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

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

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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).