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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

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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).