Synthesis of Isothiocyanates Using DMT/NMM/TsO- as a New Desulfurization Reagent.

Łukasz Janczewski,Dorota Kręgiel,Beata Kolesińska

doi:10.3390/molecules26092740

Łukasz Janczewski, Dorota Kręgiel + Show 1 more

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https://doi.org/10.3390/molecules26092740

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Abstract

Thirty-three alkyl and aryl isothiocyanates, as well as isothiocyanate derivatives from esters of coded amino acids and from esters of unnatural amino acids (6-aminocaproic, 4-(aminomethyl)benzoic, and tranexamic acids), were synthesized with satisfactory or very good yields (25–97%). Synthesis was performed in a “one-pot”, two-step procedure, in the presence of organic base (Et3N, DBU or NMM), and carbon disulfide via dithiocarbamates, with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TsO−) as a desulfurization reagent. For the synthesis of aliphatic and aromatic isothiocyanates, reactions were carried out in a microwave reactor, and selected alkyl isothiocyanates were also synthesized in aqueous medium with high yields (72–96%). Isothiocyanate derivatives of L- and D-amino acid methyl esters were synthesized, under conditions without microwave radiation assistance, with low racemization (er 99 > 1), and their absolute configuration was confirmed by circular dichroism. Isothiocyanate derivatives of natural and unnatural amino acids were evaluated for antibacterial activity on E. coli and S. aureus bacterial strains, where the most active was ITC 9e.

Highlights

The obtained dithiocarbamate 3a was subjected to a microwaveassisted reaction with 1 equiv. of DMT/NMM/TsO− (1) as a desulfurating agent, producing the target isothiocyanate 4a with 90% yield in 3 min at 90 ◦ C (Table 1, entry 1)
The synthetic procedures presented in this study enabled the rapid and simple acquisition of a library of 20 structurally diverse isothiocyanates with good or very good yields (40–97%), high purity, and in the case of optically active compounds, low racemization
The synthesis of aliphatic isothiocyanates took place in aqueous medium in the presence of organic base, with only slightly lower yields compared to those obtained in DCM

Summary

Introduction

Isothiocyanates (ITCs) with the general formula R-N=C=S can be considered as compounds derived from biologically inactive glucosinolates [1,2,3,4]. They are produced by cruciferous vegetables such as broccoli, radishes, wasabi, and cauliflower as part of their defense mechanisms [5,6]. Natural as well as synthetic ITCs may have anti-bacterial [27,28,29,30], anti-fungal [31], and anti-glioblastoma effects [32] They are used in proteomics as probes [33,34], and in organic synthesis for the preparation of thioureas [35], thioamides [36], and heterocyclic compounds [37,38]

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