A method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline

Abstract

This invention provides a method for the dehydrogenation synthesis of quinazolines from tetrahydroquinazolines. The method involves adding a tetrahydroquinazoline compound to an organic solvent, followed by the sequential addition of a catalyst, ligand, and additives, and then heating to carry out a dehydrogenation reaction to obtain the quinazoline compound. The catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper trifluoromethanesulfonate, or cuprous acetate. This method enables the efficient synthesis of quinazoline compounds under mild reaction conditions and with high product yields.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for synthesizing quinazoline compounds, specifically a method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline. Background Technology

[0002] Alkaloids, as nitrogen-containing organic compounds, are widely distributed in nature and are an important raw material in organic synthesis, with significant applications in pharmaceuticals, pesticides, and other fields. Quinazoline alkaloids, in particular, typically possess a wide range of biological activities, including antibacterial, anticonvulsant, anti-inflammatory, antihypertensive, antituberculosis, antimalarial, antiviral, and anticancer activities. Therefore, exploring the synthesis of quinazolines and their derivatives has significant research value and importance.

[0003] The synthesis of quinazoline via transition metal-catalyzed dehydrogenation of tetrahydroquinazoline compounds is one of the most direct and atom-economical strategies. Although some progress has been made in the synthesis of quinazoline via transition metal-catalyzed oxidative dehydrogenation, several challenges remain, including expensive catalysts, demanding reaction conditions, and a narrow range of applicable substrates. Therefore, developing an efficient method for the synthesis of quinazoline alkaloids is of significant research value and practical importance. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention aims to provide a method for the dehydrogenation synthesis of quinazoline from tetrahydroquinazoline, thereby achieving the synthesis of quinazoline compounds using inexpensive catalysts, simple operation, mild and environmentally friendly reaction conditions.

[0005] This invention is achieved through the following technical solution:

[0006] A method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline involves adding a tetrahydroquinazoline compound to an organic solvent, adding a catalyst, ligand and additives, and heating to carry out a dehydrogenation reaction to obtain a quinazoline compound.

[0007] The catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper trifluoromethanesulfonate, or cuprous acetate.

[0008] Preferably, the tetrahydroquinazoline compound is one of the following compounds:

[0009]

[0010] Wherein, R is an alkyl group having any number of carbon atoms from 1 to 6; R x It is one or two of -H, -Br, -Cl, -CH3, -OCH3, and -NO2.

[0011] Preferably, the ligand is pyridine, 4-dimethylaminopyridine, triethylamine, or 4-methoxypyridine.

[0012] Preferably, the additive is diethyl azodicarbonate, di-tert-butyl dicarboxylate, or dibenzyl azodicarbonate.

[0013] Preferably, the organic solvent is acetonitrile, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, or methanol.

[0014] Preferably, the molar ratio of the catalyst to the tetrahydroquinazoline compound is 1:(10-20).

[0015] Preferably, the molar ratio of the ligand to the tetrahydroquinazoline compound is 1:(5-10).

[0016] Preferably, the molar ratio of the additive to the tetrahydroquinazoline compound is 1:(10-20).

[0017] Preferably, the dehydrogenation reaction temperature is 50–70°C.

[0018] Preferably, the reaction time is 24 to 48 hours.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] This invention uses copper salt as a catalyst to catalyze the oxidative dehydrogenation of tetrahydroquinazoline to synthesize quinazoline. Furthermore, the addition of ligands and additives during the dehydrogenation reaction increases its reactivity. This invention exhibits high catalytic activity, with yields reaching up to 99%. In addition, the catalyst used in this invention is inexpensive and readily available, and the reaction operation is convenient and practical. This invention is applicable to the synthesis of quinazoline compounds.

[0021] Furthermore, the method for synthesizing quinazoline by catalytic oxidative dehydrogenation of tetrahydroquinazoline provided by this invention has mild reaction conditions and the product is easy to separate. Attached Figure Description

[0022] Figure 1 This is the nuclear magnetic resonance-hydrogen spectrum of 2-phenylquinazoline prepared in Example 1 of this invention;

[0023] Figure 2 This is the NMR-carbon spectrum of 2-phenylquinazoline prepared in Example 1 of this invention. Detailed Implementation

[0024] To further understand the present invention, the present invention will be described below with reference to embodiments. These descriptions are only for further explaining the features and advantages of the present invention and are not intended to limit the claims of the present invention.

[0025] The synthesis method of this invention is as follows: a tetrahydroquinazoline compound is added to an organic solvent, and then a catalyst, ligand, and additive are added in sequence. The mixture is heated to carry out a dehydrogenation reaction, thereby achieving the oxidative dehydrogenation of the tetrahydroquinazoline compound. The catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper trifluoromethanesulfonate, or cuprous acetate.

[0026] The chemical reaction formula of this invention is:

[0027]

[0028] Wherein, R is an alkyl group having any number of carbon atoms from 1 to 6. x It is one or two of -H, -Br, -Cl, -CH3, -OCH3, and -NO2.

[0029] The molar ratio of the catalyst to the tetrahydroquinazolin-like compound is 1:(10-20).

[0030] The ligand is pyridine, 4-dimethylaminopyridine, triethylamine, or 4-methoxypyridine. The molar ratio of the ligand to the tetrahydroquinazolin compound is 1:(5-10).

[0031] The additive is diethyl azodicarbonate (DEAD), di-tert-butyl dicarboxylate, or dibenzyl azodicarbonate. The molar ratio of the additive to the tetrahydroquinazoline compound is 1:(10-20).

[0032] The organic solvent is acetonitrile, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, or methanol;

[0033] The dehydrogenation reaction temperature is 50–70°C;

[0034] The dehydrogenation reaction time is 24–48 h.

[0035] Example 1: A method for synthesizing 2-phenylquinazoline

[0036] This embodiment provides a method for synthesizing 2-phenylquinazoline. 105.1 mg of 2-phenyl-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added sequentially to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 24 h. After the reaction was complete as detected by TLC, the product was purified by column chromatography to obtain 96.9 mg of 2-phenylquinazoline, with a yield of 94%. The chemical reaction formula is as follows:

[0037]

[0038] 2-Phenylquinazoline: White solid, 94% yield. f =0.58(petroleum ether / ethyl acetate 5:1). 1 H NMR (400MHz, Chloroform-d) δ9.47(s,1H),8.66(dd,J=7.8,2.0Hz,2H),8.10(d,J=8.7Hz,1H),7.91(d,J=7.8Hz,2H),7.57(m,J=7.5Hz,4H). 13 C NMR (100MHz, CDCl3) δ161.1,160.5,150.8,138.1,134.1,130.7,128.7,128.7,128.6,127.3,127.1,123.6.

[0039] Its nuclear magnetic resonance-hydrogen spectrum is as follows Figure 1 As shown, the NMR-carbon spectrum is as follows: Figure 2 As shown.

[0040] Examples 2-13: A method for synthesizing 2-phenylquinazoline

[0041] Examples 2 to 13 provide a method for synthesizing 2-phenylquinazoline. The synthesis methods are basically the same as those in Example 1, except that the raw materials and some process parameters are different. Specific data are shown in Table 1.

[0042] Table 1: Process parameters for the synthesis of 2-phenylquinazoline provided in Examples 2-13

[0043]

[0044]

[0045] All other steps are the same as in Example 1. All reactions involve the dehydrogenation of 2-phenyl-1,2,3,4-tetrahydroquinazoline to synthesize 2-phenylquinazoline. The reaction equation is as follows:

[0046]

[0047] The results from Examples 1-13 show that cuprous acetate has a better catalytic effect than other catalysts, and the effect is better when acetonitrile is used as a solvent. At the same time, the yield of the target product can be greatly improved when 4-dimethylaminopyridine is used as a ligand and diethyl azodicarbonate (DEAD) is used as an additive.

[0048] Example 14: A method for synthesizing 2-(4-methoxyphenyl)quinazoline

[0049] This embodiment provides a method for synthesizing 2-(4-methoxyphenyl)quinazoline. 120.2 mg of 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60 °C, and reacted for 42 h. After purification by column chromatography, 98.8 mg of 2-(4-methoxyphenyl)quinazoline was obtained, with a yield of 84%. The chemical reaction formula is as follows:

[0050]

[0051] 2-(4-Methoxyphenyl)quinazoline: White solid, 84% yield. f =0.68(petroleum ether / ethyl acetate 2:1). 1 H NMR(400MHz, CDCl3)δ9.44–9.40(m,1H),8.60(d,J=8.9Hz,2H),8.08–8.02(m,1H),7. 89(d,J=7.6Hz,2H),7.56(m,J=7.4,6.8,1.1Hz,1H),7.09–7.05(m,2H),3.91(s,3H). 13 C NMR (100MHz, CDCl3) δ161.9,160.9,160.4,150.9,134.0,130.8,130.2,128.4,127.2,126.8,123.3,114.0,55.4.

[0052] Example 15: A method for synthesizing 2-(4-methylphenyl)quinazoline

[0053] This embodiment provides a method for synthesizing 2-(4-methylphenyl)quinazoline. 112.2 mg of 2-(4-methylphenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 48 h. After purification by column chromatography, 97.9 mg of a 2-(4-methylphenyl)quinazoline was obtained, with a yield of 89%. The chemical reaction formula is as follows:

[0054]

[0055] 2-(4-Methylphenyl)quinazoline (2-(p-tolyl)quinazoline): White solid, 89% yield. f =0.60(petroleum ether / ethyl acetate 5:1). 1 H NMR (400MHz, CDCl3) δ9.45 (s, 1H), 8.58–8.51 (m, 2H), 8.08 (m, J = 9.2, 1.1Hz, 1H), 7.90 (d,J=7.7Hz,2H),7.58(m,J=7.3,6.8,1.1Hz,1H),7.37(d,J=8.0Hz,2H),2.47(s,3H). 13 C NMR (101MHz, CDCl3) δ161.1,160.4,150.8,140.9,135.4,134.0,129.4,128.9,128.6,127.1,127.0,123.5,21.5.

[0056] Example 16: A method for synthesizing 2-(4-nitrophenyl)quinazoline

[0057] This embodiment provides a method for synthesizing 2-(4-nitrophenyl)quinazoline. 127.6 mg of 2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 24 h. After purification by column chromatography, 132.2 mg of 2-(4-nitrophenyl)quinazoline was obtained, with a yield greater than 99%. The chemical reaction formula is as follows:

[0058]

[0059] 2-(4-Nitrophenyl)quinazoline: Pale yellow solid, >99% yield. f =0.29(petroleum ether / ethyl acetate 5:1). 1 H NMR (400MHz, CDCl3) δ9.54 (d, J=0.8Hz, 1H), 8.87–8.80 (m, 2H), 8.43–8.36 (m ,2H),8.19–8.06(m,1H),8.04–7.96(m,2H),7.73(m,J=7.4,6.9,1.1Hz,1H).13 C NMR (100MHz, CDCl3) δ160.7,158.8,150.6,149.2,143.9,134.6,129.4,128.9,128.4,127.2,123.9,123.8.

[0060] Example 17: A method for synthesizing 2-(4-bromophenyl)quinazoline

[0061] This embodiment provides a method for synthesizing 2-(4-bromophenyl)quinazoline. The method involves weighing 144.6 mg of 2-(4-bromophenyl)-1,2,3,4-tetrahydroquinazoline, 9.5 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD, and adding them to 3 mL of acetonitrile. The mixture is continuously stirred to dissolve, heated to 60°C, and maintained at 60°C for 36 h. After purification by column chromatography, 136.4 mg of 2-(4-bromophenyl)quinazoline is obtained, with a yield of 96%. The chemical reaction formula is as follows:

[0062]

[0063] 2-(4-Bromophenyl)quinazoline: White solid, 96% yield. f =0.47(petroleum ether / ethyl acetate 5:1). 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, Chloroform-d) δ9.44(s,1H),8.51(d,J=8.6Hz,2H),8.08(d,J=8.9Hz,1H),7.96–7.88(m,2H),7.71–7.59(m,3H). 13 C NMR (100MHz, CDCl3) 13 CNMR (101MHz, CDCl3) δ160.5,160.1,150.7,137.0,134.3,131.8,130.2,128.6,127.5,127.2,125.4,123.6.

[0064] Example 18: A method for synthesizing 2-(4-(tert-butyl)phenyl)quinazoline

[0065] This embodiment provides a method for synthesizing 2-(4-(tert-butyl)phenyl)quinazoline. 133.2 mg of 2-(4-(tert-butyl)phenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 48 h. After purification by column chromatography, 118.4 mg of 2-(4-(tert-butyl)phenyl)quinazoline was obtained, with a yield of 90%. The chemical reaction formula is as follows:

[0066]

[0067] 2-(4-(tert-butyl)phenyl)quinazoline: Whitesolid, 90% yield. f =0.53(petroleum ether / ethyl acetate 5:1).1H NMR (400MHz, Chloroform-d) δ9.47(s,1H),8.57(d,J=8.5Hz,2H),8.13–8.07(m,1H),7.95–7.86(m,2H),7.72–7.48(m,3H),1.42(s,9H). 13 C NMR (100MHz, CDCl3) δ161.1,160.5,154.0,150.8,135.3,134.0,128.6,128.4,127.1,127.1,125.7,123.5,34.9,31.3.

[0068] Example 19: A method for synthesizing 2-(4-chlorophenyl)quinazoline

[0069] This embodiment provides a method for synthesizing 2-(4-chlorophenyl)quinazoline. 122.4 mg of 2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60 °C, and maintained at 60 °C for 48 h. After purification by column chromatography, 118.7 mg of the seed 2-(4-chlorophenyl)quinazoline was obtained, with a yield of 99%. The chemical reaction formula is as follows:

[0070]

[0071] 2-(4-chlorophenyl)quinazoline: White solid, 99% yield. f =0.48(petroleum ether / ethyl acetate 5:1). 1 H NMR(400MHz,Chloroform-d)δ9.47(d,J=0.8Hz,1H),8.60(d,J=8.6Hz,2H),8.13–8.06(m,1 H),7.94(ddd,J=9.6,8.1,1.5Hz,2H),7.65(td,J=7.4,6.9,1.1Hz,1H),7.58–7.48(m,2H). 13 CNMR (100MHz, CDCl3) δ160.5,160.0,150.7,136.8,136.5,134.2,129.9,128.8,128.6,127.5,127.2,123.6.

[0072] Example 20: A method for synthesizing 2-(3-methylphenyl)quinazoline

[0073] This embodiment provides a method for synthesizing 2-(3-methylphenyl)quinazoline. 112.2 mg of 2-(3-methylphenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 48 h. After purification by column chromatography, 89.5 mg of the seed 2-(3-methylphenyl)quinazoline was obtained, with a yield of 81%. The chemical reaction formula is as follows:

[0074]

[0075] 2-(3-Methylphenyl)quinazoline: Yellow solid, 81% yield. f =0.56(petroleum ether / ethyl acetate 5:1). 1H NMR(400MHz,Chloroform-d)δ9.47(d,J=0.8Hz,1H),8.44(dt,J=9.4,1.9Hz,2H),8.14–8.07(m,1H),7.91( dd,J=8.4,7.0Hz,2H),7.61(td,J=7.3,1.1Hz,1H),7.46(t,J=7.5Hz,1H),7.37–7.32(m,1H),2.52(s,3H). 13 C NMR (101MHz, CDCl3) δ161.2,160.5,150.8,138.3,138.0,134.1,131.5,129.1,128.6,127.2,127.1,125.8,123.6,21.6.

[0076] Example 21: A method for synthesizing 2-(3,4-dimethylphenyl)quinazoline

[0077] This embodiment provides a method for synthesizing 2-(3,4-dimethylphenyl)quinazoline. 141.7 mg of 2-(3,4-dimethylphenyl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60 °C, and maintained at 60 °C for 48 h. After purification by column chromatography, 116.6 mg of the seed 2-(3,4-dimethylphenyl)quinazoline was obtained, with a yield of 84%. The chemical reaction formula is as follows:

[0078]

[0079] 2-(3,4-dimethylphenyl)quinazoline: Yellow Solid, 84% yield. f =0.58(petroleum ether / ethyl acetate 5:1). 1 H NMR(400MHz,Chloroform-d)δ9.45(s,1H),8.54–8.32(m,2H),8.09(d,J=8.5Hz,1H),7.9 0(t,J=7.6Hz,2H),7.59(t,J=7.5Hz,1H),7.32(d,J=7.9Hz,1H),2.40(d,J=19.4Hz,6H). 13C NMR (101MHz, CDCl3) δ161.3,160.4,150.8,139.6,136.9,135.7,134.0,130.1,129.6,128.5,127.1,127.0,126.2,123.5,19.9,19.9.

[0080] Example 22: A method for synthesizing 2-(furan-2-yl)quinazoline

[0081] This embodiment provides a method for synthesizing 2-(furan-2-yl)quinazoline. 102.1 mg of 2-(furan-2-yl)-1,2,3,4-tetrahydroquinazoline, 6.1 mg of cuprous acetate, 12.2 mg of 4-dimethylaminopyridine, and 8.7 mg of DEAD were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 48 h. After purification by column chromatography, 100.0 mg of 2-(3,4-dimethylphenyl)quinazoline was obtained, with a yield >99%. The chemical reaction formula is as follows:

[0082]

[0083] 2-(furan-2-yl)quinazoline: Yellow solid, >99% yield. f =0.49(petroleum ether / ethyl acetate 2:1). 1 H NMR (400MHz, CDCl3) δ9.35 (s, 1H), 8.07 (d, J = 8.7Hz, 1H), 7.87 (t, J = 7.7Hz, 2H), 7.56 (t, J = 7.5Hz, 1H), 7.45 (d, J = 3.3Hz, 1H), 6.60 (dd, J = 3.3, 1.7Hz, 1H). 13 C NMR (101MHz, CDCl3) δ161.0,154.0,149.3,142.9,132.3,128.5,127.7,127.4,125.2,112.0,107.1.

[0084] Example 23: A method for synthesizing 2-ethylquinazoline

[0085] This embodiment provides a method for synthesizing 2-ethylquinazoline. 2-Ethyl-1,2,3,4-tetrahydroquinazoline (81.1 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg), and DEAD (8.7 mg) were weighed and added to 3 mL of acetonitrile. The mixture was stirred continuously to dissolve, heated to 60°C, and maintained at 60°C for 48 h. After purification by column chromatography, 36.7 mg of 2-(3,4-dimethylphenyl)quinazoline was obtained, with a yield of 46%. The chemical reaction formula is as follows:

[0086]

[0087] 2-Ethylquinazoline: Yellow oil, 46% yield. f =0.48(petroleum ether / ethyl acetate 2:1). 1 H NMR (400MHz, CDCl3) δ9.37(s,1H),8.06–7.95(m,1H),7.89(t,J=7.7Hz,2H),7.60(td,J=7.3,1.0Hz,1H),3.17(q,J=7.6Hz,2H),1.48(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.0,154.9,149.2,132.1,127.0,123.2,126.9,126.6,32.4,12.1.

[0088] The catalyst used in this invention is inexpensive and readily available, the reaction operation is simple and practical, the conditions are mild, and the resulting product has high yield and purity. This invention is applicable to the synthesis of quinazoline compounds.

Claims

1. A method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline, characterized in that, Tetrahydroquinazoline compounds are added to an organic solvent, along with a catalyst, ligand, and additives, and then heated to carry out a dehydrogenation reaction to obtain quinazoline compounds. The catalyst is cuprous acetate; the additive is diethyl azodicarbonate; the molar ratio of the additive to the tetrahydroquinazoline compound is 1:(10~20); the ligand is 4-dimethylaminopyridine; and the organic solvent is acetonitrile. Tetrahydroquinazoline compounds are one of the following compounds: Wherein, R is a C1~C6 alkyl group; R x It is one or two of -H, -Br, -Cl, -CH3, -OCH3, and -NO2.

2. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, characterized in that, The molar ratio of the catalyst to the tetrahydroquinazoline compound is 1:(10~20).

3. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, characterized in that, The molar ratio of the ligand to the tetrahydroquinazoline compound is 1:(5~10).

4. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, characterized in that, The dehydrogenation reaction temperature is 50~70 ℃.

5. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, characterized in that, The reaction time is 24-48 h.

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