J. W. Huffman et al. / Bioorg. Med. Chem. 18 (2010) 7809–7815
7813
(petroleum ether), 0.30 g (71%) of 3-(10,10-dimethylheptyl)-
D
8-tetr-
22 after flash chromatography (petroleum ether/ether, 9:1): 1H
NMR (500 MHz, CDCl3) d 0.82 (t, J = 7.0 Hz, 3H), 1.03–1.13 (m,
2H), 1.15 (s, 3H), 1.16–1.22 (m, 6H), 1.24 (s, 3H), 1.33 (s, 6H),
1.35 (s, 6H), 1.41 (s, 3H), 1.51–1.53 (m, 3H), 1.69, (s, 3H), 2.10–
2.18 (m, 2H), 2.62 (td, J = 4.9, 10.7 Hz, 1H), 2.97 (dd, J = 4.0,
17.0 Hz, 1H), 5.44 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 7.21
(d, J = 2.0 Hz, 1H); 13C NMR (125.8 MHz) d 14.2, 18.5, 22.5, 23.1,
27.4, 28.0, 28.6, 28.9, 31.8, 32.4, 37.6, 40.1, 44.6, 45.1, 76.1, 83.2,
117.6, 119.8, 125.1, 127.9, 134.4, 148.5, 152.4; MS (EI) m/z (rel
intensity) 368 (20), 369 (75), 395 (100), 452 (80).
ahydrocannabinyl trifluoromethanesulfonate as a viscous yellow
oil: 1H NMR (500 MHz, CDCl3) d 0.84 (t, J = 7.1 Hz, 3H), 0.99–1.08
(m, 2H), 1.13 (s, 3H), 1.15–1.22 (m, 6H), 1.23 (s, 3H), 1.24 (s, 3H),
1.40 (s, 3H), 1.49–1.55 (m, 2H), 1.71 (s, 3H), 1.78 (td, J = 4.1,
11.3 Hz, 1H), 1.81–1.95 (m, 2H), 2.13–2.20 (m, 1H), 2.84 (td,
J = 4.8, 10.9 Hz, 1H), 2.93 (dd, J = 4.1, 16.5 Hz, 1H), 5.44 (d,
J = 4.2 Hz, 1H), 6.71 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H); 13C
NMR (125.8 MHz, CDCl3) d 14.0, 18.3, 22.6, 23.3, 24.5, 27.3, 27.6,
28.4, 28.6, 29.8, 31.6, 31.7, 35.6, 37.7, 44.2, 44.6, 77.5, 111.4,
115.4, 116.5, 118.6 (q, JC,F = 320 Hz), 119.4, 133.9, 148.6, 150.9,
154.8; GC/MS (EI) m/z (rel intensity) 502 (69), 487 (6), 459 (17),
446 (7), 434 (5), 419 (50), 418 (41), 417 (100), 349 (20), 285 (16),
201 (9), 121 (11).
4.10. 1-Deoxy-3-(10,10-dimethylhexyl)-D8
-
tetrahydrocannabinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(23)
4.7. 1-Deoxy-
1,3,2-dioxaborolane (27)
D
8-tetrahydrocannabinyl-4,4,5,5-tetramethyl-
Dioxaborolane 23 was prepared using the procedure employed
for the synthesis of
1,3,2-dioxaborolane (27). From 0.36 g (0.74 mmol) of 3-(10,10-dim-
ethylhexyl)-
8-tetrahydrocannabinyl trifluoromethanesulfonate
D
8-tetrahydrocannabinyl-4,4,5,5-tetramethyl-
To a suspension of 0.20 g (0.448 mmol) of
D
8-tetrahydrocanna-
D
binyl trifluoromethanesulfonate and 0.010 g (0.0135 mmol) of
10,100-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex in 15 mL of acetonitrile under argon
was slowly added 1.41 g (13.5 mmol) of triethylamine and the
reaction was stirred at reflux overnight. The mixture was cooled
to 0 °C, quenched by the addition of 10 mL of 1 M HCl, diluted with
diethyl ether, washed with brine, dried (MgSO4), and concentrated
in vacuo. The resultant red oil was purified by flash chromatogra-
phy (petroleum ether/ether, 8:2) to give 0.12 g (65%) of 1-deoxy-
there was obtained, after 4 h at reflux, 0.26 g (76%) of 24 as a yellow
oil: 1H NMR (500 MHz, CDCl3) d 0.82 (t, J = 7.3 Hz, 3H), 1.09 (sextet,
J = 7.3 Hz, 2H), 1.15 (s, 3H), 1.16–1.23 (m, 4H), 1.24 (s, 3H), 1.25 (s,
3H), 1.35 (s, 6H), 1.36 (s, 6H), 1.39 (s, 3H), 1.51–1.58 (m, 2H), 1.68 (s,
3H), 1.74 (td, J = 4.3, 11.6 Hz, 1H), 1.82–1.93 (m, 2H), 2.10–2.19 (m,
1H), 2.60 (dd, J = 4.3, 14.9 Hz, 1H), 2.99 (td, J = 4.9, 11.1 Hz, 1H), 5.44
(d, J = 3.7 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H); 13
C
NMR (125.8 MHz, CDCl3) d 14.1, 18.5, 22.5, 23.2, 24.3, 24.5, 25.2,
27.6, 28.1, 28.6, 29.0, 32.6, 33.4, 37.2, 40.4, 44.3, 45.4, 76.1, 83.4,
117.8, 120.0, 125.3, 128.1, 134.5, 148.5, 152.6; GC/MS (EI) m/z (rel
intensity) 468 (6), 467 (33), 466 (100), 465 (25), 395 (71), 383
(32), 323 (9), 311 (6), 101 (8), 83 (13), 71 (8), 57 (14).
D
8-tetrahydrocannabinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(27): 1H NMR (500 MHz, CDCl3) d 0.91 (t, J = 7.0 Hz, 3H), 1.13 (s,
3H), 1.28–1.33 (m, 4H), 1.34 (s, 3H), 1.36 (s, 6H), 1.38 (s, 6H),
1.41 (s, 3H), 1.58–1.64 (m, 2H), 1.69 (s, 3H), 1.73–1.93 (m, 2H),
2.11–2.22 (m, 1H), 2.53 (t, J = 7.0 Hz, 1H), 2.98 (dt, J = 4.0,
17.0 Hz, 1H), 5.41 (d, J = 3.0 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 7.11
(d, J = 2.0 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) d 14.0, 18.5, 22.6,
23.2, 24.1, 24.7, 25.1, 27.6, 28.2, 29.7, 30.9, 31.7, 33.5,35.4, 40.5,
45.5, 83.5, 119.9, 120.0, 128.1, 128.6, 134.5, 141.4, 152.9; MS (EI)
m/z (rel intensity) 281 (65), 341 (100), 424 (80).
4.11. 1-Deoxy-3-(10,10-dimethylheptyl)-D8
-
tetrahydrocannabinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(24)
Dioxaborolane 24 was prepared using the procedure employed
for the synthesis of dioxaborolane 27. From and 0.29 g (0.58 mmol)
of 3-(10,10-dimethylheptyl)- 8-tetrahydrocannabinyl trifluoro-
D
4.8. 1-Deoxy-3-(10,10-dimethylbutyl)-
D
8-tetrahydrocannabinyl-
methanesulfonate there was obtained, after 4 h at reflux 0.21 g
(76%) of 24 as a yellow oil: 1H NMR (500 MHz, CDCl3) d 0.84 (t,
J = 6.9 Hz, 3H), 1.02–1.12 (m, 2H), 1.15 (s, 3H), 1.16–1.23 (m, 6H),
1.24 (s, 3H), 1.25 (s, 3H), 1.35 (s, 6H), 1.36 (s, 6H), 1.39 (s, 3H),
1.52–1.58 (m, 2H), 1.68 (s, 3H), 1.74 (td, J = 4.4, 11.6 Hz, 1H),
1.82–1.93 (m, 2H), 2.10–2.19 (m, 1H), 2.60 (dd, J = 4.4, 14.9 Hz,
1H), 2.99 (td, J = 4.8, 11.1 Hz, 1H), 5.44 (d, J = 3.7 Hz, 1H, 1H),
6.82 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 14.1, 18.5, 22.7, 23.2, 24.5, 24.6, 25.2, 27.6,
28.1, 28.6, 29.0, 30.0, 31.8, 33.4, 37.2, 40.4, 44.4, 45.4, 76.1, 83.4,
117.8, 120.0, 125.3, 128.1, 134.5, 148.5, 152.6; GC/MS (EI) m/z
(rel intensity) 482 (6), 481 (35), 480 (100), 479 (23), 395 (93),
337 (16), 327 (10), 311 (10), 211 (4), 101 (10), 83 (16), 71 (10).
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21)
Dioxaborolane 21 was prepared using the procedure described
for dioxaborolane 27. From 0.37 g (0.80 mmol) of 3-(10,1’-dim-
ethylbutyl)-D
8-tetrahydrocannabinyl trifluoromethanesulfonate
there was obtained, after 4 h at reflux 0.22 g (62%) of 21 as a yellow
oil: 1H NMR (500 MHz, CDCl3) d 0.81 (t, J = 7.3 Hz, 3H), 1.05–1.14
(m, 2H), 1.15 (s, 3H), 1.25 (s, 6H), 1.35 (s, 6H), 1.36 (s, 6H), 1.39
(s, 3H), 1.50–1.57 (m, 2H), 1.68 (s, 3H), 1.74 (td, J = 4.4, 11.4 Hz,
1H), 1.82–1.93 (m, 2H), 2.10–2.19 (m, 1H), 2.60 (dd, J = 3.9,
14.9 Hz, 1H), 2.98 (td, J = 4.7, 11.0 Hz, 1H), 5.44 (d, J = 3.2 Hz, 1H),
6.83 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H); 13C NMR
(125.8 MHz, CDCl3) d 14.8, 18.0, 18.5, 23.2, 24.5, 25.2, 27.6, 28.1,
28.6, 28.9, 33.4, 37.3, 40.4, 45.4, 46.9, 76.1, 83.4, 117.8, 120.0,
125.3, 128.1, 134.5, 148.4, 152.6; GC/MS (EI) m/z (rel intensity)
438 (90), 397 (8), 396 (47), 395 (100), 394 (20), 355 (68), 327
(23), 311 (15), 295 (31), 281 (16), 207 (89), 191 (12), 133 (10),
119 (11), 101 (22), 85 (34).
4.12. 1-Bromo-1-deoxy-D
8-tetrahydrocannabinol (25, JWH-460)
To a solution of 0.20 g (0.472 mmol) of dioxaborolane 27 sus-
pended in 20 mL of H2O was added 73 mL of MeOH, followed by
0.34 g (1.52 mmol) of copper(II) bromide in 5 mL of H2O. The solu-
tion was heated at reflux for 10 h and concentrated in vacuo. The
solution was cooled to ambient temperature, diluted with ether,
washed with brine, dried (MgSO4), and concentrated in vacuo.
The resultant yellow oil was purified by flash chromatography
(petroleum ether/ether, 8:2) to give 0.13 g (75%) of 1-bromo-1-
4.9. 1-Deoxy-3-(10,10-dimethylpenty)- 8-tetrahydrocannabinyl-
D
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22)
Dioxaborolane 22 was prepared by the procedure employed for
the synthesis of dioxaborolane 27. From 0.21 g (0.421 mmol) of 3-
deoxy-D
8-tetrahydrocannabinol (25) as a colorless oil: 1H NMR
(500 MHz, CDCl3) d 0.91 (t, J = 7.0 Hz, 3H), 1.12 (s, 3H), 1.28–1.34
(10,10-dimethylpentyl)-
D
8-tetrahydrocannabinyl trifluoromethane-
sulfonate there was obtained 0.151 g (78%) of pure dioxaborolane
(m, 4H), 1.35 (s, 3H), 1.64 (s, 3H), 1.81–1.92 (m, 3H), 2.09–2.21