CN108976241B - Synthesis method of chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound - Google Patents
Synthesis method of chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound Download PDFInfo
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Abstract
The invention relates to a synthetic method of a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound. The chiral copper catalyst adopted by the method is generated in situ by copper salt and chiral P, N, N-tridentate ligand in various polar and nonpolar solvents. The invention can conveniently synthesize various chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compounds with substituent groups, and the enantiomeric excess percentage of the compounds is up to 96%. The method has the characteristics of simple operation, easily obtained raw materials, wide application range of the substrate, high enantioselectivity and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound.
Background
The pyranopyrazole heterocyclic compound is an important structural unit in the nitrogen-containing heterocyclic compound, and has various biological activities and pharmacological activities, such as anticancer, anti-inflammatory, analgesic, antibacterial, insecticidal and the like; in addition, the protein also has oncomelania killing activity and is a potential human Chk1 enzyme inhibitor. Therefore, the synthesis of the compounds has been receiving wide attention from researchers, and is one of the hot spots in the field of organic synthesis [ (a).
Chem.Rev.2006,106,17–89.(b)N.Foloppe,L.M.Fisher,R.Howes,A.Potter,A.G.S.Robertson,A.E.Surgenor,Bioorg.Med.Chem.2006,14,4792–4802.(c)J.L.Wang,D.X.Liu,Z.J.Zhang,S.M.Shan,X.B.Han,S.M.Srinivasula,C.M.Croce,E.S.Alnemri,Z.W.Huang,Proc.Natl.Acad.Sci.U.S.A.2000,97,7124–7129.(d)S.C.Kuo,L.J.Huang,H.Nakamura,J.Med.Chem.1984,27,539–544.(e)S.R.Mandha,S.Siliveri,M.Alla,V.R.Bommena,M.R.Bommineni,S.Balasubramanian,Bioorg.Med.Chem.Lett.2012,22,5272–5278.(f)M.E.A.Zaki,H.A.Soliman,O.A.Hiekal,A.E.Rashad,Z.Naturforsch C2006,61,1–5.(g)X.T.Huang,Z.P.Li,D.Y.Wang,Y.Q.Li,Chinese Journal of Catalysis 2016,37,1461–1468.(h)Abdelrazek,F.M.；Metz,P.；Metwally,N.H.；El-Mahrouky,S.F.Arch.Pharm.2006,339,456.]. Such compounds are synthesized primarily by "one-pot" Multicomponent Reactions, with two common reaction pathways: 1) three-component reactions (3CRs) using carbonyl compounds, malononitrile and the corresponding 5-pyrazolones are commonly used as catalysts such as triethylamine, triethanolamine, piperidine, N-methylmorpholine, D, L-proline, bovine serum albumin [ (a) A.M.Shostopalov, Y.M.Emeliyanova, A.A.Shostopalov, L.A.Rodinovskaya, Z.I.Niazimbetova, D.H.Evans, Tetrahedron 2003,59, 7491-Strobenzin 7496 (b) R.Gr.Redkin, L.A.Shemchuk, V.P.Chernykh, O.V.Shishkin, S.V.Shekia, Tetrahedron 2007,63, 11444-Strobenzin 11450 (c) H.G.Kathroya, R.V.Shishkin, S.V.S.S.S.S.S.S.Sohrub.201.P.P.J.S.2,77,983–991.(d)F.Lehmann,M.Holm,S.Laufer,J.Comb.Chem.2008,10,364–367.(e)S.B.Guo,S.X.Wang,J.T.Li,Synth.Commun.2007,37,2111–2120.(f)K.Eskandari,B.Karami,S.Khodabakhshi,Catal.Commun.2014,54,124–130.(g)A.M.Shestopalov,Y.M.Emeliyanova,A.A.Shestopalov,L.A.Rodinovskaya,Z.I.Niazimbetova,D.H.Evans,Org.Lett.2002,4,423–425.](ii) a 2) The four-component reaction (4CRs) is carried out by using aldehyde, malononitrile, hydrazine hydrate and ethyl acetoacetate, and the commonly used catalysts comprise triethylamine, macroporous resin A21, hexadecyltrimethylammonium chloride, molecular sieve and magnetic Fe3O4Nanoparticles, SnO2Quantum dots, L-proline, glycine, etc., (a) Y.M.Litvinov, A.A.Shestopalov, L.A.Rodinovskaya, A.M.Shestopalov, J.Comb.Chem.2009,11, 914-919 (b) M.Bihani, P.P.Bora, G.Bez, H.Askari, ACS Sustain.Chem.Eng.2013,1, 440-conk. C) M.S.Wu, Q.Q.Feng, D.H.Wan, J.Y.Ma, Synth.Comun.2013, 43, 1721-1726-d. J.B.Gujar, M.A.Chaudi, D.S.Kawai, M.S.Shiaree, Teng.Shi, Ten-Shi, Ten.H.S.70, K.Shih.Shih.S.70, K.Shih.J.H.J.J.M.J.M.H.J.M.J.J.M.J.J.M.J.J.M.J.J.J.H.J.J.J.J.J.J.J.J.H.J.J.J.70, J.70, J.H.H.H.S.70, D.J.D.H.H.H.70, D.D.D.S.H.H.70, D.S.S.J.S.J.H.D.D.H.H.H.J.J.H.70, D.70, D.S.S.70, D.D.D.D.D.D.D.D.S.S.D.D.H.S.H.H.H.H.70, K.70, D.70, D.D.D.D.D.D.D.D.D.H.D.H.H.H.D.H.S.S.J.H.S.D.D.H.D.H.70, D.D.S.H.H.H.H.H.H.D.D.D.J.S.S.J.S.H.H.J.J.J.J.S.H.H.H.H.S.S.S.S.S.H.70, D.S.70, D.H.H.70, D.S.H.S.S.70, K.D.70, D.H.70, D.70, K.70, K.D.D.D.D.D.D.J.D.D.70, K.S.S.70, K.S.S.S.S.S.S.S.S.S.S.S.S.70, D.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.70, D.S.S.S.S.S.S.S.S.S.S.S.S.H.H.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.H.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S..]. Recently, a method for preparing pyrazolopyrans using a Suzuki coupling reaction with 4-bromobenzaldehyde and phenylboronic acid followed by five-component (5CRs) reaction with malononitrile, hydrazine hydrate and ethyl acetoacetate [ Z.X.Lu, J.L.Xiao, D.Y.Wang, Y.Q.Li, Asian J.org.Chem.2015,4, 487-one 492 ] has also been reported.]. However, the method is accompanied with the defects of harsh reaction conditions, expensive part of raw materials, large catalyst dosage, long reaction time, low reaction yield and the like, and more importantly, the pyrazolopyran compounds prepared by the method have no optical activity. Therefore, a new asymmetric catalytic process was developed to simply and efficiently construct chiral 1, 4-dihydropyrano [2,3-c ]]The pyrazole compounds are very importantThe significance of (1).
Disclosure of Invention
The invention aims to provide a method for synthesizing a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound, which is a method for synthesizing the chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound by carrying out asymmetric [3+3] cycloaddition reaction on a copper-catalyzed 5-hydroxypyrazole compound and a propargyl compound. The method has the characteristics of easily obtained raw materials, simple operation, mild reaction conditions, high enantioselectivity and the like.
The invention provides a synthesis method of a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound, which is characterized in that a chiral copper catalyst is used for catalyzing a 5-hydroxypyrazole compound and a propargyl compound to synthesize the chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound through an asymmetric [3+3] cycloaddition reaction.
The method comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and P, N, N-ligand are stirred in a reaction medium for 1-2 hours according to the molar ratio of 1: 0.1-10 to prepare a chiral copper catalyst;
(2) preparation of 1, 4-dihydropyrano [2,3-c ] pyrazole compounds: dissolving a propargyl compound, a 5-hydroxypyrazole compound and an alkali additive in a reaction medium, adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, and stirring and reacting for 24 hours at 10 ℃; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;
the molar ratio of the chiral copper catalyst to the propargyl compound is 0.01-100% to 1,
the molar ratio of the alkali additive to the propargyl compound is 0.5-10: 1;
the molar ratio of the 5-hydroxypyrazole compound to the propargyl compound is 1: 1-2.
The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1, 2-dichloroethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide, and preferably at least one of methanol, ethanol or tetrahydrofuran.
The chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound has one of the following structures:
i and II are enantiomers of each other, wherein: r1，R2，R3Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group containing one or more than two oxygen, sulfur and nitrogen atoms and ester group; the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.
The 5-hydroxypyrazole compound has the following structure:
in the formula: r1，R2Is represented by formula I, II1，R2The same groups.
The propargyl compound has the following structure:
in the formula: r3Is represented by formula I, II3The same group; x is one or more than two of fluorine, chlorine, bromine, iodine, C1-C10 alkyl carboxylic ester, C1-C10 alkyl carbonate, C1-C10 alkyl sulfonate, C1-C10 alkyl phosphate, phenyl carboxylic ester and substituted phenyl carboxylic ester, phenyl carbonate and substituted phenyl carbonate, phenyl sulfonate and substituted phenyl sulfonate or phenyl phosphate and substituted phenyl phosphate; substituents on substituted phenylIs one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent groups is 1-5.
Said copper salt is a divalent copper salt such as Cu (OAc)2·H2O、CuSO4·H2O、Cu(OAc)2、CuSO4、Cu(OTf)2、CuCl2And various monovalent copper salts such as CuOAc, CuCl, CuI, CuClO4、CuOTf·0.5C6H6、Cu(CH3CN)4BF4Or Cu (CH)3CN)4ClO4Preferably Cu (OAc)2·H2O、Cu(CH3CN)4BF4、Cu(OTf)2。
The chiral P, N, N-ligand has the following structural characteristics:
in the formula: r3，R4H, alkyl in C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R5，R6is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl, nitro;
R7is C1-C40 alkyl, C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, and contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
The alkaline additive is various inorganic bases or organic bases; preferably K2CO3、Cs2CO3Or K3PO4。
The catalytic reaction conditions are preferably as follows:
temperature: 10 ℃;
reaction medium: methanol;
pressure: normal pressure;
time: for 24 hours.
The mol ratio of the chiral copper catalyst to the propargyl compound is preferably 1-10% to 1,
the molar ratio of the alkali additive to the propargyl compound is preferably 1: 1;
the molar ratio of the 5-hydroxypyrazole compound to the propargyl compound is preferably 1: 1.2.
The reaction equation of the invention is as follows:
the invention has the following advantages:
1. high reaction activity, good stereoselectivity and mild reaction conditions.
2. The starting materials are cheap and easy to obtain.
3. The chiral ligand is simple and convenient to synthesize, the catalyst is cheap and easy to obtain, and the dosage is small.
4. Compared with the traditional method, the method can conveniently synthesize various substituted 1, 4-dihydropyrano [2,3-c ] pyrazole compounds.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 1,3, 4-triphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-1 prepared in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 1,3, 4-triphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-1 prepared in example 1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of 3- (4-methoxyphenyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazolII-2 prepared in example 11;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of 3- (4-methoxyphenyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole prepared in example 11;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of 3- (2-naphthyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-3 prepared in example 12;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of 3- (2-naphthyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazolII-3 prepared in example 12;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of 3, 4-diphenyl-1- (4-methylphenyl) -1, 4-dihydropyrano [2,3-c ] pyrazolII-4 prepared in example 13;
FIG. 8 is a NMR carbon spectrum of 3, 4-diphenyl-1- (4-methylphenyl) -1, 4-dihydropyrano [2,3-c ] pyrazolII-4 prepared in example 13;
FIG. 9 is a NMR spectrum of 4- (3-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-5 prepared in example 15;
FIG. 10 is a carbon nuclear magnetic resonance spectrum of 4- (3-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-5 prepared in example 15;
FIG. 11 is a NMR spectrum of 4- (4-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-6 prepared in example 16;
FIG. 12 is a carbon nuclear magnetic resonance spectrum of 4- (4-chlorophenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-6 prepared in example 16;
Detailed Description
The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent1100 series HPLC.
Example 1
Cu(OAc)2·H2The complexation of O and L-1-1 is used as a catalyst to catalyze the reaction to generate 1, 4-dihydropyrano [2,3-c ]]Pyrazole cycloaddition product 1,3, 4-triphenyl-1, 4-dihydropyrano [2,3-c]Pyrazole II-1.
The metal precursor Cu (OAc) was added to the reaction flask2·H2O (0.015mmol, 5 mol%) and chiral ligand L-1-1(0.0165mmol, 5.5 mol%), adding under nitrogen protection1.0mL of anhydrous methanol was added thereto, and the mixture was stirred at room temperature for 1 hour. Then the reaction tube was moved to a 10 ℃ constant temperature reaction freezer, and propargyl alcohol ester IV-1 (0.36mmol, 1.2equiv), 5-hydroxypyrazole-based compound III-1 (0.3mmol, 1.0equiv) and Cs were added2CO3(0.36mmol, 1.2equiv) was dissolved in 2.0mL of anhydrous methanol, and the solution was added to the stirred catalyst solution under nitrogen protection, and the reaction was stirred at 10 ℃ for 24 h. After the reaction, the mixture was concentrated under reduced pressure until the mixture was substantially free of solvent, separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to obtain a reddish brown oily substance with 87% yield and 94% ee. The hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance of the product II-1 are shown in the figures 1 and 2:
1H NMR(400MHz,DMSO)δ7.87–7.84(m,2H),7.62–7.55(m,4H),7.41–7.37(m,1H),7.29–7.21(m,7H),7.16–7.10(m,1H),6.87(dd,J＝6.0,1.5Hz,1H),5.26(dd,J＝6.0,4.2Hz,1H),5.12(dd,J＝4.1,1.5Hz,1H)；13C NMR(101MHz,DMSO)δ147.5,145.1,138.2,138.0,133.1,129.9,129.0,128.7,128.4,128.1,127.2,127.1,126.9,121.3,108.9,97.6,37.1.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝9.0min,tR(minor)＝17.4min。
the structural formula of III-1, IV-1, II-1, L-1-1 is as follows:
example 2
L-1-2 is used as ligand to react to generate a product II-1
The ligand L-1-1 in example 1 was replaced with the ligand L-1-2, and the base additive wasiPr2NEt, room temperature, the rest of example 1. The reaction gave compound II-1 in 20% yield and 11% ee.
The structural formula of L-1-2 is as follows:
example 3
L-2-1 is used as ligand to react to generate a product II-1
The ligand L-1-1 in example 1 was replaced with ligand L-2-1, and the base additive wasiPr2NEt, room temperature, the rest of example 1. The reaction gave compound II-1 in 69% yield and 83% ee.
The structural formula of L-2-1 is as follows:
example 4
L-3 as ligand reacts to generate a product II-1
The ligand L-1-1 in example 1 was replaced with ligand L-3, and the base additive wasiPr2NEt, room temperature, the rest of example 1. The reaction gave compound II-1 in 57% yield and 42% ee.
Example 5
Cu(OTf)2Catalytically reacting with L-1-1 to produce a product II-1
Cu (OAc) in example 12·H2Cu (OTf) for O2Instead, the base additive isiPr2NEt, room temperature, the rest of example 1. Compound II-1 was obtained in 59% yield and 86% ee.
Example 6
Cu(CH3CN)4BF4Catalytically reacting with L-1-1 to produce a product II-1
Cu (OAc) in example 12·H2Cu (CH) for O3CN)4BF4Instead, the base additive isiPr2NEt, at room temperature, as in example 1 gave compound II-1 in 77% yield and 87% ee.
Example 7
iPr2NEt as base additionAdding agent to react to generate a product II-1
Cs in example 12CO3Is replaced byiPr2NEt, room temperature, the rest of example 1. Compound II-1 was obtained in 66% yield and 90% ee.
Example 8
III-2 is used as a substrate to react to generate a product 3- (4-methoxyphenyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-2
The same procedure used in example 1 except for replacing 5-hydroxypyrazole III-1 with III-2 in example 1 gave compound II-2 in 97% yield and 94% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-2 are shown in FIGS. 3 and 4:1H NMR(400MHz,CDCl3)δ7.89–7.87(m,2H),7.48–7.44(m,4H),7.30–7.21(m,5H),7.19–7.14(m,1H),6.75–6.72(m,2H),6.56(dd,J＝6.0,1.5Hz,1H),5.15(dd,J＝6.0,4.1Hz,1H),4.89(dd,J＝4.0,1.4Hz,1H),3.74(s,3H)；13C NMR(101MHz,CDCl3)δ159.3,148.0,147.4,144.8,138.4,137.3,129.1,128.8,128.3,127.7,126.8,126.2,125.8,121.0,113.6,108.5,96.9,55.2,38.0.HPLC(Chiralcel AS-H,n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):tR(major)＝8.8min,tR(minor)＝13.7min.
the structural formula of III-2 and II-2 is as follows:
example 9
III-3 is used as a substrate to react to generate a product 3- (2-naphthyl) -1, 4-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-3
The same procedure used in example 1 except for substituting 5-hydroxypyrazole III-1 with III-3 in example 1 gave compound II-3 in 96% yield and 95% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-3 are shown in FIGS. 5 and 6:1H NMR(400MHz,CDCl3)δ7.94–7.87(m,3H),7.79–7.71(m,3H),7.58–7.47(m,3H),7.41–7.37(m,2H),7.33–7.22(m,5H),7.18–7.14(m,1H),6.57(dd,J＝6.0,1.4Hz,1H),5.18(dd,J＝6.0,4.1Hz,1H),5.00(dd,J＝3.9,1.3Hz,1H)；13C NMR(101MHz,CDCl3)δ148.0,147.6,145.0,138.4,137.3,133.1,132.9,130.6,129.2,128.9,128.2,127.9,127.8,127.6,127.0,126.5,126.4,126.0,124.9,121.2,108.6,97.6,38.2.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(minor)＝14.1min,tR(major)＝19.6min.
the structural formula of III-3 and II-3 is as follows:
example 10
III-4 is used as a substrate to react to generate a product 3, 4-diphenyl-1- (4-methylphenyl) -1, 4-dihydropyrano [2,3-c ] pyrazole II-4
The same procedure used in example 1 except for substituting 5-hydroxypyrazole III-1 with III-4 in example 1 gave compound II-4 in 89% yield and 94% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-4 are shown in FIGS. 7 and 8:1H NMR(400MHz,CDCl3)δ7.76–7.74(m,2H),7.54–7.51(m,2H),7.28–7.17(m,9H),7.16–7.12(m,1H),6.55(dd,J＝6.0,1.4Hz,1H),5.14(dd,J＝6.0,4.1Hz,1H),4.92(dd,J＝4.0,1.3Hz,1H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ147.9,147.3,144.8,137.4,136.2,135.9,133.2,129.7,128.7,128.1,127.8,127.7,127.0,126.8,121.2,108.5,97.2,38.0,21.1.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝9.2min,tR(minor)＝18.9min.
the structural formula of III-4 and II-4 is as follows:
example 11
IV-2 is used as a substrate to react to generate a product 4- (3-chlorphenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-5
The propargyl alcohol ester IV-1 in example 1 was replaced by IV-2, the remainder being as in example 1, givingCompound II-5, 91% yield, 96% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-5 are shown in FIGS. 9 and 10:1H NMR(400MHz,DMSO):δ7.95-7.85(m,6H),7.59-7.44(m,6H),5.35(t,J＝2.5Hz,1H),4.81(t,J＝2.8Hz,1H),4.27(t,J＝2.6Hz,1H),3.42(s,1H)；13CNMR(101MHz,DMSO):δ163.9,163.7,162.7,140.3,133.6,132.7,131.6,129.7,129.0,128.7,128.5,128.2,128.0,126.7,126.5,126.3,125.9,108.6,88.8,52.5,51.5.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝8.8min,tR(minor)＝16.7min.
the structural formula of IV-2 and II-5 is as follows:
example 12
IV-3 is used as a substrate to react to generate a product 4- (4-chlorphenyl) -1, 3-diphenyl-1, 4-dihydropyrano [2,3-c ] pyrazole II-6
The propargyl alcohol ester IV-1 from example 1 was replaced by IV-3 and the remainder of the procedure is as in example 1 to give compound II-5 in 96% yield and 92% ee. The hydrogen and carbon nuclear magnetic resonance spectra of the product II-6 are shown in FIGS. 11 and 12:1H NMR(400MHz,DMSO):δ7.95-7.85(m,6H),7.59-7.44(m,6H),5.35(t,J＝2.5Hz,1H),4.81(t,J＝2.8Hz,1H),4.27(t,J＝2.6Hz,1H),3.42(s,1H)；13CNMR(101MHz,DMSO):δ163.9,163.7,162.7,140.3,133.6,132.7,131.6,129.7,129.0,128.7,128.5,128.2,128.0,126.7,126.5,126.3,125.9,108.6,88.8,52.5,51.5.HPLC(Chiralcel OJ-H,n-hexane/i-PrOH＝50/50,0.8ml/min,254nm,40℃):tR(major)＝9.5min,tR(minor)＝11.1min.
the structural formula of IV-3 and II-6 is as follows:
examples 13 to 26
Reaction substrate suitability
The present invention has wide substrate applicability, and many substrates can participate in the reaction according to the reaction conditions in example 1, and chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compounds can be obtained with high yield and high stereoselectivity, as shown in table 1:
TABLE 1
| entry | Ⅲ(R1) | Ⅲ(R2) | Ⅲ(R3) | Yield(％) | ee(％) | |
| 1 | | Ph | Ph | 87 | 94 | |
| 13 | 2-ClC6H4 | Ph | Ph | 39 | 70 | |
| 14 | 3-ClC6H4 | Ph | Ph | 83 | 93 | |
| 15 | 4-FC6H4 | Ph | Ph | 69 | 94 | |
| 16 | 4-ClC6H4 | Ph | Ph | 74 | 91 | |
| 17 | 4-BrC6H4 | Ph | Ph | 61 | 92 | |
| 18 | 4-MeC6H4 | Ph | Ph | 92 | 93 | |
| 19 | 2-thienyl | Ph | Ph | 72 | 91 | |
| 20 | Ph | 4-BrC6H4 | Ph | 81 | 94 | |
| 21 | Ph | 2-EtC6H4 | Ph | 49 | 93 | |
| 22 | Ph | 4-MeOC6H4 | Ph | 86 | 90 | |
| 23 | Ph | Ph | 4-FC6H4 | 86 | 90 | |
| 24 | Ph | Ph | 4-MeC6H4 | 95 | 87 | |
| 25 | Ph | Ph | 4-MeOC6H4 | 92 | 79 | |
| 26 | Ph | Ph | 4-CF3C6H4 | 85 | 94 |
Claims (4)
1. A synthetic method of chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compounds is characterized by comprising the following steps: in the presence of an alkali additive, a chiral copper catalyst catalyzes a 5-hydroxypyrazole compound and a propargyl compound to synthesize a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound through [3+3] asymmetric cycloaddition reaction in a reaction medium;
the 5-hydroxypyrazole compound has the following structure:
the propargyl compound has the following structure:
the chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound has one of the following structures:
in the above formula, I and II are each enantiomers, R1Is phenyl, substituted phenyl or thienyl; r2And R3Is phenyl or substituted phenyl; the substituent on the phenyl is one or two of C1-C40 alkyl and halogen, and the number of the substituent is 1-5;
x is alkyl carboxylate of C1-C10;
the reaction medium is methanol;
the alkaline additive isiPr2Net or Cs2CO3One or two of them;
the preparation method of the chiral copper catalyst comprises the following steps: under the protection of nitrogen, copper salt and chiral P, N, N-ligand are stirred in a reaction medium for 1-2 hours according to the molar ratio of 1: 0.1-10 to prepare the chiral P, N, N-ligand complex; the copper salt is Cu (OAc)2·H2O、Cu(OTf)2、Cu(CH3CN)4BF4One or more than two of (a);
the chiral P, N, N-ligand has the following structural characteristics:
in the formula: r8，R9H, alkyl or phenyl in C1-C10;
R5，R6is H;
R7is phenyl.
2. The method for synthesizing a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound according to claim 1, wherein: the method comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and chiral P, N, N-ligand are stirred in a reaction medium for 1-2 hours according to the molar ratio of 1: 0.1-10 to prepare a chiral copper catalyst;
(2) preparation of 1, 4-dihydropyrano [2,3-c ] pyrazole compounds: dissolving a propargyl compound, a 5-hydroxypyrazole compound and an alkali additive in a reaction medium, adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, and stirring for 0.1-24 hours at 0-10 ℃; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying in vacuum to obtain a target product;
the molar ratio of the alkali additive to the propargyl compound is 0.5-10: 1;
the molar ratio of the 5-hydroxypyrazole compound to the propargyl compound is 1: 1-2.
3. The method for synthesizing a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound according to claim 1, wherein: the catalytic reaction conditions are as follows:
temperature: 10 ℃;
reaction medium: methanol;
time: for 24 hours.
4. The method for synthesizing a chiral 1, 4-dihydropyrano [2,3-c ] pyrazole compound according to claim 2, wherein:
the molar ratio of the alkali additive to the propargyl compound is 1: 1;
the molar ratio of the 5-hydroxypyrazole compound to the propargyl compound is 1: 1.2.
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