A process for the preparation of a chlorinated aromatic compound

Abstract

The application belongs to the field of fine chemicals and related chemical technology, and provides a preparation method of chlorinated aromatic compounds, wherein N-chlorosuccinimide, naphthalenemethanol and derivatives thereof are used as raw materials, a nickel catalyst is present, a base and an additive are present, an anhydrous organic solvent is used under the condition of 25 DEG C for 12 hours, and a compound with an aromatic halogenated hydrocarbon structure is obtained. The synthesis method is a one-step reaction, has mild reaction conditions, is simple to operate, and has high yield. The compound with the efficient halogenated aromatic hydrocarbon structure synthesized by the method can be further functionalized to obtain various compounds, and is applied to the development and research of drug synthesis.

Description

Technical Field

[0001] This invention belongs to the field of fine chemicals and related chemical technology, and provides a method for preparing chlorinated aromatic compounds. Background Technology

[0002] Halogenated aromatic hydrocarbons are an extremely important class of compounds, which are of great use in organic synthesis and drug research due to their high reactivity and pharmacological activity.

[0003] The previously reported synthetic methods for compounds with haloaromatic structures employ directional ortho-lithiation, electrophilic substitution of halogen molecules, and Sandmeyer reaction [Chem. Commun., 2016, 52, 4934-4937]. However, this method requires organolithium reagents, is not very environmentally friendly, is inconvenient to operate, requires harsh conditions, and has low chemoselectivity and regioselectivity.

[0004] Aromatic alcohols are widely found in natural products and are easy to synthesize. They can be directly synthesized from aromatic compounds and formaldehyde via the Tollens reaction [Adv. Mater. Technol., 2021, 6, 2100250].

[0005] In recent years, transition metal-catalyzed halogenation reactions of aromatic compounds have gained increasing popularity due to their advantages such as simple operation and mild reaction conditions. However, no synthetic methods using transition metals as catalysts to directly obtain chloroaromatic compounds from aromatic methanol have yet been reported. Summary of the Invention

[0006] This invention provides a novel method for preparing compounds with haloaromatic structures. This synthetic method can obtain compounds with haloaromatic structures in one step, with mild reaction conditions, simple operation, and high yield.

[0007] The technical solution of this invention:

[0008] A method for preparing a chlorinated aromatic compound, using N-chlorosuccinimide, 2-methoxy-1-naphthylethanol and its derivatives as raw materials, reacts at 25°C for 12 hours in the presence of a nickel catalyst, a base, and additives, under anhydrous organic solvent conditions, to obtain the corresponding chlorinated aromatic compound. The synthetic route is as follows:

[0009]

[0010] R 1 Selected from hydrogen, bromine, phenyl, and naphthyl;

[0011] R 2Selected from methyl, methoxy, ethoxy, allyloxy, hexoxy, cyclopentoxy, and benzyloxy;

[0012] in,

[0013] The molar ratio of 2-methoxy-1-naphthaleneethanol and its derivatives to N-chlorosuccinimide is 1:3;

[0014] The molar ratio of 2-methoxy-1-naphthalenemethanol and its derivatives to the catalyst is 1:0.05;

[0015] The molar ratio of 2-methoxy-1-naphthaleneethanol and its derivatives to base is 1:1.2;

[0016] The molar concentration of 2-methoxy-1-naphthaleneethanol and its derivatives in the reaction system was 0.1 mmol / mL;

[0017] The molar concentration of N-chlorosuccinimide is 0.3 mmol / mL.

[0018] The anhydrous organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile, dimethyl sulfoxide, 1,2-dichloroethane, tetrahydrofuran, N-methylpyrrolidone, etc.; preferably 1,2-dichloroethane, tetrahydrofuran, and toluene.

[0019] The nickel catalyst is nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, bis(triphenylphosphine)dibromide nickel, bis(triphenylphosphine)dichloride nickel, nickel acetylacetonate, nickel chloride hexahydrate, preferably nickel chloride or nickel acetylacetonate;

[0020] The alkali is sodium hydroxide, potassium hydroxide, cesium fluoride, cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, sodium tert-butoxide, potassium tert-butoxide, or 4-dimethylaminopyridine. Preferably, it is triethylamine, sodium tert-butoxide, potassium tert-butoxide, or 4-dimethylaminopyridine.

[0021] The separation method was column chromatography.

[0022] When separating products using column chromatography, silica gel or neutral alumina can be used as the stationary phase, and the developing solvent is generally a mixture of polar and nonpolar solvents, such as ethyl acetate-petroleum ether, ethyl acetate-n-hexane, dichloromethane-petroleum ether, and methanol-petroleum ether.

[0023] The beneficial effects of this invention are as follows: The preparation method of this application is a one-step synthesis method with mild reaction conditions, simple operation, and high yield; this method is the first to use aromatic methanol as a raw material to synthesize compounds with haloaromatic structures. The haloaromatic compounds synthesized by this method can be further functionalized to obtain various compounds [Org. Lett. 2012, 14, 4250-4253], [RSC Adv. 2018, 8, 17806-17812], [J. Am. Chem. Soc. 2017, 139, 16100-16104], which can be applied to the development and research of pharmaceutical macromolecules. Attached Figure Description

[0024] Figure 1 It is the 1-chloro-2-methoxynaphthalene in Example 1 1 H NMR spectrum.

[0025] Figure 2 It is the 1-chloro-2-methoxynaphthalene in Example 1 13 C NMR spectrum.

[0026] Figure 3 It is the 1-chloro-2-ethoxynaphthalene in Example 2 1 H NMR spectrum.

[0027] Figure 4 It is the 1-chloro-2-ethoxynaphthalene in Example 2 13 C NMR spectrum.

[0028] Figure 5 It is the 1-chloro-2-allyloxynaphthalene in Example 3 1 H NMR spectrum.

[0029] Figure 6 It is the 1-chloro-2-allyloxynaphthalene in Example 3 13 C NMR spectrum.

[0030] Figure 7 It is the 1-chloro-2-hexyloxynaphthalene in Example 4 1 H NMR spectrum.

[0031] Figure 8 It is the 1-chloro-2-hexyloxynaphthalene in Example 4 13 C NMR spectrum.

[0032] Figure 9 It is the 1-chloro-2-cyclopentoxynaphthalene in Example 5 1 H NMR spectrum.

[0033] Figure 10 It is the 1-chloro-2-cyclopentoxynaphthalene in Example 5 13 C NMR spectrum.

[0034] Figure 11 It is the 1-chloro-2-benzyloxynaphthalene in Example 6 1 H NMR spectrum.

[0035] Figure 12 It is the 1-chloro-2-benzyloxynaphthalene in Example 6 13 C NMR spectrum.

[0036] Figure 13 It is 1-chloro-2-methylnaphthalene in Example 7 1 H NMR spectrum.

[0037] Figure 14 It is 1-chloro-2-methylnaphthalene in Example 7 13 C NMR spectrum.

[0038] Figure 15 It is 6-bromo-1-chloro-2-methoxynaphthalene in Example 8 1 H NMR spectrum.

[0039] Figure 16 It is 6-bromo-1-chloro-2-methoxynaphthalene in Example 8 13 C NMR spectrum.

[0040] Figure 17 It is 1-chloro-2-methoxy-6-phenylnaphthalene in Example 9 1 H NMR spectrum.

[0041] Figure 18 It is 1-chloro-2-methoxy-6-phenylnaphthalene in Example 9 13 C NMR spectrum.

[0042] Figure 19 It is the 5'-chloro-6'-methoxy-1,2'-binaphthylene from Example 10. 1 H NMR spectrum.

[0043] Figure 20 It is the 5'-chloro-6'-methoxy-1,2'-binaphthylene from Example 10. 13 C NMR spectrum. Detailed Implementation

[0044] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings and technical solutions.

[0045] Example 1: Synthesis of 1-chloro-2-methoxynaphthalene

[0046] In a 25 mL reactor, 2-methoxy-1-naphthyl alcohol (0.038 g, 0.2 mmol), N-chlorosuccinimide (0.08 g, 0.6 mmol), and nickel chloride (0.001 g, 0.01 mmol) were added, followed by 2 mL of anhydrous 1,2-dichloroethane. Finally, 4-dimethylaminopyridine (0.029 g, 0.24 mmol) was added, and the mixture was stirred at 25 °C under nitrogen for 12 h. Column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether: ethyl acetate = 50:1) yielded 0.037 g of 1-chloro-2-methoxynaphthalene, in 96% yield.

[0047] 1-Chloro-2-methoxynaphthalene

[0048] Pale yellow solid; 1 H NMR (400MHz, CDCl3) δ8.27(d,J=8.6Hz,1H),7.80(dd,J=15.5,8.6Hz,2H),7.65-7.57(m,1H),7.48-7.40(m,1H),7.30(d,J=9.0Hz,1H),4.04(s,3H); 13 C{ 1 H}NMR (101MHz, CDCl3) δ152.5,131.8,129.4,127.93,127.89,127.4,124.2,123.3,116.8,113.6,56.8.

[0049] Example 2: Synthesis of 1-chloro-2-ethoxynaphthalene

[0050] The procedure was the same as in Example 1, with N-chlorosuccinimide reacting with 2-ethoxy-1-naphthalenemethanol for 12 hours to obtain 0.032 g of 1-chloro-2-ethoxynaphthalene, with a yield of 78%.

[0051] 1-Chloro-2-ethoxynaphthalene

[0052] White solid; 1 H NMR (400MHz, CDCl3) δ8.28(d,J=8.6Hz,1H),7.82(d,J=8.2Hz,1H),7.77(d,J=9.0Hz,1H),7.61(dd,J=8 .5,7.0Hz,1H),7.48-7.40(m,1H),7.29(d,J=8.9Hz,1H),4.28(q,J=7.0Hz,2H),1.55(t,J=7.0Hz,3H); 13 C{ 1H}NMR(101MHz, CDCl3)δ152.0,131.9,129.5,127.9,127.8,127.3,124.2,123.5,117.5,115.3,65.7,15.0; IR(KBr):v max 3067,2981,2939,1598,1506,1464,1454,1372,1271,1112,1062,828,799,768cm -1 HRMS(EI)m / z C 12 H 11 ClO + M ·+ Theoretical value: 206.0498; Actual value: 206.0492.

[0053] Example 3: Synthesis of 1-chloro-2-allyloxynaphthalene

[0054] In a 25 mL reactor, 2-allyloxy-1-naphthalenemethanol (0.043 g, 0.2 mmol), N-chlorosuccinimide (0.08 g, 0.6 mmol), nickel acetylacetonate (0.001 g, 0.01 mmol), and 2 mL of anhydrous tetrahydrofuran were added. Finally, triethylamine (0.024 g, 0.24 mmol) was added, and the mixture was stirred at 25 °C under nitrogen for 12 h. Column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether: ethyl acetate = 50:1) yielded 0.04 g of 1-chloro-2-allyloxynaphthalene, in 92% yield.

[0055] 1-Chloro-2-allyloxynaphthalene

[0056] Pale yellow solid; 1 H NMR (400MHz, CDCl3) δ8.27(dd,J=8.6,1.1Hz,1H),7.80(dd,J=8.3,1.2Hz,1H),7.74(d,J=9.0Hz,1H),7.64-7.55(m,1H) ,7.47-7.39(m,1H),7.26(d,J=9.0Hz,1H),6.21-6.07(m,1H),5.58-5.48(m,1H),5.39-5.31(m,1H),4.79-4.72(m,2H); 13 C{ 1 H}NMR(101MHz, CDCl3)δ151.6,132.9,131.9,129.6,127.9,127.7,127.3,124.4,123.5,117.9,117.8,115.4,70.6; IR(KBr):vmax 2930,2872,1629,1593,1506,1270,1153,1049,994,805,767,750cm -1 .

[0057] Example 4: 1-Chloro-2-hexyloxynaphthalene

[0058] The procedure was the same as in Example 3, with N-chlorosuccinimide reacting with 2-hexoxy-1-naphthalenemethanol for 12 h to obtain 0.048 g of 1-chloro-2-hexoxynaphthalene, with a yield of 91%.

[0059] 1-Chloro-2-hexyloxynaphthalene

[0060] White solid; 1 H NMR (400MHz, CDCl3) δ8.11(d,J=8.6Hz,1H),7.65(d,J=8.2Hz,1H),7.59(d,J=9.0Hz,1H),7.47-7.39(m,1H),7.30-7.22(m,1H) ,7.12(d,J=9.0Hz,1H),4.02(t,J=6.6Hz,2H),1.80-1.68(m,2H),1.45-1.35(m,2H),1.32-1.18(m,4H),0.81(t,J=6.9Hz,3H); 13 C{ 1 H}NMR(101MHz, CDCl3)δ152.1,131.9,129.4,127.9,127.7,127.3,124.2,123.4,117.4,115.2,70.1,31.5,29.4,25.6,22.6,14.0; IR(KBr):v max 2955,2944,2922,1595,1506,1465,1354,1270,1064,795,765,748,733cm -1 HRMS(EI)m / z C 16 H 19 ClO + M ·+ Theoretical value: 262.1124; Actual value: 262.1119.

[0061] Example 5: Synthesis of 1-chloro-2-cyclopentoxynaphthalene

[0062] In a 25 mL reactor, 2-cyclopentoxy-1-naphthalenemethanol (0.048 g, 0.2 mmol), N-chlorosuccinimide (0.08 g, 0.6 mmol), and nickel chloride (0.001 g, 0.01 mmol) were added, followed by 2 mL of anhydrous toluene. Finally, sodium tert-butoxide (0.023 g, 0.24 mmol) was added, and the mixture was stirred at 25 °C under nitrogen for 12 h. Separation by column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether: ethyl acetate = 50:1) yielded 0.045 g of 1-chloro-2-cyclopentoxynaphthalene, in 91% yield.

[0063] 1-Chloro-2-cyclopentoxynaphthalene

[0064] Pale yellow solid; 1 H NMR (400MHz, CDCl3) δ8.27(d,J=8.5Hz,1H),7.80(d,J=8.2Hz,1H),7.74(d,J=9.0Hz,1H),7.63-7.54(m, 1H),7.46-7.38(m,1H),7.30(d,J=9.0Hz,1H),5.01-4.96(m,1H),2.04-1.89(m,6H),1.77-1.60(m,2H); 13 C{ 1 H}NMR(101MHz, CDCl3)δ151.3,132.0,129.4,127.9,127.5,127.2,124.2,123.5,118.5,116.8,81.8,32.9,23.8; IR(KBr):v max 2962,2871,1595,1504,1465,1350,1269,1245,1016,804,746cm -1 ;HRMS(EI)m / zC 15 H 15 ClO + M ·+ Theoretical value: 246.0811; Actual value: 246.0805.

[0065] Example 6: Synthesis of 1-chloro-2-benzyloxynaphthalene

[0066] The procedure was the same as in Example 5, with N-chlorosuccinimide reacting with 2-benzyloxy-1-naphthalenemethanol for 12 h to obtain 0.048 g of 1-chloro-2-benzyloxynaphthalene, yielding 90%.

[0067] 1-Chloro-2-benzyloxynaphthalene

[0068] Pale yellow solid;1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.6Hz,1H),7.81(d,J=8.2Hz,1H),7.73(d,J=9.0Hz,1H),7.61(dd,J=8.4,7. 0Hz,1H),7.56(d,J=7.5Hz,2H),7.48-7.40(m,3H),7.38(d,J=7.2Hz,1H),7.31(d,J=9.0Hz,1H),5.32(s,2H); 13 C{ 1 H}NMR(101MHz, CDCl3)δ151.7,136.7,131.9,129.7,128.6,128.0,127.9,127.8,127.4,127.2,124.5,123.5,118.1,115.7,71.7; IR(KBr):v max 2877,1626,1506,1452,1338,1272,1054,798,750,727,696cm -1 ;HRMS(EI)m / zC 17 H 13 ClO + M ·+ Theoretical value: 268.0655; Actual value: 268.0651.

[0069] Example 7: 1-Chloro-2-methylnaphthalene

[0070] In a 25 mL reactor, 0.034 g (0.2 mmol) of 2-methyl-1-naphthyl alcohol, 0.08 g (0.6 mmol) of N-chlorosuccinimide, and 0.001 g (0.01 mmol) of nickel acetylacetonate were added, followed by 2 mL of anhydrous 1,2-dichloroethane. Finally, potassium tert-butoxide (0.027 g, 0.24 mmol) was added, and the mixture was stirred at 25 °C under nitrogen for 12 h. Separation by column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether: ethyl acetate = 50:1) yielded 0.027 g of 1-chloro-2-methylnaphthalene, in 76% yield.

[0071] 1-Chloro-2-methylnaphthalene is a white solid. 1 H NMR (400MHz, CDCl3) δ8.31(d,J=8.5Hz,1H),7.82(d,J=8.2Hz,1H),7.68(d,J=8.4 Hz,1H),7.63-7.55(m,1H),7.53-7.45(m,1H),7.35(d,J=8.4Hz,1H),2.60(s,3H);13 C{ 1 H}NMR (101MHz, CDCl3) δ133.4,133.0,131.1,130.6,128.7,128.0,127.0,126.4,125.6,124.1,20.8.

[0072] Example 8: Synthesis of 6-bromo-1-chloro-2-methoxynaphthalene

[0073] The procedure was the same as in Example 7, with N-chlorosuccinimide reacting with 6-bromo-2-methoxynaphthalene methanol for 12 h to obtain 0.043 g of 6-bromo-1-chloro-2-methoxynaphthalene, with a yield of 80%.

[0074] 6-Bromo-1-chloro-2-methoxynaphthalene

[0075] Yellow solid; 1 H NMR (400MHz, CDCl3) δ8.06 (d, J = 9.1Hz, 1H), 7.91 (d, J = 2.0Hz, 1H), 7.67-7.57 (m, 2H), 7.28 (d, J = 9.0Hz, 1H), 4.03 (s, 3H); 13 C{ 1 H}NMR (101MHz, CDCl3) δ152.7,130.6,130.4,130.3,129.8,126.9,125.3,118.1,117.0,114.5,56.8.

[0076] Example 9: Synthesis of 1-chloro-2-methoxy-6-phenylnaphthalene

[0077] In a 25 mL reactor, 0.053 g (0.2 mmol) of 2-methoxy-6-phenylnaphthalene methanol, 0.08 g (0.6 mmol) of N-chlorosuccinimide, 0.001 g (0.01 mmol) of nickel chloride, 2 mL of anhydrous tetrahydrofuran, and finally 0.023 g (0.24 mmol) of sodium tert-butoxide were added. The mixture was stirred at 25 °C under nitrogen for 12 h. Column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether: ethyl acetate = 50:1) yielded 0.042 g of 1-chloro-2-methoxy-6-phenylnaphthalene, in 78% yield.

[0078] 1-Chloro-2-methoxy-6-phenylnaphthalene

[0079] Pale yellow solid; 1H NMR (400MHz, CDCl3) δ8.30(dd,J=8.9,2.2Hz,1H),8.00(d,J=2.5Hz,1H),7.85(d,J=8.7Hz,1H),7.82(dd,J=9.2 ,2.2Hz,1H),7.76-7.69(m,2H),7.54-7.46(m,2H),7.44-7.36(m,2H),7.32(dd,J=9.0,2.2Hz,1H),4.05(s,3H); 13 C{ 1 H}NMR(101MHz, CDCl3)δ152.6,140.5,137.0,131.1,129.7,128.9,128.2,127.4,127.2,127.1,125.7,124.1,116.8,114.1,56.9; IR(KBr):v max 2920,2850,1628,1597,1495,1281,1068,888,800,769,697cm -1 ;HRMS(EI)m / zC 17 H 13 ClO + M ·+ Theoretical value: 268.0655; Actual value: 268.0651.

[0080] Example 10: Synthesis of 5'-chloro-6'-methoxy-1,2'-binaphthylene

[0081] The procedure was the same as in Example 9, with N-chlorosuccinimide reacting with 2-methoxy-6-(1'-naphthyl)naphthalene methanol for 12 h to obtain 0.053 g of 5'-chloro-6'-methoxy-1,2'-binaphthyl, with a yield of 83%.

[0082] 5'-Chloro-6'-methoxy-1,2'-binaphthylene

[0083] Pale yellow solid; 1 H NMR(400MHz, CDCl3) δ8.39(d,J=8.7Hz,1H),7.98(d,J=8.7Hz,2H),7.95-7.91(m,2H),7.8 4-7.76(m,2H),7.62-7.52(m,3H),7.51-7.44(m,1H),7.34(d,J=9.0Hz,1H),4.08(s,3H); 13 C{ 1H}NMR (101MHz, CDCl3) δ152.6,139.6,136.7,133.8,131.6,131.0,130.0,129.4,128.7,128. 3,128.1,127.8,127.2,126.1,125.84,125.80,125.4,123.3,116.8,114.0,56.9; IR(KBr):v max 3044,2938,2842,1601,1486,1350,1274,1253,1072,801,778cm -1 ;HRMS(EI)m / zC 21 H 15 ClO + M ·+ Theoretical value: 318.0811; Actual value: 318.0804.

Claims

1. A method for preparing a chlorinated aromatic compound, characterized in that, Using N-chlorosuccinimide, 2-methoxy-1-naphthylethanol and their derivatives as starting materials, the corresponding chloroaromatic compounds were obtained by reacting them at 25°C for 12 hours in the presence of a nickel catalyst and a base in an anhydrous organic solvent. The synthetic route is as follows: R 1 Selected from hydrogen, bromine, phenyl, and naphthyl; R 2 Selected from methyl, methoxy, ethoxy, allyloxy, hexoxy, cyclopentoxy, and benzyloxy; in, The molar ratio of 2-methoxy-1-naphthaleneethanol and its derivatives to N-chlorosuccinimide is 1:3; The molar ratio of 2-methoxy-1-naphthalenemethanol and its derivatives to nickel catalyst is 1:0.05; The molar ratio of 2-methoxy-1-naphthaleneethanol and its derivatives to base is 1:1.2; The molar concentration of 2-methoxy-1-naphthylethanol and its derivatives in the reaction system was 0.1 mmol / mL; The molar concentration of N-chlorosuccinimide is 0.3 mmol / mL; The nickel catalyst is nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, bis(triphenylphosphine)dibromide nickel, bis(triphenylphosphine)dichloride nickel, nickel acetylacetone, and nickel chloride hexahydrate.

2. The method for preparing chlorinated aromatic compounds according to claim 1, characterized in that, The anhydrous organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile, dimethyl sulfoxide, 1,2-dichloroethane, tetrahydrofuran, or N-methylpyrrolidone.

3. The method for preparing chlorinated aromatic compounds according to claim 1 or 2, characterized in that, The alkali is sodium hydroxide, potassium hydroxide, cesium fluoride, cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, sodium tert-butoxide, potassium tert-butoxide, or 4-dimethylaminopyridine.

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