Letter pubs.acs.org/journal/ascecg
Environmentally Safe Condition for the Synthesis of Aryl and Alkyl Sulfonyl Hydrazones via One-Pot Reaction Micael R. Cunha,§,† Maurício T. Tavares,§,† Camila F. Carvalho,† Nuno A. T. Silva,† Alfredo D. F. Souza,† Gustavo J. V. Pereira,† Fábio F. Ferreira,‡ and Roberto Parise-Filho*,† †
Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Faculty of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, Sao Paulo, Sao Paulo 05508-020, Brazil ‡ Center of Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo André, Sao Paulo 09210-580, Brazil S Supporting Information *
ABSTRACT: Sulfonyl hydrazones were synthesized by onepot reaction using sulfonyl chlorides, hydrazine hydrate and aldehydes under mild, cheap and environmental safe conditions. The optimized reaction afforded nine products with yields higher than 94% and four products with yields between 34% and 83%. Also, this paper reports, for the first time, the reduction of hydrazine amount (1.2 equiv) in sulfonyl hydrazones synthesis, presenting an excellent perspective to the sustainable production of new drug candidates. KEYWORDS: Sulfonyl hydrazone, Hydrazide, Green chemistry, Green solvent, One-pot synthesis
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INTRODUCTION Hydrazones have a diverse biological and pharmacological properties and can be associated with other functional groups to generate important molecular entities.1 Sulfonyl hydrazones are well-known for their pharmacological effects,1 such as enzymatic modulation,2,3 analgesia,4 antifungal5 and antibacterial potential,6−8 and can act as anti-Alzheimer,9 antinociceptive,10,11 antidepressant,12 antineoplastic activity13−17 and antidiabetic agents18,19 (Figure 1). Commonly, several steps precede the synthesis of sulfonyl hydrazones (Figure 2). First, the reaction of thiol with oxidizing agents such as H2O2 affords the correspondent sulfonic acid.20−23 Furthermore, the addition of chlorinating agents such as SOCl2,24 POCl2,25 PCl5,26 and trichlorocyanidine27 to sulfonic acid provides the desired sulfonyl chlorides.28,29 Other
Figure 2. General scheme for the synthesis of sulfonyl hydrazones (shown in black). Highlighted in blue is our proposed approach.
possibilities involve bubbling Cl2 into aqueous solution or the use of tetraalkylammonium chloride salt with N-chlorosuccinimide, both can produce directly the sulfonyl chloride from thiol.28 Then, sulfonyl chloride reacts with excess of hydrazine hydrate, generating the sulfonyl hydrazide.2,30−33 Finally, to obtain the target compound, the addition of sulfonyl hydrazide with aldehydes or ketones can be carried out using protic or aprotic solvents, such as ethanol, methanol, tetrahydrofuran or n-butanol, with further addition of glacial acetic acid34 with or without heating.35,36 Received: January 28, 2016 Revised: February 29, 2016
Figure 1. Biological properties of sulfonyl hydrazone scaffold. © XXXX American Chemical Society
A
DOI: 10.1021/acssuschemeng.6b00193 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Letter
ACS Sustainable Chemistry & Engineering Table 1. Survey of Reaction Conditionsa
a
entry
equiv I
equiv II
equiv III
solvent
1 2 3 4
1.0 1.0 1.0 1.0
1.2 1.2 1.2 1.2
10.0 5.2 1.2 1.2
THF/MeOH EtOH EtOH EtOH
b
equiv Et3N
2.0 2.0
acid (cat)
yield (%)
HCl
63b,c −d,g −e,g 99f
c
All reactions were monitored by TLC. Two-step reaction, global yield. Reagent condition: (i) 1-butanesulfonyl chloride (1 mmol), hydrazine hydrate (10 mmol), THF, 0 °C−r.t., 1 h. (ii) vanillin (1.2 mmol), MeOH, 60 °C, 5 h. dOne-pot condition: (i) 1-butanesulfonyl chloride (1 mmol), hydrazine hydrate (5.2 mmol), EtOH, 0 °C−r.t., 1 h. (ii) vanillin (1.2 mmol), 60 °C, 5 h. eOne-pot condition: (i) 1-butanesulfonyl chloride (1 mmol), hydrazine hydrate (1.2 mmol), Et3N (2 mmol), EtOH, 0 °C−r.t., 1 h. (ii) vanillin (1.2 mmol), 60 °C, 8 h. fOne-pot condition: (i) 1butanesulfonyl chloride (1 mmol), hydrazine hydrate (1.2 mmol), Et3N (2 mmol), EtOH, 0 °C−r.t., 1 h. (ii) vanillin (1.2 mmol), HCl (cat), 60 °C, 8 h. gProduct not isolated, very low yields (
