Preparation of α-Bromoketones and Thiazoles from Ketones with NBS and Thioamides in Ionic Liquids

Ketones smoothly reacted with NBS in the presence of a catalytic amount of p-toluenesulfonic acid to give α-bromoketones in good yields in typical ionic liquids, such as [bmim]PF6 and [bmpy]Tf2N, and the ionic liquids could be repeatedly used for the same reaction after the extraction of the α-bromoketones. Then, the one-pot conversion of ketones into thiazoles by the treatment with NBS, and subsequently with thioamides could be also carried out in [bmim]PF6 and [bmpy]Tf2N, respectively Thus, [bmim]PF6 and [bmpy]Tf2N could be used as recyclable reaction media for the preparation α-bromoketones and thiazoles from ketones.


Results and Discussion
The-bromination of ketones with NBS in the presence of a catalytic amount of p-toluenesulfonic acid (p-TsOH) was carried out at room temperature in both chloroform and typical room-temperature ionic liquids, such as 1butyl-3-methylimidazolium hexafluorophosphate ([bmim] PF 6 ), N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)imidate ([bmpy]Tf 2 N), and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF 4 ), as shown in Table 1.As a result, the corresponding -bromoketones were obtained in good to high yields in chloroform, [bmim]PF 6 , and [bmpy]Tf 2 N, respectively.In contrast, the -bromination of ketones did not proceed at all in [bmim]BF 4 .It is probable that the proton derived from p-TsOH could not promote the formation of enol forms of ketones due to the interaction between the proton of p-TsOH and BF 4 -.Practically, chemical shift of a hydrogen atom at 2-position of [bmim]BF 4 is 9.42 ppm (CDCl 3 , TMS), and is lower field than that of [bmim]PF 6 (8.42 ppm, CDCl 3 , TMS).This suggests that BF 4 -in [bmim]BF 4 interacts strongly with a proton of p-TsOH.Moreover, the yields of -bromoketones in [bmim]PF 6 and [bmpy]Tf 2 N are higher overall than those in chloroform, especially when propiophenone and nonanophe- none were used as substrate (entries 6, 7).When an ionic liquid such as [bmim]PF 6 was used, -bromoketone was obtained in good yields with good purity (>80%) by simple ether extraction of the reaction mixture and the ionic liquid reaction medium could be reused for the same reaction up to the 7 th time while maintaining the high yields of -bromoketone, as shown in Table 2.
Then, the one-pot conversion of ketones to thiazoles in both chloroform and ionic liquids, such as [bmim]PF 6 and [bmpy]Tf 2 N, was studied, as shown in Table 3.After the -bromination of ketones with NBS, thioamide and potassium carbonate were added to the reaction mixture, and the obtained mixture was stirred at room temperature.Overall, the yields in [bmim]PF 6 and [bmpy] Tf 2 N were higher than those in chloroform, particularly, when propiophenone with thiobenzamide, acetophenone with p-methoxythiobenzamide, and acetophenone with thioacetamide were used (entries 6, 10, 12).In the reaction with acetophenone in [bmim]PF 6 , thiazoles were obtained in good yields with moderate purity (>70%) by ether extraction, and the ionic liquid reaction medium could be reused for the same reaction, maintaining the good yields of thiazole up to the 5 th time, as shown in Table 4.

Conclusions
Typical room temperature ionic liquids, such as [bmim] PF 6 and [bmpy]Tf 2 N could be used for the conversion of ketones to -bromoketones with NBS and the conversion of ketones to thiazoles with NBS and subsequently thioamides in a one-pot manner.-Bromoketones and thiazoles could be obtained in good yields with good purity by simple ether extraction, and the ionic liquid reaction media could be reused for the same reaction while maintaining good yields and purity of the products.The present method offers a green approach to the preparation of -bromoketones and thiazoles in good yields with good purity from ketones with NBS and subsequently thioamides at room temperature.JNM-ECX400, JEOL-JNM-ECS400, and JEOL-JNM-ECA500 spectrometers.All chemical shifts were expressed in ppm,  units down field from TMS (Me 4 Si).Mass spectra were recorded on JEOL-HX-110 and JEOL-JMS-AT15 spectrometers.Melting points were determined on Yamato melting points apparatus Model MP-21.Silica Gel 60 (Kanto Kagaku Co.) and Wakogel B-5F were used for column chromatography and preparative TLC, respectively.

Typical Procedure for Conversion of Acetophenone into p-bromoacetophenone with NBS and p-TsOH•H 2 O in Ionic Liquids
To a solution of acetophenone (1 mmol) in [Bmim]PF 6 (1.5 mL) were added p-TsOH•H 2 O (0.2 mmol) and NBS (1.2 mmol).The mixture was stirred for 9.5 h at room temperature.After the reaction, the reaction mixture was extracted with diethyl ether (10 mL × 7).Then, the extract was poured into sat.aq.Na 2 SO 3 solution.The organic layer was dried over Na 2 SO 4 .After removal of the solvent under reduced pressure, -bromoacetophenone was obtained in the crude state.Purity was estimated by 1 H-NMR to be in the range of 70% -80%.Pure -bromoacetophenone was obtained by flash short column chromatography on silica gel (CHCl 3 :Hexane = 1:1) in 90% yield.

Typical Reuse of [Bmim]PF 6
After the extraction with diethyl ether, the ionic liquid was dried with a vacuum pump for 2 h at 80˚C.

Typical Procedure for Conversion of Acetophenone into 2,4-diphenylthiazole in Ionic Liquid with NBS and Benzthioamide
To a solution of acetophenone (1 mmol) in [Bmim]PF 6 (1.5 mL) were added p-TsOH•H 2 O (0.2 mmol) and NBS (1.2 mmol).The mixture was stirred for 9 h at room temperature.Then, benzthioamide (1.2 mmol) and K 2 CO 3 (1.1 mmol) were added to the reaction mixture and the obtained mixture was stirred for 5 h at room temperature.After the reaction, the reaction mixture was extracted with diethyl ether (10 mL × 10).Then, the extract was washed with sat.aq.Na 2 SO 3 solution.The organic layer was dried over Na 2 SO 4 .After removal of the solvent under reduced pressure, 2,4-diphenylthiazole was obtained in the crude state.Pure 2,4-diphenylthiazol was obtained by flash short column chromatography on silica gel (CHCl 3 :Hexane = 1:1) in 96 % yield.