CN101817830B - Method for synthesizing Coumestan derivatives - Google Patents
Method for synthesizing Coumestan derivatives Download PDFInfo
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- CN101817830B CN101817830B CN2010101711290A CN201010171129A CN101817830B CN 101817830 B CN101817830 B CN 101817830B CN 2010101711290 A CN2010101711290 A CN 2010101711290A CN 201010171129 A CN201010171129 A CN 201010171129A CN 101817830 B CN101817830 B CN 101817830B
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Abstract
The invention discloses a method for synthesizing Coumestan derivatives (I). In the method, a 3-aryl- 4-hydroxycoumarin compound (II) is dissolved in a non-protonic solvent, and under the action of an anhydrous ferric halide (III), the sp2 carbons of aromatic rings are directly bonded with branch oxygen atoms to form the Coumestan derivatives (I), wherein the R1 represents methyl, methoxyl or hydrogen atom; and R2 represents methyl, bromine atom, methoxyl or hydrogen atom. The method has the advantages of simple operation, cheap and easily available raw materials, ideal yield, low cost and the like.
Description
Technical field
The present invention relates to a kind of method of synthetic Coumestan analog derivative.
Background technology
The Coumestan compounds is the natural compounds of a series of 6H-of having cumarones [3-2-c] [1] chromene-this mother nucleus structure of 6-ketone group, mainly be present in pulse family (Leguminosae), Papilionaceae (Papilionaceae) and composite family (Compositae) plant, have effects such as antibiotic, phytoestrogen, anti-myotoxin, hypotensive, treatment hepatitis, liver cirrhosis
[1]From gold small cup Herbia Wedeliae (Wedelia Calendulacea), separated this compounds-Wedelolactone (Wedelolactone) that obtains for the first time, and studies show that it had selective inhibitory, anastalsis and the immunoregulation effect of hepatoprotective effect, antisnake venom effect, 5-lipoxidase in 1956
[2]
For the chemosynthesis of Coumestan class natural compounds, existing a series of relevant reports now exemplify as follows:
1.Tricotet，T.；Fleming，P.；Cotter，J.；Hogan，A.L.；Strohmann，C.；Gessner，V.H.；O’Shea，D.F.J.Am.Chem.Soc.2009，131，3142-3143.
2.Sant’Ana，D.P.；Pinho，V.D.；Maior，M.C.L.S.；Costa，P.R.R.Tetrahedron?Lett.2009，50，3753-3755.
3.Kamara，B，I.；Brandt，E.V.；Ferreira，D.Tetrahedron?1999，55，861-868.
4.Gong，D.；Li，C.；Yuan，C.Chin.J.Chem.2001，19，522-527.
5.Chang，C.；Yang，L.；Chang，S.；Fang，Y.；Lee，Y.Tetrahedron?2008，64，3661-3666.
6.Kraus，G.A.；Zhang，N.J.Org.Chem.2000，65，5644-5646.
7.Li，C.C.；Xie，Z.X.；Zhang，Y.D.；Chen，J.H.；Yang，Z.J.Org.Chem.2003，68，8500-8504.
In addition, the report that also has derivative at Coumestan class natural compounds to synthesize and its biological activity is studied.
Relevant report exemplifies as follows:
1.Yao，T.；Yue，D.；Larock，R.C.J.Org.Chem.2005，70，9985-9989.
2.Emerson，O.H.；Bickoff，E.M.J.Am.Chem.Soc.，1958，80，4381-4383.
3.Pocas，E.S.C.；Lopes，D.V.S.；da?Silva，A.J.M.；Pimenta，P.H.C.；Leitao，F.B.；Netto，C.D.；Buarque，C.D.；Brito，F.V.；Costa，P.R.C.；Noel；F.Bioorg.Med.Chem.2006，14，7962-7966.
Yet in all these synthetic methods, Shang Weijian is a raw material with 3-aryl-4-hydroxy coumarin compound, under the effect of single electron transfer oxygenant with aromatic ring sp
2The direct key of carbon and pendant hydroxyl group Sauerstoffatom connects the report that obtains the Coumestan analog derivative.Similar a kind of method needs aromatic ring sp usually
2Have a halogen atom on the carbon, and then Pd catalysis makes up C-O key (Jin, Y. down; Kim, S.; Kim, Y.S.; Kim, S-A.; Kim H.S.Tetrahedron Lett.2008,49,6835-6837) obtain this compounds.
Summary of the invention
It is simpler to the purpose of this invention is to provide a kind of method, lower-cost under inexpensive one-electron oxidation agent effect with aromatic ring sp
2The direct key of carbon and pendant hydroxyl group Sauerstoffatom connects the method that (not needing the activation of aromatic ring C-H is the carbon-halogen bond process) synthesizes the Coumestan analog derivative.
Technical scheme of the present invention is summarized as follows:
The method of a kind of synthetic Coumestan analog derivative (I), 3-aryl-4-hydroxy coumarin compound (II) is dissolved in the dry anhydrous aprotic solvent, disposable then or add anhydrous three iron halide in batches, at anhydrous three iron halide (III) the effect sp of generation aromatic ring down
2The direct key of carbon and side chain Sauerstoffatom successively win Coumestan analog derivative (I); Filter, filter residue washs with a small amount of solvent, adds 1g silica gel (100-200 order) in the filtrate, and the rotation solvent evaporated is after column chromatography for separation obtains Coumestan analog derivative (I), wherein R
1Expression methyl, methoxyl group or hydrogen atom; R
2Expression methyl, bromine atoms, methoxyl group or hydrogen atom,
Described anhydrous three iron halide are FERRIC CHLORIDE ANHYDROUS or anhydrous ferric bromide.
The mol ratio of described three iron halide and described 3-aryl-4-hydroxy coumarin compound (II) is preferably 2.5-5: 1.
Described aprotic solvent is anhydrous methylene chloride or 1, the 2-ethylene dichloride.
Temperature of reaction is room temperature-reflux temperature.
Advantages such as the present invention has simple to operate, and raw material is cheap and easy to get, and yield is more satisfactory, and cost is lower.
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
Needed reaction raw materials among the embodiment, i.e. 3-aryl-4-hydroxy coumarin compound (II), the preparation of reference literature method ([1] Zhu, Q.; Wu, J.; Fathi, R.; Yang, Z.Org.Lett.2002,4,3333-3336.[2] Dittmer, D C.; Li, Q.; Avilov, D V.J.Org.Chem.2005,12,4682-4686.[3] Kalinin, A V.; Da Silva, A J.M.; Lopes, C C.; Lopes, R S.C.; Snieckus, V.Tetrahedron Lett.1998,39,4995-4998.[4] Stadlbauer, W.; Kappe, T.Monatsh.Chem.1978,109,1485-1487.[5] auspicious firm, Yang Chunhao, Wang Mingwei, Xie Yuyuan. benzopyran [4,3-b] benzazolyl compounds, Preparation Method And The Use [P]. China: CN200510110484.6,2007-05-23).
Embodiment 1
4-methyl-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-a):
With 4-hydroxyl-8-methyl-3-phenyl-2H-chromen-2-one (II-a) (0.26g) is dissolved in exsiccant 1, in the 2-ethylene dichloride (10mL), the anhydrous FeCl of stirring at room property adding next time
3(0.5g), then reflux 6h to reacting completely.Stop heating, be chilled to room temperature, diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 39) separation obtains white solid 0.18g, yield 69% to column chromatography.Fusing point: 195-197 ℃.
1H-NMR(CDCl
3，400MHz)δ：8.18～8.20(d，1H，J＝4.0Hz)，7.88～7.90(d，1H，J＝8.0Hz)，7.69～7.71(d，1H，J＝8.0Hz)，7.48～7.52(m，3H)，7.32～7.36(t，1H，J＝8.0Hz)，2.60(s，3H).
Embodiment 2:
9-methoxyl group-4-methyl-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-b):
(II-b) (0.6g) is dissolved in the dry methylene chloride (35mL) the anhydrous FeCl of stirring at room property adding next time with 4-hydroxyl-3-(4-methoxyphenyl)-8-methyl-2H-chromen-2-one
3(0.87g), stirring at room is to reacting completely.Diatomite filtration is removed filter residue, methylene dichloride (30mL) washing, and solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 4) separation obtains white solid 0.5g, yield 83% to column chromatography.Fusing point: 196 ℃.
1H-NMR(CDCl
3，400MHz)δ：8.04～8.06(d，1H，J＝8.0Hz)，7.86～7.88(d，1H，J＝8.0Hz)，7.46～7.48(d，1H，J＝8.0Hz)，7.32～7.36(t，1H，J＝8.0Hz)，7.10～7.12(d，1H，J＝8.0Hz)，3.98(s，3H)，2.61(s，3H).
Embodiment 3:
9-methyl-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-c):
With 4-hydroxyl-3-p-methylphenyl-2H-chromen-2-one (II-c) (0.5g) is dissolved in exsiccant 1, in the 2-ethylene dichloride (25mL), the anhydrous FeBr of stirring at room property adding next time
3(1.5g), then reflux 2h to reacting completely.Stop heating, be chilled to room temperature, diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 20) separation obtains white solid 0.43g, yield 86% to column chromatography.Fusing point: 198-200 ℃.
1H-NMR(CDCl
3，400MHz)δ：7.96(s，2H)，7.59(s，1H)，7.49(s，1H)，7.42(s，2H)，7.26(s，2H)，2.54(s，3H).
Embodiment 4:
3,8,9-trimethoxy-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-d):
With 3-(3, the 4-Dimethoxyphenyl)-4-hydroxyl-7-methoxyl group-2H-chromen-2-one (II-d) (0.3g) is dissolved in exsiccant 1, in the 2-ethylene dichloride (30mL), the anhydrous FeCl of stirring at room property adding next time
3(0.37g), then reflux 6h to reacting completely.Stop heating, be chilled to room temperature, diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 4) separation obtains white solid 0.14g, yield 45% to column chromatography.Fusing point: 254-256 ℃.
1H-NMR(CDCl
3，400MHz)δ：7.91～7.93(d，1H，J＝8.0Hz)，7.57(s，1H)，7.34(s，1H)，7.03～7.05(d，2H，J＝8.0Hz)，4.08(s，3H)，4.05(s，3H)，3.98(s，3H).
Embodiment 5:
8,9-dimethoxy-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-e):
With 3-(3, the 4-Dimethoxyphenyl)-4-hydroxyl-2H-chromen-2-one (II-e) (0.28g) is dissolved in exsiccant 1, in the 2-ethylene dichloride (30mL), the anhydrous FeCl of stirring at room property adding next time
3(0.46g), then room temperature reaction 12h to reacting completely.Diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 5) separation obtains white solid 0.15g, yield 53% to column chromatography.Fusing point: 217-220 ℃.
1H-NMR(CDCl
3，400MHz)δ：8.01～8.03(d，1H，J＝8.0Hz)，7.54～7.63(m，3H)，7.44～7.48(m，1H)，7.26(s，1H)，4.07(s，3H)，4.06(s，3H)。
Embodiment 6:
8,9-dimethoxy-4 '-methyl-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-f):
With 3-(3, the 4-Dimethoxyphenyl)-4-hydroxyl-8-methyl-2H-chromen-2-one (II-f) (0.31g) is dissolved in exsiccant 1, in the 2-ethylene dichloride (30mL), the anhydrous FeCl of stirring at room property adding next time
3(0.39g), then room temperature reaction 12h to reacting completely.Diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 9) separation obtains white solid 0.16g, yield 52% to column chromatography.Fusing point: 229-231 ℃.
1H-NMR(CDCl
3，400MHz)δ：7.81～7.83(d，1H，J＝8.0Hz)，7.56(s，1H)，7.44～7.46(d，1H，J＝8.0Hz)，7.32～7.34(m，1H，J＝8.0Hz)，7.22(s，1H)，4.04(s，3H)，4.07(s，3H)，2.60(s，3H)。
Embodiment 7:
9-methoxyl group-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-g):
With 4-hydroxyl-3-(4-p-methoxy-phenyl)-2H-chromen-2-one (II-g) (0.19g) is dissolved in exsiccant 1, in the 2-ethylene dichloride (30mL), the anhydrous FeCl of stirring at room property adding next time
3(0.40g), then room temperature reaction 12h to reacting completely.Diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 10) separation obtains white solid 0.13g, yield 71% to column chromatography.Fusing point: 216 ℃.
1H-NMR(CDCl
3，400MHz)δ：8.04～8.07(m，2H)，7.63～7.67(m，1H)，7.55～7.57(m，1H)，7.45～7.49(t，1H，J＝8.0Hz)，7.25～7.26(d，1H，J＝4.0Hz)，7.12～7.15(dd?1H，J＝2.0，8.4Hz)，4.02(s，3H)。
Embodiment 8:
3-methoxyl group-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-h):
With 4-hydroxyl-7-methoxyl group 3-phenyl-2H-chromen-2-one (0.23g) (II-h) be dissolved in exsiccant 1, in the 2-ethylene dichloride (30mL), the anhydrous FeCl of stirring at room property adding next time
3(0.70g), then 60 ℃ the reaction 12h.Diatomite filtration is removed filter residue, and 1,2-ethylene dichloride (30mL) washing, solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 10) separation obtains white solid 0.076g to column chromatography, reclaims raw material 0.06g, yield 45%.Fusing point: 173-175 ℃.
1H-NMR(CDCl
3，400MHz)δ：7.92～8.02(t，1H，J＝9.2Hz，J＝9.6Hz)，7.70～7.72(m，1H)，7.50～7.53(m，2H)，7.34(s，1H)，7.07～7.08(m，2H)，4.00(s，3H)。
Embodiment 9:
9-bromo-6H-cumarone [3,2-c] chromene-6-ketone (preparation of I-i):
(II-i) (0.5g) is dissolved in the exsiccant methylene dichloride (30mL) the anhydrous FeCl of stirring at room property adding next time with 3-(4-bromophenyl)-4-hydroxyl-2H-chromen-2-one
3(1.28g), then back flow reaction to reacting completely.Diatomite filtration is removed filter residue, methylene dichloride (30mL) washing, and solution added post silica gel evaporate to dryness, and (ethyl acetate: sherwood oil=1: 20) separation obtains white solid 0.25g, yield 50% to column chromatography.Fusing point: 200-202 ℃.
1H-NMR(CDCl
3)δ：8.00～8.04(t，2H，J＝8.0Hz，J＝8.8Hz)，7.86(s，1H)，7.60～7.67(m，2H)，7.52～7.547(d，1H，J＝8.4Hz)，7.43～7.47(m，1H，J＝7.6Hz)，4.00(s，3H)。
The above, only being part embodiment of the present invention, is not that the present invention is done any pro forma restriction, any simple modification that every foundation technical spirit of the present invention is done the foregoing description, equivalent variations and modification all belong in the technical solution of the present invention scope.
Claims (5)
1. the method for a synthetic Coumestan analog derivative (I) is characterized in that 3-aryl-4-hydroxy coumarin compound (II) is dissolved in the dry anhydrous aprotic solvent, and the sp of aromatic ring takes place under anhydrous three iron halide (III) effect
2The direct key of carbon and side chain Sauerstoffatom successively win Coumestan analog derivative (I); R wherein
1Expression methyl, methoxyl group or hydrogen atom; R
2Expression methyl, bromine atoms, methoxyl group or hydrogen atom,
2. method according to claim 1 is characterized in that described anhydrous three iron halide are FERRIC CHLORIDE ANHYDROUS or anhydrous ferric bromide.
3. method according to claim 1 is characterized in that the mol ratio of described three iron halide and described 3-aryl-4-hydroxy coumarin compound (II) is 2.5-5: 1.
4. method according to claim 1 is characterized in that described aprotic solvent is anhydrous methylene chloride or 1, the 2-ethylene dichloride.
5. method according to claim 1 is characterized in that temperature of reaction is room temperature-reflux temperature.
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| US11802130B1 (en) | 2023-02-22 | 2023-10-31 | King Faisal University | Benzofuro[3,2-c]chromen-6-one compounds as antibacterial agents |
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| CN1566116A (en) * | 2003-07-08 | 2005-01-19 | 北京大学 | Process for preparing wedelia lactone and application thereof |
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| CN1566116A (en) * | 2003-07-08 | 2005-01-19 | 北京大学 | Process for preparing wedelia lactone and application thereof |
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