Studies On The Synthesis Of Thiourea/Urea And Benzoazole Compounds By Isothiocyanate In Water

Isothiocyanates are important synthetic intermediates with versatile chemical reactivity in organic synthesis in the fields of biomedicine and pesticides.In addition,isothiocyanates was also used for the construction of biologically relevant sulfur-containing heterocyclic scaffolds and other compounds containing both nitrogen and sulfur/oxygen in their backbones.Therefore,it is challenging to develop mild,efficient,economical and environmental strategies by utilizing isothiocyanates as readily available and inexpensive raw materials.On the other hand,as vital structural motifs,2-aminobenzoxazole are widely used as key intermediates in the synthesis of organic reagents,medicinal,pharmaceuticals,fuels,auxiliaries,etc.Recently,it is a highly promising result on behalf of green and sustainable chemistry by using water as an ideal solvent in organic synthesis due to its inexpensive and environmentally friendly characters.In this paper,the new menthods for the synthesis of N,N’-disubstituted thiourea/urea and 2-aminobenzoxazole derivatives were established respectively,by using the self-reaction of aryl isothiocyanates or the cyclizing of isothiocyanates and othro-substituted amines to construct new C=O（S）bond or C-C/C-X（O,N,S）bonds via oxidative desulfuration or dehydrogenative/cyclization.The main research contents are as follows:1)A direct approach to N,N’-diarylsubstituted urea/thiourea from the self-condensation reactions of aryl isothiocyanates in water under four conditions has been developed（Scheme 1）.Scheme 1This access tolerated a wide range of functional groups on the aromatic ring,providing an practical and environment-friendly process to N,N’-diaryl substituted thiourea/urea in moderate to excellent yields from safe and easily available starting materials.Generally,all the reaction proceeded well under DTBP/Et₃N/K₂CO₃ system（condition B）in most cases.When sterically bulky substrate isothiocyanate was used,the KOH/DTBP system exhibited higher efficiency and reactivity;the Et₃N-catalyzed synthesis of thioureas is more suitable for the substrate bearing strong electron-withdrawing group such as p-CF₃.A plausible mechanism of the desulphurized self-condensation reaction for urea was also proposed and the role of DTBP and cupper catalyst in the present strategy was demonstrated with the help of ESI mass spectrometry of intermediate studies.The structure of products was confirmed by ¹H NMR,¹³C NMR.2)A mild,efficient,economical and environmentally friendly one-pot synthesis of 2-aminobenzoxazole derivatives was developed via the oxidative desulfuration and subsequent dehydrogenative/cyclization of aryl isothiocyanates and o-aminophenol/2-aminothiophenol or 2-aminobenzyl alcohol in water.N-substituted2-aminobenzoxazole,benzothiazole and benzoxazine compounds were obtained respectively in moderate to excellent yields by using Cu₂O as catalyst and TBAB as additive in 90 ^oC after 5h in air（Scheme 2）.Scheme 2Phenyl isothiocyanates and 2-aminothiophenol were selected as the model substrates to optimize the reaction conditions.With the optimal conditions in hand,we then evaluated the generality of this transformation.Generally,several2-aminophenols（2a-2k）and isothiocyanates（1a-1l）,could be amenable to the reaction,affording the corresponding products in 37%-99%yields smoothly.And the electronic and sterical properties have no significant effect on the reaction yields.A plausible mechanism was proposed based on control experimental results and literatures.The structure of target products was confirmed by ¹H NMR,¹³C NMR;15new compounds were further confirmed by HRMS.