A new multicomponent reaction: unexpected formation of derivatizable cyclic α-alkoxy isothioureas

Abstract

An unexpected formation of cyclic α-alkoxy isothioureas has been achieved. As is known, the heterocyclic imines 2,5-dihydro-1,3-thiazoles are convertible to bisamides with the aid of a carboxylic acid and an isocyanide (Ugi reaction). Herein, it is shown that 2,5-dihydro-1,3-thiazole S-monoxides-the respective α-sulfinyl imines-are characterized by an altered reaction behavior. In a hitherto unknown multicomponent reaction the α-sulfinyl imines react with an isocyanide under acidic conditions in an alcoholic solution to the respective α-alkoxy isothioureas in good yields. In addition to the investigations on this unexpected synthesis the regioselectivity of the acylation of the synthesized compounds is described. A rearrangement, which is accelerated by EDC and HOBt, between both possible regioisomers was found.

Cyclic Imines in Ugi and Ugi-Type Reactions

“…Accordingly, they proposed a mechanism that is shown in Scheme . The sulfoxide 127 is protonated by the carboxylic acid and the nucleophilic attack of the alcohol 131 causes a ring-opening to form the sulfenic acid 132 .…”

“…In 2012, Martens et al discovered an unexpected formation of cyclic α-alkoxy isothioureas 128 (Scheme 40). 132 They wanted to investigate the effect of the sulfoxide moiety on the reactivity of the cyclic imine in JU-3CR. They prepared 3thiazoline S-monoxides 127 as cyclic imines by A-4CR followed by oxidation with the aid of mCPBA.…”

“…Accordingly, they proposed a mechanism that is shown in Scheme 41. 132 The sulfoxide 127 is protonated by the carboxylic acid and the nucleophilic attack of the alcohol 131 causes a ring-opening to form the sulfenic acid 132. The iminium ion 134 is generated by the nucleophilic attack of the isocyanide 5, followed by ring closure.…”

Thermolysis-Induced Two- or Multicomponent Tandem Reactions Involving Isocyanides and Sulfenic-Acid-Generating Sulfoxides: Access to Diverse Sulfur-Containing Functional Scaffolds

“…Maes et al reported a three-component reaction using isocyanides, aryl amines, and thiosulfonates under Cu­(I) catalysis, which was thought to proceed through an iminomethylene sulfonium intermediate . Martens et al reported that when certain 2,2- and 5,5,-tetraalkylated 2,5-dihydro-1,3-thiazole S-monoxides were treated with isocyanides in alcoholic solvents in the presence of benzoic acid, isothiourea derivatives were generated, and the reaction was supposed to proceed through a sulfenic acid related reaction pathway . These reports are supportive of our hypothesis that the reaction between benzyl isocyanide and phenyl tert -butyl sulfoxide may also go through sulfenic acid and form an iminomethylene sulfornium intermediate (Scheme ).…”

A Unified Approach for the Synthesis of Isourea and Isothiourea from Isonitrile and N,N-Dibromoarylsulfonamides

“…Recently, Sun et al developed a methodology for the synthesis of isothiourea from sulfoxide, isocyanide, and amine (Scheme e) . Another method was developed by Martens to produce cyclic α-alkoxyisothioureas by treating 3-thiazoline S -monoxides with isocyanides and alcohols under acidic conditions . It has also been reported that the addition of aryl diazoniumfluoroborates to aryl isothiocyanate made from aryl isothiocyanates and secondary amines in the presence of a base such as Et 3 N leads to the formation of N,N -dialkyl- N′ -arylcarbamimido­thioate …”