4404 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Singer et al.
toluene (191 mL, 0.382 mol) was added as rapidly as possible,
maintaining the mixture temperature between -40 and -50
°C. Upon complete addition the viscous red suspension was
Nor p en tyl-6′-cya n o-1′,1′-d im eth ylh exyl-∆8-tetr a h yd r o-
ca n n a bin ol (1a ). To a solution of ethyl cyanoacetate (364
mg, 0.34 mL, 3.22 mmol) in DMF (dry over sieves, 10 mL) was
added NaH (60% oil dispersion, 86 mg, 2.15 mmol), and the
solution was stirred at room temperature for 30 min. Com-
pound 8 (1.00 g, 2.15 mmol) was then added, and the reaction
was heated to 110 °C (oil bath) for 1.5 h. After the mixture
cooled, saturated NH4Cl solution (5 mL) was added, and the
DMF was removed in vacuo. The residue was partitioned
between water and EtOAc. The aqueous layer was extracted
several times with EtOAc, and the combined EtOAc extract
was washed with water and brine and then dried. After
concentration in vacuo, the residue was chromatographed
on silica gel (150 g), eluting with 10% ethyl acetate/hexanes,
to give 0.67 g (63%) of norpentyl-6′-carbethoxy-6′-cyano-
1′,1′-dimethylhexyl-∆8-tetrahydrocannabinol methoxymethyl
ether: 1H NMR δ 6.57 (d, J ) 2 Hz, 1H), 6.45 (d, J ) 2 Hz,
1H), 5.41 (br s, 1H), 5.17 (s, 2H), 4.19 (q, J ) 7 Hz, 2H), 3.49
(s, 3H), 3.41 (t, J ) 7 Hz, 1H), 3.18 (dd, J ) 4 and 17 Hz, 1H),
1.70 (br s, 3H), 1.38 (s, 3H), 1.23 (s, 6H), 1.11 (s, 3H).
The above methoxymethyl ether (200 mg, 0.40 mmol) was
dissolved in anhydrous DMSO (1 mL), H2O (0.1 mL) was
added, and the solution was heated to 140 °C for 16 h. The
solution was partitioned between H2O and CH2Cl2. The
aqueous layer was extracted several times with CH2Cl2, and
the combined CH2Cl2 extract was washed with water and brine
and then dried and evaporated in vacuo. The residue was
chromatographed on silica gel (40 g), eluting with 10% ethyl
acetate/hexanes, to give 80 mg (54%) of 1a : 1H NMR δ 6.36
(d, J ) 2 Hz, 1H), 6.22 (d, J ) 2 Hz, 1H), 5.43 (br s, 1H), 4.79
(br s, 1H, D2O exchangeable), 3.20 (dd, J ) 4 and 17 Hz, 1H),
2.26 (t, J ) 7 Hz, 2H), 1.74 (br s, 3H), 1.38 (s, 3H), 1.22 (s,
6H), 1.12 (s, 3H); HRMS calcd for C25H35NO2 (M + 1) 381.2667,
found 381.2652.
stirred vigorously for 10 min, after which
a solution of
compound 4 (20.00 g, 63.6 mmol) in dry CH2Cl2 (50 mL) was
added rapidly maintaining the temperature between -40 and
-50 °C. The mixture (bright orange) was stirred vigorously
for 2 h at -45 to -35 °C; then the temperature was allowed
to rise slowly to -10 °C over 2 h with continued stirring. The
mixture was poured onto ice/water (600 mL), and the aqueous
layer was extracted with CH2Cl2 (4 × 200 mL). The combined
CH2Cl2 extract was washed with brine (200 mL), dried, and
concentrated, and the residue was chromatographed on silica
gel (500 g), eluting with 1.5-30% ethyl acetate/hexanes, to give
13.70 g (63%) of compound 5: 1H NMR δ 7.45-7.20 (m, 2H),
7.0-6.8 (m, 3H), 6.50 (d, J ) 2 Hz, 2H), 6.30 (t, J ) 2 Hz, 1H),
3.88 (t, J ) 7 Hz, 2H), 3.79 (s, 6H), 1.9-1.6 (m, 6H), 1.28 (s,
6H).
5′-Br om o-1′,1′-d im eth yl-3,5-ben zen ed iol (6). A solution
of compound 5 (10.00 g, 30 mmol) in benzene (100 mL) was
azeotroped for 2.5 h. After the mixture cooled to 5 °C, a 1 M
solution of boron tribromide in CH2Cl2 (70 mL, 70 mmol) was
added dropwise via an addition funnel over 20 min, and the
mixture stirred overnight at 23 °C. The mixture was poured
onto ice/water (500 mL), and the aqueous layer was extracted
with ether (5 × 200 mL). The combined ether extract was
washed with 5% Na2SO3 solution (300 mL), followed by water
(2 × 300 mL) and brine (200 mL), and then dried and
concentrated in vacuo. The viscous residue was chromato-
graphed on silica gel (300 g), eluting with 20% and then with
50% ether/hexanes mixture, to yield 7.47 g (85%) of the
resorcinol 6: 1H NMR δ 6.39 (d, J ) 2 Hz, 1H), 6.19 (d, J ) 2
Hz, 1H), 5.62 (br s, 1H, D2O exchangeable), 3.31 (t, J ) 7 Hz,
2H), 1.80-1.30 (m, 6H), 1.21 (s, 6H).
5′-Br om o-1′,1′-d im eth yl-∆8-tetr a h yd r oca n n a bin ol (7a ).
It was prepared by condensing the resorcinol 6 (6.13 g, 21.3
mmol) with p-menth-2-ene-1,8-diol (5.70 g, 33.4 mmol) in the
presence of p-toluenesulfonic acid (0.13 g, 0.68 mmol) in
benzene (1.2 L) according to our previously described proce-
dure.9 The gum obtained after workup was chromatographed
on silica gel (600 g), eluting with 30% ethyl acetate/hexanes,
to yield 3.72 g (41%) of 7a : 1H NMR δ 6.38 (d, J ) 2 Hz, 1H),
6.20 (d, J ) 2 Hz, 1H), 5.42 (br s, 1H), 4.74 (br s, 1H, D2O
exchangeable), 3.32 (t, J ) 7 Hz, 2H), 3.19 (dd, J ) 4 and 17
Hz, 1H), 1.73 (br s, 3H), 1.36 (s, 3H), 1.22 (s, 6H), 1.10 (s, 3H).
5′-Cya n o-1′,1′-d im eth yl-∆8-tetr a h yd r oca n n a bin ol (1b).
To a warm solution (50 °C) of 7a (2.90 g, 6.8 mmol) in DMSO
(55 mL) was added NaCN (1.20 g, 24.5 mmol), and the mixture
stirred at 50 °C for 3 h. The solvent was removed in vacuo,
and the residue was treated with water and extracted with
ether. The combined ether extract was washed with brine,
dried, and concentrated, and the residue was chromatographed
on silica gel (80 g). Elution with 30% ether/hexanes gave 1.90
g (76%) of 1b: 1H NMR δ 6.38 (d, J ) 2 Hz, 1H), 6.21 (d, J )
2 Hz, 1H), 5.45 (br s, 1H), 4.75 (s, 1H, D2O exchangeable),
3.35-3.05 (m, 1H), 2.25 (t, J ) 8.2 Hz, 2H), 1.70 (br s, 3H),
1.36 (s, 3H), 1.24 (s, 6H), 1.12 (s, 3H). Anal. (C24H33NO2) C,
H, N.
5′-Br om o-1′,1′-dim eth yl-∆8-tetr ah ydr ocan n abin ol Meth -
oxym eth yl Eth er (8). To a stirred solution of 7a (1.05 g, 2.37
mmol) in anhydrous CH3CN (10 mL) was added K2CO3 (200
mesh, 1.30 g. 9.4 mmol), and the mixture was cooled to 0 °C
for 20 min. Chloromethylmethyl ether (0.72 mL, 9.46 mmol)
was added, and the reaction mixture was allowed to stir
overnight at 23 °C. The mixture was added to water (50 mL)
and extracted with several portions of ether. The combined
ether extract was washed with water, followed by brine, then
dried, and concentrated in vacuo to give a viscous oil which
was chromatographed on silica gel (100 g). On elution with
2.5% ethyl acetate/hexanes it gave 0.87 g (79%) of 8: 1H NMR
δ 6.57 (d, J ) 2 Hz, 1H), 6.45 (d, J ) 2 Hz, 1H), 5.41 (br s,
1H), 5.18 (s, 2H), 3.50 (s, 3H), 3.33 (t, J ) 7 Hz, 2H), 3.19 (dd,
J ) 4 and 17 Hz, 1H), 1.76 (br s, 3H), 1.38 (s, 3H), 1.24 (s,
6H), 1.10 (s, 3H).
Nor p en t yl-6′-cya n o-1′,1′-d im et h yl-6′-p h en ylh exyl-∆8-
tetr a h yd r oca n n a bin ol (1c). To a solution of benzyl cyanide
(59.6 mg, 0.51 mmol) in anhydrous THF (3 mL) at 0 °C was
added dropwise 1.7 M BuLi in hexanes (0.3 mL, 0.51 mmol),
and the mixture stirred for 15 min. This was added via a
cannula to a solution of compound 8 (250 mg, 0.53 mmol) and
lithium iodide (71 mg, 0.53 mmol) in anhydrous THF (3 mL).
After the mixture stirred at room temperature for 1 h,
saturated NH4Cl (2 mL) was added to quench the reaction and
the solvents were removed in vacuo. The residue was parti-
tioned between EtOAc and water, and the aqueous layer was
extracted several times with EtOAc. The combined EtOAc
extract was washed with water and then with brine and dried.
After concentration in vacuo the residue was chromatographed
on silica gel (40 g), eluting with 5% ethyl acetate/hexanes, to
yield 190 mg (75%) of 6′-cyano-1′,1′- dimethyl-6′-phenylhexyl-
∆8-tetrahydrocannabinol methoxymethyl ether: 1H NMR δ
7.32 (br s, 5H), 6.55 (d, J ) 2 Hz, 1H), 6.43 (s, J ) 2 Hz, 1H),
5.41 (br s, 1H), 5.15 (s, 2H), 3.71 (t, J ) 7 Hz, 1H), 3.51 (s,
3H), 3.18 (dd, J ) 4 and 17 Hz, 1H), 1.70 (br s, 1H), 1.37 (s,
3H), 1.21 (s, 6H), 1.10 (s, 1H).
The above compound (130 mg, 0.26 mmol) was then depro-
tected with trimethylsilyl bromide (130 mg, 0.26 mmol) using
the same procedure as described above and gave 61 mg (50%)
of compound 1c: 1H NMR δ 7.32 (br s, 5H), 6.37 (d, J ) 2 Hz,
1H), 6.21 (d, J ) 2 Hz, 1H), 5.41 (br s, 1H), 4.79 (br s, 1H,
D2O exchangeable), 3.71 (t, J ) 7 Hz, 1H), 3.19 (dd, J ) 4 and
17 Hz, 1H),1.72 (br s, 3H), 1.36 (s, 3H), 1.25 (s, 6H), 1.12 (s,
3H). Anal. (C31H39NO2‚H2O) C, H, N.
5′-(p-Cya n op h en oxy)-1′,1′-d im eth yl-∆8-tetr a h yd r oca n -
n a bin ol (1e). To a solution of 8 (350 mg, 0.75 mmol) in
anhydrous CH3CN (5 mL) was added K2CO3 (200 mesh, 456
mg, 3.31 mmol) followed by p-cyanophenol (98 mg, 0.82 mmol),
and the reaction was heated to 60 °C overnight. After the
mixture cooled, water (50 mL) was added, and the aqueous
mixture was extracted with several portions of ether. The
combined ether extract was washed with water followed by
brine, then dried, and concentrated. The resulting viscous oil
was chromatographed on silica gel (40 g), eluting with 8% ethyl
acetate/hexanes, to give 337 mg (89%) of 5′-(p-cyanophenoxy)-