Journal of Medicinal Chemistry
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reaction mixture quenched with 70 mL of water. The precipitate was
collected by vacuum filtration, washed well with water, and
recrystallized from 80% aqueous ethanol in 51−65% yields.
3′-Carbamoyl-[1,1′-biphenyl]-3-yl Cyclohexylcarbamate (2). Ob-
tained as a white solid in 51% yield; mp 186−190 °C (lit.24 178 °C).
1H NMR (CD3OD): δ ppm 1.16−1.45 (m, 5H), 1.59−1.71 (m, 1H),
1.75−1.85 (m, 2H), 1.90−2.02 (m, 2H), 3.39−3.50 (m, 1H), 7.12 (d, J
= 7.02 Hz, 1H), 7.39−7.43 (m, 1H), 7.46 (t, J = 7.80 Hz, 1H), 7.51−
7.58 (m, 2H), 7.78−7.89 (m, 2H), 8.14 (s, 1H). 13C NMR (DMSO-
d6): δ ppm 26.32, 26.77, 34.17, 51, 121.69, 122.29, 125.04, 127.40,
128.05, 130.35, 131.0, 131.56, 135.78, 142.04, 143.07, 153.41, 156.52,
172.30. HRMS (ESI+) m/z calcd for [m + H]+ C20H23N2O3, 339.1705;
found, 339.1703.
1.50−1.62 (m, 2 H), 3.16−3.38 (m, 2 H), 5.00 (br s, 1 H), 5.33 (br s,
1 H), 6.89−6.94 (m, 1 H), 6.97−7.04 (m, 2 H), 7.35−7.52 (m, 5 H).
13C NMR (CDCl3): δ ppm 13.99, 22.53, 26.40, 29.78, 31.43, 41.31,
116.37, 122.05, 123.07, 127.96, 128.55, 129.02, 129.16,136.53, 144.43,
149.85, 155.05. HRMS (ESI+) m/z calcd for [m + H]+ C19H24NO3,
314.17562; found, 314.17561.
6-Hydroxy-[1,1′-biphenyl]-3-yl (1-Methylpiperidin-4-yl)-
carbamate (9). Obtained as a light-brown powder in 34% yield: mp
1
174−175 °C (dec.). H NMR (CDCl3): δ ppm 1.49−1.64 (m, 2H),
1.97−2.04 (m, 2H), 2.08−2.16 (m, 2H), 2.28 (s, 3H), 2.79 (d, J =
11.74 Hz, 2H), 3.50−3.66 (m, 1H), 4.92 (d, J = 7.82 Hz, 1H), 6.89−
6.95 (m, 1H), 6.97−7.04 (m, 2H), 7.36−7.51 (m, 5H). 13C NMR
(CDCl3): δ ppm 14.24, 32.35, 46.14, 54.32, 116.53, 122.05, 123.15,
128.00, 129.10, 129.18, 131.05, 136.67, 144.39, 155.10, 158.94. HRMS
(ESI+) m/z calcd for [m + H]+ C19H23N2O3, 327.17087; found,
327.17219.
3-(4,5-Dihydrooxazol-2-yl)phenyl Cyclohexylcarbamate (6). Ob-
tained as a white solid in 60% yield; mp 151−155 °C (lit.12c 151−152
12c
1
°C). H NMR was in agreement with the literature.
3-(4,5-Dihydrooxazol-2-yl)phenyl (1-Methylpiperidin-4-yl)-
carbamate (10). To a stirred solution of 13 (500 mg, 3.1 mmol)
and DIPEA (535 μL, 3.1 mmol) in 5:1 v/v CH3CN:DMSO (12 mL)
at ambient temperature under N2 was added 4-nitrophenylchlor-
oformate (617 mg, 3.1 mmol) as a solid. After 30 min, 4-amino-N-
methylpiperidine (385 μL, 3.1 mmol) was added dropwise. After 1 h,
the reaction was concentrated in vacuo and the residue was partitioned
between saturated aqueous sodium bicarbonate (15 mL) and
chloroform (15 mL). The aqueous layer was extracted twice with
chloroform (15 mL), and the combined organic layers were dried
(MgSO4) and filtered and the solvent was removed. The yellow
residue was recrystallized from ethyl acetate:hexane to give a white
3-(4,5-Dihydrooxazol-2-yl)phenyl Cyclopentylcarbamate (7). Ob-
tained as a white solid in 65% yield; mp 168−171 °C (lit.12c 166−168
12c
1
°C). H NMR was in agreement with the literature.
3-(4,5-Dihydrooxazol-2-yl)phenyl Hexylcarbamate (8). Obtained
as a white solid in 64% yield; mp 94−97 °C. 1H NMR (DMSO-d6): δ
ppm 0.83−0.93 (m, 3 H), 1.21−1.35 (m, 6 H), 1.40−1.53 (m, 2 H),
3.0−3.10 (m, 2 H), 3.96 (t, J = 9.36 Hz, 2 H), 4.41 (t, J = 9.56 Hz, 2
H), 7.24−7.30 (m, 1 H), 7.47 (t, J = 7.80 Hz, 1 H), 7.52−7.56 (m, 1
H), 7.66−7.72 (m, 1 H), 7.82 (t, J = 5.66 Hz, 1 H). 13C NMR
(DMSO-d6): δ ppm 14.35, 22.49, 26.34, 29.55, 31.38, 40.92, 54.89,
67.97, 121.26, 124.56, 125.07, 129.06, 130.12, 151.52, 154.45, 162.75.
HRMS (ESI+) m/z calcd for [m + H]+ C16H23N2O3, 291.17087;
found, 291.17128.
1
solid (360 mg, 39%): mp 129−130 °C. H NMR (CDCl3): δ ppm
1.58 (m, 2H), 2.42 (m, 4H), 2.29 (s, 3H), 2.79 (d, J = 11.6 Hz, 2H),
3.58 (m, 1H), 4.06 (t, J = 9.5 Hz, 2H), 4.43 (t, J = 9.6 Hz, 2H), 4.96
(d, J = 7.3 Hz, 1H), 7.24 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.70 (t, J =
1.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H). 13C NMR (CDCl3): δ ppm
32.4, 46.2, 48.0, 59.3, 60.0, 67.7, 121.5, 124.6, 125.0, 129.1, 129.3,
150.9, 153.4, 163.9. HRMS (ESI+) m/z calcd for [m + H]+
C16H22N3O3, 304.16612; found, 304.16655.
General Procedure for Synthesis of Carbamates 3−5, 9. A
mixture of 14 (1.0 g, 3.62 mmol) in toluene (30 mL) and 5N aq
NaOH (30 mL) was stirred at 0 °C and 10 mL of 20% phosgene in
toluene added (CAUTION! Work in well ventilated fume hood with
protective clothing and gloves). The ice-bath was removed and stirring
continued at ambient temperature for 30 min. The aqueous layer was
discarded and the toluene layer washed with 1N aq and HCl, dried
(MgSO4), and about 70% of the toluene removed on the rotary
evaporator at 40 °C. The remainder (about 10 mL) containing the
phenylchloroformate of 14 was stored at −15 °C until required. A
solution of the appropriate amine (0.4 mmol) in acetonitrile (1 mL)
was added to 1 mL of the phenylchloroformate solution followed by
triethylamine (TEA) (150 μL). After 30 min of stirring, 10 mL of 10%
aq HCl was added. The mixture was extracted twice with EtOAc, the
combined organics evaporated, and the residue taken up in MeOH (5
mL) and treated with 10%Pd/C and 1g of ammonium formate. This
mixture was heated to reflux for 15 min, cooled, and filtered through a
small pad of diatomaceous earth. Dilution of the filtrate with water
(100 mL) precipitated crude product, which was collected by vacuum
filtration, dried in vacuo, and recrystallized from ethylacetate/hexane.
6-Hydroxy-[1,1′-biphenyl]-3-yl Cyclopentylcarbamate (3). Ob-
tained as a white solid in 67% yield (from cyclopentylamine); mp
82−86 °C. 1H NMR (CDCl3): δ ppm 1.42−1.54 (m, 2H), 1.56−1.77
(m, 4H), 1.96−2.07 (m, 2H), 4.00−4.11 (m, 1H), 4.95 (d, J = 6.63
Hz, 1H), 6.87−6.92 (m, 1H), 6.96−7.00 (m, 1H), 7.00−7.02 (m, 1H),
7.38 (dq, J = 8.50, 4.31 Hz, 1H), 7.43−7.49 (m, 4H). 13C NMR
(CDCl3): δ ppm 23.77, 33.41, 58.81, 116.61, 122.30, 123.33, 128.18,
128.79, 129.27, 129.37, 136.81, 144.63, 150.09. 163.44. HRMS (ESI+)
m/z calcd for [m + H]+ C18H20NO3;, 298.14432; found, 298.14427.
6-Hydroxy-[1,1′-biphenyl]-3-yl Cyclobutylcarbamate (4). Ob-
tained as a white solid in 42% yield (from cylobutylamine): mp
[1,1′-Biphenyl]-3-yl (1-Methylpiperidin-4-yl)carbamate (11).
To a stirred solution of 15 (500 mg, 2.9 mmol) and DIPEA (511 μL,
2.9 mmol) in DCM (12 mL) under N2 at ambient temperature was
added 4-nitrophenylchloroformate (592 mg, 2.9 mmol) as a solid.
After 30 min, 4-amino-N-methylpiperidine (366 μL, 2.9 mmol) was
added dropwise. After 1 h, the reaction was concentrated in vacuo and
the residue was partitioned between saturated aqueous sodium
bicarbonate (15 mL) and chloroform (15 mL). The aqueous layer
was extracted twice with chloroform (15 mL), the combined organic
layers were dried (MgSO4) and filtered, and the solvent was removed.
The yellow residue was recrystallized from EtOAc:hexane to give a
1
white solid (298 mg, 33%): mp 132−134 °C. H NMR (CDCl3): δ
ppm 1.60 (m, 2H), 2.07 (m, 4H), 2.30 (s, 3H), 2.81 (d, J = 11.0 Hz,
2H), 3.61 (m, 1H), 4.97 (d, J = 6.6 Hz, 1H), 7.11 (m, 1H), 7.37 (m,
5H), 7.56 (m, 2H). 13C NMR (CDCl3): 32.0, 45.8, 47.8, 54.2, 120.4,
124.1, 127.0, 127.2, 127.6, 128.8, 129.6, 140.3, 142.7, 151.3, 153.8.
HRMS (ESI+) m/z calcd for [m + H]+ C19H23N2O2, 311.175695;
found, 311.17565.
6-(Benzyloxy)-[1,1′-biphenyl]-3-ol (14). To a stirred mixture of
1,1′-[biphenyl]-2,5-diol (10g, 0.054 mol) and K2CO3 (22.3g, 0.16
mol) in DMF (150 mL) at 50−60 °C was added benzyl bromide (6.42
mL, 0.053 mol) dropwise over 1 h. After 2 h, solids were filtered off,
the DMF removed on a rotary evaporator, and the residue purified by
flash chromatography (DCM:hexane (2/1)) to yield 17 (RF 0.88, 5.5
g, 28%), 16 (RF 0.39, 2.23 g, 15%), and the desired 14 (RF 0.15, 2.07 g,
1
140−142 °C. H NMR (CD3OD): δ ppm 1.62−1.78 (m, 2H), 1.94−
1
2.09 (m, 2H), 2.22−2.35 (m, 2H), 4.04−4.18 (m, 1H), 6.85−6.87 (m,
2H), 6.95 (d, J = 3.12 Hz, 1H), 7.25−7.31 (m, 1H), 7.37 (t, J = 7.41
Hz, 2H), 7.50−7.57 (m, 2H). 13C NMR (DMSO-d6): δ ppm 15.78,
31.68, 47.73, 117.40, 122.58, 124.72, 128.10, 129.19, 130.46, 130.58,
139.68, 145.47, 152.92, 156.85. HRMS (ESI+) m/z calcd for [m + H]+
C17H18NO3, 284.1273; found, 284.1281.
14%).%): mp 123−126 °C. H NMR (CDCl3): δ ppm 4.87 (s, 1H),
4.94 (s, 2H), 6.73 (dd, J = 8.79, 3.09 Hz, 1H), 6.84 (d, J = 3.09 Hz,
1H), 6.91 (d, J = 8.79 Hz, 1H), 7.21−7.46 (m, 7H), 7.53−7.61 (m,
1
2H). H NMR (DMSO-d6) d ppm 4.97 (s, 2H) 6.70−6.76 (m, 2H)
7.01 (d, J = 8.52 Hz, 1H) 7.24−7.35 (m, 5H) 7.36−7.43 (m, 2H)
7.48−7.54 (m, 2H) 9.11 (s, 1H). 13C NMR (CDCl3): δ ppm 71.29,
115.39, 116.09, 117.78, 127.55, 127.88, 128.18, 128.61, 128.93, 129.86,
132.10, 138.18, 138.95, 148.70, 152.32. HRMS (ESI+) m/z calcd for
[m + H]+ C19H17O2, 277.12285; found, 277.12226.
6-Hydroxy-[1,1′-biphenyl]-3-yl Hexylcarbamate (5). Obtained as
an off-white solid in 55% yield (from hexylamine): mp 144−148 °C.
1H NMR (CDCl3): δ ppm 0.85−0.95 (m, 3 H), 1.28−1.41 (m, 6 H),
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dx.doi.org/10.1021/jm301492y | J. Med. Chem. 2013, 56, 201−209