Catechol Binding Site Mapping
tate formed that was collected by filtration to afford 2.93 g (64.6%)
of off-white solid that was a mixture of diastereomers; mp=161–
1638C (dec.). Diastereomers: 1H NMR (500 MHz, [D6]DMSO): d=
8.02 (bs, 1.5H), 7.94 (bs, 1.5H), 7.26–7.20 (m, 1H), 6.98–6.90 (m,
1H), 4.01 (bs, 1H), 3.77 (s, 1.5H), 3.76 (s, 1.5H), 3.66 (s, 3H), 3.34–
3.27 (m, 0.5H), 2.98–2.92 (m, 0.5H), 2.92–2.86 (m, 0.5H), 2.85–2.72
(m, 1.5H), 2.21 (dd, 0.5H, J=11.6, 17.6 Hz), 2.09 (dd, 0.5H, J=11.6,
16.9 Hz), 2.01 (bd, 0.5H, J=12.9 Hz), 1.96 (bd, 0.5H, J=12.9 Hz),
1.80–1.55 (m, 6H), 1.45–1.33 (m, 1H), 1.35–0.98 ppm (m, 6H); MS
(ESI): [M+Na]+ =342; Anal. calcd (%) for C19H30ClNO3: C 64.12, H
8.50, N 3.93, found: C 64.38, H 8.35, N 4.08.
was extracted with Et2O (3ꢂ15 mL), dried over Na2SO4, filtered, and
evaporated to yield a colorless residue from which the title com-
pound crystallized after the addition of minimal Et2O (69 mg,
24.0%). The recovered oil layer was dissolved in EtOH and evapo-
rated under reduced pressure to dryness. The residue could be
crystallized from Et2O to yield the desired product as an off-white
powder (164 mg, 57.1%); mp=174–1778C (dec.); 1H NMR
(300 MHz, [D6]DMSO): d=8.14 (bs, 3H), 6.99 (d, 1H, J=8.1 Hz),
6.85 (d, 1H, J=8.1 Hz), 6.05 (bs, 1H), 3.84 (s, 2H), 3.79 (s, 3H), 3.68
(s, 3H), 2.80 (dd, 1H, J=6.9, 15.9 Hz), 2.61–2.52 (m, 1H), 1.93 (bs,
3H), 1.70–1.48 (m, 13H); MS (ESI): [M+H]+ =354; Anal. calcd (%)
for C23H32ClNO2: C 70.84, H 8.27, N 3.59, found: C 70.48, H 8.46, N
3.66.
1-(Aminomethyl)-3-adamantyl-5,6-dimethoxy-1,2,3,4-tetrahydro-
naphthalen-1-ol hydrochloride, 31c. Following the method used
for synthesizing 31b, 30c (0.75 g, 2.2 mmol) was converted into
the title compound (0.47 g, 52.6%) as a tan powder that was a
mixture of diastereomers; mp=128–1308C (dec.). Diastereomers:
1H NMR (500 MHz, [D6]DMSO): d=7.83 (bs, 3H), 7.24 (bd, 1H, J=
8.7 Hz), 6.95 (bd, 1H, J=8.7 Hz), 5.65–5.56 (2 bs, 1H), 3.77–3.76
(2 s, 3H), 3.67–3.66 (2 s, 3H), 2.96–2.92 (m, 1H), 2.84–2.77 (m, 2H),
2.31–2.22 (m, 1H), 2.12–1.96 (m, 4H), 1.79–1.30 ppm (m, 13H); MS
(ESI): [M+H-H2O]+ =354; Anal. calcd (%) for C23H34ClNO3: C 67.71,
H 8.40, N 3.43, found: C 67.77, H 8.60, N 3.52.
(5,6-Dimethoxy-3-propyl-3,4-dihydronaphthalen-1-yl)methana-
mine hydrochloride, 32e. EtOH (25 mL), 31e (150 mg, 0.48 mmol),
and one drop of 2n ethanolic HCl were placed into a single-neck
round-bottom flask. The flask was fitted with a reflux condenser
and the solution was heated at 808C and magnetically stirred over-
night. The solvent was removed by rotary evaporation and the
white solid residue was dissolved in minimal EtOH and Et2O was
added dropwise. A small amount of a granular white solid precipi-
tated immediately and was removed by filtration. Additional Et2O
was added to the filtrate and large white crystals slowly formed
and were collected by filtration to give the title compound (82 mg,
1-(Aminomethyl)-5,6-dimethoxy-3-propyl-1,2,3,4-tetrahydro-
naphthalen-1-ol hydrochloride, 31e. In a fashion analogous to
the synthesis of 31b, 30e (1.5 g, 6.1 mmol) was converted into a
diastereomeric mixture of the title compound (1.13 g, 59.2%) as a
white powdery solid; mp=150–1528C (dec.). Diastereomers:
1H NMR (500 MHz, [D6]DMSO): d=7.90 (bs, 3H), 7.27–7.21 (m, 1H),
6.97–6.93 (m, 1H), 5.65–5.56 (2 bs, 1H), 3.78–3.77 (2 s, 3H), 3.66
(2 s, 3H), 3.25 (d, 1H, J=12.9 Hz), 2.98–2.91 (m, 2H), 2.80 (dd, 1H,
J=12.6, 19.5 Hz), 2.11–1.91 (m, 2H), 1.75–1.66 (m, 1H), 1.48–1.29
(m, 4H), 0.91 ppm (t, 3H, J=7.4 Hz); MS (ESI): [M+Na]+ =302;
Anal. calcd (%) for C16H26ClNO3: C 60.85, H 8.30, N 4.43, found: C
60.72, H 8.32, N 4.52.
1
58.2%); mp=126–1288C (dec.); H NMR (300 MHz, [D6]DMSO): d=
8.18 (bs, 3H), 7.02 (d, 1H, J=8.4 Hz), 6.87 (d, 1H, J=8.4 Hz), 5.97
(d, 1H, J=3.6 Hz), 3.81 (bs, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 2.85 (dd,
1H, J=6.0, 15.3 Hz), 2.49–2.28 (m, 2H), 1.48–1.29 (m, 4H), 0.90 (t,
3H, J=6.9 Hz); MS (ESI): [M+H]+ =262; Anal. calcd (%) for
C16H24ClNO2: C 64.53, H 8.12, N 4.70, found: C 64.14, H 8.14, N 4.80.
Cis-(3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-
yl)methanamine hydrochloride, 33b. The alkene hydrochloride
32b (0.10 g, 0.30 mmol) was dissolved in EtOH (5 mL) and placed
in an Ace hydrogenation bomb along with platinum(IV) oxide cata-
lyst (0.15 g). The vessel was pressurized to 4 atm H2 and shaken for
16 h. The solution was filtered through a pad of Celite to remove
the catalyst, and evaporated under reduced pressure to produce
the HCl salt of the desired cis saturated amine as a white solid.
This solid was crystallized from EtOH/Et2O to yield 33b (0.097 g,
97.0%) as a white crystalline powder; mp=242–2448C (dec.);
1H NMR (300 MHz, [D6]DMSO): d=7.87 (bs, 3H), 7.02 (d, 1H, J=
9.0 Hz), 6.87 (d, 1H, J=9.0 Hz), 3.75 (s, 3H), 3.56 (s, 3H), 3.41 (bd,
1H, J=10.0 Hz), 3.02 (bs, 1H), 2.91–2.75 (m, 2H), 2.21–2.14 (m, 1H),
(3-Cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalen-1-yl)me-
thanamine hydrochloride, 32b. EtOH (25 mL), 31b (2.37 g,
6.67 mmol), and two drops of 2n ethanolic HCl were placed into a
single-neck round-bottom flask. The flask was fitted with a reflux
condenser and the solution was heated at 808C and magnetically
stirred for 14 h. The solvent was removed by rotary evaporation
and the colorless oily residue dissolved in Et2O (30 mL) and allowed
to stand at room temperature, during which time the product crys-
tallized as a pale-tan solid (1.64 g, 72.9%). The solid could be re-
crystallized from EtOH as tan needles; mp=148–1528C (dec.);
1H NMR (300 MHz, CDCl3): d=8.57 (bs, 3H), 6.90 (d, 1H, J=8.7 Hz),
6.73 (d, 1H, J=8.7 Hz), 6.14 (d, 1H, J=3.9 Hz), 3.94 (bd, 1H, J=
4.8 Hz), 3.84 (s, 3H), 3.77 (s, 3H) 2.85 (dd, 1H, J=6.9, 16.0 Hz), 2.72
(dd, 1H, J=9.3, 16.0 Hz), 2.20 (bs, 1H), 1.80–1.05 ppm (m, 11H);
MS (ESI): [M+H]+ =302; Anal. calcd for C19H28ClNO2: C 67.54, H
8.35, N 4.15, found: C 67.19, H 8.31, N 4.14.
2.11–2.04 (m, 1H), 1.88–0.98 ppm (m, 13H); MS (ESI): [M+H]+
=
304; Anal. calcd (%) for C19H30ClNO2: C 67.54, H 8.35, N 4.15, found:
C 67.19, H 8.31, N 4.14.
Cis-(3-adamantyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-
yl)methanamine hydrochloride, 33c. Following the prior method
for the synthesis of 33b, 32c (120 mg, 0.308 mmol) was converted
exclusively to the cis reduced product as pale-tan crystals (118 mg,
1
97.5%); mp=184–1868C (dec.); H NMR (500 MHz, [D6]DMSO): d=
(3-Adamantyl-5,6-dimethoxy-3,4-dihydronaphthalen-1-yl)me-
thanamine hydrochloride, 32c. EtOH (25 mL), 31c (300 mg,
0.74 mmol), and two drops of 2n ethanolic HCl were placed into a
single-neck round-bottom flask. The flask was fitted with a reflux
condenser and the solution was heated at 808C and magnetically
stirred overnight. The solvent was removed by rotary evaporation
and the colorless oily residue was dissolved in Et2O (10 mL) and ex-
tracted with 2n HCl (3ꢂ10 mL). An insoluble oil formed at the in-
terface of the two layers each time, and was recovered separately.
The acidic aqueous layers were combined, washed with Et2O, and
basified with concentrated aqueous NaOH. The basified solution
7.98 (bs, 3H), 7.02 (d, 1H, J=8.6 Hz), 6.86 (d, 1H, J=8.6 Hz), 3.75
(s, 3H), 3.65 (s, 3H), 3.42 (bd, 1H, J=9.4 Hz), 3.01–2.94 (m, 1H),
2.85 (bd, 1H, J=15.9 Hz), 2.79 (dd, 1H, J=9.4, 12.0 Hz), 2.23–2.15
(m, 2H), 1.98 (bs, 3H), 1.71–1.50 (m, 12H), 1.14–1.06 (m, 1H), 0.96
(q, 1H, J=12.1 Hz); MS (ESI): [M+H]+ =356; Anal. calcd for
C23H34ClNO2: C 70.48, H 8.74, N 3.57, found: C 70.13, H 8.81, N 3.57.
Cis-(5,6-dimethoxy-3-propyl-1,2,3,4-tetrahydronaphthalen-1-yl)-
methanamine hydrochloride, 33e. Following the prior method for
the synthesis of 33b, 32e (205 mg, 0.688 mmol) was converted ex-
clusively to the cis isomer of the title compound as a white crystal-
ChemMedChem 2011, 6, 1024 – 1040
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