B. V. L. Potter et al.
MED
H2O (100 mL) and extracted with EtOAc (2ꢁ60 mL). The combined
organic layers were washed with H2O (4ꢁ50 mL) and brine
(60 mL), dried (MgSO4), and the solvent was removed in vacuo. The
crude product was purified by recrystallisation twice from toluene
to give the title compound as a cream crystalline solid (4.23 g,
68%); mp: 98.5–1008C [lit. 988C][55]).
(C), 130.0 (CH), 129.9 (2ꢁCH), 129.8 (C), 128.6 (2ꢁCH), 128.0 (2ꢁ
CH), 127.9 (CH), 127.5 (2ꢁCH), 127.2 (C), 114.5 (CH), 113.0 (CH),
74.5 (CH2), 70.0 (CH2), 34.2 (CH), 31.2 (CH2), 28.5 (CH2), 25.4 (CH2),
21.7 ppm (CH3); MS (FAB): m/z (%): 422.2 (70) [M+H]+, 251.2 (75),
91.1 (100); HRMS-FAB: m/z [M]+ calcd for C25H26O4S: 422.1552,
found: 422.1564.
6-(Benzyloxy)-2-(hydroxymethylene)-3,4-dihydronaphthalen-
1(2H)-one (11). KOtBu (2.24 g, 0.02 mol) was added in small por-
tions to a cooled (ꢀ788C) solution of 10 (2.52 g, 0.01 mol) and
ethyl formate (1.48 g, 0.02 mol) in toluene (40 mL). The reaction
mixture was allowed to warm to room temperature and stirred for
2 h. Aqueous HCl (1.5m, 50 mL) was cautiously added, and the
mixture was extracted with Et2O (2ꢁ30 mL). The combined organ-
ics were washed with brine (70 mL), dried (MgSO4), and the solvent
was removed in vacuo. The crude product was purified using
Flashmaster II (EtOAc/hexane) to give the title compound as a
(ꢁ)-4-({[6-(Benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]me-
thyl}(4H-1,2,4-triazol-4-yl)amino)benzonitrile (14). Compound 8
(0.61 g, 3.30 mmol) was added in small portions to a cooled (08C)
suspension of NaH (60% in mineral oil, 0.16 g, 3.98 mmol) in DMF
(15 mL). The resulting solution was allowed to warm to room tem-
perature, and after 30 min, 13 (0.70 g, 1.66 mmol) was added, and
the reaction mixture was stirred overnight. The reaction mixture
was poured onto H2O (40 mL) and extracted with EtOAc (2ꢁ
30 mL). The combined organic layers were washed with H2O (3ꢁ
40 mL) and brine (40 mL) then dried (MgSO4), and the solvent was
removed in vacuo. The crude product was purified using Flashmas-
ter II (EtOAc/hexane) to give the title compound as a white solid
1
pale-yellow solid (2.45 g, 88%); H NMR (400 MHz, CDCl3): d=8.00
(1H, d, J=8.6, ArH), 7.99 (1H, s, CHOH), 7.50–7.36 (5H, m, ArH),
6.97 (1H, dd, J=8.0, 2.2, ArH), 6.85 (1H, d, J=2.2, ArH), 5.16 (2H, s,
CH2), 2.90 (2H, t, J=6.8, CH2), 2.60 ppm (2H, t, J=5.9, CH2);
13C NMR (100 MHz, CDCl3): d=184.4 (C), 172.7 (CH), 162.6 (C), 144.5
(C), 136.2 (C), 128.8 (CH), 128.7 (2ꢁCH), 128.3 (CH), 127.5 (2ꢁCH),
125.2 (C), 114.0 (CH), 113.6 (CH), 108.2 (C), 70.1 (CH2), 29.3 (CH2),
23.3 ppm (CH2); MS (APCI): m/z (%): 281.2 (100) [M+H]+, 214.1 (20),
157.9 (35), 140.9 (20); HRMS-FAB: m/z [M+H]+ calcd for C18H17O3:
281.1178, found: 281.1176.
1
(0.19 g, 27%); mp: 207–2098C; H NMR (270 MHz, [D6]DMSO): d=
9.09 (2H, s, 2ꢁNCHN), 7.75 (2H, AA’BB’, ArH), 7.45–7.30 (5H, m,
ArH), 6.98 (1H, d, J=8.1, ArH), 6.78–6.74 (2H, m, ArH), 6.67 (2H,
AA’BB’, ArH), 5.05 (2H, s, CH2), 3.88 (2H, d, J=7.1, CH2), 2.85 (1H,
dd, J=16.0, 4.5, CHH), 2.80–2.64 (2H, m, CH2), 2.52–2.42 (1H, m,
CHH), 2.00–1.92 (1H, m, CHH), 1.78–1.60 (1H, m, CHH), 1.52–
1.38 ppm (1H, m, CHH); 13C NMR (100 MHz, [D6]DMSO): d=156.8
(C), 152.5 (C), 144.0 (2ꢁCH), 137.8 (C), 137.6 (C), 134.4 (2ꢁCH),
130.3 (CH), 128.9 (2ꢁCH), 128.2 (CH), 128.0 (2ꢁCH), 127.9 (C), 119.6
(C), 114.7 (CH), 113.6 (2ꢁCH), 113.2 (CH), 102.7 (C), 69.5 (CH2), 59.5
(CH2), 33.3 (CH), 32.2 (CH2), 28.9 (CH2), 26.5 ppm (CH2); MS (APCI):
m/z (%): 436.0 (50) [M+H]+, 367.0 (100); HRMS-FAB: m/z [M+H]+
calcd for C27H26N5O: 436.2137, found: 436.2132.
(ꢁ)-[6-(Benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]methanol
(12). BF3·Et2O (5.76 g, 40.6 mmol) was added dropwise to a cooled
(ꢀ788C) solution of 11 (2.27 g, 8.11 mmol) and BH3·tBuNH2 (3.53 g,
40.6 mmol) in CH2Cl2 (130 mL). The reaction mixture was stirred for
1 h, then allowed to warm to room temperature and stirred for a
further 2 h. Aqueous HCl (1.5m, 60 mL) was cautiously added, and
the resultant was extracted with CH2Cl2 (3ꢁ60 mL). The combined
organic layers were washed with H2O (100 mL), dried (MgSO4), and
the solvent was removed in vacuo. The crude product was purified
using Flashmaster II (EtOAc/hexane) to give the title compound as
a colourless oil, which solidified on standing (2.09 g, 96%); mp:
(ꢁ)-4-{[(6-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)me-
thyl](4H-1,2,4-triazol-4-yl)amino}benzonitrile (15). As per general
method A using 10% Pd/C (55 mg), 14 (0.40 g, 0.94 mmol), and
THF/MeOH (1:1, 60 mL). The crude product was purified using
Flashmaster II (EtOAc/hexane) and then by flash column chroma-
tography (CHCl3/acetone) to give the title compound as a white
1
1
207–2098C; H NMR (400 MHz, CDCl3): d=7.49–7.32 (5H, m, ArH),
solid (0.19 g, 72%); H NMR (270 MHz, [D6]DMSO): d=9.06 (2H, s,
7.04 (1H, d, J=8.4, ArH), 6.80 (1H, dd, J=8.6, 2.6, ArH), 6.76 (1H, d,
J=2.6, ArH), 5.07 (2H, s, CH2), 3.72–3.62 (2H, m, CH2), 2.92–2.78
(3H, m, CHH and CH2), 2.48 (1H, dd, J=16.0, 11.0, CHH), 2.08–1.94
(2H, m, CH and CHH), 1.52–1.40 ppm (1H, m, CHH); 13C NMR
(100 MHz, CDCl3): d=156.8 (C), 137.9 (C), 137.3 (C), 130.1 (C), 128.6
(2ꢁCH), 128.3 (C), 127.9 (CH), 127.5 (2ꢁCH), 114.5 (CH), 112.8 (CH),
70.0 (CH2), 67.8 (CH2), 37.3 (CH), 31.6 (CH2), 29.1 (CH2), 25.9 ppm
(CH2); MS (APCI): m/z (%): 269.2 (60) [M+H]+; HRMS-FAB: m/z [M]+
calcd for C18H20O2: 268.1463, found: 268.1450.
2ꢁNCHN), 9.01 (1H, s, OH), 7.72 (2H, AA’BB’, ArH), 6.83 (1H, d, J=
8.2, ArH), 6.64 (2H, AA’BB’, ArH), 6.47 (1H, d, J=8.2, ArH), 6.45 (1H,
s, ArH), 3.84 (2H, d, J=6.9, CH2N), 2.83–2.58 (3H, m, CHH and CH2),
2.48–2.32 (1H, m, CHH), 1.98–1.85 (1H, m, CHH), 1.78–1.60 (1H, m,
CHH), 1.50–1.32 ppm (1H, m, CHH); 13C NMR (100 MHz, [D6]DMSO):
d=155.6 (C), 152.5 (C), 144.0 (2ꢁCH), 137.3 (C), 134.4 (2ꢁCH),
130.2 (CH), 125.8 (C), 119.6 (C), 115.2 (CH), 113.6 (2ꢁCH), 113.6
(CH), 102.7 (C), 59.6 (CH2), 33.4 (CH), 32.3 (CH2), 28.7 (CH2),
26.6 ppm (CH2); MS (APCI): m/z (%): 346.2 (100) [M+H]+; HRMS-
FAB: m/z [M+H]+ calcd for C20H20N5O: 346.1668, found: 346.1674;
HPLC (CH3CN/H2O, 70:30) tR =1.79 min (purity: 97%).
(ꢁ)-[6-(Benzyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]methyl-4-
methyl benzenesulfonate (13). p-Toluenesulfonyl chloride (0.36 g,
1.88 mmol) was added to a cooled (08C) solution of 12 (0.34 g,
1.27 mmol) and pyridine (0.20 g, 2.53 mmol) in CHCl3 (3.5 mL). The
solution was stirred for 1 h and then allowed to warm to room
temperature and stirred overnight. The solvent was removed in va-
cuo, and the crude product was purified using Flashmaster II
(EtOAc/hexane) to give the title compound as a white powder
(ꢁ)-6-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}-
5,6,7,8-tetrahydronaphthalen-2-yl sulfamate (16). As per general
method B using H2NSO2Cl (0.7m, 3.5 mL), DMA (3.5 mL), and 15
(0.12 g, 0.35 mmol). The crude product was purified by flash
column chromatography (CHCl3/acetone) to give the title com-
pound as
a
white solid (0.090 g, 61%); 1H NMR (270 MHz,
1
(0.34 g, 64%); mp: 97.5–98.58C; H NMR (270 MHz, CDCl3): d=7.79
[D6]DMSO): d=9.08 (2H, s, 2ꢁNCHN), 7.88 (2H, brs, NH2), 7.73 (2H,
AA’BB’, ArH), 7.13 (1H, d, J=9.0, ArH), 7.03–6.95 (2H, m, ArH), 6.66
(2H, AA’BB’, ArH), 3.88 (2H, d, J=6.9, CH2N), 3.00–2.65 (3H, m, CHH
and CH2), 2.60–2.50 (1H, m, CHH), 2.02–1.90 (1H, m, CHH), 1.80–
1.64 (1H, m, CHH), 1.58–1.40 ppm (1H, m, CHH); 13C NMR
(100 MHz, [D6]DMSO): d=152.5 (C), 148.5 (C), 144.0 (2ꢁCH), 138.1
(C), 134.4 (2ꢁCH), 134.2 (C), 130.5 (CH), 122.3 (CH), 120.0 (CH),
(2H, AA’BB’, ArH), 7.43–7.26 (7H, m, ArH), 6.91 (1H, d, J=8.4, ArH),
6.72 (1H, dd, J=8.4, 2.7, ArH), 6.67 (1H, d, J=2.7, ArH), 5.00 (2H, s,
CH2), 3.97 (2H, d, J=6.7, CH2), 2.81–2.69 (3H, m, CHH and CH2),
2.44 (3H, s, CH3), 2.35 (1H, dd, J=15.6, 10.6, CHH), 2.19–2.02 (1H,
m, CHH), 1.95–1.82 (1H, m, CHH), 1.45–1.30 ppm (1H, m, CHH);
13C NMR (100 MHz, CDCl3): d=157.0 (C), 144.8 (C), 137.2 (C), 133.0
1586
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ChemMedChem 2010, 5, 1577 – 1593