English

• 1.   Introduction

  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

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  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.

  2.   Results and discussion

  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 conditions^a

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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 1^a

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  In addition, substrates 1 containing aliphatic pendant groups on the terminal carbon (R²＝n-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

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  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

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  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

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  3.   Conclusions

  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.

  4.   Experimental section

  4.1   Instruments and reagents

  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.

  4.2   General experimental procedure for the synthesis of 2-benzoylaminobenzoic acids 2

  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).

  4.3   Procedure for the preparation of 2-phenyl-4H- benzo[d]^{[1, 3]}oxazin-4-one E and its conversion to the 2-benzoylaminobenzoic acid 2a

  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).

  4.4   Procedure for the synthesis of 2-benzoylamino- benzoic acids 2a via 2-(phenylethynyl)aniline

  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%.

  4.5   Procedure for the preparation of 4-[(2-azido-phenyl)ethynyl]-1, 1'-biphenyl (1v)

  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).

  4.6   Procedure for the preparation of 2-([1, 1'-bi-phenyl]-4-carboxamido)benzoic acid 2v

  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): v＝3413, 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

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  Scheme 2  Proposed mechanism

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  Scheme 3  Control experiments

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  Scheme 4  Drug synthetic application

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  Table 1.  Optimization of the reaction conditions^a

  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 1^a

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•