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

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

References and Notes

• For reviews, see:
• 1a Huang Z.-T. Wang M.-X. Heterocycles  1994,  37:  1233 
• 1b Huang Z.-T. Wang M.-X. Prog. Nat. Sci.  2002,  12:  249 
• 1c For our recent work, see: Yu C.-Y. Yang P.-H. Zhao M.-X. Huang Z.-T. Synlett  2006,  1835 
• 2 Huang Z.-T. Wang M.-X. J. Org. Chem.  1992,  57:  184 ; and references cited therein
• 3a Huang Z.-T. Wang M.-X. Synth. Commun.  1991,  21:  1167 
• 3b Huang Z.-T. Wang M.-X. Synth. Commun.  1991,  21:  1909 
• 4 Liu B. Wang M.-X. Huang Z.-T. Tetrahedron Lett.  1999,  40:  7399 
• 5 Wang M.-X. Liang J.-M. Huang Z.-T. J. Chem. Res., Synop.  1994,  166 ; J. Chem. Res., Miniprint 1994, 1001
• 6a Huang Z.-T. Liu Z.-R. Chem. Ber.  1989,  122:  95 
• 6b Wang L.-B. Yu C.-Y. Huang Z.-T. Synthesis  1994,  1441 
• 7a Huang Z.-T. Tzai L.-H. Chem. Ber.  1986,  119:  2208 
• 7b Huang Z.-T. Liu Z.-R. Heterocycles  1986,  24:  2247 
• 7c Huang Z.-T. Wang M.-X. J. Chem. Soc., Perkin Trans. 1  1993,  1085 ; and references cited therein
• 7d Jones RCF. Patel P. Hirst SC. Smallridge MJ. Tetrahedron  1998,  54:  6191 ; and references cited therein
• 8a Jones RCF. Patel P. Hirst SC. Tetrahedron Lett.  1989,  30:  5361 
• 8b Zhang J.-H. Wang M.-X. Huang Z.-T. Tetrahedron Lett.  1998,  39:  9237 
• 8c Zhang J.-H. Wang M.-X. Huang Z.-T. J. Chem. Soc., Perkin Trans. 1  1999,  2087 
• 9 Jones RCF. Patel P. Hirst SC. Turne I. Tetrahedron  1997,  53:  11781 
• 10 Zhang J.-H. Wang M.-X. Huang Z.-T. J. Chem. Soc., Perkin Trans. 1  1999,  321 
• 11a Gante J. Mohr G. Chem. Ber.  1975,  108:  174 
• 11b Gompper R. Toepfl W. Chem. Ber.  1962,  95:  2871 
• 11c Yokoyama M. Tohnishi M. Kurihara A. Imamoto T. Chem. Lett.  1982,  1933 
• 11d Seshadri S. Sanghavi NM. Naik RV. Tawate SR. Trivedi MN. Fruitwala MA. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1993,  32:  688 
• 11e Schwesinger R. Missfeldt M. Peters K. von Schnering HG. Angew. Chem.  1987,  99:  1210 
• 11f Cheng Y. Wang M.-X. Gan W.-X. Huang Z.-T. Synth. Commun.  1996,  26:  475 
• 11g Yu C.-Y. Wang L.-B. Huang Z.-T. Synth. Commun.  1996,  26:  2297 
• 12a Middleton WJ. Engelhardt VA. J. Am. Chem. Soc.  1958,  80:  2788 
• 12b Briel D. Dumke S. Wagner G. Olk B. J. Chem. Res., Miniprint  1991,  1841 
• 12c Tominaga Y. Yoshioka N. Kataoka S. Heterocycles  1996,  43:  1597 
• 12d Elgemeie GEH. Elghandour AH. Elzanate AM. Hussein AM. J. Chem. Res., Synop.  1997,  256 
• 13 Zhao W.-G. Liu Z.-X. Li Z.-M. Wang B.-L. Synth. Commun.  2003,  33:  4229 
• 14a Matsuda Y. Gotou H. Katou K. Matsumoto H. Chem. Pharm. Bull.  1989,  37:  1188 
• 14b Ram VJ. Srivastava P. Agarwal N. J. Chem. Res., Synop.  2001,  421 
• 15 Reid W. Aboul-Fetouh S. Tetrahedron  1988,  44:  7155 

16

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.

17

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