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Synlett 2012(5): 731-736  
DOI: 10.1055/s-0031-1290603
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Two-Step Synthesis of 1H-Tetrazolyl-1H-1,4-benzonitriles and 1H-Tetrazolyl-benzo[b][1,4]diazepines

Ahmad Shaabani*, Hamid Mofakham*, Sajjad Mousavifaraz
Department of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
Fax: +98(21)29903247; e-Mail: a-shaabani@cc.sbu.ac.ir;
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Publikationsverlauf

Received 10 December 2011
Publikationsdatum:
28. Februar 2012 (online)

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Abstract

A two-step synthetic protocol for the title heteroannulated diazepines has been developed. The approach includes a pseudo five-component isocyanide-based condensation reaction between diamines, ketones, isocyanides and trimethylsilyl azide and proceeds in good yields.

Key words

diazepine - tetrazole - multicomponent reactions - iso­cyanide

    References and Notes

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25

Melting points were measured with an Electrothermal 9200 apparatus. Mass spectra were recorded with a Finnigan-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. IR spectra were recorded with a Shimadzu IR-470 spectrometer. ¹H NMR spectra were recorded with a Bruker DRX-300 Avance spectrometer at 300.13 MHz; chemical shifts (δ) are reported in units of parts per million(ppm). ¹H NMR spectra are reported in the order: multiplicity, approximate coupling constant (J value) in hertz (Hz), and integration. ¹³C NMR spectra were recorded at 75.47 MHz; chemical shifts (δ) are reported in ppm. Elemental analyses were performed with an Elementar Analysensysteme GmbH VarioEL. All the products are new compounds, which were characterized by IR, ¹H and ¹³C NMR spectra and Mass spectral data.
Synthesis of 1 H -tetrazolyl-1 H -1,4-diazepine-2,3-dicarbonitriles 6a-g and 1 H -tetrazolyl-benzo[ b ]-[1,4]diazepines 7a-f; General Procedure: A solution of the diamine (1.00 mmol) and ketone (2.20 mmol) in the presence of p-TsOH˙H2O (0.095 g, 5 mol%) was stirred for 4 h in MeOH (5 mL) at ambient temperature. After completion of the reaction, as indicated by TLC (EtOAc-n-hexane, 3:1), the isocyanide (1.00 mmol) and H2O (0.50 mL) were added to the reaction mixture. The resulting mixture was stirred for 12 h at ambient temperature. After completion of the reaction, as indicated by TLC (EtOAc-n-hexane, 4:1), the product was filtered off, washed further with H2O, and then crystallized from acetone to give the 1,4-diazepine derivative.
To a solution of the 1,4-diazepine (0.50 mmol) and pyridine (3.00 mmol) in CH2Cl2 (5.00 mL) was added PCl5 (0.75 mmol) and the resulting mixture was heated to reflux. After 6 h the reaction mixture was cooled to ambient temperature and TMSN3 (2.00 mmol) was added and stirred for 24 h at ambient temperature. After completion of the reaction, as indicated by TLC (EtOAc-n-hexane, 4:1), the product was filtered off, washed further with H2O and MeOH, and then crystallized from acetone to give 6a-g and 7a-f.
5-(1-Cyclohexyl-1 H -tetrazol-5-yl)-5,7,7-trimethyl-4,5,6,7-tetrahydro-1 H -1,4-diazepine-2,3-dicarbonitrile (6a): Colorless crystals; mp 229-231 ˚C. IR (KBr): 3350, 3135, 3078, 2940, 2865, 2213, 1656, 1625, 1478, 1390 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 20 H, 5 × CH2 of c-Hex, 3 × CH3 and 1 H CH), 2.79 (ABq, J = 14.2 Hz, 1 H, CH2), 4.75 (m, 1 H, CH of c-Hex), 5.75 (s, 1 H, NH), 6.78 (s, 1 H, NH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 25.0, 25.3, 30.5, 31.6, 31.8, 33.9, 34.2, 46.5, 54.8, 56.8, 58.1, 106.0, 109.7, 116.3, 116.8, 158.8. MS: m/z = 340 (20) [M]+, 258 (15), 189 (55), 173 (20), 153 (20), 133 (100), 111 (15), 83 (20), 56 (65). Anal. Calcd for C17H24N8: C, 59.98; H, 7.11; N, 32.92. Found: C, 59.92; H, 7.00; N, 32.82.
9a-(1-Cyclohexyl-1 H -tetrazol-5-yl)-1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[ e ][1,4]diazepine-5,1′-cyclohexane]-2,3-dicarbonitrile (6b): Colorless crystals; mp >300 ˚C. IR (KBr): 3345, 3135, 2983, 2935, 2857, 2225, 2206, 1622, 1495, 1454, 1404, 1297 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 28 H, 14 × CH2 of c-Hex), 2.64 (m, 1 H, CH), 4.69 (m, 1 H, CH of c-Hex), 4.80 (s, 1 H, NH), 6.85 (s, 1 H, NH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 19.0, 20.9, 21.6, 25.0, 25.4, 30.5, 34.2, 34.8, 37.4, 46.2, 49.0, 56.5, 57.9, 59.8, 61.2, 106.1, 110.0, 116.1, 116.5, 161.1. Anal. Calcd for C23H32N8: C, 65.69; H, 7.67; N, 26.64. Found: C, 65.60; H, 7.60; N, 26.55.
4′,7-di- tert -Butyl-9a-(1-cyclohexyl-1 H -tetrazol-5-yl)-1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[ e ][1,4]-diazepine-5,1′-cyclohexane]-2,3-dicarbonitrile (6c): Colorless crystals; mp >300 ˚C. IR (KBr): 3358, 3128, 3072, 2941, 2867, 2217, 1657, 1620, 1473, 1398, 1294 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 0.76 (s, 9 H, 4 × CH3), 0.85 (s, 9 H, 4 × CH3), 1.10-2.70 (m, 27 H, 12 × CH2 of c-Hex and 3 × CH), 4.56 (s, 1 H, NH), 4.67 (m, 1 H, CH of c-Hex), 6.71 (s, 1 H, NH). Anal. Calcd for C31H48N8: C, 69.89; H, 9.08; N, 21.03. Found: C, 69.79; H, 9.01; N, 21.00.
9 a -(1-Cyclohexyl-1 H -tetrazol-5-yl)-4′,7-diphenyl-1,4,5 a ,6,7,8,9,9 a -octahydrospiro[benzo[ e ][1,4]- diazepine-5,1′-cyclohexane]-2,3-dicarbonitrile (6d): Brown powder; mp >300 ˚C. IR (KBr): 3419, 3351, 3090, 3021, 2938, 2862, 1619, 1495, 1453, 1398 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.20 (m, 24 H, 12 × CH2 of c-Hex), 2.43 (m, 1 H, CH), 2.64 (m, 1 H, CH), 3.10 (m, 1 H, CH), 4.79 (m, 1 H, CH of c-Hex), 5.02 (s, 1 H, NH), 7.03 (s, 1 H, NH), 7.00-7.15 (m, 3 H, ArH), 7.15-7.30 (m, 3 H, ArH), 7.32 (m, 4H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 25.1, 25.4, 28.1, 28.5, 29.2, 30.4, 33.4, 34.2, 34.9, 42.7, 43.0, 46.4, 58.1, 59.2, 106.2, 110.3, 116.1, 116.5, 126.3, 126.6, 127.0, 127.2, 128.7, 128.9, 146.8, 147.3, 161.1. MS: m/z = 421 (10) [M+ - 151], 309 (30), 227 (35), 184 (15), 145 (35), 117 (45), 91 (100), 55 (23). Anal. Calcd for C35H40N8: C, 73.40; H, 7.04; N, 19.56. Found: C, 73.33; H, 7.00; N, 19.46.
4′,7-di- tert -Butyl-9a-(1- tert -butyl-1 H -tetrazol-5-yl)-1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[ e ][1,4]- diazepine-5,1′-cyclohexane]-2,3-dicarbonitrile (6e): Colorless crystals; mp 170-171 ˚C. IR (KBr): 3340, 3089, 2935, 2856, 2215, 1570, 1545, 1450 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 0.80-2.40 (m, 43 H, 7 × CH2 of c-Hex, 9 × CH3 and 2 × CH), 3.03 (m, 1 H, CH), 4.70 (s, 1 H, NH), 6.67 (s, 1 H, NH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 21.8, 22.1, 22.8, 26.1, 27.5, 27.8, 31.5, 32.5, 32.8, 33.0, 33.7, 46.9, 57.3, 60.6, 65.1, 104.1, 105.8, 110.6, 115.3, 163.4. Anal. Calcd for C29H46N8: C, 68.74; H, 9.15; N, 22.11. Found: C, 68.62; H, 9.05; N, 22.07.



9a-(1- tert -Butyl-1 H -tetrazol-5-yl)-4′,7-diphenyl-1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[ e ][1,4]- diazepine-5,1′-cyclohexane]-2,3-dicarbonitrile (6f). Brown powder; mp >300 ˚C. IR (KBr): 3406, 3236, 3160, 3040, 3021, 2926, 2850, 2219, 2194, 1634, 1544, 1443, 1366, 1316 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.20 (m, 23 H, 7 × CH2 of c-Hex and 3 × CH3), 2.40 (m, 1 H, CH), 2.64 (m, 1 H, CH), 3.30 (m, 1 H, CH), 4.92 (s, 1 H, NH), 6.92 (s, 1 H, NH), 7.16 (m, 3 H, ArH), 7.18 (m, 3 H, ArH), 7.32 (m, 4 H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 27.9, 28.6, 29.3, 30.8, 31.6, 33.4, 37.7, 42.9, 43.1, 48.8, 60.7, 61.2, 65.2, 105.8, 111.6, 116.6, 117.0, 126.3, 126.6, 127.1, 127.2, 128.6, 128.8, 146.9, 147.4, 163.5. Anal. Calcd for C33H38N8: C, 72.50; H, 7.01; N, 20.50. Found: C, 72.42; H, 6.91; N, 20.41.
9a-(1-(2,4,4-Trimethylpentan-2-yl)-1 H -tetrazol-5-yl)-1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[ e ][1,4]- diazepine-5,1′-cyclohexane]-2,3-dicarbonitrile (6g): Colorless crystals; mp 167-169 ˚C. IR (KBr): 3406, 3282, 3128, 3021, 2946, 2850, 2215, 2200, 1618, 1529, 1454, 1304 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 35 H, 9 × CH2 of c-Hex, 1 × CH2 and 5 × CH3), 2.94 (m, 1 H, CH), 4.69 (s, 1 H, NH), 6.70 (s, 1 H, NH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 20.6, 20.7, 21.1, 21.6, 24.7, 25.4, 25.5, 25.6, 31.1, 31.2, 31.5, 48.8, 61.0, 61.8, 65.1, 105.7, 107.1, 111.2, 116.5, 163.4. Anal. Calcd for C25H38N8: C, 66.63; H, 8.50; N, 24.87. Found: C, 66.58; H, 8.41; N, 24.77.
2-(1-Cyclohexyl-1 H -tetrazol-5-yl)-2,4,4-trimethyl-2,3,4,5-tetrahydro-1 H -benzo[ b ][1,4]diazepine (7a): Colorless crystals; mp 241-242 ˚C. IR (KBr): 3383, 2924, 2861, 1600, 1508, 1478, 1450, 1302, 1259 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.00 (m, 20 H, 5 × CH2 of c-Hex, 3 × CH3 and 1 × CH), 2.80 (ABq, J = 13.8 Hz, 1 H, CH2), 3.99 (br s, 1 H, NH), 4.96 (t, J = 10.9 Hz, 1 H, CH of c-Hex), 5.88 (br s, 1 H, NH), 6.40-6.50 (m, 2 H, ArH), 6.57 (dd, J = 6.8, 7.4 Hz, 1 H, ArH), 6.73 (ABq, J = 7.6 Hz, 1 H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 25.0, 25.4, 31.6, 32.0, 32.5, 32.9, 34.3, 51.5, 53.2, 55.8, 57.9, 117.3, 119.2, 120.7, 120.9, 135.2, 136.9, 160.1. MS: m/z = 440 (75) [M]+, 189 (80), 173 (100), 133 (80), 90 (10), 55 (15). Anal. Calcd for C19H28N6: C, 67.03; H, 8.29; N, 24.68. Found: C, 69.90; H, 8.22; N, 24.60.
4-(1-Cyclohexyl-1 H -tetrazol-5-yl)-2,2,4-trimethyl-7-nitro-2,3,4,5-tetrahydro-1 H -benzo[ b ][1,4]diazepine (7b): Red powder; mp 196-198 ˚C. IR (KBr): 3400, 3374, 2928, 2859, 1644, 1594, 1530, 1461, 1404, 1309 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 20 H, 5 × CH2 of c-Hex, 3 × CH3 and 1 × CH), 3.09 (ABq, J = 13.2 Hz, 1 H, CH2), 4.67 (m, 1 H, CH of c-Hex), 5.75 (br s, 1 H, NH), 6.50 (br s, 2 H, ArH and ABq, J = 9.3 Hz, ArH), 6.38 (ABq, J = 7.7 Hz, 1 H, ArH), 7.76 (br s, 1 H, NH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 24.7, 24.9, 25.2, 31.0, 32.5, 33.0, 33.6, 34.4, 49.2, 53.8, 55.8, 57.7, 112.9, 116.8, 117.9, 134.7, 138.9, 144.2, 159.6. MS: m/z = 385 (50) [M]+, 234 (65), 218 (100), 177 (50), 132 (45), 83 (10), 55 (35). Anal. Calcd for C19H27N7O2: C, 59.20; H, 7.06; N, 25.44. Found: C, 59.07; H, 7.01; N, 25.34.
(4-(1-Cyclohexyl-1 H -tetrazol-5-yl)-2,2,4-trimethyl-2,3,4,5-tetrahydro-1 H -benzo[ b ][1,4]diazepin-7-yl)(phenyl)methanone (7c): Yellow powder; mp 293-295 ˚C. IR (KBr): 3349, 3084, 3040, 2970, 2935, 2850, 1631, 1570, 1492, 1402, 1342, 1301 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.28 (br s, 3 H, CH3), 1.32 (br s, 3 H, CH3), 1.44 (br s, 3 H, CH3), 1.00-2.00 (m, 11 H, 5 × CH2 of c-Hex and 1 × CH), 3.08 (ABq, J = 13.5 Hz, 1 H, CH2), 4.69 (m, 1 H, CH of c-Hex), 5.16 (br s, 1 H, NH), 6.30 (br s, 1 H, NH), 6.47 (ABq, J = 8.1 Hz, 1 H, ArH), 6.83 (ABq, J = 7.5 Hz, 1 H, ArH), 7.41 (s, 1 H, ArH), 7.45-7.60 (m, 5 H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 24.9, 25.0, 25.1, 31.2, 32.4, 33.1, 33.4, 34.5, 49.9, 53.5, 55.8, 57.6, 118.1, 119.2, 123.9, 127.7, 128.6, 129.2, 131.6, 135.1, 139.3, 141.8, 160.0, 194.2. Anal. Calcd for C26H32N6O: C, 70.24; H, 7.26; N, 18.90. Found: C, 70.15; H, 7.20; N, 18.81.
4a′-(1-Cyclohexyl-1 H -tetrazol-5-yl)-7′-nitro-1′,2′,3′,4′,4a′,5′,10′,11a′-octahydrospiro[cyclohexane-1,11′-dibenzo[ b , e ][1,4]diazepine] (7d): Red powder; mp >300 ˚C. IR (KBr): 3394, 3368, 3065, 2932, 2857, 1594, 1524, 1493, 1467, 1327, 1272 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 28 H, 14 × CH2 of c-Hex), 2.86 (m, 1 H, CH), 4.55 (m, 1 H, CH of c-Hex), 5.08 (br s, 1 H, NH), 6.39 (br s, 1 H, NH), 6.65 (ABq, J = 8.7 Hz, 1H, ArH), 7.37 (ABq, J = 6.6 Hz, 1 H, ArH), 7.72 (br s, 1 H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 21.2, 21.3, 21.5, 24.8, 24.9, 25.2, 25.4, 25.8, 31.1, 34.7, 49.0, 57.8, 58.4, 58.7, 59.4, 111.0, 115.6, 118.4, 137.6, 140.2, 141.8, 162.3. Anal. Calcd for C25H35N7O2: C, 64.49; H, 7.58; N, 21.06. Found: C, 64.39; H, 7.48; N, 21.01.
{4a′-(1-Cyclohexyl-1 H -tetrazol-5-yl)-1′,2′,3′,4′,4a′,5′,10′,11a′-octahydrospiro[cyclohexane-1,11′-dibenzo[ b , e ][1,4]-diazepine]-7′-yl}(phenyl)methanone (7e): Yellow powder; mp >300 ˚C. IR (KBr): 3381, 3354, 2926, 2856, 1625, 1575, 1500, 1445, 1398, 1336 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 28 H, 14 × CH2 of c-Hex), 2.86 (m, 1 H, CH), 4.59 (m, 2 H, CH of c-Hex and NH), 6.13 (br s, 1 H, NH), 6.60 (ABq, J = 7.7 Hz, 1 H, ArH), 6.83 (ABq, J = 8.1 Hz, 1 H, ArH), 7.38 (s, 1 H, ArH), 7.50-7.60 (m, 5 H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 21.4, 21.5, 25.0, 25.3, 25.5, 25.9, 32.0, 32.9, 34.8, 37.8, 49.6, 57.6, 58.4, 58.9, 117.7, 119.7, 122.8, 128.7, 129.3, 131.7, 137.7, 139.2, 139.4, 162.7, 194.3. Anal. Calcd for C32H40N6O: C, 73.25; H, 7.68; N, 16.02. Found: C, 73.14; H, 7.58; N, 15.93.
2-(1-Cyclohexyl-1 H -tetrazol-5-yl)-2,4,4,7-tetramethyl-2,3,4,5-tetrahydro-1 H -benzo[ b ][1,4]diazepine (7f): White powder; mp 202-204 ˚C. IR (KBr): 3381, 3306, 2928, 2862, 1600, 1525, 1478, 1451, 1398, 1309 cm-¹. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 1.00-2.10 (m, 23 H, 5 × CH2 of c-Hex, 4 × CH3 and 1 × CH), 2.78 (ABq, J = 14.1 Hz, 1 H, CH2), 4.96 (m, 1 H, CH of c-Hex), 5.69 (br s, 1 H, NH), 6.37 (br s, 1 H, ArH), 6.38 (ABq, J = 7.7 Hz, 1 H, ArH), 6.56 (br s, 1 H, NH), 6.62 (ABq, J = 7.7 Hz, 1 H, ArH). ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 20.6, 20.8, 25.1, 25.4, 31.5, 31.6, 31.8, 32.0, 32.3, 32.9, 34.3, 51.6, 53.1, 55.8, 57.9, 117.7, 121.2, 121.4, 127.8, 134.4, 135.3, 160.1. MS: m/z = 354 (80) [M]+, 203 (80), 187 (100), 147 (80), 55 (23). Anal. Calcd for C20H30N6: C, 67.76; H, 8.53; N, 23.71. Found: C, 67.69; H, 8.45; N, 23.61.