CN110372660B - Synthetic method of isocoumarin derivatives - Google Patents
Synthetic method of isocoumarin derivatives Download PDFInfo
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- CN110372660B CN110372660B CN201910572056.7A CN201910572056A CN110372660B CN 110372660 B CN110372660 B CN 110372660B CN 201910572056 A CN201910572056 A CN 201910572056A CN 110372660 B CN110372660 B CN 110372660B
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- methyl
- ethynyl
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- dimethyl sulfoxide
- benzoate
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- 125000003151 isocoumarinyl group Chemical class C1(=O)OC(=CC2=CC=CC=C12)* 0.000 title claims abstract description 6
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 40
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims abstract description 10
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 4
- -1 2-nitro-4-methylphenyl Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 9
- 230000035484 reaction time Effects 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 239000012074 organic phase Substances 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 150000002512 isocoumarins Chemical class 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- IQZZFVDIZRWADY-UHFFFAOYSA-N isocumarine Natural products C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- AUAMBAQBYXIJAX-UHFFFAOYSA-N CC=1C=CC(=C(C(=O)OC)C=1)C#CC1=CC=CC=C1 Chemical compound CC=1C=CC(=C(C(=O)OC)C=1)C#CC1=CC=CC=C1 AUAMBAQBYXIJAX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- POUOFGZHNZKBHQ-UHFFFAOYSA-N methyl 2-[2-(4-nitrophenyl)ethynyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C#CC1=CC=C([N+]([O-])=O)C=C1 POUOFGZHNZKBHQ-UHFFFAOYSA-N 0.000 description 2
- QYBKPSDUJKTDGK-UHFFFAOYSA-N methyl 5-bromo-2-ethynylbenzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1C#C QYBKPSDUJKTDGK-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- JCOKYCVTRIJHRV-UHFFFAOYSA-N BrC1=CC=C2C(=COC(C2=C1)=O)SC Chemical compound BrC1=CC=C2C(=COC(C2=C1)=O)SC JCOKYCVTRIJHRV-UHFFFAOYSA-N 0.000 description 1
- WQOXQRCZOLPYPM-UHFFFAOYSA-N Dimethyl disulfide Natural products CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 1
- NQMFCCLRQRRCTC-UHFFFAOYSA-N FC1=CC=C2C(=C(OC(C2=C1)=O)C1=CC=CC=C1)SC Chemical compound FC1=CC=C2C(=C(OC(C2=C1)=O)C1=CC=CC=C1)SC NQMFCCLRQRRCTC-UHFFFAOYSA-N 0.000 description 1
- QRFMAKASCDJRPT-UHFFFAOYSA-N FC=1C=CC(=C(C(=O)OC)C=1)C#CC1=CC=CC=C1 Chemical compound FC=1C=CC(=C(C(=O)OC)C=1)C#CC1=CC=CC=C1 QRFMAKASCDJRPT-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 240000000275 Persicaria hydropiper Species 0.000 description 1
- 235000017337 Persicaria hydropiper Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- TXDJTXJHNVBYSS-UHFFFAOYSA-N methyl 2-[2-(4-chlorophenyl)ethynyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C#CC1=CC=C(Cl)C=C1 TXDJTXJHNVBYSS-UHFFFAOYSA-N 0.000 description 1
- BKIRFGMFDGCHIV-UHFFFAOYSA-N methyl 2-[2-(4-methoxyphenyl)ethynyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C#CC1=CC=C(OC)C=C1 BKIRFGMFDGCHIV-UHFFFAOYSA-N 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- GYSYFBPOQKDJLU-UHFFFAOYSA-N n-(trifluoromethylsulfanyl)aniline Chemical compound FC(F)(F)SNC1=CC=CC=C1 GYSYFBPOQKDJLU-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing isocoumarin derivatives, which comprises the following steps: mixing the raw material 2- ((2-R) 2 ) -ethynyl) methyl benzoate (II) is dissolved in dimethyl sulfoxide or deuterated dimethyl sulfoxide, thionyl chloride is dripped in, and reaction is carried out to obtain the isocoumarin derivative (I);
Description
Technical Field
The invention relates to a synthetic method of isocoumarin derivatives.
Background
Isocoumarin derivatives are an important class of lactones, widely distributed in nature and demonstrated to possess a variety of pharmacological activities. For example, NM-3 containing isocoumarin core structure is currently entering the clinical trial stage as an angiogenesis inhibitor. The structure A separated from the polygonum hydropiper can show obvious anti-inflammatory activity (see the following structural formula).
Reports of relevant researches on preparation of 4-thioisocoumarin derivatives by taking 2-alkynyl benzoate as a raw material include the following:
[1]
A.；Godoi,B.；Pinton,S.；Back,D.F.；Menezes,P.H.；Zeni,G.J.Org.Chem.2011,76,6789.
[2]Li,Z.；Hong,J.；Weng,L.；Zhou,X.Tetrahedron2012,68,1552.
[3]Li,Y.；Li,G.；Ding,Q.E.J.Org.Chem.2014,23,5017.
however, in these methods for synthesizing 4-thioisocoumarin, zeni et al obtained 2-acetylenyl methyl benzoate and disulfide compound as raw materials, ferric trichloride as an additive, and dichloroethane as a solvent at room temperature (
A.; godoi, B.; pinton, s.; back, d.f.; menezes, p.h.; zeni, g.j.org.chem.2011,76, 6789.), but the process has a long reaction time and low yield; zhou et al, which uses 2-acetylenyl methyl benzoate and a disulfide compound as raw materials, ferric chloride as an additive, and dichloroethane as a solvent, obtain the compounds under heating conditions (80 ℃) (Li, z.; hong, j.; weng, l.; zhou, x.tetrahedron 2012,68, 1552.), but the method has a long reaction time, and the reaction conditions are not mild enough and the yield is not high. Ding et al obtained this type of compound using methyl 2-acetylenecarboxylate and N-phenyl-S-trifluoromethylthiohydroxylamine as raw materials, bismuth chloride and boron trifluoride etherate as additives, and toluene as a solvent, but this method had expensive raw materials and complicated operation. (Li, Y.; li, G.; ding, Q.E.J.org.chem.2014,23, 5017.)
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for simply synthesizing isocoumarin derivatives by realizing intramolecular esterification and methylation tandem cyclization.
The technical scheme of the invention is summarized as follows:
the synthesis method of the isocoumarin derivative comprises the following steps: mixing raw material 2- ((2-R) 2 ) -ethynyl) methyl benzoate II is dissolved in dimethyl sulfoxide or deuterated dimethyl sulfoxide, thionyl chloride is dripped in, and the reaction is carried out to obtain isocoumarin derivative I;
in the formula:
R 1 is a hydrogen atom, a methyl group, a fluorine atom or a bromine atom;
R 2 is hydrogen atom, phenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-chlorophenyl, 2-methoxycarbonylphenyl, 2-nitro-4-methylphenyl, 1-naphthyl, 2-thienyl, tert-butyl or trimethylsilyl;
R 3 is methyl or deuterated methyl.
The invention has the advantages that:
the method has the advantages of simple operation, cheap and easily obtained raw materials, mild reaction conditions, short reaction time, ideal yield and the like.
Detailed Description
Thionyl chloride (SOCl) 2 ) Analytically pure thionyl chloride purchased commercially.
Dimethyl sulfoxide (DMSO) is a commercially available absolute anhydrous dimethyl sulfoxide.
Deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated dimethyl sulfoxide was purchased commercially at 99.9% purity.
The starting material for the reaction required in the examples, i.e. 2- ((2-R) 2 ) -ethynyl) benzoic acid methyl ester (II), prepared for reference ([ 1 ] method]Kundu,N.G.；Pal,M.；Nandi,B.J.Chem.Soc.PerkinTrans.1.1998,3,561.[2]Spino,C.；Rezaei,H.；Dupont-Gaudet,K.；Belanger,F.J.Am.Chem.Soc.2004,126,9926.)。
The synthesis method of the isocoumarin derivative comprises the following steps: mixing the raw material 2- ((2-R) 2 ) -ethynyl) methyl benzoate II is dissolved in dimethyl sulfoxide or deuterated dimethyl sulfoxide, and thionyl chloride is dripped in the solution to react to obtain an isocoumarin derivative I;
in the formula:
R 1 hydrogen atom, methyl group, fluorine atom and bromine atom;
R 2 is hydrogen atom, phenyl, p-methoxyphenyl, p-nitrophenyl, p-chlorophenyl, 2-methoxycarbonylphenyl,2-nitro-4-methylphenyl, 1-naphthyl, 2-thienyl, tert-butyl or trimethylsilyl;
R 3 is methyl or deuterated methyl.
Wherein, 2- ((2-R) 2 ) -ethynyl) methyl benzoate II in a molar ratio to thionyl chloride of preferably 3.
2-((2-R 2 ) -ethynyl) methyl benzoate II has an optimal reaction concentration in dimethyl sulfoxide or deuterated dimethyl sulfoxide of 1mmol/mL.
The reaction temperature was room temperature (25 ℃).
The present invention will be further illustrated by the following specific examples.
Example 1
Preparation of 3-phenyl-4-methylthioisocoumarin l-a
Methyl 2- ((2-phenyl) -ethynyl) benzoate ll-a (0.5 mmol, 118mg) was dissolved in dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise, and the reaction was carried out at room temperature (25 ℃) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried by adding anhydrous sodium sulfate, the organic phase was evaporated to dryness on column-packed silica gel, and separated by column chromatography (ethyl acetate: petroleum ether = 5) to obtain 127mg of a white solid with a yield of 95% and a melting point of 127-128 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.36(dd,J＝7.8,1.2Hz,1H),8.24(d,J＝7.8Hz,1H),7.88-7.85(m,1H),7.80-7.78(m,2H),7.59-7.56(m,1H),7.48-7.46(m,3H),2.16(s,3H). 13 C NMR(150MHz,CDCl 3 )δ161.6,158.0,138.1,135.3,133.2,130.0,129.9,129.8,128.6,127.9,125.6,120.9,111.0,19.1.HRMS(ESI)calcd for C 16 H 13 O 2 S + [M+H + ]269.0631, found 269.0634, l-a.
Example 2
Preparation of 3- (2-thienyl) -4-methylthioisocoumarin l-b
Methyl 2- (2- (2-thienyl) -ethynyl) benzoate ll-b (0.5 mmol, 121mg) was dissolved in dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise, followed by reaction at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried by adding anhydrous sodium sulfate, the organic phase was evaporated to dryness on column-packed silica gel, and separated by column chromatography (ethyl acetate: petroleum ether = 5) to obtain 123mg of a yellow-green solid, the yield was 90%, and the melting point was 139-140 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.32(dd,J＝7.8,1.2Hz,1H),8.22(d,J＝7.8Hz,1H),8.07(dd,J＝3.6,1.2Hz,1H),7.85-7.82(m,1H),7.55-7.51(m,2H),7.16(dd,J＝5.4,4.8Hz,1H),2.32(s,3H). 13 C NMR(150MHz,CDCl 3 )δ160.8,152.5,138.6,135.3,134.0,131.4,131.3,129.9,128.1,126.9,125.5,120.4,108.0,18.6.HRMS(ESI)calcd for C 14 H 10 NaO 2 S 2 + [M+Na + ]297.0014, found 297.0016 is l-b
With methyl 2- (2- (1-naphthyl) ethynyl) benzoate
In place of methyl 2- (2- (2-thienyl) -ethynyl) benzoate from this example, the following was prepared in an otherwise identical manner to this example:
3- (1-naphthyl) -4-methylthio-isocoumarin.
Example 3
Preparation of 3-phenyl-4-methylthio-7-methylisotalol l-c
Methyl 2- ((2-phenyl) -ethynyl) -5-methylbenzoate ll-c (0.5 mmol, 125mg) was dissolved in dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise, and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL. Times.3), the organic phases were combined and the mixture was diluted with waterThe organic phase was washed with brine, dried by adding anhydrous sodium sulfate to the organic phase, dried by passing through a column chromatography silica gel, and separated by column chromatography (ethyl acetate: petroleum ether =5, 95) to obtain 131mg of a white solid, a yield of 93%, and a melting point of 142-143 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.17(s,1H),8.11(d,J＝8.4Hz,1H),7.80-7.78(m,2H),7.67(dd,J＝8.4,1.8Hz,1H),7.47-7.46(m,3H),2.51(s,3H),2.15(s,3H). 13 C NMR(150MHz,CDCl 3 )δ161.8,157.2,138.9,136.5,135.6,133.2,129.9,129.8,129.7,127.9,125.6,120.8,111.0,21.3,19.1.HRMS(ESI)calcd for C 17 H 15 O 2 S + [M+H + ]283.0787, found 283.0787, l-c.
Example 4
Preparation of 3-phenyl-4-methylthio-7-fluoroisocoumarin l-d
Methyl 2- ((2-phenyl) -ethynyl) -5-fluorobenzoate ll-d (0.5 mmol, 127mg) was dissolved in dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise, and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness on column chromatography silica gel, and column chromatography (ethyl acetate: petroleum ether = 5) was performed to obtain 127mg of a white solid, the yield was 89%, and the melting point was 147-148 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.26(dd,J＝9.0,4.8Hz,1H),8.00(dd,J＝8.4,3.0Hz,1H),7.79-7.78(m,2H),7.59-7.56(m,1H),7.48-7.46(m,3H),2.15(s,3H). 13 C NMR(150MHz,CDCl 3 )δ162.2(d, 1 J C-F ＝249.6Hz),160.7(d, 4 J C-F ＝3.3Hz),157.5(d, 5 J C-F ＝2.6Hz),134.7(d, 4 J C-F ＝2.4Hz),132.8,130.1,129.7,128.4(d, 3 J C-F ＝7.8Hz),128.0,123.4(d, 2 J C-F ＝22.7Hz),122.6(d, 3 J C-F ＝8.1Hz),115.4(d, 2 J C-F ＝23.3Hz),110.5.HRMS(ESI)calcd for C 16 H 12 FO 2 S + [M+H + ]287.0537, found 287.0538 is l-d.
Example 5
Preparation of 3- ((4-nitrophenyl) ethynyl) -4-methylthioisocoumarin l-e
Methyl 2- (2- (4-nitrophenyl) ethynyl) benzoate ll-e (0.5 mmol, 140mg) was dissolved in dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise and the reaction was carried out at room temperature (25 ℃) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness on silica gel column chromatography, and the yellow solid was isolated by column chromatography (ethyl acetate: petroleum ether = 10) in 83% yield with a melting point of 168-169 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.38(dd,J＝7.8,0.6Hz,1H),8.33(d,J＝9.0Hz,2H),8.26(d,J＝7.8Hz,1H),8.03-8.01(m,2H),7.93-7.91(m,1H),7.66-7.64(m,1H),2.20(s,3H). 13 C NMR(150MHz,CDCl 3 )δ160.8,155.3,148.3,139.1,137.3,135.6,130.9,130.1,129.4,125.9,123.1,121.1,113.1,19.1.HRMS(ESI)calcd for C 16 H 12 NO 4 S + [M+H + ]314.0482, found 314.0483, l-e.
Using 2- (2- (2-methoxycarbonyl phenyl) ethynyl) methyl benzoate,
in place of methyl 2- (2- (4-nitrophenyl) ethynyl) benzoate from this example, the following was prepared:
3- ((2-methoxycarbonyl) phenyl) -4-methylthioisocoumarin.
Example 6
Preparation of 3- (4-chlorophenyl) -4-methylthioisocoumarin l-f
Methyl 2- (2- (4-chlorophenyl) ethynyl) benzoate ll-f (0.5 mmol, 136mg) was dissolved in dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried by adding anhydrous sodium sulfate, the organic phase was evaporated to dryness on column silica gel, and separated by column chromatography (ethyl acetate: petroleum ether = 5) to obtain 129mg of a white solid with a yield of 86% and a melting point of 133-134 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.37(d,J＝7.8Hz,1H),8.24(d,J＝8.4Hz,1H),7.89-7.86(m,1H),7.78-7.76(m,2H),7.60(t,J＝7.8Hz,1H),7.46-7.44(m,2H),2.17(s,3H). 13 C NMR(150MHz,CDCl 3 )δ161.4,156.8,137.9,136.1,135.3,131.5,131.2,130.0,128.8,128.2,125.7,120.9,111.4,19.0.HRMS(ESI)calcd for C 16 H 12 ClO 2 S + [M+H + ]303.0241, found 303.0241, l-f.
Example 7
Preparation of 3- (4-methoxyphenyl) -4-methylthioisocoumarin l-g
Methyl 2- (2- (4-methoxyphenyl) ethynyl) benzoate ll-g (0.5 mmol, 133mg) was dissolved in dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise, followed by reaction at room temperature (25 ℃) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was put on a column, silica gel was evaporated to dryness, column chromatography (ethyl acetate: petroleum ether = 5) was carried out to separate 138mg of a white solid, the yield was 93%, and the melting point was 119-120 ℃. 1 H NMR(600MHz,DMSO)δ8.23(dd,J＝7.8,1.2Hz,1H),8.18(d,J＝8.4Hz,1H),8.02-7.99(m,1H),7.74-7.72(m,2H),7.69-7.66(m,1H),7.09-7.07(m,2H),3.85(s,3H),2.20(s,3H). 13 C NMR(150MHz,DMSO)δ160.7,160.4,157.5,137.6,135.7,131.2,129.2,128.6,125.4,125.2,120.1,113.3,109.4,55.3,18.5.HRMS(ESI)calcd for C 17 H 15 O 3 S + [M+H + ]299.0736, found 299.0738 in l-g.
Example 8
Preparation of 3- (2-nitro-4-methylphenyl) -4-methylthioisocoumarin l-h
Methyl 2- (2- (2-nitro-4-methylphenyl) ethynyl) benzoate ll-h (0.5 mmol, 148mg) was dissolved in dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise, and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate was added, and the organic phase was evaporated onto column silica gel and subjected to column chromatography (ethyl acetate: petroleum ether = 5). 1 H NMR(600MHz,CDCl 3 )δ8.37(dd,J＝7.8,1.2Hz,1H),8.13(d,J＝7.8Hz,1H),8.03(d,J＝0.6Hz,1H),7.89-7.86(m,1H),7.63-7.60(m,1H),7.56(dd,J＝7.8,1.2Hz,1H),7.48(d,J＝7.8Hz,1H),2.54(s,3H),2.11(s,3H). 13 C NMR(150MHz,CDCl 3 )δ161.1,155.4,147.3,141.8,137.3,135.4,134.0,132.1,130.2,128.9,126.1,125.3,125.1,121.1,111.7,21.3,18.4.HRMS(ESI)calcd for C 17 H 14 NO 4 S + [M+H + ]328.0638, found 328.0639, l-h.
Example 9
Preparation of 3-trimethylsilyl-4-methylthio isocoumarin l-i
Methyl 2- ((2-trimethylsilyl) -ethynyl) benzoate ll-i (0.5mmol, 116mg) was dissolved in dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5mmol, 179mg) was added dropwiseReaction was carried out at room temperature (25 ℃) until TLC showed complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness on column chromatography silica gel, and the white solid was isolated by column chromatography (ethyl acetate: petroleum ether = 5) at 122mg, a yield of 93%, a melting point of 43-44 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.32(dd,J＝7.8,1.2Hz,1H),8.00(d,J＝7.8Hz,1H),7.84-7.81(m,1H),7.58-7.55(m,1H),2.26(s,3H),0.45(s,9H). 13 C NMR(150MHz,CDCl 3 )δ168.9,163.3,137.1,135.5,130.4,129.5,125.1,123.6,122.5,20.4,0.0.HRMS(ESI)calcd for C 13 H 17 O 2 SSi + [M+H + ]265.0713 and found 265.0716 as l-i.
With methyl 2- ((2-tert-butyl) -ethynyl) benzoate,
in place of methyl 2- ((2-trimethylsilyl) -ethynyl) benzoate of this example, the following was prepared:
3-tert-butyl-4-methylthio-isocoumarin.
Example 10
Preparation of 4-methylthio-7-bromoisocoumarin l-j
Methyl 2-ethynyl-5-bromobenzoate ll-j (0.5 mmol, 120mg) was dissolved in dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness on column chromatography silica gel, and column chromatography (ethyl acetate: petroleum ether = 5) was performed to separate 68mg of a pale yellow solid, the yield was 51%, and the melting point was 84-85 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.45(d,J＝1.8Hz,1H),7.93(dd,J＝8.4,1.8Hz,1H),7.83(d,J＝9.0Hz,1H),7.57(s,1H),2.34(s,3H). 13 C NMR(150MHz,CDCl 3 )δ160.3,147.2,138.3,135.4,132.8,126.4,122.84,122.80,114.2,19.0.HRMS(ESI)calcd for C 10 H 8 BrO 2 S + [M+H + ]272.9402 and found 272.9403 are l-j.
Example 11
Preparation of 3-phenyl-4-deuterated methylthio isocoumarin l-k
Methyl 2- ((2-phenyl) -ethynyl) benzoate ll-k (0.5 mmol, 118mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate was added, the organic phase was evaporated to dryness on column chromatography silica gel, and separated by column chromatography (ethyl acetate: petroleum ether = 5) to give 126mg of a white solid, the yield was 92%, and the melting point was 120-121 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.37(dd,J＝8.4,1.2Hz,1H),8.24(d,J＝8.4Hz,1H),7.89-7.86(m,1H),7.79(dd,J＝7.2,3.6Hz,2H),7.60-7.57(m,1H),7.49-7.47(m,3H). 13 C NMR(150MHz,CDCl 3 )δ161.6,158.0,138.1,135.2,133.2,129.99,129.96,129.8,128.5,127.9,125.6,120.9,110.9,18.6-18.2(m,C-D 3 ).HRMS(ESI)calcd for C 16 H 9 D 3 NaO 2 S+[M+Na + ]294.0639, found 294.0638, is
l-k。
With methyl 2- ((2-trimethylsilyl) -ethynyl) benzoate
In place of methyl 2- ((2-phenyl) -ethynyl) benzoate of this example, the following was prepared:
3-trimethylsilyl-4-deuterated methylthio isocoumarin.
Example 12
Preparation of 3-phenyl-4-deuterated methylthio-7-methylisojacin l-l
Methyl 2- ((2-phenyl) -ethynyl) -5-methylbenzoate ll-l (0.5 mmol, 125mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), thionyl chloride (1.5 mmol, 179mg) was added dropwise, and the reaction was carried out at room temperature (25 ℃) until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 3), the organic phases were combined, the organic phase was washed with saturated brine, dried by adding anhydrous sodium sulfate to the organic phase, the organic phase was evaporated to dryness on silica gel column chromatography, and the mixture was separated by column chromatography (ethyl acetate: petroleum ether = 5) to give 130mg of a white solid, yield 91%, melting point 142-143 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.17(s,1H),8.12(d,J＝8.4Hz,1H),7.80-7.78(m,2H),7.68-7.67(m,1H),7.46(t,J＝3.0Hz,3H),2.51(s,3H). 13 C NMR(150MHz,CDCl 3 )δ161.8,157.1,138.9,136.5,135.7,133.2,129.9,129.8,129.7127.9,125.6,120.8,110.9,21.3,18.7-18.1(m,C-D 3 ).HRMS(ESI)calcd for C 17 H 12 D 3 O 2 S + [M+H + ]286.0976, found 286.0977 is l-l.
With methyl 2-ethynyl-5-bromobenzoate,
in place of the methyl 2- ((2-phenyl) -ethynyl) -5-methylbenzoate of this example, the following was prepared in analogy to this example:
4-deuterated methylthio-7-bromoisocoumarin.
Example 13
Preparation of 3- (2-thienyl) -4-deuterated methylthio isocoumarin l-m
Methyl 2- (2- (2-thienyl) -ethynyl) benzoate ll-m (0.5 mmol, 121mg) was dissolved in deuterated dimethyl sulfoxide (0.5 mL), and thionyl chloride (1.5 mmol, 179mg) was added dropwise and the reaction was carried out at room temperature (25 ℃ C.) until TLC indicated complete reaction of the substrate. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine, and anhydrous sulfur was addedThe sodium salt was dried, the organic phase was evaporated to dryness on column silica gel, and column chromatography (ethyl acetate: petroleum ether =5, 95) was performed to isolate 124mg of a yellow-green solid in 90% yield with a melting point of 134-135 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.31(d,J＝7.8Hz,1H),8.21(d,J＝8.4Hz,1H),8.06(d,J＝3.6Hz,1H),7.82(t,J＝7.8Hz,1H),7.52(dd,J＝16.2,7.8Hz,2H),7.14(t,J＝4.2Hz,1H). 13 C NMR(150MHz,CDCl 3 )δ160.8,152.5,138.6,135.3,134.1,131.4,131.3,129.9,128.1,126.9,125.5,120.5,108.0,18.0-17.7(C-D 3 ).HRMS(ESI)calcd for C 14 H 8 D 3 O 2 S 2 + [M+H + ]278.0383 and found 278.0384, and is l-m.
With methyl 2- (2- (2-bromophenyl) ethynyl) -benzoate,
in place of methyl 2- (2- (2-thienyl) -ethynyl) benzoate from this example, the following was prepared in an otherwise identical manner to this example:
3- (2-bromophenyl) -4-deuterated methylthio isocoumarin.
The above description is only a partial example of the present invention, and is not intended to limit the present invention in any way, and any simple modifications, equivalent changes and modifications made to the above embodiment according to the technical essence of the present invention are within the technical scope of the present invention.
Claims (1)
1. The synthesis method of the isocoumarin derivative is characterized by comprising the following steps: mixing raw material 2- ((2-R) 2 ) -ethynyl) methyl benzoate (II) is dissolved in dimethyl sulfoxide or deuterated dimethyl sulfoxide, thionyl chloride is dripped in, and reaction is carried out to obtain the isocoumarin derivative (I);
in the formula:
R 1 is a hydrogen atom, a methyl group, a fluorine atom or a bromine atom;
R 2 is hydrogen atom, phenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-chlorobenzene2-methoxycarbonylphenyl, 2-nitro-4-methylphenyl, 1-naphthyl, 2-thienyl, tert-butyl or trimethylsilyl;
R 3 is methyl or deuterated methyl.
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| Regioselective Synthesis of Isochromenones by Iron(III)/PhSeSePh-Mediated Cyclization of 2-Alkynylaryl Esters;Adriane Speranca et al.;《The Journal of Organic Chemistry》;20111231 * |
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