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Article

Switchable Site-Selective Benzanilide C(sp2)-H Bromination via Promoter Regulation

by
Yonghui Sun
*,†,
Qiyu He
†,
Xucheng Lv
,
Naizhen Zhang
,
Wei Yan
,
Jianghui Sun
and
Lili Zhuang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(12), 2861; https://doi.org/10.3390/molecules29122861
Submission received: 1 May 2024 / Revised: 11 June 2024 / Accepted: 14 June 2024 / Published: 16 June 2024
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
Regioselective benzanilide bromination that generates either regioisomer from the same starting material is desirable. Herein, we develop switchable site-selective C(sp2)-H bromination by promoter regulation. This protocol leads to regiodivergent brominated benzanilide starting from the single substrate via selection of promoters. The protocol demonstrates excellent regioselectivity and good tolerance of functional groups with high yields. The utility effectiveness of this method has been well exemplified in the late-stage modification of biologically important molecules.

1. Introduction

Brominated benzanilides are an important class of structures essential for the function of almost all modern pharmaceuticals and agrochemicals [1,2,3,4]. Because of the steric hindrance of -Br, the bromo group located in the ortho or para position of the benzanilide molecule produces different biological activities [5,6]. Indeed, in anti-hypertensive compounds and anti-cancer agents, the bromo group is in the ortho position, while it is in the para position in anti-depressant drugs or anti-microbials agents (Figure 1). Therefore, the acquisition and rapid screening of small molecule libraries containing diverse brominated benzanilides is an essential aspect of hit compounds discovery. More importantly, based on the diversity-oriented synthesis (DOS) strategy, C-C or C-N bond formation via cross coupling starting from brominated benzanilides will efficiently generate structurally diverse compound libraries, such as benzidine, phenylenediamine, etc. [7,8,9,10,11,12]. To date, various important small molecule modulators have been identified for “undruggable” targets from unbiased phenotypic screening of DOS-derived compound libraries [13,14,15,16]. However, the classic approach to the generation of brominated benzanilides involves a two-step process: bromination of aniline followed by the benzoylation of the resulting brominated product, which suffers from limitations such as poor selectivity, low yields, complex purification method, etc. (Scheme 1a) [17,18,19].
Because of the challenge of selectivity and efficiency, the practical application of regioselective halogenation of C-H activation in a substrate containing two or more arenes is still uncommon [20,21]. Over the past decade, direct functionalization of C(sp2)-H bonds has emerged as a powerful tool for generating new CAr-halogen bonds [22,23,24,25,26]. Among these, direct C-H cleavage, transition-metal-catalyzed functionalization of anilids [27,28,29,30], and hexafluoroisopropanol [31,32,33,34] (HFIP) promoted C-H activation of anilines are the most similar. Although these impressive approaches can be employed to construct halogenated anilids, to the best of our knowledge, directed C-H halogenation in terms of regioselectivity has not been previously described. For instance, knowledge about regioselective C(sp2)-H bromination of N-methyl-benzanilides and its corresponding application in synthesis of biologically important chemicals is still surprisingly underdeveloped. Stimulated by the previous diversification of bioactive agents by a controlled catalyst or photo-induced construction of C-halogen bonds reported by Yu [35,36,37] and MacMillan [38,39,40,41], we envisioned that the regioselective C-H functionalization of benzanilides could be achieved via utility of different catalysts (Scheme 1b). Herein, we report the use of HFIP and Pd(II) as promoters for regioselective C-H bromination of benzanilides to provide a convenient route for synthesis of diverse brominated benzanilide derivatives. When Pd(II) is employed as promoter, bromination occurs on the ortho position of aniline, while a reversed regioselective product is obtained with an HFIP promoter. Preliminary studies of regioselective bromination on other acylanilide substrates are also described.

2. Results and Discussion

Since different promoters generate various types of transition states based on the detailed mechanisms, regioselective bromination of benzanilides may occur with different promoters by activating distinct protons. To test our hypothesis, we conducted a model study using benzanilide (1) in the presence of NBS in the TFA/TFAA solvent system with Na2S2O8 as the terminal oxidant (Table 1). After the screening of palladium catalysts, we discovered that only Pd(OAc)2 and Pd(TFA)2 could promote C-H activation, and bromination occurred on the ortho position of the amino group to provide the brominated product 2a (entry 3–4). In contrast, PdCl2 and Pd/C failed to give the brominated benzanilides. Next, we turned our attention to other transition metal catalysts. However, cobalt, copper or nickel failed to promote the transformations (entry 7–8, 10–11). Delightfully, after a comprehensive screening of additives, we found that brominated product 2b could also be readily prepared under the condition of hexafluoroisopropanol (HFIP), and the bromination reaction occurred on the para position of the amino group (entry 9). The reactions typically proceeded to completion within 3 h at 70 °C. This initial result showed that Pd(II)- or HFIP-promoted regioselective bromination, with anilid as an effective directing group, could occur under optimized conditions (entry 6, 12).
With these results of the optimized conditions of Pd(II)- or HFIP-promoted regioselectivity in hand, we set out to explore the scope and robustness of this new method. As illustrated in Figure 2 and Figure 3, a variety of benzanilides were smoothly transformed into the corresponding brominated anilide products (2a–2j, 3a–3j) in excellent yields. The para-, meta-, and ortho-substituted benzoyl groups were well tolerated; only specific regioselective brominated benzanilides were observed. It is worth mentioning that different substrates use different reaction temperatures. Some substrates with electron-withdrawing groups (CF3- and NO2-) may require a higher reaction temperature because they have lower electron cloud density. Therefore, in these reactions, conditions should be tough. With all substrates, the corresponding regioselective bromination products could be consistently obtained. When Pd(OAc)2 was used as a catalyst, the bromination reaction occurred on the ortho position of the amino group, and para bromobenzanilides were obtained when HFIP was involved. Notably, a special example was 2-chloro-N-methyl-N-phenylacetamide. We were delighted to observe that anilide, containing an aliphatic acyl group rather than the benzoyl motif, could also be employed successfully to provide regioselective bromination products (2j, 3j). This phenomenon expands the application scope of this novel method for regioselective modification of anilides and benefits the diversity of small molecule libraries available for further bioactivity screening.
Since brominated iodobenzanilides are widely utilized in bioactive agents [42,43,44,45], to prove both the synthetic utility effectiveness of this method for large-scale synthesis, we prepared 2f and 3f on a gram scale under the optimized reaction conditions with only a 5 mol% catalyst (Scheme 2). Compared with conventional approaches requiring brominated alkylanilines, which are generally expensive, this method with operational simplicity is advantageous for rapid access to various kinds of ortho and para brominated benzanilides. We further showed the feasibility of this new reaction by performing the synthesis of biologically important molecules (Figure 2 and Figure 3). With Pd(II) as a catalyst, 2-fluoro-N-methyl-N-phenylbenzamide was readily converted to brominated compound 2i as an RORγ inverse agonists analogue in a good yield [46]. RORγ is mainly expressed in immune cells, promoting the differentiation of Th17 cells and producing the key factor IL-17. RORγ plays the corresponding biological functions in a variety of important inflammatory pathways. Recent studies have found that an RORγ inverse agonist is a new therapy for the treatment of castration-resistant prostate cancer (CRPC). This type of brominated compounds can be conveniently synthesized by our method with excellent chemoselectivity, which provides an opportunity to generate novel anti-malignancy agents, such as a the DUBTAC ligand for stabilizing RORγ from degradation. Accordingly, HFIP-promoted bromination could conveniently transform 2-chloro-N-methyl-N-phenylacetamide into anti-microbicidal agent 3j [47], while its ortho-brominated analogue was readily synthesized via a Pd(II) catalyst with good regioselectivity.
Further studies were performed to gain insight into the mechanisms, which are shown in Scheme 3. A consistent and significant kinetic isotopic effect value of 2.2 was observed with Pd(II) as a catalyst, indicating that C–H cleavage might be involved in the rate-limiting step of the ortho-bromination reaction. In parallel, with HFIP as the promoter, a KIE value of 1.6 was obtained, suggesting that the C–H activation step in para-bromination was partially turnover limiting. Taken together, during the whole transformation, other elementary steps (such as the ligand exchange step) either before or after C–H activation were also critical to the catalytic turnover rate.
Although detailed mechanisms remain to be ascertained, with all these results in hand, the proposed mechanisms of ortho and para bromination are shown in Scheme 4 and Scheme 5, respectively. With Pd(II) as the promoter, the catalytic cycle is proposed to involve four steps: (i) the ligand was transfered to form Pd(TFA)2, and palladacycle B was generated, (ii) oxidation by NBS to provide Pd(IV) intermediate C, (iii) a C–Br bond was formed via reductive elimination, (iv) Pd(II) was released to coordinate a new substrate. On the other hand, HFIP-promoted bromination also required an amide bond as the directing group. However, due to the steric repulsion from HFIP, intermediate D was more crowded, so the C–Br bond formation occurred on the para position of the amino group.

3. Materials and Methods

3.1. Materials

All commercial materials (Bidepharm (Shanghai, China), J&K Chemical Ltd. (Beijing, China), Energy Chemical (Shanghai, China), Alfa Aesar (Shanghai, China), Konoscience (Beijing, China), Mreda (Beijing, China) and Aladdin (Shanghai, China) were utilized without further purification. All benzoic acids, N-methylanilines, and anilines were purchased. All solvents were of analytical grade. The NMR spectra were generated on a Bruker AVANCE NEO 700 MHz (Bruker, Karlsruhe, Germany), JEOL JNM-ECZL600G 600 MHz (JEOL, Tokyo, Japan), JEOL-JNM-ECZ500R 500 MHz (JEOL, Tokyo, Japan), Q.ONE INSTRUMENTS-Quantum-1 400 MHz (Q.ONE INSTRUMENTS, Wuhan, China), Bruker AVANCEIII400 MHz (Bruker, Karlsruhe, Germany) spectrometer in CDCl3 using a solvent peak as the standard. Mass spectral analyses were performed with Thermo Scientific Q Exactive™ Plus (Thermo Scientific, Waltham, MA, USA). Flash column chromatography was performed on Qingdao Haiyang Chemical Co., Ltd. (Yantai, China) silica gel 60 (200–300 mesh). Analytical TLC was performed on Yantai Chemical Industry Research Institute (Yantai, China) silica gel 60 F254 plates, and the rotavapor was EYELA Rotavapor N-1300D-WB (EYELA, Tokyo, Japan).

3.2. General Procedure for N-Methyl-Benzanilides Preparation

A mixture of corresponding benzoic acid (5 mmol), EDCI (5.5 mmol), HOBT (5.5 mmol), and DMAP (0.5 mmol) in DMF (30 mL) was stirred for 2 min at room temperature in a round bottom flask. Then, Et3N (15 mmol) was added. After 5 minutes, N-methylaniline (4.5 mmol) was slowly added. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water, and the mixture was washed once with saturated aqueous NaCl and extracted with EtOAc. The organic layer was dried with anhydrous Na2SO4 and evaporated in vacuum to give the crude product, which was then purified by silica gel column chromatography to give N-methylbenzanilide.

3.3. General Procedure for Palladium-Catalyzed Bromination of Benzanilides

To a 15 mL sealed-tube were added benzanilide (0.10 mmol, 1.0 equiv), Na2S2O8 (0.12 mmol, 1.2 equiv), NBS (1.2 mmol, 1.2 equiv), Pd(OAc)2 (0.01 mmol, 0.1 equiv), and TFAA (0.1 mL). The reaction system was stirred at room temperature for 2 min. Then, TFA (0.9 mL) was added. The tube was sealed and heated. After completion of the reaction as determined by TLC (DCM:MeOH = 300:1), the reaction solution was allowed to cool to room temperature. Saturated aqueous NaHCO3 was added to the reaction solution and washed with dichloromethane. Then the organic phase was separated and dried over anhydrous Na2SO4. After removing the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired product.

3.4. General Procedure for HFIP-Catalyzed Bromination of Benzanilides

To a 15 mL sealed-tube were added benzanilide (0.10 mmol, 1.0 equiv), NBS (0.12 mmol, 1.2 equiv), TFAA (0.12 mmol, 1.2 equiv), and HFIP (1 mL). The tube was sealed and heated. After completion of the reaction as determined by TLC (DCM:MeOH = 300:1), the reaction solution was allowed to cool to room temperature. Saturated aqueous NaHCO3 was added to the reaction solution and washed with dichloromethane. Then the organic layer phase was separated and was dried over anhydrous Na2SO4. After removing the solvent in vacuo, the residue was purified by silica gel column chromatography to give the desired product.

3.5. Procedure for Gram Scale Reaction

3.5.1. N-(2-Bromophenyl)-4-Iodo-N-Methylbenzamide

To a 100 mL round bottom flask, following the general procedure 3.3, 4-iodo-N-methyl-N-phenylbenzamide (1.0 g, 2.97 mmol), Na2S2O8 (858 mg, 3.56 mmol), NBS (634 mg, 3.56 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), TFAA (3 mL), and TFA(27 mL) were added. The reaction mixture was stirred at 50 °C for 3 h. After completion of the reaction as determined by TLC, the residue was purified by silica gel column chromatography with a mixture DCM and MeOH as the eluent. (DCM:MeOH = 900:1).

3.5.2. N-(4-Bromophenyl)-4-Iodo-N-Methylbenzamide

To a 75 mL sealed tube, following the general procedure 3.4, 4-iodo-N-methyl-N-phenylbenzamide (1.0 g, 2.97 mmol) NBS (633.5 mg, 3.56 mmol), and TFAA (504.5 μL, 3.56 mmol) were used, with HFIP (25 mL) as the solvent. The reaction mixture was stirred at 85 °C in the sealed tube for 5 h. After completion of the reaction as determined by TLC, the residue was purified by silica gel column chromatography with a mixture of DCM and MeOH as the eluent. (DCM:MeOH = 900:1).

3.6. Characterization of Representative Substrates in Details

3-bromo-N-methyl-N-phenylbenzamide. Following the general procedure 3.2, 3-bromo-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1). 1H NMR (500 MHz, CDCl3) δ (ppm) 6.77 (t, J = 1.8 Hz, 1H), 6.62 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 6.52 (td, J = 7.0, 1.6 Hz, 2H), 6.46–6.42 (m, 1H), 6.40 (d, J = 7.8 Hz, 1H), 6.32–6.24 (m, 3H), 2.75 (s, 1H). 13C NMR (125 MHz, CDCl3) δ (ppm) 168.3, 143.7, 137.2, 132.0, 131.2, 128.7, 128.6, 126.5, 126.3, 126.3, 121.3, 37.8. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12BrNO [M+H]+: 290.0102, found 290,0206.
3-fluoro-N-methyl-N-phenylbenzamide. Following the general procedure 3.2, 3-fluoro-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel(eluent: petroleum ether/ethyl acetate = 20:1). 1H NMR (500 MHz, CDCl3) δ (ppm) 7.26–7.22 (m, 2H), 7.17 (dt, J = 8.3, 1.6 Hz, 1H), 7.14–7.10 (m, 1H), 7.03 (dt, J = 6.7, 3.4 Hz, 4H), 6.95–6.90 (m, 1H), 3.49 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 167.8, 160.6 (d, JC-F = 246.9 Hz), 143.0, 136.6 (d, JC-F = 7.1 Hz), 127.9 (d, JC-F = 7.9 Hz), 127.9, 125.5, 125.4, 123.0 (d, JC-F = 3.6 Hz), 115.3 (d, JC-F = 21.2 Hz), 114.3 (d, JC-F = 23.2 Hz), 37.0. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12FNO [M+H]+: 230.0981, found 230.0998.
2-fluoro-N-methyl-N-phenylbenzamide. Following the general procedure 3.2, 2-fluoro-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1). 1H NMR (500 MHz, CDCl3) δ (ppm) 7.33–7.27 (m, 1H), 7.23–7.14 (m, 3H), 7.15–7.09 (m, 1H), 7.08–7.02 (m, 2H), 6.98 (t, J = 7.7 Hz, 1H), 6.79 (t, J = 9.1 Hz, 1H), 3.48 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 165.7, 157.0 (d, JC-F = 248.9 Hz), 142.5, 130.1 (d, JC-F = 9.3 Hz), 128.4 (d, JC-F = 4.6 Hz), 127.9, 126.1, 125.9, 124.3 (d, JC-F = 18.3 Hz), 122.9, 114.5 (d, JC-F = 22.7 Hz), 36.5. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12FNO [M+H]+: 230.0981, found 230.0997.
4-iodo-N-methyl-N-phenylbenzamide. Following the general procedure 3.2, 4-iodo-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 15:1). 1H NMR (500 MHz, CDCl3) δ (ppm) 7.49 (dt, J = 8.8, 2.3, 1.8 Hz, 2H), 7.26–7.21 (m, 2H), 7.18–7.13 (m, 1H), 7.00 (d, J = 8.1 Hz, 4H), 3.47(s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 169.7, 144.7, 137.0, 135.4, 130.5, 129.5, 126.9, 126.9, 96.4, 38.6. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12INO [M+H]+: 338.0042, found 338.0038.
4-chloro-N-methyl-N-phenylbenzamide. Following the general procedure 3.2, 4-chloro-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1). 1H NMR (500 MHz, CDCl3) δ (ppm) δ7.26–7.19 (m, 4H), 7.16 (d, J = 7.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 3.47(s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 169.6, 144.8, 135.8, 134.4, 130.3, 129.4, 128.1, 127.0, 126.9, 38.6. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12ClNO [M+H]+: 246.0686, found 246.0680.
4-fluoro-N-methyl-N-phenylbenzamide. Following the general procedure 3.2, 4-fluoro-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1). 1H NMR (500 MHz, CDCl3) δ (ppm) 7.95–7.04 (m, 6H), 7.11–7.07 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.89–6.62 (m, 1H), 3.40 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 168.3, 161.9 (d, JC-F = 248.4 Hz), 143.6, 130.7, 129.8 (d, JC-F = 10.8 Hz), 128.0, 125.6, 125.4, 113.5 (d, JC-F = 23.1 Hz), 37.2. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12FNO [M+H]+: 230.0981, found 230.0973.
N-methyl-N-phenyl-4-(trifluoromethyl)benzamide. Following the general procedure 3.2, 4-fluoro-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1). 1H NMR (500 MHz, CDCl3) δ (ppm) δ 7.66–7.31 (m, 5H), 7.30–7.09 (m, 3H), 7.07–6.93 (m, 1H), 3.45(s, 3H) 13C NMR (125 MHz, CDCl3) δ (ppm) 167.9, 142.9, 138.1, 130.1 (q, JC-F = 32.9 Hz), 128.1, 127.7, 125.7, 125.6, 123.5 (q, JC-F = 3.9 Hz), 116.7, 37.1. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C15H12F3NO [M+H]+: 280.0949, found 280.0940.
N-methyl-4-nitro-N-phenylbenzamide. Following the general procedure 3.2, 4-fluoro-N-methyl-N-phenylbenzamide was obtained by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 5:1). 1H NMR (500 MHz, CDCl3) δ (ppm) 7.99 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.17–7.13 (m, 1H), 6.99 (d, J = 7.6 Hz, 2H), 3.49 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 167.7, 147.3, 143.1, 141.4, 128.9, 128.9, 126.7, 126.3, 122.3, 37.6. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12N2O3 [M+H]+: 257.0926, found 257.0918.

3.7. Characterization of Products in Details

N-(2-Bromophenyl)-N-methylbenzamide (2a). Following the general procedure 3.3, N-methyl-N-phenylbenzamide (21.1 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol), and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 70 °C in a sealed tube for 1.5 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2a in 60% yield. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.53 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.2 Hz, 3H), 7.09–7.05 (m, 2H), 3.39 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 171.1, 143.8, 133.8, 130.8, 129.9, 129.1, 128.5, 128.2, 127.7, 127.0, 122.8, 37.2. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12BrNO [M+H]+: 290.0102, found 290,0176.
N-(2-Bromophenyl)-N-methyl-4-(trifluoromethyl)benzamide (2b). Following the general procedure 3.3, N-methyl-N-phenyl-4-(trifluoromethyl)benzamide (28 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol), and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as the solvent. The reaction system was stirred at room temperature in a sealed tube for 12 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2b in 63% yield.1H NMR (500 MHz, CDCl3) δ (ppm) 7.56–7.52 (m, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.22–7.16 (m, 1H), 7.13–7.07 (m, 2H), 3.40 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 169.6, 143.0, 139.3, 134.0, 132.7, 131.7 (q, JC-F = 37.5 Hz), 130.6, 129.6, 128.8, 128.4, 124.8 (q, JC-F = 3.9 Hz), 122.8, 37.2. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C15H11BrF3NO [M+H]+: 357.9976, found 358.0049.
N-(2-bromophenyl)-4-fluoro-N-methylbenzamide (2c). Following the general procedure 3.3, 4-fluoro-N-methyl-N-phenylbenzamide (22.9 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol), and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as the solvent. The reaction system was stirred at room temperature in the sealed tube for 12 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2c in 70% yield. 1H-NMR (500 MHz, CDCl3) δ (ppm) 7.59–7.50 (m, 1H), 7.35 (dd, J = 8.6, 5.4 Hz, 2H), 7.18 (d, J = 6.8 Hz, 1H), 7.09 (dd, J = 6.7, 4.1 Hz, 2H), 6.83 (t, J = 8.5 Hz, 2H), 3.37 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 170.0, 164.4 (d, JC-F = 251.0 Hz), 143.7, 133.9, 131.8 (d, JC-F = 3.6 Hz), 130.6 (d, JC-F = 5.2 Hz), 130.5, 129.3, 128.7, 122.8, 114.9 (d, JC-F = 22.0 Hz), 37.3. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H11BrFNO [M+H]+: 308.0008, found 308.0081.
N-(2-Bromophenyl)-4-chloro-N-methylbenzamide(2d). Following the general procedure 3.3, 4-chloro-N-methyl-N-phenylbenzamide (24.6 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 50 °C in the sealed tube for 3 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2d in 95% yield. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.59 (d, J = 7.9 Hz, 1H), 7.36–7.28 (m, 2H), 7.23 (d, J = 6.3 Hz, 1H), 7.20–7.06 (m, 4H), 3.42 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 169. 9, 143.5, 133.9, 132.6, 130.6, 129.7, 129.3, 128.7, 128.3, 128.0, 122.8, 37.2. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H11BrClNO [M+H]+: 323.9713, found 323.9796.
4-Bromo-N-(2-bromophenyl)-N-methylbenzamide (2e). Following the general procedure 3.3, 4-bromo-N-methyl-N-phenylbenzamide (29.0 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 60 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2e in 79% yield. 1H-NMR (500 MHz, CDCl3) δ (ppm) 7.57–7.49 (m, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.23–7.15 (m, 3H), 7.09 (t, J = 7.3 Hz, 2H), 3.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 170.0, 143.4, 135.2, 134.6, 134.0, 131.0, 130.6, 129.9, 129.4, 128.7, 124.4, 37.3. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H11Br2NO [M+H]+: 367.9207, found 367.9289.
N-(2-Bromophenyl)-4-iodo-N-methylbenzamide (2f). Following the general procedure 3.3, 4-iodo-N-methyl-N-phenylbenzamide (33.7 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 50 °C in the sealed tube for 3 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2f in 81% yield. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.55 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1H), 7.15–7.03 (m, 4H), 3.37 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 170.1, 143.4, 136.9, 135.2, 133.9, 130.6, 129.8, 129.4, 128.7, 122.8, 96.5, 37.3. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrINO [M+H]+: 415.9069, found 415.9142.
N-(2-Bromophenyl)-3-fluoro-N-methylbenzamide (2g). Following the general procedure 3.3, 3-fluoro-N-methyl-N-phenylbenzamide (22.9 mg, 0.1 mmol), NBS (26.7 mg, 0.15 mmol), Na2S2O8 (35.7 mg, 0.15 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 30 °C in the sealed tube for 12 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2g in 76% yield. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.55 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 8.5 Hz, 2H), 7.14–7.08 (m, 4H), 6.93 (d, J = 8.8 Hz, 1H), 3.39 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 169.6, 162.0 (d, JC-F = 246.0 Hz), 143.3, 137.9 (d, JC-F = 7.3 Hz), 133.9, 130.6, 129.4 (d, JC-F = 4.0 Hz), 128.6, 126.9, 123.8, 122.8, 117.0 (d, JC-F = 21.4 Hz), 115.4 (d, JC-F = 22.8 Hz), 37.2. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrFNO [M+H]+: 308.0086, found 308.0085.
3-Bromo-N-(2-bromophenyl)-N-methylbenzamide (2h). Following the general procedure 3.3, 3-bromo-N-methyl-N-phenylbenzamide (29.0 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 50 °C in the sealed tube for 3 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2h in 78% yield. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.55 (d, J = 6.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.3 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 7.00 (t, J = 8.0 Hz, 1H), 3.37 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 169.3, 143.2, 137.6, 133.9, 132.9, 131.4, 130.6, 129.4, 129.2, 128.7, 126.5, 122.8, 121.8, 37.2. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11Br2NO [M+H]+: 367.9207, found 367.9287.
N-(2-Bromophenyl)-2-fluoro-N-methylbenzamide (2i). Following the general procedure 3.3, 2-fluoro-N-methyl-N-phenylbenzamide (22.9 mg, 0.1 mmol), NBS (21 mg, 0.12 mmol), Na2S2O8 (28.6 mg, 0.12 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at room temperature in the sealed tube for 12 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2i in 86% yield. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.49 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.22–7.13 (m, 2H), 7.06 (t, J = 7.7 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.85 (t, J = 9.0 Hz, 1H), 3.41 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 166.7, 158.2 (d, JC-F = 249.0 Hz), 157.3, 142.2, 133.5, 131.2 (d, JC-F = 8.2 Hz), 130.2 (d, JC-F = 2.6 Hz), 129.6, 128.5 (d, JC-F = 3.6 Hz), 128.3, 125.0 (d, JC-F = 17.1 Hz), 123.7 (d, JC-F = 3.5 Hz), 123.0, 115.5 (d, JC-F = 21.6 Hz), 36.4. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrFNO [M+H]+: 308.0008, found 308.0085.
N-(2-Bromophenyl)-2-chloro-N-methylacetamide (2j). Following the general procedure 3.3, 2-chloro-N-methyl-N-phenylacetamide (18.4 mg, 0.1 mmol), NBS (23.4 mg, 0.13 mmol), Na2S2O8 (31 mg, 0.13 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 80 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2j in 54% yield. 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.80 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.43–7.35 (m, 1H), 3.87 (q, J = 13.3 Hz, 2H), 3.34 (s, 3H). 13C NMR (150 MHz, CDCl3) δ(ppm) 166.2, 141.3, 134.2, 130.6, 130.0, 129.3, 123.2, 41.8, 36.7. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C9H9BrClNO [M+H]+: 261.9556, found 261.9637.
N-(2-bromophenyl)-N-methyl-4-nitrobenzamide (2k) Following the general proce-dure 3.3, N-methyl-4-nitro-N-phenylbenzamide (25.6 mg, 0.1 mmol), NBS (21.4 mg, 1.2 mmol), Na2S2O8 (28.6 mg, 1.2 mmol) and Pd(OAc)2 (10 mol%, 0.01 mmol) were used with TFA:TFAA = 0.9 mL:0.1 mL as solvent. The reaction system was stirred at 70 °C in the sealed tube for 3 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2l in 53% yield. 1H-NMR (700 MHz, CDCl3) δ (ppm) 8.03 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.18–7.09 (m, 2H), 3.42 (s, 3H). 13C NMR (175 MHz, CDCl3) δ(ppm) 168.8, 148.2, 142.5, 141.8, 134.1, 130.5, 129.9, 129.0, 128.9, 123.0, 122.8, 37.1. 13C NMR data were derived from Bruker AVANCE NEO 700 MHz. HRMS (ESI) calcd for C14H11BrN2O3 [M+H]+:335.0031, found 335.0040.
N-(4-Bromophenyl)-N-methylbenzamide (3a). Following the general procedure 3.4, N-methyl-N-phenylbenzamide (21.1 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (28 μL, 0.2 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 70 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3a in 73% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.38 (d, J = 8.7 Hz, 2H), 7.35–7.28 (m, 3H), 7.24 (d, J = 7.4 Hz, 2H), 6.98–6.90 (m, 2H), 3.50 (s, 3H). 13C NMR (125 MHz, CDCl3) δ(ppm) 170.6, 144.1, 135.6, 132.4, 130.0, 128.7, 128.5, 128.0, 120.0, 38.4. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H12BrNO [M+H]+: 290.0102, found 290.0179.
N-(4-Bromophenyl)-N-methyl-4-(trifluoromethyl)benzamide (3b). Following the general procedure 3.4, N-methyl-N-phenyl-4-(trifluoromethyl)benzamide (35.8 mg, 0.1 mmol), NBS (19.6 mg, 0.11 mmol), and TFAA (25 μL, 0.18 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 100 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3b in 82% yield. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.46 (d, J = 8.2 Hz, 2H), 7.40–7.34 (m, 4H), 6.90 (d, J = 8.5 Hz, 2H), 3.46 (s, 3H). 13C NMR (125MHz, CDCl3) δ(ppm) 169.1, 143.4, 132.7, 131.6 (q, JC-F = 32.7 Hz), 129.6, 129.0, 128.5, 125.1 (q, JC-F = 4.0 Hz), 122.6, 120.7, 38.5. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C15H11BrF3NO[M+H]+: 357.9976, found 358.0051.
N-(4-Bromophenyl)-4-fluoro-N-methylbenzamide (3c). Following the general procedure 3.4, 4-fluoro-N-methyl-N-phenylbenzamide (22.9 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (28 μL, 0.2 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 90 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3c in 83% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.40 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5, 2H), 6.95–6.89 (m, 4H), 3.50 (s, 3H). 13C NMR (125 MHz, CDCl3) δ(ppm) 169.5, 164.4 169.52, 163.43 (d, JC-F = 251.1 Hz), 144.0, 132.6, 131.6 (d, JC-F = 3.6 Hz), 131.1 (d, JC-F = 8.6 Hz), 128.4, 120.2, 115.1 (d, JC-F = 21.8 Hz), 38.5. 13C NMR data were derived from a JEOL-JNM-ECZ500R 500 MHz. HRMS (ESI) calcd for C14H11BrFNO [M+H]+: 308.0008, found 308.0088.
N-(4-Bromophenyl)-4-chloro-N-methylbenzamide (3d). Following the general procedure 3.4, 4-chloro-N-methyl-N-phenylbenzamide (24.6 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (28 μL, 0.20 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 90 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3d in 79% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.45–7.37 (m, 2H), 7.34–7.26 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.99–6.88 (m, 2H), 3.50 (s, 3H). 13C NMR (150 MHz, CDCl3) δ(ppm) 169.4, 143.8, 136.1, 133.9, 132.6, 130.2, 128.4, 128.3, 120.3, 38.5. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrClNO [M+H]+: 323.9713, found 323.9788.
4-Bromo-N-(4-bromophenyl)-N-methylbenzamide (3e). Following the general procedure 3.4, 4-bromo-N-methyl-N-phenylbenzamide (29 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (17 μL, 0.12 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 85 °C in the sealed tube for 5 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3e in 75% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.45–7.34 (m, 4H), 7.23–7.16 (m, 2H), 6.97–6.90 (m, 2H), 3.49 (s, 3H). 13C NMR (150 MHz, CDCl3) δ(ppm) 169.4, 143.8, 134.4, 132.6, 131.3, 130.4, 128.4, 128.4, 124.5, 120.4, 38.4. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11Br2NO [M+H]+: 367.9207, found 367.9278.
N-(4-Bromophenyl)-4-iodo-N-methylbenzamide (3f). Following the general procedure 3.4, 4-iodo-N-methyl-N-phenylbenzamide (33.7 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (17 μL, 0.12 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 85 °C in the sealed tube for 5 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3f in 73% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.61–7.51 (m, 2H), 7.37 (dd, J = 8.5, 1.6 Hz, 2H), 7.07–6.98 (m, 2H), 6.96–6.83 (m, 2H), 3.45 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 169.6, 143.7, 137.2, 135.0, 132.6, 130.4, 128.4, 120.4, 96.7, 38.5. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrINO [M+H]+: 415.9069, found 415.9145.
N-(4-Bromophenyl)-3-fluoro-N-methylbenzamide (3g). Following the general procedure 3.4, 3-fluoro-N-methyl-N-phenylbenzamide (22.9 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (17 μL, 0.12 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 85 °C in the sealed tube for 5 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3g in 86% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.40 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.25–7.14 (m, 1H), 7.08–6.97 (m, 2H), 6.95 (d, J = 8.2 Hz, 2H), 3.49 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 169.1, 162.2 (d, JC-F = 247.4 Hz), 143.6, 137.7 (d, JC-F = 7.2 Hz), 132.5, 129.7 (d, JC-F = 8.1 Hz), 128.4, 124.4 (d, JC-F = 3.1 Hz), 120.4, 117.1 (d, JC-F = 21.1 Hz), 115.9 (d, JC-F = 23.1 Hz), 38.4. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrFNO [M+H]+: 308.0086, found 308.0083.
3-Bromo-N-(4-bromophenyl)-N-methylbenzamide (3h). Following the general procedure 3.4, N-(4-bromophenyl)-N-methylbenzamide (29 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (17 μL, 0.12 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 85 °C in the sealed tube for 5 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3h in 96% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.53 (s, 1H), 7.45–7.32 (m, 3H), 7.11 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 7.4 Hz, 2H), 3.45 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 168.9, 143.5, 137.6, 133.0, 132.6, 131.8, 129.5, 128.4, 127.1, 122.2, 120.5, 38.4. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11Br2NO [M+H]+: 367.9207, found 367.9292.
N-(4-Bromophenyl)-2-fluoro-N-methylbenzamide (3i). Following the general procedure 3.4, 2-fluoro-N-methyl-N-phenylbenzamide (22.9 mg, 0.1 mmol), NBS (21.4 mg, 0.12 mmol), and TFAA (17 μL, 0.12 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 100 °C in the sealed tube for 5 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3i in 79% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.41–7.19 (m, 4H), 7.10–6.88 (m, 3H), 6.87–6.78 (m, 1H), 3.45 (s, 3H). 13C NMR (150 MHz, CDCl3) δ (ppm) 166.5, 157.93 (d, JC-F = 249.0Hz), 142.6, 132.1, 131.5 (d, JC-F = 8.1 Hz), 129.4, 128.5, 124.8 (d, JC-F = 17.0 Hz), 124.2, 120.7, 115.8 (d, JC-F = 21.6 Hz), 37.5. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C14H11BrFNO [M+H]+: 308.0008, found 308.0084.
N-(4-Bromophenyl)-2-chloro-N-methylacetamide (3j). Following the general procedure 3.4, 2-chloro-N-methyl-N-phenylacetamide (18.4 mg, 0.1 mmol), NBS (19.6 mg, 0.11 mmol), and TFAA (17 μL, 0.12 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 70 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 3j in 76% yield. 1H NMR (700 MHz, CDCl3) δ (ppm) 7.59 (s, 1H), 7.58 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H), 3.83 (s, 2H), 3.29 (s, 3H) 13C NMR (150 MHz, CDCl3) δ (ppm) 166.2, 141.8, 133.4, 128.9, 122.5, 41.3, 38.0. 13C NMR data were derived from JNM-ECZL600G 600 MHz. HRMS (ESI) calcd for C9H9BrClNO [M+H]+: 261.9556, found 261.9634.
N-(4-bromophenyl)-N-methyl-4-nitrobenzamide (3k) Following the general proce-dure 3.3, N-methyl-4-nitro-N-phenylbenzamide (25.6 mg, 0.1 mmol), NBS (26.7 mg, 0.15 mmol), and TFAA (21 μL, 0.15 mmol) were used with HFIP (1 mL) as the solvent. The reaction system was stirred at 70 °C in the sealed tube for 2 h. After the reaction was completed, the residue was purified by silica gel column chromatography to give 2l in 82% yield. 1H-NMR (700 MHz, CDCl3) δ (ppm) 8.07 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), 7.26 (d, J = 1.6 Hz, 2H), 6.91 (d, J = 6.9 Hz, 2H), 3.49 (s, 3H). 13C NMR (175 MHz, CDCl3) δ(ppm) 168.3, 148.2, 141.7, 132.8, 129.6, 129.0, 128.5, 123.3, 121.0, 38.4. 13C NMR data were derived from Bruker AVANCE NEO 700 MHz. HRMS (ESI) calcd for C14H11BrN2O3 [M+H]+:335.0031, found 335.0036.

4. Conclusions

In summary, a novel regioselective modification strategy was developed for the facile synthesis of a broad range of brominated benzanilides from easily accessible starting materials. When Pd(II) was utilized as a catalyst, bromination occured on the ortho position of the amino group. In contrast, a reversed site-selective product was obtained via an HFIP-promoted transformation. This method was found to be widely useful for the generation of a broad range of brominated anilides with excellent regioselectivity. These two types of small molecules are widely used in early-stage drug discovery. It was shown that C–H bromination could even be carried out at room temperature. The switchable reactions demonstrated excellent regioselectivity, good functional group tolerance, and high yields. Further studies into the mechanism and applications of this novel strategy are currently underway in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29122861/s1, 1H, 13C-NMR spectral data of all compounds are presented in the Supporting Information file.

Author Contributions

Y.S. performed the project; Y.S., Q.H., X.L., N.Z., W.Y., and L.Z. prepared all the products; Y.S. and J.S. provided the funding and conducted the data analysis; Y.S. prepared and checked the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2023-RC350-02).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Dudkin, V.; Fraley, M.; Wang, C.; Steen, J. Aminobenzotriazole Derivatives. WO 2010/114726, 7 October 2010. [Google Scholar]
  2. Wang, Q.; Guo, J.; Wang, Z.; Liu, Y.; Song, H.; Li, Y. Preparation of Trifluoromethylthiotryptamine Derivative and Their Application in Controlling Plant Virus and Fungicides. CN 113024562, 25 June 2021. [Google Scholar]
  3. Usui, S.; Oyama, K.; Araki, K.; Ushie, M.; Fukuchi, T. Novel 4-Pyridinecarboxamide Derivative and Agricultural and Horticultural Agents Containing Same as Active Ingredient. WO 2016/175017, 3 November 2016. [Google Scholar]
  4. De Colli, A.A.; Koolik, I.M.; Seminara, A.B.; Hatzios, S.K. A Propeptide-based Biosensor For The Selective Detection of Vibrio Cholerae Using an Environment-sensitive Fluorophore. Cell Chem. Biol. 2022, 29, 1505–1516. [Google Scholar] [CrossRef]
  5. Ibbeson, B.M.; Laraia, L.; Alza, E.; O’Connor, C.J.; Tan, Y.S.; Davies, H.M.L.; McKenzie, G.; Venkitaraman, A.R.; Spring, D.R. Diversity-oriented Synthesis as a Tool for Identifying New Modulators of Mitosis. Nat. Commun. 2014, 5, 3155. [Google Scholar] [CrossRef]
  6. Edkins, K.; Tweedy, J.; Fung, S.; Edkins, R.M. Steric Influence on Solvate Formation—A Comparison of Resorcylic Acid and Two Brominated Derivatives. Cryst. Eng. Comm. 2022, 24, 1368–1376. [Google Scholar] [CrossRef]
  7. Wang, Y.; Nguyen, H.P.; Xue, P.; Xie, Y.; Yi, D.; Lin, F.; Dinh, J.; Viscarra, J.A.; Ibe, N.U.; Duncan, R.E.; et al. ApoL6 Associates with Lipid Droplets and Disrupts Perilipin1-HSL Interaction to Inhibit Lipolysis. Nat. Commun. 2024, 15, 186. [Google Scholar] [CrossRef]
  8. Liu, S.; Dou, K.; Liu, B.; Pang, M.; Ma, P.A.; Lin, J. Construction of Multiform Hollow-Structured Covalent Organic Frameworks via a Facile and Universal Strategy for Enhanced Sonodynamic Cancer Therapy. Angew. Chem. Int. Ed. Engl. 2023, 62. [Google Scholar] [CrossRef]
  9. Rahman, A.A.; Butcko, A.J.; Songyekutu, E.; Granneman, J.G.; Mottillo, E.P. Direct Effects of Adipocyte Lipolysis on AMPK through Intracellular Long-chain Acyl-CoA Signaling. Sci. Rep. 2024, 14, 19. [Google Scholar] [CrossRef] [PubMed]
  10. Li, M.; Xiong, T.; Du, J.; Tian, R.; Xiao, M.; Guo, L.; Long, S.; Fan, J.; Sun, W.; Shao, K.; et al. Superoxide Radical Photogenerator with Amplification Effect: Surmounting The Achilles’ Heels Of Photodynamic Oncotherapy. J. Am. Chem. Soc. 2019, 141, 2695–2702. [Google Scholar] [CrossRef] [PubMed]
  11. Hotra, A.; Ragunathan, P.; Ng, P.S.; Seankongsuk, P.; Harikishore, A.; Sarathy, J.P.; Saw, W.G.; Lakshmanan, U.; Sae-Lao, P.; Kalia, N.P.; et al. Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and Its Potency in Combination with Diarylquinolines. Angew. Chem. Int. Ed. Engl. 2020, 59, 13295–13304. [Google Scholar] [CrossRef]
  12. Luo, R.; Lv, H.; Liao, Q.; Wang, N.; Yang, J.; Li, Y.; Xi, K.; Wu, X.; Ju, H.; Lei, J. Intrareticular Charge Transfer Regulated Electrochemiluminescence of Donor–acceptor Covalent Organic Frameworks. Nat. Commun. 2021, 12, 6808. [Google Scholar] [CrossRef]
  13. Gerry, C.J.; Schreiber, S.L. Chemical Probes and Drug Leads from Advances in Synthetic Planning and Methodology. Nat. Rev. Drug Discov. 2018, 17, 333–352. [Google Scholar] [CrossRef]
  14. Schreiber, S.L. Molecular Diversity by Design. Nature 2009, 457, 153–154. [Google Scholar] [CrossRef] [PubMed]
  15. Hajduk, P.J.; Galloway, W.R.J.D.; Spring, D.R. A Question Of Library Design. Nature 2011, 470, 42–43. [Google Scholar] [CrossRef] [PubMed]
  16. Yu, C.; Mannan, A.M.; Yvone, G.M.; Ross, K.N.; Zhang, Y.-L.; Marton, M.A.; Taylor, B.R.; Crenshaw, A.; Gould, J.Z.; Tamayo, P.; et al. High-throughput Identification of Genotype-specific Cancer Vulnerabilities in Mixtures of Barcoded Tumor Cell Lines. Nat. Biotechnol. 2016, 34, 419–423. [Google Scholar] [CrossRef] [PubMed]
  17. Chen, A.-J.; Wong, S.-T.; Hwang, C.-C.; Mou, C.-Y. Highly Efficient and Regioselective Halogenation over Well Dispersed Rhenium-Promoted Mesoporous Zirconia. ACS Catal. 2011, 1, 786–793. [Google Scholar] [CrossRef]
  18. Ritschel, B.; Poater, J.; Dengel, H.; Bickelhaupt, F.M.; Lichtenberg, C. Double CH Activation of a Masked Cationic Bismuth Amide. Angew. Chem. Int. Ed. Engl. 2018, 57, 3825–3829. [Google Scholar] [CrossRef] [PubMed]
  19. Hering, T.; Mühldorf, B.; Wolf, R.; König, B. Halogenase-Inspired Oxidative Chlorination Using Flavin Photocatalysis. Angew. Chem. Int. Ed. Engl. 2016, 55, 5342–5345. [Google Scholar] [CrossRef] [PubMed]
  20. Rogge, T.; Kaplaneris, N.; Chatani, N.; Kim, J.; Chang, S.; Punji, B.; Schafer, L.L.; Musaev, D.G.; Wencel-Delord, J.; Roberts, C.A.; et al. C–H Activation. Nat. Rev. Methods Primes 2021, 1, 43. [Google Scholar] [CrossRef]
  21. Goswami, N.; Bhattacharya, T.; Maiti, D. Transient Directing Ligands for Selective Metal-catalysed C–H activation. Nat. Rev. Chem. 2021, 5, 646–659. [Google Scholar] [CrossRef]
  22. Barranco, S.; Zhang, J.; López-Resano, S.; Casnati, A.; Pérez-Temprano, M.H. Transition Metal-catalysed Directed C–H functionalization with Nucleophiles. Nat. Synth. 2022, 1, 841–853. [Google Scholar] [CrossRef]
  23. Dutta, U.; Maiti, S.; Bhattacharya, T.; Maiti, D. Arene Diversification Through Distal C(sp2)−H Functionalization. Science 2021, 372, eabd5992. [Google Scholar] [CrossRef]
  24. Bakanas, I.; Lusi, R.F.; Wiesler, S.; Hayward Cooke, J.; Sarpong, R. Strategic Application of C–H Oxidation in Natural Product total Synthesis. Nat. Rev. Chem. 2023, 7, 783–799. [Google Scholar] [CrossRef] [PubMed]
  25. Meng, G.; Lam, N.Y.S.; Lucas, E.L.; Saint-Denis, T.G.; Verma, P.; Chekshin, N.; Yu, J.-Q. Achieving Site-Selectivity for C–H Activation Processes Based on Distance and Geometry: A Carpenter’s Approach. J. Am. Chem. Soc. 2020, 142, 10571–10591. [Google Scholar] [CrossRef] [PubMed]
  26. Loup, J.; Dhawa, U.; Pesciaioli, F.; Wencel-Delord, J.; Ackermann, L. Enantioselective C−H Activation with Earth-Abundant 3D Transition Metals. Angew. Chem. Int. Ed. Engl. 2019, 58, 12803–12818. [Google Scholar] [CrossRef] [PubMed]
  27. Xiong, X.; Yeung, Y.Y. Highly Ortho-Selective Chlorination of Anilines Using a Secondary Ammonium Salt Organocatalyst. Angew. Chem. Int. Ed. Engl. 2016, 55, 16101–16105. [Google Scholar] [CrossRef] [PubMed]
  28. Sun, X.Y.; Shan, G.; Sun, Y.H.; Rao, Y. Regio-and Chemoselective C-H Chlorination/Bromination of Electron-Deficient Arenes by Weak Coordination and Study of Relative Directing-Group Abilities. Angew. Chem. Int. Ed. Engl. 2013, 52, 4440–4444. [Google Scholar] [CrossRef] [PubMed]
  29. Choi, S.; Dong, G. Rapid and Modular Access to Multifunctionalized 1,2-Azaborines via Palladium/Norbornene Cooperative Catalysis. J. Am. Chem. Soc. 2024, 146, 9512–9518. [Google Scholar] [CrossRef]
  30. Liang, Y.; Lin, F.; Adeli, Y.; Jin, R.; Jiao, N. Efficient Electrocatalysis for the Preparation of (Hetero)Aryl Chlorides and Vinyl Chloride With 1,2-Dichloroethane. Angew. Chem. Int. Ed. Engl. 2019, 58, 4566–4570. [Google Scholar] [CrossRef] [PubMed]
  31. Colomer, I.; Chamberlain, A.E.R.; Haughey, M.B.; Donohoe, T.J. Hexafluoroisopropanol as a Highly Versatile Solvent. Nat. Rev. Chem. 2017, 1, 88. [Google Scholar] [CrossRef]
  32. Robertson, J.C.; Coote, M.L.; Bissember, A.C. Synthetic Applications of light, Electricity, Mechanical Force and Flow. Nat. Rev. Chem. 2019, 3, 290–304. [Google Scholar] [CrossRef]
  33. Ito, M.; Kubo, H.; Itani, I.; Morimoto, K.; Dohi, T.; Kita, Y. Organocatalytic C–H/C–H′ Cross-Biaryl Coupling: C-Selective Arylation of Sulfonanilides with Aromatic Hydrocarbons. J. Am. Chem. Soc. 2013, 135, 14078–14081. [Google Scholar] [CrossRef]
  34. Cai, S.; Tang, H.; Li, B.; Shao, Y.; Zhang, D.; Zheng, H.; Qiao, T.; Chu, X.; He, G.; Xue, X.-S.; et al. Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol. J. Am. Chem. Soc. 2024, 146, 5952–5963. [Google Scholar] [CrossRef] [PubMed]
  35. Zhuang, Z.; Yu, J.-Q. Lactonization As A General Route To β-C(sp3)–H Functionalization. Nature 2019, 577, 656–659. [Google Scholar] [CrossRef]
  36. Herron, A.N.; Liu, D.; Xia, G.; Yu, J.-Q. δ-C–H Mono- And Dihalogenation of Alcohols. J. Am. Chem. Soc. 2020, 142, 2766–2770. [Google Scholar] [CrossRef]
  37. Chen, Y.-Q.; Singh, S.; Wu, Y.; Wang, Z.; Hao, W.; Verma, P.; Qiao, J.X.; Sunoj, R.B.; Yu, J.-Q. Pd-Catalyzed γ-C(sp3)–H Fluorination of Free Amines. J. Am. Chem. Soc. 2020, 142, 9966–9974. [Google Scholar] [CrossRef] [PubMed]
  38. Garry, O.L.; Heilmann, M.; Chen, J.; Liang, Y.; Zhang, X.; Ma, X.; Yeung, C.S.; Bennett, D.J.; MacMillan, D.W.C. Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes. J. Am. Chem. Soc. 2023, 145, 3092–3100. [Google Scholar] [CrossRef]
  39. Chen, T.Q.; Pedersen, P.S.; Dow, N.W.; Fayad, R.; Hauke, C.E.; Rosko, M.C.; Danilov, E.O.; Blakemore, D.C.; Dechert-Schmitt, A.-M.; Knauber, T.; et al. A Unified Approach to Decarboxylative Halogenation of (Hetero)Aryl Carboxylic Acids. J. Am. Chem. Soc. 2022, 144, 8296–8305. [Google Scholar] [CrossRef]
  40. Lovett, G.H.; Chen, S.; Xue, X.-S.; Houk, K.N.; MacMillan, D.W.C. Open-Shell Fluorination of Alkyl Bromides: Unexpected Selectivity in A Silyl Radical-Mediated Chain Process. J. Am. Chem. Soc. 2019, 141, 20031–20036. [Google Scholar] [CrossRef]
  41. Liu, W.; Lavagnino, M.N.; Gould, C.A.; Alcázar, J.; MacMillan, D.W.C. A Biomimetic SH2 Cross-coupling Mechanism for Quaternary sp3-carbon Formation. Science 2021, 374, 1258–1263. [Google Scholar] [CrossRef] [PubMed]
  42. Dahlgren, M.K.; Kauppi, A.M.; Olsson, I.-M.; Linusson, A.; Elofsson, M. Design, Synthesis, And Multivariate Quantitative Structure−Activity Relationship of SalicylanilidesPotent Inhibitors of Type III Secretion in Yersinia. J. Med. Chem. 2007, 50, 6177–6188. [Google Scholar] [CrossRef]
  43. Mihara, J.; Araki, K.; Mori, T.; Murata, T.; Yoneta, Y.; Watanabe, Y.; Shimojo, E.; Ichihara, T.; Ataka, M.; Shibuya, K.; et al. Pesticidal Carboxamides. WO 2011/018170, 17 February 2011. [Google Scholar]
  44. Yoneda, T.; Yoshida, K.; Tazawa, Y.; Kani, T.; Cho, Y.; Noujima, A.; Murai, Y. N-(4-Pyridyl)Benzamide Compound or Salt Thereof, and Pest Control Agent Containing Compound or Salt Thereof as Active Ingredient. WO 2017/222037, 28 December 2017. [Google Scholar]
  45. Costa, P.C.S.; Barsottini, M.R.O.; Vieira, M.L.L.; Pires, B.A.; Evangelista, J.S.; Zeri, A.C.M.; Nascimento, A.F.Z.; Silva, J.S.; Carazzolle, M.F.; Pereira, G.A.G.; et al. N-Phenylbenzamide Derivatives as Alternative Oxidase Inhibitors: Synthesis, Molecular Properties, 1H-STD NMR, and QSAR. J. Mol. Struct. 2020, 1208, 127903. [Google Scholar] [CrossRef]
  46. Chao, J.; Enyedy, I.; Van Vloten, K.; Marcotte, D.; Guertin, K.; Hutchings, R.; Powell, N.; Jones, H.; Bohnert, T.; Peng, C.-C.; et al. Discovery of Biaryl Carboxylamides as Potent RORγ Inverse Agonists. Bioorg. Med. Chem. Lett. 2015, 25, 2991–2997. [Google Scholar] [CrossRef] [PubMed]
  47. Janicka, M.; Tyihak, E.; Moricz, A.M.; Oscik-Mendyk, B. Crucial Role of Formaldehyde and Its reaction Products in the Antiproliferative Activity of Some Potential Pesticides. JPC-J. Planar. Chromat. 2008, 21, 161–166. [Google Scholar] [CrossRef]
Molecules 29 02861 g001
Figure 1. Biologically important molecules containing brominated benzanilides.
Figure 1. Biologically important molecules containing brominated benzanilides.
Molecules 29 02861 g001
Molecules 29 02861 sch001
Scheme 1. Region-selective synthesis for accessing brominated benzanilides by C(sp2)-H functionalization.
Scheme 1. Region-selective synthesis for accessing brominated benzanilides by C(sp2)-H functionalization.
Molecules 29 02861 sch001
Molecules 29 02861 g002
Figure 2. Substrate scope of Pd(II) in C(sp2)-H bromination (isolated yield).
Figure 2. Substrate scope of Pd(II) in C(sp2)-H bromination (isolated yield).
Molecules 29 02861 g002
Molecules 29 02861 g003
Figure 3. Substrate scope of HFIP in C(sp2)-H bromination (isolated yield).
Figure 3. Substrate scope of HFIP in C(sp2)-H bromination (isolated yield).
Molecules 29 02861 g003
Molecules 29 02861 sch002
Scheme 2. Gram-scale synthesis application of ortho-brominated benzanilides.
Scheme 2. Gram-scale synthesis application of ortho-brominated benzanilides.
Molecules 29 02861 sch002
Molecules 29 02861 sch003
Scheme 3. Mechanism study of the bromination reaction via kinetic isotope effect experiments.
Scheme 3. Mechanism study of the bromination reaction via kinetic isotope effect experiments.
Molecules 29 02861 sch003
Molecules 29 02861 sch004
Scheme 4. Proposed mechanism of ortho-bromination of N-methyl-benzanilides.
Scheme 4. Proposed mechanism of ortho-bromination of N-methyl-benzanilides.
Molecules 29 02861 sch004
Molecules 29 02861 sch005
Scheme 5. Proposed mechanism of para-bromination of N-methyl-benzanilides.
Scheme 5. Proposed mechanism of para-bromination of N-methyl-benzanilides.
Molecules 29 02861 sch005
Table 1. Optimization of conditions for selective bromination of benzanilide a.
Table 1. Optimization of conditions for selective bromination of benzanilide a.
Molecules 29 02861 i001
entrypromoter2a2b
yield b (%)yield b (%)
1 cnone<5<5
2Pd/C<5<5
3Pd(OAc)256<5
4Pd(TFA)242<5
5PdCl2<5<5
6 dPd(OAc)272<5
7Co(acac)2<5<5
8Cu(OAc)2<5<5
9 eHFIP<568
10Cp*Co(CO)I2<5<5
11Ni(TFA)2<5<5
12 fHFIP<583
a Reaction conditions: benzanilide (0.1 mmol, 1.0 eq), NBS (1.2 eq), promoter (0.1 eq), Na2S2O8 (1.2 eq), in TFAA (0.1 mL)/TFA (0.9 mL) RT, 10 h. b Conversion ratio. c Reaction conditions: benzanilide (0.1 mmol, 1.0 eq), NBS (1.2 eq), Na2S2O8 (1.2 eq), in TFAA (0.1 mL)/TFA (0.9 mL), RT, 10 h. d Reaction conditions: benzanilide (0.1 mmol, 1.0 eq), NBS (1.2 eq), Na2S2O8 (1.2 eq), in TFAA (0.1 mL)/TFA (0.9 mL), 70 °C, 1 h. e Reaction conditions: benzanilide (0.1 mmol, 1.0 eq), NBS (1.2 eq), TFAA (2.0 eq) in HFIP (1 mL), RT, 10 h. f Reaction conditions: benzanilide (0.1 mmol, 1.0 eq), NBS (1.2 eq), TFAA (2.0 eq) in HFIP (1 mL) 70 °C 2 h.
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Sun, Y.; He, Q.; Lv, X.; Zhang, N.; Yan, W.; Sun, J.; Zhuang, L. Switchable Site-Selective Benzanilide C(sp2)-H Bromination via Promoter Regulation. Molecules 2024, 29, 2861. https://doi.org/10.3390/molecules29122861

AMA Style

Sun Y, He Q, Lv X, Zhang N, Yan W, Sun J, Zhuang L. Switchable Site-Selective Benzanilide C(sp2)-H Bromination via Promoter Regulation. Molecules. 2024; 29(12):2861. https://doi.org/10.3390/molecules29122861

Chicago/Turabian Style

Sun, Yonghui, Qiyu He, Xucheng Lv, Naizhen Zhang, Wei Yan, Jianghui Sun, and Lili Zhuang. 2024. "Switchable Site-Selective Benzanilide C(sp2)-H Bromination via Promoter Regulation" Molecules 29, no. 12: 2861. https://doi.org/10.3390/molecules29122861

APA Style

Sun, Y., He, Q., Lv, X., Zhang, N., Yan, W., Sun, J., & Zhuang, L. (2024). Switchable Site-Selective Benzanilide C(sp2)-H Bromination via Promoter Regulation. Molecules, 29(12), 2861. https://doi.org/10.3390/molecules29122861

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