Palladium-catalyzed ortho-halogenations of acetanilides with N-halosuccinimides via direct sp2 C–H bond activation in ball mills

A solvent-free palladium-catalyzed ortho-iodination of acetanilides using N-iodosuccinimide as the iodine source has been developed under ball-milling conditions. This present method avoids the use of hazardous organic solvents, high reaction temperature, and long reaction time and provides a highly efficient methodology to realize the regioselective functionalization of acetanilides in yields up to 94% in a ball mill. Furthermore, the current methodology can be extended to the synthesis of ortho-brominated and ortho-chlorinated products in good yields by using the corresponding N-halosuccinimides.


Results and Discussion
To begin our study, N-(p-tolyl)acetamide (1a) was chosen as the model substrate to react with NIS using Pd(OAc) 2 as the catalyst to optimize reaction parameters such as additive, reaction time and reagent ratio.The reaction of 1a (0.4 mmol) with NIS (0.4 mmol) was initially performed under the catalysis of Pd(OAc) 2 (10 mol %) in a Spex SamplePrep 8000 mixer mill at a frequency of 875 cycles per minute at room temperature for 3 h.Unfortunately, the desired iodinated product was not detected (Table 1, entry 1).Then, various acids were examined because the addition of acids into the reaction system could promote the C-H bond halogenation according to the previous literature [46].As desired, compound 2a was isolated in 87% yield when p-toluenesulfonic acid (PTSA) was employed (Table 1, entry 2).A control experiment was conducted for the reaction of 1a with NIS in the absence of Pd(OAc) 2 , yet still with PTSA as the promoter, and no iodinated product was furnished (Table 1, entry 3).The use of D-camphorsulfonic acid (D-CSA) or mesitylenesulfonic acid dihydrate provided inferior results than that obtained in the presence of PTSA (Table 1, entries 4 and 5 vs entry 2).Furthermore, no desired product was obtained when pyridine-2-sulfonic acid, 2-nitrobenzoic acid, 2-aminoethanesulfonic acid or tungstophosphoric acid hydrate (HPA) was used in the reaction (Table 1, entries 6-9).Thus, the combination of Pd(OAc) 2 with PTSA was essential for the reaction to take place effectively.Subsequently, the ratio of substrates was investigated, and the results demonstrated that the amount of both NIS and PTSA affected the product yield.Decreasing or increasing the amount of PTSA was not beneficial to the reaction (Table 1, entries 10 and 11).When the amount of NIS was increased from 1.0 equiv to 1.5 equiv and 2.0 equiv, the yield of the iodinated product did not further go up (Table 1, To demonstrate the generality of this protocol, the regioselective iodination of a series of acetanilides was then examined in the presence of Pd(OAc) 2 and PTSA under the ball-milling conditions (Table 2).Gratifyingly, the ortho-iodinated acetanilides were obtained in moderate to good isolated yields.
Both p-Me and m-Me-substituted acetanilides provided products 2a and 2b in excellent yields of 87% and 80%, respectively (Table 2, entries 1 and 2).As expected, 3,4-dimethylacetanilide underwent iodination successfully at the less sterically hindered ortho-position and gave product 2c in 85% yield (Table 2, entry 3).The unsubstituted acetanilide provided the desired product 2d in 77% yield (Table 2, entry 4).It is worth mentioning that the presence of a potentially reactive group, such as fluoro, chloro, and bromo substituents in the acetanilides was tolerable, and products 2e-i were isolated in 51-94% yields (Table 2, entries 5-9), highlighting the functional group compatibility of the current protocol.The presence of an acetyl group at the para-position of the phenyl ring of acetanilide 1j decreased the yield of the corresponding product 2j to 11% (Table 2, entry 10).Unfortunately, substrates bearing a strong electron-donating methoxy group and a strong electronwithdrawing nitro group could not afford any desired products, and the reason is not quite clear right now.
In an aim to investigate the influence of the milling frequency, the model reaction of 1a with NIS was conducted by employing different types of mixer mills with different milling frequencies.Ortho-iodized acetanilide 2a was furnished in 90% yield after milling for 2 h by using a Retsch MM 200 mixer mill (30 Hz, Scheme 1a).At a milling frequency of 50 Hz in a Spex SamplePrep 5100 mixer mill, the iodination was accomplished within 1.5 h to afford the corresponding product 2a in 92% yield (Scheme 1b).According to the above experimental results, it could be concluded that the higher milling frequency had a beneficial effect on the reaction efficiency in terms of product yield and reaction time.

Scheme 1:
The influence of the milling frequency on the reaction of 1a with NIS.
To illustrate the superiority of the ball-milling technique, the reaction was also investigated in an organic solvent.The reaction of 1a with NIS conducted in toluene at room temperature for 3 h provided the desired product 2a in only 49% yield, which was inferior to those obtained by our mechanochemical approaches (Scheme 2).
The plausible mechanism is proposed and depicted in Scheme 3. The addition of PTSA was essential for the present reaction.It is believed the more active Pd(OTs) 2 is formed in situ from Pd(OAc) 2 and TsOH [46,47].The formed Pd(OTs) 2 inserts into the ortho C-H bond of the anilides after coordination to the oxygen atom of the amide moiety, affording the species A. Oxidative addition of the species A with NIS generates the Pd(IV) complex B. Finally, the iodinated product is provided by reductive elimination along with regeneration of Pd(OTs) 2 in the presence of TsOH.It was intriguing to find that N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) could also be used as reaction partners to react with the representative acetanilide 1a under identical ball-milling conditions.The corresponding ortho-brominated and ortho-chlorinated products 3a and 4a were obtained in 73% and 77% yields, respectively (Scheme 4).

Conclusion
In summary, we have developed a solvent-free and efficient protocol to synthesize ortho-iodinated acetanilide derivatives with Pd(OAc) 2 as the catalyst and N-iodosuccinimide as the halogen source under mechanical milling conditions.This protocol shows its advantages in terms of high regioselectivity, simple operation and environmentally friendliness.In addition, the present protocol can be extended to the synthesis of orthobrominated and chlorinated acetanilides delivering good yields by using the corresponding N-halosuccinimides.

Table 1 :
Optimization of the reaction conditions.a 2 :NIS:additive.c Isolated yield.N.R. = no reaction.

Table 2 :
Substrate scope.a
c Isolated yield.