CN117924176A - Method for synthesizing chiral 1, 4-dienylpyrazole derivative - Google Patents
Method for synthesizing chiral 1, 4-dienylpyrazole derivative Download PDFInfo
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- CN117924176A CN117924176A CN202410105251.XA CN202410105251A CN117924176A CN 117924176 A CN117924176 A CN 117924176A CN 202410105251 A CN202410105251 A CN 202410105251A CN 117924176 A CN117924176 A CN 117924176A
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000003446 ligand Substances 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 14
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 pyrazole derivative compound Chemical class 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- 229910052786 argon Inorganic materials 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 150000003217 pyrazoles Chemical class 0.000 claims description 19
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 230000035484 reaction time Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000010791 quenching Methods 0.000 abstract description 3
- 230000000171 quenching effect Effects 0.000 abstract description 3
- 230000006340 racemization Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000012300 argon atmosphere Substances 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000008300 phosphoramidites Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- LLVWLCAZSOLOTF-UHFFFAOYSA-N 1-methyl-4-[1,4,4-tris(4-methylphenyl)buta-1,3-dienyl]benzene Chemical compound C1=CC(C)=CC=C1C(C=1C=CC(C)=CC=1)=CC=C(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 LLVWLCAZSOLOTF-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000005913 hydroamination reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical group [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2221—At least one oxygen and one phosphorous atom present as complexing atoms in an at least bidentate or bridging ligand
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
Abstract
The invention discloses a method for synthesizing chiral 1, 4-dienylpyrazole derivative compounds with high chemistry, regioselectivity and enantioselectivity. In particular to a method for preparing a chiral 1, 4-dienyl pyrazole derivative compound by catalyzing racemization 1, 4-dienyl allyl alcohol and a pyrazole derivative compound to carry out substitution reaction through iridium catalyst and chiral ligand combination, which belongs to the field of organic synthesis. The specific operation steps are as follows: under the protection of argon, an iridium catalyst and a chiral ligand are added into a reaction tube, then 1, 4-dienylallyl alcohol, a pyrazole derivative compound and an additive are added, then the reaction is carried out at 0 ℃, and after the reaction is complete, the chiral 1, 4-dienylpyrazole derivative compound is obtained after quenching and purification. The method has the advantages of good substrate applicability and mild reaction conditions. High chemoselectivity, regioselectivity and enantioselectivity.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing chiral 1, 4-dienylpyrazole derivatives with high chemical, regio-and enantioselectivity.
Background
Chiral pyrazole compounds are common organic synthesis intermediates and widely exist in natural products and various medical intermediates. Small molecule drugs such as ruxolitinib, MK-0893, zebutinib, etc. on the market all have chiral pyrazole backbone units. The reported synthesis of chiral pyrazole compounds is based on the strategy of catalyzing asymmetric reductive hydroamination of olefinic compounds and pyrazole compounds (see :(a).A.M.Haydl,K.Xu,B.Breit,Angew.Chem.Int.Ed.2015,54,7149-7153;(b)L.J.Hilpert,S.V.Sieger,A.M.Haydl,B.Breit,Angew.Chem.Int.Ed.2019,58,3378-3381;(c)A.Y.Jiu,H.S.Slocumb,C.S.Yeung,X.-H.Yang,V.M.Dong,Angew.Chem.Int.Ed.2021,60,19660-19664). for details, wherein olefinic substrates comprise compounds such as diene and 1, 3-diene, most of which are not easy to synthesize, and have extremely limited types, and the limitation of substrates severely restricts the synthesis and development of chiral pyrazole derivative compounds.
Catalyzing asymmetric N-alkylation is an important method for constructing chiral amine compounds. However, the N-asymmetric alkylation reaction of pyrazole derivatives has not been carried out at present because of the weak nucleophilicity of pyrazole derivatives and the like.
Disclosure of Invention
In view of the limitations of the methods developed above, the present invention provides a commercially available pyrazole compound and a readily available 1, 4-dienyl alcohol as a reaction raw material, and a method for synthesizing chiral 1, 4-dienylpyrazole compounds with high chemical, regio-and enantioselectivity, by utilizing an asymmetric catalytic allylation strategy.
In order to achieve the purpose of the invention, the technical scheme adopted is as follows:
A method for synthesizing chiral 1, 4-dienylpyrazole compounds with high chemical, regional and enantioselectivity comprises the step of carrying out substitution reaction on racemic 1, 4-dienylpyrazole and pyrazole derivatives under the catalysis of an iridium catalyst to generate a series of chiral 1, 4-dienylpyrazole compounds.
Further, the method comprises the following steps: under the protection of argon, the iridium catalyst and the chiral ligand L are dissolved in a dichloromethane solvent and placed in a tube seal, and stirred for 5 minutes. And then sequentially adding the 1, 4-dienylallyl alcohol, the pyrazole derivative and the additive into the tube sealing, replacing argon, then reacting for 2 hours at the temperature of 0 ℃, and quenching and purifying to obtain the chiral 1, 4-dienylpyrazole compound.
The specific reaction equation is as follows (Scheme 1):
scheme 1 reaction equation
The structural formula of the racemized 1, 4-dienyl allyl alcohol is as follows:
Wherein R 1 can be alkyl or aryl.
Further, the structural formula of the pyrazole derivative is as follows:
wherein R 2 is alkyl, aryl, halogen and nitro.
Further, the molar ratio of the 1, 4-dienylallyl alcohol and the pyrazole derivative is 1 to 2:1, and more preferably 1.5:1, and the yield is highest at the molar ratio.
Further, the solvent is dichloromethane, dichloroethane, toluene, diethyl ether. Of which dichloromethane is the most preferred solvent.
Further, the iridium catalyst is 1, 5-cyclooctadiene iridium chloride dimer; the dosage of the iridium catalyst is 2% -4% of the equivalent of the pyrazole derivative; preferably, the iridium catalyst is used in an amount of 4% of the pyrazole derivative equivalent.
Further, the chiral ligand L is a chiral phosphoramidite ligand, and the structural formula is as follows:
Further, the chiral phosphoramidite ligand L is in an S-configuration, and the chiral ligand dosage is 200-400% of the iridium catalyst equivalent; wherein, the yield of the iridium catalyst is 400 percent of the molar quantity of the iridium catalyst.
Further, the additive is ytterbium triflate Yb (OTf) 3, equivalent which is 10 to 100 percent of the equivalent of the pyrazole derivative. The highest yields have been achieved when the catalytic amount is 20%.
The beneficial effects are that:
The method of the invention realizes asymmetric allyl substitution reaction of pyrazole derivatives by designing a catalytic system and screening conditions and using easily prepared 1, 4-dienyl alcohol and commercially available pyrazole derivative compounds as reaction raw materials, and prepares a series of chiral pyrazole compounds with high selectivity. The method has the advantages of good substrate applicability and mild reaction conditions; high chemoselectivity, regioselectivity and enantioselectivity.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 3 aa;
FIG. 2 is a 3aa nuclear magnetic resonance carbon spectrum;
FIG. 3 is a chiral high performance liquid chromatogram of 3 aa;
FIG. 4 is a 3aa high resolution analysis.
Detailed Description
The invention is further described below in connection with examples, but is not limited thereto.
Pyrazole starting materials 2a-2c are commercially available in the following examples of the present invention. Other reagents of the invention, not specifically described, are commercially available.
The dienyl alcohols 1a-1f in the following specific examples were prepared according to the following general procedure:
The steps are as follows: 10mmol of the corresponding unsaturated enal IV are dissolved in 20mL of dry tetrahydrofuran solution. The reaction was cooled to 0℃in an ice bath. 12mmol of vinyl magnesium chloride were slowly added dropwise with a syringe. After the addition was completed, stirring was continued for 1 hour. Then adding saturated ammonium chloride solution for quenching, extracting by using 50mL of ethyl acetate, evaporating to dryness in a rotary manner, and separating by using a silica gel column to obtain a target product.
Example 1
Synthesis of (3 aa):
to the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) under argon atmosphere, (S) -L (8.0 mg,16 mol%) and methylene chloride (1.5 mL) and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol,27.3 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (12.4 mg,0.02 mmol). The tube was then sealed and the reaction was allowed to react at 0℃for 2h. Purification of the crude product by TLC prep plate gave 3aa (27.8 mg,95% ee, yield :76％).1H NMR(300MHz,CDCl3)δ7.94-7.74(m,2H),7.39(t,J＝7.4Hz,3H),7.34-7.23(m,1H),7.14(s,1H),6.41(t,J＝6.7Hz,1H),6.25(ddd,J＝16.7,10.4,6.2Hz,1H),5.89(dd,J＝15.4,7.2Hz,1H),5.79-5.65(m,1H),5.24-5.14(m,2H),3.90(s,3H),2.06(q,J＝6.9Hz,2H),1.42-1.22(m,10H),0.86(t,J＝6.6Hz,3H).13C NMR(75MHz,CDCl3)δ160.4,150.3,137.4,134.8,132.9,132.7,128.7,128.1,127.9,125.8,116.7,108.3,64.5,52.1,32.4,31.9,29.3,29.2,29.1,22.8,14.2.
HRMS (ESI) m/z calculated molecular weight C 23H31N2O2[M+H]+: 367.2380, found 367.2382.Hplc: enantiomeric excess, determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK OD column (mobile phase: n-hexane/isopropanol=99:1), flow rate: 1.0mL/min, λ=254 nm, retention time: t R(major)＝5.17min,tR (minor) =4.17 min.e.e. =98%.
Example 2
Synthesis of (3 ab):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) chiral ligand L (8.0 mg,16 mol%) and dichloromethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol,27.3 mg), 2b (0.1 mmol,13.3 mg) and Yb (OTf) 3 (10 mg,0.12 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. Purification of the crude product by TLC prep plate gave 3ab (18.1 mg,97% ee, yield :58％).1HNMR(300MHz,CDCl3)δ8.17(s,1H),8.11(s,1H),6.15-5.99(m,1H),5.82(dt,J＝15.4,6.6Hz,1H),5.72-5.63(m,1H),5.40(d,J＝10.4Hz,1H),5.33(t,J＝6.6Hz,1H),5.29-5.21(m,1H),2.13(q,J＝6.9Hz,2H),1.50-1.24(m,10H),0.88(t,J＝6.6Hz,3H).13C NMR(75MHz,CDCl3)δ138.1,135.9,134.5,127.4,125.0,119.5,67.4,32.4,31.9,29.24,29.18,28.8,22.8,14.2.HRMS(ESI)m/z calculated molecular weight C 15H24N3O2[M+H]+: 278.1863, found: 278.1796HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IC column (mobile phase: n-hexane/isopropanol=95:5), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝5.65min,tR (minor) =5.33 min.e.e.=97%).
Example 3
Synthesis of (3 ac):
to the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) chiral ligand L (8.0 mg,16 mol%) and dichloromethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol,27.3 mg), 2c (0.1 mmol,14.4 mg) and Yb (OTf) 3 (10 mg,0.12 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. Purification of the crude product by TLC preparative plate gave 3ac (22.1 mg,96% ee, yield :72％).1H NMR(300MHz,CDCl3)δ7.86-7.76(m,2H),7.44-7.35(m,3H),7.31-7.25(m,1H),6.57(d,J＝2.4Hz,1H),6.14(ddd,J＝17.1,10.3,5.7Hz,1H),5.81-5.64(m,2H),5.41(t,J＝5.3Hz,1H),5.28(dd,J＝10.3,1.1Hz,1H),5.21-5.11(m,1H),2.10(q,J＝6.8Hz,2H),1.44-1.25(m,10H),0.88(t,J＝6.5Hz,3H).13C NMR(75MHz,CDCl3)δ151.4,136.6,135.6,133.8,129.1,128.6,127.6,127.1,125.8,117.5,102.9,66.0,32.5,31.9,29.26,29.25,29.1,22.8,14.2.HRMS(ESI)m/z calculated molecular weight C 21H29N2[M+H]+: 309.2331, found 309.2321.hplc: enantiomeric excess, determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK OD-H column (mobile phase: n-hexane/isopropanol=90:10), flow rate: 1.0mL/min, λ=225 nm, t R (major) =7.37 min, retention time: t R (minor) =6.78 min.e.e. =97%.
Example 4
Synthesis of (3 ba):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) under argon atmosphere, (S) -L (8.0 mg,16 mol%) and methylene chloride (1.5 mL) and stirred at room temperature for 5 minutes. Subsequently, 1b (0.15 mmol,19.0 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (12.4 mg,0.02 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. The crude product was purified by TLC prep plate to give 3ba (22.5 mg,99% ee, yield :73％).1H NMR(300MHz,CDCl3)δ7.83-7.80(m,2H),7.44-7.36(m,2H),7.34-7.27(m,1H),7.14(s,1H),6.41(t,J＝6.7Hz,1H),6.25(ddd,J＝16.8,10.4,6.2Hz,1H),5.90(ddt,J＝15.4,7.1,1.2Hz,1H),5.71(dt,J＝15.0,6.6Hz,1H),5.24-5.14(m,2H),3.90(s,3H),2.04(q,J＝7.3Hz,2H),1.48-1.34(m,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(75MHz,CDCl3)δ160.4,150.3,137.5,134.5,132.9,132.7,128.8,128.2,128.1,125.8,116.7,108.3,64.6,52.1,34.5,22.3,13.8.
HRMS (ESI) m/z calculated molecular weight C 19H23N2O2[M+H]+: 311.1754, found 311.1754.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IC column (mobile phase: n-hexane/isopropanol=99:1), flow rate: 1.0mL/min, λ=254 nm, retention time: t R(major)＝5.58min,tR (minor) =4.00 min.e.e. >99%.
Example 5
Synthesis of (3 ca):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) chiral ligand L (8.0 mg,16 mol%) and dichloromethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1c (0.15 mmol,28.5 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (10 mg,0.12 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. The crude product was purified by TLC prep plate to give 3ca (31.7 mg,90% ee, yield :85％).1H NMR(300MHz,CDCl3)δ7.85-7.81(m,2H),7.43-7.28(m,5H),7.16(s,1H),6.87-6.79(m,2H),6.65-6.43(m,3H),6.35(ddd,J＝17.3,10.1,6.1Hz,1H),5.32-5.23(m,2H),3.91(s,3H),3.79(s,3H).13C NMR(75MHz,CDCl3)δ160.4,159.6,150.5,137.0,132.82,132.78,132.4,129.3,128.8,128.14,128.06,125.8,125.4,117.3,114.1,108.4,64.7,55.4,52.1.
HRMS (ESI) m/z calculated molecular weight C 23H23N2O3[M+H]+: 375.1703, found 375.1703.Hplc: enantiomeric excess, determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IC column (mobile phase: n-hexane/isopropanol=99:1), flow rate: 1.0mL/min, λ=254 nm, retention time: t R(major)＝12.19min,tR (minor) =8.28 min.e.e. =90%.
Example 6
Synthesis of (3 da):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) chiral ligand L (8.0 mg,16 mol%) and dichloromethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1d (0.15 mmol,25.0 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (10 mg,0.12 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. The crude product was purified by TLC prep plate to give 3da (24.5 mg,98% ee, yield) :71％).1H NMR(300MHz,CDCl3)δ7.87-7.79(m,2H),7.45-7.26(m,3H),7.14(s,1H),6.43(t,J＝6.7Hz,1H),6.32-6.18(m,1H),5.92(dd,J＝15.4,7.2Hz,1H),5.80-5.66(m,1H),5.43-5.27(m,2H),5.23-5.13(m,2H),3.89(s,3H),2.16-2.11(m,4H),2.07-1.95(m,2H),0.93(t,J＝7.5Hz,3H).
13C NMR(75MHz,CDCl3)δ160.3,150.3,137.3,133.9,132.9,132.7,132.3,128.7,128.4,128.2,128.1,125.8,116.8,108.3,64.4,52.0,32.5,26.7,20.7,14.4.
HRMS (ESI) m/z calculated molecular weight C 22H27N2O2[M+H]+: 351.2067, found 351.2066.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IA column (mobile phase: n-hexane/isopropanol=99.5:0.5), flow rate: 1.0mL/min, λ=225 nm, retention time: tR (major) =5.81 min, tR (minor) =5.12 min.e.e. >99%.
Example 7
Synthesis of (3 ea):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) chiral ligand L (8.0 mg,16 mol%) and dichloromethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1e (0.15 mmol,25 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (10 mg,0.12 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. The crude product was purified by TLC prep plate to give 3ea (26.5 mg,99% ee, yield) :76％).1H NMR(300MHz,CDCl3)δ7.85-7.79(m,2H),7.43-7.36(m,2H),7.34-7.27(m,1H),7.13(s,1H),6.39(t,J＝6.7Hz,1H),6.24(ddd,J＝16.6,10.3,6.1Hz,1H),5.85(ddd,J＝15.6,7.2,0.9Hz,1H),5.67(dd,J＝15.6,6.4Hz,1H),5.23-5.12(m,2H),3.89(s,3H),2.03-1.94(m,1H),1.74-1.63(m,5H),1.33-1.01(m,5H).
13C NMR(75MHz,CDCl3)δ160.3,150.3,140.3,137.6,132.9,132.7,128.7,128.0,125.8,125.6,116.6,108.3,64.7,52.0,40.5,32.75,32.73,26.3,26.1.
HRMS (ESI) m/z calculated molecular weight C 22H27N2O2[M+H]+: 351.2067, found 351.2066.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IC column (mobile phase: n-hexane/isopropanol=90:10), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝3.99min,tR (minor) =3.66 min.e.e. =99%.
Example 8
Synthesis of (3 fa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) chiral ligand L (8.0 mg,16 mol%) and dichloromethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1f (0.15 mmol,28.2 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (10 mg,0.12 mmol). The tube was then capped and the reaction was allowed to react at 0deg.C for 2 hours. The crude product was purified by TLC prep plate to give 3fa (23.7 mg,97% ee, yield :64％).1H NMR(300MHz,CDCl3)δ7.84-7.79(m,2H),7.43-7.37(m,2H),7.34-7.21(m,3H),7.19-7.12(m,4H),6.42(t,J＝6.6Hz,1H),6.29-6.16(m,1H),5.92(dd,J＝15.5,7.2Hz,1H),5.75(dt,J＝15.4,6.4Hz,1H),5.23-5.10(m,2H),3.90(s,3H),2.70(t,J＝7.2Hz,2H),2.38(q,J＝7.0Hz,2H).
13C NMR(75MHz,CDCl3)δ160.3,150.4,141.7,137.2,133.5,132.8,132.7,128.8,128.7,128.6,128.4,128.1,125.9,125.8,116.8,108.3,64.4,52.1,35.5,34.2.
HRMS (ESI) m/z calculated molecular weight C 24H25N2O2[M+H]+: 373.1911, found 373.1909.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IC column (mobile phase: n-hexane/isopropanol=99:1), flow rate: 1.0mL/min, λ=234 nm, retention time: tR (major) =7.88 min, tR (minor) =5.42 min.e.e. =97%.
Example 9
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (1.3 mg,2 mol%) under argon atmosphere, (S) -L (4.0 mg,8 mol%) and methylene chloride (1.5 mL) and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol,27.3 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (12.4 mg,0.02 mmol). The tube was then sealed and the reaction was allowed to react at 0℃for 2h. The crude product was purified by TLC prep plate to give 3aa (18.3 mg,95% ee, yield: 50%).
Example 10
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) under argon atmosphere, (S) -L (8.0 mg,16 mol%) and methylene chloride (1.5 mL) and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol,27.3 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (12.4 mg,0.02 mmol). The tube was then capped and the reaction was allowed to react for 2h at 25 ℃. The crude product was purified by TLC prep plate to give 3aa (27.8 mg,92% ee, yield: 76%).
Example 11
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) under argon atmosphere, (S) -L (8.0 mg,16 mol%) and toluene (1.5 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol,27.3 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (12.4 mg,0.02 mmol). The tube was then sealed and the reaction was allowed to react at 0℃for 2h. The crude product was purified by TLC prep plate to give 3aa (14.0 mg,92% ee, yield: 38%).
Example 12
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,4 mol%) under argon atmosphere, (S) -L (8.0 mg,16 mol%) and methylene chloride (1.5 mL) and stirred at room temperature for 5 minutes. Subsequently, 1a (0.2 mmol,36.0 mg), 2a (0.1 mmol,20.2 mg) and Yb (OTf) 3 (12.4 mg,0.02 mmol). The tube was then sealed and the reaction was allowed to react at 0℃for 2h. The crude product was purified by TLC prep plate to give 3aa (27.8 mg,94% ee, yield: 76%).
The examples are preferred embodiments of the present invention, but the present invention is not limited to the above-described embodiments, and any obvious modifications, substitutions or variations that can be made by one skilled in the art without departing from the spirit of the present invention are within the scope of the present invention.
Claims (8)
1. A method for synthesizing chiral 1, 4-dienylpyrazole derivatives, characterized in that: the method comprises the following steps: under the protection of argon, an iridium catalyst and a chiral ligand L are dissolved in an organic solvent and placed in a tube sealing; sequentially adding racemic 1, 4-dienylallyl alcohol, pyrazole derivatives and additives into the tube sealing tube to replace argon, and carrying out substitution reaction on the racemic 1, 4-dienylallyl alcohol and pyrazole derivatives to obtain chiral 1, 4-dienylazole derivatives; the structural formula of the racemized 1, 4-dienylallyl alcohol isWherein R 1 is alkyl or aryl; the structural formula of the pyrazole derivative compound is as follows: /(I)Wherein R 2 is one of alkyl, aryl, halogen or nitro.
2. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative according to claim 1, characterized in that: the molar ratio of the 1, 4-dienylallyl alcohol to the pyrazole derivative is 1-2:1.
3. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative according to claim 1, characterized in that: the organic solvent is one or more of dichloromethane, dichloroethane, toluene and diethyl ether.
4. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative according to claim 1, characterized in that: the iridium catalyst is 1, 5-cyclooctadiene iridium chloride dimer; the iridium catalyst is used in an amount of 2% -4% of the equivalent weight of the pyrazole derivative.
5. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative according to claim 1, characterized in that: the additive is Yb (OTf) 3; the additive equivalent is 10-100% of the pyrazole derivative equivalent.
6. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative compound according to claim 1, characterized in that: the chiral ligand L is of S-configuration, and has the structural formula of。
7. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative compound according to claim 6, characterized in that: the dosage of the chiral ligand L is 200-400% of the iridium catalyst equivalent.
8. The method for synthesizing a chiral 1, 4-dienylpyrazole derivative compound according to claim 1, characterized in that: the reaction temperature of the substitution reaction is 0 ℃ and the reaction time is 2 h.
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