Yb?OTf?₃-Catalyzed Cyclization Reaction Of Donor-acceptor Oxiranes With N,N'-disubstituted Thioureas:A Domino Process To Trans-dihydropyrimidines

A number of five-membered oxa-heterocycles as important motifs are widely present in pharmaceutically active molecules.Donor-Acceptor oxiranes?D-A oxiranes?participating in[3+2]cycloaddition reactions with various unsaturated bonds as dipolarophiles have emerged as a powerful tool for the construction of various five-membered oxa-heterocycles.Recently aldehydes,ketone,imines,indoles,alkenes,alkynes,and nitriles as unsaturated compounds have been reported.To the best of our knowledge,C=S bonds as dipolarophiles participating in[3+2]cycloaddition with D-A oxiranes have been rarely reported.In this work,the N,N'-disubstituted thioureas were selected as potential dipolarophiles to react with D-A oxiranes in the presence of Lewis acids.Surprisingly,we did not obtain the expected 5-membered oxa-heterocycles in the presence of Yb?OTf?₃.Instead,we observed the unexpected formation of6-membered heterocyclic trans-dihydropyrimidines and elemental sulfur?S₈?,as determined by X-ray analysis.Of particular interest,the oxygen atom on the ring of the D-A oxiranes was directly transferred to the carbonyl oxygen at position C2 of trans-dihydropyrimidine,the O¹⁸-labeling experiments and additional experiments were also performed to gain further evidence.To gain mechanistic insights into this reaction,a series of experiments were conducted.In light of the above results and previous reports,the likely mechanism is proposed that:D-A oxirane 1a first underwent C-O bond cleavage in the presence of Yb?OTf?₃ to generate the 1,3-dipoles,which then reacted with N,N'-disubstituted thiourea 2 to form the[3+2]-cycloaddition A,in the case of CH₃NH group as the strong nucleophilic substituent,the intramolecular amine-ester exchange of A could take place to produce the bicyclo[2.2.1]B,which then underwent successive cleavage of C-S bond?bound to the NHCH₃?and C-O?bound to the CO₂Et?to complete oxygen-sulfur exchange,forming the thiirane analogue D.Subsequently,the addition of one free D to activated thiirane analogue Yb³⁺-D resulted in the formation of a thiiranium/thiolate zwitterion E that eliminated 3aa'to yield the dithietane intermediate F.Once F was formed,it quickly decomposed to yield3aa'and S₈.Moreover,the model reaction was performed in the presence of Zn?OTf?₂,affording 3aa'and intramolecular Michael addition of 3aa'occurred to afford trans-dihydropyrimidine,this reaction proves our conjecture.We report the unprecedented cyclization reaction of donor-acceptor oxiranes with N,N'-disubstituted thioureas to construct trans-dihydropyrimidines in this work.Preliminary reaction mechanism studies demonstrated that the reaction underwent sequential cycloaddition/amine-ester exchange/oxygen-sulfur exchange/desulfuration/Michael addition process,which provides a new way for the synthesis of trans-dihydropyrimidine compounds,and is closely combined with the modification of nucleoside compounds studied by our research group.