English

• 4H-3, 1-Benzoxazin-4-ones are very important core structures in organic chemistry due to their presence in a myriad of bioactive compounds and pharmaceutical drugs, ^[1]such as inhibitor of human leukocyte (Ⅰ), ^[2] cetillistat (Ⅱ), ^[3] chymotrypsin inactivator (Ⅲ)^[4] and HSV-1 protease inhibitor (Ⅳ)^[5] (Figure 1). They are also utilized as valuable synthetic intermediates in organic chemistry.^[6] Because of those, an immense number of convenient and efficient methodologies for the construction of 4H-3, 1-benzoxazin-4-ones 3 have been established over the years.^[7] Those have hitherto included the palladium catalyzed transformtion of 2-alkynyl arylazides 1 in the presence of oxone via aminopalladation/oxidative rearrangement, which afforded the corresponding 4H-3, 1-benzo-xazin-4-ones 3 (Scheme 1).^[7h] While this synthetic method was shown to be reliable and suitable rout to the heterocycles, the reactions were reported to rely on the combination of a base, heating and lightless requirement, which led to the formation of 4H-3, 1-benzoxazin-4-ones in low yields after long reaction time. In this regard, the establishing of mild and efficient synthetic methods to get substituted 4H-3, 1-benzoxazin-4-ones from 2-alkynyl arylazides is desirable.

  Figure1. 4H-3, 1-Benzoxazin-4-ones with bioactivities

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  Scheme1. Design for gold-catalyzed oxidation rearrangement of 2-alkynyl arylazides 1

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  Gold-catalyzed tandem reactions^[8] of 2-alkynyl arylazides have become one of the most versatile and efficient method for the access to N-containing heterocycles via α-imino gold carbenes intermediate generated in situ.^[9]As part of an ongoing program exploring the gold-catalyzed transformation of 2-alkynyl arylazides, ^[10] we recently reported intermolecular trapping of α-imino gold carbenes by carboxylic acids for the synthesis of 1H-indol-3-yl esters.^[10d] Very interestingly, the 2-phenyl-1H-indol-3-yl (4) stored in fridge was slowly converted to the oxidative compound 2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3a), which was isolated in 95% yield after two months. On the basis of these earlier studies, we reasoned that a novel synthetic method to 4H-benzo[d][1, 3]oxazin-4-ones (3) could be achieved through the use of suitable oxidants. Herein, we report a one-pot, one-step tBuXPhosAuNTf₂ catalyzed oxidative rearrangement at room temperature in the presence of acetic acid and m-CPBA (Scheme 1). In most cases, the desired 4H-3, 1-benzoxazin-4-one products were obtained in moderate to excellent yields within 1 h.

  1   Results and discussion

  Initially, we chose to focus our attention on the reaction of 1-azido-2-(phenylethynyl)benzene (1a) and acetic acid (2) by different oxidants to establish the reaction conditions. This revealed treating a solution of reaction containing 1a (1 equiv.), m-CPBA (2 equiv.) and acetic acid (1 mL) with 2 mol% tBuXPhosAuNTf₂ at room temperature for 0.5 h gave the best result (Table 1, Entry 1). Under these conditions, 4H-3, 1-benzoxazin-4-one (2a) was provided in 86% yield. On the other hand, a similar product yield was observed when the reaction temperature was increased to 60 ℃ (Table 1, Entry 2). In contrast, while the use of oxone and TBHP as the oxidants afforded 2a in markedly lower yields of 40%~67%, the expected 2a was not obtained employing air (Table 1, Entries 3~5). In this latter case, the reaction was found to result in the formation of 2-phenyl-1H-indol-3-yl acetate (4) at 60 ℃ after 24 h, which was provided in 85% yield. Lower product yield was observed when the reaction was conducted in MeCN, PhCl or (CH₂Cl)₂ in place of HOAc as the solvent (Table 1, Entries 6~8). Additional control experiment with HOAc at 40% of concentration led to lower product yield (Table 1, Entry 9). 69% yield of 3a was obtained when 1.5 equiv. of m-CPBA was used (Table 1, Entry 10). Only starting material was left when the reaction was conducted without catalyst, which was confirmed by TLC and crude ¹H NMR analysis (Table 1, Entry 11).

  Table 1.  Optimization of reaction conditions^a

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  Entry	Oxidant	Solvent	Time/h	Yieldb/%
  1	m-CPBA	HOAc	0.5	86
  2c	m-CPBA	HOAc	0.5	85
  3c, d	Air	HOAc	24	—
  4e	oxone	HOAc	0.5	67
  5	TBHP	HOAc	0.5	40
  6f	m-CPBA	MeCN	0.5	49
  7f	m-CPBA	PhCl	0.5	39
  8f	m-CPBA	(CH2Cl)2	0.5	54
  9g	m-CPBA	(CH2Cl)2	0.5	34
  10h	m-CPBA	HOAc	0.5	69
  11i	m-CPBA	HOAc	0.5	NR
  aUnless stated otherwise, all reactions were performed at room temperature in 1 mL of HOAc with tBuXPhosAuNTf2:1a:oxidant ratio = 0.02:1:2. bIsolated yield. c At 60 ℃.d 85% of 4a obtained.e12% of 4a was obtained. f0.4 mL of HOAc was used.g Without HOAc.h1.5 equiv of m-CPBA was used.iWithout catalyst. NR＝no reaction

  To define the scope of the present procedure, we next turned our attention to the reactions of a variety of 2-alkynyl arylazides 1 with acetic acid (Table 2). Reactions of 2-alkynyl arylazides with a pendant electron-donating or electron-withdrawing group on the alkyne carbon with acetic acid gave the desired 4H-3, 1-benzoxazin-4-ones in good to excellent yields (Table 2, 3a~3f). We also tested the effect of substituted group R¹ on the aromatic ring and found that for substrates R¹ = substituted halogen, CF₃, or Me, excellent yields were obtained (Table 2, 3g~3k, 3n~3o). Substrate with R¹＝R²＝Cl was also provided the desired product in 85% yield (Table 2, 3l). In contrast, ester, di-substituted methyl, and ether functional groups on the aromatic ring were also examined, which were afforded the corresponding compounds in 52%~56% yields (Table 2, 3m, 3p~3q).

  Table 2.  Synthesis of 4H-3, 1-benzoxazin-4-ones 3^{a, b}

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  aUnless stated otherwise, all reactions were performed at room temperature in 1 mL of HOAc with t-BuXPhosAuNTf2:1a:m-CPBA ratio＝0.02:1:2. bIsolated yield.

  On the other hand, reactions of 2-alkynyl arylazides with aliphatic substituted group on the alkyne carbon were also tested under the standard reaction conditions. Interestingly, the reactions of substrates with R²＝n-C₄H₉, n-C₅H₁₁, cyclopropyl, and t-But were found to proceed well and provide the anthranilic acid products 5 in excellent yields, which were due to the hydrolysis of corresponding 4H-3, 1-benzoxazin-4-ones (Table 3, 5a~5d).

  Table 3.  Synthesis of anthranilic acids 5^{a, b}

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  a Unless stated otherwise, all reactions were performed at room temperature in 1 mL of HOAc with t-BuXPhosAuNTf2:1a:m-CPBA ratio＝0.02:1:2. bNMR yield (mixed with 3-chlorobenzoic acid).

  Based on the above results, we tentatively propose the tBuXPhosAuNTf₂-catalyzed 4H-3, 1-benzoxazin-4-ones forming reaction to proceed by the mechanism outlined in Scheme 2, although it is highly speculative. This could involve the activation of the 1-azido-2-(phenylethynyl)-benzene (1a) through coordination of the gold catalyst with alkyne bond, which was then attacked by azide to deliver the intermediate A. After the releasing of N₂, α-imino gold carbene species B was afforded, which was then trapped by acetic acid to deliver the complex C. Subsequent protondemetalation step would then give the intermediate 2-phenyl-1H-indol-3-yl acetate 4, which was oxidized by m-CPBA to form intermediate D. Rearrangement of D led to form E, which could be oxidized by air to provide the desired product 4H-3, 1-benzoxazin-4-one 3a.

  Scheme2. Proposed mechanism for the formation of 3a

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  2   Conclusions

  In summary, a mild and efficient synthetic route to 4H-3, 1-benzoxazin-4-ones via one-pot one-step gold-cata-lyzed oxidative rearrangement of 2-alkynyl arylazides has been reported. These results show that the reaction tolerates a structurally diverse set of 2-alkynyl arylazides. This method can also provided the anthranilic acids in excellent yields. Our studies show that the reaction can be performed well in very short time by using acetic acid as solvent. Efforts are currently underway to apply the method for the synthesis of biologically active compounds.

  3   Experimental section

  3.1   General considerations

  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 and ¹³C NMR spectra were measured on a Bruker AVANCE Ⅲ 400 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 (HRMS) spectra were obtained using an LTQ Orbitrap.

  3.2   General procedure for gold-catalyzed formation of 4H-3, 1-benzoxazin-4-ones (3a~3q)

  A pressure tube equipped with a magnetic stirrer bar was charged with tBuXPhosAuNTf₂(2 mol%), 2-alkynyl arylazides 1 (0.1 mmol), m-CPBA (0.2 mmol, 2 equiv.), and acetic acid 2 (1 mL). The reaction solution was stirred for 30 min at room temperature. Then the mixture was washed several times with saturated sodium bicarbonate solution and extracted with DCM (10 mL×2). The combined organic layer was washed with brine (10 mL) and dried over anhydrous MgSO₄. After removing the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, V:V＝1:10), providing the desired compound 3.

  2-Phenyl-4H-benzo[d][1, 3]oxazin-4-one  (3a)^[7h]: 90% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.31~8.33 (m, 2H), 8.24~8.26 (m, 1H), 7.81~7.86 (m, 1H), 7.70 (d, J＝8.1 Hz, 1H), 7.56~7.59 (m, 1H), 7.50~7.54 (m, 3H).

  2-(p-Tolyl)-4H-benzo[d][1, 3]oxazin-4-one (3b)^[7h]: 74% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.19~8.25 (m, 3H), 7.77~7.83 (m, 1H), 7.68 (d, J＝7.6 Hz, 1H), 7.50 (t, J＝7.6 Hz, 1H), 7.31 (d, J＝8.0 Hz, 2H), 2.45 (s, 3H).

  2-(4-Methoxyphenyl)-4H-benzo[d][1, 3]oxazin-4-one (3c)^[7a]: 81% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.20~8.26 (m, 3H), 7.80 (t, J＝7.1 Hz, 1H), 7.64 (d, J＝8.0 Hz, 1H), 7.47 (t, J＝7.2 Hz, 1H), 6.99 (d, J＝8.9 Hz, 2H), 3.89 (s, 3H).

  2-(4-Chlorophenyl)-4H-benzo[d][1, 3]oxazin-4-one (3d)^[7h]: 75% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.23~8.27 (m, 3H), 7.82~7.86 (m, 1H), 7.68 (d, J＝7.6 Hz, 1H), 7.54 (t, J＝7.6 Hz, 1H), 7.49 (d, J＝8.8 Hz, 2H).

  Methyl 4-(4-oxo-4H-benzo[d][1, 3]oxazin-2-yl)benzoate (3e)^[7a]: 80% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.38 (d, J＝8.6 Hz, 2H), 8.26 (d, J＝7.8 Hz, 1H), 8.17 (d, J＝8.6 Hz, 2H), 7.86 (t, J＝8.2 Hz, 1H), 7.72 (d, J＝7.7 Hz, 1H), 7.56 (t, J＝6.9 Hz, 1H), 3.97 (s, 3H).

  2-(3-Fluorophenyl)-4H-benzo[d][1, 3]oxazin-4-one (3f)^[7a]: 82% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.24 (d, J＝7.8 Hz, 1H), 8.10 (d, J＝7.8 Hz, 1H), 7.99~8.02 (m, 1H), 7.82~7.86 (m, 1H), 7.70 (d, J＝8.0 Hz, 1H), 7.46~7.56 (m, 2H), 7.25~7.29 (m, 1H).

  6-Chloro-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3g)^[7h]: 93% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.29~8.31 (m, 2H), 8.20 (d, J＝2.4 Hz, 1H), 7.75~7.78 (m, 1H), 7.57~7.66 (m, 2H), 7.50~7.54 (m, 2H).

  7-Chloro-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3h)^[11]: 85% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.30 (d, J＝7.2 Hz, 2H), 8.17 (d, J＝8.4 Hz, 1H), 7.70 (d, J＝2.0 Hz, 1H), 7.60 (t, J＝7.4 Hz, 1H), 7.52 (t, J＝7.2 Hz, 2H), 7.46~7.49 (m, 1H), 3.97 (s, 3H).

  2-Phenyl-6-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-4-one (3i)^[7h]: 89% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.52 (s, 1H), 8.33 (d, J＝7.3 Hz, 2H), 8.02~8.05 (m, 1H), 7.81 (d, J＝8.5 Hz, 1H), 7.52~7.64 (m, 3H).

  2-Phenyl-7-(trifluoromethyl)-4H-benzo[d][1, 3]oxazin-4-one (3j)^[11]: 83% yield. ¹H NMR (CDCl₃, 400 MHz): 8.39 (d, J＝8.2 Hz, 1H), 8.35 (d, J＝7.2 Hz, 2H), 8.00 (s, 1H), 7.75 (d, J＝8.2 Hz, 1H), 7.64 (t, J＝7.4 Hz, 1H), 7.56 (t, J＝7.2 Hz, 2H).

  6-Fluoro-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3k)^[7a]: 92% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.28~8.30 (m, 2H), 7.87~7.90 (m, 1H), 7.69~7.73 (m, 1H), 7.50~7.60 (m, 4H).

  7-Chloro-2-(4-chlorophenyl)-4H-benzo[d][1, 3]oxazin-4-one (3l)^[7a]: 86% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.24 (d, J＝8.7 Hz, 2H), 8.17 (d, J＝8.4 Hz, 1H), 7.69 (s, 1H), 7.48~7.51 (m, 3H).

  Methyl 4-oxo-2-phenyl-4H-benzo[d][1, 3]oxazine-6-car-boxylate (3m)^[7a]: 56% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.90 (d, J＝1.92 Hz, 1H), 8.44~8.46 (m, 1H), 8.32~8.34 (m, 2H), 7.74 (d, J＝8.4 Hz, 1H), 7.59~7.63 (m, 1H), 7.51~7.55 (m, 2H), 3.98 (s, 3H).

  6, 8-Dichloro-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3n)^[12]: 77% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.35 (d, J＝7.2 Hz, 2H), 8.12 (d, J＝2.4 Hz, 1H), 7.87 (d, J＝2.4 Hz, 1H), 7.60~7.64 (m, 1H), 7.52~7.55 (m, 2H).

  6-Methyl-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3o)^[7h]: 82% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.30 (d, J＝7.1 Hz, 2H), 8.04 (s, 1H), 7.49~7.65 (m, 5H), 2.49 (s, 3H).

  6, 8-Dimethyl-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3p)^[11]: 52% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.32 (d, J＝6.9 Hz, 2H), 7.88 (s, 1H), 7.48~7.54 (m, 4H), 2.62 (s, 3H), 2.44 (s, 3H).

  7-Methoxy-2-phenyl-4H-benzo[d][1, 3]oxazin-4-one (3q)^[6b]: 54% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 8.31 (d, J＝7.1 Hz, 2H), 8.14 (d, J＝8.7 Hz, 1H), 7.49~7.59 (m, 3H), 7.11 (d, J＝2.5 Hz, 1H), 7.04~7.07 (m, 1H), 3.96 (s, 3H).

  3.3   General procedure for the synthesis of 2-phenyl-1H-indol-3-yl acetate (4)

  To a solution of 1-azido-2-(phenylethynyl)benzene (1a) (0.1 mmol) and acetic acid 2 (1 mL) was added gold catalyst (2 mol %). The mixture was stirred at 60 ℃ and monitored by TLC analysis. On completion, the reaction mixture was directly subjected to purification by flash column chromatography on silica gel (petrol ether/ethyl acetate, V:V＝20:1 to 10:1) to give the desired product 2-phenyl-1H-indol-3-yl acetate (4)^[10d], 80% yield. ¹H NMR (CDCl₃, 400 MHz) δ: 2.41 (s, 3H), 7.12~7.16 (m, 1H), 7.18~7.22 (m, 1H), 7.28~7.35 (m, 2H), 7.41~7.45 (m, 3H), 7.61 (d, J＝7.5 Hz, 2H), 8.10 (br, 1H).

  3.4   General procedure for the synthesis of anthranilic acids (5a~5d)

  A pressure tube equipped with a magnetic stirrer bar was charged with tBuXPhosAuNTf₂ (2 mol%), 2-alkynyl arylazides 1 (0.1 mmol), m-CPBA (0.2 mmol, 2 equiv), and acetic acid 2 (1 mL). The reaction solution was stirred for 30 min at room temperature. Removing the solvent 2 under reduced pressure with proper heating, the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, V:V＝1:4), providing the desired compound 5.

  2-Pentanamidobenzoic acid (5a): 91% yield, white solid. m.p. 73.2 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 10.95 (s, 1H), 8.76~8.78 (d, J＝8.5 Hz, 1H), 8.13~8.15 (dd, J＝8.0, 1.6 Hz, 1H), 7.59~7.63 (m, 1H), 7.11~7.15 (m, 1H), 2.47~2.50 (m, 2H), 1.72~1.80 (m, 2H), 1.40~1.49 (m, 2H), 0.97 (t, J＝7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 13.8, 22.3, 27.6, 38.4, 114.0, 120.6, 122.7, 131.8, 135.7, 142.1, 172.5, 172.7; IR (neat) v: 3324, 2958, 2927, 2860, 1686, 1649, 1584, 1242, 956, 758, 654 cm^－1; HRMS (ESI) calcd for C₁₂H₁₆NO₃ [M+H]⁺ 222.1130, found 222.1128.

  2-Hexanamidobenzoic acid (5b): 97% yield, yellow solid. m.p. 77.4 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 10.97 (s, 1H), 8.76~8.78 (d, J＝8.5 Hz, 1H), 8.13~8.15 (dd, J＝8.0, 1.3 Hz, 1H), 7.59~7.63 (m, 1H), 7.11~7.15 (m, 1H), 2.46~2.50 (m, 2H), 1.74~1.81 (m, 2H), 1.36~1.44 (m, 4H), 0.92 (t, J＝7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ:13.9, 22.4, 25.2, 31.3, 38.7, 113.9, 120.6, 122.7, 131.8, 135.7, 142.1, 172.5, 172.7; IR (neat) v: 3330, 2954, 2929, 2856, 1691, 1672, 1586, 1264, 900, 755, 653 cm^－1; HRMS (ESI) calcd for C₁₃H₁₈NO₃ [M+H]⁺ 236.1287, found 236.1285.

  2-(Cyclopropanecarboxamido)benzoic acid (5c): 88% yield, brown solid. m.p. 98.3 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 11.20 (s, 1H), 8.72~8.74 (d, J＝8.5 Hz, 1H), 8.11~8.13 (dd, J＝8.0, 1.6 Hz, 1H), 7.55~7.59 (m, 1H), 7.08~7.12 (m, 1H), 1.62~1.68 (m, 1H), 1.11~1.15 (m, 2H), 0.88~0.92 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ: 8.3, 16.8, 114.3, 120.5, 122.4, 131.7, 135.3, 142.1, 173.0, 173.0; IR (neat) v: 3349, 2925, 2854, 1689, 1662, 1582, 1271, 957, 757, 660 cm^－1; HRMS (ESI) calcd for C₁₁H₁₂NO₃ [M+H]⁺ 206.0817, found 206.0815.

  2-Pivalamidobenzoic acid (5d): 82% NMR yield (mixed with 3-chlorobenzoic acid). ¹H NMR (CDCl₃, 400 MHz) δ: 11.20 (s, 1H), 8.82~8.79 (d, J＝8.5 Hz, 1H), 8.17~8.14 (dd, J＝8.5, 1.6 Hz, 1H), 7.61~7.58 (m, 1H), 7.14~7.10 (m, 1H), 1.36 (s, 9H).

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  Figure 1  4H-3, 1-Benzoxazin-4-ones with bioactivities

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  Scheme 1  Design for gold-catalyzed oxidation rearrangement of 2-alkynyl arylazides 1

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  Scheme 2  Proposed mechanism for the formation of 3a

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  Table 1.  Optimization of reaction conditions^a

  Entry	Oxidant	Solvent	Time/h	Yieldb/%
  1	m-CPBA	HOAc	0.5	86
  2c	m-CPBA	HOAc	0.5	85
  3c, d	Air	HOAc	24	—
  4e	oxone	HOAc	0.5	67
  5	TBHP	HOAc	0.5	40
  6f	m-CPBA	MeCN	0.5	49
  7f	m-CPBA	PhCl	0.5	39
  8f	m-CPBA	(CH2Cl)2	0.5	54
  9g	m-CPBA	(CH2Cl)2	0.5	34
  10h	m-CPBA	HOAc	0.5	69
  11i	m-CPBA	HOAc	0.5	NR
  aUnless stated otherwise, all reactions were performed at room temperature in 1 mL of HOAc with tBuXPhosAuNTf2:1a:oxidant ratio = 0.02:1:2. bIsolated yield. c At 60 ℃.d 85% of 4a obtained.e12% of 4a was obtained. f0.4 mL of HOAc was used.g Without HOAc.h1.5 equiv of m-CPBA was used.iWithout catalyst. NR＝no reaction

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  Table 2.  Synthesis of 4H-3, 1-benzoxazin-4-ones 3^{a, b}

  aUnless stated otherwise, all reactions were performed at room temperature in 1 mL of HOAc with t-BuXPhosAuNTf2:1a:m-CPBA ratio＝0.02:1:2. bIsolated yield.

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  Table 3.  Synthesis of anthranilic acids 5^{a, b}

  a Unless stated otherwise, all reactions were performed at room temperature in 1 mL of HOAc with t-BuXPhosAuNTf2:1a:m-CPBA ratio＝0.02:1:2. bNMR yield (mixed with 3-chlorobenzoic acid).

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