CN115974825B - Method for preparing 3-substituted chromanone by metal-free catalytic hydrogenation - Google Patents
Method for preparing 3-substituted chromanone by metal-free catalytic hydrogenation Download PDFInfo
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- -1 3-substituted chromanone Chemical class 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000009903 catalytic hydrogenation reaction Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 65
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229910000085 borane Inorganic materials 0.000 claims abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 33
- 239000000758 substrate Substances 0.000 claims abstract description 5
- 230000003197 catalytic effect Effects 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 62
- 238000002360 preparation method Methods 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 238000012856 packing Methods 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims 4
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000012014 frustrated Lewis pair Substances 0.000 abstract description 2
- 238000012546 transfer Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 80
- 238000010200 validation analysis Methods 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- HLWSQLFDQRUYCA-UHFFFAOYSA-N 1-(2-hydroxyphenyl)-3-methylbutan-1-one Chemical compound CC(C)CC(=O)C1=CC=CC=C1O HLWSQLFDQRUYCA-UHFFFAOYSA-N 0.000 description 2
- GDLZSXQEWAHRNQ-UHFFFAOYSA-N CC(C)C(C(C1=C2)=O)=COC1=CC=C2C1=CC=CC=C1 Chemical compound CC(C)C(C(C1=C2)=O)=COC1=CC=C2C1=CC=CC=C1 GDLZSXQEWAHRNQ-UHFFFAOYSA-N 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 150000004777 chromones Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052755 nonmetal Inorganic materials 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VKACUMNDDKMYEC-SSDOTTSWSA-N (3R)-3-methyl-3,4-dihydrochromen-2-one Chemical compound C[C@@H]1Cc2ccccc2OC1=O VKACUMNDDKMYEC-SSDOTTSWSA-N 0.000 description 1
- CTMWKJOXBLLKAO-JTQLQIEISA-N (3S)-3-propan-2-yl-3,4-dihydrochromen-2-one Chemical compound CC(C)[C@@H]1Cc2ccccc2OC1=O CTMWKJOXBLLKAO-JTQLQIEISA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 1
- GXPDDAOEKYZEAZ-UHFFFAOYSA-N 3-(2-methylphenyl)chromen-4-one Chemical compound CC1=CC=CC=C1C1=COC2=CC=CC=C2C1=O GXPDDAOEKYZEAZ-UHFFFAOYSA-N 0.000 description 1
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 description 1
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 1
- CYEKUDPFXBLGHH-UHFFFAOYSA-N 3-tert-Butylphenol Chemical compound CC(C)(C)C1=CC=CC(O)=C1 CYEKUDPFXBLGHH-UHFFFAOYSA-N 0.000 description 1
- JKJULDMNNQSLHL-UHFFFAOYSA-N 6-bromo-3-propan-2-ylchromen-4-one Chemical compound CC(C)C1=COC2=C(C=C(Br)C=C2)C1=O JKJULDMNNQSLHL-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ORVYBDBNRJTDHS-UHFFFAOYSA-N C(CCCC)C1C(OC2=CC=CC=C2C1)=O Chemical compound C(CCCC)C1C(OC2=CC=CC=C2C1)=O ORVYBDBNRJTDHS-UHFFFAOYSA-N 0.000 description 1
- NAHZTROOKZITSE-UHFFFAOYSA-N CC(C)C(C(C1=C2)=O)=COC1=CC=C2C(C=C1)=CC=C1OC Chemical compound CC(C)C(C(C1=C2)=O)=COC1=CC=C2C(C=C1)=CC=C1OC NAHZTROOKZITSE-UHFFFAOYSA-N 0.000 description 1
- ZHJROHRBXMCCBU-UHFFFAOYSA-N CC(C)C(C(C1=C2)=O)=COC1=CC=C2C1=CC=C(C(F)(F)F)C=C1 Chemical compound CC(C)C(C(C1=C2)=O)=COC1=CC=C2C1=CC=C(C(F)(F)F)C=C1 ZHJROHRBXMCCBU-UHFFFAOYSA-N 0.000 description 1
- XPANJUQWWRQCLT-UHFFFAOYSA-N CC(C)C1=COC2=CC(C)=CC=C2C1=O Chemical compound CC(C)C1=COC2=CC(C)=CC=C2C1=O XPANJUQWWRQCLT-UHFFFAOYSA-N 0.000 description 1
- SGTVXVBLTQCYGA-JTQLQIEISA-N CC(C)[C@H](CC(C(O1)=C2)=CC=C2Br)C1=O Chemical compound CC(C)[C@H](CC(C(O1)=C2)=CC=C2Br)C1=O SGTVXVBLTQCYGA-JTQLQIEISA-N 0.000 description 1
- MYYMSLWKDHVRBT-JTQLQIEISA-N CC(C)[C@H](CC1=CC(Br)=CC=C1O1)C1=O Chemical compound CC(C)[C@H](CC1=CC(Br)=CC=C1O1)C1=O MYYMSLWKDHVRBT-JTQLQIEISA-N 0.000 description 1
- LNSSLMGEFCCGGD-KRWDZBQOSA-N CC(C)[C@H](CC1=CC(C(C=C2)=CC=C2OC)=CC=C1O1)C1=O Chemical compound CC(C)[C@H](CC1=CC(C(C=C2)=CC=C2OC)=CC=C1O1)C1=O LNSSLMGEFCCGGD-KRWDZBQOSA-N 0.000 description 1
- QEYHMQIBJQWMPF-INIZCTEOSA-N CC(C)[C@H](CC1=CC(C2=CC=C(C(F)(F)F)C=C2)=CC=C1O1)C1=O Chemical compound CC(C)[C@H](CC1=CC(C2=CC=C(C(F)(F)F)C=C2)=CC=C1O1)C1=O QEYHMQIBJQWMPF-INIZCTEOSA-N 0.000 description 1
- DDLPQMLJGLWTCY-JTQLQIEISA-N CC(C)[C@H](CC1=CC(Cl)=CC=C1O1)C1=O Chemical compound CC(C)[C@H](CC1=CC(Cl)=CC=C1O1)C1=O DDLPQMLJGLWTCY-JTQLQIEISA-N 0.000 description 1
- UVFUFSUQJSIAAH-NSHDSACASA-N CC(C)[C@H](CC1=CC=C(C)C=C1O1)C1=O Chemical compound CC(C)[C@H](CC1=CC=C(C)C=C1O1)C1=O UVFUFSUQJSIAAH-NSHDSACASA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- JHYXBPPMXZIHKG-CYBMUJFWSA-N Dihydrodaidzein Natural products C1=CC(O)=CC=C1[C@@H]1C(=O)C2=CC=C(O)C=C2OC1 JHYXBPPMXZIHKG-CYBMUJFWSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- VNLZLLDMKRKVEX-UHFFFAOYSA-N cyclohex-3-enone Chemical compound O=C1CCC=CC1 VNLZLLDMKRKVEX-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- JHYXBPPMXZIHKG-UHFFFAOYSA-N dihydrodaidzein Chemical compound C1=CC(O)=CC=C1C1C(=O)C2=CC=C(O)C=C2OC1 JHYXBPPMXZIHKG-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- ABJKIHHNDMEBNA-UHFFFAOYSA-N methylchromone Chemical compound C1=CC=C2C(=O)C(C)=COC2=C1 ABJKIHHNDMEBNA-UHFFFAOYSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Abstract
The invention discloses a method for preparing 3-substituted chromanone compounds by metal-free catalytic hydrogenation. The method comprises the following steps: in a catalytic system of borane shown in a formula I and chiral phosphoric acid shown in a formula II, a compound shown in a formula III reacts with hydrogen to obtain the chiral phosphoric acid. According to the invention, a hindered Lewis acid-base pair (FLPs) is formed by using an achiral borane catalyst and a 3-substituted chromone substrate (shown in formula III), low-cost hydrogen is used as a hydrogen source, chiral phosphoric acid is used as a proton transfer catalyst, a series of 3-substituted chromanone compounds (shown in formula IV) with high enantioselectivity are efficiently obtained, and the method has high practical application value. The method has the advantages of easy synthesis of the catalyst, mild reaction condition, simple operation, high stereoselectivity and the like, and the ee value of the product is up to 95%, and the yield is up to 98%.
Description
Technical Field
The invention relates to a method for preparing 3-substituted chromanone by metal-free catalytic hydrogenation, in particular to a method for preparing 3-substituted chromanone by relay catalytic hydrogenation by using a nonmetal catalyst-borane and a chiral phosphoric acid catalyst, belonging to the technical field of organic synthesis.
Background
In the past, hydrogenation studies on chromone substrates have been mostly limited to 2-substituted chromone substrates, but currently, asymmetric hydrogenation studies on 3-substituted chromone compounds are few; in addition, the reduced 3-substituted chromanone compounds are important units of a plurality of bioactive molecules, such as dihydrodaidzein, and have a certain function of protecting cardiac muscle. However, current implementations of such conversions often require the use of metal catalysts, which may have metal residues that affect their biological activity. Therefore, the development of a novel method for preparing 3-substituted chromanone compounds with high efficiency and high selectivity by nonmetal catalysis has a great application prospect.
Disclosure of Invention
The invention aims to protect borane shown in a formula I and a chiral phosphoric acid compound shown in a formula II from being subjected to relay catalytic hydrogenation to prepare 3-substituted chromanone shown in a formula IV.
In the formula II, ar represents an aromatic group, and specifically can be phenyl or 3, 5-dimethylphenyl;
specifically, the chiral phosphoric acid compound represented by the above formula II may be any one of the following compounds:
in the formula III and the formula IV, R 1 Represents a substituent on the benzene ring, and specifically may be H, a straight or branched alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, a substituted or unsubstituted furan substituent, a substituted or unsubstituted thiophene substituent or halogen;
wherein the substituent in the substituted phenyl, the substituted furan substituent and the substituted thiophene substituent can be alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, halogen substituted alkyl with 1-4 carbon atoms and benzyloxy;
R 2 can be straight-chain or branched alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms or substituted or unsubstituted phenyl, wherein the substituent in the substituted phenyl can be alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, halogen substituted alkyl with 1-4 carbon atoms and benzyloxy;
more specifically, R 1 Can be hydrogen, fluorine, chlorine, bromine, methyl, tert-butyl, phenyl, trifluoromethyl substituted phenyl, methoxy substituted phenyl, benzyloxy substituted phenyl, furan substituents or thiophene substituents; r is R 2 In particular methyl, isopropyl, isobutyl, n-pentyl, cyclohexyl or methyl-substituted benzeneA base;
the 3-substituted chiral chromanone compound shown in the formula IV can be specifically the following compounds:
the preparation method of the 3-substituted chiral chromanone compound shown in the formula IV provided by the invention comprises the following steps:
in a catalytic system of borane shown in a formula I and chiral phosphoric acid compound shown in a formula II, reacting a compound shown in a formula III with hydrogen to obtain the chiral phosphoric acid compound;
in the preparation method, the molar ratio of the borane shown in the formula I, the chiral phosphoric acid compound shown in the formula II and the compound shown in the formula IV can be 4:1:10-4:1:500, specifically 4:1:200;
in the preparation method, the reaction is carried out in an autoclave, and the pressure of the hydrogen gas can be 10-80bar, and particularly can be 40bar;
in the preparation method, the reaction is carried out in an organic solvent, and the organic solvent can be toluene;
in the preparation method, the reaction temperature can be 30-100 ℃, specifically can be 60 ℃, and the reaction time can be 8-72 hours, specifically can be 24 hours;
in the preparation method, after the reaction is finished, the method also comprises the step of separating and purifying the 3-substituted chiral chromanone compound shown in the formula IV by column chromatography;
the conditions for the column chromatography were as follows:
the column packing is silica gel with 200-300 meshes; the eluent is as follows: the volume ratio is 5:1 with methylene chloride.
The invention takes various substituted chromone compounds (shown in a formula III) as raw materials, and takes hydrogen as a hydrogen source under the catalysis of borane shown in a formula I and chiral phosphoric acid compounds shown in a formula II, so that the 3-substituted chromane compounds (shown in a formula IV) are efficiently and highly selectively synthesized. The method has the advantages of easy synthesis of the catalyst, mild reaction condition, simple operation, high stereoselectivity and the like, and the ee value of the product is up to 95%, and the yield is up to 98%.
According to the invention, a hindered Lewis acid-base pair (FLPs) is formed by using an achiral borane catalyst and a 3-substituted chromone substrate, low-cost hydrogen is used as a hydrogen source, chiral phosphoric acid is used as a proton transfer catalyst, a series of 3-substituted chromanone compounds are obtained with high efficiency and high enantioselectivity, and the method has high practical application value.
Drawings
FIG. 1 is a synthetic scheme for the target compound of example 1.
FIG. 2 is a synthetic scheme for the target compound of example 2.
FIG. 3 is a synthetic scheme for the target compound of example 3.
FIG. 4 is a synthetic scheme for the target compounds of example 4.
FIG. 5 is a synthetic route pattern of the target compound in example 5.
FIG. 6 is a synthetic route pattern of the target compound in example 6.
FIG. 7 is a synthetic route pattern of the target compound in example 7.
FIG. 8 is a synthetic scheme for the target compound of example 8.
FIG. 9 is a synthetic route for the target compound of example 9.
FIG. 10 is a synthetic route pattern of the target compound in example 10.
FIG. 11 is a synthetic route for the target compound of example 11.
FIG. 12 is a synthetic route for the target compound of example 12.
FIG. 13 is a synthetic route for the target compound of example 13.
FIG. 14 is a synthetic route for the target compound of example 14.
FIG. 15 is a synthetic route pattern of the target compound in example 15.
FIG. 16 is a synthetic route for the target compound of example 16.
FIG. 17 is a synthetic route pattern of the target compound in example 17.
FIG. 18 is a synthetic route for the target compound of example 18.
FIG. 19 is a synthetic route for the target compound of example 19.
Detailed Description
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The invention provides a preparation method of a 3-substituted chiral chromanone compound shown in a formula IV, which comprises the following steps:
in a catalytic system of borane shown in a formula I and chiral phosphoric acid compound shown in a formula II, reacting a compound shown in a formula III with hydrogen to obtain the chiral phosphoric acid compound;
the invention takes various substituted chromone compounds (shown in a formula III) as raw materials, and takes hydrogen as a hydrogen source under the catalysis of borane shown in a formula I and chiral phosphoric acid compounds shown in a formula II, so that the 3-substituted chromane compounds (shown in a formula IV) are efficiently and highly selectively synthesized. The method has the advantages of easy synthesis of the catalyst, mild reaction condition, simple operation, high stereoselectivity and the like, and the ee value of the product is up to 95%, and the yield is up to 98%.
The borane of formula I is prepared according to document 1.
Chiral phosphate compounds of formula II are prepared according to documents 2 and 3.
The chromone compound shown in the formula III is prepared by modifying the chromone compound according to documents 4,5 and 6.
[1].Gao,B.；Feng,X.；Meng,W.；Du,H.Angew.Chem.,Int.Ed.2020,59,4498-4504.
[2].Storer,R.I.；Carrera,D.E.；Ni,Y.；MacMillan,D.W.C.J.Am.Chem.Soc.2006,128,84-86.
[3].Zhou,Q.；Meng,W.；Feng,X.；Du,H.；Yang,J.Tetrahedron Lett.2020,61,151394.
[4].E.；/>K.；/>J.；/>P.；/>I.A.；Pravdíková,K.；Kolbabová,L.；Hergeselová,T.；/>P.；Jansová,H.；/>M.；Jirkovská,A.；Richardson,V.；Lane,D.J.R.；Kalinowski,D.S.；Richardson,D.R.；Vávrová,K.；/>T.PloS One 2014,9,e112059.
[5].Bohlmann,F.；Vorwerk,E.Chem.Ber.1980,113,261.
[6]Gobbi,S.；Hu,Q.；Zimmer,C.；Engel,M.；Belluti,F.；Rampa,A.；Hartmann,R.W.；Bisi,A.J.Med.Chem.2016,59,2468-2477.
The compounds of formula III-a in the examples below were prepared by the following methods:
(2-hydroxyphenyl) -3-methyl-1-butanone (7.1293 g,40mmol,1 equiv) and N, N-dimethylformamide dimethyl acetal (95.3280 g,800mmol,20 equiv) of the formula V-a were added to a two-necked flask under nitrogen at room temperature, and heated under reflux at 120℃for 10 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (50 ml) was slowly added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (50 ml x 3) and the combined organic phases were washed twice with saturated brine (100 ml x 2) and dried over anhydrous sodium sulfate. Filtering, concentrating the reaction solution, purifying by silica gel column chromatography (column filler is 200-300 meshes of silica gel; eluent is mixed solution of petroleum ether and dichloromethane with volume ratio of 10:1) to obtain 4.7638g of 3-isopropyl ketone shown in formula III-a, and the yield is 63%.
The structure validation results are as follows: pale yellow oily liquid. 1 H NMR(500MHz,CDCl 3 ,ppm):δ8.23(dd,J＝8.0,1.0Hz,1H),7.73(s,1H),7.66-7.60(m,1H),7.42(d,J＝8.5Hz,1H),7.40-7.34(m,1H),3.22-3.11(m,1H),1.24(d,J＝7.0Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm):177.6,156.4,151.4,133.4,130.4,126.2,124.9,124.2,118.1,25.2,21.7.
Singh,P.；Kumar,A.；Kaur,S.；Kaur,J.；Singh,H.Chem.Comm.2016,52,2936-2939.
Wherein (2-hydroxyphenyl) -3-methyl-1-butanone represented by formula V-a is prepared by the following method: to a suspension of magnesium (6.0678 g,249.6mmol,4.05 equiv.) in anhydrous tetrahydrofuran (70 ml) under nitrogen, 1-bromo-2-methylpropane (33.7617 g,246.4mmol,4 equiv.) was slowly added, a small portion was added first, the reaction system was heated with a blower until the reaction was initiated, and then the remaining halide was slowly added dropwise. The reaction was cooled to room temperature and was then brought to 50℃under reflux for 2 hours. The preparation of the isogrignard reagent was completed, cooled to room temperature, and a solution of 2-hydroxybenzonitrile (7.3378 g,61.6mmol,1 equiv) in anhydrous tetrahydrofuran (70 ml) was slowly added dropwise thereto, and refluxing was continued at 50℃for 2 hours. Ice water (110 ml) and ice concentrated sulfuric acid (10 ml) were then slowly added to the reaction system under ice bath conditions until it was an acidic solution (ph=1), followed by refluxing at 80 ℃ for 1 hour. At the end of the reaction, the mixture was extracted twice with diethyl ether (50 ml x 2), washed twice with saturated sodium chloride solution (100 ml x 2), and dried over anhydrous sodium sulfate. After filtration and concentration, silica gel column chromatography purification (column filler is 200-300 meshes of silica gel; eluent is mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 40:1) is carried out, 10.6732g of (2-hydroxyphenyl) -3-methyl-1-butanone shown in a formula V-a is obtained, and the yield is 97%.
The structure validation results are as follows: IR (film): 2960,1640cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ12.47(s,1H),7.75(dd,J＝8.1,1.2Hz,1H),7.51-7.41(m,1H),6.98(d,J＝8.1Hz,1H),6.94-6.84(m,1H),2.85(d,J＝6.9Hz,2H),2.40-2.20(m,1H),1.02(d,J＝6.6Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ206.9,162.8,136.4,130.4,119.8,119.0,118.7,47.3,25.7,22.9；HRMS(ESI)calcd.for C 11 H 13 O 2 (M-H):177.0921,Found:177.0910.
Lo,H.-J.；Lin,C.-Y.；Tseng,M.-C.；Chein,R.-J.Angew.Chem.,Int.Ed.2014,53,9026-9029.
The compounds of the following examples are prepared by referring to the preparation of the compounds of the above formula III-a.
The structure validation results are as follows: white solid. m.p.115-116 ℃ IR (film): 2958,1642,831cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm):δ8.35(d,J＝2.0Hz,1H),7.75-7.67(m,2H),7.32(d,J＝8.8Hz,1H),3.22-3.08(m,1H),1.23(d,J＝7.2Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm):176.2,155.2,151.6,136.4,130.6,128.8,125.5,120.1,118.3,25.3,21.6；HRMS(APCI)calcd.for C 12 H 12 O 2 Br(M+H):267.0015,Found:267.0010.
The compounds of the following examples are prepared by referring to the preparation of the compounds of the above formula III-a.
The structure validation results are as follows: white solid. m.p.106-107 ℃ IR (film): 2961,1640,815cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm):8.19(d,J＝2.4Hz,1H),7.72(s,1H),7.38(d,J＝9.2Hz,1H),3.21-3.09(m,1H),1.24(d,J＝7.2Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm):176.4,154.7,151.6,133.7,130.8,130.5,125.6,125.1,119.9,25.3,21.6；HRMS(APCI)calcd.for C 12 H 12 O 2 Cl(M+H):223.0520,Found:223.0517.
The compounds of the following examples are prepared by referring to the preparation of the compounds of the above formula III-a.
The structure was confirmed as follows, white solid. m.p.53-54 ℃ IR (film): 2957,1645cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.23(d,J＝8.0Hz,1H),7.73(s,1H),7.68-7.60(m,1H),7.45-7.34(m,2H),2.32(d,J＝7.2Hz,2H),2.06-1.91(m,1H),0.94(d,J＝6.4Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ178.1,156.7,152.7,133.4,126.2,125.0,124.2,123.8,118.2,35.2,27.2,22.6；HRMS(ESI)calcd.for C 13 H 15 O 2 (M+H):203.1067,Found:203.1072.
The compounds of formula III-r in the examples below were prepared by reference to the methods for preparing the compounds of formula III-a described above.
The structure was confirmed as a pale yellow liquid. IR (film): 2929,1645cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.23(d,J＝8.0Hz,1H),7.76(s,1H),7.67-7.60(m,1H),7.45-7.34(m,2H),2.46(t,J＝7.6Hz,2H),1.65-1.52(m,2H),1.42-1.28(m,4H),0.90(t,J＝6.8Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ178.1,156.7,152.1,133.4,126.1,125.0,124.9,124.1,118.2,31.8,28.3,26.0,22.7,14.2；HRMS(APCI)calcd.for C 14 H 17 O 2 (M+H):217.1223,Found:217.1220.
The compounds of the following examples are prepared by reference to the preparation of the compounds of the above formula III-a.
The structure was confirmed as follows, white solid. 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.24(d,J＝8.0Hz,1H),7.80(s,1H),7.68-7.60(m,1H),7.46-7.34(m,2H),2.04(s,3H)；13C NMR(100MHz,CDCl3,ppm)δ178.5,156.9,151.9,133.4,126.0,125.0,123.8,120.9,118.2,11.4.
The compounds of the following examples are prepared by referring to the preparation of the compounds of the above formula III-a.
The structure was confirmed as follows, white solid. m.p.43-44℃IR (film): 3092,2949,2927,2850,1638,1608,1468,757cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.23(dd,J＝8.1,1.5Hz,1H),7.70(d,J＝0.6Hz,1H),7.67-7.58(m,1H),7.45-7.33(m,2H),2.91-2.77(m,1H),1.99-1.88(m,2H),1.88-1.70(m,3H),1.54-1.36(m,2H),1.36-1.15(m,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ177.5,156.3,151.8,133.4,129.8,126.3,124.9,124.2,118.1,34.6,32.5,26.9,26.5；HRMS(ESI)calcd.for C 15 H 17 O 2 (M+H):229.1223,Found:229.1222.
The compounds of the following examples are prepared by reference to the preparation of the compounds of the above formula III-a.
The structure was confirmed as follows, white solid. m.p.64-65 ℃ IR (film): 2960,1628,785cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.11(d,J＝8.1Hz,1H),7.68(s,1H),7.23-7.14(m,2H),3.24-3.07(m,1H),2.47(s,3H),1.23(d,J＝6.9Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ177.5,156.6,151.2,144.6,130.2,126.5,125.9,122.0,117.8,25.2,22.0,21.7；HRMS(APCI)calcd.for C 13 H 15 O 2 (M+H):203.1067,Found:203.1063.
The compounds of the following examples are prepared by reference to the preparation of the compounds of the above formula III-a.
The structure was confirmed as follows, white solid. m.p.61-62 ℃ IR (film): 2961,1646,1601,1428,873,782cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm):δ8.09(d,J＝8.4Hz 1H),7.68(d,J＝0.6Hz,1H),7.62(d,J＝1.8Hz,1H),7.49(dd,J＝8.4,1.5Hz,1H),3.22-3.06(m,1H),1.23(d,J＝6.9Hz,6H)； 13 C NMR(125MHz,acetone-d 6 ,ppm)176.7,157.4,153.0,131.2,129.3,128.3,127.9,124.0,122.1,26.2,21.7；HRMS(APCI)calcd.for C 12 H 12 O 2 Br(M+H):267.0015,Found:267.0010.
The compounds of the following examples are prepared by referring to the preparation of the compounds of the above formula III-a.
The structure validation results are as follows: white solid. m.p.64-65 ℃ IR (film): 2960,1647cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.24(dd,J＝9.2,7.2Hz,1H),7.70(s,1H),7.15-7.07(m,2H),3.21-3.08(m,1H),1.24(d,J＝7.2Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ176.7,165.6(d,J＝253.0Hz),157.4(d,J＝14.0Hz),151.6(d,J＝1.0Hz),130.6,128.8(d,J＝10.0Hz),121.1(d,J＝2.0Hz),113.8(d,J＝23.0Hz),104.6(d,J＝25.0Hz),25.2,21.7； 19 F NMR(377MHz,CDCl 3 ,ppm)δ-103.8；HRMS(ESI)calcd.for C 12 H 12 O 2 F(M+H):207.0816,Found:207.0821.
The compounds of formulas III-m in the examples below were prepared by the following methods:
the compounds of formula V-m were prepared according to the following equation:
the specific operation is as follows: pyridine (2.6103 g,33mmol,1.1 equiv) was added to a dichloromethane solution (50 ml) of 3-tert-butylphenol (4.5066 g,30mmol,1 equiv) under nitrogen, and isovaleryl chloride (4.4418 g,33mmol,1.1 equiv) was slowly added dropwise at reflux at 40℃for 12 hours. Cooling to room temperature, adding 1M hydrochloric acid solution (30 ml) to quench the reaction, extracting the aqueous phase with dichloromethane three times (25 ml x 3), washing the organic phase with saturated sodium chloride solution three times (100 ml x 3), drying with anhydrous sodium sulfate, filtering, concentrating, spin-drying, purifying by silica gel column chromatography (column packing is 200-300 meshes of silica gel; eluent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 100:1), and directly adding the colorless liquid without continuing purification. Aluminum trichloride (16.0008, 120mmol,4 quiv) was added to a 1, 2-dichloroethane (50 ml) solution of the intermediate (3-tert-butylphenyl) -3-methylbutyrate in portions under nitrogen protection, refluxed at 140℃for 12 hours, cooled to room temperature, quenched by slowly adding ice water (50 ml), then adding 1M hydrochloric acid solution (30 ml), extracting the aqueous phase three times (50 ml x 3) with diethyl ether, washing the organic phase three times (100 ml x 3) with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by silica gel column chromatography (column packing is 200-300 mesh silica gel; eluent: a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1), to obtain (4-tert-butyl-2-hydroxyphenyl) -3-methyl-1-butanone 4.4036g of the formula V-M, yield 63%.
Structure validation results such asThe following steps: pale yellow oily liquid. IR (film): 2962,1640cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm):δ12.47(s,1H),7.67(d,J＝8.8Hz,1H),6.99(d,J＝2.0Hz,1H),6.92(dd,J＝8.4,1.6Hz,1H),2.81(d,J＝6.8Hz,1H),2.37-2.21(m,1H),1.31(s,9H),1.01(d,J＝6.4Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm):δ206.2,162.8,161.0,130.1,117.6,116.7,115.4,47.2,35.5,31.0,25.9,23.0；HRMS(ESI)calcd.for C 15 H 21 O 2 (M-H):233.1547,found:233.1546.
The specific operation is as follows: (4-tert-butyl-2-hydroxyphenyl) -3-methyl-1-butanone (4.4036 g,18.8mmol,1 equiv) and N, N-dimethylformamide dimethyl acetal (44.7842 g,376mmol,20 equiv) of the formula V-m were added to a two-necked flask under nitrogen at room temperature, and heated under reflux at 120℃for 10 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (25 ml) was slowly added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (25 ml x 3) and the combined organic phases were washed twice with saturated brine (50 ml x 2) and dried over anhydrous sodium sulfate. Filtering, concentrating the reaction solution, purifying by silica gel column chromatography (column filler is 200-300 mesh silica gel; eluent is mixed solution of petroleum ether and ethyl acetate with volume ratio of 20:1) to obtain 1.2016g of 7-tert-butyl-3-isopropyl ketone shown in formula III-m with yield of 26%.
The structure was confirmed as follows, red solid. m.p.51-52 ℃ IR (film): 2962,1652cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.15(d,J＝8.4Hz,1H),7.70(s,1H),7.42(dd,J＝8.4,1.5Hz),7.38(d,J＝1.5Hz,1H),3.25-3.08(m,1H),1.37(s,9H),1.23(d,J＝6.9Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ177.4,157.8,156.5,151.3,130.3,125.7,122.9,121.9,114.3,35.5,31.2,25.2,21.8；HRMS(APCI)calcd.for C 16 H 21 O 2 (M+H):245.1536,Found:245.1528.
The compounds of formulas III-d in the examples below were prepared by the following methods:
the specific operation is as follows: 6-bromo-3-isopropyl-chromone (1.2020 g,4.5mmol,1 equiv.) of formula III-b, phenylboronic acid (0.9602 g,7.875mmol,1.75 equiv.), tetrakis triphenylphosphine palladium (0.5200 g,0.45mmol,10 mol%), na 2 CO 3 Aqueous solution (2M, 6.0 ml) and 1, 2-dichloroethane (Na 2 CO 3 The aqueous solution and 1, 2-dichloroethane were pre-bubbled for 20 minutes), and heated to reflux at 90℃for 12 hours. After the completion of the reaction, cooled to room temperature, filtered through celite, and the organic phase was diluted with dichloromethane (80 ml), and then washed with saturated ammonium chloride solution (70 ml), saturated sodium chloride solution (90 ml) and dried over anhydrous sodium sulfate, respectively. Filtering, concentrating the reaction solution, purifying by silica gel column chromatography (column filler is 200-300 mesh silica gel; eluent is mixed solution of petroleum ether and ethyl acetate with volume ratio of 20:1) to obtain 0.8412g of 3-isopropyl-6-phenylchromone shown in formula III-d with yield of 71%.
The structure validation results are as follows: a pale yellow liquid. IR (film): 2960,2872,1645,1473,763cm -1 ； 1 H NMR(500MHz,CDCl 3 ,ppm)δ8.45(d,J＝2.0Hz,1H),7.88(dd,J＝9.0,2.5Hz,1H),7.75(s,1H),7.66(d,J＝8.0Hz,2H),7.53-7.43(m,3H),7.41-7.35(m,1H),3.25-3.14(m,1H),1.26(d,J＝7.0Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ173.5,151.7,147.3,135.6,133.9,128.2,126.3,125.0,123.8,123.2,120.2,119.9,114.6,21.2,17.6；HRMS(APCI)calcd.for C 18 H 17 O 2 (M+H):265.1223,Found:265.1219.
The compounds of formulas III-e in the examples below were prepared by reference to the methods of compounds of formulas III-d.
The structure validation results are as follows: white solid. m.p.78-79 ℃ IR (film): 2960,1639,1478,820cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.40(d,J＝2.1Hz,1H),7.84(dd,J＝8.7,2.4Hz,1H),7.74(d,J＝0.9Hz,1H),7.60(d,J＝9.0Hz,1H),7.47(d,J＝9.0Hz,1H),7.00(d,J＝2.1Hz,2H),3.86(s,3H),3.28-3.11(m,1H),1.26(d,J＝6.9Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ177.6,159.7,155.5,151.4,137.7,132.2,132.0,130.3,128.4,124.3,123.3,118.6,114.6,55.6,25.2,21.7；HRMS(APCI)calcd.for C 19 H 19 O 3 (M+H):295.1329,Found:295.1322.
The compounds of formulas III-f in the examples below were prepared by reference to the methods of compounds of formulas III-d.
The structure validation results are as follows: white solid. m.p.118-119 ℃ IR (film): 2965,1641,1616,818cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.47(d,J＝2.4Hz,1H),7.88(dd,J＝8.7,2.4Hz,1H),7.80-7.69(m,5H),7.54(d,J＝8.7Hz,1H),3.28-3.10(m,1H),1.26(d,J＝6.9Hz,6H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ177.4,156.3,151.5,143.2,136.5,132.2,130.6,130.0(q,J＝32.5Hz),127.6,126.1(q,J＝3.8Hz),124.5,124.38,124.37(q,J＝270.0Hz),119.0,25.3,21.7； 19 F NMR(377MHz,CDCl 3 ,ppm)δ-62.5；HRMS(APCI)calcd.for C 19 H 16 O 2 F 3 (M+H):333.1097,Found:333.1090.
The compounds of formulas III-g in the examples below were prepared by reference to the methods of compounds of formulas III-d.
The structure validation results are as follows: colorless liquid. IR (film): 2961,1642cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.40(d,J＝2.1Hz,1H),7.91(dd,J＝8.7,2.1Hz,1H),7.73(s,1H),7.41(d,J＝8.4Hz,2H),7.36-7.26(m,6H),7.11-7.01(m,2H),5.10(s,2H),3.28-3.11(m,1H),1.26(d,J＝6.9Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ177.4,155.7,155.4,151.2,137.0,135.5,135.2,131.1,130.2,129.7,129.3,128.6,127.8,127.1,126.4,123.9,121.6,117.3,113.2,70.5,25.2,21.7；HRMS(APCI)calcd.for C 25 H 23 O 3 (M+H):371.1642,Found:371.1640.
The compounds of formulas III-h in the examples below were prepared by reference to the methods of compounds of formulas III-d.
The structure validation results are as follows: white solid. m.p.64-65 ℃ IR (film): 2961,1645cm -1 .1H NMR(300MHz,CDCl 3 ,ppm)δ8.48(d,J＝2.1Hz,1H),7.95(dd,J＝8.7,2.1Hz,1H),7.72(s,1H),7.50(s,1H),7.44(d,J＝8.7Hz,1H),6.76(d,J＝3.3Hz,1H),6.52-6.47(m,1H),3.26-3.09(m,1H),1.25(d,J＝6.9Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ177.4,155.5,152.8,151.4,142.8,130.4,129.1,128.1,124.3,120.7,118.7,112.1,106.1,25.2,21.7；HRMS(APCI)calcd.for C 16 H 15 O 3 (M+H):255.1016,Found:255.1016.
The compounds of formula III-i in the examples below were prepared by reference to the methods of the compounds of formula III-d.
The structure validation results are as follows: white solid. m.p.55-56 ℃ IR (film): 2961,1645cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.44(s,1H),7.87(d,J＝8.8Hz,1H),7.73(s,1H),7.44(d,J＝8.8Hz,1H),7.40(d,J＝3.2Hz,1H),7.32(d,J＝5.2Hz,1H),3.25-3.11(m,1H),1.25(d,J＝6.8Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ177.3,155.6,151.4,142.9,131.5,131.1,130.3,128.4,125.7,124.3,124.0,122.4,118.8,25.3,21.6；HRMS(APCI)calcd.for C 16 H 15 O 2 S(M+H):271.0787,Found:271.0785.
The compounds of formulas III-n in the examples below were prepared by reference to the methods of compounds of formulas III-d.
The structure validation results are as follows: white solid. m.p.101-102 ℃ IR (film): 2957,1630, cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.29(d,J＝8.7Hz,1H),7.75(d,J＝0.6Hz,1H),7.70-7.58(m,4H),7.54-7.38(m,3H),3.27-3.10(m,1H),1.26(d,J＝6.9Hz,6H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ177.4,156.8,151.5,146.6,139.5,130.5,129.3,128.8,127.6,126.7,124.1,123.0,116.1,25.2,21.7；HRMS(APCI)calcd.for C 18 H 17 O 2 (M+H):265.1223,Found:265.1223.
The compounds of formulas III-s in the examples below were prepared by reference to the methods of compounds of formulas III-d.
The structure validation results are as follows: white solid. 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.31(dd,J＝8.0,1.2Hz,1H),7.89(s,1H),7.75-7.66(m,1H),7.51(d,J＝8.4Hz,1H),7.47-7.40(m,1H),7.35-7.27(m,2H),7.27-7.21(m,1H),7.21-7.16(m,1H),2.26(m,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ176.2,156.6,153.8,138.3,133.8,131.8,130.7,130.4,128.9,126.7,126.6,126.0,125.4,124.6,118.3,20.3.
Zhou,Y.；Liang,H.；Sheng,Y.；Wang,S.；Gao,Y.；Zhan,L.；Zheng,Z.；Yang,M.；Liang,G.；Zhou,J.；Deng,J.；Song,Z.J.Org.Chem.2020,85,9230-9243.
Example 1 preparation of Compounds of formula IV-a
A compound of formula IV-a was prepared according to the reaction equation shown in fig. 1:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) shown in a formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) shown in a formula II-a, 3-isopropyl ketone (0.2823 g,1.5 mmol) shown in a formula III-a and 1mL toluene are added into a reaction tube at room temperature, stirred at room temperature to be dissolved, then the mixture is transferred into a high-pressure reaction kettle to be filled with hydrogen (40 bar), the mixture is stirred at 60 ℃ for 24 hours, a rotary evaporator is used for concentrating the reaction liquid, and silica gel column chromatography is used for purification (column packing is silica gel with 200-300 meshes; eluent is a mixture of petroleum ether and dichloromethane with a volume ratio of 5:1), and the yield is 96 percent and the ee value is 92 percent.
The structure validation results are as follows: [ alpha ]] D 24 ＝+33.2(c 0.94,CHCl 3 )(92％ee)； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.89(d,J＝7.6Hz,1H),7.49-7.42(m,1H),7.04-6.97(m,1H),6.94(d,J＝8.4Hz,1H),4.50(d,J＝5.2Hz,2H),2.42-2.24(m,2H),1.04(d,J＝6.4Hz,3H),1.01(d,J＝6.8Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.5,161.6,135.8,127.5,121.4,121.2,117.7,68.7,52.3,25.7,20.7,19.8.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl chromanone shown in the formula IV-a.
Example 2 preparation of Compounds of formula IV-b
The compound of formula IV-b was prepared according to the reaction equation shown in fig. 2:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II, 6-bromo-3-isopropyl ketone (0.4007 g,1.5 mmol) of formula III-b, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 96%, and the ee value was 90%.
The structure validation results are as follows: [ alpha ]] D 27 ＝+41.0(c 1.15,CHCl 3 )(90％ee)； 1 H NMR(500MHz,CDCl 3 ,ppm)δ7.99(d,J＝2.0Hz,1H),7.52(dd,J＝8.5,2.0Hz,1H),6.85(d,J＝8.5Hz,1H),4.54-4.44(m,2H),2.39-2.33(m,1H),2.33-2.22(m,1H),1.04(d,J＝6.5Hz,3H),1.00(d,J＝7.0Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ193.2,160.5,138.4,130.0,122.5,119.9,114.1,68.8,52.1,25.8,20.7,19.8.
The compound synthesized through structural identification is the target compound (S) -6-bromo-3-isopropyl chromanone shown in the formula IV-b.
Example 3 preparation of Compounds of formula IV-c
A compound of formula IV-c was prepared according to the reaction equation shown in fig. 3:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 6-chloro-3-isopropyl ketone (0.3340 g,1.5 mmol) of formula III-c, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, purified by silica gel column chromatography, the yield was 96%, and the ee value was 88%.
The structure validation results are as follows: [ alpha ]] D 27 ＝+45.3(c 1.09,CHCl 3 )(88％ee)； 1 H NMR(500MHz,CDCl 3 ,ppm)δ7.84(d,J＝8.5Hz,1H),7.39(dd,J＝8.5,2.5Hz,1H),6.91(d,J＝9.0Hz,1H),4.55-4.42(m,2H),2.40-2.33(m,1H),2.33-2.23(m,1H),1.04(d,J＝6.5Hz,3H),1.01(d,J＝6.5Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ193.3,160.0,135.6,127.0,126.9,122.0,119.5,68.9,52.1,25.8,20.7,19.8.
The compound synthesized through structural identification is the target compound (S) -6-chloro-3-isopropyl chromanone shown in the formula V-c.
Example 4 preparation of Compounds of formulas III-d
The compounds of formulas IV-d were prepared according to the reaction equation shown in fig. 4:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II, 3-isopropyl-6-phenylchromone (0.3965 g,1.5 mmol) of formula III-d, 1mL of toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60 ℃ for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 95%, and the ee value was 92%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+58.7(c 0.87,CHCl 3 )(92％ee)； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.13(d,J＝2.4Hz,1H),7.71(d,J＝8.7,2.7Hz,1H),7.61-7.53(m,2H),7.47-7.39(m,2H),7.37-7.29(m,1H),7.03(d,J＝8.7Hz,1H),4.54(d,J＝4.8Hz,2H),2.46-2.25(m,2H),1.07(d,J＝6.6Hz,3H),1.03(d,J＝6.6Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ194.5,161.0,139.9,134.6,134.5,129.0,127.4,126.9,125.6,121.3,118.3,68.8,52.5,25.8,20.8,19.9.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl-6-phenyl chromanone shown in the formula V-d.
Example 5 preparation of Compounds of formula V-e
The compounds of formula IV-e were prepared according to the reaction equation shown in fig. 5:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 3-isopropyl-6- (4-methoxyphenyl) chromone (0.4415 g,1.5 mmol) of formula III-e, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography with a yield of 98% and ee value 93%.
The structure validation results are as follows: [ alpha ]] D 22 ＝+59.4(c 1.11,CHCl 3 )(93％ee)； 1 H NMR(400MHz,CDCl 3 ,ppm)δ8.07(s,1H),7.67(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,2H),7.00(d,J＝8.8Hz,1H),6.96(d,J＝8.4Hz,2H),4.52(d,J＝4.4Hz,2H),3.85(s,3H),2.43-2.28(m,2H),1.06(d,J＝6.4Hz,3H),1.03(d,J＝6.8Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.6,160.6,159.3,134.3,134.2,132.5,128.0,125.0,121.2,118.2,114.5,68.8,55.6,52.5,25.8,20.8,19.9.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl-6- (4-methoxyphenyl) chromanone shown in the formula IV-e.
Example 6 preparation of Compounds of formulas IV-f
Compounds of formulas IV-f were prepared according to the reaction equation shown in fig. 6:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 3-isopropyl-6- (4-trifluoromethylphenyl) chromone (0.4985 g,1.5 mmol) of formula III-f, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to an autoclave, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography with a yield of 97% and ee value of 95%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+61.2(c 0.85,CHCl 3 )(95％ee)； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.14(d,J＝2.4Hz,1H),7.75-7.66(m,5H),7.06(d,J＝8.7Hz,1H),4.55(d,J＝5.1Hz,2H),2.47-2.26(m,2H),1.07(d,J＝6.6Hz,3H),1.04(d,J＝6.6Hz,3H)； 13 C NMR(125MHz,acetone-d 6 ,ppm)δ194.1,162.7,144.6,135.2,133.4,129.7(q,J＝32.5Hz),128.2,126.9(q,J＝3.8Hz),126.3,125.6(q,J＝268.8Hz),122.4,119.6,69.7,52.8,26.6,20.9,20.0； 19 F NMR(377MHz,CDCl 3 ,ppm)δ-62.4.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl-6- (4-trifluoromethyl phenyl) chromanone shown in the formula IV-f.
Example 7 preparation of Compounds of formulas IV-g
Compounds of formulas IV-g were prepared according to the reaction equation shown in fig. 7:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 6- (2-benzyloxyphenyl) -3-isopropyl-primary-ketone (0.5557 g,1.5 mmol) of formula III-g, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography with a yield of 98% and an ee value of 93%.
The structure validation results are as follows: [ alpha ]] D 23 ＝+23.6(c 1.00,CHCl 3 )(93％ee)；IR(film):2961,1689cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.12(d,J＝2.1Hz,1H),7.73(dd,J＝8.7,2.1Hz,1H),7.40-7.27(m,7H),7.08-7.00(m,2H),6.96(d,J＝8.7Hz,1H),5.01(s,2H),4.53(d,J＝4.8Hz,2H),2.44-2.26(m,2H),1.06(d,J＝6.6Hz,3H),1.03(d,J＝6.6Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ194.4,160.6,155.7,137.4,137.2,131.9,130.9,129.9,128.9,128.7,128.3,127.9,127.2,121.6,120.9,117.2,113.3,70.6,68.8,52.5,25.8,20.8,19.9.HRMS(APCI)calcd for C 25 H 25 O 3 (M+H):373.1798,Found:373.1783.
The compound synthesized through structural identification is the target compound 6- (2-benzyloxy phenyl) -3-isopropyl chromanone shown in the formula IV-g.
Example 8 preparation of Compounds of formula IV-h
Compounds of formulas IV-h were prepared according to the reaction equation shown in fig. 8:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 6- (2-furyl) -3-isopropyl-primary ketone (0.3814 g,1.5 mmol) of formula III-h, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60 ℃ for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography with a yield of 97% and ee value 93%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+75.8(c 0.88,CHCl 3 )(93％ee)；IR(film):2962,1692cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.16(d,J＝2.1Hz,1H),7.78(dd,J＝8.7,2.4Hz,1H),7.44(d,J＝1.2Hz,1H),6.98(d,J＝8.7Hz,1H),6.60(d,J＝3.3Hz,1H),6.46(dd,J＝3.3,1.8Hz,1H),4.52(d,J＝4.8Hz,2H),2.44-2.22(m,2H),1.06(d,J＝6.6Hz,3H),1.02(d,J＝6.9Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ194.3,160.7,153.1,142.1,131.4,125.0,122.6,121.2,118.3,111.9,104.7,68.8,52.4,25.8,20.8,19.9；HRMS(APCI)calcd for C 16 H 17 O 3 (M+H):257.1172,Found:257.1173.
The compound synthesized through structural identification is the target compound (S) -6- (2-furyl) -3-isopropyl chromanone shown in the formula IV-h.
Example 9 preparation of Compounds of formula IV-i
The compound of formula IV-i was prepared according to the reaction equation shown in fig. 9:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 3-isopropyl-6- (2-thienyl) chromone (0.4026 g,1.5 mmol) of formula III-I, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography with a yield of 94% and ee value of 94%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+70.6(c 0.80,CHCl 3 )(94％ee)；IR(film):2961,1691cm -1 ； 1 H NMR(300MHz,CDCl 3 ,ppm)δ8.11(d,J＝2.4Hz,1H),7.70(dd,J＝8.4,2.4Hz,1H),7.30-7.21(m,2H),7.06(dd,J＝4.8,3.6Hz,1H),6.97(d,J＝8.7Hz,1H),4.52(d,J＝5.1Hz,2H),2.44-2.23(m,2H),1.06(d,J＝6.6Hz,3H),1.03(d,J＝6.6Hz,3H)； 13 C NMR(100MHz,acetone-d 6 ,ppm)194.1,161.9,143.8,133.9,129.4,128.9,125.9,124.4,124.2,122.3,119.5,69.6,52.8,26.6,20.9,20.0；HRMS(APCI)calcd for C 16 H 17 O 2 S(M+H):273.0944,Found:273.0943.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl-6- (2-thienyl) chromanone shown in the formula V-i.
Example 10 preparation of Compounds of formula IV-j
Compounds of formula IV-j were prepared according to the reaction equation shown in fig. 10:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 7-fluoro-3-isopropyl ketone (0.3093 g,1.5 mmol) of formula III-j, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60 ℃ for 24 hours, the reaction solution was concentrated by a rotary evaporator, purified by silica gel column chromatography, the yield was 93%, and the ee value was 92%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+32.2(c 1.14,CHCl 3 )(92％ee)；IR(film):2964,1695cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.94-7.86(m,1H),6.76-6.69(m,1H),6.63(dd,J＝9.6,2.0Hz,1H),4.55-4.47(m,2H),2.42-2.22(m,2H),1.04(d,J＝6.8Hz,3H),1.01(d,J＝6.8Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ193.0,167.4(d,J＝254.0Hz),163.4(d,J＝13.0Hz),130.0(d,J＝12.0Hz),118.2(d,J＝2.0Hz),109.8(d,J＝22.0Hz),104.5(d,J＝25.0Hz),69.2,52.0,25.8,20.7,19.8； 19 F NMR(377MHz,CDCl 3 ,ppm)δ–101.3；HRMS(ESI)calcd.for C 12 H 12 FO 2 (M-H):207.0827,Found:207.0822.
The compound synthesized through structural identification is the target compound (S) -7-fluoro-3-isopropyl chromanone shown in the formula IV-j.
Example 11 preparation of Compounds of formula IV-k
The compounds of formula IV-k were prepared according to the reaction equation shown in fig. 11:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 7-bromo-3-isopropyl ketone (0.4007 g,1.5 mmol) of formula III-k, 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, purified by silica gel column chromatography, the yield was 98%, and the ee value was 92%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+16.0(c 1.04,CHCl 3 )(92％ee)； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.74(d,J＝8.8Hz,1H),7.17-7.11(m,2H),4.54-4.45(m,2H),2.40-2.33(m,1H),2.33-2.21(m,1H),1.03(d,J＝6.8Hz,3H),1.00(d,J＝6.8Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ193.6,161.8,130.2,128.8,125.1,121.0,120.1,69.1,52.2,25.8,20.7,19.8.
The compound synthesized through structural identification is the target compound (S) -7-bromo-3-isopropyl chromanone shown in the formula IV-k.
Example 12 preparation of Compounds of formula IV-l
The compound of formula IV-l was prepared according to the reaction equation shown in fig. 12:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of the formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of the formula II-a, 3-isopropyl-7-methylchromone (0.3034 g,1.5 mmol) of the formula III-l and 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, purified by silica gel column chromatography, the yield was 96%, and the ee value was 92%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+42.8(c 0.94,CHCl 3 )(92％ee)； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.78(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),6.74(s,1H),4.47(d,J＝4.4Hz,2H),2.41-2.24(m,5H),1.03(d,J＝6.4Hz,3H),1.00(d,J＝6.4Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.3,161.6,147.3,127.5,122.8,119.0,117.8,68.7,52.3,25.9,22.1,20.8,19.9.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl-7-methyl chromanone shown in the formula IV-l.
Example 13 preparation of Compounds of formula IV-m
The compounds of formulas IV-m were prepared according to the reaction equation shown in fig. 13:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of the formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of the formula II-a, 7-tert-butyl-3-isopropyl ketone (0.3665 g,1.5 mmol) of the formula III-m and 1mL of toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 88%, and the ee value was 91%.
The structure validation results are as follows: [ alpha ]] D 21 ＝+22.2(c 1.10,CHCl 3 )(91％ee)；IR(film):2963,1689cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.81(d,J＝8.4Hz,1H),7.05(d,J＝8.4Hz,1H),6.93(s,1H),4.53-4.43(m,2H),2.37-2.24(m,2H),1.31(s,9H),1.04(d,J＝6.4Hz,3H),1.01(d,J＝6.4Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.3,161.6,160.4,127.2,119.3,118.8,114.3,68.8,52.4,35.5,31.1,25.8,20.8,19.9；HRMS(ESI)calcd for C 16 H 23 O 2 (M+H):247.1693,Found:247.1691.
The compound synthesized through structural identification is the target compound (S) -7-tertiary butyl-3-isopropyl chromanone shown in the formula V-m.
Example 14 preparation of Compounds of formula IV-n
Compounds of formulas IV-n were prepared according to the reaction equation shown in fig. 14:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of the formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of the formula II-a, 3-isopropyl-7-phenylchromone (0.3965 g,1.5 mmol) of the formula III-n and 1mL of toluene were added to a reaction tube at room temperature, dissolved by stirring at room temperature, then transferred to a high-pressure reaction vessel, filled with hydrogen (40 bar), stirred at 60 ℃ for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 98%, and the ee value was 92%.
The structure validation results are as follows: [ alpha ]] D 24 ＝+14.7(c 0.94,CHCl 3 )(92％ee)；IR(film):2961,1687,1614cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.95(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,2H),7.50-7.43(m,2H),7.43-7.37(m,1H),7.30-7.23(m,1H),7.16(s,1H),4.54(d,J＝5.2Hz,2H),2.44-2.28(m,2H),1.07(d,J＝6.4Hz,3H),1.03(d,J＝6.8Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.3,161.9,148.8,139.8,129.1,128.7,128.1,127.4,120.6,120.0,115.9,68.9,52.4,25.8,20.8,19.9；HRMS(APCI)calcd for C 18 H 19 O 2 (M+H):267.1380,Found:267.1380.
The compound synthesized through structural identification is the target compound (S) -3-isopropyl-7-phenyl chromanone shown in the formula IV-n.
Example 15 preparation of Compounds of formula IV-o
A compound of formula IV-o was prepared according to the reaction equation shown in fig. 15:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0065 g,0.0075 mmol) of formula II-a, 3-cyclohexenone (0.3424 g,1.5 mmol) of formula III-o, 1mL of toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60 ℃ for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 95%, and ee value was 60%.
The structure validation results are as follows: [ alpha ]] D 21 ＝+28.5(c 0.92,CHCl 3 )(60％ee)；IR(film):2924,1690cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.89(d,J＝8.0Hz,1H),7.49-7.41(m,1H),7.04-6.97(m,1H),6.94(d,J＝8.4Hz,1H),4.53(dd,J＝11.6,6.0Hz,1H),4.46(dd,J＝12.0,3.6Hz,1H),2.41-2.32(m,1H),2.03-1.91(m,1H),1.91-1.82(m,1H),1.80-1.70(m,2H),1.70-1.58(m,2H),1.36-1.01(m,5H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.4,161.6,135.8,127.6,121.4,121.3,117.8,68.7,51.9,35.3,31.2,30.3,26.5.26.4,26.3；HRMS(APCI)calcd for C 15 H 19 O 2 (M+H):231.1380,Found:231.1371.
The compound synthesized through structural identification is the target compound (S) -3-cyclohexyl chromanone shown in the formula IV-o.
EXAMPLE 16 preparation of Compounds of formula IV-p
Compounds of formula IV-p were prepared according to the reaction equation shown in fig. 16:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0078 g,0.0075 mmol) of formula II-b, 3-methylchromone (0.2403 g,1.5 mmol) of formula III-p, 1mL of toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high-pressure reactor, charged with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 94%, ee value 29%.
The structure validation results are as follows: [ alpha ]] D 21 ＝+18.5(c 0.85,CHCl 3 )(29％ee)； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.90(d,J＝7.6Hz,1H),7.50-7.42(m,1H),7.05-6.99(m,1H),6.96(d,J＝8.4Hz,1H),4.50(dd,J＝11.2,4.8Hz,1H),4.20-4.10(m,1H),2.93-2.80(m,1H),1.22(d,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ195.0,161.9,135.9,127.5,121.5,120.7,117.9,72.4,40.9,10.9.
The compound synthesized through structural identification is the target compound (R) -3-methyl chromanone shown in the formula IV-p.
Example 17 preparation of Compounds of formula IV-q
Compounds of formulas IV-q were prepared according to the reaction equation shown in fig. 17:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0078 g,0.0075 mmol) of formula II-b, 3-iso Ding Jise ketone (0.3034 g,1.5 mmol) of formula III-q, 1mL of toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 98%, ee value was 51%.
The structure validation results are as follows: [ alpha ]] D 21 ＝+8.8(c 0.91,CHCl 3 )(51％ee)；IR(film):2957,1691cm -1 ； 1 H NMR(500MHz,CDCl 3 ,ppm)δ7.92(dd,J＝8.0,1.5Hz,1H),7.52-7.45(m,1H),7.08-7.00(m,1H),6.98(d,J＝8.0Hz,1H),4.53(dd,J＝11.5,4.5Hz,1H),4.26(dd,J＝11.0,8.5Hz,1H),2.81-2.70(m,1H),1.87-1.70(m,2H),1.42-1.29(m,1H),1.00(d,J＝6.0Hz,3H),0.96(d,J＝6.0Hz,3H)； 13 C NMR(125MHz,CDCl 3 ,ppm)δ195.0,161.6,135.8,127.6,121.5,120.8,117.8,70.8,44.2,35.3,25.7,23.2,22.2；HRMS(ESI)calcd for C 13 H 17 O 2 (M+H):205.1223,Found:205.1222.
The compound synthesized through structural identification is the target compound 3-isobutyl chromanone shown in the formula IV-q.
Example 18 preparation of Compounds of formula IV-r
A compound of formula IV-r was prepared according to the reaction equation shown in fig. 18:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0078 g,0.0075 mmol) of formula II-b, 3-amyl chromone (0.3244 g,1.5 mmol) of formula III-r, 1mL toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high pressure reactor, charged with hydrogen (40 bar), stirred at 60℃for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 96%, ee value was 35%.
The structure validation results are as follows: [ alpha ]] D 21 ＝+18.5(c 1.22,CHCl 3 )(35％ee)；IR(film):2927,1691cm -1 ； 1 H NMR(400MHz,CDCl 3 ,ppm)δ7.92(d,J＝8.0Hz,1H),7.52-7.44(m,1H),7.07-7.00(m,1H),6.97(d,J＝8.0Hz,1H),4.54(dd,J＝11.2,4.0Hz,1H),4.31(dd,J＝10.8,8.4Hz,1H),2.71-2.62(m,1H),1.96-1.82(m,1H),1.58-1.26(m,7H),0.91(t,J＝6.4Hz,3H)； 13 C NMR(100MHz,CDCl 3 ,ppm)δ194.8,161.6,135.8,127.6,121.5,120.8,117.8,70.7,46.1,31.9,26.9,26.5,22.6,14.2；HRMS(ESI)calcd for C 14 H 19 O 2 (M+H):219.1380,Found:219.1379.
The compound synthesized through structural identification is the target compound 3-amyl chromanone shown in the formula IV-r.
Example 19 preparation of Compounds of formula IV-s
Compounds of formulas IV-s were prepared according to the reaction equation shown in fig. 19:
the specific operation is as follows: in a glove box, borane (0.0127 g,0.03 mmol) of formula I, chiral phosphoric acid (0.0078 g,0.0075 mmol) of formula II-b, 3- (2-methylphenyl) chromone (0.3544 g,1.5 mmol) of formula III-s, 1mL of toluene were added to a reaction tube at room temperature, stirred at room temperature to dissolve, then transferred to a high-pressure reactor, filled with hydrogen (40 bar), stirred at 60 ℃ for 24 hours, the reaction solution was concentrated by a rotary evaporator, and purified by silica gel column chromatography, the yield was 97%, and the ee value was 53%.
The structure validation results are as follows: [ alpha ]] D 26 ＝-2.8(c 1.01,CHCl 3 )(53％ee)； 1 H NMR(300MHz,CDCl 3 ,ppm)δ7.99(dd,J＝7.8,1.5Hz,1H),7.57-7.47(m,1H),7.25-7.15(m,3H),7.13-7.00(m,3H),4.66-4.52(m,2H),4.30(dd,J＝9.9,6.9Hz,1H),2.39(s,3H)； 13 C NMR(100MHz,acetone-d 6 ,ppm)δ192.7,162.8,138.3,136.8,135.5,131.5,129.2,128.4,128.2,127.1,122.6,122.4,118.9,72.0,49.9,20.2.
The compound synthesized through structural identification is the target compound 3- (2-methylphenyl) chromanone shown in the formula IV-s.
Claims (7)
1. The application of borane shown in a formula I and chiral phosphoric acid compound shown in a formula II in preparing 3-substituted chromanone shown in a formula IV by relay catalytic hydrogenation of 3-substituted chromanone substrate shown in a formula III;
in the formula II, ar represents an aromatic group, which is phenyl or 3, 5-dimethylphenyl;
in the formula III and the formula IV, R 1 Represents a substituent on the benzene ring, which is H, a straight or branched alkyl group with 1-4 carbon atoms, a substituted or unsubstituted phenyl group, a substituted or unsubstituted furan substituent, a substituted or unsubstituted thiophene substituent or halogen;
wherein the substituent groups in the substituted phenyl, the substituted furan substituent and the substituted thiophene substituent groups are alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, halogen substituted alkyl groups with 1-4 carbon atoms and benzyloxy groups;
R 2 is a straight-chain or branched alkyl group with 1-6 carbon atoms, a cycloalkyl group with 3-6 carbon atoms or a substituted or unsubstituted phenyl group, wherein the substituent in the substituted phenyl group can be an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, a halogen substituted alkyl group with 1-4 carbon atoms or a benzyloxy group.
2. The preparation method of the 3-substituted chiral chromanone compound shown in the formula IV comprises the following steps:
in a catalytic system of borane shown in a formula I and chiral phosphoric acid compound shown in a formula II, reacting a compound shown in a formula III with hydrogen to obtain a 3-substituted chiral chromanone compound shown in a formula IV;
in the formula II, ar represents an aromatic group, which is phenyl or 3, 5-dimethylphenyl;
in the formula III and the formula IV, R 1 Represents a substituent on the benzene ring, which is H, a straight or branched alkyl group with 1-4 carbon atoms, a substituted or unsubstituted phenyl group, a substituted or unsubstituted furan substituent, a substituted or unsubstituted thiophene substituent or halogen;
wherein the substituent groups in the substituted phenyl, the substituted furan substituent and the substituted thiophene substituent groups are alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, halogen substituted alkyl groups with 1-4 carbon atoms and benzyloxy groups;
R 2 is a straight-chain or branched alkyl group with 1-6 carbon atoms, a cycloalkyl group with 3-6 carbon atoms or a substituted or unsubstituted phenyl group, wherein the substituent in the substituted phenyl group can be an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, a halogen substituted alkyl group with 1-4 carbon atoms or a benzyloxy group.
3. The preparation method according to claim 2, characterized in that: in the preparation method, the molar ratio of the borane shown in the formula I, the chiral phosphoric acid compound shown in the formula II and the compound shown in the formula IV is 4:1:10-4:1:500.
4. the preparation method according to claim 2, characterized in that: in the preparation method, the reaction is carried out in an autoclave, and the pressure of the hydrogen is 10-80bar.
5. The preparation method according to claim 2, characterized in that: in the preparation method, the reaction is carried out in an organic solvent, wherein the organic solvent is toluene.
6. The preparation method according to claim 2, characterized in that: the reaction temperature is 30-100 ℃ and the reaction time is 8-72 hours.
7. The preparation method according to claim 2, characterized in that: in the preparation method, after the reaction is finished, the method also comprises the step of separating and purifying the 3-substituted chiral chromanone compound shown in the formula IV by column chromatography;
wherein, the conditions of the column chromatography are as follows:
the column packing is silica gel with 200-300 meshes; the eluent is as follows: the volume ratio is 5:1 with methylene chloride.
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| Chiral phosphoric acid catalyzed asymmetric transfer hydrogenation of bulky aryl ketones with ammonia borane;Qiwen Zhou et al.;Tetrahedron Letters;第61卷;第1-4页 * |
| Relay Catalysis by Achiral Borane and Chiral Phosphoric Acid in the Metal-Free Asymmetric Hydrogenation of Chromones;Jingjing Chen et al.;Org. Lett.;第23卷;第8565−8569页 * |
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