2.2. 7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylaminophenyl)-5,6,7,8-tetrahydroisoquinoline-3(2H)-thione (1).
A mixture of 2,4-diacetyl-5-hydroxy-5-methyl-3-(4-(N,N-dimethylaminophenyl) cyclohexanone (10 mmol), 2-cyanothioacetamide (10 mmol) and piperidine (0.8 mL, 10 mmol) in ethanol (100 mL) was refluxed for 2 h. The yellow crystals that formed on cooling were collected, washed with methanol, and dried in air to give compound 1. Yield: 98%; m. p: 283–284°C. IR: 3432 (O-H), 3273 (N-H); 3142 (C-H, sp2); 2885 (C-H, sp3); 2216 (C ≡ N); 1709 (C = O); 1619 (C = N). 1H NMR: δ 13.78 (s, 1H, NH); 6.88 (d, 2H, J = 10 Hz, Ar-H); 6.61 (d, J = 10 Hz, 2H, Ar-H), 4.83 (s, 1H, OH); 4.27 (d, J = 10 Hz, 1H, C8H); 3.45 (d, J = 10 Hz, 2H: C5H and C7H), 3.28(s,1H, C6H) 2.87 (m, 7H: C5H and N(CH3)2); 2.09 (s, 3H, CH3 ,attached to C-1); 1.90 (s, 3H, COCH3); 1.24 (s, 3H, CH3) ppm. 13C NMR: δ 209.97, 182.75, 178.99, 174.94, 155.49, 155.41, 152.98, 149.21, 129.18, 129.03, 125.05, 116.90, 113.88, 113.01, 68.16, 68.07, 66.22, 56.49, 31.55, 28.11, 28.01, 19.01 ppm. Anal. Calcd. for C22H25N3O2S (395.17): C, 66.81; H, 6.37; N, 10.62%. Found: C, 66.61; H, 6.40; N, 10.78%.
2.3. Reaction of compound 1 with methyl iodide, ethyl chloroacetate, 2-chloroacetamide, chloroacetonitrile or N-aryl-2-chloroacetamides 2a-e; Synthesis of compounds 3, 4, 5, 6 and 7a-e.
A mixture of 1 (3.95 g, 10 mmol), methyl iodide, ethyl chloroacetate, 2-chloroacetamide, chloroacetonitrile or N-aryl-2-chloroacetamide 2a-e (10 mmol), and sodium acetate trihydrate (1.50 g, 11 mmol) in ethanol (100 mL) was refluxed for one hour. The reaction mixture was then allowed to stand at room temperature overnight. The precipitate that formed was collected and recrystallized from ethanol as colorless crystals of title compounds 3, 4, 5, 6, and 7a-e respectively.
2.3.1. 7-Acetyl-4-cyano-1,6-dimethyl-3-methylthio-6-hydroxy-8-(4-N,N-dimethyl-aminophenyl)-5,6,7,8-tetrahydroisoquinoline (3): Yield: 94%; m.p.: 162–163°C. IR: 3510 (O-H); 2967, 2909 (C-H, sp2); 2217 (C ≡ N); 1696 (C = O, acetyl); 1612 (C = N). 1H NMR: δ 6.83 (d, 2H, J = 5 Hz, Ar-H); 6.61 (t, J = 5 Hz, 2H, Ar-H); 4.78 (s, 1H, OH), 4.39 (d, J = 5 Hz, 1H, C8H), 3.18 (dd, J = 7,10 Hz, 3H: C7H and C5H2), 2.86 (m, 9H: SCH3 and N(CH3)2), 2.11(d, J = 7 Hz, 3H,at C-1), 2.00 (s, 3H, CH3, COCH3), 1.25(d, J = 10 Hz, 3H, CH3) ppm. 13C NMR: δ 209.69, 165.72, 161.03, 157.43, 149.23, 148.72, 130.71, 130.08, 128.60, 115.30, 112.40, 104.17, 67.58, 66.31, 43.28, 42.06, 31.12, 27.61, 24.78, 23.73, 14.54. Anal. Calcd. for C23H27N3O2S (409.18): C, 67.45; H, 6.65; N, 10.26%. Found: C, 67,42; H: 6.58, N; 10.30%.
2.3.2. Ethyl 2-((7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio)acetate (4): Yield: 78%; m.p.: 159–160°C. IR: 3506 (O-H); 2983, 2964, 2809 (C-H, sp3); 2215 (C ≡ N); 1740 (C = O, ester); 1695 (C = O, acetyl). 1H NMR: δ 6.81 (d, J = 10 Hz, 2H, Ar-H), 6.58 (d, J = 10 Hz, 2H, Ar-H), 4.81 (s, 1H, OH), 4.38 (d, J = 9 Hz, 1H, C8H), 4.05 (m, 4H: SCH2 and OCH2), C5H and), 3.22 (d, J = 10 Hz, 1H, C5H), 2.87 (d, J = 10 Hz, 8H: C7H, C5H and N(CH3)2), 2.11 (s, 3H, CH3, at C-1), 1.93 (s, 3H, COCH3), 1.25 (s, 3H, CH3), 1.12 (d, J = 5Hz, 3H, CH3 of ester group) ppm. 13C NMR: δ 209.62, 168.58, 160.96, 156.15, 149.43, 148.74, 130.57, 128.63, 115.09, 112.38, 103.71, 67.59, 66.28, 60.90, 42.02, 40.00, 31.98, 31.10, 27.58, 24.49, 14.00. Anal. Calcd. for C26H31N3O4S(481.20): C, 64.84; H, 6.49; N, 8.72%. Found: C, 64.98; H, 6.44; N, 8.51%.
2.3.3. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio]acetamide (5): Yield: 85%; m.p.: 196–197°C. IR: 3562 (O-H); 3436, 3295, 3181 (NH2); 2971, 2809 (C-H, sp3); 2219 (C ≡ N); 1698 (C = O, acetyl); 1667 (C = O, amide). 1H NMR: δ 7.50 (s, 1H, NH), 7.05 (s, 1H, NH), 6.82 (d, J = 10 Hz, 2H, Ar-H), 6.60 (d, J = 9 Hz, 2H, Ar-H), 4.75 (s, 1H, OH), 4.39 (d, J = 15Hz, 1H, C8H), 3.88 (d, J = 12 Hz, 15 Hz, 2H, SCH2), C5H and), 3.26 (d, J = 10 Hz, 1H, C5H), 2.89 (m, 8H: C7H, C5H and N(CH3)2), 2.11 (s, 3H, CH3, at C-1), 1.99 (s, 3H, COCH3), 1.26 (s, 3H, CH3) ppm. 13C NMR: δ 210.02, 169.55, 161.45, 157.33, 149.80, 149.20, 131.21, 130.84, 129.14, 115.73, 112.95, 104.19, 68.07, 66.77, 43.77, 42.50, 33.82, 31.59, 28.07, 25.11.
Anal. Calcd. for C24H28N4O3S (452.19): C, 63.69; H, 6.24; N, 12.38%. Found: C, 63.37; H, 6.18; N, 12.41%.
2.3.4.. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio]acetonitrile (6): Yield:90%; m.p.: 145°C. IR: 3537 (O-H); 2966, 2924,2801 (C-H, sp3); 2246 (C ≡ N, non conjugated); 2217 (C ≡ N, conjugated); 1698 (C = O, acetyl). 1H NMR: δ 6.85 (d, J = 10 Hz, 2H, Ar-H), 6.61 (d, J = 10 Hz 2H, Ar-H), 4.79 (s, 1H, OH), 4.44 (d, J = 8 Hz, 1H, C8H), 4.32 (s, 2H, SCH2), 3.27 (d, 1H, C5H), 2.92(d, J = 8 Hz, 2H, C7H and C5H), 2.89 (d, J = 10 Hz, 6H: N(CH3)2), 2.12 (s, 3H, CH3, at C-1), 2.07 (s, 3H,COCH3), 1.27 (s, 3H, CH3) ppm. 13C NMR: δ 210.26, 162.04, 154.32, 150.40, 149.25, 132.05, 130.91, 129.19, 118.20, 115.25, 112.95, 104.66, 68.09, 66.69, 43.83, 42.55, 31.63, 27.98, 25.14, 15.74 ppm. Anal. Calcd. for C24H26N4O2S (434.18): C, 66.33; H, 6.03; N, 12.89%. Found: C, 65.72; H, 5.71; N, 13.09%.
2.3.5.. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio]- N -phenylacetamide (7a). Yield: 80%; m.p.: 209–210°C. IR: 3459 (O-H); 3247 (N-H); 2971, 2805 (C-H, sp3); 2211 (C ≡ N); 1706 (C = O, acetyl); 1683 (C = O, amide). 1H NMR: δ 10.21 (s, 1H, NH), 7.52 (d, J = 10 Hz, 2H,Ar-H), 7.27 (t, J = 10 Hz, 2H, Ar-H), 7.02 (m, 1H, Ar-H), 6.80 (d, J = 10Hz, 2H, Ar-H), 6.57 (d, J = 10Hz, 2H, Ar-H), 4.80 (s, 1H, OH), 4.37 (d, J = 10Hz, 1H, C8H), 4.1 (dd, J = 10, 13 Hz, 2H, SCH2), 3.23(d, J = 17 Hz, 1H, C5H), 2.87 (m, 4H: C7H and C5H), 2.83 (s, 6H, N(CH3)2), 2.10 (s, 3H, CH3, at C-1), 1.92 (s, 3H, COCH3), 1.24 (s, 3H,CH3). 13C NMR: δ 217.44, 209.63, 166.10, 160.95, 156.74, 149.35, 148.72, 138.90, 130.61, 130.48, 128,69, 128.61, 123.26, 119.04, 115.19, 112.38, 103.66, 67.57, 66.28, 43.29, 41.99, 34.68, 31.06, 27.58, 24.54. Anal. Calcd. for C30H32N4O3S (528.22): C, 68.16; H, 6.10; N, 10.60%. Found: C, 68.10; H, 6.15; N, 10.46%.
2.3.6. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio]- N -(4-tolyl)acetamide (7b). Yield: 95%; m.p.:198–199°C. IR: 3436 (O-H); 3251 (N-H); 3119 (C-H, sp2); 2964,2908 (C-H, sp3); 2216 (C ≡ N); 1706 (C = O, acetyl); 1675 (C = O, amide). 1H NMR: δ 10.11 (s, 1H, NH), 7.39 (d, J = 9 Hz, 2H, Ar-H), 7.07 (d, J = 8Hz, 2H, Ar-H), 6.80 (d, J = 9 Hz, 2H, Ar-H), 6.57 (d, J = 9 Hz, 2H, Ar-H), 4.79 (s, 1H, OH), 4.37 (d, J = 10 Hz, 1H, C8H), 4.085 (dd, J = 4, 7 Hz, 2H, SCH2), 3.23 (d, J = 17.1Hz, 1H, C5H), 2.87 (m, 2H, C7H and C5H), 2.83 (s, 6H, N(CH3)2), 2.22 (s, 3H, CH3 of 4-tolyl group), 2.10 (s, 3H, CH3, at C-1), 1.92 (s, 3H, COCH3), 1.24 (s, 3H, CH3) ppm. 13C NMR: δ 209.62, 165.83, 160.93, 156.77, 149.33, 148.70, 136.40, 132.16, 130.61,130.45, 129.06, 128.61, 119.05, 115.18, 112.37, 103.64, 67.56, 66.27, 43.28, 41.98, 34.64, 31.05, 27.57, 24.53, 20.38 ppm. Anal. Calcd. For C31H34N4O3S (542.24): C, 68.61; H, 6.31; N, 10.32%. Found: C, 68.52; H, 6.45; N, 10.11%.
2.3.7. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-,5,6,7,8-tetrahydroisoquinolin-3-yl)thio]-N-(4-chlorophenyl)acetamide (7c)
Yield: 96%; m.p.: 214–215°C. IR: 3458 (O-H); 3242 (N-H); 2966, 2804 (C-H, sp3); 2214 (C ≡ N); 1685 (2C = O, acetyl and amide); 1610 (C = N). 1H NMR: δ 10.36 (s, 1H, NH), 7.55 (d, J = 10Hz, 2H, Ar-H), 7.32 (t, J = 10Hz, 2H, Ar-H), 6.80 (d, J = 9Hz, 2H, Ar-H), 6.57 (d, J = 8Hz, 2H, Ar-H), 4.80 (s, 1H, OH), 4.37 (d, J = 10 Hz, 1H, C8H), 4.11 (dd, J = 12,15 Hz 2H, SCH2), 3.23 (d, J = 17Hz, 1H, C5H), 2.89 (m, 2H, C7H and C5H), 2.84 (s, 6H, N(CH3)2), 2.10 (s, 3H, CH3, at C-1), 1.90 (s, 3H, COCH3), 1.25 (s, 3H, CH3) ppm. 13C NMR: δ 209.62, 166.32, 160.93, 156.67, 149.34, 148.71, 137.86, 130.58, 130.49,128.60, 126.81, 120.56, 115.16, 112.36, 103.66, 67.51, 66.26, 43.28, 41.99, 34.69, 31.07, 27.57, 24.50 ppm. Anal. Calcd. For C30H31ClN4O3S (562.18): C, 63.99; H, 5.55; N, 9.95%. Found: C, 64.15; H, 5.48; N, 9.84%.
2.3.8. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio]-N-(4-acetylphenyl)acetamide (7d)
Yield:93%; m.p.: 205°C. IR: 3490 (O-H); 3244 (N-H); 3033 (C-H, sp2); 2922 (C-H, sp3); 2215 (C ≡ N); 1690 (3C = O, acetyl and amide); 1614 (C = N). 1H NMR: δ 10.62 (s, 1H, NH), 7.89 (d, J = 10 Hz, 2H, Ar-H), 7.67 (d, J = 10 Hz, 2H, Ar-H), 6.80 (d, J = 13 Hz, 2H, Ar-H), 6.55 (d, 2H, Ar-H), 4.80 (s, 1H, OH), 4.36 (d, J = 10 Hz, 1H, C8H), 4.15 (dd, J = 11, 13 Hz 2H, SCH2), 3.23 (d, J = 20 Hz, 1H, C5H), 2.87 (d, J = 12 Hz, 2H, C7H and C5H), 2.82 (s, 6H, N(CH3)2), 2.50 (s, 3H, COCH3 attached to phenyl group and overlapped with solvent proton), 2.10 (s, 3H, CH3, at C-1), 1.88 (s, 3H, COCH3), 1.24 (s, 3H, CH3). 13C NMR: δ 209.26, 196.36, 166.83, 160.75, 156.63, 149.38, 148.70 ,143.72, 131.68, 130.57, 129.45, 128.61, 118.22,115.33, 112.57, 103.72, 67.57, 66.27, 43.28, 41.97, 34.82, 31.05, 27.57, 26.34, 24.47. Anal. Calcd. for: C32H34N4O4S: (570.23): C, 67.35; H, 6.00; N, 9.82%. Found: C, 67.00; H, 5.88; N, 9.79%.
2.3.9. 2-[(7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-N,N-dimethylamino-phenyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)thio]- N-(naphthalen-1-yl)acetamide (7e) Yield: 88%; m.p.: 194–195°C. IR: 3506 (O-H); 3288 (N-H); 3114 (C-H, sp2); 2968 − 2804 (C-H, sp3); 2217 (C ≡ N); 1696 (2 C = O, acetyl and amide); 1611 (C = N). 1H NMR: δ 10.20 (s, 1H, NH), 7.94 (d, J = 10 Hz, 2H, Ar-H), 7.75 (d, J = 7 Hz, 1H, Ar-H), 7.57 (d, J = 8 Hz, 1H, Ar-H), 7.46 (d, J = 10, 2H, Ar-H), 7.33 (m, 1H, Ar-H), 6.85 (d, J = 9 Hz, 2H, Ar-H), 6.59 (d, J = 8 Hz, 2H, Ar-H), 4.83 (s, 1H, OH), 4.42 (d, J = 10Hz, 1H, C8H), 4.30 (dd, J = 15, 17 Hz, 2H, SCH2), 3.27 (d, J = 20 Hz, 1H, C5H), 2.93 (d, J = 10 Hz, 1H, C7H), 2.86 (m, 7H: C5H and N(CH3)2), 2.12 (s, 3H, CH3, at C-1), 2.04 (s, 3H, COCH3), 1.27 (s, 3H, CH3). 13C NMR: δ 202.84, 166.93, 161.10, 156.89, 149.39, 148.73, 133.61, 130.86, 128.69, 128.03, 125.48, 122.72, 121.71, 115.36, 112.24, 103.43, 67.61, 66.28, 43.33, 42.07, 34.17, 31.14, 27.60, 24.69. Anal. Calcd. for: C34H34N4O3S (578.24): C, 70.56; H, 5.92; N, 9.68%. Found: C, 70.43; H, 5.89; N, 9.85%.