CN108148084A - A kind of synthetic method of N- acyl indols chirality boron compound - Google Patents
A kind of synthetic method of N- acyl indols chirality boron compound Download PDFInfo
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- CN108148084A CN108148084A CN201611101859.7A CN201611101859A CN108148084A CN 108148084 A CN108148084 A CN 108148084A CN 201611101859 A CN201611101859 A CN 201611101859A CN 108148084 A CN108148084 A CN 108148084A
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- 150000001639 boron compounds Chemical class 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003446 ligand Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- -1 acyl indol Chemical compound 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000002585 base Substances 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 12
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- HGTBZFMPHBAUCQ-KHZPMNTOSA-N cyclopentane;dicyclohexyl-[(1r)-1-(2-diphenylphosphanylcyclopentyl)ethyl]phosphane;iron Chemical compound [Fe].[CH]1[CH][CH][CH][CH]1.[C]1([C@@H](C)P(C2CCCCC2)C2CCCCC2)[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 HGTBZFMPHBAUCQ-KHZPMNTOSA-N 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- AJNZWRKTWQLAJK-VGWMRTNUSA-N (2s,5s)-1-[2-[(2s,5s)-2,5-dimethylphospholan-1-yl]phenyl]-2,5-dimethylphospholane Chemical compound C[C@H]1CC[C@H](C)P1C1=CC=CC=C1P1[C@@H](C)CC[C@@H]1C AJNZWRKTWQLAJK-VGWMRTNUSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 4
- 229910052794 bromium Inorganic materials 0.000 claims 4
- 229910052801 chlorine Inorganic materials 0.000 claims 4
- 239000000460 chlorine Substances 0.000 claims 4
- 229910052731 fluorine Inorganic materials 0.000 claims 4
- 239000011737 fluorine Substances 0.000 claims 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 235000003642 hunger Nutrition 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 125000001041 indolyl group Chemical group 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 27
- 238000001228 spectrum Methods 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 0 CC(C)(*1)C(C)(C)O*1*1OC(C)(C)C(C)(C)O1 Chemical compound CC(C)(*1)C(C)(C)O*1*1OC(C)(C)C(C)(C)O1 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 4
- 150000001728 carbonyl compounds Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SXZIJKWEJKWRKE-VOTSOKGWSA-N CC1C=C(/C=C/C([n]2c3ccccc3cc2)=O)SC1 Chemical compound CC1C=C(/C=C/C([n]2c3ccccc3cc2)=O)SC1 SXZIJKWEJKWRKE-VOTSOKGWSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of the N acyl indol chirality boron compounds with potential source biomolecule activity.With α, β unsaturation N acyl indols are raw material with duplex pinacol base diborane, and chiral ligand mantoquita is catalyst, carry out asymmetric boronation reaction synthesis of chiral boron compound.Compared with the method for having reported synthesis of chiral boron compound, raw material of the present invention is easy to get, is easy to operate, applied widely and reaction condition is mild, containing indoles substituent group in product, has potential bioactivity.
Description
Technical field
The invention discloses a kind of synthetic methods of the N- acyl indol chirality boron compounds with potential source biomolecule activity.With
α, β-unsaturation N- acyl indols are raw material with duplex pinacol base diborane, and chiral ligand mantoquita is catalyst, and it is not right to carry out
Claim boronation reaction synthesis of chiral boron compound.Compared with the method for having reported synthesis of chiral boron compound, raw material of the present invention is easy
, easy to operate, applied widely and reaction condition it is mild, containing indoles substituent group in product, have the potential biology living
Property.
Background technology
Chiral boron compound is important organic reagent, has in industry, agricultural and medicine and other fields very extensive
Purposes.Indolyl radical is particularly important functional group, can greatly change the bioactivity and physical property of compound, great Liang Ying
For drug molecule and functional material in.
At present, there are many method for synthesis of chiral boron compound (Schiffner etc., Angew.Chem.Int.Ed.2010,
49,1194-1196；Calow etc., Org.Biomol.Chem.2012,10,5485-5497).Wherein, by α, beta-unsaturated carbonyl
The method of compound asymmetry boronation is one of approach for quickly and efficiently preparing chiral boron compound, and related manufacturing processes have：
1) copper catalysis alpha, beta-unsaturated carbonyl compound asymmetry boronation reaction (Kobayashi etc.,
Angew.Chem.Int.Ed.2012,51,12763-12766)；2) nickel catalysis alpha, beta-unsaturated carbonyl compound asymmetry boronation
It reacts (Lillo etc., Org.Biomol.Chem.2009,7,4674-4676)；3) rhodium catalysis alpha, beta-unsaturated carbonyl compound is not
Symmetrical boronation reaction (Shiomi etc., Chem.Commun., 2009,5987-5989)；4) organic catalysis alpha, beta-unsaturated carbonyl
Close object asymmetry boronation reaction (Radomkit etc., Angew.Chem.Int.Ed.2014,53,3387-3391).However, α, β-
Unsaturated N- acyl indols are applied to not yet in asymmetric boronation reaction, and indolyl radical is contained in product, has potential life
Object activity.
For the present invention using α, it is anti-that β-unsaturation N- acyl indols 2 with duplex pinacol base diborane 3 carry out asymmetric boronation
Should, synthesize a series of N- acyl indols chirality boron compounds 1.
Invention content
It is easy to get the purpose of the present invention is to provide a kind of raw material, reaction condition is mild, wide adaptability, can simply and easily close
Into the method with potential source biomolecule activity N- acyl indol chirality boron compounds.
To achieve these goals, technical scheme is as follows：
Using mantoquita such as cuprous iodide CuI as catalyst precarsor, chiral ligand such as (R, S)-Josiphos and alkali such as phosphorus are added in
Sour potassium K3PO4, in organic solvent such as tertriary amylo alcohol, heating condition carries out α, β-unsaturation N- acyl indols 2 and duplex pinacol base
Diborane 3 asymmetric boronation reaction (reaction equation (1)), after reaction by silica gel column separating purification carry out product separation and
Characterization, obtains N- acyl indol chirality boron compounds.
Technical solution is characterized in that：
1. the molar ratio of the starting material α, β-unsaturation N- acyl indols 2 and duplex pinacol base diborane 3 is 1:
1-1:2, preferred molar ratio 1:1-1:1.5；
2. the catalyst be mantoquita, be stannous chloride, cuprous bromide or cuprous iodide in one kind or two kinds or three kinds,
It is preferred that cuprous iodide；The chiral ligand is (R)-BINAP, (R)-(S)-NMe2-PPh2-Mandyphos、(R,S)-
In Josiphos, (S, S)-Me-Duphos, (S, S, R, R)-Tangphos, (R, R)-Walphos or (S, S)-Taniaphos
Any one or two kinds or more, preferably (R, S)-Josiphos；Mole of α, β-unsaturation N- acyl indols and chiral ligand
Than being 1:0.03-1:0.15, preferred molar ratio 1:0.05-1:0.10；Mole of α, β-unsaturation N- acyl indols and mantoquita
Than being 1:0.02-1:0.10, preferred molar ratio 1:0.03-1:0.08.
3. the alkaline condition is any one in potassium carbonate, sodium carbonate or potassium phosphate or item existing for two kinds or three kinds
The ratio of the integral molar quantity of part, preferably potassium phosphate, the mole of α, β-unsaturation N- acyl indols and above-mentioned three kinds of substances is 1:
0.04-1:0.20, it is preferably in a proportion of 1:0.05-1:0.15.
4. the solvent of the asymmetry boronation reaction is in 1,4- dioxane, tetrahydrofuran, the tert-butyl alcohol or tertriary amylo alcohol
One or two or more kinds, preferably tertriary amylo alcohol, α, β-molar concentration of unsaturation N- acyl indols in a solvent are 0.01-1.0M,
It is preferred that molar concentration is 0.05-0.5M；
5. the reaction time of the asymmetry boronation reaction is 10-30 hours, preferred reaction time is 12-24 hours, instead
It is 0-100 DEG C to answer temperature, and preferable reaction temperature is 20-80 DEG C.
The present invention has the following advantages：
1) reaction raw materials α, β-unsaturation N- acyl indols have structure diversity, can be used for synthesizing with various substitutions
The N- acyl indol chirality boron compounds of base.
2) reaction raw materials duplex pinacol base diborane commercially available, it is easily prepared.
3) N- acyl indols chirality boron compound synthetic reaction condition is mild, step is simple, product yield and mapping select
Property it is high and applied widely.
4) product contains indoles substituent group and carbon chiral centre, has potential source biomolecule activity.
In short, the present invention, using α, the asymmetric boronation of β-unsaturation N- acyl indols and duplex pinacol base diborane is anti-
The N- acyl indol chirality boron compounds with various substituent groups should be synthesized, raw material is cheap and easily-available, easy to operate, and target product is received
Rate and enantioselectivity are high.
Specific embodiment
The present invention with α, β-unsaturation N- acyl indols for starting material and reaction raw materials duplex pinacol base diborane into
Row asymmetry boronation reaction, synthesizes N- acyl indol chirality boron compounds.Contribute to further understand this by following embodiments
Invention, but present disclosure is not limited to that.
Embodiment 1
Under nitrogen protection, sequentially added into 25mL Schlenk reaction bulbs cuprous iodide CuI (1.9mg,
0.01mmol), (R, S)-Josiphos (9.6mg, 0.015mmol), potassium phosphate K3PO4(4.2mg, 0.02mmol), tertriary amylo alcohol t-
AmOH (1.0mL) adds in duplex pinacol base diborane 3 (55.9mg, 0.22mmol) and spy penta after stirring 30 minutes at room temperature
Alcohol t-AmOH (0.5mL) is stirred 10 minutes at room temperature.Then add in (E)-N- (3- phenyl acryloyls) indoles 2a (50mg,
0.2mmol) and tertriary amylo alcohol t-AmOH (0.5mL), it stirs 20 hours at 25 DEG C.It is filtered after being cooled to room temperature through diatomite, filter cake is used
Ethyl acetate (20mL) washs, filtrate decompression concentration.(eluent is detached through silica gel column chromatography：Petroleum ether (60-90 DEG C)/acetic acid
Ethyl ester, v/v=60:1) white solid product 1a (71mg, yield 96%, ee values 95%), is obtained.Target product is total to by nuclear-magnetism
Spectrum of shaking and high resolution mass spectrum measure are confirmed, and ee values are measured by chiral high performance liquid chromatography.
Embodiment 2
Reaction step is with operation with embodiment 1, and difference from Example 1 is, mantoquita is cuprous bromide.Stop anti-
Should, it is post-treated to obtain target product 1a (64mg, yield 85%, ee values 95%).Illustrate that cuprous bromide can also be used as reaction
Catalyst, but be not best catalyst.
Embodiment 3
Reaction step is with operation with embodiment 1, and difference from Example 1 is, alkali is sodium carbonate.Stop reaction, warp
Post processing obtains target product 1a (56mg, yield 75%, ee values 90%).Illustrate that sodium carbonate can also be used as the alkali of reaction, but
It is not best alkali.
Embodiment 4
With operation with embodiment 1, difference from Example 1 is reaction step, chiral ligand for (R, R)-
Taniaphos.Stop reaction, it is post-treated to obtain target product 1a (12mg, yield 16%, ee values 99%).Illustrate (R, R)-
Taniaphos can also be used as the chiral ligand of reaction, but not be best chiral ligand.
Embodiment 5
Reaction step is with operation with embodiment 1, and difference from Example 1 is, solvent for use is the tert-butyl alcohol in reaction.
Stop reaction, it is post-treated to obtain target product 1a (70mg, yield 93%, ee values 90%).Illustrate that the tert-butyl alcohol can be used as instead
The solvent answered, but be not best solvent.
Embodiment 6
Reaction step is with operation with embodiment 1, and difference from Example 1 is, α, β-unsaturation N- acyl indols
(E)-N- (3- phenyl acryloyls) indoles 2a and 3 molar ratio of duplex pinacol base diborane are 1:1.Stop reaction, after
Reason obtains target product 1a (49mg, yield 65%, ee values 94%).(E)-N- (3- phenyl acryloyls) indoles 2a and duplex frequency
Which 3 molar ratio of alcohol radical diborane is 1:1 reaction can also occur, but not be best molar ratio.
Embodiment 7
Reaction step is with operation with embodiment 1, and difference from Example 1 is, reaction time 6h.Stop reaction,
It is post-treated to obtain target product 1a (30mg, yield 40%, ee values 93%).Illustrate shorten the reaction time be unfavorable for reaction into
Row.
Embodiment 8
Reaction step is with operation with embodiment 1, and difference from Example 1 is, reaction temperature is 60 DEG C.Stop anti-
Should, it is post-treated to obtain target product 1a (71mg, yield 95%, ee values 94%).Illustrate that increasing reaction temperature is unfavorable for reacting
Progress, 60 DEG C be not reaction optimum temperature.
Embodiment 9
Reaction step is with operation with embodiment 1, and difference from Example 1 is, reaction temperature is 0 DEG C.Stop reaction,
It is post-treated to obtain target product 1a (4mg, yield 5%, ee values 93%).Illustrate reduce reaction temperature be unfavorable for reaction into
Row, 0 DEG C is not the optimum temperature reacted.
Embodiment 10
With operating with embodiment 1, difference from Example 1 is reaction step, the α added in reaction system, β-no
Saturation N- acyl indols are 2b (55mg, 0.2mmol).Stop reaction, it is post-treated to obtain desired product as white solid 1b
(77mg, yield 95%, ee values 92%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measure.
Embodiment 11
With operating with embodiment 1, difference from Example 1 is reaction step, the α added in reaction system, β-no
Saturation N- acyl indols are 2c (56mg, 0.2mmol).Stop reaction, it is post-treated to obtain desired product as white solid 1c
(76mg, yield 93%, ee values 95%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measure.
Embodiment 12
With operating with embodiment 1, difference from Example 1 is reaction step, the α added in reaction system, β-no
Saturation N- acyl indols are 2d (52mg, 0.2mmol).Stop reaction, it is post-treated to obtain desired product as white solid 1d
(75mg, yield 96%, ee values 90%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measure.
Embodiment 13
With operating with embodiment 1, difference from Example 1 is reaction step, the α added in reaction system, β-no
Saturation N- acyl indols are 2e (53mg, 0.2mmol).Stop reaction, it is post-treated to obtain desired product as white solid 1e
(71mg, yield 90%, ee values 95%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measure.
Embodiment 14
With operating with embodiment 1, difference from Example 1 is reaction step, the α added in reaction system, β-no
Saturation N- acyl indols are 2f (51mg, 0.2mmol).Stop reaction, it is post-treated to obtain desired product as white solid 1f
(69mg, yield 91%, ee values 96%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measure.
Embodiment 15
With operating with embodiment 1, difference from Example 1 is reaction step, the α added in reaction system, β-no
Saturation N- acyl indols are 2g (37mg, 0.2mmol).Stop reaction, it is post-treated to obtain desired product as white solid 1g
(59mg, yield 95%, ee values 92%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measure.
Typical compound characterize data
The white solid 1a that embodiment 1-9 is obtained, fusing point:90-92 DEG C of .H spectrum δ 8.53 (d, J=8.2Hz, 1H,
Aromatic CH), 7.59 (d, J=7.7Hz, 1H, aromatic CH), 7.46 (d, J=3.5Hz, 1H, aromatic CH),
7.40-7.25 (m, 7H, aromatic CH), 6.63 (d, J=3.6Hz, 1H, aromatic CH), 3.55 (dd, J=17.2,
11.2Hz) 3.32 (dd, J=17.2,5.1Hz, 1 of and:1H, COCH2), 2.97 (dd, J=11.1,5.0Hz, 1H, CH),
1.32and 1.24(s each,6:6H,4×CH3)；Carbon spectrum δ 171.3 (Cq, C=O), 130.4 (Cq of 141.2,135.7, and
each),128.7,128.5,126.0,125.0,124.7,123.6,120.8,116.6,and 109.0(aromatic CH),
83.7(Cq,2×OC(CH3)2),40.1(COCH2),24.7and 24.5(4×CH3) .HRMS theoretical values [M+H]+
C23H27BNO3:376.2084；Measured value:376.2084.
Claims (6)
1. a kind of synthetic method of N- acyl indols chirality boron compound, N- acyl indol chirality 1 structural formulas of boron compound are as follows,
It is abbreviated as
Wherein R1For the one or two or more kinds in methyl, methoxyl group, bromine, chlorine or fluorine, R2For C1-C4Alkyl, phenyl, phenyl ring
Above any one in the aryl with substituent group, naphthalene or heterocyclic aryl, the substituent group carried on above-mentioned phenyl ring are C1-C4's
One or two or more kinds in alkyl, methoxyl group, bromine, chlorine, fluorine, acetyl group, trifluoromethyl, the number of benzene ring substituents is 1-
3；
The structure of raw material α, β-unsaturation N- acyl indols 2 is as follows,
Wherein R1For methyl, methoxyl group, bromine, chlorine, fluorine one or two or more kinds, R2For C1-C4Alkyl, phenyl, band on phenyl ring
Any one in the aryl of substituted base, naphthalene or heterocyclic aryl, the substituent group carried on above-mentioned phenyl ring is C1-C4Alkane
One or two or more kinds in base, methoxyl group, bromine, chlorine, fluorine, acetyl group, the number of benzene ring substituents is 1-3；
The structure of raw material duplex pinacol base diborane 3 is as follows, is abbreviated as B2pin2,
Synthetic route as shown in following reaction equations,
It is characterized in that：With α, β-unsaturation N- acyl indols 2 are starting material with duplex pinacol base diborane 3, are being catalyzed
Under the conditions of agent and chiral ligand are existing, heating under alkaline condition carries out asymmetric boronation reaction, synthesizes N- acyl indol hands
Property boron compound 1.
2. synthetic method according to claim 1, it is characterised in that：The starting material α, β-unsaturation N- acyl groups Yin
The molar ratio of diindyl 2 and duplex pinacol base diborane 3 is 1:1-1:2, preferred molar ratio 1:1-1:1.5.
3. synthetic method according to claim 1 or 2, it is characterised in that：The catalyst is mantoquita, is protochloride
One kind in copper, cuprous bromide or cuprous iodide or two kinds or three kinds, preferably cuprous iodide；The chiral ligand for (R)-
BINAP、(R)-(S)-NMe2-PPh2-Mandyphos、(R,S)-Josiphos、(S,S)-Me-Duphos、(S,S,R,R)-
Any one in Tangphos, (R, R)-Walphos or (S, S)-Taniaphos or two kinds or more, preferably (R, S)-
Josiphos；The molar ratio of α, β-unsaturation N- acyl indols and chiral ligand is 1:0.03-1:0.15, preferred molar ratio 1:
0.05-1:0.10；The molar ratio of α, β-unsaturation N- acyl indols and mantoquita is 1:0.02-1:0.10, preferred molar ratio 1:
0.03-1:0.08。
4. according to the synthetic method described in claim 1,2 or 3, it is characterised in that：The alkaline condition is potassium carbonate, sodium carbonate
Or condition, preferably potassium phosphate existing for any one in potassium phosphate or two kinds or three kinds；α, β-unsaturation N- acyl indols 2 rub
It is 1 that you, which are measured with the ratio of the integral molar quantity of alkali,:0.04-1:0.20, it is preferably in a proportion of 1:0.05-1:0.15.
5. according to any synthetic methods of claim 1-4, it is characterised in that：The solvent of the asymmetry boronation reaction
For the one or two or more kinds in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, the tert-butyl alcohol or tertriary amylo alcohol, preferably tertriary amylo alcohol；α, β-insatiable hunger
It is 0.01-1.0M with the molar concentration of N- acyl indols in a solvent, preferably molar concentration is 0.05-0.5M.
6. according to any synthetic methods of claim 1-5, it is characterised in that：The reaction of the asymmetry boronation reaction
Time is 10-30 hours, and preferred reaction time is 12-24 hours, and reaction temperature is 0-100 DEG C, preferable reaction temperature 20-80
℃。
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| 刘媛媛等: "铜催化烯烃的不对称加成硼化反应研究进展", 《有机化学》 * |
| 刘强等: "铜催化的 α,β-不饱和化合物的不对称共轭硼化反应研究进展", 《有机化学》 * |
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