钯催化氧化/水解2-炔基芳基叠氮一锅法合成2-苯甲酰胺基苯甲酸

圣戎 李萍 周志强 胡贵文 张小祥

引用本文: 圣戎, 李萍, 周志强, 胡贵文, 张小祥. 钯催化氧化/水解2-炔基芳基叠氮一锅法合成2-苯甲酰胺基苯甲酸[J]. 有机化学, 2020, 40(2): 462-469. doi: 10.6023/cjoc201909005 shu
Citation:  Sheng Rong, Li Ping, Zhou Zhiqiang, Hu Guiwen, Zhang Xiaoxiang. Pd-Catalyzed One-Pot Oxidation/Hydrolysis for the Synthesis of 2-Benzoylaminobenzoic Acids from 2-Alkynyl Arylazides[J]. Chinese Journal of Organic Chemistry, 2020, 40(2): 462-469. doi: 10.6023/cjoc201909005 shu

钯催化氧化/水解2-炔基芳基叠氮一锅法合成2-苯甲酰胺基苯甲酸

    通讯作者: 张小祥, E-mail: zhangxiaoxiang@njfu.edu.cn
  • 基金项目:

    江苏省研究生创新计划(No.KYCX18_0967)、国家自然科学基金(No.21302096)、江苏省自然科学基金(No.BK20171449)、江苏高校“青蓝工程”资助项目

摘要: 描述了通过钯催化2-炔基芳基叠氮一锅法氧化/水解制备2-苯甲酰胺基苯甲酸的合成方法.在温和的反应条件下,反应以良好至极好的产率完成.

English

  • The anthranilic acids are a kind of important core structures in organic chemistry, which are widely found in many natural products and biologically active compounds.[1] They were also used as key intermediates for the construction of valuable nitrogen-containing compounds.[2] Moreover, some of the anthranilic acids protected by acyl group were reported as useful inhibitors of bacterial RNA polymerase and human recombinant AKR1C3 in pharmaceutical chemistry.[3] In the past decade, a lot of synthetic methods have been established for the synthesis of 2-benzoylaminbenzoic acids 2.[4] Most of these methods need harsh reaction conditions and complex reaction procedures as well as long reaction time (Scheme 1, a), [5] or low yields (Scheme 1, b and c).[6]

    Scheme 1

    Scheme 1.  Methods of generating 2-benzoylaminobenzoic acids

    Recent research has shown that 4H-3, 1-benzoxa- zin-4-ones could be converted to 2-benzoylaminbenzoic acids 2 through hydrolysis step. However, the desired products were obtained in very low yields.[7] Therefore, it would be necessary to develop a simple and efficient synthetic method for the preparation of 2-benzoylaminoben- zoic acids.

    As part of our continued interest in Pd-catalyzed synthesis of nitrogen-containing compounds[8] via α-imino metal carbene[9, 10] intermediate generated in situ from 2-alkynyl arylazides 1, we would like to expand our one-pot oxidation reaction to prepare 2-benzoylaminobenzoic acids 2. Herein, we disclosed a novel and efficient palladium-cata- lyzed one-pot oxidation/hydrolysis method for the synthesis of 2-benzoylaminobenzoic acids 2 from 2-alkynyl arylazides 1.

    At the outset of this study, 1-azido-2(phenylethynyl) benzene (1a) was chosen as the model substrate to explore the optimal conditions (Table 1). This revealed that treating a solution of reaction containing 1a (1 equiv.) and Oxone (2 equiv.) with 5 mol% Pd(OAc)2 in MeCN (0.5 mL)/H2O (0.5 mL) at 90 ℃ for 45 min gave the best result (Entry 1). Under these conditions, the reaction mixture was directly purified by flash column chromatography on silica to give the desired product 2-benzamidobenzoic acid (2a) in 90% yield, which was confirmed by 1H NMR analysis. It was found that the reaction was repeated at 60 ℃ to give a slightly lower yield of 83% (Entry 2). Under the same reaction conditions, other solvent combination system was also examined. When 1, 4-dioxane/H2O, 1, 2-di- chloroethane/H2O, chlorobenzene/H2O or DMSO/H2O was employed as mixed solvent, which led to either lower yield of 66% or no desired product. Most of the starting material 1a was recovered (Entries 3~6). In contrast, MeCN was used as sole solvent, which gave trace amount of desired product and provided the intermediate 2-phenyl-4H-benzo- [d][1, 3]oxazin-4-one in 60% yield (Entry 7). Water was also examined as single solvent, which led to trace amount of product and most of starting material 1a was recovered (Entry 8). Different oxidants were also examined under the same reaction conditions. K2S2O8 and Selectfluor used as oxidants gave the desired product in 36%~60% yields (Entries 9, 10). When 2-iodoxybenzoic acid (IBX) was employed, the desired product was obtained in 22% yield and the intermediate 2-phenyl- 3H-indol-3-one Dwas detected by thin-layer chromatography (TLC) (Entry 11). When m-CPBA was used as oxidant, trace amount of product 2a and 36% yield of 2-phenyl-4H-benzo[d][1, 3]- oxazin-4-one were obtained, respectively (Entry 12). In the absence of any oxidants, the reaction could not occur and most of the starting material 1a was recovered (Entry 13). A relatively low product yield of 84% was obtained when the amount of Oxone was decreased to 1.5 equiv (Entry 14). Pd(OAc)2 was changed to PdCl2 also gave similar product yield (Entry 15). However, Pd(NO3)2•2H2O was used as a catalyst led to significant low product yield (Entry 16).

    表 1

    Table 1.  Optimization of the reaction conditionsa
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    Entry Solvent Oxidant Temp./℃ Time/min Yieldb/%
    1 MeCN/H2O Oxone 90 45 90
    2 MeCN/H2O Oxone 60 45 83
    3 Dioxane/H2O Oxone 90 45 66
    4 DCE/H2O Oxone 90 90 n.r.c
    5 Cl-C6H5/H2O Oxone 90 90 n.r.c
    6 DMSO/H2O Oxone 90 90 n.r.c
    7 MeCN Oxone 90 45 Trace
    8 H2O Oxone 90 45 Trace
    9 MeCN/H2O K2S2O8 90 90 60
    10 MeCN/H2O Selectflor 90 90 36
    11 MeCN/H2O IBX 90 90 22d
    12 MeCN/H2O m-CPBA 90 90 Tracee
    13 MeCN/H2O 90 90 n.r.c
    14 MeCN/H2O Oxone 90 45 84f
    15 MeCN/H2O Oxone 90 45 83g
    16 MeCN/H2O Oxone 90 45 44h
    a Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (5 mol%), Oxone (2 equiv.), MeCN (0.5 mL)/H2O (0.5 mL). b Isolated yield. c 1a was recovered. d 2-phenyl- 3H-indol-3-one was observed. e 2-phenyl-4H-benzo[d][1, 3]oxazin-4-one was obtained in 36% yield. f 1.5 equiv. of Oxone was used. g PdCl2 was used as catalyst.h Pd(NO3)2•2H2O was used as catalyst.

    To define the scope of the Pd-catalyzed one-pot synthesis of 2-benzamidobenzoic acids 2, a series of 2-alkynyl arylazides 1 were examined. The results were shown in Table 2. As shown in Table 2, the one-pot oxidation/hy- drolysis reaction of 2-alkynyl arylazides 1 bearing electron-withdrawing and electron-donating groups was first examined. Under the optimized reaction conditions, it was found that the reactions of 2-alkynyl arylazides 1 bearing an electron-withdrawing or electron-donating group on the aromatic ring proceeded in moderate to excellent yields of 57%~92% (2a~2o).

    表 2

    Table 2.  Substrates scope of the 2-alkynyl arylazides 1a
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    In addition, substrates 1 containing aliphatic pendant groups on the terminal carbon (R2n-C6H13, n-C5H11, n-C4H9, cyclopropyl and t-Bu) were also examined, which provided the corresponding products in 70%~88% yields (2p~2t). When the substituted group R2 was changed to hetero aryl group, the desired product 2u was also obtained in 87% yield.

    According to the above results, a possible mechanism in Scheme 2 was tentatively proposed for the formation of 2a from 1a, although it is highly speculative. This could involve activation of 1a through coordination of the palladium catalyst with triple bonds. This delivers a Pd-coor- dinated intermediate A, which could undergo amination to form species B. The α-imino palladium carbene C formed by releasing the N2 would be oxidized by Oxone to gene- rated intermediate 2-phenyl-3H-indol-3-one (D)[11] which was further transformed to 2-phenyl-4H-benzo[d]-[1, 3]- oxazin-4-one (E) via Baeyer-Villiger oxidation rearrangement.[12] In the presence of water, 2-phenyl-4H-benzo[d]-[1, 3]oxazin-4-one (E) was finally converted to 2a after hydrolysis.

    Scheme 2

    Scheme 2.  Proposed mechanism

    To further confirm the mechanism, some control experiments were conducted and the key intermediate 2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (E) was isolated successfully (Scheme 3). To confirm that Oxone played an important role during the hydrolysis step, we continued to perform some control experiments. In contrast, the hydro- lysis reaction was still occurred in the absence of Oxone, which provided the product in 77% yield after 8 h. These control experiments showed that Oxone could promote hydrolysis process, which provided the high yield product in short time.

    Scheme 3

    Scheme 3.  Control experiments

    To study the application of our synthetic method in pharmaceutical chemistry, a reaction to prepare 2-((1, 1'- biphenyl)-4-carboxamido)benzoic acid (2v) was performed, which can be used as the inhibitor of plasmodium falciparum[13] or the treatment of pseudomonas aeruginosa infections (Scheme 4).[14] Under the standard reaction conditions, the desired product 2v was obtained in 70% yield after 1.5 h.

    Scheme 4

    Scheme 4.  Drug synthetic application

    In conclusion, an efficient palladium-catalyzed one-pot oxidation/hydrolysis reaction for the synthesis of 2-benza- midobenzoic acids has been reported. The desired products 2-benzamidobenzoic acids were obtained in good to excellent yields under mild reaction conditions. These results showed that the reaction tolerated various 2-alkynyl arylazides. Further applications of this strategy are currently underway and will be reported in the future.

    Analytical thin layer chromatography (TLC) was performed using Merck 60 F254 pre-coated silica gel plate. Visualization was achieved by UV light (254 nm). Flash chromatography was performed using a Merck silica gel 60 with freshly distilled solvents. Unless otherwise stated, 1H NMR and 13C NMR spectra were measured on a Bruker AVANCE III 600 MHz spectrometer. Unless otherwise stated, chemical shifts were recorded with respect to TMS in CDCl3. Infrared spectra were recorded on a NICOLET 6700 FTIR Spectrometer. High resolution mass spectra (HRMS) were obtained using an LTQ Orbitrap. Reagents were purchased from Energy Chemical.

    To a 5 mL test tube was added 2-alkynyl arylazides 1 (0.1 mmol, 1 equiv.), Oxone (0.2 mmol, 2 equiv.), Pd(OAc)2 (5 mol%) and MeCN (0.5 mL)/H2O (0.5 mL). The reaction mixture was stirred at 90 ℃ and monitored by TLC analysis. On completion then the reaction mixture was directly purified by flash column chromatography on silica gel to give the desired 2-benzoylaminobenzoic acids 2. (eluent: petrol ether/ethyl acetate, V:V=4:1 to 2:1).

    To a solution of 1-azido-2-(phenylethynyl)benzene (1a) (0.1 mmol) in MeCN (1 mL) was added Pd(OAc)2 (5 mol%) and Oxone (0.1 mmol). The reaction mixture was stirred at 90 ℃ and monitored by TLC analysis. On completion, the reaction solution was directly purified by flash column chromatography on silica gel to give the desired product 2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (E), whi- ch was isolated in 79% yield. 17.5 mg, white solid (eluent: petrol ether/ethyl acetate, V:V=20:1 to 8:1).

    To a solution of 2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (E) (0.075 mmol, 16.7 mg) in MeCN (0.5 mL)/H2O (0.5 mL) was added Oxone (0.075 mmol). The reaction mixture was stirred at 90 ℃ and monitored by TLC analysis. After 1.5 h, the reaction solution was directly purified by flash column chromatography to give the desired product 2-benzoylaminobenzoic acid (2a) in 95% yield. (17.1 mg, white solid (eluent: petrol ether/ethyl acetate, V:V=4:1 to 2:1).

    The intermediate 2-phenyl-4H-benzo[d][1, 3]oxazin-4- one (E) was obtained in 81% yield after repeating the reaction of 1a to E (18.1 mg, white solid). Without adding Oxone, the reaction solution of 2-phenyl-4H-benzo[d]- [1, 3] oxazin-4-one (E) (0.075 mmol, 16.7 mg) in MeCN (0.5 mL)/H2O (0.5 mL) was stirred at 90 ℃, which was monitored by TLC analysis. After 8 h, the reaction was still not finished and then purified by flash column chromatography to give the desired product 2-benzoylamino- benzoic acid (2a) in 77% yield. 3.9 mg, white solid (eluent: petrol ether/ethyl acetate, V:V=4:1 to 2:1).

    To a 5 mL test tube was added 2-(phenylethynyl)aniline (3a) (0.1 mmol, 1 equiv.), Oxone (0.2 mmol, 2 equiv.), Pd(OAc)2 (5 mol%) and MeCN (0.5 mL)/H2O (0.5 mL). The reaction mixture was stirred at 90 ℃ and monitored by TLC analysis. On completion then the reaction mixture was directly purified by flash column chromatography on silica gel to give the desired 2-benzoylaminobenzoic acid (2a) in 24% yield. (eluent: petrol petrol ether/ethyl acetate, V:V=4:1 to 2:1). The reaction was repeated in 60 ℃ and got 2-benzoylaminobenzoic acid (2a) in 21%.

    To a solution of 2-iodoaniline (5 mmol), ethynyltrimethylsilane (6 mmol, 1.2 equiv.) in Et3N (60 mL) was added 2 mol% PdCl2(PPh3)2 and 5 mol% CuI. The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. On completion, the reaction solution was concentrated under reduced pressure and purification by flash column chromatography on silica gel to give the desired product 2-((trimethylsilyl)ethynyl)aniline (c) in 76% yield, 718.2 mg, black liquid (eluent: petrol ether/ ethyl acetate, V:V=20:1 to 8:1).

    Then, the reaction solution of 2-((trimethylsilyl)- ethynyl)aniline (c) (567 mg, 3 mmol) in MeOH (20 mL) was added K2CO3 (678 mg, 5 mmol), which was stirred at room temperature overnight. On completion, the reaction solution was concentrated under reduced pressure and purification by flash column chromatography on silica gel to give the desired product 2-ethynylaniline (d) in 86% yield, 309.4 mg, yellow liquid (eluent: petrol ether: ethyl aceta- te=20:1 to 8:1).

    To a solution of 2-ethynylaniline (d) (292.5 mg, 2.5 mmol) in CH3CN (30 mL) with 10% H2SO4 (20 mL) was added NaNO2 (1.2 equiv.), which was stirred at 0 ℃. After 0.5 h, NaN3 (1.2 equiv.) was added to the reaction solution. On completion, the reaction solution was concentrated under reduced pressure and purification by flash column chromatography on silica gel to give the desired product 1-azido-2-ethynylbenzene (e) in 63% yield, 225 mg, brown liquid (eluent: petrol ether/ethyl acetate, V:V=40:1).

    To a solution of 1-azido-2-ethynylbenzene (e) (1.5 mmol), 4-iodo-1, 1'-biphenyl (f) (3 mmol, 1.5 equiv.) in Et3N (30 mL) was added 2 mol% PdCl2(PPh3)2 and 5 mol% CuI. The reaction solution was stirred at room temperature overnight under N2 atmosphere. On completion, the reaction solution was concentrated under reduced pressure and purification by flash column chromatography on silica gel to give the desired product 1v in 11% yield, 47.8 mg, yellow solid (eluent: petrol ether/ethyl acetate, V:V=20:1 to 8:1).

    To a solution of 4-[(2-azidophenyl)ethynyl]-1, 1'-bi- phenyl (1v) (0.1 mmol) in MeCN (0.5 mL)/H2O (0.5 mL) was added Oxone (0.2 mmol). The resulting solution was stirred at 90 ℃ and monitored by TLC analysis. On completion, the reaction solution was directly subjected to purification by flash column chromatography on silica gel to give the desired product 2-((1, 1'-biphenyl)-4-carboxamido) benzoic acid (2v) in 70% yield, 22.0 mg, Yellow soild (eluent: petrol ether/ethyl acetate, V:V=2:1 to 0:1).

    2-Benzamidobenzoic acid (2a):[2] 90% yield. 1H NMR (600 MHz, DMSO-d6) δ: 7.20 (d, J=7.4 Hz, 1H), 7.56~7.60 (m, 2H), 7.62~7.66 (m, 2H), 7.96 (d, J=7.3 Hz, 2H), 8.06 (d, J=7.8 Hz, 1H), 8.72 (d, J=8.3 Hz, 1H), 12.20 (s, 1H).

    2-Benzamido-5-dimethylbenzoic acid (2b): 84% yield. Yellow solid, m.p. 189.4~191.3℃; 1H NMR (600 MHz, DMSO-d6) δ: 2.31 (s, 3H), 7.45~7.47 (m, 1H), 7.56~7.59 (m, 2H), 7.61~7.64 (m, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.93 (d, J=7.3 Hz, 2H), 8.56 (d, J=8.5 Hz, 1H), 12.10 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 20.3, 116.7, 120.0, 127.1, 129.1, 131.4, 132.2, 134.7, 134.9, 138.2, 164.6, 170.2; IR (KBr) v: 3423, 2927, 2854, 1608, 1589, 1544, 1510, 1448, 1224, 759 cm-1; HRMS (ESI) calcd for C15H14NO3 [M+H]+ 256.0974, found 256.0979.

    2-Benzamido-3, 5-dimethylbenzoic acid (2c): 92% yield. Yellow solid, m.p. 52.4~53.5 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 2.20 (s, 3H), 2.33 (s, 3H), 7.31 (s, 1H), 7.50~7.53 (m, 3H), 7.56~7.59 (m, 1H), 7.97 (d, J=7.2 Hz, 2H), 9.91 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 18.1, 20.4, 127.6, 128.4, 128.4, 128.8, 131.5, 133.6, 134.4, 134.7, 135.4, 136.3, 165.3, 168.0; IR (KBr) v: 3259, 2929, 2854, 1689, 1589, 1525, 1450, 1243, 757 cm-1; HRMS (ESI) calcd for C16H16NO3 [M+H]+ 270.1130, found 270.1138.

    2-Benzamido-5-chlorobenzoic acid (2d): 80% yield. Yellow solid, m.p. 238.5~240.1 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.57~7.60 (m, 2H), 7.65~7.66 (m, 1H), 7.72 (dd, J=9.0, 2.6 Hz, 1H), 7.94 (dd, J=7.2, 1.3 Hz, 2H), 7.98 (d, J=2.6 Hz, 1H), 8.71 (d, J=9.0 Hz, 1H), 12.13 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 118.8, 121.9, 126.6, 127.1, 129.1, 130.5, 132.4, 133.9, 134.3, 139.9, 164.8, 168.8; IR (KBr) v: 3413, 2925, 2852, 1610, 1513, 1378, 1301, 1195, 696 cm-1; HRMS (ESI) calcd for C14H11ClNO3 [M+H]+ 276.0427, found 276.0433.

    2-Benzamido-5-fluorobenzoic acid (2e): 80% yield. White solid, m.p. 216.5~218.2 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.51~7.55 (m, 1H), 7.56~7.59 (m, 2H), 7.62~7.65 (m, 1H), 7.75 (dd, J=9.3, 3.1 Hz, 1H), 7.94 (d, J=7.3 Hz, 2H), 8.68 (m, 1H), 12.01 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 117.5 (d, J=24.0 Hz), 119.4 (d, J=7.5 Hz), 121.5 (d, J=21.0 Hz), 122.7 (d, J=7.5 Hz), 127.5, 129.4 132.7, 134.8, 137.9 (d, J=3.0 Hz), 157.4 (d, J=240.0 Hz), 165.1, 169.3; IR (KBr) v: 3398, 2921, 2850, 1710, 1546, 1498, 1218, 1180, 698 cm-1; HRMS (ESI) calcd for C14H11FNO3 [M+H]+ 260.0723, found 260.0730.

    2-Benzamido-5-(trifluoromethyl)benzoic acid (2f): 57% yield. Yellow solid, m.p. 238.5~240.1 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.59~7.61 (m, 2H), 7.65~7.68 (m, 1H), 7.95 (d, J=1.2 Hz, 2H), 8.00 (dd, J=8.8, 1.9 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H), 8.91 (d, J=8.8 Hz, 1H), 12.38 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 117.0, 120.4, 122.8 (q, J=32.9 Hz), 124.7, 127.2, 128.0 (q, J=3.0 Hz), 128.1 (q, J=286.5 Hz), 130.8 (q, J=3.1 Hz), 132.6, 134.0, 144.3, 165.1, 168.9; IR (KBr) v: 3426, 2925, 2607, 1704, 1652, 1592, 1523, 1326, 1232, 1118, 1091, 848, 711, 674 cm-1; HRMS (ESI) calcd for C15H11F3NO3 [M+H]+ 310.0691, found 310.0699.

    2-Benzamido-5-(methoxycarbonyl)benzoic acid (2g): 81% yield. White solid, m.p. 241.3~243.0 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 3.85 (s, 3H), 7.57~7.60 (m, 2H), 7.63~7.66 (m, 1H), 7.95 (d, J=7.6 Hz, 2H), 8.15 (d, J=8.8 Hz, 1H), 8.59 (s, 1H), 8.82 (d, J=8.8 Hz, 1H), 12.55 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 52.2, 116.6, 119.5, 123.5, 127.2, 129.1, 132.5, 132.6, 134.1, 134.7, 145.0, 165.0, 165.2, 169.5; IR (KBr) v: 3423, 2931, 2852, 1726, 1662, 1602, 1525, 1400, 1284, 1214, 1114, 761, 698 cm-1; HRMS (ESI) calcd for C16H14NO5 [M+H]+ 300.0872, found 300.0881.

    2-Benzamido-4-(trifluoromethyl)benzoic acid (2h): 72% yield. Yellow solid, m.p. 215.6~216.8 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.52 (d, J=7.0 Hz, 1H), 7.58~7.61 (m, 2H), 7.64~7.66 (m, 1H), 7.95 (d, J=7.8 Hz, 2H), 8.22~8.23 (m, 1H), 9.06 (s, 1H), 12.31 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 116.3, 119.2, 120.4 (q, J=1.5 Hz), 122.7 (q, J=271.1 Hz), 127.2, 129.1, 132.5 (q, J=9.0 Hz), 132.6, 133.3 (q, J=31.5 Hz), 134.0, 141.4, 165.2, 169.0; IR (KBr) v:3436, 3131, 2964, 1662, 1612, 1548, 1450, 1390, 1317, 1213, 754, 655 cm-1; HRMS (ESI) calcd for C15H11F3NO3 [M+H]+ 310.0691, found 310.0695.

    2-Benzamido-4-chlorobenzoic acid (2i): 76% yield. Yellow solid, m.p. 200.1~202.7 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.26 (dd, J=8.5, 2.1 Hz, 1H), 7.58~7.60 (m, 2H), 7.64~7.67 (m, 1H), 7.94 (d, J=7.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H), 8.81 (d, J=2.1 Hz, 1H, 12.43 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 119.2, 122.9, 127.2, 129.2, 132.6, 133.1, 134.2, 138.6, 142.2, 165.1, 169.5; IR (KBr) v: 3426, 2923, 2859, 1652, 1606, 1571, 1213, 1099, 890, 777, 703 cm-1; HRMS (ESI) calcd for C14H11ClNO3 [M+H]+ 276.0427, found 276.0432.

    5-Chloro-2-(4-chlorobenzamido)benzoic acid (2j): 69% yield. Yellow solid, m.p. 237.6~238.3 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.26 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.04 (d, J=8.5 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 12.53 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 119.1, 122.9, 129.0, 129.1, 131.1, 132.9, 133.0, 137.3, 138.3, 141.9, 163.8, 169.4; IR (KBr) v: 3446, 3116, 2923, 1668, 1581, 1527, 1415, 1228, 1099, 781, 744 cm-1; HRMS (ESI) calcd for C14H10Cl2NO3 [M+H]+ 310.0038, found 310.0042.

    5-Chloro-2-(4-methylbenzamido)benzoic acid (2k): 76% yield. Yellow solid, m.p. 122.8~124.5 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 2.40 (s, 3H), 7.24~7.26 (m, 1H), 7.39~7.40 (m, 2H), 7.85~7.86 (m, 2H), 8.05 (d, J=8.5 Hz, 1H), 8.82 (d, J=2.1 Hz, 1H), 12.54 (s, 1H); 13C NMR (DMSO-d6, 150 MHz): δ=21.1, 119.0, 122.6, 126.1, 127.1, 129.6, 131.3, 133.0, 138.5, 142.3, 142.7, 164.9, 169.5; IR (KBr) v: 3430, 2927, 2854, 1668, 1610, 1450, 1309, 1214, 750, 719 cm-1; HRMS (ESI) calcd for C15H13ClNO3 [M+H]+ 290.0584, found 290.0588.

    2-(3-Fluorobenzamido)benzoic acid (2l): 76% yield. Yellow solid, m.p. 192.5~193.8 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.21~7.23 (m, 1H), 7.47~7.50 (m, 1H), 7.62~7.70 (m, 3H), 7.78 (d, J=7.8 Hz, 1H), 8.05 (dd, J=7.9, 1.5 Hz, 1H), 8.63 (d, J=7.9 Hz, 1H), 12.17 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 114.1 (d, J=22.5 Hz), 117.1, 119.2 (d, J=21.0 Hz), 120.2, 123.1 (d, J=2.7 Hz), 123.4, 131.3 (d, J=9.5 Hz), 134.4, 137.0(d, J=7.5 Hz), 140.8, 162.2 (d, J=244.5 Hz), 163.5, 170.1; IR (KBr) v: 3421, 2925, 2852, 1589, 1432, 1336, 1170, 1126, 701 cm-1; HRMS (ESI) calcd for C14H11FNO3 [M+H]+ 260.0723, found 260.0729.

    2-(4-Chlorobenzamido)benzoic acid (2m): 82% yield. Yellow solid, m.p. 195.7~197.5 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.21~7.22 (m, 1H), 7.64~7.66 (m, 3H), 7.94~7.95 (m, 2H), 8.05 (dd, J=7.9, 1.5 Hz, 1H), 8.65 (d, J=7.7 Hz, 1H), 12.18 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 116.9, 120.1, 123.2, 129.0, 129.1, 131.3, 133.3, 134.3, 137.1, 140.9, 163.7, 170.1; IR (KBr) v: 3322, 2929, 2852, 1662, 1606, 1542, 1407, 1263, 1170, 1087, 761, 661 cm-1; HRMS (ESI) calcd for C14H11ClNO3 [M+H]+ 276.0427, found 276.0431.

    2-(4-Ethylbenzamido)benzoic acid (2n): 77% yield. Yellow solid, m.p. 199.7~200.9 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 1.20 (t, J=5.4 Hz, 3H), 2.67 (q, J=6.0 Hz, 2H), 7.19~7.20 (m, 1H), 7.40~7.41 (m, 2H), 7.65~7.66 (m, 1H), 7.87 (d, J=7.9 Hz, 2H), 8.05 (d, J=7.5 Hz, 1H), 8.72 (d, J=8.2 Hz, 1H), 12.16 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 15.3, 28.1, 119.8, 122.8, 125.1, 127.2, 128.4, 131.3, 132.0, 134.4, 141.3, 148.5, 164.7, 170.1; IR (KBr) v: 3438, 3116, 2960, 1662, 1581, 1525, 1492, 1409, 1218, 1103, 781, 740 cm-1; HRMS (ESI) calcd for C16H16NO3 [M+H]+ 270.1130, found 270.1136.

    2-(4-Methylbenzamido)benzoic acid (2o): 72% yield. Yellow solid, m.p. 178.1~180.0 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 2.39 (s, 3H), 7.18~7.21 (m, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.64~7.67 (m, 1H), 7.85 (d, J=8.1 Hz, 2H), 8.06 (dd, J=8.0, 1.3 Hz, 1H), 8.71 (d, J=8.3 Hz, 1H), 12.16 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 21.1, 116.4, 119.8, 122.9, 127.1, 129.6, 131.3, 131.8, 134.4, 141.3, 142.4, 164.7, 170.1; IR (KBr) v: 3425, 2921, 1679, 1577, 1508, 1415, 1278, 1240, 1095, 1022, 742 cm-1; HRMS (ESI) calcd for C15H14NO3 [M+H]+ 256.0974, found 256.0979.

    2-Heptanamidobenzoic acid (2p): 80% yield. Brown liquid; 1H NMR (600 MHz, DMSO-d6) δ: 0.85 (t, J=6.8 Hz, 3H), 1.26~1.33 (m, 6H), 1.60~1.63 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 7.11~7.14 (m, 1H), 7.55~7.58 (m, 1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 8.49 (d, J=7.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 14.0, 22.0, 25.0, 28.2, 31.0, 37.7, 116.4, 119.9, 122.4, 131.1, 134.0, 141.0, 169.6, 171.3; IR (KBr): v3413, 2923, 2852, 1693, 1484, 1307, 1197, 705 cm-1; HRMS (ESI) calcd for C14H20NO3 [M+H]+ 250.1443, found 250.1448.

    2-Pentanamidobenzoic acid (2q):[3] 79% yield. 1H NMR (CDCl3, 600 MHz) δ: 0.96 (t, J=7.4 Hz, 3H), 1.42~1.45 (m, 2H), 1.73~1.78 (m, 2H), 2.47 (t, J=7.6 Hz, 2H), 7.10~7.13 (m, 1H), 7.58~7.61 (m, 1H), 8.12 (d, J=7.9 Hz, 1H), 8.76 (d, J=8.5 Hz, 1H), 10.99 (s, 1H).

    2-Hexanamidobenzoic acid (2r):[3] 70% yield. 1H NMR (CDCl3, 600 MHz) δ: 0.92 (t, J=7.0 Hz, 3H), 1.36~1.40 (m, 4H), 1.75~1.80 (m, 2H), 2.47 (t, J=7.6 Hz, 2H), 7.11~7.14 (m, 1H), 7.59~7.61 (m, 1H), 8.13 (m, 1H), 8.76 (d, J=8.3 Hz, 1H), 10.97 (s, 1H).

    2-(Cyclopropanecarboxamido)benzoic acid (2s):[3] 70% yield. 1H NMR (CDCl3, 600 MHz) δ: 0.89~0.92 (m, 2H), 1.11~1.14 (m, 2H), 1.62~1.66 (m, 1H), 7.09~7.11 (m, 1H), 7.56~7.59 (m, 1H), 8.12 (dd, J=8.0, 1.4 Hz, 1H), 8.72 (d, J=8.4 Hz, 1H), 11.17 (s, 1H).

    2-Pivalamidobenzoic acid (2t):[3] 70% yield. 1H NMR (CDCl3, 600 MHz) δ: 1.35 (s, 9H), 7.10~7.13 (m, 1H), 7.58~7.61 (m, 1H), 8.14 (d, J=7.9, 1H), 8.80 (d, J=8.5 Hz, 1H), 11.16 (s, 1H).

    2-(Thiophene-2-carboxamido)benzoic acid (2u): 87% yield. White solid, m.p. 203.7~206.4 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 7.18~7.20 (m, 1H), 7.53 (dd, J=5.1, 1.3 Hz, 1H), 7.63~7.66 (m, 1H), 7.73 (dd, J=5.0, 2.9 Hz, 1H), 8.04 (dd, J=7.9, 1.6 Hz, 1H), 8.25 (dd, J=2.9, 1.3 Hz, 1H), 8.64 (d, J=7.6 Hz, 1H), 12.01 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 116.4, 119.9, 122.9, 126.0, 128.2, 130.1, 131.3, 134.4, 137.9, 141.1, 166.1, 170.0; IR (KBr) v: 3442, 3156, 2929, 1587, 1450, 1220, 754, 649 cm-1; HRMS (ESI) calcd for C12H10NO3S [M+H]+ 248.0381, found 248.0386.

    2-([1, 1'-Biphenyl]-4-carboxamido)benzoic acid (2v):[4] 70% yield. Yellow solid; 1H NMR (600 MHz, DMSO-d6) δ: 7.20~7.23 (m, 1H), 7.42~7.44 (m, 1H), 7.50~7.52 (m, 2H), 7.66~7.68 (m, 1H), 7.76 (d, J=7.6 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 8.04~8.08 (m, 3H), 8.75 (d, J=8.3 Hz, 1H), 12.30 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 116.6, 119.9, 122.9, 127.0, 127.2, 127.7, 128.3, 129.1, 131.3, 133.3, 134.3, 138.9, 141.2, 143.7, 164.4, 170.1.

    2-Phenyl-4H-benzo[d][1, 3]oxazin-4-one E:[3] 79% yield. 1H NMR (CDCl3, 600 MHz) δ: 7.51~7.54 (m, 3H), 7.57~7.60 (m, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.82~7.85 (m, 1H), 8.25 (dd, J=7.8, 1.1 Hz, 1H), 8.32 (dd, J=7.3, 1.3 Hz, 2H).

    Supporting Information NMR spectra of compounds 2a~2v and E. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.


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  • Scheme 1  Methods of generating 2-benzoylaminobenzoic acids

    Scheme 2  Proposed mechanism

    Scheme 3  Control experiments

    Scheme 4  Drug synthetic application

    Table 1.  Optimization of the reaction conditionsa

    Entry Solvent Oxidant Temp./℃ Time/min Yieldb/%
    1 MeCN/H2O Oxone 90 45 90
    2 MeCN/H2O Oxone 60 45 83
    3 Dioxane/H2O Oxone 90 45 66
    4 DCE/H2O Oxone 90 90 n.r.c
    5 Cl-C6H5/H2O Oxone 90 90 n.r.c
    6 DMSO/H2O Oxone 90 90 n.r.c
    7 MeCN Oxone 90 45 Trace
    8 H2O Oxone 90 45 Trace
    9 MeCN/H2O K2S2O8 90 90 60
    10 MeCN/H2O Selectflor 90 90 36
    11 MeCN/H2O IBX 90 90 22d
    12 MeCN/H2O m-CPBA 90 90 Tracee
    13 MeCN/H2O 90 90 n.r.c
    14 MeCN/H2O Oxone 90 45 84f
    15 MeCN/H2O Oxone 90 45 83g
    16 MeCN/H2O Oxone 90 45 44h
    a Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (5 mol%), Oxone (2 equiv.), MeCN (0.5 mL)/H2O (0.5 mL). b Isolated yield. c 1a was recovered. d 2-phenyl- 3H-indol-3-one was observed. e 2-phenyl-4H-benzo[d][1, 3]oxazin-4-one was obtained in 36% yield. f 1.5 equiv. of Oxone was used. g PdCl2 was used as catalyst.h Pd(NO3)2•2H2O was used as catalyst.
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    Table 2.  Substrates scope of the 2-alkynyl arylazides 1a

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  • 发布日期:  2020-02-25
  • 收稿日期:  2019-09-02
  • 修回日期:  2019-09-27
  • 网络出版日期:  2019-02-12
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