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L. Paloque et al. / European Journal of Medicinal Chemistry 46 (2011) 2984e2991
4.1.3.1. 4-{5-Benzyl-5-methyl-3-[4-(trifluoromethyl)phenylsulfonyl]-
4,5-dihydrofuran-2-yl}benzonitrile (14). White solid, mp 152e153 ꢀC
129.0 (2CH), 130.1 (2CH), 130.3 (2CH), 131.4 (2CH), 132.8 (C), 133.2
(C), 135.4 (C), 159.2 (C), 163.1 (C). Anal. Calcd for C26H23NO4S
(445.53 g molꢂ1): C, 70.09; H, 5.20; N, 3.14. Found: C, 69.76; H, 5.43;
N, 3.52.
(isopropyl alcohol) 1H NMR (CDCl3),
d: 1.54 (s, 3H, CH3), 2.78e3.08
(m, 4H, 2CH2), 7.02e7.07 (m, 2H, 2CH), 7.13e7.20 (m, 3H, 3CH), 7.56
(d, J ¼ 8.4, 2H, 2CH), 7.64e7.69 (m, 6H, 6CH). 13C NMR (CDCl3),
d
: 27.7
4.1.3.4.4. 4-{5-Benzyl-5-methyl-2-[4-(trifluoromethyl) phenyl]-
4,5-dihydrofuran-3-ylsulfonyl}benzonitrile (21). White solid, mp
(CH3), 41.2 (CH2), 46.4 (CH2), 89.3 (C), 110.7 (C), 114.6 (C), 118.0 (C),
123.1 (q, J ¼ 273.0, C), 126.2 (q, J ¼ 3.7, 2CH), 127.1 (CH), 127.2 (2CH),
128.3 (2CH),130.0 (2CH), 130.2 (2CH), 131.6 (2CH),132.8 (C),134.5 (q,
J ¼ 32.9, C), 135.1 (C), 144.6 (C), 161.6 (C). Anal. Calcd for
C26H20F3NO3S (483.50 g molꢂ1): C, 64.59; H, 4.17; N, 2.90. Found: C,
64.53; H, 4.37; N, 2.89.
198e200 ꢀC (isopropyl alcohol) 1H NMR (CDCl3),
d: 1.55 (s, 3H, CH3),
2.80e3.11 (m, 4H, 2CH2), 7.08e7.12 (m, 2H, 2CH), 7.18e7.24 (m, 3H,
3CH), 7.50 (d, J ¼ 8.1, 2H, 2CH), 7.62e7.66 (m, 6H, 6CH). 13C NMR
(CDCl3), d: 27.1 (CH3), 41.2 (CH2), 46.4 (CH2), 89.2 (C), 109.7 (C),116.4
(C),117.2 (C), 123.6 (q, J ¼ 273.0, C),124.9 (q, J ¼ 3.7, 2CH),127.1 (CH),
127.2 (2CH), 128.3 (2CH), 129.7 (2CH), 130.3 (2CH), 131.8 (C), 132.7
(2CH), 135.3 (C), 145.5 (C), 162.9 (C). 1 (C) not observed in these
conditions. HMRS (EI): m/z calcd for C26H20F3NO3S M þ Hþ:
484.1189. Found: 484.1189.
4.1.3.2. 4-[5-Benzyl-3-(4-fluorophenylsulfonyl)-5-methyl-4,5-dihy-
drofuran-2-yl]benzonitrile (15). Yellow solid, mp 147e148 ꢀC (iso-
propyl alcohol) 1H NMR (CDCl3),
d
: 1.51 (s, 3H, CH3), 2.81e3.07 (m,
4H, 2CH2), 7.03e7.11 (m, 4H, 4CH), 7.20e7.24 (m, 2H, 2CH),
7.45e7.52 (m, 3H, 3CH), 7.67e7.72 (m, 4H, 4CH). 13C NMR (CDCl3),
4.1.3.4.5. 4-[5-Benzyl-2-(4-fluorophenyl)-5-methyl-4,5-dihy-
d:
drofuran-3-ylsulfonyl]benzonitrile (22). Yellow oil 1H NMR (CDCl3),
d:
27.4 (CH3), 41.6 (CH2), 46.4 (CH2), 89.0 (C), 111.6 (C), 114.3 (C), 116.3
(d, J ¼ 22.7, 2CH), 118.1 (C), 127.1 (CH), 128.3 (2CH), 129.5 (d, J ¼ 9.5,
2CH), 130.0 (2CH), 130.3 (2CH), 131.5 (2CH), 133.0 (C), 135.3 (C),
137.3 (d, J ¼ 3.3, C), 160.4 (C), 165.2 (d, J ¼ 255.8, C). Anal. Calcd for
C25H20FNO3S (433.49 g molꢂ1): C, 69.27; H, 4.65; N, 3.23. Found:
C, 68.96; H, 4.77; N, 3.19.
1.52 (s, 3H, CH3), 2.83 (d, J ¼ 14.0, 1H, CH2), 2.88 (d, J ¼ 14.5, 1H, CH2),
3.05 (d, J ¼ 14.5, 1H, CH2), 3.06 (d, J ¼ 14.0, 1H, CH2), 7.03e7.13 (m, 4H,
4CH), 7.19e7.25 (m, 3H, 3CH), 7.47 (d, J ¼ 8.4, 2H, 2CH), 7.54e7.64 (d,
4H, 4CH). 13C NMR (CDCl3),
d: 27.6 (CH3), 41.3 (CH2), 46.4 (CH2), 88.6
(C), 108.2 (C), 115.2 (d, J ¼ 22.0, 2CH), 116.1 (C), 117.3 (C), 124.3 (d,
J ¼ 3.3, C), 127.0 (3CH), 128.3 (2CH), 130.4 (2CH), 131.6 (d, J ¼ 8.8,
2CH), 132.6 (2CH), 135.4 (C), 145.9 (C), 163,5 (C), 164.3 (d, J ¼ 252.9,
C). HMRS (EI): m/z calcd for C25H20FNO3S M þ Hþ: 434.1221. Found:
434.1225.
4.1.3.3. 4-[5-Benzyl-3-(4-chlorophenylsulfonyl)-5-methyl-4,5-dihy-
drofuran-2-yl]benzonitrile (16). White solid, mp 144e146 ꢀC (iso-
1
propyl alcohol) H NMR (CDCl3),
d: 1.52 (s, 3H, CH3), 2.79e3.06 (m,
4.1.3.4.6. 4-[5-Benzyl-2-(4-chlorophenyl)-5-methyl-4,5-dihy-
4H, 2CH2), 7.04e7.08 (m, 2H, 2CH), 7.20e7.23 (m, 3H, 3CH), 7.35 (d,
drofuran-3-ylsulfonyl]benzonitrile (23). Yellow oil, 1H NMR (CDCl3),
d:
J ¼ 8.8, 2H, 2CH), 7.40 (d, J ¼ 8.8, 2H, 2CH), 7.64e7.72 (m, 4H, 4CH).13C
1.52 (s, 3H, CH3), 2.79e3.10 (m, 4H, 2CH2), 7.07e7.12 (m, 2H, 2CH),
7.20e7.25 (m, 2H, 2CH), 7.29e7.41 (m, 3H, 3CH), 7.46e7.54 (m, 4H,
NMR (CDCl3), d: 27.5 (CH3), 41.5 (CH2), 46.4 (CH2), 89.1 (C), 111.3 (C),
114.4 (C), 118.1 (C), 127.1 (CH), 128.1 (2CH), 128.3 (2CH), 129.3 (2CH),
130.1 (2CH), 130.2 (2CH), 131.5 (2CH), 132.9 (C), 135.2 (C), 139.5 (C),
139.7 (C),160.7 (C). Anal. Calcd for C25H20ClNO3S (449.95 g molꢂ1): C,
66.73; H, 4.48; N, 3.11. Found: C, 66.51; H, 4.67; N, 3.02.
4CH), 7.63 (d, J ¼ 8.4, 2H, 2CH). 13C NMR (CDCl3),
d: 27.6 (CH3), 41.4
(CH2), 46.4 (CH2), 88.7 (2C), 108.6 (C), 116.2 (C), 117.3 (C), 126.6 (CH),
127.0 (C), 127.1 (2CH), 128.3 (2CH), 130.4 (2CH), 130.6 (2CH), 131.6
(2CH), 132.7 (2CH), 135.4 (C), 145.9 (C), 163.4 (C). HMRS (EI): m/z
calcd for C25H20ClNO3S M þ Hþ: 450.0925. Found: 450.0917.
4.1.3.4. 4-[5-Benzyl-3-(4-bromophenylsulfonyl)-5-methyl-4,5-dihy-
drofuran-2-yl]benzonitrile (17) [14]
4.1.3.5. 4-[5-Benzyl-2-(4-bromophenyl)-5-methyl-4,5-dihydrofu–
ran-3-ylsulfonyl]benzonitrile (24) [14]
4.1.3.4.1. 4-[5-Benzyl-3-(4-iodophenylsulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl]benzonitrile (18). White solid, mp 176e177 ꢀC
4.1.3.5.1. 4-[5-Benzyl-2-(4-iodophenyl)-5-methyl-4,5-dihy-
(isopropyl alcohol) 1H NMR (CDCl3),
d: 1.52 (s, 3H, CH3), 2.79e3.06
drofuran-3-ylsulfonyl]benzonitrile (25). Yellow solid, mp 72 ꢀC
(m, 4H, 2CH2), 7.02e7.07 (m, 2H, 2CH), 7.15e7.26 (m, 5H, 5CH),
(isopropyl alcohol) 1H NMR (CDCl3),
d: 1.51 (s, 3H, CH3), 2.81 (d,
7.64e7.72 (m, 4H, 4CH), 7.75 (d, J ¼ 8.6, 2H, 2CH). 13C NMR (CDCl3),
J ¼ 14.0, 1H, CH2), 2.86 (d, J ¼ 14.6, 1H, CH2), 3.01 (d, J ¼ 14.6, 1H,
CH2), 3.05 (d, J ¼ 14.0, 1H, CH2), 7.06e7.11 (m, 2H, 2CH), 7.20e7.30
(m, 5H, 5CH), 7.48 (d, J ¼ 8.5, 2H, 2CH), 7.63 (d, J ¼ 8.5, 2H, 2CH), 7.74
d: 27.5 (CH3), 41.4 (CH2), 46.4 (CH2), 89.1 (C), 100.5 (C), 111.2 (C),
114.4 (C), 118.1 (C), 127.1 (CH), 128.1 (2CH), 128.3 (2CH), 130.1 (2CH),
130.2 (2CH), 131.5 (2CH), 132.9 (C), 135.2 (C), 138.3 (2CH), 140.8 (C),
160.7 (C). Anal. Calcd for C25H20INO3S (541.40 g molꢂ1): C, 55.46;
H, 3.72; N, 2.59. Found: C, 55.18; H, 3.85; N, 2.53.
(d, J ¼ 8.5, 2H, 2CH). 13C NMR (CDCl3),
d: 27.6 (CH3), 41.3 (CH2), 46.4
(CH2), 88.8 (C), 98.1 (C), 108.6 (C), 116.1 (C), 117.3 (C), 127.0 (CH),
127.1 (2CH), 127.7 (C), 128.2 (2CH), 130.3 (2CH), 130.7 (2CH), 132.7
(2CH), 135.3 (C), 137.1 (2CH), 145.7 (C), 163.5 (C). HMRS (EI): m/z
calcd for C25H20INO3S M þ Hþ: 542.0281. Found: 542.79.
4.1.3.4.2. 4-[5-Benzyl-5-methyl-3-(4-nitrophenylsulfonyl)-4,5-
dihydrofuran-2-yl]benzonitrile (19). Yellow solid, mp 189e190 ꢀC
(isopropyl alcohol) 1H NMR (CDCl3),
d: 1.55 (s, 3H, CH3), 2.78e3.11 (m,
4.1.3.5.2. 134-[5-Benzyl-5-methyl-2-(4-nitrophenyl)-4,5-dihy-
drofuran-3-ylsulfonyl]benzonitrile (26). Yellow oil 1H NMR (DMSO-
4H, 2CH2), 7.05e7.21 (m, 5H, 5CH), 7.57 (d, J ¼ 8.9, 2H, 2CH), 7.66 (d,
J ¼ 8.8, 2H, 2CH), 7.72 (d, J ¼ 8.8, 2H, 2CH), 8.20 (d, J ¼ 8.9, 2H, 2CH).
d6), d: 1.49 (s, 3H, CH3), 2.80e3.04 (m, 4H, 2CH2), 7.14e7.27 (m, 5H,
13C NMR (CDCl3),
d: 27.8 (CH3), 41.1 (CH2), 46.4 (CH2), 89.5 (C), 110.1
5CH), 7.62e7.74 (m, 4H, 4CH), 8.02 (d, J ¼ 8.0, 2H, 2CH), 8.30 (d,
(C), 114.7 (C), 117.9 (C), 124.3 (2CH), 127.1 (CH), 127.8 (2CH), 128.3
(2CH),130.0 (2CH),130.3 (2CH),131.6 (2CH),132.5 (C),135.1 (C),146.7
(C),150.0 (C),162.3 (C). Anal. Calcd for C25H20N2O5S (460.50 g molꢂ1):
C, 65.20; H, 4.38; N, 6.08. Found: C, 65.46; H, 4.47; N, 5.77.
J ¼ 8.0, 2H, 2CH). 13C NMR (DMSO-d6),
d: 25.6 (CH3), 41.8 (CH2), 45.5
(CH2), 90.1 (C), 110.6 (C), 115.8 (C), 117.7 (C), 123.3 (2CH), 126.9 (CH),
127.3 (2CH), 128.1 (2CH), 128.3 (C), 130.4 (2CH), 130.7 (2CH), 133.8
(2CH), 135.7 (C), 144.7 (C), 148.8 (C), 161.5 (C). HMRS (EI): m/z calcd
for C25H20N2O5S M þ Hþ: 461.1166. Found: 461.1161.
4.1.3.4.3. 4-[5-Benzyl-3-(4-methoxyphenylsulfonyl)-5-methyl-
4,5-dihydrofuran-2-yl]benzonitrile
(20). Yellow
solid,
mp
155e156 ꢀC (isopropyl alcohol) 1H NMR (CDCl3),
d
: 1.47 (s, 3H, CH3),
4.1.4. General procedure for amidoxime synthesis from nitriles
A suspension of hydroxylamine hydrochloride (1.7 mmol, 0.12 g,
10 eq.) in 8 mL of DMSO was stirred under inert atmosphere and
cooled to 5 ꢀC. Then, potassium tertiobutylate (1.7 mmol, 0.19 g,
10 eq.) was slowly added. The reaction mixture was stirred at room
temperature for 30 min, and the corresponding nitrile (0.17 mmol,
2.79e3.08 (m, 4H, 2CH2), 3.86 (s, 3H, CH3), 6.87 (d, J ¼ 8.9, 2H, 2CH),
7.04e7.11 (m, 2H, 2CH), 7.18e7.23 (m, 3H, 3CH), 7.46 (d, J ¼ 8.9, 2H,
2CH), 7.66 (d, J ¼ 8.8, 2H, 2CH), 7.71 (d, J ¼ 8.8, 2H, 2CH). 13C NMR
(CDCl3), d: 27.0 (CH3), 41.9 (CH2), 46.4 (CH2), 55.6 (CH3), 88.7 (C),
112.5 (C), 114.1 (C), 114.2 (2CH), 118.2 (C), 127.0 (CH), 128.3 (2CH),