Brønsted Acidic Ionic Liquid Accelerated Halogenation of Organic Compounds with N-Halosuccinimides (NXS)

The Brønsted-acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate [BMIM(SO3H)][OTf] was demonstrated to act efficiently as solvent and catalyst for the halogenation of activated organic compounds with N-halosuccinimides (NXS) under mild conditions with short reaction times. Methyl aryl ketones were converted into α-halo and α,α-dihaloketones, depending on the quantity of NXS used. Ketones with activated aromatic rings were selectively halogenated, however in some cases mixtures of α-halogenated ketone and ring-halogenated ketones were obtained. Activated aromatics were regioselectively ring halogenated to give mono- and dihalo-substituted products. The [BMIM(SO3H)][OTf] ionic liquid (IL-A) was successfully reused eight times in a representative monohalogenation reaction with no noticeable decrease in efficiency. An effective halogenation scale-up in this IL is also presented. The reactivity trend and the observed chemo- and regioselectiivities point to an ET process in these IL-promoted halofunctionalization reactions.


Introduction
Halogenated organic compounds are highly versatile starting materials and intermediates in organic and organometallic chemistry and their production has been under constant investigation. The topic has been extensively reviewed [1][2][3][4]. Halogenation reactions are often associated with extensive waste production and relatively high process costs. Increasing environmental and climate changes urge the development of safer and "greener" synthetic pathways at reduced costs. The main reaction waste is usually the organic solvent used as reaction medium; moreover volatile organics have severe environmental and health issues.
N-halosuccinimides are very popular as halogen-transfer reagents [5][6][7][8][9]; however they are usually not reactive enough for direct halogenation and require a Lewis acid or a Brønsted acid catalyst. The catalysts employed are usually moisture sensitive, they are often metallic or strongly acidic, produce toxic waste, and are costly.

Results and Discussion
Halogenation of acetophenone (1) with NIS, NBS and NCS was studied in IL-A and IL-B (Figure 1), and α-halogenation took place with all three reagents ( Table 1). Iodination of 1 with 1.1 equiv. of NIS at 55 °C gave 2a with significantly higher conversion in IL-A than in IL-B; albeit with slightly lower selectivity (Table 1, entries 1 and 2). Similar results were obtained in bromination with NBS (entries 3 and 4). Bromination with 2.2 equiv. of NBS in IL-A resulted in quantitative dibromination, whereas in IL-B only monobromination took place (entries 5 and 6). Chlorofunctionalization with 1.1 equivalents of NCS in the both IL-A and IL-B gave 2c as the main product; whereas regioselectivity in IL-A changed after prolonged heating and 3c was obtained as the mayor product (entries [7][8][9]. Reaction with 2.2 equiv. of NCS in IL-B gave 2c as major and 3c as minor products, whereas 3c was formed exclusively in IL-A (entries 10 and 11). The results confirm the superior catalytic effect of the Brønsted acidic IL-A. Focusing on the effect of the structure of aryl methyl ketones 4 on halogenation with N-halosuccinimides in IL-A (Table 2), compound 4a was selectively converted into its α-iodo derivative 5a (entry 1). Functionalization of 4a with 1.1 equiv. of NBS was less selective, furnishing α-bromo-and α,α-dibromo-substituted ketones 6a and 7a (entry 2), while reaction with 2.2 equiv of NBS yielded 7a in excellent yield (entry 3). Chlorination with 2.2 equiv. of NCS selectively produced the α,α-dichloroketone 8a (entry 4).
2-Methylthiophene (40) was selectively converted into its 5-iodo derivative 41 in high yield with 1.1 equiv. of NIS. Reaction of 40 with NCS and NBS were also carried out successfully, however the isolated yields were low due to the volatility of the products.
Having discovered these highly efficient halofunctionalization reactions we then explored the possibility to make the process more economical through recycling and reuse of the IL. To explore this possibility, halogenation of acetophenone (1) with 1.1 equiv. of NIS was selected as a prototype reaction and the reaction was successfully repeated in reused/recycled IL-A for 8 cycles (Table 3) with no notable decrease in the conversions. To address the question of relative reactivity of the NXS reagent versus recycling and reuse, bromofunctionalization of 1 with 2.2 equivalents of NBS was examined (Table 3) over 5 repeated cycles, showing a gradual decrease in the dibromo derivative 3b with concomitant increase in monobromo product 2b. The data underscores the importance of IL-A as a promoter in these halogen-transfer reactions. Finally to explore the feasibility to perform these reactions on larger scales than reported thus far, bromination of 1 was carried out on a 9 mmol scale (a 9 fold increase), by using 19.8 mmols of NBS, and 27 mmol of IL-A. The 2,2-dibromo-1-phenylethanone 3b was obtained in 90% isolated yield after 40 minutes at 70 °C.
Concerning a plausible mechanism for halofunctionalization with NXS/[BMIM(SO 3 H)][OTf] systems, previous studies [44][45][46][47] have shown that ring halogenations of activated aromatics with NIS, NBS and NCS proceed through an electron transfer (ET) pathway as the main reaction channel. Based on the fact that in the present study under the reaction conditions employed only activated aromatics could be halogenated, and considering the observed chemo-and regioselectivity patterns, in all probability the ET reaction pathway is also most likely operating in these reactions. The role of acidic IL as a catalyst is to enhance the electrophilic character of NXS reagents by additional polarization of N-X bond. In halogenation of phenyl methyl ketones the acidic IL could also act as enolization catalyst, accelerating electrophilic addition of halogen. With the studied ketones, side chain halogenation is the primary event with ring halogenation manifesting only when the ring is highly activated (two methoxy groups).

General
All chemicals were purchased from commercial sources and used without further purification. Column chromatography was carried out using silica gel 60 (particle size: 0.063-0.2 mm) and preparative thin layer chromatography using PLC Silica gel 60 F 254 , 2 mm plates. Melting points were obtained with a Büchi 535 apparatus. For obtaining IR spectra on FTS3000-MX spectrometer, either a KBr pellet of the product was made or NaCl plates were used based on the physical state of product. NMR spectra were recorded on a Bruker Avance 300 DPX instrument ( 1 H: 300 MHz, 13 C: 75.5 MHz). The 1 H spectra were referred to an internal standard (0 ppm for TMS) or to the residual 1 H signal of CHCl 3 at 7.26 ppm and for CD 3 COCD 3 at 2.05 ppm (central line). The 13 C spectra were referred to the residual signal of CDCl 3 (77.0 ppm, central line) or CD 3 COCD 3 (30.8 ppm, central line). Elemental analysis was performed on a Perkin-Elmer 2400-Series 2 apparatus.

Scale up Experiment
To a stirred mixture of acetophenone (1, 9 mmol, 1.08 g) in IL-A (27 mmol, 9.95 g), N-bromo succinimide (19.8 mmol, 3.52 g) was added. The reaction mixture was stirred at 70 °C for 40 min. Then the mixture was cooled to room temperature and washed three times with dichloromethane. The combined organic fractions were washed with aqueous Na 2 S 2 O 3 and NaHCO 3 , dried over anhydrous Na 2 SO 4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was analyzed with 1 H-NMR. Purification of crude reaction mixture by chromatography yielded 2.25 g (90%) of 3b.

Recycling/Reuse of IL-A in Iodination of Acetophenone (1) with NIS
To a stirred mixture of acetophenone (1, 1 mmol, 120 mg) in IL-A (3 mmol, 368 mg), N-iodo succinimide (1.1 mmol, 225 mg) was added. The reaction mixture was stirred at 55 °C for 10 minutes. Then the mixture was cooled to room temperature and washed three times with dichloromethane. The combined organic fractions were washed with aqueous Na 2 S 2 O 3 and NaHCO 3 , dried over anhydrous Na 2 SO 4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was analyzed with 1 H-NMR. Purification of crude reaction mixture with chromatography yielded 212 mg (86%) of 2a. The IL-A from reaction was dried under reduced pressure and reused.

Conclusions
In summary, the Brønsted acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate ([BMIM(SO 3 H)][OTf]; IL-A) exhibited a notable catalytic effect in the halofunctionalization of aromatics with NXS and transformations were significantly faster as compared to IL-B. Aryl methyl ketones were α-and α,α-dihalogenated with high selectivity and in respectable yields. In the case of methoxy-substituted acetophenones, competing ring halogenation occurred. Activated arenes were selectively mono-and dihalogenated. A noteworthy feature is exclusive para-halogenation of anisole with NXS/IL-A. Recycling and reuse of [BMIM(SO 3 H)][OTf] was demonstrated in a prototype iodination reaction in eight cycles with no decrease in the conversion. The catalytic role of IL-A in dibromination with NBS is manifested in higher mono-to dihalogenation ratios when the reaction is repeated in the used IL. The feasibility for scale-up was also demonstrated in a representative case.