A method for synthesizing an o-iodoaniline derivative

Abstract

The invention discloses a synthesis method of o-iodoaniline derivatives, belonging to the technical field of organic synthesis. Using iodoaryl diacetate 1 as a reaction raw material and N-methoxyamide 2 as an amidation reagent, the reaction is carried out at room temperature in an organic solvent to obtain o-iodoaniline derivatives 3. The synthesis method of the invention is convenient to operate, has mild reaction conditions, a wide range of applicable substrate functional groups, good reaction chemoselectivity and regioselectivity, and good yields.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing o-iodoaniline derivatives and belongs to the technical field of organic synthesis. Background Art

[0002] Aniline derivatives and iodoarene compounds are important synthetic intermediates in the field of organic synthesis and are used to construct aromatic heterocyclic compounds and biaryl compounds.

[0003] Currently, there is no reported method for directly synthesizing o-iodoarylamine derivatives in one step. Based on the retrosynthetic analysis strategy, traditional synthetic methods generally use arylamine derivatives as starting materials. However, in the subsequent aromatic electrophilic iodination step, it is very easy to generate a variety of iodination mixtures, namely p-iodoarylamine derivatives, o-iodo compounds, and o,p-diiodo compounds. Moreover, due to the large steric hindrance at the ortho position, the main product is generally the p-iodoarylamine derivative, and the regioselectivity of the reaction is poor, which further leads to difficult purification. Furthermore, the aromatic ring of arylamine derivatives generally cannot carry strong electron-withdrawing groups such as ester groups, otherwise it is very difficult to carry out aromatic electrophilic iodination reactions.

[0004] Based on the deficiencies of the above methods, the present invention realizes the mild, efficient, and convenient synthesis of o-iodoaniline derivatives through the selective direct amidation reaction of N-methoxyamide, which is simple and easily available, with iodoarene diacetate. Summary of the Invention

[0005] In order to solve the deficiencies of the existing synthesis methods, the present invention provides a method for synthesizing iodoaniline derivatives with mildness, simple operation, high yield, and high regioselectivity. Using iodoarene diacetate as the reaction raw material and N-methoxyamide as the amidation reagent, the reaction is stirred in an organic solvent to obtain o-iodoaniline derivatives. The synthesis method of the present invention is convenient to operate, has mild conditions, a simple process, a wide range of applicable substrate functional groups, good regioselectivity of the reaction, and high yield.

[0006] The method for synthesizing o-iodoaniline derivatives according to the present invention includes the following steps: using iodoarene diacetate 1 and N-methoxyamide 2 as raw materials, reacting in an organic solvent to obtain o-iodoaniline derivatives 3; the reaction equation is as follows:

[0007]

[0008] Wherein: R 1 is selected from hydrogen, C1-C4 alkyl, phenyl, halogen, ester group; R 2 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen; R 2Selected from C1-C4 alkyl, phenyl, substituted phenyl, and the substituents in the substituted phenyl are halogen, trifluoromethyl, ester group, C1-C4 alkyl, and C1-C4 alkoxy group.

[0009] Further, in the above technical solution, the organic solvent is selected from hexafluoroisopropanol, trifluoromethylbenzene or trifluoroethanol. Preferably hexafluoroisopropanol.

[0010] Further, in the above technical solution, the molar ratio of iodobenzene diacetate to N-methoxyamide is 1-2:1.

[0011] Further, in the above technical solution, the reaction temperature is 20-25 °C.

[0012] Advantages of the invention:

[0013] The reaction conditions of the present invention are mild, and the reaction has strong generality. It can be applied to substrates substituted with various substituents, and high ortho regioselectivity is obtained; it forms good technical complementarity with the prior art in obtaining para products. Specific embodiments

[0014] The reaction conditions were optimized experimentally, and the specific results are as follows:

[0015]

[0016]

[0017] a Aminating reagent (0.5 mmol), PhI(OAc) 2 (0.6 mmol) and HFIP (3 mL), 20 minutes at room temperature; b Using CH 2 Br 2 as an internal standard 1 1H NMR yield, the isolated yield is in parentheses; c 0 °C. d 1.0 eq PhI(OAc) 2 . e PhI(1.5 eq) and AcOOH(1.5 eq). f PhI(1.5 eq) and mCPBA(1.5 eq). g PhI(1.5 eq) and mCPBA(1.5 eq).

[0018] Example 1

[0019] In a 50 mL reaction flask with magnetic stirring, add N-methoxybenzamide (0.5 mmol), PhI(OAc) 2(0.75 mmol, 1.5 eq) and HFIP (3 mL). Then the reaction mixture was sealed and stirred at room temperature for 20 minutes. After the reaction was completed, the solvent was evaporated to dryness, and the product was purified by column chromatography. The reaction results are as follows:

[0020]

[0021] Representative product characterization data:

[0022] N-(2-Iodophenyl)-N-methoxybenzamide (1aa) Yellow solid, melting point 61 - 63 °C; 1 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 1H), 7.69 (s, 2H), 7.48 - 7.22 (m, 5H), 7.07 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H). 13 13C{ 1 1H}NMR (150 MHz, CDCl3) δ 168.8 (1C), 140.4 (1C), 134.3 (1C), 131.1 (1C), 130.6 (1C), 130.1 (1C), 129.3 (1C), 128.6 (2C), 128.1 (3C), 99.7 (1C), 61.9 (1C). HR MS (ESI / QTOF) m / z: calcd for C 14 13 12 H 2 11 + INNaO

[0023] N-(4-Iodophenyl)-N-methoxybenzamide (1aa’) Yellow oil; 1 1H NMR (600 MHz, CDCl3) δ 7.74 - 7.67 (m, 2H), 7.66 - 7.60 (m, 2H), 7.49 - 7.43 (m, 1H), 7.42 - 7.35 (m, 2H), 7.35 - 7.22 (m, 2H), 3.65 (s, 3H). 13 13C{ 1 1H}NMR (150 MHz, CDCl3) δ 168.3, 139.1, 138.1, 134.3, 131.1, 128.5, 128.22, 125.2, 91.3, 62.0. HRMS (ESI / QTOF) m / z: calcd for C 14 13 12 H 2 11+ 375.9805, found 375.9799.

[0024] 2-Chloro-N-(2-iodophenyl)-N-methoxybenzamide (2aa) off-white solid; melting point 109 - 111 °C; 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.99 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.50 (s, 3H), 7.48 - 7.29 (m, 2H), 7.28 - 7.02 (m, 1H), 3.60 (s, 3H). 13 C{ 1 H}NMR (150 MHz, DMSO-d 6 ) δ 141.1, 140.4, 135.6, 131.6, 131.5, 130.5, 130.4, 130.0, 129.8, 128.3, 127.3, 99.9, 62.0. HRMS (ESI / QTOF) m / z): calcd for C 14 H 11 ClINNaO 2 [M + Na] + 409.9415, found 409.9404.

[0025] 2-Chloro-N-(4-iodophenyl)-N-methoxybenzamide (2aa’) yellow oil; 1 H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 7.8 Hz, 2H), 7.41 - 7.29 (m, 6H), 3.59 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDCl3) δ 138.1, 131.0, 130.6, 129.7, 127.9, 126.6, 124.6, 62.10. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 ClINNaO 2 [M + Na] + 409.9415, found 409.9405.

[0026] N-(2-Iodophenyl)-N-methoxy-2-methylbenzamide (3aa) light yellow oil; 11H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 1H), 7.55 - 7.42 (m, 1H), 7.38 (s, 2H), 7.30 - 7.24 (m, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.16 (s, 1H), 7.06 (t, J = 6.6 Hz, 1H), 3.63 (s, 3H), 2.52 (s, 3H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3) δ 169.4, 143.6, 141.7, 140.2, 135.9, 135.1, 130.5, 130.5, 129.6, 129.2, 128.5, 126.7, 125.2, 119.7, 99.1, 61.9, 19.8. HRMS (ESI / QTOF) m / z: calcd for C 15 13 14 17 2 [M + Na] + 389.9961, found 389.9953.

[0027] N-(4-iodophenyl)-N-methoxy-2-methylbenzamide (3aa’) Pale yellow oil; 1 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 9.0 Hz, 2H), 7.32 - 7.28 (m, 4H), 7.20 (d, J = 8.4 Hz, 2H), 3.55 (s, 3H), 2.36 (s, 3H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3) δ 169.3, 138.7, 138.2, 135.6, 135.3, 130.4, 129.7, 126.7, 125.5, 124.5, 90.9, 62.2, 19.4. HRMS (ESI / QTOF) m / z: calcd for C 15 13 14 17 2 [M + Na] + 389.9961, found 389.9958.

[0028] 2-Ethyl-N-(2-iodophenyl)-N-methoxybenzamide (4aa) Pale yellow solid, mp 92 - 93 °C; 11H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.39 (s, 2H), 7.36 - 7.31 (m, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 7.06 (t, J = 6.6 Hz, 1H), 3.60 (s, 3H), 2.87 (q, J = 7.8 Hz, 2H), 1.32 (t, J = 7.8 Hz, 3H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3) δ 169.6, 142.1, 141.8, 140.2, 134.8, 130.4, 129.8, 129.3, 128.9, 126.7, 125.2, 99.2, 61.8, 26.6, 15.6. HRMS (ESI / QTOF) m / z: calcd for C 16 13 16 H 2 11 + INNaO

[0029] N-(2-Iodophenyl)-N,2-dimethoxybenzamide (5aa); dark yellow oil; 1 1H NMR (600 MHz, DMSO-d 6 6) δ 7.89 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 9.0 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.59 (s, 3H). 13 13C{ 1 1H} NMR (150 MHz, DMSO-d 6 6) δ 156.3, 141.9, 140.2, 131.4, 131.2, 130.6, 129.4, 128.2, 126.0, 120.5, 112.4, 100.0, 79.2, 61.8, 56.3. HRMS (ESI / QTOF) m / z: calcd for C 15 13 14 H 3 11 + INNaO

[0030] 3-Fluoro-N-(2-iodophenyl)-N-methoxybenzamide(6aa); light yellow oil 1 H NMR(600MHz,CDCl3)δ7.94(d,J=7.8Hz,1H),7.49(d,J=7.2Hz,1H),7.44(d,J=8.4Hz,1H),7.40(t,J=7.8Hz,1H),7.37(d,J=7.2Hz,1H),7.35 - 7.30(m,1H),7.13(t,J=7.2Hz,1H),7.08(td,J=7.8,1.8Hz,1H),3.77(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3)δ167.3,162.4(d,J=245.7Hz,1C),142.04,140.52,136.5(d,J=7.2Hz,1C),130.78,130.08,129.8(d,J=8.0Hz,1C),129.32,124.4(d,J=2.3Hz,1C),118.0(d,J=21.0Hz,1C),115.8(d,J=23.3Hz,1C),99.5,61.9. 19 F NMR(565MHz,CDCl3)δ-112.3.HRMS(ESI / QTOF)m / z:calcd forC 14 H 11 FINNaO 2 [M+Na] + 393.9711,found 393.9704.

[0031] 3-Fluoro-N-(4-iodophenyl)-N-methoxybenzamide(6aa’); sticky oil 1 H NMR(600MHz,CDCl3)δ7.76 - 7.68(m,2H),7.45(d,J=7.8Hz,1H),7.40(d,J=10.2Hz,1H),7.37 - 7.35(m,1H),7.29(d,J=8.4Hz,2H),7.19 - 7.14(m,1H),3.64(s,3H). 13 C{ 11H NMR (150 MHz, CDCl3) δ 166.98, 162.3 (d, J = 246 Hz, 1C), 138.8, 138.19, 136.5 (d, J = 7.1 Hz, 1C), 129.8 (d, J = 7.8 Hz, 1C), 125.0, 124.2 (d, J = 2.6 Hz, 1C), 117.9 (d, J = 21.2 Hz, 1C), 115.7 (d, J = 23.1 Hz, 1C), 91.3, 62.1. 19 19F NMR (565 MHz, CDCl3) δ -112.2. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 FINNaO 2 [M + Na] + 393.9711, found 393.9708.

[0032] 3-Chloro-N-(2-iodophenyl)-N-methoxybenzamide (7aa); Pale yellow oil 1 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.58 (d, J = 6.6 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 3.77 (s, 3H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3) δ 167.3, 142.0, 140.6, 136.3, 134.3, 131.2, 130.8, 130.1, 129.5, 129.4, 128.9, 126.8, 99.5, 62.0. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 ClINNaO 2 [M + Na] + 409.9415, found 409.9402.

[0033] N-(2-Iodophenyl)-N-methoxy-3-methylbenzamide (8aa); Off-white solid, mp 78 - 80 °C 11H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.22 (s, 2H), 7.06 (t, J = 7.2 Hz, 1H), 3.78 (s, 3H), 2.34 (s, 3H). At 328 K, 13 C{ 1 1H} NMR (150 MHz, CDCl3) δ 169.0, 142.6, 140.4, 137.9, 134.5, 131.8, 130.5, 130.1, 129.3, 129.2, 127.9, 125.6, 99.6, 61.9, 21.4. HRMS (ESI / QTOF) m / z: calcd for C 15 1 14 1 2 [M + Na] + 389.9961, found 389.9954.

[0034] N-(4-iodophenyl)-N-methoxy-3-methylbenzamide (8aa’) yellow oil; 1 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 9.0 Hz, 2H), 7.48 (s, 1H), 7.42 - 7.41 (m, 1H), 7.30 - 7.23 (m, 4H), 3.64 (s, 3H), 2.37 (s, 3H). 13 C{ 1 1H} NMR (150 MHz, CDCl3) δ 168.6, 139.4, 138.1, 137.9, 134.5, 131.6 3129.0, 127.9, 125.44 125.1, 90.9, 61.9, 21.3. HRMS (ESI / QTOF) m / z: calcd for C 15 1 14 1 2 [M + Na] + 389.9961, found 389.9952.

[0035] Example 2

[0036] According to the reaction conditions in Example 1, only changing the reaction substrates, the reaction results are as follows:

[0037] Representative product characterization data:

[0038] N-(2 / 3-chloro-5-iodophenyl)-N-methoxybenzamide(1ab) 1 H NMR(600MHz,DMSO-d 6 )δ8.02 - 7.91(m,0.89H),7.82 - 7.73(m,0.22H),7.68(d,J=7.4Hz,1.46H),7.64 - 7.57(m,1.09H),7.50(t,J=7.4Hz,0.96H),7.47 - 7.38(m,1.94H),7.35(d,J=8.4Hz,0.2H),7.31 - 7.19(m,0.73H),3.70(s,3H). 13 C{ 1 H}NMR(150MHz,DMSO-d 6 )δ168.7,168.3,144.0,141.5,139.9,139.4,139.0,135.0,134.7,134.3,133.2,132.4,131.3,131.1,130.3,128.5,128.5,128.4,128.3,97.8,91.8,62.3,62.2.HRMS(ESI / QTOF)m / z:calcd forC 14 H 11 ClINNaO 2 [M+Na] + 409.9415,found 409.9413.

[0039] N-(5 / 2-bromo-2 / 5-iodophenyl)-N-methoxybenzamide(1ac) 1 H NMR(600MHz,CDCl3)δ7.82 - 7.71(m,2.55H),7.69(d,J=7.2Hz,0.43H),7.54(d,J=1.8Hz,0.8H),7.51(d,J=7.2Hz,0.27H),7.46 - 7.42(m,1.11H),7.40 - 7.34(m,2.2H),7.19(d,J=8.4Hz,0.76H),3.73(s,3H). 13 C{ 11H NMR (150 MHz, CDCl3) δ 168.9, 168.9, 143.7, 141.1, 140.4, 139.4, 138.9, 135.1, 134.1, 134.0, 133.5, 132.5, 131.3, 128.6, 128.5, 128.2, 123.7, 122.6, 97.6, 91.9, 62.2, 62.1. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 BrINNaO 2 [M + Na] + 453.8910, found 453.8915.

[0040] Methyl 4-iodo-3-(N-methoxybenzamido)benzoate (1ae) off-white solid, mp 107 - 109 °C; 1 1H NMR (600 MHz, CDCl3) δ 8.01 (dd, J = 4.8, 3.6 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.70 (dd, J = 8.4, 1.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 3.92 (s, 3H), 3.76 (s, 3H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3) δ 169.0, 165.7, 143.0, 140.6, 134.3, 131.9, 131.3, 130.9, 130.5, 128.6, 128.2, 105.7, 62.1, 52.6. HRMS (ESI / QTOF) m / z: calcd for C 16 H 14 INNaO 4 [M + Na] + 433.9860, found 433.9846.

[0041] N-(4-iodo-[1,1'-biphenyl]-3-yl)-N-methoxybenzamide (1af) 39%, white solid, mp 116 - 118 °C; 11H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 1.8 Hz, 1H), 7.75 (dd, J = 8.4, 1.8 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.33 (dt, J = 8.4, 4.8 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.21 (d, J = 4.8 Hz, 4H), 7.09 (d, J = 8.4 Hz, 1H), 3.70 (s, 3H). 13 13C{ 1 1H}NMR (150 MHz, CDCl3) δ 169.2, 141.0, 139.0, 138.6, 137.9, 134.2, 132.8, 130.8, 129.0, 128.5, 128.4, 128.1, 127.9, 92.4, 62.2. HRMS (ESI / QTOF) m / z: calcd for C 20 18 16 11 2 INNaO + [M + Na]+ 452.0118, found 452.0110.

[0042] N-(4'-iodo-[1,1'-biphenyl]-2-yl)-N-methoxybenzamide (1af’) 13%, white solid, mp 129 - 131 °C. 1 1H NMR (600 MHz, CDCl3) δ 7.74 - 7.69 (m, 2H), 7.54 (dd, J = 7.8, 1.8 Hz, 1H), 7.44 (dtd, J = 16.2, 7.2, 1.8 Hz, 2H), 7.35 - 7.30 (m, 2H), 7.25 - 7.15 (m, 4H), 7.05 (d, J = 8.4 Hz, 2H), 3.73 (s, 3H). 13 13C{ 1 1H}NMR (150 MHz, CDCl3) δ 169.1, 140.3, 138.4, 137.6, 134.3, 131.2, 131.1, 130.7, 129.7, 129.6, 128.9, 128.5, 127.8, 93.8, 62.0. HRMS (ESI / QTOF) m / z: calcd for C 20 18 16 11 2 [M + Na]+ + 452.0118, found 452.0112.

[0043] N-(4'-iodo-[1,1'-biphenyl]-4-yl)-N-methoxybenzamide (1af”) 13%, white solid, melting point 78 - 80 °C. 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.56 (s, 4H), 7.44 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDCl3) δ 168.5, 140.0, 139.2, 138.7, 138.2, 135.0, 130.9, 129.0, 128.7, 128.2, 127.5, 124.3, 93.4, 62.0. HRMS (ESI / QTOF) m / z: calcd for C 20 H 16 INNaO 2 [M+Na] + 452.0118, found 452.0110. N-(2-iodo-3-methylphenyl)-N-methoxybenzamide (1ag), off-white solid, melting point 83 - 85 °C. 1 H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 6.6 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 3.77 (s, 3H), 2.53 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDCl3) δ 168.7, 144.5, 142.7, 134.7, 130.9, 130.2, 128.6, 128.1, 127.4, 106.9, 61.7, 29.5. HRMS (ESI / QTOF) m / z: calcd for C 15 H 14 INNaO 2 [M+Na] + 389.9961, found 389.9952.

[0044] N-(4 / 2-fluoro-2 / 4-iodophenyl)-N-methoxybenzamide(1ah)43%, yellow oil; 1 H NMR(600MHz,DMSO-d 6 )δ7.76(d,J = 8.4Hz,0.55H),7.64 - 7.60(m,1.81H),7.55(d,J = 7.8Hz,1.41H),7.45 - 7.42(m,2.32H),7.38 - 7.35(m,1.88H),7.27(q,J = 8.4,7.8Hz,0.92H),7.20(q,J = 7.8Hz,0.54H),3.73(s,1.8H),3.68(s,1.2H). 13 C{ 1 H}NMR(150MHz,DMSO-d 6 )δ168.8,168.4,158.8(d,J = 253.7Hz,1C),157.4(d,J = 255.8Hz,1C),136.15(d,J = 2.7Hz,1C),134.8(d,J = 3.8Hz,1C),134.5(d,J = 7.4Hz,1C),133.4(d,J = 8.9Hz,1C),131.6,131.4,128.6,128.5,128.3,128.1,126.1(d,J = 22.7Hz,1C),117.2(d,J = 21.2Hz,1C),101.9,94.7,62.4,62.3. 19 F NMR(565MHz,CDCl3)δ - 112.0,-115.4.HRMS(ESI / QTOF)m / z:calcd for C 14 H 11 FINNaO 2 [M+Na] + 393.9711,found 393.9708.

[0045] N-(2-fluoro-6-iodophenyl)-N-methoxybenzamide(1ah”)22%, yellow oil; 1 HNMR(600MHz,CDCl3)δ7.69(d,J = 7.8Hz,2H),7.62(dd,J = 7.8,3.0Hz,1H),7.45 - 7.40(m,1H),7.35(t,J = 7.8Hz,2H),7.32(dd,J = 9.0,5.4Hz,1H),7.13 - 7.06(m,1H),3.75(s,3H).13 C{ 1 H} NMR (150 MHz, CDCl3) δ 169.0, 161.9 (d, J=253.5 Hz, 1C), 138.9, 134.4, 131.2, 130.9 (d, J=9.0 Hz, 1C), 128.6, 128.2, 127.3 (d, J=25.5 Hz, 1C), 116.4 (d, J=22.5 Hz, 1C), 99.7 (d, J=9.0 Hz, 1C), 61.9. 19 F NMR (565 MHz, CDCl3) δ -119.2. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 FINNaO 2 [M + Na] + 393.9711, found 393.9708.

[0046] N-(4-chloro-2-iodophenyl)-N-methoxybenzamide (1ai) 49%, yellow oil; 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.99 (d, J=2.4 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.52 (dd, J=8.5, 2.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 3.71 (s, 3H). 13 C{ 1 H} NMR (150 MHz, DMSO-d 6 ) δ 168.3, 141.8, 139.4, 137.7, 135.0, 134.8, 132.6, 131.6, 131.3, 131.1, 129.7, 129.6, 128.5, 128.5, 128.4, 128.3, 100.6, 62.0. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 ClINNaO 2 [M + Na] + 409.9415, found 409.9406.

[0047] N-(2-chloro-6 / 4-iodophenyl)-N-methoxybenzamide (1ai’) and (1ai”) 19%, off-white solid; 11H NMR (600 MHz, CDCl3) δ 7.96 - 7.89 (m, 2H), 7.87 (dd, J = 8.4, 1.2 Hz, 1H), 7.77 (dd, J = 8.4, 1.2 Hz, 1H), 7.56 (dd, J = 8.4, 1.2 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.50 - 7.45 (m, 2H), 7.37 - 7.30 (m, 2H), 7.24 - 7.17 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 4.10 (s, 3H), 3.66 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDCl3) δ 168.7, 168.3, 140.9, 139.3, 139.1, 138.6, 134.9, 134.9, 133.9, 131.8, 131.2, 131.1, 130.8, 130.7, 128.4, 128.2, 127.9, 102.2, 101.4, 63.1, 62.8. HRMS (ESI / QTOF) m / z: calcd for C 14 H 11 ClINNaO 2 [M + Na] + 409.9415, found 409.9411.

[0048] Example 3

[0049] Product 1aa can be diversely derivatized, as shown by the reaction equation below:

[0050]

[0051] Example 4

[0052]

[0053] Under nitrogen protection, Pd(Ph 3 P) 2 Cl 2 (28 mg, 0.04 mmol), compound 1aa (141 mg, 0.4 mmol), KOAc (118 mg, 1.2 mmol) and DMF (4.0 mL) were added into a Schlenk tube, sealed and heated to 80 °C for reaction for 12 hours. The mixture was cooled to room temperature, diluted with 30 mL of ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After filtration and concentration, 68 mg of product 1aq was obtained by silica gel column chromatography as a white solid, with a yield of 76% and a melting point of 96 - 98 °C. 11H NMR (600 MHz, CDCl3) δ 8.60 - 8.49 (m, 1H), 8.22 (t, J = 7.1 Hz, 2H), 7.78 - 7.71 (m, 1H), 7.69 - 7.61 (m, 1H), 7.60 - 7.51 (m, 2H), 7.37 - 7.28 (m, 1H), 4.12 (s, 3H). 13 C{ 1 13C{1H} NMR (150 MHz, CDCl3) δ 157.3, 135.8, 133.0, 132.7, 130.0, 128.5, 128.1, 126.3, 123.3, 122.0, 118.6, 112.7, 62.8.

[0054] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing an o-iodoaniline derivative, characterized in that, it comprises the following steps: using iodoaryl diacetate 1 and N-methoxyamide 2 as raw materials, reacting in an organic solvent to obtain an o-iodoaniline derivative 3; the reaction equation is as follows: Wherein: R 1 is selected from hydrogen, C1-C4 alkyl, phenyl, halogen, ester group; R 2 is selected from C1-C4 alkyl, phenyl, substituted phenyl, and the substituent in the substituted phenyl is halogen, trifluoromethyl, ester group, C1-C4 alkyl, C1-C4 alkoxy group; the organic solvent is selected from hexafluoroisopropanol.

2. The method for synthesizing an o-iodoaniline derivative according to claim 1, characterized in that: the molar ratio of the iodoaryl diacetate to the N-methoxyamide is 1-2:

1.

3. The method for synthesizing an o-iodoaniline derivative according to claim 1, characterized in that: the reaction temperature is 20-25 °C.

Images