10.1002/ejoc.201900059
European Journal of Organic Chemistry
COMMUNICATION
2’-(4-Methoxybenzene)-(–)-trans-Δ8-tetrahydrocannabinol
(10c):
MHz, CDCl3) δ 6.29 (d, J = 2.7 Hz, 1H), 6.16 (d, J = 2.6 Hz, 1H), 5.47–5.44
(m, 1H), 4.88 (s, 1H), 2.71–2.62 (m, 1H), 2.60–2.55 (m, 3H), 2.21–2.10 (m,
1H), 1.87–1.81 (m, 3H), 1.70 (s, 3H), 1.67–1.57 (m, 2H), 1.36 (s, 3H),
1.35–1.23 (m, 4H), 1.06 (s, 3H), 0.94–0.86 (m, 3H). 13C NMR (126 MHz,
CDCl3) δ 154.94, 154.55, 143.99, 134.64, 120.13, 117.21, 109.24, 102.19,
76.35, 46.63, 38.86, 33.53, 33.47, 32.07, 31.07, 28.49, 27.59, 23.61, 22.67,
18.25, 14.22. HRMS (m/z): [M+H]+ calcd for C21H30O2: 315.23240; found:
315.23200.
Synthesized according to general procedure I from 2’-bromo-(–)-trans-Δ8-
tetrahydrocannabinol (6, 98.0 mg, 68 µmol) and potassium (4-
methoxyphenyl) trifluoroborate (25, 104 mg, 485 µmol) to afford 10c (24.0
mg, 23%) as a colorless oil. TLC (EtOAc/n-heptane, 1/9 v/v): Rf = 0.07. 1H
NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H),
6.29 (d, J = 0.6 Hz), 5.28 (m, 1H), 4.72 (s, 1H), 3.85 (s, 3H), 2.86 (td, J =
10.9, 4.8 Hz, 1H), 2.13–2.06 (m, 1H), 1.76–1.69 (m, 2H), 1.58–1.52 (m,
1H), 1.45–1.40 (m, 1H), 1.38 (s, 3H), 1.35–1.33 (m, 3H), 1.22 (s, 3H). 13
C
2’-Ortho-n-propyl-(–)-trans-Δ8-tetrahydrocannabinol
(12b):
NMR (126 MHz, CDCl3) δ 158.70, 155.14, 154.35, 143.56, 135.50, 134.66,
129.10, 118.93, 116.34, 113.89, 110.62, 102.94, 76.41, 55.37, 45.11,
36.70, 32.68, 27.99, 27.50, 23.29, 18.34. HRMS (m/z): [M+H]+ calcd for
C23H26O3: 351.19602; found: 351.19571.
Synthesized according to general procedure III from 2’-bromo-(–)-trans-
Δ8-tetrahydrocannabinol (6, 130 mg, 402 µmol) and potassium n-
propylboron trifluoride (22, 90.5 mg, 603 µmol). Silica gel column
chromatography (0→8% EtOAc/n-heptane) afforded 12b (63.9 mg, 56%)
as an inseparable mixture with 6. TLC (Toluene): Rf = 0.05. 1H NMR (500
MHz, CDCl3) δ 6.29 (d, J = 2.8Hz, 1H), 6.16 (d, J = 2.7 Hz, 1H), 5.48–5.43
(m, 1H), 4.97–4.89 (m, 1H), 2.71–2.62 (m, 1H), 2.60 (m, 1H), 2.56 (t, J =
7.9 Hz, 2H), 2.18–2.10 (m, 1H), 1.88–1.79 (m, 3H), 1.70 (s, 3H), 1.65–1.59
(m, 2H), 1.36 (s, 3H), 1.06 (s, 3H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 154.94, 154.56, 143.78, 134.65, 120.15, 117.28, 109.22,
102.24, 76.35, 46.65, 38.88, 35.62, 33.48, 28.50, 27.59, 24.54, 23.64,
18.25, 14.29. HRMS (m/z): [M+H]+ calcd for C19H26O2: 287.20110; found:
287.20130.
4’-Styrene-(–)-trans-Δ8-tetrahydrocannabinol
(11a):
Synthesized
according to general procedure II from 4’-bromo-(–)-trans-Δ8-
tetrahydrocannabinol (7, 20.0 mg, 62 µmol) and potassium (E)-styryl
trifluoroborate (21.0 mg, 99 µmol) to afford 11a (4.8 mg, 27%) as a
colorless oil. TLC (EtOAc/n-heptane, 1/9 v/v): Rf = 0.27. 1H NMR (500 MHz,
CDCl3) δ 7.49–7.45 (m, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.24 (m 1H), 7.02 (d,
J = 16.3 Hz, 1H), 6.92 (d, J = 16.3 Hz, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.44
(d, J = 1.7 Hz, 1H3’), 5.45–5.43 (m, 1H), 4.81 (s, 1H), 3.21 (dd, J = 15.9,
4.5 Hz, 1H), 2.74 (td, J = 10.8, 4.7 Hz, 1H), 2.20–2.12 (m, 1H), 1.92–1.78
(m, 3H), 1.72 (s, 3H), 1.40 (s, 3H), 1.13 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ 155.48, 155.31, 137.44, 137.04, 134.81, 128.80, 128.77, 128.21, 127.71,
126.64, 119.51, 113.30, 108.77, 105.63, 77.06, 44.99, 36.08, 31.98, 28.03,
27.71, 23.65, 18.68. HRMS (m/z): [M+H]+ calcd for C24H26O2: 347.20110;
found: 347.20105.
[9]
(–)-trans-Δ8-tetrahydrocannabinol (13a):
5-Pentylbenzene-1,3-diol
(1a, 1.18 g, 6.60 mmol) and (S)-cis-verbenol (1.00 g, 6.60 mmol) were
stirred at rt in dry DCM (70 mL). Trifluoromethanesulfonic acid (145 µL,
1.64 mmol) was added dropwise at 0 °C and the reaction was left stirring
for 2 h. To stop the reaction saturated aqueous NaHCO3 (70 mL) was
added and the mixture was extracted with DCM (2 x 70 mL). The combined
organic layers were dried over MgSO4, concentrated in vacuo and purified
through silica gel column chromatography (0→4% EtOAc/n-heptane) to
afford 1 (691 mg, 33%) as a yellow oil. TLC (EtOAc/n-heptane, 1/9 v/v): Rf
= 0.38. 1H NMR (400 MHz, CDCl3) δ 6.29 (d, J = 1.5 Hz, 1H), 6.11 (d, J =
1.5 Hz, 1H), 5.44 (d, J = 4.8 Hz, 1H), 4.93 (s, 1H) 3.22 (dd, J = 15.8, 4.2
Hz, 1H), 2.71 (td, J = 10.8, 4.6 Hz, 1H), 2.44 (td, J = 7.4, 2.0 Hz, 2H), 2.20–
2.11 (m, 1H), 1.91–1.76 (m, 3H), 1.71 (s, 3H), 1.62–1.53 (m, 2H), 1.39 (s,
3H), 1.34–1.26 (m, 4H), 1.12 (s, 3H), 0.91–0.87 (m, 3H). 13C NMR (100
MHz, CDCl3) δ 154.93, 154.92, 142.83, 134.89, 119.45, 110.70, 110.20,
107.83, 76.86, 45.05, 36.17, 35.59, 31.74, 31.72, 30.74, 28.04, 27.70,
23.63, 22.69, 18.63, 14.16. HRMS (m/z): [M+H]+ calcd for C21H30O2:
315.23240; found: 315.23343.
4’-Naphthalene-(–)-trans-Δ8-tetrahydrocannabinol (11b): Synthesized
according to general procedure II from 4’-bromo-(–)-trans-Δ8-
tetrahydrocannabinol (7, 25.0 mg, 77 µmol) and potassium (1-
naphthalene) trifluoroborate (24, 29.0 mg, 120 µmol) to afford 11b (17.1
mg, 60%) as a colorless oil. TLC (EtOAc/n-heptane, 1/9 v/v): Rf = 0.27. 1H
NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H),
7.82 (d, J = 8.1 Hz, 1H), 7.51–7.44 (m, 2H), 7.44–7.39 (m, 2H), 6.59 (d, J
= 1.7 Hz, 1H), 6.41 (d, J = 1.7 Hz, 1H), 5.49–5.47 (m, 1H), 4.98 (s, 1H),
3.30 (dd, J = 17.2, 4.7 Hz, 1H), 2.83 (td, J = 10.8, 4.8 Hz, 1H), 2.24–2.16
(m, 1H), 2.01–1.84 (m, 3H), 1.74 (s, 3H), 1.42 (s, 3H), 1.19 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 155.15, 154.85, 140.27, 139.85, 134.92, 133.90,
131.60, 128.29, 127.65, 126.69, 126.42, 126.01, 125.83, 125.44, 119.52,
112.43, 112.33, 109.44, 77.08, 45.10, 36.13, 31.95, 28.10, 27.75, 23.67,
18.76. HRMS (m/z): [M+H]+ calcd for C26H26O2: 371.20110; found:
371.20176.
(–)-Trans-Δ8-tetrahydrocannabinol (13a): Synthesized according to
general procedure III from 4’-bromo-(–)-trans-Δ8-tetrahydrocannabinol (7,
52.1 mg, 161 µmol) and potassium n-pentylboron trifluoride (23, 43.0 mg,
242 µmol) to afford 13a (17.4 mg, 34%) as a yellow oil. Spectral data were
in agreement with previously synthesized 1 and hence no further
purification was executed.
4’-(4-Methoxybenzene)-(–)-trans-Δ8-tetrahydrocannabinol
(11c):
Synthesized according to general procedure II from 4’-bromo-(–)-trans-Δ8-
tetrahydrocannabinol (7, 100 mg, 309 µmol) and potassium (4-
methoxyphenyl) trifluoroborate (25, 106 mg, 495 µmol) to afford 11c (31.0
mg, 29%) as a colorless oil. TLC (EtOAc/n-heptane, 1/9 v/v): Rf = 0.17. 1H
NMR (500 MHz, CDCl3) 7.47 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H),
6.65 (d, J = 1.7 Hz, 1H), 6.48 (d, J = 1.8 Hz, 1H), 5.45 (d, J = 5.4 Hz, 1H),
4.87 (s, 1H), 3.83 (s, 3H), 3.23 (dd, J = 16.4, 4.5 Hz, 1H), 2.76 (td, J = 10.8,
4.6 Hz, 1H), 2.21–2.09 (m, 1H), 1.89–1.80 (m, 3H), 1.72 (s, 3H), 1.41 (s,
3H), 1.14 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 158.89, 155.55, 155.39,
143.91, 135.73, 134.85, 127.91, 119.51, 114.20, 112.61, 108.76, 105.89,
77.06, 55.46, 45.03, 36.12, 31.81, 28.05, 27.73, 23.65, 18.72. HRMS
(m/z): [M+H]+ calcd for C23H26O3: 351.19602; found: 351.19740.
4’-Propyl-(–)-trans-Δ8-tetrahydrocannabinol (13b): 5-Propylbenzene-
1,3-diol (1c, 150 mg, 986 µmol) and (S)-cis-verbenol (150 g, 986 µmol)
were stirred at rt in dry DCM (20 mL). Trifluoromethanesulfonic acid (26.2
µL, 296 µmol) was added dropwise at 0 °C and the reaction was left stirring
for 3 h. To stop the reaction saturated aqueous NaHCO3 (20 mL) was
added and the mixture was extracted with DCM (2 x 40 mL). The combined
organic layers were dried over MgSO4, concentrated in vacuo and purified
through silica gel column chromatography (0→4% EtOAc/n-heptane) to
afford 2 (55.9 mg, 20%) as a yellow oil. TLC (EtOAc/n-heptane, 1/9 v/v):
Rf = 0.29. 1H NMR (400 MHz, CDCl3) δ 6.28 (d, J = 1.7 Hz, 1H), 6.10 (d, J
= 1.6 Hz, 1H), 5.45–5.41 (m, 1H), 4.82 (s, 1H), 3.25–3.15 (m, 1H), 2.71 (td,
J = 10.8, 4.6 Hz, 1H), 2.42 (td, J = 7.4, 2.4 Hz, 2H), 2.19–2.10 (m, 1H),
1.91–1.77 (m, 3H), 1.71 (s, 3H), 1.59 (t, J = 7.4 Hz, 2H), 1.38 (s, 3H), 1.11
(s, 3H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 154.94,
154.89, 142.58, 134.89, 119.46, 110.72, 110.31, 107.85, 76.83, 45.04,
Ortho-n-pentyl-(–)-trans-Δ8-tetrahydrocannabinol (12a): Synthesized
according to general procedure III from 2’-bromo-(–)-trans-Δ8-
tetrahydrocannabinol (6, 77.9 mg, 241 µmol) and potassium n-pentylboron
trifluoride (23, 64.4 mg, 362 µmol). Silica gel column chromatography
(0→8% EtOAc/n-heptane) afforded 12a (38.8 mg, 51%) as an inseparable
1
mixture with 6. TLC (EtOAc/n-heptane, 1/9 v/v): Rf = 0.23. H NMR (500
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