CN106243072B - The method that alkali-free, condition of no solvent prepare furane derivative by Feist-Benary reactions - Google Patents
The method that alkali-free, condition of no solvent prepare furane derivative by Feist-Benary reactions Download PDFInfo
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- CN106243072B CN106243072B CN201610566687.4A CN201610566687A CN106243072B CN 106243072 B CN106243072 B CN 106243072B CN 201610566687 A CN201610566687 A CN 201610566687A CN 106243072 B CN106243072 B CN 106243072B
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- VICYTAYPKBLQFB-UHFFFAOYSA-N CCOC(C(CBr)=O)=O Chemical compound CCOC(C(CBr)=O)=O VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- DJFBXWMJRCYRIX-UHFFFAOYSA-N CCOC(c1c[o]c(C)c1C(C)=O)=O Chemical compound CCOC(c1c[o]c(C)c1C(C)=O)=O DJFBXWMJRCYRIX-UHFFFAOYSA-N 0.000 description 1
- GEKWXPNXQKNHCS-UHFFFAOYSA-N Cc1c(C)[o]c(CCC2)c1C2=O Chemical compound Cc1c(C)[o]c(CCC2)c1C2=O GEKWXPNXQKNHCS-UHFFFAOYSA-N 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N O=C(CCC1)CC1=O Chemical compound O=C(CCC1)CC1=O HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention provides a kind of method preparing furane derivative, i.e., under alkali-free, condition of no solvent, α halogenated ketones react to obtain polysubstituted furan compounds with beta-dicarbonyl compound.The preparation method of polysubstituted furan compounds of the present invention, raw material is easy to get, of low cost, and reaction condition is mild, it is easy to operate easily-controllable, side reaction is less, and post-processing is simple, and product yield is higher, without any catalysts and solvents, production cost is greatly saved, there is preferable environmental benefit and economic benefit, be suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation methods of polysubstituted furan compounds, and in particular to α-halogenatedketone and beta-dicarbonyl compound
The method for efficiently synthesizing polysubstituted furan compounds for raw material.
Background technology
Furans is important five member ring heterocyclic compound, plays important role in chemistry, biology and drug research, very
More natural products all contain furan nucleus nuclear structure, these furan derivatives usually all have certain bioactivity, such as anti-
Bacterium, desinsection, it is antitumor, calm the effects that.
Synthesis about furan compound has many document reports, such as under bronsted acid or Louis acid catalysis,
Isosorbide-5-Nitrae-dicarbonyl compound occurs condensation reaction and prepares (Paal-Knorr furans synthetic reaction);Using alkene, alkynes as substrate, lead to
Transition metal-catalyzed cyclization is crossed to prepare;Structural modification is carried out as substrate prepare complicated furan compound etc. using simple furans
Deng.Wherein most classical is Feist-B é nary furans synthetic reactions, and this method is directly with α-halogenatedketone or aldehyde and beta-dicarbonyl
Compound is substrate, and preparing synthesis by two-step reaction obtains furane derivative.
Being reacted by the Feist-B é nary of raw material of α-halogenatedketone for document report, is usually required for two steps.The first step, alkali
Dihydrofuran IV is catalyzed and synthesized, and is needed with excessive alkali come generated acid in neutralization reaction.Used alkali includes:Ammonia
Gas, triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride etc..Used solvent
Including ether, dichloromethane, toluene, methanol, water, DMF etc. (1. K.Ghosh, R.Karmakar, D.Mal,
Eur.J.Org.Chem.2013,2013,4037-4046;2. Stetter, H.;Lauterbach, R., Synthese des
Evodons und Menthofurans.Chem.Ber.1960,93,603-607;3. R.Aranda, K.Villalba, E.C.F.Masaguer, J.Brea, F.Areias, E.Dom í nguez, J.Selent, L.L ó pez, F.Sanz,
M.Pastor, M.I.Loza, J.Med.Chem.2008,51,6085-6094).Second step needs acid catalysis heating to carry out dihydro
The dehydration of furans IV, finally to prepare furane derivative III.Used acid includes hydrochloric acid, acetic acid, sulfuric acid etc..
As it can be seen that although Feist-B é nary furans synthetic reactions are the most classical modes of current synthesis furan compound, but
Usually it is required for two steps to synthesize, first step reaction needs that excessive alkali is added to be catalyzed reaction, and is generated during neutralization reaction
Acid;The dihydrofuran intermediate of generation needs again acid adding heating that could be dehydrated and wait until corresponding furans product again.The reaction needs
A large amount of solvent, and two-step reaction are wanted, cumbersome, yield is relatively low.
Invention content
The purpose of the present invention is to provide one kind not needing alkali or acid, does not need solvent, with good chemical specificity, instead
Answer condition simple, post-processing is simple, the preparation method of the much lower substituted furan compound of production cost.
Purpose of the present invention is to what is be achieved through the following technical solutions:
The method that alkali-free, condition of no solvent prepare furane derivative by Feist-B é nary reactions:In alkali-free and without molten
Under the conditions of agent, beta-dicarbonyl shown in α-halogenatedketone and general formula (IIa) or (IIb) shown in general formula (Ia), (Ib) or (Ic)
Conjunction object, which reacts, respectively obtains polysubstituted furan compounds shown in general formula (IIIa), (IIIb) or (IIIc), and chemistry is anti-
Answer formula (A), (B) and (C) as follows:
Wherein, R1For H, C1-C4Alkyl or phenyl;R2For H, C1-C4Alkyl or phenyl;R3For C1-C4Alkyl;R4For C1-C4
Alkyl;R5For C1-C4Alkyl;R6For C1-C4Alkyl;R7For C1-C4Alkyl or C1-C4Alkoxy;Or R6With R7Be connected to each other cyclization,
Composition-(CH2)3-;X is bromine or chlorine atom.
Preferably, the R1For H or phenyl;R2For H, methyl or phenyl;R3For C1-C2Alkyl;R4For C1-C2Alkyl;R5For
C1-C2Alkyl;R6For C1-C2Alkyl;R7For C1-C2Alkyl or C1-C2Alkoxy;Or R6With R7Be connected to each other cyclization, constitute-
(CH2)3-;X is bromine or chlorine atom.
Wherein, the reaction temperature is 0-120 DEG C, and the reaction time is 0.5-100 hours.
Wherein, the molar ratio of both the α-halogenatedketone and described beta-dicarbonyl compound is 1-10: 1.
The method for preparing furane derivative, operating procedure are as follows:Under stiring, the α-halogenatedketone and described
Beta-dicarbonyl compound reacts, and reaction process is monitored with TLC, waits for after reaction, through isolating and purifying to obtain described take more
For furan compound.
The method for preparing furane derivative, concrete operation step are as follows:Under stiring, the α-halogenatedketone and
The beta-dicarbonyl compound is reacted at 0-120 DEG C, until becoming uniform liquid, reaction process is monitored with TLC, after reaction
The mixture arrived carries out silica gel column chromatography separation, obtains the polysubstituted furan compounds.
Compared with existing Feist-B é nary furans synthetic reactions, the present invention has the following advantages that:
1) method that the present invention prepares polysubstituted furan compounds is not necessarily to any catalysts and solvents, reduces and be produced into
This, reduces environmental pollution.
2) preparation method of the present invention, reaction condition is mild, one pot reaction, easy to operate.
3) synthetic method of the present invention, regioselectivity is good, and side reaction is less, and product is easily separated, and post-processing is simple,
And achieve preferable yield (70-85%).
To sum up, synthetic method (one pot reaction) of the present invention, raw material is easy to get, of low cost, reaction condition temperature
With easy to operate easily-controllable, side reaction is less, and post-processing is simple, and product yield is higher, is not necessarily to any catalysts and solvents, significantly
Production cost has been saved, there is preferable environmental benefit and economic benefit, be suitable for industrialized production.
Specific implementation mode
It is illustrated in detail by way of the following examples the present invention, but the present invention is not only limitted in embodiment.
Embodiment 1:1- chlroacetones and 1, hydroresorcinol reaction
In 50mL round-bottomed flasks, 1- chlorine cyclohexanone (10mmol) and 1, hydroresorcinol (5mmol) is added.In stirring
Slowly heating rises to 60 DEG C, and mixture becomes uniform liquid, constantly monitors reaction in reaction with TLC.It obtains after reaction
Mixture directly carries out silica gel column chromatography separation, and it is yellow oil, yield 85% to obtain furans IIIa1.
1H NMR (400MHz, CDCl3) δ 7.06 (s, 1H), 2.82 (t, J=6.3Hz, 2H), 2.46 (dd, J=7.2,
5.8Hz, 2H), 2.19 (d, J=1.3Hz, 3H), 2.18-2.10 (m, 2H);13C NMR (101MHz, CDCl3) δ 195.73,
167.42,138.93,120.44,119.10,38.31,23.64,22.76,9.09;IR (KBr, cm-1) 2952,1667,1462,
1411,1071,573;MS(ESI)calcd for C9H11O2(M+H)+:151.1, Found:151.2.
Embodiment 2:3-BrPA ethyl ester and 1, hydroresorcinol reaction
In 50mL round-bottomed flasks, 3-BrPA ethyl ester (10mmol) and 1, hydroresorcinol (5mmol) is added.It is stirring
Slowly heating rises to 80 DEG C of mixtures and becomes uniform liquid in mixing, and constantly monitors reaction in reaction with TLC.It obtains after reaction
Mixture directly carry out silica gel column chromatography separation, obtain furans IIIc1 be pale yellow oil, yield 76%.
1H NMR (400MHz, CDCl3) δ 7.85 (s, 1H), 4.31 (q, J=7.1Hz, 2H), 2.88 (t, J=6.3Hz,
2H), 2.61-2.44 (m, 2H), 2.24-2.07 (m, 2H), 1.34 (t, J=7.1Hz, 3H);13C NMR (101MHz, CDCl3)δ
191.98,168.33,161.91,147.77,118.73,117.48,60.94,38.71,23.60,22.17,14.19;IR
(KBr, cm-1):3451,3120,1736,1554,1455,1300,1183,1002,878,769,586;MS(ESI)calcd
for C11H13O4(M+H)+:209.0, Found:209.1
Embodiment 3:3-BrPA ethyl ester and 1, the reaction of 3- pentanediones
In 50mL round-bottomed flasks, 3-BrPA ethyl ester (10mmol) and 1,3- pentanediones (5mmol) is added.It is stirring
In slowly heating rise to 100 DEG C of mixtures and become uniform liquid, reaction is constantly monitored in reaction with TLC.It obtains after reaction
Mixture directly carry out silica gel column chromatography separation, obtain furans IIIc2 be yellow oil, yield 81%.
Embodiment 4:3-BrPA ethyl ester is reacted with ethyl acetoacetate
In 50mL round-bottomed flasks, 3-BrPA ethyl ester (10mmol) and ethyl acetoacetate (5mmol) is added.It is stirring
Slowly heating rises to 100 DEG C of mixtures and becomes uniform liquid in mixing, and constantly monitors reaction in reaction with TLC.After reaction
The mixture arrived directly carries out silica gel column chromatography separation, and it is yellow oil, yield 72% to obtain furans IIIc3.
Embodiment 5:2- chloroacetyl acetacetic esters and 1, hydroresorcinol reaction
In 50mL round-bottomed flasks, 2- chloroacetyl acetacetic esters (10mmol) and 1, hydroresorcinol (5mmol) is added.
Slowly heating rises to 60 DEG C of mixtures and becomes uniform liquid in stirring, constantly monitors reaction in reaction with TLC.After reaction
The mixture arrived directly carries out silica gel column chromatography separation, and it is light colorless oil, yield 75% to obtain furans IIIb1.
1H NMR (400MHz, CDCl3) δ 4.37 (q, J=7.1Hz, 2H), 2.91 (t, J=6.3Hz, 2H), 2.55 (s,
3H), 2.53-2.46 (m, 2H), 2.23-2.09 (m, 2H), 1.38 (t, J=7.1Hz, 3H);13C NMR (101MHz, CDCl3)δ
195.11,168.69,159.51,140.19,129.70,121.72,60.94,38.41,23.78,22.20,14.37,
10.39;MS(ESI)calcd for C12H15O4(M+H)+:223.1, Found:223.0.
Embodiment 6:Chloro- 1, the 3- diphenyl acetones of 1- and 1, hydroresorcinol reaction
In 50mL round-bottomed flasks, chloro- 1, the 3- diphenyl acetones (10mmol) of 1- and 1, hydroresorcinol is added
(5mmol).Slowly heating rises to 100 DEG C of mixtures and becomes uniform liquid in stirring, constantly monitors reaction in reaction with TLC.
The mixture obtained after reaction directly carries out silica gel column chromatography separation, and it is red solid, yield to obtain furans IIIa2
73%.
1H NMR (400MHz, CDCl3) δ 7.47-7.38 (m, 4H), 7.38-7.29 (m, 3H), 7.29-7.19 (m, 3H),
4.00 (s, 2H), 2.89 (t, J=6.3Hz, 2H), 2.51 (t, J=6.3Hz, 2H), 2.27-2.10 (m, 2H);13C NMR
(101MHz, CDCl3) δ 194.04,166.48,150.42,138.00,131.52,129.82,128.66,128.45,
128.00,127.41,126.64,120.52,119.78,38.66,32.09,23.78,22.49;IR (KBr, cm-1):3423,
3414,1670,1574,1428,1073,1009,773,502;MS(ESI)calcd for C21H19O2(M+H)+:303.1
Found:303.0.
Embodiment 7:The chloro- 2- butanone of 3- and 1, hydroresorcinol reaction
In 50mL round-bottomed flasks, the chloro- 2- butanone (10mmol) of 3- and 1, hydroresorcinol (5mmol) is added.It is stirring
In slowly heating rise to 80 DEG C of mixtures and become uniform liquid, reaction is constantly monitored in reaction with TLC.It obtains after reaction
Mixture directly carries out silica gel column chromatography separation, and it is brown oil, yield 83% to obtain furans IIIa3.
1H NMR (400MHz, CDCl3) δ 2.78 (t, J=6.3Hz, 2H), 2.46-2.39 (m, 2H), 2.17 (s, 3H),
2.14-2.07 (m, 2H), 2.10 (s, 3H);13C NMR (101MHz, CDCl3) δ 195.84,165.18,147.49,121.03,
112.60,38.28,23.48,22.76,10.85,8.98;IR (KBr, cm-1):2950,1671,1585,1438,1296,
1193,1009,896,677,560;MS(ESI)calcd for C10H13O2(M+H)+:165.0, Found:165.4.
Embodiment 8:3-BrPA methyl esters is reacted with methyl acetoacetate
In 50mL round-bottomed flasks, 3-BrPA methyl esters (40mmol) and methyl acetoacetate (5mmol) is added.It is stirring
Slowly heating rises to 50 DEG C of mixtures and becomes uniform liquid in mixing, and constantly monitors reaction in reaction with TLC.It obtains after reaction
Mixture directly carry out silica gel column chromatography separation, obtain furans IIIc3 be yellow oil, yield 72%.
Claims (3)
1. the method that alkali-free, condition of no solvent prepare furane derivative by Feist-B é nary reactions, it is characterised in that:In nothing
Under alkali and condition of no solvent, β-shown in α-halogenatedketone and general formula (IIa) or (IIb) shown in general formula (Ia), (Ib) or (Ic)
Dicarbonyl compound, which reacts, respectively obtains polysubstituted furan compounds shown in general formula (IIIa), (IIIb) or (IIIc),
Its chemical equation (A), (B) and (C) is as follows:
Wherein, the R1For H or phenyl;R2For H, methyl or phenyl;R3For C1-C2Alkyl;R4For C1-C2Alkyl;R5For C1-C2Alkane
Base;R6For C1-C2Alkyl;R7For C1-C2Alkyl or C1-C2Alkoxy;Or R6With R7Be connected to each other cyclization, composition-(CH2)3-;X is
Bromine or chlorine atom;Its concrete operation step is as follows:Under stiring, the α-halogenatedketone and the beta-dicarbonyl compound are in 0-
120 DEG C of reactions monitor reaction process, the mixture obtained after reaction carries out silica gel column layer until becoming uniform liquid with TLC
Analysis separation, obtains the polysubstituted furan compounds.
2. the method according to claim 1 for preparing furane derivative, wherein the reaction temperature is 0-120 DEG C, reaction
Time is 0.5-100 hours.
3. the method according to claim 1 for preparing furane derivative, wherein the α-halogenatedketone and the beta-dicarbonyl
The molar ratio of both compounds is 1-10: 1.
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