CN117447313A - Preparation method of 1-aryl-3-trifluoromethyl azulene compound - Google Patents
Preparation method of 1-aryl-3-trifluoromethyl azulene compound Download PDFInfo
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- CN117447313A CN117447313A CN202311400531.5A CN202311400531A CN117447313A CN 117447313 A CN117447313 A CN 117447313A CN 202311400531 A CN202311400531 A CN 202311400531A CN 117447313 A CN117447313 A CN 117447313A
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- trifluoromethyl
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- azulene
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- CUFNKYGDVFVPHO-UHFFFAOYSA-N Azulene Natural products C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 title claims description 14
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 abstract description 48
- -1 1-phenyl-3-trifluoromethyl azulene compound Chemical class 0.000 abstract description 38
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 150000001545 azulenes Chemical class 0.000 abstract description 5
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 65
- WOZVHXUHUFLZGK-UHFFFAOYSA-N dimethyl terephthalate Chemical compound COC(=O)C1=CC=C(C(=O)OC)C=C1 WOZVHXUHUFLZGK-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 229940125904 compound 1 Drugs 0.000 description 14
- 125000000217 alkyl group Chemical group 0.000 description 8
- 238000002955 isolation Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- HPJYKMSFRBJOSW-JHSUYXJUSA-N Damsin Chemical compound C[C@H]1CC[C@H]2C(=C)C(=O)O[C@H]2[C@]2(C)C(=O)CC[C@@H]12 HPJYKMSFRBJOSW-JHSUYXJUSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JHFRTVPGJFJJIJ-UHFFFAOYSA-N 1-(trifluoromethyl)azulene Chemical compound C1=CC=CC=C2C(C(F)(F)F)=CC=C21 JHFRTVPGJFJJIJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NARQSHREEUXZBT-UHFFFAOYSA-N egualen Chemical compound C1=C(C(C)C)C=CC=C2C(CC)=CC(S(O)(=O)=O)=C21 NARQSHREEUXZBT-UHFFFAOYSA-N 0.000 description 1
- 229950005370 egualen Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/30—Azulenes; Hydrogenated azulenes
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of compound preparation, and discloses a preparation method of a 1-phenyl-3-trifluoromethyl azulene compound. The compound shown in the general formula I is obtained by taking the compound shown in the general formula II as a raw material and reacting in the presence of protonic acid according to the following reaction formula.
Description
Technical Field
The invention belongs to the field of compound preparation, and relates to a preparation method of a 1-aryl-3-trifluoromethyl azulene compound.
Background
Azulene, IUPAC name bicyclo [5.3.0] decapentaene, has conjugated seven-membered and five-membered ring structure, and is important non-benzene aromatic hydrocarbon. Azulenes have unique molecular structures exhibiting biological activity and unique optoelectronic properties. Therefore, the azulene derivative has wide application in the fields of medicines, fragrances, photoelectric materials, cosmetics and the like. Guaazulene, sodium azulene sulfonate and egualen sodium have been marketed as anti-inflammatory drugs, and azulene derivatives have also been found in commodity components such as high-grade cosmetics, perfumes, toothpaste and the like (chem. Asian J.,2020,15,1904-1915; med. Chem. Res.,2021,30,834-846.).
On the other hand, fluorine atoms have the characteristics of large electronegativity, small radius and the like, so that fluorine-containing compounds often have unique physical properties, chemical properties and biological activities. As the most common fluorine-containing group, trifluoromethyl has a strong electron withdrawing ability and a large hydrophobicity. The introduction of trifluoromethyl groups into the molecule has become an effective means of increasing the pharmaceutical activity and improving the properties of materials. Trifluoromethyl substituted azulenes have excellent properties such as strong electron accepting ability (Angew.chem.int.ed.2013, 52,4871-4874; chem.Commun.2014,50, 6263-6266.) and deserve further investigation.
However, the synthesis method of the fluorine-containing azulene derivative is still deficient, and the development of a new construction method of trifluoromethyl azulene is of great significance for researching the properties of the compound and developing functional molecules such as medicines, photoelectric materials and the like with better performance. In recent years, the ring-expanding cyclization reaction of 2-alkynyl biphenyl or phenyl eneyne provides an efficient means for constructing an azulene ring skeleton. However, these methods use relatively expensive metal reagents and the reaction conditions are relatively severe, thus greatly limiting the application of such methods (Angew.Chem, int.Ed.,2013,52,6492-6495; org. Lett.,2014,16,4662-4665; angel. Chem. Int. Ed.,2018,57,12966-12970; acs catalyst., 2022,12,676-686.).
Disclosure of Invention
In order to make up the defects of the prior art, the invention designs a synthesis method of a 1-aryl-3-trifluoromethyl azulene derivative (a compound shown in a general formula I). The invention only uses the proton acid which is cheap and easy to obtain as the catalyst, and realizes the synthesis of the azulene under mild conditions.
Specifically, the method takes easily available trifluoromethyl eneyne (a compound shown in a general formula II) as a raw material, takes protonic acid as a catalyst, and reacts in a solvent according to the following reaction formula:
wherein,
R 1 selected from H, C1-C4 alkyl, phenyl, halogen, methoxy; r is R 2 Selected from H, C1-C4 alkyl, phenyl, halogen, methoxy;
the protonic acid is one of trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and sulfuric acid;
the solvent is one of acetonitrile, toluene, chlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform and carbon tetrachloride, the dosage of the solvent meets the reaction requirement, preferably the ratio of the amount of the compound shown in the general formula II to the volume of the solvent is 1mmol (5-20 mL), more preferably 1mmol:12.5mL.
Unless otherwise indicated, the terms used herein have the following meanings:
the term "alkyl" as used herein includes both straight chain alkyl and branched alkyl groups. If a single alkyl group such as "methyl" is mentioned, only straight chain alkyl groups are specified, if a single branched alkyl group such as "isopropyl" is mentioned, only branched alkyl groups are specified. For example, "C4 or lower alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the like. Similar rules apply to other groups used in this specification.
The term "halogen" as used herein includes fluorine, chlorine, bromine, iodine.
In the synthesis method of the 1-aryl-3-trifluoromethyl azulene compound, the amount of the substance of the protonic acid is 0.1 to 1.5 times of that of the compound shown in the general formula II; the reaction can be carried out at-35-80 ℃, and the preferable reaction time is 4 min-72 h.
A preferable technical scheme of the invention is as follows:
using easily available trifluoromethyl eneyne (compound shown in a general formula II) as a raw material and trifluoro methane sulfonic acid as a catalyst, and carrying out reaction in 1, 2-dichloroethane according to the following reaction formula at 40 ℃:
wherein:
R 1 selected from F, cl, br, CH 3 ,OMe,tBu,iPr,Ph；R 2 Selected from F, cl, et, tBu, CH 3 ,OMe,Ph；
The proton acid is preferably trifluoromethanesulfonic acid, and the dosage is 0.3-1.0 times of the dosage of the substance of the compound II;
the structures, physical properties and the like of the specific compounds I-1 to I-11 synthesized according to the present invention are shown below 1 H NMR、 13 The present invention is not limited to these compounds, although the present invention is not limited to the C NMR and mass spectrum data.
7.23(d,J＝10.3Hz,1H,ArH),7.08-7.02(m,2H,ArH),3.89(s,3H,OCH 3 ),2.68(s,3H,CH 3 ). 13 C NMR(101MHz,CDCl 3 ) (one less carbon signal) δ 158.8,152.1,136.7,136.2,135.3 (q, j=2.6 Hz), 134.9,133.6 (q, j=3.7 Hz), 130.8,129.7,128.9,127.2,127.0,125.0 (q, j=268.1 Hz), 116.3,115.8 (q, j=33.7 Hz), 55.4,28.0.hrms (EI) m/z calculated C 19 H 15 F 3 O[M +· ]316.1075, found: 316.1065.
Hz,2H,ArH),6.98-6.87(m,2H,ArH),3.95(s,3H,OCH 3 ),3.90(s,3H,OCH 3 ). 13 C NMR(101MHz,CDCl 3 ) δ 169.0,158.8,137.0,135.2,133.0,132.1 (q, j=2.5 Hz), 130.7,130.6,130.5 (q, j=3.7 Hz), 129.1,125.0 (q, j= 268.2 Hz), 116.5 (q, j=33.7 Hz), 114.3,113.3,111.8,56.1,55.4, hrms (EI) m/z: calculated value C 19 H 15 F 3 O 2 [M +· ]332.1024, found: 332.1016.
6.99(d,J＝11.1Hz,1H,ArH),6.96-6.90(m,2H,ArH),3.88(s,3H,OCH 3 ),3.86(s,3H,OCH 3 ). 13 C NMR(101MHz,CDCl 3 ) δ 165.8,157.9,137.7,136.3,135.4 (q, j=2.5 Hz), 134.7 (q, j=3.8 Hz), 132.6,131.3,129.1,124.9 (q, j= 269.1 Hz), 124.4 (q, j=1.5 Hz), 120.6,116.8 (q, j=33.6 Hz), 112.5,110.2,55.9,55.3.hrms (EI) m/z: calculated value C 19 H 15 F 3 O 2 [M +· ]332.1024, found: 332.1018.
7.43-7.28(m,2H,ArH),7.11-7.00(m,2H,ArH),3.90(s,3H,OCH 3 ). 13 C NMR(101MHz,CDCl 3 ) δ 158.9,139.7,137.7,137.6,136.7 (q, j=2.8 Hz), 135.7,135.1 (q, j=3.8 Hz), 130.9,129.8,128.7,125.6,125.5,124.8 (q, j= 269.3 Hz), 115.9 (q, j=33.9 Hz), 114.3,55.4.Hrms (EI) m/z calculated C 19 H 15 F 3 O 2 [M +· ]302.0918, found: 302.0912.
Hz,1H,ArH),7.29(d,J＝10.5Hz,1H,ArH),7.07(d,J＝8.7Hz,2H,ArH),3.91(s,3H,OCH 3 ),3.12(hept,J＝6.9Hz,1H,CH),1.39(d,J＝6.9Hz,6H,(CH 3 ) 2 ). 13 C NMR(101MHz,CDCl 3 ) (one less carbon signal) δ 162.6,158.9,137.4,136.4,135.5 (q, j=3.3 Hz), 133.8 (q, j=3.7 Hz), 130.8,129.6,129.0,125.1 (q, j= 269.1 Hz), 125.1,124.8,115.6 (q, j=33.9 Hz), 114.4,55.4,39.8,24.2.Hrms (EI) m/z calculated C 21 H 19 F 3 O[M +· ]344.1388, found: 344.1381.
ArH),3.89(s,3H,OCH 3 ),1.48(s,9H,(CH 3 ) 3 ). 13 C NMR(101MHz,CDCl 3 ) (one less carbon signal) δ 164.4,158.8,136.7,136.4,135.6 (q, j=2.4 Hz), 134.9,134.0 (q, j=3.7 Hz), 130.8,129.3,129.0,125.1 (q, j=269.2 Hz), 123.7,115.4 (q, j=33.8 Hz), 114.3,55.4,38.8,31.8.Hrms (EI) m/z calculated C 22 H 21 F 3 O[M +· ]358.1544, found: 358.1541.
10.3Hz,1.7Hz,1H,ArH),7.57-7.43(m,6H,ArH),7.12-7.05(m,2H,ArH),3.91(s,3H,OCH 3 ). 13 C NMR(101MHz,CDCl 3 ) (one less carbon signal) δ 158.9,153.6,144.3,136.9,136.2,135.5 (q, j=2.8 Hz), 135.0,134.7 (q, j=3.6 Hz), 130.8,130.1,129.0,128.7,128.6,128.6,126.1,126.0,124.8 (q, j=269.2 Hz), 116.2 (q, j=34.0 Hz), 114.4,55.4.Hrms (EI) m/z calculated C 24 H 17 F 3 O[M +· ]378.1231, found: 378.1226.
-7.15(m,1H,ArH),7.15-7.09(m,1H,ArH),7.09-7.04(m,2H,ArH),3.90(s,3H,OCH 3 ). 13 C NMR(101MHz,CDCl 3 ) Delta 169.0 (d, j=253.2 Hz), 159.1,136.9 (d, j=16.8 Hz), 134.9,134.7,134.0-133.9 (m), 133.4-133.7 (m), 131.9 (d, j=2.4 Hz), 130.8,128.2,124.5 (q, j=269.5 Hz), 117.9 (qd, j=34.1 Hz,2.4 Hz), 114.4,113.7 (d, j=34.6 Hz), 113.2 (d, j=34.7 Hz), 55.4.hrms (EI) m/z: calculated value C 18 H 12 F 4 O[M +· ]320.0824, found: 320.0815.
ArH),7.21(dd,J＝19.9Hz,10.9Hz,1H,ArH),7.02-6.95(m,2H,ArH),3.88(s,3H). 13 C NMR(151MHz,CDCl 3 ) δ166.0 (d, j= 265.6 Hz), 158.7,137.4 (d, j=17.9 Hz), 136.7-136.4 (m), 136.4 (dq, j=20.8 Hz,2.7 Hz), 136.0,131.2 (d, j=3.8 Hz), 130.0 (d, j=3.0 Hz), 128.7 (d, j=3.1 Hz), 124.3 (q, j=268.5 Hz), 123.3 (d, j=4.0 Hz), 122.9 (d, j=17.8 Hz), 118.4 (q, j=34.1 Hz), 115.1 (d, j=34.7 Hz), 113.3,55.3.hrms (EI) m/z: calculated value C 18 H 12 F 4 O[M +· ]320.0824, found: 320.0817.
10.6Hz,1H,ArH),7.07-7.03(m,2H,ArH),3.90(s,3H,OCH 3 ). 13 CNMR(101MHz,CDCl 3 ) (one less carbon signal) delta 159.2,147.0,135.7,135.6,135.2-135.0 (m), 133.6,131.7,130.8,128.0,125.9,125.7,124.4 (q, j= 269.1 Hz), 117.8 (q, j=34.1 Hz), 114.4,55.4.Hrms (EI) m/z calculated C 18 H 12 ClF 3 O[M +· ]336.0529, found: 336.0521.
(dd,J＝10.7Hz,1.9Hz,1H,ArH),7.52-7.38(m,2H,ArH),7.13-6.96(m,2H,ArH),3.89(s,3H,OCH 3 ). 13 C NMR(101MHz,CDCl 3 ) (one less carbon signal) δ 159.2,137.4,136.0-135.9 (m), 135.7,135.5 (q, j=3.7 Hz), 135.2 (q, j=2.8 Hz), 133.7,131.8,130.8,128.9,128.8,128.0,124.4 (q, j= 269.6 Hz), 117.9 (q, j=34.1 Hz), 114.4,55.4.Hrms (EI) m/z calculated C 18 H 12 BrF 3 O[M +· ]380.0024, found: 380.0020.
compared with the prior art, the invention has the beneficial effects that:
the method directly uses the protonic acid with low cost and widely available raw materials as the catalyst, uses the trifluoromethyl eneyne which is easy to synthesize as the raw material, provides a convenient and low-cost method for synthesizing trifluoromethyl substituted azulene compounds, and simultaneously avoids using expensive and unstable trifluoromethyl reagents and metal reagents.
Detailed Description
In order that those skilled in the art will better understand the technical solution of the present invention, the present invention will be further described with reference to the following specific examples, which are not intended to limit the present invention in any way.
The test methods described in the following examples, unless otherwise specified, are all conventional; the reagents and materials, unless otherwise specified, are commercially available.
Example 1
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound I-1)
To a 25mL reaction flask were successively added 316mg (1 mmol) of 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene, 5mL of anhydrous solvent 1, 2-dichloroethane, 30mg (20 mol%,0.2 mmol) of trifluoromethanesulfonic acid, and the mixture was stirred at 40℃for 0.5 hours. After dichloromethane extraction, the organic phases are combined, the solvent is removed by reduced pressure rotary evaporation, the target compound is obtained by column chromatography, the filling material is silica gel, and the eluent is petroleum ether: ethyl acetate=50:1 (volume ratio), isolated in 80%.
Example 2
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methoxyazulene (Compound I-2)
The same procedures were repeated except for changing 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 to 1-methoxy-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount and increasing the amount of trifluoromethanesulfonic acid to 1 equivalent were conducted in the same manner as in example 1 to obtain 48% isolated yield of the objective compound.
Example 3
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-4-methoxyazulene (Compound I-3)
The isolation yield of the target compound was 61% by the same procedures as in example 1 except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 1-methoxy-2- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount.
Example 4
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl azulene (Compound I-4)
The same procedures as in example 1 were repeated except for changing 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene to 1- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount and increasing the amount of trifluoromethanesulfonic acid to 1 equivalent were conducted to obtain 57% isolated yield of the objective compound.
Example 5
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-isopropylazulene (Compound I-5)
The isolation yield of the target compound was 66% by the same procedures as in example 1 except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 1-isopropyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount.
Example 6
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-tert-butylazulene (Compound I-6)
The isolation yield of the target compound was 74% except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to an equimolar amount of 1-tert-butyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene.
Example 7
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-phenyl azulene (Compound I-7)
The isolation yield of the target compound was 75% by the same procedures as in example 1 except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) -1,1' -biphenyl in the same molar amount.
Example 8
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-fluoroazulene (Compound I-8)
The isolation yield of the target compound was 79% by the same procedures as in example 1 except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 1-fluoro-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount.
Example 9
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-4-fluoroazulene (Compound I-9)
The isolation yield of the target compound was 48% by the same procedures as in example 1 except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 1-fluoro-2- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount.
Example 10
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-chloroazulene (Compound I-10)
The isolation yield of the target compound was 74% by the same procedures as in example 1 except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 1-chloro-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount.
Example 11
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-bromoazulene (Compound I-11)
The isolation yield of the target compound was 69% by the same procedure as in example 1, except that 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in example 1 was changed to 1-bromo-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene in the same molar amount.
Example 12
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
To a 25mL reaction flask were successively added 316mg (1 mmol) of 1-methyl-4- (4-p-methoxyphenyl-2-trifluoromethbut-1-en-3-yn-1-yl) benzene, 5mL of acetonitrile and 45mg (30 mol%,0.3 mmol) of trifluoromethanesulfonic acid, and the mixture was stirred at 40℃for reaction for 24 hours. After water and dichloromethane are added and the organic phases are combined and the solvent is removed by rotary evaporation under reduced pressure, dimethyl terephthalate is added as an internal standard, and the yield of the target compound is determined to be 66% by nuclear magnetic resonance hydrogen spectrum.
Example 13
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was measured at 48% (based on dimethyl terephthalate) in the same manner as in example 12, except that acetonitrile in example 12 was changed to chlorobenzene in the same volume, the reaction time was adjusted to 3 hours, and the temperature was adjusted to 25 ℃.
Example 14
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was 72% (based on dimethyl terephthalate) in the same manner as in example 12, except that acetonitrile in example 12 was changed to the same volume of methylene chloride, the reaction time was adjusted to 2 hours, and the temperature was adjusted to 25 ℃.
Example 15
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the target compound was 58% (based on dimethyl terephthalate) was measured in the same manner as in example 12, except that acetonitrile in example 12 was changed to chloroform of the same volume, the reaction time was adjusted to 2 hours, and the temperature was adjusted to 25 ℃.
Example 16
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was 54% (based on dimethyl terephthalate) by the same method as in example 12, except that acetonitrile was changed to the same volume of 1, 2-dichloroethane, the reaction time was changed to 5 hours, and the temperature was changed to 0 ℃.
Example 17
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was 78% (based on dimethyl terephthalate) by the same method as in example 12, except that acetonitrile was changed to the same volume of 1, 2-dichloroethane, the temperature was changed to 50℃and the reaction time was changed to 18 minutes in example 12.
Example 18
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was measured at 76% (based on dimethyl terephthalate) in the same manner as in example 12, except that acetonitrile was changed to the same volume of 1, 2-dichloroethane, the temperature was changed to 60℃and the reaction time was changed to 10 minutes in example 12.
Example 19
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was measured at 76% (based on dimethyl terephthalate) in the same manner as in example 12, except that acetonitrile was changed to the same volume of 1, 2-dichloroethane, the temperature was changed to 80℃and the reaction time was changed to 4 minutes in example 12.
Example 20
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was 72% (based on dimethyl terephthalate) in the same manner as in example 12, except that the amount of trifluoromethanesulfonic acid used in example 12 was changed to 10mol%, acetonitrile was changed to the same volume of 1, 2-dichloroethane, and the reaction time was changed to 70 minutes.
Example 21
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was 72% (based on dimethyl terephthalate) in the same manner as in example 12, except that the amount of trifluoromethanesulfonic acid used in example 12 was 40mol%, acetonitrile was the same volume of 1, 2-dichloroethane, and the reaction time was 20 minutes.
Example 22
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound was 80% (based on dimethyl terephthalate) by the same method as in example 12, except that the amount of trifluoromethanesulfonic acid used in example 12 was adjusted to 1 equivalent, acetonitrile was adjusted to the same volume of 1, 2-dichloroethane, and the reaction time was adjusted to 5 minutes.
Example 23
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The nuclear magnetic resonance yield of the objective compound (based on dimethyl terephthalate) was measured in the same manner as in example 12, except that the amount of trifluoromethanesulfonic acid used in example 12 was adjusted to 1.5 equivalents, acetonitrile was adjusted to the same volume of 1, 2-dichloroethane, the temperature was adjusted to 0℃and the reaction time was adjusted to 3 hours.
Comparative example 1
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The reaction was carried out in the same manner as in example 12 except that trifluoroacetic acid (or acetic acid, aluminum trichloride, stannous chloride) and acetonitrile were adjusted to the same amounts in example 12, and 1-2-dichloroethane were reacted for 1-24 hours, whereby the starting materials were not reacted and the objective compound could not be obtained.
Comparative example 2
Preparation of 1- (4-methoxyphenyl) -3-trifluoromethyl-6-methyl azulene (Compound 1)
The same procedure as in example 12 was repeated except that acetonitrile as a solvent in example 12 was changed to N, N-dimethylformamide (or dioxane or isopropanol) in the same volume, whereby the objective compound was not obtained.
The above-described embodiments are only preferred embodiments of the invention, and not all embodiments of the invention are possible. Any obvious modifications thereof, which would be apparent to those skilled in the art without departing from the principles and spirit of the present invention, should be considered to be included within the scope of the appended claims.
Claims (9)
1. A preparation method of a 1-aryl-3-trifluoromethyl azulene compound, which is characterized in that a compound trifluoromethyl eneyne shown in a general formula II is taken as a raw material, protonic acid is taken as a catalyst, and the reaction is carried out in a solvent according to the following reaction formula:
wherein R is 1 Selected from H, C1-C4 alkyl, phenyl, halogen, methoxy; r is R 2 Selected from H, C1-C4 alkyl, phenyl, halogen, methoxy.
2. The process for preparing a 1-aryl-3-trifluoromethyl azulene compound according to claim 1, wherein said protic acid is one of trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid.
3. The process for preparing 1-aryl-3-trifluoromethyl azulene compound according to claim 1, wherein the solvent is one of acetonitrile, toluene, chlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride.
4. The process for preparing 1-aryl-3-trifluoromethyl azulene compounds according to claim 1, wherein the ratio of the amount of substance of the compound of formula ii to the volume of solvent is 1mmol (5-20 mL).
5. The process for preparing 1-aryl-3-trifluoromethyl azulene compound according to claim 1, wherein the ratio of the amount of substance of the compound of formula ii to the volume of solvent is 1 mmol/12.5 ml.
6. The process for the preparation of 1-aryl-3-trifluoromethyl azulene compounds according to claim 1, wherein the amount of the substance of the protic acid is 0.1 to 1.5 times the amount of the substance of the compound of formula II.
7. The process for preparing 1-aryl-3-trifluoromethyl azulene compound according to claim 1, wherein the preparation is carried out at-35 ℃ to 80 ℃ and the reaction time is 4min to 72h.
8. The process for the preparation of 1-aryl-3-trifluoromethyl azulene compounds according to claim 1, wherein the reaction is carried out in 1, 2-dichloroethane at 40 ℃ using a compound of formula II, trifluoromethyl eneyne as starting material and trifluoromethanesulfonic acid as catalyst according to the following reaction scheme:
wherein: r is R 1 Selected from F, cl, br, CH 3 ,OMe,tBu,iPr,Ph；R 2 Selected from F, cl, et, tBu, CH 3 ,OMe,Ph。
9. The process for preparing 1-aryl-3-trifluoromethyl azulene compounds according to claim 8, wherein the protic acid is trifluoromethanesulfonic acid in an amount of 0.3 to 1.0 times the amount of compound II substance.
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