Organoiodine(III) mediated one-pot synthesis of N-substituted 2-aminothiazoles\jl

The synthesis of N-substituted 2-aminothiazoles has been achieved in one-pot by the su.:cessive treatment of acetophenones with [hydroxy(tosyloxy)iodo)benzene (HTIB), potassium thiocyanate and appropriate aniline.

2-Aminothiazoles are utilized as agents based on cyclogenase inhibition and also have application in therapy 1 , e.g. one of the first commercial synthetic drugs containing thiazole, 'sulphathiazole', (a sulphamide antibiotic) was derived from a 2-aminothiazole. There are two important routes which are commonly employed for the synthesis of 2-amino/substituted aminothiazoles. The first one is wellknown Hantzsch thiazole synthesis making the use of ahaloketones (HK) which are made to react with thioureas 2 . The second method involves preparation of a-thiocyanatoketones from the reaction of a-haloketones and potassium/ ammonium thiocyanate. The thiocyanatoketones on reaction with amines giveN-substituted 2-aminothiazoles. This method is known as Tcherniac's synthesis 3 . Since both of these routes involve HK which are associated with problems of handling and preparation due to highly lachrymatory nature, synthetic methods avoiding the use of HK are always preferred.
With this objective in mind, we have earlier shown that the use of a-tosyloxyketones readily accessible through the oxidation of enolizable ketones with [hydroxy-(tosyloxy) iodo]benzene (HTIB) can offer a superior replacement of HK in the Hantzsch thiazole synthesis. An important advantage of TK mediated syntheses reported by us is that it is possible to carry out these syntheses by using one-pot procedure starting from ketones 4 . In continuation of our previous results involving HTIB/ TK, we now report a new synthesis of N-substituted 2aminothiazoles as a superior alternative to the reported Tcherniac's synthesis.

Results and discussion
Based on our earlier strategies, it was expected that a-tosyloxyacetophenone (la) accessible through the oxidation of acetophenone with HTIB 5 , might undergo nucleophilic displacement by the attack of potassium thiocyanate to form a-thiocyanatoacetophenone (2a) 6 . a-Thiocyanatoacetophenone should then conveniently provide 4-phenyl-2-(N-phenylamino)thiazole (3a) by the action of aniline.
To examine the feasibility of the proposed strategy, acetophenone was subjected to oxidation with one equivalent of HTIB in acetonitrile to afford la. The latter was treated with one equivalent of potassium thiocyanate in ethanol. a-Thiocyanatoacetophenone (2a), thus obtained, was made to react with aniline. The reaction gave 3a in excellent yield (81%) (Method A) (Scheme l ).
Schemel Ja Encouraged by successful preparation of 3a according to Method A involving separation of the intermediates Ia and 2a, we carried out the conversion la~3a in one-pot generating the intermediates Ia and 2a in situ (Method B). The method, indeed, afforded 3a in 74% yield.
The approach was fut1her generalized by using different acetophenones, propiophenone and anilines to obtain variously N-substituted 2-aminothiazoles.

Note
The known products were identified by comparing their melting points and spectral data with those reported in literature. It is to be noted that the compound 3d is already known in literature. However, the reported m.p. (110°) 7 did not agree with the m.p. of the product obtained from the present study. So, we confirmed the structure by its spectral and analytical data (Experimental). The structures of new thiazoles 3e-h obtained from this study were confirmed by spectral and analytical data ( 1 H NMR and HRMS).
In conclusion, the Jlll mediated approach involving TK offers a new example of one-pot convenient synthesis of N-substituted 2-aminothiazoles.

Experimental
Melting points were taken in open capillaries and are not corrected. 1 H NMR were taken on a Brucker 300 MHz instrument using TMS as internal standard.

Method B. One-pot synthesis of 4-phenyl-2-( N-phenylamino)thiazole (3a) :
To a solution of acetophenone ( 1.20 g, 10 mmol) in acetonitrile (20 cm 3 ) was added HTIB (4.31 g, II mmol) and the resulting solution was refluxed for 2 h. The solvent was distilled off in vacuo and 20 cm 3 of methanol was added to it. To the resulting suspension was added KSCN (0.97 g, 10 mmol) and the mixture was refluxed for I 0 min. Subse-• quent addition of aniline (0.93 g, 10 mmol) followed by refluxing for 5 hand usual work up (as given in Method A) gave 3a, m.p. l3r (lit. 139°), yield 1.86 g (74%).