English

• 1.   Introduction

  Aromatic nitro compounds are widely applied in preparation of dyes, nonlinear optics, pharmaceuticals, and functional materials.^[1] Considerable attention has been paid to develop a practical and facile method for the nitration of arenes. Up to now, the most common approachs to nitroarenes have been focused on electrophilic aromatic substitution with nitrating agents.^[2] However, the nitration of benzoic acid needs a harsh reaction system (conc. H₂SO₄/ HNO₃) and always suffers from regioselectivity and functional group tolerance problems that remain difficult to overcome.^[3] Alternatively, nitroarenes could be synthesized via ipso-nitration of aryl halides, arylmetals, or aryl carboxylic acids, ^[4] while the use of prefunctionalized starting materials restricted the practical application in organic synthesis. As a consequence, it would be beneficial if nitroarenes could be accessed by chelation-assisted ortho-C—H activation with high chemoselectivity, broad substrate tolerance, and obviating prefunctionalization of the starting materials.^[5] Following this strategy, several groups have made great development in chelation-assisted aromatic C—H nitration.^[6] For example, Liu and co- workers reported Pd-catalyzed direct ortho-nitration of N-heterocycles.^[6a~6b] Rh(Ⅲ)-catalyzed C—H nitration of arenes has been developed by Li and co-workers.^[6e] Moreover, Cu catalyzed nitration of anilines using HNO₃ as the nitration agent has also been reported by Carretero and co-workers.^[6f] A silver-satalyzed chemo- and regio- selective nitration of anilides using sodium nitrite as a nitrating source was demonstrated by Nasab and co-workers in 2018.^[6g] However, most of the reported protocols suffered several drawbacks such as the use of expensive metal catalysis, as well as a narrow substrate scope.

  Chelation-assisted C—H bond functionalizations using bidentate-directing groups have emerged as a powerful tool for the synthesis of value-added organic molecules due to the pioneering work of Daugulis and co-workers for the Pd-catalyzed arylation of C_sp2—H bond.^[7] Then diverse C—H bond functionalization methods employing various directing groups have demonstrated the success of this chelation-assisted strategy utilizing relatively cheaper first-row metal catalysts such as iron^[8], cobalt^[9], nickel^[10] and copper^[11]. As for Cu salts, copper-catalyzed or copper-medi- ated C—H bond functionalization including sulfenylation, amination, fluorination, etherification, hydroxylation, alkynylation and trifluoromethylation have been reported by Daugulis, Yu and other groups.^[7m~7w] On the other hand, copper-mediated ortho-nitration of (hetero)arenecarboxy- lates was first reported by Gooβen and co-workers on the use of 8-aminoquinoline as a bidentate directing group recently.^[6h] The costly AgNO₂ as nitration source and the external oxidant N-methylmorpholine N-oxide (NMO) implies that there exists plenty of room to improve the method. Our laboratory has reported copper-mediated direct aryloxylation and alkoxylation of arenes using an N, O-bidentate directing group.^[12] As part of our interest in the field, ^{[9e~9f, 12]} we herein present the copper-promoted direct nitration of arenes using NaNO₂ as the nitration source under external-oxidant-free conditions.

  2.   Results and discussion

  Initially, 2-benzamidopydidine 1-oxide (1a) was subjected to the reaction conditions (0.5 equiv. CuF₂•2H₂O, 2.0 equiv. NaNO₂, 130 ℃, 0.5 mL DMSO, 12 h, Table 1, Entry 1) and the desired nitration product was achieved in 17% yield. After various Cu salts were investigated (Table 1, Entries 2~4), CuCl₂•2H₂O exhibited the best efficiency in 31% yield (Table 1, Entry 4). The addition of additives failed to give a satisfactory result (see the Supporting Information). Changing from DMSO to other solvents (see the Supporting Information), N-methyl-2-pyrrolidone (NMP) provided a higher nitration conversion efficiency (Table 1, Entry 5). Decreasing the reaction temperature and increasing the amount of NaNO₂ were beneficial for the reaction (Table 1, Entries 6~7), as the formation of by-product 2-(2-hydroxybenzamido)pyridine 1-oxide was diminished. To our delight, the further increase (2 equiv of CuCl₂•2H₂O) led to improved yields of the nitration product to 62% (Table 1, Entries 8~9). No product was obtained in the absence of copper salts (Table 1, Entry 10). Thus, the optimized reaction conditions was presented as follows: 1a (0.2 mmol), CuCl₂•2H₂O (0.4 mmol, 2 equiv.), NaNO₂ (1.6 mmol, 8.0 equiv.), NMP (0.5 mL) under an air atmosphere at 110 ℃ for 12 h.

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Cu salt	Yield/%
  1	CuF2•2H2O	17
  2	Cu(NO3)2•3H2O	< 5
  3	Cu(OAc)2•H2O	0
  4	CuCl2•2H2O	31
  5b	CuCl2•2H2O	34
  6b, c	CuCl2•2H2O	36
  7b, c, d	CuCl2•2H2O	40
  8b, c, d, e	CuCl2•2H2O	45
  9b, c, d, f	CuCl2•2H2O	62
  10	0	0
  a Reaction conditions: [Cu] (0.1 mmol), NaNO2 (0.4 mmol), 1a (0.2 mmol), DMSO (0.5 mL), air atmosphere, 130 ℃, 12 h, isolated yields. b NMP (0.5 mL) as solvent. c Run at 110 ℃. d NaNO2 (1.6 mmol). e CuCl2•2H2O (0.2 mmol). f CuCl2•2H2O (0.4 mmol). NMP＝N-methyl-2-pyrrolidone.

  Other bidentate directing groups (A~C) including 8-aminoquinoline were also examined to verify the paralleled property of N, O-auxiliary, and the result showed that no reaction occurred under the optimized reaction conditions. In addition, no products were found in structurally similar monodentate groups (D~G) by TLC analysis. These experiments indicate that 2-aminopyridine 1-oxide auxiliary is essential under our reaction system (Figure 1).

  Figure 1

  

  Figure 1.  Screening of other directing groups

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  We next examined the reaction scope with the respect to the aromatic amides, and the results were listed in Table 2. The nitration of C_sp2—H bond exclusively took place at the ortho-position of aromatic ring. Substrates possessing electron-withdrawing or electron-donating groups proceeded nitration smoothly to afford corresponding products (2a~2q) in moderate to good yields. In the case of meta-substituted substrate (1c), nitration occurred at the less hindered position of arenes. Aromatic amide derivatives bearing methyl, methoxy, tert-butyl, halogen groups on the para-position could successfully yield the corresponding nitration products as well, indicating that the reaction system exhibits a broad functional group compatibility. For ortho-substituted substrates (1b, 1h, and 1i), the reaction underwent well to afford the products in good yields. Moreover, the polycyclic substrate (1n) furnished the nitration compound in 54% yield. In all cases, the formation of the dinitrated product was not detected under the optimized reaction conditions.

  Table 2

  

  Table 2.  Scope with respect to amides^a

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  The mechanism was investigated by several control experiments. The addition of the radical quenchers, 2, 2, 6, 6- tetramethyl-1-piperidinyloxy (TEMPO, 1.0 equiv.) to the reaction system did not suppress product formation (Scheme 1a).^[13] When [D₅]-1a was treated with CuCl₂•2H₂O and NMP in the absence of the NaNO₂ for 12 h, no obvious hydrogen incorporation was detected (Scheme 1b). These results suggested that the C—H cleavage step was largely irreversible. A 1:1 mixture of [D₅]-1a and 1a, performed under the optimized reaction conditions, resulted in a kinetic isotope effect (KIE) of 1.6 (see the Supporting Information), which confirmed that C—H bond activation might be the rate limiting step (Scheme 1c). Whereas these control experiments and the mechanistic findings reported by Stahl^[14] and metallacycle intermediated heteroarylation proposed by Miura, ^[11i] a plausible mechanism involving Cu(Ⅲ) species was proposed for the ortho-nitration of arenes.

  Scheme 1

  

  Scheme 1.  Controlled experiments

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  Finally, the N, O-bidentate directing group could be easily removed in one step. As shown in Scheme 2, the nitration product 2a was treated with NaOH in EtOH at 90 ℃ for 24 h, affording 2-nitrobenzoic acid in high yield.

  Scheme 2

  

  Scheme 2.  Removal of the directing group

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  3.   Conclusions

  In conclusion, a copper-promoted chelation-assisted C—H nitration of aromatic amides was developed using NaNO₂ as the coupling partner. The nitration selectively took place at the ortho-position of aromatic ring with the help of N, O-bidentate directing group. Various functional groups were tolerated in the reaction system, and the protocol is operationally simple. Moreover, the directing group could be removed easily, providing a new way for the synthesis of ortho- nitro benzoic acids.

  4.   Experimental section

  4.1   General information

  ¹H NMR and ¹³C NMR spectra were recorded at 600 MHz and 150 MHz, respectively on a Bruker DPX 600 instrument using tetramethylsilane as an internal standard. Compounds for HRMS were analyzed on a Waters Q-Tof Micro MS/MS System ESI spectrometer. Melting points were measured on a WC-1 instrument and uncorrected. Unless otherwise noted, materials were obtained from commercial suppliers without further purification and all procedures were performed under ambient air.

  4.2   General procedure for nitration of sp²-C—H bonds

  A 15 mL screw cap tube was equipped with a magnetic stir bar and charged with aromatic amides 1 (0.2 mmol), CuCl₂•2H₂O (67.6 mg, 0.4 mmol, 2 equiv), NaNO₂ (110 mg, 1.6 mmol, 8 equiv.), and NMP (0.5 mL). The reaction system was stirred evenly at room temperature and heated at 110 ℃ for 12 h, then cooled to room temperature. The reaction system was diluted with 50 mL of ethylacetate, and filtered through a celite pad. The filtrate was quenched with aqueous 1 mol•L^－1 HCl solution (10 mL), and then washed with 50 mL saturated brines. The organic layer was collected and dried over Na₂SO₄. Product 2 was purified by preparative TLC on silica gel (ethylacetate/ MeOH, V:V＝10:1).

  2-(2-Nitrobenzamido)pyridine 1-oxide (2a): Yellow solid, yield 62%. m.p. 191~192 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.41 (s, 1H), 8.58 (d, J＝8.4 Hz, 1H), 8.27 (d, J＝6.4 Hz, 1H), 8.16 (d, J＝8.1 Hz, 1H), 7.77 (t, J＝7.4 Hz, 1H), 7.70 (t, J＝7.9 Hz, 2H), 7.43 (t, J＝8.0 Hz, 1H), 7.09 (t, J＝7.0 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.5, 146.5, 144.0 137.2, 134.0, 131.6, 131.5, 128.4, 128.3, 124.9, 119.5, 115.2. HRMS (positive, ESI) calcd for C₁₂H₁₀N₃O₄ [M+H]⁺ 260.0666, found 260.0667.

  2-(2-methyl-6-nitrobenzamido)pyridine 1-oxide (2b): Yellow solid, yield 71%. m.p. 208~209 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.25 (s, 1H), 8.63 (dd, J＝8.5, 1.6 Hz, 1H), 8.24 (dd, J＝6.5, 0.9 Hz, 1H), 8.10 (d, J＝8.1 Hz, 1H), 7.62 (d, J＝7.6 Hz, 1H), 7.55 (t, J＝7.9 Hz, 1H), 7.43 (td, J＝9.0, 4.5 Hz, 1H), 7.11~7.04 (m, 1H), 2.50 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.0, 145.7, 143.9 137.7, 137.2, 136.6, 131.4, 130.3, 128.3, 122.3, 119.4, 115.2, 19.1. HRMS (positive, ESI) calcd for C₁₃H₁₂N₃O₄ [M+ H]⁺ 274.0823, found 274.0824.

  2-(5-Methyl-2-nitrobenzamido)pyridine 1-oxide (2c): Yellow solid, yield 26%. m.p. 156~157 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.33 (s, 1H), 8.58 (d, J＝8.2 Hz, 1H), 8.27 (d, J＝6.2 Hz, 1H), 8.08 (d, J＝8.2 Hz, 1H), 7.44 (dd, J＝22.2, 8.2 Hz, 3H), 7.08 (t, J＝6.5 Hz, 1H), 2.51 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.9, 145.8, 144.0 137.2, 137.1, 131.7, 131.7, 128.9, 128.5, 124.9, 119.4, 115.3, 21.5. HRMS (positive, ESI) calcd for C₁₃H₁₂N₃O₄ [M+H]⁺ 274.0823, found 274.0825.

  2-(4-Methyl-2-nitrobenzamido)pyridine 1-oxide (2d): Yellow solid, yield 50%. m.p. 189~190 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.37 (s, 1H), 8.56 (d, J＝8.3 Hz, 1H), 8.27 (d, J＝6.1 Hz, 1H), 7.93 (s, 1H), 7.56 (dd, J＝18.0, 7.4 Hz, 2H), 7.42 (t, J＝8.0 Hz, 1H), 7.07 (t, J＝6.9 Hz, 1H), 2.53 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 170.4, 151.4, 148.6 147.2, 143.0, 139.8, 134.1, 134.0, 132.5, 129.5, 125.5, 120.7, 25.8. HRMS (positive, ESI) calcd for C₁₃H₁₂N₃O₄ [M+H]⁺ 274.0823, found 274.0824.

  2-(3, 5-Dimethoxy-2-nitrobenzamido)pyridine 1-oxide (2e): Yellow solid, yield 20%. m.p. 219~220 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.60 (s, 1H), 8.50 (d, J＝7.6 Hz, 1H), 8.27 (s, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 6.67 (d, J＝21.8 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 162.89, 162.14, 153.82, 143.93, 137.12, 133.62, 131.43, 128.30, 119.44, 115.15, 103.69, 102.19, 56.83, 56.21. HRMS (positive ESI) calcd for C₁₄H₁₄N₃O₆ [M+H]⁺ 320.0877, found 320.0879.

  2-(5-Methoxy-2-nitrobenzamido)pyridine 1-oxide (2f): Yellow solid, yield 54%. m.p. 162~163 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.35 (s, 1H), 8.58 (dd, J＝8.4, 1.5Hz, 1H), 8.26~8.18 (m, 2H), 7.46~7.39 (m, 1H), 7.11~7.02 (m, 3H), 3.94 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.68, 164.00, 143.96, 138.63, 137.19, 134.14, 128.30, 127.45, 119.40, 115.78, 115.24, 113.49, 56.37. HRMS (positive, ESI) calcd for C₁₃H₁₂N₃O₅ [M+H]⁺ 290.0772, found 290.0772.

  2-(4-Methoxy-2-nitrobenzamido)pyridine 1-oxide (2g): Yellow solid, yield 13%. m.p. 187~188 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.40 (s, 1H), 8.55 (d, J＝8.3 Hz, 1H), 8.27 (d, J＝6.3 Hz, 1H), 7.63 (d, J＝8.4 Hz, 1H), 7.56 (s, 1H), 7.41 (t, J＝7.9 Hz, 1H), 7.21 (d, J＝8.4 Hz, 1H), 7.07 (t, J＝6.9 Hz, 1H), 3.95 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.1, 161.8, 148.5, 144.1, 137.1, 129.7, 128.3, 123.3, 119.3, 118.9, 115.1, 110.2, 56.2. HRMS (positive, ESI) calcd for C₁₃H₁₂N₃O₅ [M+H]⁺ 290.0772, found 290.0774.

  2-(2, 4-Dimethyl-6-nitrobenzamido)pyridine 1-oxide (2h): Yellow solid, yield 47%. m.p. 219~220 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.17 (s, 1H), 8.62 (d, J＝8.3 Hz, 1H), 8.26 (d, J＝6.1 Hz, 1H), 7.90 (s, 1H), 7.43 (m, 2H), 7.08~7.06 (t, J＝6.72 Hz, 1H), 2.47 (s, 3H), 2.45 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.2, 145.8, 144.0 141.1, 137.3, 137.2, 137.1, 128.8, 128.3, 122.7, 119.3, 115.1, 21.1, 19.0. HRMS (positive ESI) calcd for C₁₄H₁₄N₃O₄ [M+H]⁺ 288.0979, found 288.0981.

  2-(3, 6-Dimethyl-2-nitrobenzamido)pyridine 1-oxide (2i): Yellow solid, yield 39%. m.p. 209~210 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.30 (s, 1H), 8.61 (dd, J＝8.3, 1.0 Hz, 1H), 8.17 (d, J＝6.2 Hz, 1H), 7.87 (s, 1H), 7.41 (t, J＝8.0 Hz, 2H), 7.05 (t, J＝6.3 Hz, 1H), 2.46 (s, 3H), 2.44 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.3, 145.7, 144.0 141.0, 137.3, 137.1, 128.8, 128.4, 122.6, 119.2, 115.2, 21.1, 19.1. HRMS (positive ESI) calcd for C₁₄H₁₄N₃O₄ [M+H]⁺ 288.0979, found 288.0980.

  2-(3, 5-Dimethoxy-2-nitrobenzamido)pyridine 1-oxide (2j): Beige solid, yield 30%. m.p. 175~176 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.70 (d, J＝67.9 Hz, 1H), 8.52 (d, J＝8.0 Hz, 1H), 8.29 (d, J＝4.7 Hz, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 2.46 (d, J＝11.6 Hz, 3H), 2.40 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 163.4, 147.5, 141.6, 137.1, 135.5, 132.1, 128.7, 128.3, 126.1, 119.3, 115.1, 21.2, 17.8. HRMS (positive ESI) calcd for C₁₄H₁₄N₃O₄ [M+H]⁺ 288.0979, found 288.0981.

  2-(4, 5-Dimethoxy-2-nitrobenzamido)pyridine 1-oxide (2k): Yellow solid, yield 63%. m.p. 216~217 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.38 (s, 1H), 8.58 (dd, J＝8.4, 1.5 Hz, 1H), 8.25~8.17 (m, 1H), 7.68 (s, 1H), 7.48~7.39 (m, 1H), 7.10~7.03 (m, 1H), 7.01 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.9, 153.6, 150.0, 144.0, 138.8, 137.2, 128.3, 126.0, 119.3, 115.2, 109.7, 107.3, 56.8, 56.7. HRMS (positive, ESI) calcd for C₁₄H₁₄N₃O₆ [M+H]⁺ 320.0877, found 320.0878.

  2-(4-(tert-Butyl)-2-nitrobenzamido)pyridine 1-oxide (2l): White solid, yield 46%. m.p. 220~221 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.46 (s, 1H), 8.56 (dd, J＝8.4, 1.6 Hz, 1H), 8.23 (d, J＝6.2 Hz, 1H), 8.13 (d, J＝1.8 Hz, 1H), 7.75 (dd, J＝8.0, 1.8 Hz, 1H), 7.61 (d, J＝8.0 Hz, 1H), 7.43~7.39 (m, 1H), 7.07~7.04 (m, 1H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.6, 156.1, 146.7, 144.1 137.2, 130.8, 128.7, 128.3, 128.2, 121.9, 119.3, 115.2, 35.4, 30.9. HRMS (positive, ESI) calcd for C₁₆H₁₈N₃O₄ [M+H]⁺ 316.1292, found 316.1293.

  2-(3-Nitro-[1, 1'-biphenyl]-4-ylcarboxamido)pyridine 1- oxide (2m): White solid, yield 35%. m.p. 186~188 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.48 (s, 1H), 8.58 (dd, J＝8.5, 1.6 Hz, 1H), 8.33 (d, J＝1.7 Hz, 1H), 8.21 (d, J＝5.9 Hz, 1H), 7.93 (dd, J＝7.9, 1.7 Hz, 1H), 7.75 (d, J＝7.9 Hz, 1H), 7.65~7.63 (m, 2H), 7.55~7.46 (m, 3H), 7.43~7.38 (m, 1H), 7.05~7.01 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.4, 147.2, 145.0 144.0, 137.5, 131.9, 129.7, 129.4, 129.3, 128.9, 128.4, 127.2, 123.1, 119.4, 115.3. HRMS (positive, ESI) calcd for C₁₈H₁₄N₃O₄ [M+H]⁺ 336.0979, found 336.0981.

  2-(2-Nitro-1-naphthamido)pyridine 1-oxide (2n): Yellow solid, yield 54%. m.p. 224~225 ℃ (decompose). ¹H NMR (600 MHz, CDCl₃) δ 10.43 (s, 1H), 8.75 (d, J＝8.2 Hz, 1H), 8.27 (d, J＝9.0 Hz, 1H), 8.21 (d, J＝6.3 Hz, 1H), 8.10 (d, J＝9.14 Hz, 1H), 8.06 (d, J＝8.5 Hz, 1H), 8.00 (d, J＝8.2 Hz, 1H), 7.74 (t, J＝7.39 Hz, 1H), 7.69 (t, J＝7.6 Hz, 1H), 7.48 (t, J＝7.9 Hz, 1H), 7.09 (t, J＝6.6 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ: 164.6, 144.0, 142.3, 137.3, 135.7, 131.4, 130.5, 130.2, 129.34, 129.31, 128.5, 128.3, 126.9, 119.6, 119.5, 115.3. HRMS (positive ESI) calcd for C₁₆H₁₂N₃O₄ [M+H]⁺ 310.0823, found 310.0824.

  2-(4-Fluoro-2-nitrobenzamido)pyridine 1-oxide (2o): Yellow solid, yield 24%. m.p. 192~193 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.43 (s, 1H), 8.55 (d, J＝8.3 Hz, 1H), 8.27 (d, J＝6.2 Hz, 1H), 7.86 (d, J＝7.7 Hz, 1H), 7.71 (dd, J＝7.8, 5.4 Hz, 1H), 7.48 (t, J＝7.6 Hz, 1H), 7.43 (t, J＝8.0 Hz, 1H), 7.09 (t, J＝6.8 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 163.4, 143.8, 137.2, 130.33 (J_C—F＝8.01 Hz), 128.3, 127.8 (J_C—F＝4.67 Hz), 121.1, 121.0 (J_C—F＝22.6 Hz), 119.6, 115.2, 113.1, 112.9 (J_C—F＝26.7 Hz). HRMS (positive ESI) calcd for C₁₂H₉FN₃O₄ [M+H]⁺ 278.0572, found 278.0575.

  2-(4-Chloro-2-nitrobenzamido)pyridine 1-oxide (2p): Yellow solid, yield 22%. m.p. 163~164 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.54 (s, 1H), 8.52 (d, J＝8.2 Hz, 1H), 8.22 (d, J＝5.6 Hz, 1H), 8.12 (s, 1H), 7.71 (d, J＝7.5 Hz, 1H), 7.63 (d, J＝8.1 Hz, 1H), 7.42 (t, J＝7.8 Hz, 1H), 7.07 (d, J＝6.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 163.5, 147.1, 143.8, 137.7, 137.2, 133.9, 129.7, 129.5, 128.4, 125.2, 119.6, 115.3. HRMS (positive ESI) calcd for C₁₂H₉ClN₃O₄ [M+H]⁺ 294.0276, found 294.0278.

  2-(4-Bromo-2-nitrobenzamido)pyridine 1-oxide (2q): Yellow solid, yield 28%. m.p. 184~185 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.56 (s, 1H), 8.53 (d, J＝8.3 Hz, 1H), 8.27 (s, 1H), 8.21 (d, J＝5.8 Hz, 1H), 7.87 (d, J＝7.9 Hz, 1H), 7.56 (d, J＝8.0 Hz, 1H), 7.42 (t, J＝8.0 Hz, 1H), 7.07 (t, J＝6.8 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 163.6, 147.0, 143.8, 137.2 136.9, 130.1, 129.6, 128.4, 127.9, 125.1, 119.6, 115.3. HRMS (positive ESI) calcd for C₁₂H₉BrN₃O₄ [M+H]⁺ 337.9771, found 337.9773.

  Supporting Information    ¹H NMR and ¹³C NMR spectra of compounds 2a~2q. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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  Figure 1  Screening of other directing groups

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  Scheme 1  Controlled experiments

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  Scheme 2  Removal of the directing group

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction conditions^a

  Entry	Cu salt	Yield/%
  1	CuF2•2H2O	17
  2	Cu(NO3)2•3H2O	< 5
  3	Cu(OAc)2•H2O	0
  4	CuCl2•2H2O	31
  5b	CuCl2•2H2O	34
  6b, c	CuCl2•2H2O	36
  7b, c, d	CuCl2•2H2O	40
  8b, c, d, e	CuCl2•2H2O	45
  9b, c, d, f	CuCl2•2H2O	62
  10	0	0
  a Reaction conditions: [Cu] (0.1 mmol), NaNO2 (0.4 mmol), 1a (0.2 mmol), DMSO (0.5 mL), air atmosphere, 130 ℃, 12 h, isolated yields. b NMP (0.5 mL) as solvent. c Run at 110 ℃. d NaNO2 (1.6 mmol). e CuCl2•2H2O (0.2 mmol). f CuCl2•2H2O (0.4 mmol). NMP＝N-methyl-2-pyrrolidone.

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  Table 2.  Scope with respect to amides^a

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