CN108976186A - A method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation - Google Patents

A method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation Download PDF

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CN108976186A
CN108976186A CN201710403643.4A CN201710403643A CN108976186A CN 108976186 A CN108976186 A CN 108976186A CN 201710403643 A CN201710403643 A CN 201710403643A CN 108976186 A CN108976186 A CN 108976186A
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CN108976186B (en
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胡向平
刘振婷
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Dalian Institute of Chemical Physics of CAS
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    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
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    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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Abstract

The present invention provides a kind of method of four substituted furan class compound of preparation based on carbon-hydrogen link activation, belongs to organic synthesis field.The present invention relates to a kind of strategy activated using c h bond, the method that four substituted furan class compounds are synthesized by [3+2] cycloaddition reaction by beta-ketoester and propargyl class compound.The copper catalyst of use is by mantoquita and 1,10- aza-phenanthrenes class ligand in-situ preparation in various polarity and nonpolar solvent.The present invention synthesizes various four substituted furans class compounds in which can be convenient, and yield is up to 94%.The present invention have the characteristics that easy to operate, raw material be easy to get, wide application range of substrates, reactivity it is high.

Description

A method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of four substituted furan class of preparation based on carbon-hydrogen link activation The method of compound.
Background technique
Furans is a kind of critically important five member ring heterocyclic compound, and many furans ring derivatives all have bioactivity and pharmacology Activity is widely used in medicine, pesticide and biochemistry etc..And derivative of the furane derivative as furans, it is not only The structural unit of natural products, important drugs, and be important intermediate [(a) Dean, F.M.Naturally of organic synthesis Occurring Oxygen Ring Compounds, Butterworths, London, 1963, pp.1~28. (b) Donnelly,D.M.X.；Meegan,M.J.In Comprehensive Hetero-cyclic Chemistry,Vol.4, Ed.:Katrizky, A.R., Pergamon Press, New York, 1984, pp.657~712. (c) Landquist, J.K.In Comprehensive Heterocyclic Chemistry,Vol.1,Ed.:Katrizky,A.R.,Pergamon Press, New York, 1984, pp.144~184. (d) Cacchi, S.J.Organomet.Chem.1999,576,42. (e) Lipshutz,B.H.Chem.Rev.1986,86,795.(f)Wong,H.N.C.；Yang,Y.Tetrahedron 1994,50, 9583.(g)Lee,H.-K.,Chan,K.-F.,Hui,C.-W.,Yim,H.-K.,Wu,X.-W.,Wong,H.N.C.Pure Appl.Chem.2005,77,139.(h)Reichstein A.,Vortherms S.,Bannwitz S.,Tentrop J., Prinz H.,Müller K.Journal of Medicinal Chemistry 2012 55(16),7273-7284.(i) Schulte G.,Scheuer J.-P.,Mc Connell J.-O.Helv.Chim.Acta.1980,63:2159-2167.]。
For four substituted furans synthesis there are mainly two types of approach, first is that carrying out annulation by non-ring compound obtains furan It mutters structural unit；Obtain furan derivatives second is that further reacting already present furan nucleus, the substrate being related to mainly have with Under several classes: acetylenic ketone, alkynol, eneyne ketone, eneyne alcohol, connection ketenes, alkynyl epoxides etc. [(a) Melanie S.B.Wills, Rick L.Danheiser J.Am.Chem.Soc.1998,120,9378-9379.(b)Yoshiaki Nishibayashi, Masato Yoshikawa,Youichi Inada,Marilyn Daisy Milton,Masanobu Hidai,Sakae Uemura.Angew.Chem.Int.Ed.,2003,42,2681-2684.(c)Suhre H.M.,Reif M.,Kirsch F.S.Org.Lett.2005,7,3925-3927.(d)Sydnes K.L.,Holmelid B.,Sengee M.,Hanstein M.J.Org.Chem.2009,74,3430-3443.(e)Hu J.,Wei Y.B.,Tong X.F.Org.Lett.2011,13, 3068-3071.(f)Srinivasa Reddy Mothe,Sherman Jun Liang Lauw,Prasath Kothandaraman,Philip Wai Hong Chan.J.Org.Chem.2012,77,6937-6947.(g)Masahiro Yoshida,Shoko Ohno,and Kozo Shishido.Chem.Eur.J.2012,18:1604-1607.(h)Li W.B., Zhang J.L..Chem.Commun.2010,46:8839-8841.(i)Zhang X.B.,Lu Z.,Fu C.L.,Ma S.M.J.Org.Chem.2010,75:2589-2598.(j)Yao T.L.,Zhang X.X., Larock.C.L.J.Am.Chem.Soc.2004,126:11164-11165.(k)Ma S.M.,Yu Z.Q.Angew.Chem.Int.Ed.2002,41,1775-1778.(l)Ma S.M.,Lu L.H.,Zhang J.L.J.Am.Chem.Soc.2004,126,9645-9660.].Above method is usually required using noble metal, price it is higher and It is seriously polluted, thus limit its application, therefore, develop new catalyst system, simply, efficiently to construct four substituted furan classes Compound has a very important significance.
Summary of the invention
The object of the present invention is to provide the beta-ketoesters and propargyl class chemical combination of a kind of copper catalysis based on carbon-hydrogen link activation The method that object prepares four substituted furan class compounds by [3+2] cycloaddition reaction.The present invention is easy to get with raw material, operation letter Singly, the features such as reaction condition is easily realized, reactivity is high.
The present invention provides a kind of methods of four substituted furan class compound of preparation based on carbon-hydrogen link activation, are aoxidizing In the presence of agent, copper catalyst is catalyzed beta-keto acid ester type compound and propargyl class compound in reaction medium and passes through [3+2] Cycloaddition reaction prepares four substituted furan class compounds.
Specific steps are as follows:
(1) preparation of copper catalyst: under nitrogen protection, by mantoquita and 1,10- phenanthroline class ligand 1:0.1 in molar ratio ~10 stir 0.5~2 hour obtained copper catalyst in reaction medium；
The preparation of (2) four substituted furan class compounds: by beta-keto acid ester type compound and propargyl class compound and oxidation Agent is dissolved in reaction medium, is then added to the solution under nitrogen protection in the solution of the above-mentioned copper catalyst being stirred, Return stirring reacts 1~24 hour, and acid is then added or alkali continues 0.5~8h of back flow reaction；End of reaction is concentrated under reduced pressure into base This is solvent-free, and silica gel column chromatography separation is concentrated under reduced pressure, and vacuum drying obtains target product；
The molar ratio of the copper catalyst and beta-keto acid ester type compound is 0.01~100%:1；
The molar ratio of the alkali additive and beta-keto acid ester type compound is 0.5~10:1；
The molar ratio of the oxidant and beta-keto acid ester type compound is 0~10:1；
The molar ratio of the beta-keto acid ester type compound and propargyl class compound is 1:1~4.
The reaction medium is methanol, ethyl alcohol, toluene, benzene, dimethylbenzene, methylene chloride, 1,2- dichloroethanes, ether, four In at least one of hydrogen furans, dimethyl sulfoxide or n,N-Dimethylformamide, preferably methanol, ethyl alcohol or tetrahydrofuran It is at least one.
The four substituted furans class compound has a structure that
In formula: in formula: R1, R2, R3For the alkyl of C1-C40, the naphthenic base of C3-C12, the C3-C12 cycloalkanes with substituent group Base, phenyl, substituted-phenyl, benzyl, substituted benzyl, containing one or two or more oxygen, sulphur, five yuan of nitrogen-atoms or hexa-member heterocycle virtue One or more of perfume base group or ester group；On the substituent group and benzyl on substituent group, phenyl in C3-C12 naphthenic base Substituent group be one or more of C1-C40 alkyl, the alkoxy of C1-C40, halogen, nitro, ester group or cyano.
The beta-keto acid ester type compound has a structure that
In formula: R1, R2For with R in above structure Formulas I1, R2Identical group.
The propargyl class compound has a structure that
In formula: R3For with R in above structure Formulas I3Identical group.
The mantoquita is Cu (OAc)2·H2O、CuSO4·H2O、Cu(OAc)2、CuSO4、Cu(OTf)2、CuCl2、CuOAc、 CuCl、CuBr、CuI、CuClO4、CuOTf·0.5C6H6、Cu(CH3CN)4BF4Or Cu (CH3CN)4ClO4.It is preferred that CuBr2、 CuCl2, at least one of CuBr, CuI.
The structural formula of the 1,10- phenanthroline class ligand are as follows:
In formula: R4, R5For H, alkyl, the naphthenic base in C3~C8, phenyl and substituted-phenyl or benzyl in C1~C10 and Substituted benzyl；Substituent group on substituted-phenyl or substituted benzyl be C1~C40 alkyl, the alkoxy of C1~C40, halogen, nitro, One or more of ester group or cyano.
The alkali additive is various inorganic bases or organic base, preferably DBU.
The catalytic reaction condition is preferred are as follows:
Temperature: 80 DEG C；
Reaction medium: ethyl alcohol；
Pressure: normal pressure；
Time: 24 hours.
The molar ratio of the copper catalyst and beta-keto acid ester type compound is preferably 1-10%:1；
The molar ratio of the alkali additive and beta-keto acid ester type compound is preferably 1.2:1；
The molar ratio of the oxidant and beta-keto acid ester type compound is preferably 1.2:1；
The molar ratio of the beta-keto acid ester type compound and propargyl class compound is preferably 1:2.2.
Reaction equation of the invention are as follows:
The invention has the following advantages that
1, starting material is cheap and easy to get.
2, catalyst is cheap and easy to get, and dosage is few.
3, reactivity is good, and reaction condition is easily realized.
4, it is compared with the traditional method compared with this method can more easily synthesize four substituted furan class compounds.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 prepared by embodiment 1；
Fig. 2 is the carbon-13 nmr spectra of 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 prepared by embodiment 1；
Fig. 3 is the nuclear-magnetism of 2- (3- chlorphenyl) -5- methyl 4-phenyl furans -3- carboxylic acid, ethyl ester I -2 prepared by embodiment 12 Resonate hydrogen spectrum；
Fig. 4 is the nuclear-magnetism of 2- (3- chlorphenyl) -5- methyl 4-phenyl furans -3- carboxylic acid, ethyl ester I -2 prepared by embodiment 12 Resonate carbon spectrum；
Fig. 5 is the core of 2- (4- aminomethyl phenyl) -5- methyl 4-phenyl furans -3- carboxylic acid, ethyl ester I -3 prepared by embodiment 13 Magnetic resonance hydrogen spectrum；
Fig. 6 is the core of 2- (4- aminomethyl phenyl) -5- methyl 4-phenyl furans -3- carboxylic acid, ethyl ester I -3 prepared by embodiment 13 Magnetic resonance carbon spectrum；
Fig. 7 is the nuclear magnetic resonance spectroscopy of 5- methyl -2,4- diphenyl furans -3- carboxylate methyl ester I -4 prepared by embodiment 14；
Fig. 8 is the carbon-13 nmr spectra of 5- methyl -2,4- diphenyl furans -3- carboxylate methyl ester I -4 prepared by embodiment 14；
Fig. 9 is the nuclear-magnetism of 4- (3- fluorophenyl) -5- methyl -2- benzofurane -3- carboxylic acid, ethyl ester I -5 prepared by embodiment 15 Resonate hydrogen spectrum；
Figure 10 is the core of 4- (3- fluorophenyl) -5- methyl -2- benzofurane -3- carboxylic acid, ethyl ester I -5 prepared by embodiment 15 Magnetic resonance carbon spectrum；
Figure 11 is the core of 4- (4- fluorophenyl) -5- methyl -2- benzofurane -3- carboxylic acid, ethyl ester I -6 prepared by embodiment 16 Magnetic resonance hydrogen spectrum；
Figure 12 is the core of 4- (4- fluorophenyl) -5- methyl -2- benzofurane -3- carboxylic acid, ethyl ester I -6 prepared by embodiment 16 Magnetic resonance carbon spectrum；
Specific embodiment
The following examples will be further described the present invention, but not thereby limiting the invention.Nuclear-magnetism is total Vibration is by Bruker nmr determination.
Embodiment 1
Cu(OTf)2It is reacted with L-1 complexing as catalyst, generates four methyl -2 substituted furan class addition product 5-, 4- diphenyl furans -3- carboxylic acid, ethyl ester I -1.
Metal precursor Cu (OTf) is added in reaction flask2(0.01mmol, a 5mol%) and water phenanthroline ligand L-1 (0.011mmol, 5.5mol%) 1.0mL anhydrous methylene chloride is added under nitrogen protection, is stirred at room temperature 1 hour.Then by phenylpropyl alcohol Alkynes III -1 (0.44mmol, 2.2equiv), ethyl benzoylacetate II -1 (0.2mmol, 1.0equiv), Et3N (0.24mmol, 1.2equiv) and Ag2CO3(0.24mmol, 1.2equiv) is dissolved in 2.0mL anhydrous methylene chloride, then should Solution is added under nitrogen protection in the solution of the above-mentioned catalyst being stirred, and 40 DEG C are stirred to react for 24 hours；Then DBU is added (0.24mmol, 1.2equiv) is continued at 40 DEG C and is heated to reflux, TLC monitoring reaction.End of reaction is concentrated under reduced pressure into basic Solvent-free, silica gel column chromatography separation is concentrated under reduced pressure, is dried in vacuo give light yellow oil I -1,73% yield.
Nuclear magnetic resonance spectroscopy and the carbon-13 nmr spectra difference of product I -1 are as shown in Figure 1 and Figure 2:1H NMR(400MHz, CDCl3) δ 7.85-7.82 (m, 2H), 7.43-7.29 (m, 8H), 4.09 (q, J=7.1Hz, 2H), 2.32 (s, 3H), 0.97 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ164.7,154.0,148.5,133.0,130.1,129.6,128.8, 128.2,128.0,127.6,127.0,123.0,114.8,60.5,13.7,12.1.
The structural formula of II -1, III -1, I -1, L-1 are as follows:
Embodiment 2
L-2 generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 as ligand reaction.
Ligand L -1 in embodiment 1 ligand L -2 is replaced, remaining is the same as embodiment 1.Reaction obtains chemical compounds I -1, 41% yield.
The structural formula of L-2 is as follows:
Embodiment 3
L-3 generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 as ligand reaction.
Ligand L -1 in embodiment 1 ligand L -3 is replaced, remaining is the same as embodiment 1.Reaction obtains chemical compounds I -1, 64% yield.
The structural formula of L-3 is as follows:
Embodiment 4
L-4 generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 as ligand reaction.
Ligand L -1 in embodiment 1 ligand L -4 is replaced, remaining is the same as embodiment 1.Reaction obtains chemical compounds I -1, 42% yield.
Embodiment 5
L-5 generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 as ligand reaction.
Ligand L -1 in embodiment 1 ligand L -5 is replaced, remaining is the same as embodiment 1.Reaction obtains chemical compounds I -1, 74% yield.
Embodiment 6
Cu(OAc)2·H2O and L-1 catalysis reaction generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1.
By Cu (OTf) in embodiment 12With Cu (OAc)2·H2O is replaced, remaining is the same as embodiment 1.Reaction obtains chemical compounds I- 1,64% yield.
Embodiment 7
CuI and L-1 catalysis reaction generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1.
By the Cu (OTf) in embodiment 12It is replaced with CuI, remaining obtains chemical compounds I -1,88% yield with embodiment 1.
Embodiment 8
Toluene generates 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 as solvent reaction.
Dichloromethane solvent in embodiment 1 is replaced with into toluene, Cu (OTf)2It is replaced with CuI, reaction temperature 110 DEG C, remaining obtains chemical compounds I -1,54% yield with embodiment 1.
Embodiment 9
Ethyl alcohol generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1 as solvent reaction.
Dichloromethane solvent in embodiment 1 is replaced with into alcohol solvent, Cu (OTf)2It is replaced with CuI, reaction temperature is 80 DEG C, remaining obtains chemical compounds I -1,91% yield with embodiment 1.
Embodiment 10
N, N- diisopropylethylamine generate product 5- methyl -2,4- diphenyl furans -3- carboxylic acid as alkali additive reaction Ethyl ester I -1.
Dichloromethane solvent in embodiment 1 is replaced with into alcohol solvent, Cu (OTf)2It is replaced with CuI, reaction temperature is 80 DEG C, n,N-diisopropylethylamine obtains chemical compounds I -1,93% yield as alkali additive.
Embodiment 11
Alkali-free additive reaction generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid, ethyl ester I -1.
Dichloromethane solvent in embodiment 1 is replaced with into alcohol solvent, Cu (OTf)2It is replaced with CuI, reaction temperature is 80 DEG C, alkali-free additive obtains chemical compounds I -1,93% yield.
Embodiment 12
M-chloro ethyl benzoylacetate II -2 generates product 2- (3- chlorphenyl) -5- methyl -4- benzene as substrate reactions Base furans -3- carboxylic acid, ethyl ester I -2
Ethyl benzoylacetate II -1 in embodiment 11 is replaced with II -2, remaining obtains chemical combination with embodiment 11 Object I -2,91% yield.
Nuclear magnetic resonance spectroscopy and the carbon-13 nmr spectra difference of product I -2 are as shown in Figure 3, Figure 4:
1H NMR(400MHz,CDCl3)δ7.86–7.85(m,1H),7.77–7.74(m,1H),7.41–7.24(m,8H), 4.11 (q, J=7.1Hz, 2H), 2.32 (s, 3H), 1.00 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ 164.4,152.2,149.0,134.2,132.7,131.7,129.6,129.5,128.7,128.1,127.5,127.2, 125.6,123.3,115.7,60.7,13.6,12.1.
II -2, I -2 structural formula is as follows:
Embodiment 13
Product 2- (4- aminomethyl phenyl) -5- methyl-is generated as substrate reactions to toluyl ethyl II -3 4- benzofurane -3- carboxylic acid, ethyl ester I -3
Ethyl benzoylacetate II -1 in embodiment 11 is replaced with II -3, remaining obtains chemical combination with embodiment 11 Object I -3,94% yield.
Nuclear magnetic resonance spectroscopy and the carbon-13 nmr spectra difference of product I -3 are as shown in Figure 5, Figure 6:
1H NMR(400MHz,CDCl3)δ7.74–7.72(m,2H),7.40–7.36(m,2H),7.3–7.28(m,3H), 7.23-7.21 (m, 2H), 4.08 (q, J=7.1Hz, 2H), 2.38 (s, 3H), 2.31 (s, 3H), 0.98 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ164.7,154.4,148.1,138.8,133.2,129.6,128.9,128.0, 127.6,127.4,127.0,122.9,114.3,60.4,21.4,13.7,12.1.
II -3, I -3 structural formula is as follows:
Embodiment 14
Methyl benzoylacetate II -4 generates product 5- methyl -2,4- diphenyl furans -3- carboxylic acid first as substrate reactions Ester I -4
Ethyl benzoylacetate II -1 in embodiment 11 is replaced with II -4, remaining obtains chemical combination with embodiment 11 Object I -4,91% yield.
Nuclear magnetic resonance spectroscopy and the carbon-13 nmr spectra difference of product I -4 are as shown in Figure 7, Figure 8:1H NMR(400MHz, CDCl3)δ7.73-7.71(m,2H),7.34-7.28(m,5H),7.25-7.21(m,3H),3.52(s,3H),2.25(s,3H) ；13C NMR(101MHz,CDCl3)δ165.2,154.1,148.6,132.9,130.1,129.5,128.8,128.3,128.1, 127.6,127.1,122.9,114.5,51.5,12.1.
II -4, I -4 structural formula is as follows:
Embodiment 15
3- fluorobenzene propine III -2 generates product 4- (3- fluorophenyl) -5- methyl -2- benzofurane -3- carboxylic as substrate reactions Acetoacetic ester I -5
Phenyl-allylene III -1 in embodiment 11 is replaced with III -2, remaining obtains chemical compounds I -5,94% with embodiment 11 Yield.
Nuclear magnetic resonance spectroscopy and the carbon-13 nmr spectra difference of product I -5 are as shown in Figure 9, Figure 10:1H NMR(400MHz, CDCl3) δ 7.85-7.82 (m, 2H), 7.44-7.32 (m, 4H), 7.09-7.00 (m, 3H), 4.11 (q, J=7.1Hz, 2H), 2.32 (s, 3H), 1.01 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3) δ 164.3,162.5 (d, J= 245.2Hz), 154.4,148.7,135.3 (d, J=8.4Hz), 129.9,129.4 (d, J=8.5Hz), 129.0,128.2, 127.7,125.4 (d, J=2.8Hz), 122.0,116.7 (d, J=21.7Hz), 114.5,113.9 (d, J=21.0Hz), 60.6,13.6,12.1.
III -2, I -5 structural formula is as follows:
Embodiment 16
4- fluorobenzene propine III -3 generates product 4- (4- fluorophenyl) -5- methyl -2- benzofurane -3- carboxylic as substrate reactions Acetoacetic ester I -6
Phenyl-allylene III -1 in embodiment 11 is replaced with III -3, remaining obtains chemical compounds I -6,96% with embodiment 11 Yield.
The nuclear magnetic resonance spectroscopy and carbon-13 nmr spectra of product I -6 are respectively as shown in Figure 11, Figure 12:1H NMR(400MHz, CDCl3)δ7.83–7.81(m,2H),7.44–7.36(m,3H),7.29–7.24(m,3H),7.10–7.06(m,2H),4.10 (q, J=7.2Hz, 2H), 2.29 (s, 3H), 1.01 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ164.4, 162.0 (d, J=246.0Hz), 154.4,148.6,131.3 (d, J=8.0Hz), 130.0,129.0 (d, J=3.4Hz), (129.0,128.2,127.8,122.0,114.9 d, J=21.4Hz), 114.6,60.5,13.7,12.0.
III -3, I -6 structural formula is as follows:
Embodiment 17-34
Reaction substrate applicability
The present invention has extensive substrate applicability, and according to the reaction condition in embodiment 11, many substrates can participate in this Reaction, obtains four substituted furan class compounds in high yield, is shown in Table 1:
Table 1
Embodiment R1 R2 R3 Yield (%)
11 Ph Et Ph 93
17 2-ClC6H4 Et Ph 53
18 4-ClC6H4 Et Ph 90
19 4-FC6H4 Et Ph 89
20 4-BrC6H4 Et Ph 82
21 4-MeO C6H4 Et Ph 88
22 2-naphthyl Et Ph 89
23 2-thienyl Et Ph 94
24 Me Et Ph 92
25 iPr Et Ph 81
26 Ph Et 2-FC6H4 86
27 Ph Et 4-ClC6H4 34
28 Ph Et 4-BrC6H4 49
29 Ph Et 4-MeC6H4 55
30 Ph Et 4-MeOC6H4 72
31 Ph Et 4-CF3C6H4 53
32 Ph Et 2-naphthyl 42
33 Ph Et 2-thienyl 40
34 Ph Et PhCH2CH2 60

Claims (12)

1. a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation, it is characterised in that: urged in metallic copper In the presence of agent, oxidant and alkali additive, propargyl class compound is reacted with beta-keto acid ester type compound, in reaction medium Middle back flow reaction 1-24h, acid or alkali, which is then added, makes it be converted into four substituted furan class compounds.
2. a kind of method of four substituted furan class compound of preparation based on carbon-hydrogen link activation described in accordance with the claim 1, Be characterized in that: specific step is as follows for this method:
(1) preparation of copper catalyst: under nitrogen protection, by mantoquita and 1,10- aza-phenanthrenes class ligand exists 1:0.1~10 in molar ratio 0.5-2 hours obtained copper catalysts are stirred in reaction medium；
The preparation of (2) four substituted furan class compounds: by propargyl class compound, beta-keto acid ester type compound, oxidant and alkali Additive is dissolved in reaction medium, then which is added to the solution of the above-mentioned copper catalyst being stirred under nitrogen protection In, temperature is 0~120 DEG C, back flow reaction 1-24 hours；It is subsequently added into acid or alkali continues return stirring 0.5-8h；End of reaction, It is concentrated under reduced pressure into substantially solvent-free, silica gel column chromatography separation, reduced pressure, vacuum drying obtains target product；
The molar ratio of the copper catalyst and beta-keto acid ester type compound is 0.01~100%:1；
The molar ratio of the alkali additive and beta-keto acid ester type compound is 0~10:1；
The molar ratio of the oxidant and beta-keto acid ester type compound is 0~10:1；
The molar ratio of the beta-keto acid ester type compound and propargyl class compound is 1:1~4.
3. according to a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation as claimed in claim 1 or 2, It is characterized by: the reaction medium is methanol, ethyl alcohol, toluene, benzene, dimethylbenzene, methylene chloride, dichloroethanes, ether, tetrahydro At least one of furans, dimethyl sulfoxide or N,N-dimethylformamide.
4. according to a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation as claimed in claim 1 or 2, It is characterized by: its general structure of the four substituted furans class compound are as follows:
In formula: R1, R2, R3For the alkyl of C1-C40, the naphthenic base of C3-C12, the C3-C12 naphthenic base with substituent group, phenyl, Substituted-phenyl, benzyl, substituted benzyl, containing one or two or more oxygen, sulphur, five yuan of nitrogen-atoms or hexa-member heterocycle aromatic group or One or more of ester group；The substituent group on the substituent group and benzyl on substituent group, phenyl in C3-C12 naphthenic base For one or more of C1-C40 alkyl, the alkoxy of C1-C40, halogen, nitro, ester group or cyano.
5. according to a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation as claimed in claim 1 or 2, It is characterized by: the beta-ketoester has a structure that
In formula: R1, R2For the alkyl of C1-C40, the naphthenic base of C3-C12, the C3-C12 naphthenic base with substituent group, phenyl, substitution Phenyl, benzyl, substituted benzyl, containing one or two or more oxygen, sulphur, five yuan of nitrogen-atoms or hexa-member heterocycle aromatic group or ester group One or more of；The substituent group on the substituent group and benzyl on substituent group, phenyl in C3-C12 naphthenic base is C1- One or more of C40 alkyl, the alkoxy of C1-C40, halogen, nitro, ester group or cyano.
6. according to a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation as claimed in claim 1 or 2, It is characterized by: the propargyl class compound has a structure that
In formula: R3For the alkyl of C1-C40, the naphthenic base of C3-C12, the C3-C12 naphthenic base with substituent group, phenyl, substituted benzene Base, benzyl, substituted benzyl, containing in one or two or more oxygen, sulphur, five yuan of nitrogen-atoms or hexa-member heterocycle aromatic group or ester group One or more；The substituent group on the substituent group and benzyl on substituent group, phenyl in C3-C12 naphthenic base is C1- One or more of C40 alkyl, the alkoxy of C1-C40, halogen, nitro, ester group or cyano.
7. special according to a kind of method of four substituted furan class compound of preparation based on carbon-hydrogen link activation described in claim 2 Sign is: the mantoquita is Cu (OAc)2·H2O、CuSO4·H2O、Cu(OAc)2、CuSO4、Cu(OTf)2、CuCl2、CuBr2、 CuOAc、CuCl、CuBr、CuI、CuClO4、CuOTf·0.5C6H6、Cu(CH3CN)4BF4、Cu(CH3CN)4ClO4In at least one Kind.
8. special according to a kind of method of four substituted furan class compound of preparation based on carbon-hydrogen link activation described in claim 2 Sign is: the structural formula of the 1,10- aza-phenanthrenes class ligand are as follows:
In formula: R4, R5Alkyl, the naphthenic base in C3~C8, phenyl and substituted-phenyl or benzyl and substitution for H, in C1~C10 Benzyl；Substituent group on substituted-phenyl or substituted benzyl is C1~C40 alkyl, the alkoxy of C1~C40, halogen, nitro, ester One or more of base or cyano.
9. according to a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation as claimed in claim 1 or 2, It is characterized by: the oxidant is BQ, 2,6-DMBQ, 2,5-DMBQ, Ag2CO3、Ag2SO4、AgOAc、Ag2O、AgNO3、MnO2 Or at least one of TBHP.
10. according to a kind of method of the four substituted furan class compound of preparation based on carbon-hydrogen link activation as claimed in claim 1 or 2, It is characterized by: the alkali additive is various inorganic bases and organic base, preferably DBU；.
11. synthetic method according to claim 1 or 2, it is characterised in that: the catalytic reaction condition are as follows:
Temperature: 80 DEG C；
Reaction medium: ethyl alcohol；
Time: 24 hours.
12. according to a kind of method of four substituted furan class compound of preparation based on carbon-hydrogen link activation described in claim 2, It is characterized in that this method optimum condition is as follows:
The molar ratio of the copper catalyst and beta-keto acid ester type compound is 1~10%:1；
The molar ratio of the oxidant and beta-keto acid ester type compound is 1.2:1；
The molar ratio of the alkali additive and beta-keto acid ester type compound is 1.2:1
The molar ratio of the beta-keto acid ester type compound and propargyl class compound is 1:2.2.
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