Synthesis Of Proline Thiohydantoin And Trisubstituted Thioureas

Thioureas can be used in various areas,such as pesticides,ion recognition,coordination chemistry and asymmetric catalysis etc.However,the synthesis of these compounds were mainly dependent on isothiocyanate,currently.The paper study the synthesis of proline thiohydantoin and tri-substituted thiourea derivatives by one-pot method using carbon disulfide as the thiocarbonyl instead of isothiocyanate.And it is divided into the following three parts.In the first part,firstly,through the screening of additive and temperature,the amino acid esters-substituted proline thiohydantoin derivatives were obtained in35-88%yields by employing an optimized protocol:amino acid esters?1.5 equiv.?,carbon disulfide?0.5 equiv.?,L-proline methyl ester hydrochloride?2.0 equiv.?and Et₃N?1.0 equiv.?in Toluene/H₂O?20:1?at 120 ^oC under Nitrogen for 24 h.Then,the primary aliphatic amines-substituted proline thiohydantoin derivatives were obtained in 28-78%yields by employing an optimized protocol:primary aliphatic amines?1.5 equiv.?,carbon disulfide?0.5 equiv.?,L-proline methyl ester hydrochloride?2.0 equiv.?and Et₃N?1.0 equiv.?in Toluene/H₂O?20:1?at 80 ^oC under Nitrogen for 24 h.The reaction system displayed well,and 5a was confirmed by single crystal diffraction.Considering the special structure of L-proline methyl ester hydrochloride that has a chiral carbon,in the second part,through the screening of additive,temperature and the equivalent of substrates,the optimized conditions were obtained as following:aniline?0.75 equiv.?,carbon disulfide?0.5 equiv.?,L-proline methyl ester hydrochloride?1.0 equiv.?and Et₃N?1.0 equiv.?in Toluene/H₂O?20:1?at 80 ^oC under Nitrogen for 24 h.And we constructe the tri-substituted thiourea compounds which contain aromatic amine structure and chiral center in 33-65%yields.Thus,we broke the challenge in the synthesis of these substances.The third part focuses on synthesizing tri-substituted thiourea derivatives that containing?-aminophosphonate by using diethyl??-aminobenzyl?phosphonate hydrochloride?1.5 equiv.?,secondary aliphatic amines?2.0 equiv.?,X?1.0 equiv.?and carbon disulfide?0.5 equiv.?in Toluene/H₂O?20:1?at 80 ^oC under Nitrogen for24 h.And the yield of products are 61-82%.The reliance on the isothiocyanate was eliminated.And enriching the types of thiourea derivatives in further.In addition,the products were characterized by ¹H NMR,¹³C NMR and HRMS.