CN118221589A - Synthesis method of chiral 1, 3-pentadienyl-5- (2H) -indazole compound - Google Patents
Synthesis method of chiral 1, 3-pentadienyl-5- (2H) -indazole compound Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000003446 ligand Substances 0.000 claims abstract description 19
- -1 indazole compound Chemical class 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000010948 rhodium Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 11
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000008300 phosphoramidites Chemical class 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- 238000006467 substitution reaction Methods 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 18
- RXPAYNWWOUGGHI-UHFFFAOYSA-K cycloocta-1,5-diene;rhodium(3+);trichloride Chemical group Cl[Rh](Cl)Cl.C1CC=CCCC=C1 RXPAYNWWOUGGHI-UHFFFAOYSA-K 0.000 claims description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 9
- 235000019253 formic acid Nutrition 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 150000002473 indoazoles Chemical class 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 3
- 239000003960 organic solvent Substances 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- YBEOQWQBKVOTNV-UHFFFAOYSA-K [Sc+3].CS(=O)(=O)O.[F-].[F-].[F-] Chemical compound [Sc+3].CS(=O)(=O)O.[F-].[F-].[F-] YBEOQWQBKVOTNV-UHFFFAOYSA-K 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 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
- 238000004128 high performance liquid chromatography Methods 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
- 239000000203 mixture Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000002955 isolation Methods 0.000 description 9
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+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 HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- MMFCJPPRCYDLLZ-CMDGGOBGSA-N (2E)-dec-2-enal Chemical compound CCCCCCC\C=C\C=O MMFCJPPRCYDLLZ-CMDGGOBGSA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 238000007105 allylic amination reaction Methods 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- MMFCJPPRCYDLLZ-UHFFFAOYSA-N dec-2-enal Natural products CCCCCCCC=CC=O MMFCJPPRCYDLLZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment 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
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound, the structural formula of which is shown as the following, wherein R 1 is straight-chain alkyl, branched-chain alkyl or cycloalkyl; r 2 is hydrogen, halogen, alkyl or methoxy. The method for selectively synthesizing the chiral 1, 3-pentadienyl-5- (2H) -indazole compound by combining a rhodium catalyst and a chiral phosphoramidite ligand and catalyzing 1, 4-dienyl-3-alcohol and indazole compound to carry out substitution reaction. The method belongs to the field of organic synthesis. The method has the advantages of simple and easily obtained raw materials, mild reaction conditions, high regioselectivity and enantioselectivity, wide substrate application range and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a chiral 1, 3-pentadienyl-5- (2H) -indazole compound.
Background
Chiral 1, 3-pentadienyl-5- (2H) -indazole is a common framework structure, is a common organic synthesis intermediate, and is a common fragment of natural products and medical intermediates. Up to now, no literature has been reported on the synthesis of N 2 -selectively synthesized chiral 1, 3-pentadienyl-5- (2H) -indazole compounds. The construction of chiral (2H) -indazoles presents a great challenge, mainly because: indazoles exist at both competing nucleophilic sites of N 1 and N 2, and nucleophilicity N 1>N2. Thus, the indazolyl-alkylated product is often an N1 substituted product or a mixture of N 1/N2 substitutions (see more fully :(1).A.M.Haydl,K.Xu,B.Breit,Angew.Chem.Int.Ed.2015,54,7149-7153;(2)L.J.Hilpert,S.V.Sieger,A.M.Haydl,B.Breit,Angew.Chem.Int.Ed.2019,58,3378-3381;(3)A.Y.Jiu,H.S.Slocumb,C.S.Yeung,X.-H.Yang,V.M.Dong,Angew.Chem.Int.Ed.2021,60,19660-19664).
Catalyzing asymmetric allylic amination reactions is a common strategy for constructing chiral allylic hybrid cyclizations. Based on this, an asymmetric allylamine amination reaction was attempted to selectively synthesize 1, 3-pentadienyl-5- (2H) -indazole compounds.
Disclosure of Invention
In view of the fact that no method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compounds has been reported. The invention provides a commercially available indazole compound and 1, 4-dienyl alcohol which is easy to prepare and store, which are used as reaction raw materials to synthesize chiral 1, 3-pentadienyl-5- (2H) -indazole compounds.
In order to achieve the purpose of the invention, the technical scheme adopted is as follows:
a method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound comprises the step of carrying out substitution reaction on racemic dienyl alcohol and indazole compound under the catalysis of rhodium catalyst and ligand to generate a series of chiral 1, 3-pentadienyl-5- (2H) -indazole compounds.
The structural formula of the chiral 1, 3-pentadienyl-5- (2H) -indazole compound is shown as the following formula:
Wherein R 1 is straight chain alkyl, branched alkyl, or cycloalkyl; r 2 is hydrogen, halogen, alkyl or methoxy.
Further, the method comprises the following steps: under the protection of argon, the rhodium catalyst and the chiral phosphoramidite ligand are dissolved in methylene dichloride solvent and placed in a sealed tube, and the mixture is stirred for about 5 minutes to be fully mixed. Then sequentially adding the 1, 4-dienyl-3-alcohol compound, the indazole compound and the additive into the tube sealing, replacing argon, then reacting for 24-48H at the temperature of-20-25 ℃, and purifying to obtain the chiral 1, 3-pentadienyl-5- (2H) -indazole compound.
The specific reaction equation is as follows (Scheme 1):
Wherein [ Rh (cod) Cl ] 2 is a rhodium catalyst, and L is the chiral phosphoramidite ligand.
Further, the 1, 4-dienyl-3-ol compound R 1 may be a linear alkyl group, a branched alkyl group, or a cycloalkyl group.
More specifically, the 1, 4-dienyl-3-ol compound is any one of the following structural formulas:
Further, the indazole compound may be unsubstituted indazole or an electron withdrawing group such as halogen, or an alkyl or methoxy substituted indazole compound, wherein R 2 is an electron withdrawing group.
Specifically, the indazole compound is any one of the following structural formulas:
Further, the molar ratio of the 1, 4-dienyl alcohol to the indazole compound is 1.5:1 to 3:1, and more preferably 2:1, at which molar ratio the yield is maximized.
Furthermore, the rhodium catalyst is used in an amount of 2% -4% of the molar equivalent of the indazole compound, and more preferably 4%.
Further, the rhodium catalyst is 1, 5-cyclooctadiene rhodium chloride dimer.
Furthermore, the chiral phosphoramidite ligand L is in an (S) -configuration, and the use amount of the chiral phosphoramidite ligand L is 8-16% of the molar amount of indazole compounds.
Further, the chiral phosphoramidite ligand structure is:
Further, the dosage of the additive is 200% -500% of the molar equivalent of indazole compounds; preferably 400%.
Further, the additive is any one of formic acid, acetic acid, trifluoro formic acid and scandium trifluoro methane sulfonate. Formic acid is preferred.
Further, the reaction temperature of the substitution reaction is-20 ℃.
Further, the reaction time of the substitution reaction was 24 hours.
The process of the present invention uses a commercially available indazole and a one-step preparable 1, 4-dienyl alcohol as reaction starting materials. The reaction operation is simple, the condition is mild, the substrate applicability is good, and the target chiral 1, 3-pentadienyl-5- (2H) -indazole compound is obtained with high regioselectivity and stereoselectivity.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 3 aa;
FIG. 2 is a nuclear magnetic resonance chromatogram of 3 aa;
FIG. 3 is a chiral high performance liquid chromatogram of 3 aa;
FIG. 4 is a high resolution analysis of 3 aa.
Detailed Description
The invention is further described below in connection with examples, but is not limited thereto.
Pyrazole starting materials in the following examples of the present invention are all commercially available. Other reagents of the invention, not specifically described, are commercially available.
Equation for synthesis of racemic 1, 4-dienyl-3-alcohols:
taking 1a as an example, 10mmol decenal was dissolved in 20mL 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, saturated ammonium chloride solution was added for quenching, extraction was performed with 50mL of ethyl acetate, and spin-drying was performed, whereby compound 1a was obtained in 1.64g by silica gel column separation in 90% yield. In this way, compounds 1a to 1e were synthesized.
Example 1
Synthesis of 3 aa:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,36 mg), 2a (0.1 mmol,11.8 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Isolation and purification gave oil 3aa (20.9 mg, yield) :74％,92％ee).1H NMR(300MHz,CDCl3)δ7.92(s,1H),7.74(dd,J＝8.7,0.7Hz,1H),7.64(d,J＝8.4Hz,1H),7.30-7.24(m,1H),7.09-7.04(m,1H),6.32(dt,J＝16.6,10.0Hz,1H),6.18(dd,J＝15.0,10.2Hz,1H),6.01(dd,J＝15.0,7.2Hz,1H),5.32-5.09(m,2H),4.99(q,J＝7.3Hz,1H),2.27-2.15(m,1H),2.08-1.92(m,1H),1.39-1.11(m,10H),0.85(t,J＝6.7Hz,3H).13C NMR(75MHz,CDCl3)δ148.6,135.9,133.3,132.3,125.8,121.64,121.60,121.4,120.2,118.8,117.7,65.9,35.5,31.8,29.2,29.1,26.1,22.7,14.2.HRMS(ESI)m/z calculated for C19H27N2[M+H]+:283.2169,found:283.2167.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IA column (mobile phase: n-hexane/isopropanol=98:2), flow rate: 1.0mL/min, λ=254 nm, retention time: t R(major)＝8.18min,tR (minor) =9.53 min.e.e. =92%.
Example 2
Synthesis of 3 ab:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,36 mg), 2b (0.1 mmol,14.8 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Purification and isolation gave 3aa (22.8 mg, yield :73％,92％ee,).1H NMR(300MHz,CDCl3)δ7.79(s,1H),7.63(d,J＝9.3Hz,1H),6.98(dd,J＝9.3,2.4Hz,1H),6.87(d,J＝2.2Hz,1H),6.32(dt,J＝16.7,10.1Hz,1H),6.16(dd,J＝15.1,10.2Hz,1H),5.99(dd,J＝15.1,7.1Hz,1H),5.25-5.09(m,2H),4.94(q,J＝7.2Hz,1H),3.82(s,3H),2.22-2.12(m,1H),2.06-1.93(m,1H),1.32-1.10(m,10H),0.85(t,J＝6.7Hz,3H).13C NMR(75MHz,CDCl3)δ155.1,145.3,135.9,133.1,132.5,121.5,120.51,120.46,119.1,118.7,96.7,65.7,55.4,35.4,31.8,29.3,29.2,26.1,22.7,14.2.
HRMS(ESI)m/z calculated for C20H29N2O[M+H]+:313.2274,found:313.2277.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IA column (mobile phase: n-hexane/isopropanol=90:10), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝10.42min,tR (minor) =13.15 min.e.e. =92%.
Example 3
3Ac synthesis:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,36 mg), 2c (0.1 mmol,13.2 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Purification by isolation gave 3ac (21.3 mg, yield: 72%,95% ee).
1H NMR(300MHz,CDCl3)δ7.91(s,1H),7.56(d,J＝8.7Hz,1H),7.18(dd,J＝8.7,6.7Hz,1H),6.83(d,J＝6.7Hz,1H),6.33(dt,J＝16.6,10.0Hz,1H),6.19(dd,J＝15.1,10.2Hz,1H),6.02(dd,J＝15.1,7.2Hz,1H),5.22(d,J＝16.3Hz,1H),5.16-5.08(m,1H),4.99(q,J＝7.3Hz,1H),2.52(s,3H),2.31-2.15(m,1H),2.09-1.93(m,1H),1.35-1.11(m,10H),0.85(t,J＝6.7Hz,3H).
13C NMR(75MHz,CDCl3)δ148.7,136.0,133.3,132.5,130.4,126.2,123.0,120.9,120.4,118.8,115.1,65.9,35.5,31.9,29.3,29.2,26.1,22.7,19.3,14.2.
HRMS(ESI)m/z calculated for C20H29N2[M+H]+:297.2325,found:297.2325.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IA column (mobile phase: n-hexane/isopropanol=90:10), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝4.36min,tR (minor) =4.76 min.e.e. =95%.
Example 4
3Ad synthesis:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,36 mg), 2d (0.1 mmol,19.7 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Purification by isolation gave 3ad (27.3 mg, yield: 76%,90% ee).
1H NMR(300MHz,CDCl3)δ7.95(d,J＝0.6Hz,1H),7.67(d,J＝8.6Hz,1H),7.24(dd,J＝6.1,5.7Hz,1H),7.13(dd,J＝8.5,7.2Hz,1H),6.34(dt,J＝16.5,10.2Hz,1H),6.21(dd,J＝15.0,10.2Hz,1H),6.00(dd,J＝15.0,7.4Hz,1H),5.34-5.11(m,2H),4.99(q,J＝7.4Hz,1H),2.28-2.16(m,1H),2.09-1.95(m,1H),1.36-1.15(m,10H),0.85(t,J＝6.8Hz,3H).
13C NMR(75MHz,CDCl3)δ148.7,135.8,133.8,131.8,126.6,124.3,123.7,122.5,119.2,117.0,113.1,66.3,35.5,31.8,29.2,29.2,26.1,22.7,14.2.
HRMS(ESI)m/z calculated for C19H26BrN2[M+H]+:361.1274,found:361.1276.
HPLC: enantiomeric excess was 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, retention time: t R(major)＝4.05min,tR (minor) =4.63 min.e.e. =90%.
Example 5
Synthesis of 3 ba:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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, 1b (0.2 mmol,22.4 mg), 2a (0.1 mmol,11.8 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Isolation and purification gave 3ba (13.8 mg, yield) :65％,90％ee).1H NMR(300MHz,CDCl3)δ7.93(d,J＝0.9Hz,1H),7.74(dd,J＝8.7,0.9Hz,1H),7.65(dt,J＝8.4,0.9Hz,1H),7.33-7.15(m,1H),7.10-7.04(m,1H),6.33(dt,J＝16.6,10.0Hz,1H),6.19(dd,J＝15.0,10.2Hz,1H),6.02(dd,J＝15.1,7.2Hz,1H),5.26-5.10(m,2H),4.91(q,J＝7.3Hz,1H),2.32-2.15(m,1H),2.14-1.98(m,1H),0.87(t,J＝7.4Hz,3H).
13C NMR(75MHz,CDCl3)δ148.7,135.9,133.5,132.0,125.8,121.7,121.6,121.5,120.3,118.9,117.7,67.3,28.7,10.7.
HRMS(ESI)m/z calculated for C14H17N2[M+H]+:213.1386,found:213.1385.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IB column (mobile phase: n-hexane/isopropanol=95:5), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝7.78min,tR (minor) =6.36 min.e.e. =90%.
Example 6
Synthesis of 3 ca:
to the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,30.8 mg), 2a (0.1 mmol,11.8 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Separation and purification gave 3ca (15.8 mg, yield) :62％,95％ee).1H NMR(300MHz,CDCl3)δ7.96(d,J＝0.6Hz,1H),7.74(dd,J＝8.7,0.7Hz,1H),7.64(d,J＝8.4Hz,1H),7.31-7.23(m,1H),7.07(ddd,J＝8.2,6.7,0.7Hz,1H),6.28(dt,J＝16.9,9.9Hz,1H),6.09(dd,J＝15.2,9.7Hz,1H),5.99(dd,J＝15.1,6.8Hz,1H),5.25-5.07(m,3H),2.33(dd,J＝14.5,8.3Hz,1H),1.92(dd,J＝14.5,5.0Hz,1H),0.84(s,9H).13C NMR(75MHz,CDCl3)δ148.4,135.9,134.1,132.5,125.8,121.8,121.7,121.4,120.2,118.8,117.7,63.2,48.5,30.8,29.5.HRMS(ESI)m/z calculated for C17H23N2[M+H]+:255.1856,found:255.1854.
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: t R(major)＝12.61min,tR (minor) =14.43 min.e.e. =95%.
Example 7
3Da synthesis:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,30.4 mg), 2a (0.1 mmol,11.8 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. Isolation and purification gave 3da (16.4 mg, yield :65％,91％ee).1H NMR(300MHz,CDCl3)δ7.94(s,1H),7.74(dd,J＝8.7,0.6Hz,1H),7.65(d,J＝8.4Hz,1H),7.30-7.25(m,1H),7.12-7.02(m,1H),6.32(dt,J＝16.7,9.8Hz,1H),6.22-6.03(m,2H),5.20(dd,J＝16.7,1.2Hz,1H),5.11(dd,J＝9.9,1.3Hz,1H),4.70(dd,J＝10.2,7.4Hz,1H),2.79-2.65(m,1H),1.93-1.80(m,1H),1.75-1.07(m,7H).13C NMR(75MHz,CDCl3)δ148.5,136.0,133.8,131.8,125.8,121.7,121.6,121.5,120.3,118.8,117.7,71.1,44.9,30.2,30.1,25.5,25.1.HRMS(ESI)m/z calculated for C17H21N2[M+H]+:253.1699,found:253.1698.
HPLC: enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IA column (mobile phase: n-hexane/isopropanol=99:1), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝14.25min,tR (minor) =16.31 min.e.e. =91%.
Example 8
Synthesis of 3 ea:
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2 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 (0.2 mmol,44.4 mg), 2a (0.1 mmol,11.8 mg) and HCO 2 H (20 mg,0.4 mmol). The tube was then sealed and the reaction was allowed to react at-20℃for 24 hours. The crude product was purified by TLC prep plate to give 3ea (20.6 mg, yield) :64％,93％ee).1H NMR(300MHz,CDCl3)δ7.93(d,J＝0.6Hz,1H),7.74(dd,J＝8.7,0.7Hz,1H),7.65(d,J＝8.4Hz,1H),7.33-7.23(m,1H),7.11-7.02(m,1H),6.33(dt,J＝16.6,10.0Hz,1H),6.18(dd,J＝15.0,10.2Hz,1H),6.01(dd,J＝15.1,7.2Hz,1H),5.79(td,J＝16.9,6.7Hz,1H),5.27-5.18(m,1H),5.13(dd,J＝9.8,1.1Hz,1H),5.05-4.89(m,3H),2.25-2.15(m,1H),2.09-1.94(m,3H),1.39-1.11(m,12H).13C NMR(75MHz,CDCl3)δ148.6,139.3,135.9,133.4,132.3,125.8,121.7,121.6,121.4,120.3,118.9,117.7,114.3,65.9,35.5,33.9,29.45,29.44,29.3,29.2,29.0,26.1.
HRMS(ESI)m/z calculated for C22H31N2[M+H]+:323.2482,found:323.2485.HPLC: Enantiomeric excess was determined by high performance liquid chromatography, specific conditions: DAICEL CHIRALPAK IA column (mobile phase: n-hexane/isopropanol=98:2), flow rate: 1.0mL/min, λ=225 nm, retention time: t R(major)＝8.28min,tR (minor) =10.02 min.e.e. =93%.
Example 9
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (1 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,36.0 mg), 2a (0.1 mmol,11.8 mg) and formic acid (20 mg,0.4 mmol). The tube was then sealed and the reaction was carried out at-20℃for 24h. Purification by isolation gave 3aa (11.3 mg, yield: 40%,90% ee).
Example 10
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2.0 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,11.8 mg) and formic acid (20.0 mg,0.4 mmol). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Purification by isolation gave 3aa (19.8 mg, yield: 70%,82% ee).
Example 11
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2.0 mg,4 mol%) under argon atmosphere, (S) -L (8.0 mg,16 mol%) and toluene (1.5 mL) and stirred at room temperature for 5 minutes. Subsequently, 1a (0.2 mmol,36 mg), 2a (0.1 mmol,11.8 mg) and formic acid (20.0 mg,0.4 mmol). The tube was then sealed and the reaction was carried out at-20℃for 24h. Purification by isolation gave 3aa (10.0 mg, yield: 35%,52% ee).
Example 12
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene rhodium chloride dimer (2.0 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,11.8 mg) and formic acid (10 mg,0.2 mmol). The tube was then sealed and the reaction was carried out at-20℃for 24h. The crude product was purified by TLC prep plate to give 3aa (13.5 mg, yield: 48%,90% ee).
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 (10)
1. A method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound is characterized in that: under the catalysis of rhodium catalyst, the racemized 1, 4-dienyl-3-alcohol compound and indazole compound undergo substitution reaction to generate chiral 1, 3-pentadienyl-5- (2H) -indazole compound; the structural formula of the chiral 1, 3-pentadienyl-5- (2H) -indazole compound is shown as the following formula:
，
Wherein R 1 is straight chain alkyl, branched alkyl, or cycloalkyl; r 2 is hydrogen, halogen, alkyl or methoxy.
2. The method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 1, characterized in that: the synthesis method comprises the following steps: under the protection of argon, dissolving a rhodium catalyst and a chiral phosphoramidite ligand in an organic solvent, placing the organic solvent in a sealed tube, and stirring to fully mix the rhodium catalyst and the chiral phosphoramidite ligand; sequentially adding a1, 4-dienyl-3-alcohol compound, an indazole compound and an additive, replacing argon, carrying out substitution reaction, and purifying and separating to obtain a chiral 1, 3-pentadienyl-5- (2H) -indazole compound;
。
3. The synthesis method of chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 1 or2, characterized in that: the molar ratio of the 1, 4-dienyl-3-alcohol compound to the indazole compound is 1.5-3:1.
4. The synthesis method of chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 1 or 2, characterized in that: the reaction temperature ranges from minus 20 ℃ to 25 ℃ and the reaction time ranges from 24h to 48h.
5. The synthesis method of chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 1 or 2, characterized in that: the 1, 4-dienyl-3-alcohol compound is any one of the following structural formulas:
、/>、/>、、/>。
6. The synthesis method of chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 1 or 2, characterized in that: the indazole compound is any one of the following structural formulas:
、/>、/>、/>。
7. The method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 2, characterized in that: the dosage of the rhodium catalyst is 2% -4% of the molar equivalent of the indazole compound; the dosage of the chiral phosphoramidite ligand is 8% -16% of the molar equivalent of indazole compounds; the dosage of the additive is 200% -500% of the molar equivalent of the indazole compound.
8. The method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 2, characterized in that: the organic solvent is any one of dichloromethane, chloroform, toluene and diethyl ether.
9. The method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 2, characterized in that: the rhodium catalyst is 1, 5-cyclooctadiene rhodium chloride dimer; the additive is any one of formic acid, acetic acid, trifluoro formic acid and trifluoro scandium methane sulfonate.
10. The method for synthesizing chiral 1, 3-pentadienyl-5- (2H) -indazole compound according to claim 2, characterized in that: the chiral phosphoramidite ligand has the structure that:。
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