Chromatography‐Free Multicomponent Synthesis of Thioureas Enabled by Aqueous Solution of Elemental Sulfur

Abstract

The development of a new three-component chromatographyfree reaction of isocyanides, amines and elemental sulfur allowed us the straightforward synthesis of thioureas in water. Considering a large pool of organic and inorganic bases, we first optimized the preparation of aqueous polysulfide solution from elemental sulfur. Using polysulfide solution, we were able to omit the otherwise mandatory chromatography, and to isolate the crystalline products directly from the reaction mixture by a simple filtration, retaining the sulfur in the solution phase. A wide range of thioureas synthesized in this way confirmed the reasonable substrate and functional group tolerance of our protocol.

Convenient Multicomponent One‐Pot Synthesis of 2‐Iminothiazolines and 2‐Aminothiazoles Using Elemental Sulfur Under Aqueous Conditions

“…Starting from 2,6-dimethylphenyl isocyanide (1 a), benzylamine (2 a) and the aqueous polysulfide solution made of 1.0 M PMDTA and 0.4 M sulfur, we synthesized the thiourea 3 a at 80°C in 0.5 hour through an isothiocyanate intermediate detected by HPLC-MS. [54][55][56] Next, we did not isolate 3 a, but aimed to transform it using 2'-bromoacetophenone (4 a) to the corresponding iminothiazoline 5 a. Under basic conditions, however, the ring annulation with 4 a could not reach full conversion, a mixture of the product 5 a and the intermediate 6 a could be observed in HPLC-MS.…”

“…The reaction of 1 a, 2 a and the aqueous polysulfide solution made of 1.0 M PMDTA and 0.4 M sulfur at 80°C provide the thiourea 3 a in 89 % yield in 0.5 hour in water (Table 1, entry 1, see ref. [54] and supplementary information for detailed experimental description). Applying sulfur powder with no external base in the reaction of 1 a and 2 a at 80°C, we only observed traces of the expected thiourea in water (Table 1, entry 2).…”

“…[53] Certain nucleophiles, such as aliphatic amines are able to activate sulfur, generating open-chain ionic polysulfide anions which can be used in the atom efficient sulfuration of isocyanides leading to isothiocyanates. [54][55][56][57] Recently, we have published the preparation of aqueous solutions of sulfur that we applied in the chromatography-free and continuous flow synthesis of thioureas starting from isocyanides and both aliphatic and aromatic amines. [54,56] These methodologies enable the synthesis of symmetric or asymmetric thioureas from the isothiocyanate precursor isocyanides and the isolation of the pure products by a simple filtration.…”

“…[54][55][56][57] Recently, we have published the preparation of aqueous solutions of sulfur that we applied in the chromatography-free and continuous flow synthesis of thioureas starting from isocyanides and both aliphatic and aromatic amines. [54,56] These methodologies enable the synthesis of symmetric or asymmetric thioureas from the isothiocyanate precursor isocyanides and the isolation of the pure products by a simple filtration. In continuation of our interest in multicomponent reactions [58][59][60] and reactions involving elemental sulfur [54][55][56]61] we have aimed to further elaborate the application of aqueous polysulfide solutions.…”

“…[54,56] These methodologies enable the synthesis of symmetric or asymmetric thioureas from the isothiocyanate precursor isocyanides and the isolation of the pure products by a simple filtration. In continuation of our interest in multicomponent reactions [58][59][60] and reactions involving elemental sulfur [54][55][56]61] we have aimed to further elaborate the application of aqueous polysulfide solutions. Herein we present the multicomponent one-pot synthesis of diverse 2-iminothiazolines and 2-aminothiazoles starting from isocyanides, sulfur, amines, and 2'-bromoacetophenones (Scheme 1, eq.…”