CN115850336A - Aryl-pyrazole axis chiral compound and preparation method and application thereof - Google Patents
Aryl-pyrazole axis chiral compound and preparation method and application thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- -1 nitro, amino, hydroxy, p-toluenesulfonyloxy Chemical group 0.000 claims description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000001624 naphthyl group Chemical group 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 14
- 125000004185 ester group Chemical group 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 150000004714 phosphonium salts Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
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- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000013078 crystal Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
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- 229940126062 Compound A Drugs 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
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- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
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- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
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- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 150000003839 salts Chemical group 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- CBNBGETWKBUTEL-UHFFFAOYSA-K tripotassium;phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O CBNBGETWKBUTEL-UHFFFAOYSA-K 0.000 claims description 2
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 claims description 2
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- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 28
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- 238000012512 characterization method Methods 0.000 description 13
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 12
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- 229910000073 phosphorus hydride Inorganic materials 0.000 description 6
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- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 4
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 3
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- 238000007239 Wittig reaction Methods 0.000 description 2
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
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Abstract
The invention discloses an aryl-pyrazole axis chiral compound, and a preparation method and application thereof. The preparation method is simple, the reaction condition is mild, the yield is high, the enantioselectivity of the product is excellent, and a new method is provided for the construction of the axial chiral compound; the aryl-pyrazole axis chiral compound constructed by the invention is an important ligand with catalytic activity, and has wide prospect in asymmetric catalysis and drug synthesis.
Description
Technical Field
The invention relates to the technical field of chemical engineering and medicine, in particular to an aryl-pyrazole axis chiral compound and a preparation method and application thereof.
Background
Axial chiral compounds are widely found in natural products and, by virtue of their rigidity and precise structure, have become one of the most attractive ligands and catalysts in asymmetric synthesis and catalysis. The asymmetric catalytic synthesis strategies reported at present mainly comprise: the metal catalyzes aryl carbon-carbon bond cross coupling, central chirality to axial chirality transfer, kinetic resolution and dynamic kinetic resolution, directly constructs aromatic ring to synthesize axial chirality compound, and non-chiral aryl-pyrazole compound to inhibit selective conversion. Despite the relative maturity of the development of these five approaches, a series of challenges remain, for example, due to the activity of the substrate molecules, most of the reported examples require transition metal catalysis; in the construction of axial chiral compounds by asymmetric or kinetic/dynamic kinetic resolution, the catalyst system and substrate range is quite limited, etc. The catalytic asymmetric synthesis of axial chiral compounds, especially axial chiral compounds with catalytically active functional groups, still has many challenges, and is always one of the research frontiers and difficulties of organic synthetic chemistry. Therefore, the development of a high-efficiency catalytic asymmetric synthesis method for realizing the accurate and high-efficiency construction of the axial chiral compound has important scientific research significance and value.
Disclosure of Invention
In order to solve the above defects in the prior art, the present invention aims to provide an aryl-pyrazole axis chiral compound, and a preparation method and applications thereof.
The technical scheme for solving the technical problems is as follows: provided is an aryl-pyrazole axis chiral compound comprising:
structural general formula I and its corresponding racemate, enantiomer, diastereoisomer, salt or crystal form:
wherein R is C 1-20 A linear or branched alkyl, aryl or substituted aryl, ketocarbonyl or substituted ketocarbonyl, ester or substituted ester group, cyano, trifluoromethyl, diarylphosphine oxide or substituted diarylphosphine oxide, dialkylphosphine oxide or substituted dialkylphosphine oxide, diarylphosphine or substituted diarylphosphine, dialkylphosphine or substituted dialkylphosphine, diarylphosphine oxide or substituted diarylphosphine oxide, dialkoxyphosphine oxide or substituted dialkoxyphosphine oxide;
R 1 is hydrogen, aryl or substituted aryl，C 1-20 Straight or branched chain alkyl, ketocarbonyl or substituted ketocarbonyl, halogen, ester group or substituted ester group;
R 2 is hydrogen, alkoxy, ester, trifluoromethyl, aryl or substituted aryl, C 1-20 A straight or branched chain alkyl, ketocarbonyl, halogen, nitro, amino, hydroxy, p-toluenesulfonyloxy, diarylphosphine oxide or substituted diarylphosphine oxide, diarylphosphine or substituted diarylphosphine;
R 3 is hydrogen, C 1-20 Linear or branched alkyl, benzyl, ketocarbonyl;
R 4 is hydrogen, aryl or substituted aryl, heterocycle or substituted heterocycle, diaryloxyphosphine or substituted diaryloxyphosphine, ketocarbonyl, C 1-20 Straight or branched chain alkyl or cycloalkyl, hydroxy, nitro, p-toluenesulfonyloxy, halogen, ester or substituted ester groups, TBDPSO, naphthyl;
On the basis of the technical scheme, the invention can be further improved as follows:
further, R is C 1-20 A straight or branched chain alkyl, ketocarbonyl or substituted ketocarbonyl, naphthyl, cyano, trifluoromethyl, ester or substituted ester group (e.g., methyl, ethyl, butyl, etc.) diarylphosphine oxide or substituted diarylphosphine oxide (e.g., methyl, butyl, methoxy, trifluoromethyl, halogen, cyano, nitro, etc.) dialkylphosphine oxide or substituted dialkylphosphine oxide, diarylphosphine oxide or substituted diarylphosphine oxide, dialkoxyphosphine oxide or substituted dialkoxyphosphine oxide, diarylphosphine or substituted diarylphosphine, dialkylphosphine or substituted dialkylphosphine;
R 1 hydrogen, phenyl or substituted phenyl (e.g. substituted by halogen, methyl, nitro, methoxy, trifluoromethyl, phenyl, cyano, triflate, etc.), naphthyl, C 1-20 Straight-chain or branched alkyl, ketocarbonyl or substituted ketocarbonyl, ester or substituted ester, halogenAn element;
R 2 is hydrogen, phenyl or substituted phenyl (such as halogen, methyl, methoxy, phenyl, trifluoromethyl, cyano, nitro, ester group and the like), pyridine, thiophene, furan, triflate, methoxy, halogen, acetoxy, C 1-20 Linear or branched alkyl, acetyl, trifluoromethyl, methyl ester, ethyl methyl ester, amino, hydroxy, t-butyloxycarbonyl, p-toluenesulfonyloxy, benzyloxy, diarylphosphinoxy or substituted diarylphosphinoxy, diarylphosphine or substituted diarylphosphine;
R 3 is hydrogen, methyl, benzyl, tert-butyloxycarbonyl;
R 4 is hydrogen, phenyl or substituted phenyl, furan, thiophene, pyridine, diaryloxyphosphine or substituted diaryloxyphosphine, methoxy, C 1-20 Linear or branched alkyl, hydroxy, nitro, p-toluenesulfonyloxy, cyclohexane, halogen, ester or substituted ester, TBDPSO, bocO, naphthyl, pyrene, pyrrole or substituted pyrrole (e.g. methyl, etc);
phenyl, pyridine, pyrrole.
Further, the aryl-pyrazole axis chiral compound has the following specific structural formula:
the preparation method of the aryl-pyrazole axis chiral compound comprises the following steps:
dissolving a compound A and a compound B in an organic solvent, adding an alkaline substance, and reacting under the action of a chiral quaternary phosphonium salt catalyst to obtain an aryl-pyrazole axis chiral compound, namely a compound shown in a formula I; the synthetic route is as follows:
further, the organic solvent is one or more of 1, 4-dioxane, acetonitrile, methanol, ethyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, 1, 2-dichloroethane, chloroform, toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, petroleum ether, n-hexane, cyclohexane and n-pentane.
Further, the basic substance is triethylamine, diisopropylethylamine, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate heptahydrate, potassium phosphate trihydrate, potassium fluoride, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, or lithium hydroxide.
Further, the reaction temperature is-60-50 ℃, and the reaction time is 6-72 h.
Further, the chiral quaternary phosphonium salt catalyst is:
wherein in the compound IV, R 1 Is hydrogen, C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl,heterocyclic or substituted heterocyclic; r is 5 Is Boc, ts, acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r 6 Is C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF 4 OTf, OAc or NO 3 ；
In the compound V, R 4 Is hydrogen, C 1-6 Alkyl, boc, ts, benzyl or substituted benzyl, silyl; r 5 Is Boc, ts, acyl or substituted acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r 6 Is C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF 4 OTf, OAc or NO 3 。
Further, the chiral quaternary phosphonium salt catalyst is:
further, the preparation method of the chiral quaternary phosphonium salt catalyst IV comprises the following steps:
chiral trivalent phosphine is subjected to wittig reaction to prepare the quaternary phosphonium salt catalyst in one step, and the synthetic route is as follows:
dissolving trivalent phosphine in DCM, adding methyl iodide, stirring for 3 hours at room temperature, and directly concentrating to obtain a product; or adding benzyl bromide, refluxing the methylbenzene for 2 hours, cooling, spin-drying and recrystallizing to obtain a product;
wherein R is 1 Is hydrogen, C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, heterocycle or substituted heterocycle,R 5 is Boc, ts, acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl, preferably thioureido or substituted thioureido; r is 6 Is C 1-6 Alkyl, benzyl or substituted benzyl, phenyl or substituted phenyl, naphthyl or substituted naphthyl, heterocycle; x is halogen, BF 4 ，BF 6 Or an OAc.
The preparation method of the chiral quaternary phosphonium salt catalyst V comprises the following steps:
chiral trivalent phosphine is subjected to wittig reaction to prepare the quaternary phosphonium salt catalyst in one step, and the synthetic route is as follows:
dissolving trivalent phosphine in DCM, adding methyl iodide, stirring for 3 hours at room temperature, and directly concentrating to obtain a product; or adding benzyl bromide, refluxing with toluene for 2 hours, cooling, spin-drying and recrystallizing to obtain a product;
wherein R is 4 Is hydrogen, C 1-6 Alkyl, boc, ts, benzyl or substituted benzyl, silicon-based (preferably TBDPS, TBS, TES, TMS, TIPS, TPS); r 5 Is Boc, ts, acyl or substituted acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl, preferably thioureido or substituted thioureido; r 6 Is C 1-6 Alkyl, benzyl or substituted benzyl, phenyl or substituted phenyl, naphthyl or substituted naphthyl; x is halogen (F, cl, br, I), BF 4 ，BF 6 Or an OAc.
The preparation process of the trivalent phosphine is carried out by adopting the prior art.
The aryl-pyrazole axis chiral compound is applied to catalyst or ligand synthesis or asymmetric catalytic reaction.
The invention has the following beneficial effects:
(1) The invention realizes the high-efficiency construction of the aryl-pyrazole axis chiral compound through asymmetric cyclization/aromatization reaction, has simple synthesis method, mild condition, high yield, excellent product enantioselectivity, convenient operation, no transition metal and environmental protection.
(2) The catalyst used in the synthesis process is a chiral quaternary phosphonium salt catalyst which is very stable to air and water, has good water solubility and is environment-friendly.
(3) The aryl-pyrazole axis chiral compound, namely the axis chiral phosphorus (phosphine) compound, is an important ligand with catalytic activity, can be used for synthesizing a series of chiral catalysts/ligands with catalytic activity through simple derivation in several steps, and has wide prospects in asymmetric catalysis and drug synthesis.
Drawings
FIG. 1 is a single crystal structural diagram of Compound I-7 in example 1.
FIG. 2 is a racemic HPLC chromatogram of Compound I-1 of example 1.
FIG. 3 is an HPLC chromatogram of chiral product of compound I-1 of example 1.
FIG. 4 is a racemic HPLC chromatogram of Compound I-7 of example 2.
FIG. 5 is an HPLC chromatogram of chiral product of compound I-7 of example 2.
FIG. 6 is a racemic HPLC chromatogram of Compound I-33 from example 3.
FIG. 7 is an HPLC chromatogram of chiral product of compound I-33 of example 3.
FIG. 8 is a HPLC chromatogram of racemate of compound I-36 in example 4.
FIG. 9 is an HPLC chromatogram of chiral product of compound I-36 of example 4.
FIG. 10 is a racemic HPLC chromatogram of Compound I-38 from example 5.
FIG. 11 is an HPLC chromatogram of the chiral product of compound I-38 of example 5.
FIG. 12 is a racemic HPLC chromatogram of Compound I-59 of example 6.
FIG. 13 is an HPLC chromatogram of chiral product of compound I-59 of example 6.
FIG. 14 is a racemic HPLC chromatogram of Compound I-81 from example 7.
FIG. 15 is an HPLC chromatogram of chiral product of compound I-81 of example 7.
FIG. 16 is a racemic HPLC chromatogram of Compound I-82 from example 8.
FIG. 17 is an HPLC chromatogram of chiral product of compound I-82 from example 8.
FIG. 18 is a racemic HPLC chromatogram of Compound I-83 from example 9.
FIG. 19 is an HPLC chromatogram of chiral product of compound I-83 from example 9.
FIG. 20 is a racemic HPLC chromatogram of Compound I-163 from example 10.
FIG. 21 is an HPLC chromatogram of chiral product of compound I-163 of example 10.
FIG. 22 is a racemic HPLC chromatogram of Compound I-171 of example 11.
FIG. 23 is an HPLC chromatogram of chiral product of compound I-171 of example 11.
FIG. 24 is a racemic HPLC chromatogram of compound I-195 from example 12.
FIG. 25 is an HPLC chromatogram of chiral product of compound I-195 of example 12.
FIG. 26 is a racemic HPLC chromatogram of Compound I-198 from example 13.
FIG. 27 is an HPLC chromatogram of chiral product of compound I-198 of example 13.
Detailed Description
The following examples are given for the purpose of illustration only and are not intended to limit the scope of the invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Preparation of diphenyl (5-phenyl-4- (2-phenyl-1-naphthyl) -1H-pyrazol-3-yl) phosphine oxide (I-1):
70.3mg of compound 1a (0.2 mmol) and 53.3mg of compound 1b (0.22 mmol), cesium carbonate 130.3mg (0.4 mmol), catalyst IV-27 (0.002 mmol) and 4mL of ethyl acetate were added to a reaction flask, stirred and mixed well, reacted at 25 ℃ for 10h, TLC showed complete consumption of the starting material 1a, column chromatography was concentrated (petroleum ether/ethyl acetate, v/v = 1/1) to give 108.2mg of product I-1.
Characterization data: 99% yield, hundred color solids, melting point: 250.0-257.3 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.78–7.62(m,2H),7.5–7.3(m,3H),7.35–7.25(m,3H),7.25–7.05(m,12H),7.0–6.9(m,4H),6.89–6.75(m,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ150.3(d,J＝11.3Hz),141.2,139.3,134.4(d,J＝120.4Hz),133.7,132.3,132.0,131.9(d,J＝2.8Hz),131.8(d,J＝2.9Hz),131.5(d,J＝11.2Hz),131.1(d,J＝11.2Hz),130.1(d,J＝111.5Hz),129.5,128.7,128.5,128.4,128.3,128.0,127.7,127.6,127.1(d,J＝102,7Hz),127.0(d,J＝13.2Hz),126.8,126.7,126.6,126.5,126.4,125.7,122.2(d,J＝16.1Hz)；
HRMS(ESI)m/z calcd for C 37 H 27 N 2 OP[M+Na] + ＝569.1753,found＝569.1751；
The ee value was 90％,t R (major)＝5.6min,t R (minor)＝9.1min(Chiralcel ADH,λ＝
254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 2
Preparation of 4- (1, 1' -biphenyl) -2-naphthyl-5-phenylpyrazol-3-yl) diphenylphosphine oxide (I-7):
85.5mg of compound 6a (0.2 mmol) and 53.3mg of compound 1b (0.22 mmol), cesium carbonate 130.3mg (0.4 mmol), catalyst IV-27 (0.002 mmol) and 4mL of ethyl acetate were added to a reaction flask, and after stirring and mixing well, reaction was carried out at 25 ℃ for 10h, TLC showed complete consumption of the starting material 1a, column chromatography was concentrated (petroleum ether/ethyl acetate, v/v = 1/1) to give 122.0mg of product I-7, the single crystal structure of which is shown in FIG. 1.
Referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 12h.
Characterization data: <xnotran> 98%yield, , : </xnotran> 177.1-185.7 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.74(t,J＝10.3Hz,2H),7.61(d,J＝8.1Hz,1H),7.55–7.32(m,8H),7.30–7.16(m,6H),7.15–6.92(m,6H),6.90–6.71(m,4H),6.65(d,J＝8.6Hz,1H),6.16(d,J＝7.6Hz,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ149.9(d,J＝10.7Hz),140.3,140.2,139.1,138.8,134.9(d,J＝121.2Hz),133.7,132.4,132.0(d,J＝8.2Hz),131.8(d,J＝8.2Hz),131.4(d,J＝11.1Hz),131.1(d,J＝11.2Hz),130.3(d,J＝114.1Hz),130.0,129.4(d,J＝117.1Hz),128.9,128.8,128.5,128.4,128.3,127.9,127.9,127.6,127.4,127.0,126.9,126.8,126.8,126.7,126.6,126.6,126.5,125.7,125.2,122.0(d,J＝16.3Hz)；
HRMS(ESI)m/z calcd for C 43 H 31 N 2 OP[M+H] + ＝623.2247,found＝623.2247.
The ee value was 99％,t R (major)＝5.0min,t R (minor)＝9.3min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 3
Preparation of (5-phenyl-4- (2-pyridin-3-yl) naphthyl-1-naphthyl-1H-pyrazol-3-yl) diphenylphosphine oxide (I-33):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 12h.
Characterization data: 99% yield, white solid, melting point: 200.0-207.1 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ8.36(dd,J＝5.0,1.7Hz,1H),7.99(d,J＝2.3Hz,1H),7.80–7.70(m,2H),7.39(dt,J＝7.2,3.3Hz,3H),7.35–7.27(m,3H),7.22–7.08(m,8H),7.09–6.94(m,7H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ148.7,(d,J＝9.0Hz),146.3,138.4(d,J＝117.2Hz),137.5,137.5,135.6,133.5,132.7,132.1(d,J＝2.8Hz),131.9(d,J＝2.8Hz),131.4(d,J＝10.0Hz),131.3(d,J＝10.0Hz),130.4,130.2(d,J＝111.3Hz),129.7(d,J＝111.0Hz),129.0,128.6,128.3,128.3,128.2,127.9,127.8,127.6(d,J＝13.0Hz),127.3,126.6,126.6,126.6,126.2,122.8,120.9(d,J＝16.8Hz).
HRMS(ESI)m/z calcd for C 36 H 26 N 3 OP[M+H] + ＝548.1887,found＝548.1883.
The ee value was 86％,t R (major)＝53.0min,t R (minor)＝60.3min(Chiralcel ADH,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).
example 4
Preparation of (5-phenyl-4- (2-thiophen-2-yl) naphthalen-1-yl-1H-pyrazol-3-yl) diphenylphosphino-o-imine oxide (I-36):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 10h.
Characterization data: 99% yield, white solid, melting point: 194.7 to 202.5 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.60(d,J＝8.8Hz,2H),7.44(d,J＝8.6Hz,1H),7.39–7.28(m,5H),7.24–7.17(m,2H),7.16–6.94(m,10H),6.95–6.85(m,1H),6.85–6.80(m,1H),6.77(td,J＝7.7,3.2Hz,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ150.4(d,J＝10.9Hz),143.0,135.1(d,J＝120.3Hz),132.4,132.3,131.9(d,J＝3.0Hz),s131.7(d,J＝3.0Hz),131.62,131.4(d,J＝11.2Hz),131.0(d,J＝11.1Hz),130.6,129.5,128.9,128.4,128.3,128.2,128.0(d,J＝113.7Hz),127.8,127.5,127.2,127.1,127.0,126.9,126.7,126.7(d,J＝2.1Hz),126.6,126.2,125.9,121.5(d,J＝16.6Hz)；
HRMS(ESI)m/z calcd for C 35 H 25 N 2 OPS[M+H] + ＝553.1498,found＝553.1500.
The ee value was 88％,t R (major)＝8.8min,t R (minor)＝11.9min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 5
Preparation of 1- (3- (diphenylphosphoric acid) -5-phenyl-1H-pyrazol-4-naphthalen-2-yl trifluorotoluene sulfonate (I-38):
referring to the synthesis method of example 1, only the substrate substituents and the reaction conditions were changed, and chloroform was used as a solvent in the preparation process, the reaction temperature was-20 ℃, and the reaction time was 48 hours.
Characterization data: 97% yield, white solid, melting point: 246.0 to 251.3 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.72(d,J＝8.6Hz,2H),7.65–7.53(m,2H),7.52–7.40(m,3H),7.40–7.25(m,5H),7.22(d,J＝7.7Hz,2H),7.17–7.02(m,5H),6.93(td,J＝7.7,3.2Hz,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ148.5(d,J＝9.4Hz),145.4,137.7(d,J＝120.7Hz),133.7,132.5(d,J＝2.9Hz),131.9,131.9,131.9,131.8,131.3(d,J＝10.9Hz),130.9,130.5(d,J＝117.4Hz),130.4,128.9(d,J＝112.4Hz),128.5,128.3,128.3,128.2,127.8(d,J＝18.0Hz),127.5(d,J＝13.1Hz),126.9,126.6,122.6,118.7,118.1(q,J＝320.1Hz),115.5(d,J＝16.1Hz)；
HRMS(ESI)m/z calcd for C 32 H 22 F 3 N 2 O 4 PS[M+H] + ＝619.1063,found＝619.1063；
The ee value was 66％,t R (major)＝6.2min,t R (minor)＝7.5min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 6
Preparation of 5- (3-chlorophenyl) -4- (2-phenyl-1-naphthyl) -1H-pyrazol-3-yl) diphenylphosphine oxide (I-59):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 12h.
Characterization data: 99% yield, white solid, melting point: 243.1-247.0 deg.C;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.66(t,J＝8.9Hz,2H),7.51(s,1H),7.45–7.32(m,2H),7.30–7.15(m,4H),7.15–6.95(m,9H),6.95–6.85(m,5H),6.78(td,J＝7.7,3.2Hz,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ149.9(d,J＝11.8Hz),141.0,139.2,134.3,134.2,133.5(d,J＝118.2Hz),133.4,132.3,132.1(d,J＝3.0Hz),131.9(d,J＝2.9Hz),131.4(d,J＝11.2Hz),131.1(d,J＝11.3Hz),129.7(d,J＝112.4Hz),129.5,129.4,128.9,128.6,128.4,128.1,128.0,127.6(d,J＝8.0Hz),127.5(d,J＝113.4Hz),127.0,127.0,126.9,126.6(d,J＝5.4Hz),126.4,126.3,125.8,124.5,122.4(d,J＝15.9Hz)；
HRMS(ESI)m/z calcd for C 37 H 26 ClN 2 OP[M+H] + ＝581.1544,found＝581.1543；
The ee value was 92％,t R (major)＝5.8min,t R (minor)＝7.4min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 7
Preparation of 5-methyl-4- (2-phenyl-1-naphthyl) -1H-pyrazol-3-yl) diphenylphosphine oxide (I-81):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 16h.
Characterization data: 97% yield, white solid, melting point: 254.4-261.3 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝5:1)δ7.72–7.70(m,2H),7.43–7.35(m,2H),7.30(dd,J＝8.4,1.9Hz,1H),7.28–7.02(m,14H),6.90(td,J＝7.8,3.0Hz,2H),2.01(s,3H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝5:1)δ145.4(d,J＝10.4Hz),141.3,139.7,136.4(d,J＝113.1Hz),133.2,132.3,132.0(d,J＝2.8Hz),131.9(d,J＝2.9Hz),131.5(d,J＝11.0Hz),131.2(d,J＝11.0Hz),130.3(d,J＝104.2Hz),129.5,129.2(d,J＝4.7Hz),128.5,128.4(d,J＝101.1Hz),128.3(d,J＝13.0Hz),128.0,127.8,127.6,127.2(d,J＝13.2Hz),126.6,126.2(d,J＝20.2Hz),125.9,125.6,123.3(d,J＝17.1Hz),10.7；
HRMS(ESI)m/z calcd for C 32 H 25 N 2 OP[M+H] + ＝485.1777,found＝485.1781；
The ee value was 72％,t R (major)＝8.1min,t R (minor)＝10.3min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 8
Preparation of 5-bromo-4- (2-phenyl-1-naphthyl) -1H-pyrazol-3-yl) diphenylphosphine oxide (I-82):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 16h.
Characterization data: 89% yield, yellow solid, melting point: 229.0 to 232.1 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝5:1)δ7.67(m,2H),7.4(m,2H),7.40(m,2H),7.36–7.22(m,5H),7.21–7.16(m,2H),7.16–7.08(m,3H),6.98–6.88(m,3H),6.77(m,2H),6.67(td,J＝7.7,3.3Hz,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝5:1)δ141.0,139.8,132.3(d,J＝122.2Hz),133.0,132.3(d,J＝2.9Hz),132.1(d,J＝3.7Hz),131.3(d,J＝11.4Hz),130.9(d,J＝11.5Hz),129.6,129.3,128.8(d,J＝116.2Hz),128.7,128.6,128.4,127.7,127.5,126.9,126.9,126.8,126.6,126.3(d,J＝116.4Hz),126.0,125.7,125.4(d,J＝15.3Hz),124.5；
HRMS(ESI)m/z calcd for C 31 H 22 BrN 2 OP[M+H] + ＝549.0726,found＝549.0728；
The ee value was 94％,t R (minor)＝8.4min,t R (major)＝12.1min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 9
Preparation of 3- (diphenylphosphoryl) -4- (2-phenyl-1-naphthyl) -1H-pyrazole-5-carboxylic acid ethyl ester (I-83):
referring to the synthesis method of example 1, only the substrate substituent was changed, and the reaction time was 12h.
Characterization data: 93% yield, yellow solid, melting point: 172.1-180.4 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.63(d,J＝8.3Hz,2H),7.43–7.36(m,1H),7.37–7.30(m,1H),7.30–7.16(m,5H),7.15–7.03(m,5H),7.0(m,3H),6.88–6.79(m,2H),6.88–6.79(m,2H).4.23–3.95(m,2H),0.84(td,J＝7.1,1.4Hz,3H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ161.3,143.9(d,J＝118.0Hz),141.4,138.5,134.6(d,J＝118.0Hz),133.2,132.1,132.0,131.9,131.4(d,J＝11.1Hz),131.1(d,J＝11.3Hz),129.7,129.3(d,J＝111.2Hz),128.6,128.4,128.2,127.7,127.5(d,J＝15.6Hz),127.4,127.3(d,J＝113.1Hz)127.0,126.8,126.6,126.1,125.9,125.4,60.7,13.5；
HRMS(ESI)m/z calcd for C 34 H 27 N 2 O 3 P[M+H] + ＝543.1832,found＝543.1832；
The ee value was 80％,t R (major)＝7.8min,t R (minor)＝14.0min(Chiralcel ADH,λ＝254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 10
Preparation of phenyl (5-phenyl-4- (2-phenylnaphthalen-1-yl) -1H-pyrazol-3-yl) methanone (I-163):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 24h.
Characterization data: 91% yield, yellow solid, melting point: 152.1-155.1 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1) 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J＝8.3Hz,2H),7.76(d,J＝8.4Hz,1H),7.66–7.57(m,2H),7.51–7.34(m,4H),7.30–7.19(m,4H),7.18–7.00(m,6H),6.94–6.83(m,2H).； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ187.6,177.6,146.5,144.6,141.7,139.9,136.9,133.0,132.8,132.7,129.8,129.4,129.3,128.7,128.5,128.5,128.2,128.0,127.8,127.6,127.3,126.7,126.4,126.4,126.0,125.7,119.2；
HRMS(ESI)m/z calcd for C 32 H 22 N 2 O[M+H] + ＝451.1805,found＝451.1805；
The ee value was 90％,t R (major)＝4.3min,t R (minor)＝6.6min(Chiralcel ADH,λ＝
254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 11
Preparation of 3-diphenylphosphino-5-phenyl-4- (2-phenylnaphthalen-1-yl) pyrazole (I-171):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 18h.
Characterization data: 78% yield, white solid, melting point: 194.1 to 197.0 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝20:1)δ7.99(d,J＝8.5Hz,1H),7.92(d,J＝8.2Hz,1H),7.60–7.52(m,2H),7.46(ddd,J＝8.1,6.7,1.2Hz,2H),7.31–7.21(m,10H),7.18–7.11(m,4H),7.10–6.99(m,4H),6.94(td,J＝7.7,7.3,1.6Hz,2H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝20:1)δ149.3(d,J＝6.3Hz),141.8,140.6,140.0(d,J＝27.7Hz),135.0(d,J＝9.5Hz),134.7(d,J＝8.5Hz),134.1(d,J＝8.1Hz),133.6,133.4,133.2,132.8,132.7,132.6,131.9,129.6,129.0,128.6,128.6,128.5,128.4,128.3,128.0,127.8,127.5,126.6,126.5,126.3(d,J＝9.1Hz),125.7,124.6(d,J＝30.3Hz)； 31 P NMR(162MHz,Chloroform-d:Acetic acid-d 4 ＝20:1)δ-37.5；
HRMS(ESI)m/z calcd for C 37 H 27 N 2 P[M+H] + ＝531.1985,found＝531.1981；
The ee value was>99％,t R (major)＝4.7min,t R (minor)＝6.1min(Chiralcel IC,λ＝254
nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).
example 12
Preparation of 1-methyl-5-phenyl-4- (2-phenylnaphthalen-1-yl) -1H-pyrazol-3-yl) diphenylphosphine oxide (I-195):
70.3mg of compound 1a (0.2 mmol), 53.3mg of compound 1b (0.22 mmol), cesium carbonate (130.3 mg, 0.4 mmol), catalyst IV-27 (0.002 mmol) and 4mL of ethyl acetate were added to a reaction flask, and after stirring and mixing, reaction was carried out at 25 ℃ for 10h, TLC showed complete consumption of the starting material 1a, and then methyl iodide (31.2 mg, 0.22 mmol) was added, and stirring was continued for 3h, and after completion of the reaction, column chromatography was concentrated (petroleum ether/ethyl acetate, v/v = 4/1) to obtain 105.3mg of product I-195.
Characterization data: 94% yield, hundred color solids, melting point: 233.1-236.3 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ7.67(dd,J＝8.5,3.2Hz,2H),7.47–7.40(m,1H),7.39–7.31(m,5H),7.31–7.26(m,1H),7.21(ddd,J＝8.4,6.7,1.3Hz,1H),7.18–6.91(m,12H),6.88(d,J＝8.2Hz,2H),6.80(td,J＝7.7,3.3Hz,2H),3.6(s,3H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ150.5(d,J＝11.2Hz),139.3,138.2,136.1,134.0(d,J＝120.1Hz),133.6,132.2(d,J＝7.2Hz),131.9(d,J＝2.9Hz),131.7(d,J＝3.0Hz),131.5(d,J＝11.2Hz),131.0(d,J＝11.2Hz),130.1(d,J＝111.6Hz),129.4,128.7,128.7,128.4,128.3,128.2,128.1,127.8(d,J＝108.1Hz),127.7,127.5,126.9(d,J＝13.2Hz),126.7,126.6,126.5,126.4,125.5,122.4(d,J＝16.1Hz),49.1； 31 P NMR(162MHz,Chloroform-d:Acetic acid-d 4 ＝50:1)δ22.9；
HRMS(ESI)m/z calcd for C 38 H 29 N 2 OP[M+H] + ＝561.2090,found＝561.2095；
The ee value was 92％,t R (major)＝6.2min,t R (minor)＝10.5min(Chiralcel ADH,λ＝
254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
example 13
Preparation of 4- (7-methoxy-2-phenylnaphthalen-1-yl) -5-phenyl-1H-pyrazol-3-yl) diphenylphosphine oxide (I-198):
referring to the synthesis of example 1, only the substrate substituents were changed and the reaction time was 12h.
Characterization data: 92% yield, white solid, melting point: 143.3 to 145.6 ℃;
1 H NMR(400MHz,Chloroform-d:Acetic acid-d 4 ＝20:1)δ7.64(dd,J＝8.5,2.9Hz,2H),7.41(td,J＝7.5,1.7Hz,1H),7.37–7.23(m,5H),7.22–7.00(m,9H),7.00–6.91(m,2H),6.88(d,J＝8.6Hz,2H),6.80(td,J＝7.7,3.2Hz,2H),6.63(d,J＝8.7Hz,2H),3.81(s,3H)； 13 C NMR(101MHz,Chloroform-d:Acetic acid-d 4 ＝20:1)δ150.2(d,J＝11.1Hz),139.0,134.2(d,J＝112.5Hz),133.5,132.1,132.1(d,J＝2.9Hz),131.9(d,J＝2.9Hz),131.8,131.5(d,J＝11.2Hz),131.0(d,J＝11.3Hz),130.6,129.8(d,J＝111.9Hz),128.7,128.5,128.4,128.3,128.0,127.9,127.6(d,J＝114.7Hz),127.5,127.1,126.9,126.6,126.5,126.4,126.3,125.5,122.5(d,J＝15.9Hz),113.5,55.1； 31 P NMR(162MHz,Chloroform-d:Acetic acid-d 4 ＝20:1)δ23.4；
HRMS(ESI)m/z calcd for C 38 H 29 N 2 O 2 P[M+H] + ＝577.2040,found＝577.2038；
The ee value was 88％,t R (major)＝8.2min,t R (minor)＝12.9min(Chiralcel ADH,λ＝
254nm,30％i-PrOH/hexane,flow rate＝1.0mL/min).
the above compounds and the preparation method thereof are only some examples listed in the invention, and the rest of the compounds protected by the invention and the preparation method thereof can be used for completing the preparation of different compounds according to alternative raw materials, thereby obtaining different compounds. Example application of aryl-pyrazole axis chiral compound in catalyst/ligand synthesis and asymmetric catalysis
1. Synthesis of aryl-pyrazole axis chiral catalyst/ligand
2. Asymmetric catalytic examples of aryl-pyrazole axis chiral catalysts/ligands
The aryl-pyrazole axial chiral compound provided by the invention can be used for synthesizing a series of axial chiral phosphine catalysts/ligands with catalytic activity through three-step simple derivatization, and has wide application prospects in asymmetric catalysis (such as asymmetric allyl substitution reaction) and drug synthesis.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. An aryl-pyrazole axis chiral compound comprising: structural general formula I and its corresponding racemate, enantiomer, diastereoisomer, salt or crystal form:
wherein R is C 1-20 A linear or branched alkyl, aryl or substituted aryl, ketocarbonyl or substituted ketocarbonyl, ester or substituted ester group, cyano, trifluoromethyl, diarylphosphine oxide or substituted diarylphosphine oxide, dialkylphosphine oxide or substituted dialkylphosphine oxide, diarylphosphine or substituted diarylphosphine, dialkylphosphine or substituted dialkylphosphine, diarylphosphine oxide or substituted diarylphosphine oxide, dialkoxyphosphine oxide or substituted dialkoxyphosphine oxide;
R 1 is hydrogen, aryl or substituted aryl, C 1-20 Straight or branched chain alkyl, ketocarbonyl or substituted ketocarbonyl, halogen, ester group or substituted ester group;
R 2 is hydrogen, alkoxy, ester, trifluoromethyl, aryl or substituted aryl, C 1-20 Linear or branched alkyl, ketocarbonyl, halogen, nitro, amino, hydroxy, p-toluenesulfonyloxy, diarylphosphine oxide or substituted diarylphosphine oxide, diarylphosphine or substituted diarylphosphine;
R 3 is hydrogen, C 1-20 Linear or branched alkyl, benzyl, ketocarbonyl;
R 4 is hydrogen, aryl or substituted aryl, heterocyclic or substituted heterocyclic, diaryloxyphosphine or substituted diaryloxyphosphine, a ketoneCarbonyl group, C 1-20 Straight or branched chain alkyl or cycloalkyl, hydroxy, nitro, p-toluenesulfonyloxy, halogen, ester or substituted ester groups, TBDPSO, naphthyl;
2. Aryl-pyrazole axial chiral compounds according to claim 1, characterized in that R is C 1-20 A linear or branched alkyl, ketocarbonyl or substituted ketocarbonyl, naphthyl, cyano, trifluoromethyl, ester or substituted ester group, diarylphosphine oxide or substituted diarylphosphine oxide, dialkylphosphine oxide or substituted dialkylphosphine oxide, diarylphosphine oxide or substituted diarylphosphine oxide, dialkoxyphosphine oxide or substituted dialkoxyphosphine oxide, diarylphosphine or substituted diarylphosphine, dialkylphosphine or substituted dialkylphosphine;
R 1 is hydrogen, phenyl or substituted phenyl, naphthyl, C 1-20 Straight or branched chain alkyl, ketocarbonyl or substituted ketocarbonyl, ester or substituted ester group, halogen;
R 2 is hydrogen, phenyl or substituted phenyl, pyridine, thiophene, furan, triflate, methoxy, halogen, acetoxy, C 1-20 Linear or branched alkyl, acetyl, trifluoromethyl, methyl ester, ethyl methyl ester, amino, hydroxy, tert-butoxycarbonyl, p-toluenesulfonyloxy, benzyloxy, diarylphosphinoxy or substituted diarylphosphinoxy, diarylphosphine or substituted diarylphosphine;
R 3 is hydrogen, methyl, benzyl, tert-butyloxycarbonyl;
R 4 is hydrogen, phenyl or substituted phenyl, furan, thiophene, pyridine, diaryloxyphosphine or substituted diaryloxyphosphine, methoxy, C 1-20 Linear or branched alkyl, hydroxy, nitro, p-toluenesulfonyloxy, cyclohexane, halogen, ester or substituted ester groups, TBDPSO, bocO, naphthyl, pyrene, pyrrole or substituted pyrroles;
3. The aryl-pyrazole axis chiral compound of claim 2, having the following specific structural formula:
4. a process for the preparation of aryl-pyrazole axis chiral compounds according to any of claims 1 to 3, comprising the steps of:
dissolving a compound A and a compound B in an organic solvent, adding an alkaline substance, and reacting under the action of a chiral quaternary phosphonium salt catalyst to obtain an aryl-pyrazole axis chiral compound, namely a compound shown in a formula I; the synthetic route is as follows:
5. the method for preparing aryl-pyrazole chiral compounds according to claim 4, wherein the organic solvent is one or more selected from the group consisting of 1, 4-dioxane, acetonitrile, methanol, ethyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, 1, 2-dichloroethane, chloroform, toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, petroleum ether, n-hexane, cyclohexane and n-pentane.
6. The method for preparing an aryl-pyrazole axis chiral compound according to claim 4, wherein the basic substance is triethylamine, diisopropylethylamine, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate heptahydrate, potassium phosphate trihydrate, potassium fluoride, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, or lithium hydroxide.
7. The method for preparing aryl-pyrazole axis chiral compounds according to claim 4, wherein the reaction temperature is-60 to 50 ℃ and the reaction time is 6 to 72 hours.
8. The method for preparing aryl-pyrazole axis chiral compounds according to claim 5, wherein the chiral quaternary phosphonium salt catalyst is:
wherein in the compound IV, R 1 Is hydrogen, C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, heterocycle or substituted heterocycle; r 5 Boc, ts, acyl, ureido, thioureido or substituted thioureido,a carbonyl or substituted carbonyl; r 6 Is C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF 4 OTf, OAc or NO 3 ；
In the compound V, R 4 Is hydrogen, C 1-6 Alkyl, boc, ts, benzyl or substituted benzyl, silyl; r 5 Is Boc, ts, acyl or substituted acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r is 6 Is C 1-6 Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF 4 OTf, OAc or NO 3 。
9. The method for preparing aryl-pyrazole axis chiral compounds according to claim 8, wherein the chiral quaternary phosphonium salt catalyst is:
10. use of an aryl-pyrazole axis chiral compound according to any of claims 1 to 3 in catalyst or ligand synthesis or asymmetric catalytic reactions.
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