CN117229222A - Method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline - Google Patents
Method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline Download PDFInfo
- Publication number
- CN117229222A CN117229222A CN202311174886.7A CN202311174886A CN117229222A CN 117229222 A CN117229222 A CN 117229222A CN 202311174886 A CN202311174886 A CN 202311174886A CN 117229222 A CN117229222 A CN 117229222A
- Authority
- CN
- China
- Prior art keywords
- tetrahydroquinazoline
- quinazoline
- dehydrogenation
- synthesizing
- cuprous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 31
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000006356 dehydrogenation reaction Methods 0.000 title claims abstract description 22
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title claims abstract description 20
- -1 quinazoline compound Chemical class 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 239000000654 additive Substances 0.000 claims abstract description 12
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 12
- 150000003246 quinazolines Chemical class 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims abstract description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims abstract description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims abstract description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 4
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 229940045803 cuprous chloride Drugs 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 30
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 17
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- XQABVLBGNWBWIV-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1 XQABVLBGNWBWIV-UHFFFAOYSA-N 0.000 claims description 3
- IRJKSAIGIYODAN-ISLYRVAYSA-N benzyl (ne)-n-phenylmethoxycarbonyliminocarbamate Chemical compound C=1C=CC=CC=1COC(=O)/N=N/C(=O)OCC1=CC=CC=C1 IRJKSAIGIYODAN-ISLYRVAYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- CCHHLMXZPYYAEI-UHFFFAOYSA-N tert-butyl formate Chemical compound C(C)(C)(C)OC=O.C(C)(C)(C)OC=O CCHHLMXZPYYAEI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 24
- 238000003786 synthesis reaction Methods 0.000 abstract description 19
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000005303 weighing Methods 0.000 description 11
- ILJWFVOQKKAMNA-UHFFFAOYSA-N 2-phenylquinazoline Chemical compound C1(=CC=CC=C1)C1=NC2=CC=CC=C2C=N1.C1(=CC=CC=C1)C1=NC2=CC=CC=C2C=N1 ILJWFVOQKKAMNA-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- ANAHWDNCIRVTSN-UHFFFAOYSA-N CC(C=C1)=C(C)C=C1C1=NC2=CC=CC=C2C=N1 Chemical compound CC(C=C1)=C(C)C=C1C1=NC2=CC=CC=C2C=N1 ANAHWDNCIRVTSN-UHFFFAOYSA-N 0.000 description 6
- NMJRUVIOYRDYQN-UHFFFAOYSA-N 2-(4-chlorophenyl)quinazoline Chemical compound C1=CC(Cl)=CC=C1C1=NC=C(C=CC=C2)C2=N1 NMJRUVIOYRDYQN-UHFFFAOYSA-N 0.000 description 4
- ISXXPTVVLCNRRS-UHFFFAOYSA-N 2-(4-tert-butylphenyl)quinazoline Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=NC=C(C=CC=C2)C2=N1 ISXXPTVVLCNRRS-UHFFFAOYSA-N 0.000 description 4
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- HDOUIOVWSANABQ-UHFFFAOYSA-N 2-(3-methylphenyl)quinazoline Chemical compound CC1=CC=CC(C=2N=C3C=CC=CC3=CN=2)=C1 HDOUIOVWSANABQ-UHFFFAOYSA-N 0.000 description 3
- VNAVDRAEEFUSOQ-UHFFFAOYSA-N 2-(4-bromophenyl)quinazoline Chemical compound C1=CC(Br)=CC=C1C1=NC=C(C=CC=C2)C2=N1 VNAVDRAEEFUSOQ-UHFFFAOYSA-N 0.000 description 3
- WVGOZBCLJFXGTE-UHFFFAOYSA-N 2-(4-methoxyphenyl)quinazoline Chemical compound C1=CC(OC)=CC=C1C1=NC=C(C=CC=C2)C2=N1 WVGOZBCLJFXGTE-UHFFFAOYSA-N 0.000 description 3
- BYHOMJKKAFHBRI-UHFFFAOYSA-N 2-(4-methylphenyl)quinazoline Chemical compound C1=CC(C)=CC=C1C1=NC=C(C=CC=C2)C2=N1 BYHOMJKKAFHBRI-UHFFFAOYSA-N 0.000 description 3
- WLBBZOBVXHZYGJ-UHFFFAOYSA-N 2-(4-nitrophenyl)quinazoline Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=NC=C(C=CC=C2)C2=N1 WLBBZOBVXHZYGJ-UHFFFAOYSA-N 0.000 description 3
- ASVSCPGASITWDJ-UHFFFAOYSA-N 2-ethylquinazoline Chemical compound C1=CC=CC2=NC(CC)=NC=C21 ASVSCPGASITWDJ-UHFFFAOYSA-N 0.000 description 3
- GWBVDHNRTRASFL-UHFFFAOYSA-N 2-(furan-2-yl)quinazoline Chemical compound C1=COC(C=2N=C3C=CC=CC3=CN=2)=C1 GWBVDHNRTRASFL-UHFFFAOYSA-N 0.000 description 2
- ZPOOXQHMBHARAH-UHFFFAOYSA-N 2-phenyl-1,2,3,4-tetrahydroquinazoline Chemical compound N1C2=CC=CC=C2CNC1C1=CC=CC=C1 ZPOOXQHMBHARAH-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- BCHYIVDIHGVKHC-UHFFFAOYSA-N 2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC(Cl)=CC=C1C1NC2=CC=CC=C2CN1 BCHYIVDIHGVKHC-UHFFFAOYSA-N 0.000 description 1
- DKBMMCHWCMHPFE-UHFFFAOYSA-N 2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1NC2=CC=CC=C2CN1 DKBMMCHWCMHPFE-UHFFFAOYSA-N 0.000 description 1
- IZBKYCMKBIGPKJ-UHFFFAOYSA-N 2-(furan-2-yl)-1,2,3,4-tetrahydroquinazoline Chemical compound N1C2=CC=CC=C2CNC1C1=CC=CO1 IZBKYCMKBIGPKJ-UHFFFAOYSA-N 0.000 description 1
- ZBOMZBGIMUTCEX-UHFFFAOYSA-N 2-ethyl-1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NC(CC)NCC2=C1 ZBOMZBGIMUTCEX-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229930002339 quinazoline alkaloid Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline, which comprises the steps of adding tetrahydroquinazoline compounds into an organic solvent, sequentially adding a catalyst, a ligand and an additive, and heating to perform dehydrogenation reaction to obtain quinazoline compounds; the catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper triflate or cuprous acetate. The method can realize the efficient synthesis of the quinazoline compound, and has mild reaction conditions and high product yield.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a method for synthesizing quinazoline compounds, in particular to a method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline.
Background
The alkaloid is taken as a nitrogenous organic compound, widely exists in nature, is an important production raw material in organic synthesis, and has important application value in the fields of pharmacy, pesticide and the like. Among them, quinazoline alkaloids are generally rich in biological activity, including antibacterial, anticonvulsant, anti-inflammatory, antihypertensive, antitubercular, antimalarial, antiviral, anticancer, etc. biological activities. Therefore, the exploration of the synthesis of quinazoline and its derivatives is of great research value and significance.
The synthesis of quinazoline by the dehydrogenation reaction of transition metal catalyzed tetrahydroquinazoline compounds is one of the most direct and most atomic economic strategies. Although research on synthesizing quinazolines by catalytic oxidative dehydrogenation of transition metals has been advanced, problems still exist in the research, including expensive catalysts, harsh reaction conditions, narrow application range of substrates and the like. Therefore, the high-efficiency method is researched to realize the synthesis of the quinazolinone alkaloid, and the method has important research value and practical significance.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline, so as to achieve the purpose of synthesizing quinazoline compounds by utilizing reaction conditions of low catalyst, simple and convenient operation, mildness and environmental friendliness.
The invention is realized by the following technical scheme:
a method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline comprises the steps of adding tetrahydroquinazoline compounds into an organic solvent, adding a catalyst, a ligand and an additive, and heating to perform dehydrogenation reaction to obtain quinazoline compounds;
wherein the catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper triflate or cuprous acetate.
Preferably, the tetrahydroquinazoline compound is one of the following compounds:
wherein R is an alkyl group having 1 to 6 carbon atoms; r is R x is-H, -Br, -Cl, -CH 3 、-OCH 3 and-NO 2 One of (a)Or both.
Preferably, the ligand is pyridine, 4-dimethylaminopyridine, triethylamine or 4-methoxypyridine.
Preferably, the additive is diethyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate.
Preferably, the organic solvent is acetonitrile, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene or methanol.
Preferably, the molar ratio of the catalyst to the tetrahydroquinazoline compound is 1 (10-20).
Preferably, the molar ratio of the ligand to the tetrahydroquinazoline compound is 1 (5-10).
Preferably, the molar ratio of the additive to the tetrahydroquinazoline compound is 1 (10-20).
Preferably, the dehydrogenation reaction temperature is 50 to 70 ℃.
Preferably, the reaction time is 24 to 48 hours.
Compared with the prior art, the invention has the following beneficial effects:
the invention adopts copper salt as a catalyst to catalyze the oxidative dehydrogenation of tetrahydroquinazoline to synthesize quinazoline, and the ligand and the additive are added in the dehydrogenation reaction process, so that the reaction activity of the dehydrogenation reaction can be increased, and the catalytic activity of the invention is high, and the highest yield can reach 99%. In addition, the catalyst adopted by the invention is cheap and easy to obtain, the reaction operation is convenient and practical, and the method is suitable for synthesizing quinazoline compounds.
Furthermore, the method for synthesizing quinazoline by catalyzing the oxidative dehydrogenation of tetrahydroquinazoline provided by the invention has the advantages of mild reaction conditions and easy separation of products.
Drawings
FIG. 1 is a nuclear magnetic resonance-hydrogen spectrum of 2-phenylquinazoline prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance-carbon spectrum of 2-phenylquinazoline prepared in example 1 of the present invention.
Detailed Description
For a further understanding of the present invention, the present invention is described below in conjunction with the following examples, which are provided to further illustrate the features and advantages of the present invention and are not intended to limit the claims of the present invention.
The synthesis method of the invention comprises the following steps: and adding the tetrahydroquinazoline compound into an organic solvent, sequentially adding a catalyst, a ligand and an additive, and heating to perform dehydrogenation reaction to realize oxidative dehydrogenation of the tetrahydroquinazoline compound, wherein the catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper triflate or cuprous acetate.
The chemical reaction formula of the invention is as follows:
wherein R is an alkyl group having 1 to 6 carbon atoms. R is R x is-H, -Br, -Cl, -CH 3 、-OCH 3 and-NO 2 One or two of them.
The molar ratio of the catalyst to the tetrahydroquinazoline compound is 1 (10-20).
The ligand is pyridine, 4-dimethylaminopyridine, triethylamine or 4-methoxypyridine. The molar ratio of the ligand to the tetrahydroquinazoline compound is 1 (5-10).
The additive is diethyl azodicarboxylate (DEAD), di-tert-butyl diformate or dibenzyl azodicarboxylate. The mol ratio of the additive to the tetrahydroquinazoline compound is 1 (10-20).
The organic solvent is acetonitrile, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene or methanol;
the dehydrogenation reaction temperature is 50-70 ℃;
the dehydrogenation reaction time is 24-48 h.
Example 1 Synthesis of 2-phenylquinazoline
This example provides a method for synthesizing 2-phenylquinazoline, which comprises the steps of weighing 2-phenyl-1, 2,3, 4-tetrahydroquinazoline (105.1 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, sequentially adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature for reaction at 60 ℃ for 24 hours, and purifying by column chromatography after the TLC detection reaction is finished, thus obtaining 96.9mg of 2-phenylquinazoline with a yield of 94%. The chemical reaction formula is:
2-Phenylquinazoline (2-Phenylquinazoline) White solid,94% yield. R 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,CDCl 3 )δ161.1,160.5,150.8,138.1,134.1,130.7,128.7,128.7,128.6,127.3,127.1,123.6.
The nuclear magnetic resonance-hydrogen spectrum is shown in figure 1, and the nuclear magnetic resonance-carbon spectrum is shown in figure 2.
EXAMPLES 2 to 13 Synthesis method of 2-phenylquinazoline
Examples 2 to 13 each provide a synthesis of 2-phenylquinazoline, which is substantially the same as example 1, except that the raw materials and part of the process parameters are different, and the specific data are shown in table 1.
Table 1: process parameter Table for Synthesis method of 2-phenylquinazoline provided in examples 2 to 13
The other steps are the same as in example 1, the reactions are all 2-phenyl-1, 2,3, 4-tetrahydroquinazoline, and the 2-phenylquinazoline is synthesized by dehydrogenation, and the reaction equation is as follows:
from the results of examples 1 to 13, it can be seen that the cuprous acetate catalyst effect is better than other catalysts, the acetonitrile is adopted as the solvent to better than other solvents, and the 4-dimethylaminopyridine is adopted as the ligand and the diethyl azodicarboxylate (DEAD) is adopted as the additive to greatly improve the yield of the target product.
EXAMPLE 14 Synthesis of 2- (4-methoxyphenyl) quinazoline
This example provides a method for synthesizing 2- (4-methoxyphenyl) quinazoline, which comprises the steps of weighing 2- (4-methoxyphenyl) -1,2,3, 4-tetrahydroquinazoline (120.2 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, reacting for 42h, and purifying by column chromatography to obtain 98.8mg of 2- (4-methoxyphenyl) quinazoline, wherein the yield is 84%. The chemical reaction formula is:
2- (4-Methoxyphenyl) quinazoline (2- (4-Methoxyphenyl) quinazoline): white solid,84% yield. R f ＝0.68(petroleum ether/ethyl acetate 2:1). 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )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.
Example 15 Synthesis of 2- (4-methylphenyl) quinazoline
This example provides a 2- (4-methylphenyl) quinazoline synthesis method, respectively weighing 2- (4-methylphenyl) -1,2,3, 4-tetrahydroquinazoline (112.2 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg), adding into 3mL acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining at 60 ℃ for 48h, purifying by column chromatography to obtain 97.9mg of 2- (4-methylphenyl) quinazoline, and the yield is 89%. The chemical reaction formula is:
2- (4-methylphenyl) Quinazoline (2- (p-tolyl) Quinazoline): white solid,89% yield. R f ＝0.60(petroleum ether/ethyl acetate 5:1). 1 H NMR(400MHz,CDCl 3 )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.
EXAMPLE 16 Synthesis of 2- (4-nitrophenyl) quinazoline
This example provides a method for synthesizing 2- (4-nitrophenyl) quinazoline, which comprises the steps of weighing 2- (4-nitrophenyl) -1,2,3, 4-tetrahydroquinazoline (127.6 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature to react for 24 hours, and purifying by column chromatography to obtain 132.2mg of 2- (4-nitrophenyl) quinazoline, wherein the yield is more than 99%. The chemical reaction formula is:
2- (4-Nitrophenyl) quinazoline (2- (4-Nitrophenyl) quinazoline): pale yellow solid the number of the individual pieces of the plastic,>99％yield.R f ＝0.29(petroleum ether/ethyl acetate 5:1). 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )δ160.7,158.8,150.6,149.2,143.9,134.6,129.4,128.9,128.4,127.2,123.9,123.8.
EXAMPLE 17 Synthesis of 2- (4-bromophenyl) quinazoline
The present example provides a method for synthesizing 2- (4-bromophenyl) quinazoline, which comprises the steps of weighing 2- (4-bromophenyl) -1,2,3, 4-tetrahydroquinazoline (144.6 mg), cuprous acetate (9.5 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature for reaction at 60 ℃ for 36h, and purifying by column chromatography to obtain 136.4mg of 2- (4-bromophenyl) quinazoline, wherein the yield is 96%. The chemical reaction formula is:
2- (4-Bromophenyl) quinazoline (2- (4-Bromophenyl) quinazoline): white solid,96% yield. R f ＝0.47(petroleum ether/ethyl acetate 5:1). 1 H NMR(400MHz,CDCl 3 ) 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,CDCl 3 )δ160.5,160.1,150.7,137.0,134.3,131.8,130.2,128.6,127.5,127.2,125.4,123.6.
EXAMPLE 18 Synthesis of 2- (4- (tert-butyl) phenyl) quinazoline
This example provides a method for synthesizing 2- (4- (tert-butyl) phenyl) quinazoline, which comprises the steps of weighing 2- (4- (tert-butyl) phenyl) -1,2,3, 4-tetrahydroquinazoline (133.2 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining at 60 ℃ for 48h, and purifying by column chromatography to obtain 118.4mg of 2- (4- (tert-butyl) phenyl) quinazoline, wherein the yield is 90%, and the chemical reaction formula is:
2- (4- (tert-butyl) phenyl) quinazoline: white solid,90% yield.R 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,CDCl 3 )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.
Example 19 Synthesis of 2- (4-chlorophenyl) quinazoline
This example provides a method for synthesizing 2- (4-chlorophenyl) quinazoline, which comprises the steps of weighing 2- (4-chlorophenyl) -1,2,3, 4-tetrahydroquinazoline (122.4 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature for 48h, and purifying by column chromatography to obtain 118.7mg of 2- (4-chlorophenyl) quinazoline, wherein the yield is 99%. The chemical reaction formula is:
2- (4-chlorophenyl) quinazoline: white solid,99% yield.R 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,1H),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,CDCl 3 )δ160.5,160.0,150.7,136.8,136.5,134.2,129.9,128.8,128.6,127.5,127.2,123.6.
Example 20 Synthesis of 2- (3-methylphenyl) quinazoline
This example provides a method for synthesizing 2- (3-methylphenyl) quinazoline, which comprises the steps of weighing 2- (3-methylphenyl) -1,2,3, 4-tetrahydroquinazoline (112.2 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature for 48h, and purifying by column chromatography to obtain 89.5mg of 2- (3-methylphenyl) quinazoline, wherein the yield is 81%. The chemical reaction formula is:
2- (3-Methylphenyl) quinazoline (2- (3-Methylphenyl) quinazoline): yellow solid,81% yield.R f ＝0.56(petroleum ether/ethyl acetate 5:1). 1 H 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,CDCl 3 )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.
Example 21 Synthesis of 2- (3, 4-dimethylphenyl) quinazoline
This example provides a method for synthesizing 2- (3, 4-dimethylphenyl) quinazoline, which comprises the steps of weighing 2- (3, 4-dimethylphenyl) -1,2,3, 4-tetrahydroquinazoline (141.7 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature for 48h to react at 60 ℃, and purifying by column chromatography to obtain 116.6mg of seed 2- (3, 4-dimethylphenyl) quinazoline, wherein the yield is 84%. The chemical reaction formula is:
2- (3, 4-dimethylphenyl) quinazoline: yellow Solid,84% yield. R 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),7.90(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). 13 C NMR(101MHz,CDCl 3 )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.
EXAMPLE 22 Synthesis of 2- (furan-2-yl) quinazoline
This example provides a method for synthesizing 2- (furan-2-yl) quinazoline, which comprises the steps of weighing 2- (furan-2-yl) -1,2,3, 4-tetrahydroquinazoline (102.1 mg), cuprous acetate (6.1 mg), 4-dimethylaminopyridine (12.2 mg) and DEAD (8.7 mg) respectively, adding into 3mL acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature to react for 48h, and purifying by column chromatography to obtain 100.0mg of seed 2- (3, 4-dimethylphenyl) quinazoline, wherein the yield is more than 99%. The chemical reaction formula is:
2- (furan-2-yl) quinazoline (2- (furan-2-yl) quinazoline): the light solid of the Yellow body of the glass,>99％yield.R f ＝0.49(petroleum ether/ethyl acetate 2:1). 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )δ161.0,154.0,149.3,142.9,132.3,128.5,127.7,127.4,125.2,112.0,107.1.
example 23 Synthesis of 2-ethylquinazoline
This example provides a method for synthesizing 2-ethylquinazoline, which comprises the steps of weighing 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) respectively, adding into 3mL of acetonitrile, continuously stirring and dissolving, heating to 60 ℃, maintaining the temperature for 48h, and purifying by column chromatography to obtain 36.7mg of 2- (3, 4-dimethylphenyl) quinazoline, wherein the yield is 46%. The chemical reaction formula is:
2-ethylquinazoline: yellow oil,46% yield. R f ＝0.48(petroleum ether/ethyl acetate 2:1). 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )δ170.0,154.9,149.2,132.1,127.0,123.2,126.9,126.6,32.4,12.1.
The catalyst used in the invention is cheap and easy to obtain, the reaction operation is simple and practical, the condition is mild, and the yield and purity of the obtained product are high. The invention is suitable for the synthesis of quinazoline compounds.
Claims (10)
1. A method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline is characterized in that tetrahydroquinazoline compounds are added into an organic solvent, and a catalyst, a ligand and an additive are added, and dehydrogenation reaction is carried out by heating to obtain quinazoline compounds;
wherein the catalyst is cuprous iodide, cuprous bromide, cuprous chloride, copper triflate or cuprous acetate.
2. The method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline according to claim 1, wherein the tetrahydroquinazoline compound is one of the following compounds:
wherein R is C1-C6 alkyl; r is R x is-H, -Br, -Cl, -CH 3 、-OCH 3 and-NO 2 One or two of them.
3. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, wherein the ligand is pyridine, 4-dimethylaminopyridine, triethylamine or 4-methoxypyridine.
4. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, wherein the additive is diethyl azodicarboxylate, di-tert-butyl diformate or dibenzyl azodicarboxylate.
5. The method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline according to claim 1, wherein the organic solvent is acetonitrile, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene or methanol.
6. The method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline according to claim 1, wherein the molar ratio of the catalyst to the tetrahydroquinazoline compound is 1 (10-20).
7. The method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline according to claim 1, wherein the molar ratio of the ligand to the tetrahydroquinazoline compound is 1 (5-10).
8. The method for synthesizing quinazoline by dehydrogenating tetrahydroquinazoline according to claim 1, wherein the molar ratio of the additive to the tetrahydroquinazoline compound is 1 (10-20).
9. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, wherein the dehydrogenation reaction temperature is 50 to 70 ℃.
10. The method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline according to claim 1, wherein the reaction time is 24 to 48 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311174886.7A CN117229222A (en) | 2023-09-12 | 2023-09-12 | Method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311174886.7A CN117229222A (en) | 2023-09-12 | 2023-09-12 | Method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117229222A true CN117229222A (en) | 2023-12-15 |
Family
ID=89094100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311174886.7A Pending CN117229222A (en) | 2023-09-12 | 2023-09-12 | Method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117229222A (en) |
-
2023
- 2023-09-12 CN CN202311174886.7A patent/CN117229222A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111777637A (en) | Axial chiral oxindole-derived styrene phosphine oxide catalyst and preparation method and application thereof | |
| CN105772094A (en) | Chiral nitrogen heterocycle carbene type catalyst and application thereof | |
| CN112159417A (en) | Thienothiazole and derivative and synthesis method thereof | |
| CN117229222A (en) | Method for synthesizing quinazoline by dehydrogenation of tetrahydroquinazoline | |
| CN112940002A (en) | Method for synthesizing eight-membered bridged ring compound through palladium-catalyzed asymmetric ring addition reaction | |
| CN114478245A (en) | Asymmetric synthesis method of chiral gamma-alkynyl-alpha-keto acid ester compound | |
| CN114380790A (en) | Polysubstituted thiopyran derivative and synthetic method thereof | |
| CN113511986A (en) | Preparation method of aryl acetonitrile derivative | |
| CN113651827A (en) | Preparation of pyrano [2,3-b]Process for preparing indol-2-ones | |
| CN111732552A (en) | Method for synthesizing 1, 3-oxazole-2-thioketone by palladium catalysis | |
| CN111499600A (en) | Synthesis method of polysubstituted 2, 3-dihydrofuran compound | |
| CN111499648A (en) | Axial chiral bidentate ligand, catalyst, preparation method and application thereof | |
| CN111229312A (en) | Solvent-free catalyst and preparation method and application thereof | |
| CN113336786B (en) | Diastereoselective polysubstituted naphthenic compound and preparation method thereof | |
| CN115466171B (en) | Preparation method of 2, 3-dihydro-1H-cyclopenteno [ a ] naphthalene derivative | |
| CN115155658B (en) | Synthetic method for synthesizing selenium-sulfur compounds based on VAPOL | |
| CN113173884B (en) | Method for synthesizing pyridine and derivative thereof by catalyzing hans ester 1, 4-dihydropyridine compound with titanocene dichloride | |
| CN110759845B (en) | Microwave synthesis method of 1,2,3, 5-tetrasubstituted azacyclopentadiene compound | |
| CN112239456B (en) | Preparation method of substituted 2, 3-dihydroquinolone compound | |
| CN112920220B (en) | Method for aqueous phase synthesis of trifluoromethyl-containing C-2 phosphonoindole | |
| CN111533649B (en) | Synthesis method of acid compound | |
| CN113735826B (en) | Preparation method of 3-benzylidene-2, 3-dihydroquinolone compound | |
| CN113845550B (en) | Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof | |
| CN113372279B (en) | Synthetic method of 4, 5-dicyanoimidazole derivative | |
| CN110577483B (en) | Green synthesis method of 3, 3-disubstituted-2-indolone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |