Introduction
Thiophosgene, also known as thiocarbonyl chloride, is a red-orange liquid with a strong and suffocating odor. Thiophosgene is irritant to eyes (lachrymatory), skin and respiratory tracts; nevertheless, it is less toxic than phosgene. Thiophosgene reacts with nucleophilic sites in a number of functional groups like amines, alcohols, phenols, thiols, oximes, among others. A variety of heterocycles can be constructed when there are two nucleophiles close. As a consequence, thiophosgene has many applications in organic synthesis. It can be used to prepare isothiocyanates which serve as important scaffolds to provide compounds such as thioureas, thiazoles[1 ]
[2 ] or thiocarbamates.[3 ] Besides, thiones,[4 ] oxadiazolones,[5 ] thiocarbonates,[6 ] chlorothioformates,[7 ] and heptathiodicarbonates[8 ] can be synthetized with the employment of this reagent.
Thiophosgene was first prepared in small amounts in 1870 by Rathke;[9 ] then in 1887, Klason[10 ] developed a more efficient methodology via reduction of trichloromethanesulfenyl chloride with zinc.
Table 1 Use of Thiophosgene
(A) Recently, in the search of novel selective antitumor agents with more selectivity to destroy malignant cells, a group of optically active amines 1 were converted into isothiocyanates 2 using a solution of thiophosgene. Isothiocyanates were used as intermediates in the synthesis of a series of active thioureas and 2-aminobenzothiazoles evaluated in biological tests.[1 ]
(B) Figadère and co-workers[4 ] described the formation of a group of achiral 5,5-disubstituted N -acetyloxazolidine-2-thiones 4 using different amino alcohols 3 , thiophosgene and Et3 N in THF and subsequent acetylation on the nitrogen. The yields reported in the first step range from 20 to 44%. These heterocycles were studied as achiral auxiliaries in the C -glycosylation of lactol acetates.
(C) In 2011, Rozen’s group[6 ] reported a novel methodology for preparing aromatic difluoromethylene dioxides 8 from deactivated or mildly deactivated aromatic rings (5 ,6 ) using bromine trifluoride (BrF3 ). In order to introduce the fluorides without radical side reactions, they rationalized the inclusion of sulfur as a soft base using cyclic thiocarbonates 7 as intermediates, which were obtained by the reaction of aromatic derivatives with thiophosgene in 90–95% yields.
(D) Hagooly et al.[7 ] described a methodology to afford ROCF2 Cl ethers 10 , avoiding the formation of trifluoromethyl ethers as byproducts. First, the alcohol dissolved in Et3 N reacted with a solution of thiophosgene forming the respective chlorothioformates 9 in 80–95% yields. Then, the reaction of BrF3 with chlorothioformates provided the desired products in short reaction times.
(E) In 2013,[8 ] Weber et al. described the utility of thiophosgene in the synthesis of four-membered 1,3-dithietane rings in the search of a new pathway to form heptathiodicarbonates as potential RAFT reagents. The potassium salts 11 , 14 and 17 were treated with thiophosgene resulting in the formation of products characterized as 13 , 16 and 19 . Either the yields of the global reaction or the isolation of intermediates (12 and 18 ) depended on the solvent and the mode of addition of thiophosgene.
(F) In the synthesis of BODIPYs, Wang et al.[11 ] used the formation of dipyrrylketones 22 as the key step; such compounds were obtained in two stages: first, the reaction of pyrrole derivatives 20 and thiophosgene to get the corresponding dipyrrylthioketones 21 in 40 and 43% yield and then a subsequent oxidative hydrolysis.
(G) With the aim of finding new active molecules as potent HIV-1 TR inhibitors, Monforte and co-workers[12 ] designed a synthesis of a series of novel benzimidazolones and analogues. In this group of compounds, a derivative with a thiocarbonyl moiety 24 was synthesized; this product was obtained by the reaction of 23 with thiophosgene in acetone in 14% yield and showed high inhibitory potency.
