Efficient conversion of substituted aryl thioureas to 2-aminobenzothiazoles using benzyltrimethylammonium tribromide

The reaction of molecular bromine (Br-2) with arylthioureas is known to produce 2-aminobenzothiazoles (Hugerschoff reaction). We show here that benzyltrimethylammonium tribromide (1, PhCH2NMe3Br3), a stable, crystalline organic ammonium tribromide (OATB), can be readily utilized as an alternative electrophilic bromine source. It is easier to control the stoichiometry of addition with an OATB, which minimizes aromatic bromination caused by excess reagent. We have developed a direct procedure from isothio-cyanates and amines using tetrabutylammonium thiocyanate (Bu4NSCN) and PhCH2NMe3Br3 to afford functionalized 2-aminobenzothiazoles. 2-Aminobenzothiazoles are broadly found in bioorganic and medicinal chemistry with applications in drug discovery and development for the treatment of diabetes,(1) epilepsy,2,3,4 inflammation 5 amyotrophic lateral sclerosis,(6) analgesia,(7) tuberculosis 8 and viral infections.(9) Investigations into the preparation of 2-aminobenzothiazoles can be traced to the early 1900s with the work of Hugerschoff, who found that an arylthiourea can be cyclized with liquid bromine in chloroform to form an 2-aminobenzothiazole (eq 1).(10,11) Although this reaction usually proceeds efficiently at room temperature, several drawbacks are associated with the use of liquid bromine, which is a highly toxic and corrosive reagent, and can be difficult to manipulate on small scale. As an alternative reagent to liquid bromine, organic ammonium tri-bromides (OATBs) such as benzyltrimethylammonium tribromide (1, PhCH2NMe3Br3) and tetrabutylammonium tribromide (2, Bu4NBr3) are high molecular weight, stable, crystalline solids, which can deliver a stoichiometric amount of bromine where small amounts are necessary for microscale reactions. For example, Bu4NBr3 and PhCH2NMe3Br3 are effective alternatives to bromine for the bromination of activated aromatic substrates,(12-14) alkenes,(14) and ketones.(15) To date, OATBs have not been reported as a substitute for bromine in the preparation of 2-alkylaminobenzothiazoles from arylthioureas. Herein, we describe an efficient method for the facile conversion of aryl thioureas to 2-aminobenzothiazoles with an equimolar amount of PhCH2NMe3Br3 under a variety of reaction conditions. In addition, this reagent has been used to prepare 2-aminobenzothiazoles via a one-pot procedure from isothiocyanates and amines or a substituted aniline and tetrabutylammonium. thiocyanate (Bu-4-NSCN).