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Synlett 2009(12): 2020-2022  
DOI: 10.1055/s-0029-1217529
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Highly Substituted Pyridines via a One-Pot, Three-Component Cascade Reaction of Malononitrile with Aldehydes and S-Alkylisothiouronium Salts in Water

Zhong-qing Wang, Ze-mei Ge*, Tie-ming Cheng, Run-tao Li*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. of China
Fax: +86(10)82716956; e-Mail: lirt@mail.bjmu.edu.cn;
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Publication History

Received 6 March 2009
Publication Date:
01 July 2009 (online)

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Abstract

A novel methodology for the synthesis of 2-amino-4-aryl(alkyl)-6-sulfanyl pyridine-3,5-dicarbonitriles via a one-pot, three-component reaction of structurally diversified aldehydes with various S-alkylisothiouronium salts and malononitrile in water has been developed. Utilization of S-alkylisothiouronium salts as thiol equivalents greatly broadens the application of the current method, and also makes the reaction more environmentally friendly.

Key words

Multicomponent reactions - 2-amino-4-aryl(alkyl)-6-sulfanyl pyridine-3,5-dicarbonitrile - S-alkylisothiouronium salts - thiols - green chemistry

    References and Notes

  • 1a Weber L. Curr. Med. Chem.  2002,  9:  2085 
    Search in Google Scholar
  • 1b Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 
    Search in Google Scholar
  • 1c Ramon DJ. Miguel Y. Angew. Chem. Int. Ed.  2005,  44:  1602 
    Search in Google Scholar
  • 1d Orru RVA. de Greef M. Synthesis  2003,  1471 
  • 1e Ugi I. Heck S. Comb. Chem. High Throughput Screening  2001,  4:  1 
    Search in Google Scholar
  • 1f Weber L. Illgen K. Almstetter M. Synlett  1999,  366 
  • 2a Cocco MT. Congiu C. Lilliu V. Onnis V. Eur. J. Med. Chem.  2005,  40:  1365 ; and references cited therein
    Search in Google Scholar
  • 2b Perrier V. Wallace AC. Kaneko K. Safar J. Prusiner SB. Cohen FE. Proc. Natl. Acad. Sci. U.S.A.  2000,  97:  6073 
    Search in Google Scholar
  • 2c Reddy TRK. Mutter R. Heal W. Guo K. Gillet VJ. Pratt S. Chen B. J. Med. Chem.  2006,  49:  607 
    Search in Google Scholar
  • 2d Guo K. Mutter R. Heal W. Reddy TRK. Cope H. Pratt S. Thompson MJ. Chen B. Eur. J. Med. Chem.  2008,  43:  93 
    Search in Google Scholar
  • 2e Beukers MW. Chang LCW. von Frijtag Drabbe Künzel JK. Mulder-Krieger T. Spanjersberg RF. Brussee J. Ijzerman AP. J. Med. Chem.  2004,  47:  3707 
    Search in Google Scholar
  • 2f Chang LCW. von Frijtag Drabbe Künzel JK. Mulder-Krieger T. Spanjersberg RF. Roerink SF. van den Hout G. Beukers MW. Brussee J. Ijzerman AP. J. Med. Chem.  2005,  48:  2045 
    Search in Google Scholar
  • 3a Kambe S. Saito K. Synthesis  1981,  531 
  • 3b Matrosova SV. Zav’yalova VK. Litvinov VP. Sharanin YA. Izv. Akad. Nauk SSSR, Ser. Khim.  1991,  1643 
  • 3c Elnagdi MH. Elghandour AHH. Ibrahim MKA. Hafiz ISA. Z. Naturforsch., B: Chem. Sci.  1992,  47:  572 
    Search in Google Scholar
  • 3d Dyachenko VD. Krivokolysko SG. Nesterov VN. Litvinov VP. Chem. Heterocycl. Compd.  1997,  33:  1430 
    Search in Google Scholar
  • 3e Dyachenko VD. Litvinov VP. Chem. Heterocycl. Compd.  1998,  34:  188 
    Search in Google Scholar
  • 3f Dyachenko VD. Litvinov VP. Russ. J. Org. Chem.  1998,  34:  557 
    Search in Google Scholar
  • 3g Quintela JM. Peinador C. Veiga MC. Botana LM. Alfonso A. Riguera R. Eur. J. Med. Chem.  1998,  887 
  • 3h Attia AME. Ismail AE.-HAA. Tetrahedron  2003,  59:  1749 
    Search in Google Scholar
  • 3i Evdokimov NM. Magedov IV. Kireev A. Kornienko A. Org. Lett.  2006,  8:  899 
    Search in Google Scholar
  • 3j Evdokimov NM. Kireev AS. Yakovenko AA. Antipin MY. Magedov IV. Kornienko A. J. Org. Chem.  2007,  72:  3443 
    Search in Google Scholar
  • 3k Ranu BC. Jana R. Sowmiah S. J. Org. Chem.  2007,  72:  3152 
    Search in Google Scholar
  • 4a Zhao Y. Ge ZM. Cheng TM. Li RT. Synlett  2007,  10:  1529 
    Search in Google Scholar
  • 4b Lei M. Shi LX. Li G. Chen S. Fang WH. Ge ZM. Cheng TM. Li RT. Tetrahedron  2007,  63:  7892 
    Search in Google Scholar
  • 5a Starks C. M., Liotta C. L., Halpern M.; Phase-Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives   Chapman & Hall; New York: 1994. 
  • 5b Halpern ME. Benefts and Challenges of Applying Phase-Transfer Catalysis Technology in the Pharmaceutical Industry, In Process Chemistry in the Pharmaceutical Industry   Gadamasetti KG. Marcel Dekker; New York: 1999.  p.283 
  • 5c Masaya I. Org. Process Res. Dev.  2008,  12:  698 
    Search in Google Scholar
  • 5d Takuya H. Keiji M. Chem. Rev.  2007,  107:  565 
    Search in Google Scholar
6

Representative Procedure for the Synthesis of Compound 3a
A mixture of benzaldehyde (106 mg, 1 mmol), malononitrile (132 mg, 2 mmol), NaOH (120 mg, 3 mmol), and SDS (29 mg, 0.1 mmol) in H2O (10 mL) was stirred for 10 min at r.t. The S-methylisothiouronium sulfate (139 mg, 1 mmol) was added. The reaction mixture was further stirred for 50 min until the completion of the reaction (monitored by TLC). The reaction mixture was then filtered and washed with H2O to give the crude solid, which was recrystallized from MeCN to furnish the crystals of 2-amino-4-phenyl-6-methyl-sulfanylpyridine-3,5-dicarbonitrile (238 mg, 89%); mp 295-296 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 2.59 (s, 3 H, SCH3), 5.67 (br s, 2 H, NH2), 7.50-7.55 (m, 5 H, Ph). ¹³C NMR (75 MHz, DMSO-d 6): δ = 12.79, 85.55, 93.49, 115.31, 115.46, 128.42, 128.71, 130.33, 133.98, 158.17, 159.72, 167.53. Anal. Calcd for C14H10N4S2: C, 63.14; H, 3.78; N, 21.04. Found: C, 63.13; H, 3.96; N, 21.24.
This procedure was followed for all the reactions listed in Table  [¹] . The unknown compounds were properly characterized by their spectroscopic (¹H NMR, ¹³C NMR) and elemental analysis. The known compounds were confirmed by ¹H NMR and mp which were consistent with the reported data (see Supporting Information).