Sustainable Three‐Component Synthesis of Isothioureas from Isocyanides, Thiosulfonates, and Amines

Abstract

Multiple applications of isothioureas as fine chemicals (or their precursors) are known, but a general sustainable method for their synthesis was hitherto unavailable. We report a novel general approach towards S-alkyl and S-aryl isothioureas through a copper(I)-catalyzed three-component reaction between amines, isocyanides, and thiosulfonates. The formal synthesis of a superpotent sweetener further illustrates the applicability of our method.

Copper‐Catalyzed N‐Aryl‐β‐enaminonitrile Synthesis Utilizing Isocyanides as the Nitrogen Source

“…Ther esults suggest that CuI does not act as as imple Lewis acid in this reaction. [26] Va riousk inds of bases were also screened. Cesium carbonate,w hich is not strong enough to deprotonate the benzylic proton of benzylc yanide,g avet he product in ap oory ield of 14% (Table 4, entry 7).…”

Copper‐Catalyzed Reaction of Aryl Isocyanides with Active Methylene Isocyanides and Arylsulfonothioates: Synthesis of Sulfur‐Containing Trisubstituted Imidazoles

“…Other copper catalysts including Cu, CuI, CuO as well as nickel catalyst NiO and iron catalyst Fe(acac) 3 were also investigated under similar reaction conditions (Table 1, entries 3-7). Other solvents such as THF, elicited a similar reactivity, while DCE, Toluene, DMSO or DMF could not improve the yield of the target product (Table 1, entries [10][11][12][13][14]. Screening different amounts of the Cu 2 O revealed that 15 mol% of Cu 2 O was the ideal amount ( Table 1, entries [8][9].…”

“…While, there are only five methodologies based on the concept of two components of isocyanide-isocyanide [3 + 2] cyclo-addition to construct imidazoles have been reported in the literature (Scheme 1, b). [10][11][12][13][14] Many groups such as Xu's group, [10] Song'group, [11] Orru's group, [12] Hosoya's group, [13a] and Reddy's group [13b] have been successfully constructed sulfur-containing compounds with arylsulfonothioates. CÀ S bond formation reactions have attracted increasing attention for their importance in natural products and functional materials.…”

“…In the past few years, arylsulfonothioates as thiolating agents have received increasing attention from the synthetic community of researchers. [10][11][12][13][14] Many groups such as Xu's group, [10] Song'group, [11] Orru's group, [12] Hosoya's group, [13a] and Reddy's group [13b] have been successfully constructed sulfur-containing compounds with arylsulfonothioates. Very recently, the reactions involving arylsulfonothioates have been well studied in our group.…”

“…To our delight, the desired product methyl 1-(4-nitrophenyl)-5-(phenylthio)-1H-imidazole-4-carboxylate (4 a) was formed in 74% yield after 4 h. The structure of 4 a was confirmed by NMR, HRMS and X-ray analysis (see the Supporting Information). When CuTC applied to the reaction instead of Cu 2 O, the reaction proceed smoothly to give 4 a in 64% yield ( [10][11][12][13][14]. Notably, increasing the concentration of the reaction revealed that 1 mL of CH 3 CN was the ideal amount ( Table 1, entry 15).…”