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Synlett 2007(5): 0761-0764  
DOI: 10.1055/s-2007-970757
LETTER
© Georg Thieme Verlag Stuttgart · New York

Reaction of Heterocyclic Ketene Aminals with Bis(methylthio)methylene Malononitrile: Synthesis of Polyfunctionalized Pyridine-Fused 1,3-Diaza-heterocycles from Heterocyclic Ketene Aminals

Jiang-Peng Liaoa,b, Ti Zhanga,b, Chu-Yi Yu*a, Zhi-Tang Huang*a
a Beijing National Laboratory for Molecular Sciences (BNLMS), Laboratory for Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. of China
b Graduate University, Chinese Academy of Sciences, Beijing 100049, P. R. of China
Fax: +86(10)62554449; e-Mail: yucy@iccas.ac.cn;
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Publication History

Received 22 November 2006
Publication Date:
08 March 2007 (online)

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Abstract

A simple method for the synthesis of polyfunctionalized pyridine-fused 1,3-diazaheterocycles has been developed via reaction of heterocyclic ketene aminals (HKAs) with bis(methyl­thio)methylene malononitrile.

Key words

heterocyclic ketene aminals - polyfunctionalized pyridine - 1,3-diazaheterocycles - synthesis - cascade reaction

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General Procedure for the Reactions of HKAs 1 or 2 with Bis(methylthio)methylene Malononitrile (3)
A stirred solution of 1.0 mmol of heterocyclic ketene animals 1 or 2 and 1.5 mmol of bis(methylthio)methylene malononitrile(3) in 40 mL of xylene was refluxed for 4-8 h. The reactions were monitored by TLC. When TLC indicated the formation of the products and the disappearance of the starting materials, solvents were removed by distillation under vacuum and the resulting residue was purified by column chromatography on silica gel (EtOAc) to afford the products.
Compound 4a: orange solid; mp 200 °C. IR (KBr): 3415, 3301, 2200, 1627, 1591, 1553, 767 cm-1. 1H NMR (300 MHz, CDCl3): d = 10.38 (s, 1 H, NH), 7.60-7.38 (m, 5 H, PhH), 7.26-6.30 (br, 1 H, NH), 4.17 (t, J = 5.5 Hz, 2 H, CH2), 3.53 (t, J = 5.5 Hz, 2 H, CH2), 2.26 (s, 3 H, SCH3), 2.19-2.11 (m, 2 H, CH2). 13C NMR (75 MHz, CDCl3): δ = 194.2, 157.5, 155.2, 153.3, 141.8, 131.8, 128.7, 128.2, 117.2, 98.4, 91.5, 41.8, 38.6, 20.0, 19.3. ESI-MS: m/z = 325 [M+ + 1]. Anal. Calcd for C17H16N4OS: C, 62.94; H, 4.97; N, 17.27. Found: C, 62.75; H, 5.06; N, 17.29.
Compound 4b: yellow solid; mp 184-185 °C. IR (KBr): 3310, 2198, 1614, 1575 cm-1. 1H NMR (300 MHz, CDCl3): δ = 10.12 (br, 1 H, 1NH), 7.52 (d, J = 8.43 Hz, 2 H, PhH), 7.37 (d, J = 8.43 Hz, 2 H, 2 PhH), 4.14 (t, J = 5.85, 6.00 Hz, 2 H, CH2), 3.51 (t, J = 5.73, 5.85 Hz, 2 H, CH2), 2.26 (s, 3 H, CH3), 2.19-2.11 (m, 2 H, CH2). 13C NMR (75 MHz, CDCl3): δ = 192.6, 157.1, 155.1, 153.4, 140.1, 138.0, 130.1, 128.5, 117.0, 98.1, 91.8, 41.8, 38.6, 19.9, 19.2. ESI-MS: m/z = 359 [M+ + 1]. Anal. Calcd for C17H15ClN4OS: C, 56.90; H, 4.21; N, 15.61. Found: C, 56.79; H, 4.19; N, 15.39.
Compound 4c: yellow solid; mp 208-210 °C. IR (KBr): 3311, 2197, 1616, 1599, 1572 cm-1. 1H NMR (300 MHz, CDCl3): δ = 10.31 (s, 1 H, NH), 7.64-7.58 (m, 2 H, PhH), 7.55-7.12 (br, 1 H, NH), 7.13-7.06 (m, 2 H, PhH), 4.12 (t, J = 5.8 Hz, 2 H, CH2), 3.49 (t, J = 5.8 Hz, 2 H, CH2), 2.26 (s, 3 H, CH3), 2.19-2.11 (m, 2 H, CH2). 13C NMR (75 MHz, CDCl3): δ = 192.6, 166.7, 163.3, 157.2, 155.1, 153.3, 137.8, 137.8, 117.1, 115.5, 115.2, 98.0, 91.5, 41.8, 38.6, 19.9, 19.2. ESI-MS: m/z = 343 [M+ + 1]. Anal. Calcd for C17H15FN4OS: C, 59.63; H, 4.42; N, 16.36. Found: C, 59.26; H, 4.44; N, 16.16.
Compound 4d: yellow solid; mp 160-162 °C. IR (KBr): 3313, 2197, 1600, 1568, 752 cm-1. 1H NMR (300 MHz, CDCl3): δ = 10.20 (br, 1 H, NH), 7.61-7.58 (m, 2 H, ArH), 6.91-6.88 (m, 2 H, ArH), 4.16-4.12 (t, J = 6.0 Hz, 2 H, CH2), 3.87 (s, 3 H, OCH3), 3.50-3.46 (t, J = 6.0 Hz, 2 H, CH2), 2.26 (s, 3 H, SCH3), 2.15-2.08 (m, 2 H, CH2). 13C NMR (75 MHz, CDCl3): δ = 193.0, 163.1, 157.3, 155.5, 152.8, 133.7, 131.2, 117.3, 113.5, 98.3, 90.1, 55.5, 41.9, 38.6, 19.8, 19.3. ESI-MS: m/z = 355 [M+ + 1]. HRMS-FAB: m/z calcd for C18H19N4O2S [M + H]+: 355.1223; found: 355.1218.
Compound 4e: yellow solid; mp 195-196 °C. IR (KBr): 3311, 2197, 1605, 1571, 763 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 10.21 (br, 1 H, NH), 7.43-7.40 (d, J = 7.7 Hz, 2 H, PhH), 7.13-7.11 (d, J = 7.7 Hz, 2 H, PhH), 6.90-5.60 (br, 1 H, NH), 4.08 (t, J = 5.9 Hz, 2 H, CH2), 3.42 (t, J = 5.9 Hz, 2 H, CH2), 2.33 (s, 3 H, CH3), 2.18 (s, 3 H, CH3), 2.09 (m, 2 H, CH2); 13C NMR (75 MHz, CDCl3): δ = 194.0, 157.6, 155.3, 153.1, 142.8, 138.8, 129.0, 128.9, 117.3, 98.3, 91.0, 41.8, 38.6, 21.7, 20.0, 19.3. ESI-MS: m/z = 339 [M+ + 1]. HRMS-FAB: m/z calcd for C18H19N4OS [M + H]+: 339.1274; found: 339.1273.
Compound 4f: yellow solid; mp 167-169 °C. IR (KBr): 3314, 2199, 1615, 1574 cm-1. 1H NMR (300 MHz, CDCl3): δ = 11.11 (br, 1 H, NH), 7.31-7.07 (m, 4 H, PhH), 7.00-6.40 (br, 1 H, NH), 4.12 (t, J = 5.8 Hz, 2 H, CH2), 3.50 (t, J = 5.8 Hz, 2 H, CH2), 2.40 (s, 3 H, CH3), 2.25 (s, 3 H, CH3), 2.17-2.09 (m, 2 H, CH2). 13C NMR (75 MHz, CDCl3): δ = 195.4, 158.0, 155.1, 153.8, 142.8, 136.7, 131.2, 130.0, 127.7, 125.3, 117.2, 100.7, 92.8, 41.8, 38.5, 20.2, 20.1, 19.2. ESI-MS: m/z = 339 [M+ + 1]. Anal. Calcd for C18H18N4OS: C, 63.88; H, 5.36; N, 16.56. Found: C, 63.43; H, 5.33; N, 16.19.
Compound 4g: yellow solid; mp 174-176 °C. IR (KBr): 3314, 2198, 1615, 1575, 1559, 758 cm-1. 1H NMR (300 MHz, CDCl3): δ = 10.31 (br, 2 H, 2 NH), 7.68-7.36 (m, 9 H, ArH), 7.20-6.60 (br, 1 H, NH), 4.16 (t, J = 5.9 Hz, 2 H, CH2), 3.51 (t, J = 5.9 Hz, 2 H, CH2), 2.28 (s, 3 H, CH3), 2.17-2.10 (m, 2 H, CH2). 13C NMR (75 MHz, CDCl3): δ = 193.7, 157.4, 155.3, 153.3, 144.6, 140.4, 139.9, 129.4, 128.9, 128.1, 127.2, 126.8, 117.3, 98.4, 91.3, 41.8, 38.6, 20.0, 19.3. ESI-MS: m/z = 401 [M+ + 1]. Anal. Calcd for C23H20N4OS: C, 68.98; H, 5.03; N, 13.99. Found: C, 69.65; H, 5.11; N, 13.98.
Compound 5a: yellow solid; mp 107-110 °C. IR (KBr): 3315, 2195, 1614, 1566, 1310, 751 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.60-7.38 (m, 7 H, PhH, 2 NH), 4.28-4.22 (m, 2 H, CH2), 3.98-3.92 (m, 2 H, CH2), 2.28 (s, 3 H, SCH3). 13C NMR (75 MHz, CDCl3): δ = 193.1, 158.8, 156.5, 152.9, 140.5, 132.2, 128.6, 128.2, 116.5, 98.4, 92.1, 45.0, 43.1, 20.0. ESI-HRMS: m/z calcd for C16H15N4OS [M + H]+: 311.0961; found: 311.0963.
Compound 5b: yellow solid; mp 150-152 °C. IR (KBr): 3315, 2196, 1589, 1311, 753 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 7.83 (d, J = 8.2 Hz, 2 H, ArH), 7.57 (d, J = 8.2 Hz, 2 H, ArH), 3.87-3.78 (q, 4 H, CH2CH2), 2.28 (s, 3 H, CH3). 13C NMR (75 MHz, DMSO-d 6): δ = 190.9, 153.8, 152.5, 146.2, 138.0, 136.2, 131.0, 130.8, 128.8, 128.3, 117.7, 51.2, 45.4, 17.9. ESI-HRMS: m/z calcd for C16H14ClN4OS [M + H]+: 345.0571; found: 345.0569.
Compound 5c: yellow solid; mp 201-204 °C. IR (KBr): 3351, 2195, 1593, 1311, 1232 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 8.31-7.96 (br, 2 H, 2 NH), 7.91-7.87 (m, 2 H, ArH), 7.34-7.28 (t, J = 8.8 Hz, 2 H, ArH), 3.90-3.74 (m, 4 H, CH2CH2), 2.28 (s, 3 H, CH3). 13C NMR (75 MHz, DMSO-d 6): δ = 191.2, 167.2, 163.8, 154.3, 152.9, 134.6, 132.5, 132.4, 118.3, 116.3, 116.0, 52.0, 45.9, 18.4. ESI-HRMS: m/z calcd for C16H14FN4OS [M + H]+: 329.0867; found: 329.0869.
Compound 5d: yellow solid; mp 129-131 °C. IR (KBr): 3311, 2191, 1616, 1599 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 7.71 (d, J = 8.3 Hz, 2 H, PhH), 7.55 (br, 2 H, 2 NH), 6.93 (d, J = 8.5 Hz, 2 H, PhH), 3.74 (s, 7 H, CH2CH2, OCH3), 2.18 (s, 3 H, SCH3). 13C NMR (75 MHz, DMSO-d 6): δ = 191.2, 163.8, 154.4, 152.9, 144.6, 131.9, 130.7, 118.5, 114.4, 114.1, 71.0, 56.0, 52.4, 45.8, 18.3. ESI-MS: m/z = 341 [M+ + 1]. Anal. Calcd for C17H16N4O2S: C, 59.98; H, 4.74; N, 16.46. Found: C, 60.27; H, 4.46; N, 16.16.
Compound 5e: yellow solid; mp 99-101 °C. IR (KBr): 3315, 2193, 1605, 1561, 1315, 754 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.52 (d, J = 8.1 Hz, 2 H, ArH), 7.36 (s, 2 H, 2 NH), 7.22 (d, J = 8.1 Hz, 2 H, ArH), 4.27-4.21 (m, 2 H, CH2), 3.98-3.92 (m, 2 H, CH2), 2.41 (s, 3 H, CH3), 2.28 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 192.8, 158.8, 156.5, 153.0, 143.2, 137.6, 128.9, 128.8, 116.6, 98.3, 91.9, 45.0, 43.1, 21.7, 19.9. ESI-MS: m/z = 325 [M+ + 1]. Anal. Calcd for C17H16N4OS: C, 62.94; H, 4.97; N, 17.27. Found: C, 62.88; H, 5.02; N, 16.95.
Compound 5g: yellow solid; mp 133-136 °C. IR (KBr): 3315, 2195, 1600, 1311, 755 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 7.91-7.73 (m, 6 H, ArH), 7.53-7.40 (m, 3 H, ArH), 3.88-3.80 (q, 4 H, CH2CH2), 2.30 (s, 3 H, CH3). 13C NMR (75 MHz, DMSO-d 6): δ = 192.1, 154.3, 153.0, 145.1, 139.5, 136.7, 130.2, 129.5, 128.8, 127.5, 127.4, 118.3, 52.0, 45.9, 18.4. ESI-HRMS calcd for C22H19N4OS [M + H]+: 387.1274; found: 387.1274.

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The crystal structure of 4a has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number: CCDC 633314.