3.36 (s, 3H), 3.45
(d, J ) 1.6 Hz, 1H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 19.9, 25.8, 38.7, 48.9, 50.1, 50.4, 52.2, 56.7, 94.0, 118.7, 132.5,
172.8, 198.4; MS (70 eV) m/z (rel intensity) 306 (87), 304
(M+ - CO, 100), 275 (21), 273 (25), 259 (20), 257 (22), 75 (41);
1648, 1461, 1282, 1055 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.32 (s, 3H), 1.87 (dd, J ) 13.7, 2.4 Hz, 1H), 2.40 (dd, J )
13.7, 3.5 Hz, 1H), 3.34 (s, 3H), 3.36 (s, 3H), 3.59 (s, 1H), 3.72
(s, 3H), 3.91 (dd, J ) 3.5, 2.4 Hz, 1H), 3.90-4.15 (m, 4H), 5.6
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 24.7, 32.4, 39.9, 47.5, 49.8,
49.9, 52.5, 65.2, 65.4, 66.4, 93.4, 100.8, 117.5, 140.8, 174.9,
198.8; MS (70 eV) m/z (rel intensity) 378 (10), 376 (M+ - CO,
10), 347 (10), 345 (10), 303 (8), 301 (8), 66 (40), 103 (100), 75
HRMS (EI) calcd for
C
13H17O579Br (M+) 332.0259, found
332.0367; HRMS (EI) calcd for C13H17O581Br 334.0239, found
334.0248.
(10); HRMS (EI) calcd for
C
16H21O779Br 404.0470, found
404.0478. Anal. Calcd for C16H21O7Br: C, 47.42; H, 5.22.
Found: C, 47.24; H, 5.18.
Met h yl (1R*,2S*,4R*)-5-Br om o-8,8-d im et h oxy-2,6-d i-
m eth yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (27b).
Following the general procedure (Method C), MOB 23 gener-
ated in situ from phenol 19 was reacted with MA and the
residue was purified by column chromatography (EtOAc/
hexanes 1:4) to furnish 27b (62% yield) as a colorless liquid.
(1R*,4S*,7S*)-7-Acet yl-6-b r om o-3,3-d im et h oxy-5-(1,3-
d ioxola n -2-yl)bicyclo[2.2.2]oct-5-en e-2-on e (28c). Follow-
ing the general procedure (Method D), MOB 24 generated in
situ from phenol 20 was reacted with MVK and the crude
product was crystallized from EtOAc-hexanes to give 28c
(96% yield) as a colorless solid. Mp 116-117 °C (from EtOAc-
hexanes); IR (film) 1740, 1708, 1640, 1205, 1050 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.76 (ddd, J ) 12.4, 6.4, 3.2 Hz, 1H), 2.22
(s, 3H), 2.28 (ddd, J ) 12.4, 9.0, 3.2 Hz, 1H), 3.14 (ddd, J )
9.0, 6.4, 2.0 Hz, 1H), 3.38 (s, 3H), 3.35 (s, 3H), 3.47 (dd, J )
3.2, 3.2 Hz, 1H), 3.72 (d, J ) 2.0 Hz, 1H), 3.90-4.10 (m, 4H),
5.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 24.7, 28.1, 39.4,
47.9, 49.8, 50.1, 59.4, 65.1, 65.3, 93.3, 100.7, 116.2, 140.5, 198.0,
204.4; MS (70 eV) m/z (rel intensity) 348, 346 (M+ - CO, 12),
314 (15), 303 (10), 271 (15), 223 (80), 199 (13), 192 (10), 151
(16), 119 (8), 103 (50), 89 (40), 73 (100), 59 (16); HRMS (EI)
calcd for C15H19O679Br (M+) 374.0365, found 374.0360; HRMS
(EI) calcd for C15H19O681Br 376.0345, found 376.0345. Anal.
Calcd for C15H19O6Br: C, 48.02; H, 5.10. Found: C, 47.95; H,
5.06.
IR (film) 1737, 1715, 1648, 1290, 1117 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.27 (s, 3H), 1.82 (s, 3H), 1.87 (dd, J ) 13.8,
3.0 Hz, 1H), 2.47 (dd, J ) 13.8, 3.0 Hz, 1H), 3.21 (dd, J ) 3.0,
3.0 Hz, 1H), 3.32 (s, 1H), 3.33 (s, 3H), 3.36 (s, 3H), 3.67 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 19.7, 25.2, 32.7, 46.3, 49.2,
49.9, 50.5, 52.4, 63.5, 94.1, 119.3, 134.0, 175.7, 199.7; MS (70
eV) m/ z (rel intensity) 320 (94), 318 (M+ - CO, 100), 289 (15),
287 (16), 273 (22), 271 (22), 261 (19), 259 (19), 239 (26), 229
(18), 227 (18), 105 (29), 75 (59); HRMS (EI) calcd for
C
14H19O579Br (M+) 346.0416, found 346.0407; HRMS (EI)
calcd for C14H19O581Br 348.0396, found 348.0373.
(1R*,4R*,7S*)-7-Acetyl-5-br om o-3,3-d im eth oxy-6-m eth -
ylbicyclo[2.2.2]oct-5-en -2-on e (27c). Following the general
procedure (Method C), MOB 23 generated in situ from phenol
19 was reacted with 3 with MVK and the residue was
subjected to column chromatography (EtOAc/hexanes 2:7) to
afford 27c (90% yield) as a colorless solid. Mp 126-127 °C
(from hexanes); IR (film) 1739, 1714, 1261, 1057 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.78 (ddd, J ) 12.8, 6.8, 3.2 Hz, 1H), 1.89
(1R*,8S*)-11-Br om o-4,8-d im et h yl-5-h yd r oxy-6,10,10-
t r im et h oxyt r icyclo[6.2.2.02,7]d od eca -2,4,6,11-t et r a en -9-
on e (29). A byproduct formed in the preparation of MOB 22
J . Org. Chem, Vol. 67, No. 18, 2002 6501