Abstract
Isothiocyanates (ITCs) are biologically active molecules found in several natural products and pharmaceutical ingredients. Moreover, due to their high and versatile reactivity, they are widely used as intermediates in organic synthesis. This review considers the best practices for the synthesis of ITCs using elemental sulfur, highlighting recent developments. First, we summarize the in situ generation of thiocarbonyl surrogates followed by their transformation in the presence of primary amines leading to ITCs. Second, carbenes and amines afford isocyanides, and the further reaction of this species with sulfur readily generates ITCs under thermal, catalytic or basic conditions. Additionally, we also reveal that in the catalyst-free reaction of isocyanides and sulfur, two—until this time overlooked and not investigated—different mechanistic pathways exist.
Highlights
Isothiocyanates (ITCs) are biologically active molecules occurring in cruciferous vegetables such as broccoli, watercress, cabbage and cauliflower suggested to have anti-tumour activity [1,2,3]
They are represented among natural products and pharmaceutical ingredients by the biologically relevant welwitindolinone and hapalindole alkaloids isolated from various algae species [4]
ITCs express significant antiproliferative activity as well [3,9], and the anti-microbial nature of certain ITCs makes them useful in food preservation [10]. They have been applied as covalent warheads for labelling cysteine or lysine residues in medicinal chemistry and chemical biology applications [11,12,13,14]. Due to their high and versatile reactivity, they are widely used as intermediates in organic synthesis [15,16]
Summary
Isothiocyanates (ITCs) are biologically active molecules occurring in cruciferous vegetables such as broccoli, watercress, cabbage and cauliflower suggested to have anti-tumour activity [1,2,3]. ITCs express significant antiproliferative activity as well [3,9], and the anti-microbial nature of certain ITCs makes them useful in food preservation [10] They have been applied as covalent warheads for labelling cysteine or lysine residues in medicinal chemistry and chemical biology applications [11,12,13,14]. The process is based on the nucleophilic attack of in situ generated carbene functionalities (1) on sulfur that behaves as an electrophile due to its empty d-orbitals [37] This approach leads to thiocarbonyl surrogates (2), usually dihalogenides, reacting with primary amines (3) to provide ITCs (4). Nucleophilic activation of sulfur, inducing the transformation of isocyanide (5) to ITC (4)
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