2114 J . Org. Chem., Vol. 63, No. 7, 1998
Katritzky et al.
2-(Ben zot r ia zol-1-yl)-1-p h en yl-2-(m et h ylt h io)h exa n e
(3f). Benzene:diethyl ether (95:5) was used as the eluent to
give a white solid, mp 84-87 °C (72%): 1H NMR δ δ 0.91 (t,
J ) 7.0 Hz, 3 H), 1.20-1.45 (m, 3 H), 1.65 (s, 3 H), 1.68-1.84
(m, 1 H), 2.28 (td, J 1 ) 12.5 Hz, J 2 ) 3.6 Hz, 1 H), 2.47 (td, J 1
) 12.5 Hz, J 2 ) 4.5 Hz, 1 H), 3.55 (d, J ) 14.2 Hz, 1 H), 3.92
(d, J ) 14.2 Hz, 1 H), 6.76 (d, J ) 7.7 Hz, 2 H), 7.10-7.23 (m,
2 H); 7.24-7.56 (m, 3H), 8.10 (d, J ) 8.3 Hz, 1 H), 8.23 (d, J
) 8.3 Hz, 1 H); 13C NMR δ 11.2, 14.0, 22.5, 26.1, 34.4, 41.1,
76.0, 113.8, 120.1, 124.0, 126.7, 127.2, 128.1, 130.0, 132.2,
134.6, 146.9. Anal. Calcd for C19H23N3S: N, 12.91. Found:
N, 13.30.
(m, 3 H), 7.35 (t, J ) 8.2 Hz, 1 H), 7.45-7.40 (m, 3 H), 8.02
(d, J ) 8.2 Hz, 1 H), 8.45 (d, J ) 8.2 Hz, 1 H);
13C NMR δ
12.8, 21.3, 24.9, 25.6, 31.6, 31.7, 78.8, 84.6, 116.8, 118.8, 123.4,
126.6, 126.7, 127.7, 131.4, 136.9, 145.6, 147.3. Anal. Calcd
for C18H27N3OS: C, 64.47; H, 8.16. Found: C, 64.47; H, 8.14.
n -Bu tyl 3-(Ben zotr ia zol-1-yl)-3-(m eth ylth io)octa n oa te
(10). Hexanes:ethyl acetate (10:1) was used as the eluent to
give a colorless oil, (40%): 1H NMR δ 0.85 (t, J ) 7.2 Hz, 3
H), 0.92 (t, J ) 7.4 Hz, 3 H), 1.20-1.40 (m, 6 H), 1.65 (s, 3 H),
2.21 (dd, J 1 ) 7.2 Hz, J 2 ) 5.0 Hz, 1 H), 2.26 (dd, J 1 ) 7.4 Hz,
J 2 ) 5.0 Hz, 1 H), 2.50-2.70 (m, 2 H), 2.80 (dt, J 1 ) 10.8 Hz,
J 2 ) 5.4 Hz, 1 H), 3.06 (ddd, J 1 ) 10.8 Hz, J 2 ) 5.4 Hz, J 3
)
2-(Be n zot r ia zol-1-yl)-4-m e t h yl-1-p h e n yl-2-(m e t h yl-
th io)p en ta n e (3g). Hexanes:ethyl acetate (10:1) was used
as the eluent to give a white solid, mp 68 °C (92%): 1H NMR
δ 0.31 (d, J ) 6.6 Hz, 3 H), 0.95 (d, J ) 6.6 Hz, 3 H), 1.58 (s,
3 H), 2.06 (dd, J 1 ) 15.4 Hz, J 2 ) 8.5 Hz, 1 H), 2.07-2.18 (m,
5.0 Hz, 4 H), 4.05 (t, J ) 7.4 Hz, 4 H), 7.40 (t, J ) 8.2 Hz, 1
H), 7.45 (t, J ) 8.2 Hz, 1 H), 8.10 (d, J ) 8.2 Hz, 1 H), 8.15 (d,
J ) 8.2 Hz, 1 H); 13C NMR δ 10.9, 13.6, 13.7, 19.0, 22.4, 25.3,
29.1, 29.9, 30.5, 35.1, 64.6, 74.8, 113.4, 120.1, 124.0, 126.7,
131.6, 146.5, 172.4. Anal. Calcd for C19H29N3O3S: C, 64.47;
H, 8.16. Found: C, 64.47; H, 8.14.
1 H), 2.35 (dd, J 1 ) 15.4 Hz, J 2 ) 4.0 Hz, 1 H), 3.79 (d, J 1
)
14.5 Hz, 1 H), 4.12 (d, J 1 ) 14.5 Hz, 1 H), 7.05-7.15 (m, 2 H),
7.20-7.28 (m, 3 H), 7.38 (t, J ) 8.3 Hz, 1 H), 7.44 (t, J ) 8.3
Hz, 1 H), 8.08 (d, J ) 8.3 Hz, 1 H), 8.22 (d, J ) 8.3 Hz, 1 H);
13C NMR δ 11.3, 22.4, 24.4, 24.5, 40.8, 43.8, 75.9, 113.9, 119.9,
123.9, 126.6, 127.1, 127.9 (2C), 130.8 (2C), 132.4, 134.9, 146.8.
Anal. Calcd for C16H25N3OS: C, 70.12; H, 7.12; N, 12.91.
Found: C, 70.33; H, 7.22; N, 12.85.
N-P h en yl 1-(Ben zot r ia zol-1-yl)-2-m et h yl-1-(m et h yl-
th io)bu ta n a m id e (12a ). The crude material was recrystal-
lized from ethanol to give white crystals, mp 155 °C (75%):
1H NMR δ 1.30-1.50 (m, 6 H), 1.70 (s, 3 H), 3.55 (qv, J ) 6.5
Hz, 1 H), 7.10-7.50 (m, 5 H), 7.60-7.80 (m, 4 H), 8.80 (s, 1 H,
NH); 13C NMR δ 12.5, 18.6, 19.1, 34.5, 81.8, 113.1, 119.3, 120.6,
124.2, 127.4, 125.2, 129.1, 132.8, 136.9, 146.0, 164.0. Anal.
Calcd for C18H20N4OS: C, 63.53; H, 5.88; N, 16.47. Found:
C, 63.49; H, 5.97; N, 16.49.
4-(Ben zot r ia zol-1-yl)-1,7-d ip h en yl-4-(m et h ylt h io)-1,6-
h ep ta d ien e (3h ). Benzene:diethyl ether (95:5) was used as
the eluent to give a yellow oil (65%): 1H NMR δ 1.70 (s, 3 H),
3.34 (dd, J 1 ) 14.6 Hz, J 2 ) 7.5 Hz, 2 H), 3.56 (dd, J 1 ) 14.6
Hz, J 2 ) 7.5 Hz, 2 H), 6.08 (dt, J 1 ) 15.7 Hz, J 2 ) 7.5 Hz, 2
H), 6.46 (dt, J 1 ) 15.7 Hz, J 2 ) 7.5 Hz, 2 H), 7.10-7.30 (m, 10
H), 7.45 (d, J ) 8.3 Hz, 1 H), 7.50 (d, J ) 8.3 Hz, 1 H), 8.10 (d,
J ) 8.3 Hz, 1 H), 8.22 (d, J ) 8.3 Hz, 1 H); 13C NMR δ 11.2,
39.6 (2C), 74.4, 113.7, 120.2, 122.2 (2C), 124.2, 126.3 (4C),
126.9, 127.6 (2C), 128.5 (4C), 131.8, 134.9 (2C), 136.8 (2C),
147.0. Anal. Calcd for C26H25N3S: N, 10.21. Found: N, 10.10.
1-(Be n zot r ia zol-1-yl)-1-cyclop e n t yl-1-(m e t h ylt h io)-
eth a n e (3i). The crude compound was pure (by NMR), as a
yellow oil (94%); 1H NMR δ 1.00-1.70 (m, 6 H), 1.90-2.00 (m,
1 H), 2.10-2.25 (m, 1 H), 2.70 (s, 3 H), 3.10-3.20 (m, 1 H),
7.30-7.50 (m, 2 H), 8.10 (d, J ) 8.2 Hz, 1 H), 8.22 (d, J ) 8.2
Hz, 1 H); 13C NMR δ 11.1, 20.9, 25.2, 25.9, 27.1, 28.3, 48.6,
75.0, 113.8, 119.6, 123.9, 126.4, 131.7, 146.7. HRMS (POS
FAB) calcd for C14H20N3S (M + 1): 262.1378, found 262.1370.
2-(Ben zot r ia zol-1-yl)-1-h yd r oxy-1-p h en yl-2-(m et h yl-
th io)h exa n e (5a ). The crude product (3.56 g) was separated
by flash column chromatography on silica gel (175 g), eluting
with benzene:Et2O (95:5). A mixture of two diastereoisomers
were obtained. The first one (2.08 g, 61%) decomposed in a
few days, in the presence of atmospheric humidity, into product
6a , the second (0.48 g, 29%) was obtained as white crystals,
mp 110.5-113 °C (overall reaction yield 90%): 1H NMR δ 0.80
(t, J ) 7.2 Hz, 3 H), 1.10-1.30 (m, 2 H), 1.50-1.65 (m, 2 H),
1.92 (s, 3 H), 2.50 (td, J 1 ) 7.4 Hz, J 2 ) 3.9 Hz, 2 H), 4.20 (br
s, 1 H, OH), 6.10 (s, 1 H), 7.20-7.40 (m, 3 H), 7.40-7.50 (m,
4 H), 8.10-8.20 (m, 2 H); 13C NMR δ 13.6, 14.0, 22.4, 25.8,
36.0, 77.9, 78.7, 113.6, 120.0, 124.4, 127.4, 127.6, 128.4, 128.5,
132.6, 137.7, 146.2. Anal. Calcd for C19H23N3OS: C, 66.83;
H, 6.79; N, 12.31. Found: C, 66.93; H, 6.80; N, 12.09.
1-(Ben zotr ia zol-2-yl)-1-(1-h yd r oxycycloh exyl)-1-(m eth -
ylth io)h exa n e (7a ). Recrystallized from hexanes:diethyl
ether to give a white solid, mp 40-45 °C (80%): 1H NMR δ
0.90 (t, J ) 7.2 Hz, 3 H), 0.90-1.00 (m, 2 H), 1.01-1.24 (m, 2
H), 1.30-1.80 (m, 10 H), 2.20 (s, 3 H) 2.40 (td, J 1 ) 7.4 Hz, J 2
) 3.9 Hz, 1 H), 2.90 (td, J 1 ) 7.4 Hz, J 2 ) 3.9 Hz, 1 H), 4.40
(br s, 1 H, OH), 7.40 (dd, J 1 ) 8.2 Hz, J 2 ) 1.8 Hz, 2 H), 7.90
(dd, J 1 ) 8.2 Hz, J 2 ) 1.8 Hz, 2 H); 13C NMR δ 13.9, 14.8,
21.6, 21.7, 23.1, 25.4, 27.2, 32.4, 32.7, 33.7, 79.2, 88.1, 118.2,
126.7, 143.1. Anal. Calcd for C18H27N3OS: C, 64.47; H, 8.16.
Found: C, 64.47; H, 8.14.
N-P h en yl 1-(Ben zot r ia zol-1-yl)-1-(m et h ylt h io)h exa n -
a m id e (12b). The crude material was recrystallized from
ethanol to give white crystals, mp 142-143 °C (75%): 1H NMR
δ 1.00 (t, J ) 7.2 Hz, 3 H), 1.40-1.80 (m, 4H), 1.65 (s, 3 H),
2.80-3.10 (m, 2 H), 7.10-7.20 (m, 2 H), 7.21-7.50 (m, 5 H),
7.65-7.80 (m, 2 H), 9.45 (s, 1 H, NH); 13C NMR δ 11.1, 13.9,
22.6, 26.1, 36.5, 78.6, 112.2, 118.8, 120.7, 124.7, 125.0, 127.6,
128.9, 131.7, 137.3, 146.0, 165.7. Anal. Calcd for C19H22N4-
OS: C, 64.40; H, 6.21; N, 15.82. Found: C, 64.78; H, 6.60; N,
15.82.
2-(Ben zotr ia zol-1-yl)-1-oxo-1-ph en ylh exa n e (9). 1-(Ben-
zotriazol-1-yl)-1-(methylthio)pentane 2b (2.35 g, 10 mmol) was
dissolved in THF (50 mL), and a solution of n-BuLi (1.6 N in
hexane, 6.6 mL, 10.5 mmol) was added at -78 °C under
nitrogen while stirring. After 1 h, ethyl benzoate (1.65 g, 11
mmol) was added, and the reaction mixture was stirred at -78
°C for 2 h and then at room temperature for 12 h. The reaction
was refluxed for 2 h and finally quenched with 100 mL of NaCl
5%. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 25 mL). The joint organic extracts
were dried over MgSO4, and the solvent was removed in vacuo.
The residue (3.57 g) was purified by flash column chromatog-
raphy on silica gel (175 g) eluting with benzene:Et2O (95:5).
The main fraction obtained was a yellow solid, which was
recrystallized from ethanol, mp 104-104.5 °C (1.38 g, 40%):
1H NMR δ 0.85 (t, J ) 7.2 Hz, 3 H), 1.00-1.20 (m, 1 H), 1.22-
1.50 (m, 3 H), 2.45 (t, J ) 7.2 Hz, 2 H), 6.60 (dd, J 1 ) 7.2 Hz,
J 2 ) 3.9 Hz, 1 H), 7.25-7.68 (m, 7 H), 8.00-8.10 (m, 2 H); 13
C
NMR δ 13.7, 22.0, 27.9, 29.6, 63.8, 110.7, 120.1, 124.0, 127.6,
128.7, 128.9, 132.1, 134.0, 134.5, 146.5, 193.7. Anal. Calcd
for C18H19N3O: C, 73.70; H, 6.53; N, 14.32. Found: C, 73.23;
H, 6.62; N, 14.46.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Ket on es
4a -e. The appropriate R-benzotriazolylalkyl thioether 3a -e
(1 mmole) was solubilized in methanol (1 mL), and sulfuric
acid 5% (1.1 mL) was added. The mixture was stirred at room
temperature for 24 h for compounds 3a and 3d and heated at
60 °C for 4 h for compounds 3b,c,e then treated with water
(10 mL) and diethyl ether (25 mL). The two layers were
separated in a separatory funnel, and the aqueous layer was
extracted with diethyl ether (10 mL). The combined ethereal
fractions were subsequently washed with sodium hydroxide
10% (2 × 10 mL) and saturated ammonium chloride (2 × 10
mL), and then the organic extract was dried over anhydrous
sodium sulfate. Evaporation of the solvent gave the expected
product.
1-[1-(Ben zotr ia zol-1-yl)-2-p h en yl-1-(m eth ylth io)eth yl]-
1-h yd r oxycycloh exa n e (7b). Recrystallized from ethanol to
give a white solid, mp 143-145 °C (85%): 1H NMR (DMSO-
d6) δ 0.90 (s, 3 H), 1.20-1.80 (m, 10 H), 3.65 (d, J ) 14.2 Hz,
1 H), 4.82 (d, J ) 14.2 Hz, 1 H), 5.04 (s, 1H, OH), 7.10-7.20