C. Cano et al. / Bioorg. Med. Chem. 15 (2007) 7480–7493
7489
(4 mL). Reaction time 24 h. Yield 31 (0.027 g of yellow
solid, 57%); mp = 194–196 ꢂC. 1H NMR (300 MHz,
CDCl3) d: 8.1 (s, 1H, NH); 7.54 (d, 2H, J = 8.5 Hz, H-
2Ph); 7.43–7.14 (m, 3H, Hs Bn); 7.19 (d, 2H,
J = 8.5 Hz, H-3Ph); 6.91 (s, 1H, H-4); 6.85 (dd, 2H,
J = 7.1, 1.7 Hz, H-2Bn); 5.00 (s, CH2(Bn)); 2.81 (m,
4H, H-2Pip); 1.74 (m, 4H, H-3Pip); 1.44 (m, 2H, H-
4Pip). 13C NMR (75 MHz, CDCl3) d: 161.6 (C-5);
161.2 (C-3); 157.5 (CO); 134.7 (C-1Bn); 132.3 (C-3Ph);
131.5 (C-4Ph); 129.8 (C-2Ph); 128.7 (C-3Bn); 128.3 (C-
4Bn); 127.2 (C-2Bn); 126.6 (C-1Ph); 104.1 (C-4); 56.8
(C-2Pip); 52.0 (CH2(Bn)); 25.1 (C-3Pip); 23.1 (C-2Pip).
MS (ES+): [M+H]+ 503 (92%), [M+H+2]+ 505 (100%).
Anal. (C22H23BrN4O3S, 503.41): C, H, N, S.
base was liberated by treatment with 20 mL of 5%
NaOH and extraction with Et2O (2· 20 mL), 2 M
Al(CH3)3 in hexane (0.25 mL, 0.5 mmol) in freshly dis-
tilled CH2Cl2 (5 mL). Reaction time 24 h. Yield 34
(0.035 g of yellow solid, 76%); mp = 180–182 ꢂC. 1H
NMR (400 MHz, CDCl3) d: 7.51 (da, 1H, J = 9.7 Hz,
NH); 7.38 (d, 1H, J = 8.8 Hz, H-5Ph); 7.22 (m, 3H, Hs
Bn); 7.14 (m, 2H, H-6 and H-2 Ph); 6.93 (s, 1H, H-4);
6.91 (m, 2H, H-2Bn); 4.99 (s, 2H, CH2-Bn); 3.66 (d,
1H, J = 9.7 Hz, H-1Bi); 2.29 (s, 3H, CH3Ph); 1.81 (m,
1H, H-4Bi); 1.71 (m, 1H, H-5eqBi); 1.68 (m, 1H, H-
7Bi); 1.50 (m, 1H, H-5axBi); 1.39 (m, 1H, H-6axBi);
1.28 (m, 1H, H-7Bi); 1.24 (m, 1H, H-6eqBi); 1.13 (s,
3H, CH3(3)eqBi); 1.04 (s, 3H, CH3(1)Bi); 0.84 (s, 3H,
CH3(3)axBi). 13C NMR (125 MHz, CDCl3) d: 161.8
(C-5); 161.4 (C-3); 161.3 (CO); 138.4 (C-3Ph); 137.4
(C-4Ph); 135.2 (C-1Bn); 131.2 (C-1Ph); 131.0 (C-2Ph);
129.8 (C-5Ph); 128.7 (C-3Bn); 128.2 (C-4Bn); 127.3 (C-
2Bn); 127.0 (C-6Ph); 104.2 (C-4); 64.2 (C-1Bi); 52.5
(CH2(Bn)); 48.8 (C-1Bi); 48.1 (C-4Bi); 42.7 (C-7Bi);
39.8 (C-3Bi); 30.9 (CH3(3)eqBi); 27.1 (C-6Bi); 25.9 (C-
5Bi); 21.2 (CH3(3)axBi); 19.9 (CH3Ph); 19.6 (CH3(1)Bi).
MS (ES+): [M+H]+ 526 (100%); [M+H+2]+ 528 (33%).
Anal. (C28H32ClN3O3S, 526.09): C, H, N, S.
5.2.24.
N-(Piperidin-1-yl)-3-(4-bromophenyl)-2-cyclo-
hexyl-1,1-dioxo-1,2-dihydro-1k6-1,2,6-thiadiazine-5-car-
boxamide (32). From 17 (0.008 g, 0.018 mmol), N-1-
aminopiperidine (0.01 mL, d = 0.928, 0.09 mmol), 2 M
Al(CH3)3 in hexane (0.04 mL, 0.09 mmol) in freshly dis-
tilled CH2Cl2 (3 mL). Reaction time 24 h. Yield 32
(0.004 g of yellow solid, 44%); mp = 85–87 ꢂC. 1H
NMR (400 MHz, CDCl3) d: 8.06 (s, 1H, NH); 7.66 (d,
2H, J = 8.6 Hz, H-2Ph); 7.36 (d, 2H, J = 8.6 Hz, H-
3Ph); 6.85 (s, 1H, H-4); 3.80 (m, 1H, H-1Cy); 2.80 (m,
2H, H-2Pip); 2.21 (m, 2H, H-2axCy); 2.01 (m, 2H, H-
2eqCy); 1.84 (m, 2H, H-3axCy); 1.74 (m, 4H, H-3Pip);
1.13 (m, 2H, H-4Pip); 0.93–1.13 (m, 4H, HsCy). 13C
NMR (100 MHz, CDCl3) d: 161.7 (C-5); 161.3 (C-3);
157.7 (CO); 135.2 (C-4Ph); 132.4 (C-3Ph); 129.4 (C-
3Ph); 126.5 (C-1Ph); 104.1 (C-4); 65.2 (C-1Cy); 56.9
(C-2Pip); 31.6 (C-2Cy); 26.1 (C-3Cy); 25.1 (C-3Pip);
24.5 (C-4Cy); 23.1 (C-4Pip). MS (ES+): [M+H]+ 495
(88%); [M+H+2]+ 497 (100%); Anal. (C21H27BrN4O3S,
495.43): C, H, N, S.
5.2.27. N-(Piperidin-1-yl)-2-benzyl-3-(4-chloro-3-methyl-
phenyl)-1,1-dioxo-1,2-dihydro-1k6-1,2,6-thiadiazine-5-
carboxamide (35). From 19 (0.056 g, 0.13 mmol),
N-aminopiperidine (0.06 mL, d = 0.928, 0.6 mmol),
2 M Al(CH3)3 in hexane (0.25 mL, 0.6 mmol) in freshly
distilled CH2Cl2 (5 mL). Reaction time 24 h. Yield 35
(0.034 g of yellow solid, 56%,); mp = 145–147 ꢂC. 1H
NMR (400 MHz, CDCl3) d: 8.1 (br s 1H, NH); 7.38
(d, 1H, H-5Ph); 7.22 (m, 3H, H-3 and H-4 Bn); 7.12
(m, 2H, H-2 and H-6Ph); 6.90 (s, 1H, H-4); 6.88 (2H,
m, H-2Bn); 4.98 (s, 2H, CH2(Bn)); 2.80 (m, 4H, H-
2Pip); 2.28 (s, 3H, CH3-Ph); 1.74 (4H, m, H-3Pip);
1.45 (2H, m, H-4Pip). 13C NMR (100 MHz, CDCl3) d:
161.7. 161.6 (C-3 and C-5); 157.6 (CO); 138.4 (C-3Ph);
137.4 (C-4Ph); 135.1 (C-1Bn); 131.0 (C-1Ph); 130.9 (C-
2Ph); 129.7 (C-5Ph); 128.7 (C-3Bn); 128.2 (C-4Bn);
127.2 (C-2Bn); 126.9 (C-6); 104.0 (C-4); 56.8 (C-2Pip);
52.3 (CH2(Bn)); 25.1 (C-3Pip); 23.1 (C-4Pip); 19.9
(CH3(Ph)). MS (ES+): [M+H]+ 473 (100%);
[M+H+2]+ 475 (33%). Anal. (C23H25ClN4O3S, 472.99):
C, H, N, S.
5.2.25. N-(Piperidin-1-yl)-2-(2,4-dichlorobenzyl)-3-(4-
bromophenyl)-1,1-dioxo-1,2-dihydro-1k6-1,2,6-thiadi-
azine-5-carboxamide
(33).
From
18
(0.065 g,
0.12 mmol), N-aminopiperidine (0.07 mL, d = 0.928,
0.6 mmol), 2 M Al(CH3)3 in hexane (0.3 mL, 0.6 mmol)
in freshly distilled CH2Cl2 (4 mL). Reaction time 24 h.
Yield 33 (0.046 g of orange solid, 65%,); mp = 215–
1
217 ꢂC. H NMR (400 MHz, CDCl3) d: 8.1 (br s 1H,
NH); 7.38 (d, 2H, J = 8.6 Hz, H-2Ph); 7.26 (d, 2H,
J = 8.6 Hz, H-3Ph); 7.25 (m, 1H, H-5Bn); 7.22 (m, 1H,
J = 2.2 Hz, H-3Bn); 7.19 (d, 1H, J = 8.8 Hz, H-6); 6.98
(s, 1H, H-4); 5.05 (s, 2H, CH2(Bn)); 2.83 (m, 4H, H-
2Pip); 1.76 (4H, m, H-3Pip); 1.46 (2H, m, H-4Pip). 13C
NMR (100 MHz, CDCl3) d: 162.0 (C-5); 161.6 (C-3);
157.4 (CO); 134.8 (C-1Bn); 133.0 (C-2Bn); 132.6 (C-
3Ph); 131.4 (C-4Bn); 131.1 (C-4Ph); 129.5 (C-2Ph and
C-3Bn); 129.1 (C-3Bn); 127.8 (C-5Bn); 127.1 (C-1Ph);
104.1 (C-4); 56.9 (C-2Pip); 49.5 (CH2(Bn)); 25.1 (C-
3Pip); 23.1 (C-4Pip). MS (ES+): [M+H]+ 573 (100%);
5.2.28. N-Cyclohexyl-2-(2,4-dichlorobenzyl)-3-(4-chloro-
3-methylphenyl)-1,1-dioxo-1,2-dihydro-1k6-1,2,6-thiadi-
azine-5-carboxamide (36). From 20 (0.037 g, 0.08 mmol),
N-cyclohexylamine (0.04 mL, d = 0.867, 0.4 mmol), 2 M
Al(CH3)3 in hexane (0.2 mL, 0.4 mmol) in freshly dis-
tilled CH2Cl2 (5 mL). Reaction time 24 h. Yield 36
(0.028 g of yellow solid, 68%); mp = 147–149 ꢂC. 1H
NMR (500 MHz, CDCl3) d: 10.4 (br s 1H, NH); 7.48
(d, 1H, J = 8.0 Hz, H-5Ph); 7.41 (d, 2H, J = 8.6 Hz, H-
3Bn); 7.34 (d, 1H, J = 8.3 Hz, H-6Bn); 7.24 (d, 2H,
J = 1.8 Hz, H-2Ph); 7.22 (dd, 1H, J = 8.3, 2.2 Hz, H-
5Bn); 7.13 (dd, 1H, J = 8.0, 1.8 Hz, H-6Ph); 5.67 (s,
1H, H-4); 4.95 (s, 2H, CH2(Bn)); 3.56 (m, 1H, H-
1axCy); 2.45 (s, 3H, CH3-Ph); 1.88 (m, 2H, H-2eqCy);
1.78 (m, 2H, H-3eqCy); 1.54 (m, 3H, H-2ax, H-4eqCy);
1.28 (m, 3H, H-3ax, H-4axCy). 13C NMR (125 MHz,
571
(C22H21BrCl2N4O3S, 572.3): C, H, N, S.
(61%)
[M+H+2]+
575
(55%).
Anal.
5.2.26. N-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-2-benzyl-
3-(4-chloro-3-methylphenyl)-1,1-dioxo-1,2-dihydro-1k6-
1,2,6-thiadiazine-5-carboxamide (34). From 19 (0.037 g,
0.08 mmol), N-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl-
amine hydrochloride (0.083 g, 0.5 mmol), which free-