CN116589426B - Method for synthesizing chiral 1, 3-benzoxazine derivative - Google Patents
Method for synthesizing chiral 1, 3-benzoxazine derivative Download PDFInfo
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- CN116589426B CN116589426B CN202310407704.XA CN202310407704A CN116589426B CN 116589426 B CN116589426 B CN 116589426B CN 202310407704 A CN202310407704 A CN 202310407704A CN 116589426 B CN116589426 B CN 116589426B
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- allyl alcohol
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- CGACGSHTSCXSSO-UHFFFAOYSA-N 2h-1,3-benzoxazine Chemical class C1=CC=C2C=NCOC2=C1 CGACGSHTSCXSSO-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- -1 2-hydroxyphenyl allyl alcohol Chemical compound 0.000 claims abstract description 28
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 17
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- XXROGKLTLUQVRX-UHFFFAOYSA-N hydroxymethylethylene Natural products OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims abstract description 16
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 239000000654 additive Substances 0.000 claims abstract description 9
- 238000007115 1,4-cycloaddition reaction Methods 0.000 claims abstract description 8
- 229910052786 argon Inorganic materials 0.000 claims abstract description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 11
- 230000000996 additive effect Effects 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 229910052736 halogen Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 239000000758 substrate Substances 0.000 abstract description 4
- 125000003363 1,3,5-triazinyl group Chemical class N1=C(N=CN=C1)* 0.000 abstract 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000012300 argon atmosphere Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 13
- 238000010626 work up procedure Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 150000000182 1,3,5-triazines Chemical class 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XWXVKXXKKLBDDJ-UHFFFAOYSA-N 7-chloro-3,3a-dihydro-2h-[1,2]oxazolo[3,2-b][1,3]benzoxazin-9-one Chemical compound O1C2CCON2C(=O)C2=CC(Cl)=CC=C21 XWXVKXXKKLBDDJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229950002093 seclazone Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/16—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with only hydrogen or carbon atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
Abstract
本发明公开了一种合成手性1,3‑苯并噁嗪衍生物的方法。具体来说是通过铱催化剂和手性配体组合，催化消旋的2‑羟基苯基烯丙基醇和1,3,5‑三嗪化合物发生不对称[4+2]‑环加成反应制备一系列手性1,3‑苯并噁嗪类衍生物的方法，该方法属于有机合成领域。具体操作步骤为：在氩气保护下，向反应管中加入铱催化剂和手性配体，随后加入2‑羟基苯基烯丙基醇，1,3,5‑三嗪化合物和添加剂，然后在25℃下反应，待反应完全，纯化分离，得到手性1,3‑苯并噁嗪类衍生物。该方法具有底物适用性好，反应条件温和，区域选择性以及对映选择性高的优点。
The invention discloses a method for synthesizing chiral 1,3-benzoxazine derivatives. Specifically, a method for preparing a series of chiral 1,3-benzoxazine derivatives by combining an iridium catalyst and a chiral ligand, catalyzing asymmetric [4+2]-cycloaddition reaction of racemic 2-hydroxyphenyl allyl alcohol and 1,3,5-triazine compounds, and the method belongs to the field of organic synthesis. The specific operation steps are: under argon protection, an iridium catalyst and a chiral ligand are added to a reaction tube, followed by adding 2-hydroxyphenyl allyl alcohol, 1,3,5-triazine compounds and additives, and then reacting at 25°C, until the reaction is complete, purifying and separating, and obtaining chiral 1,3-benzoxazine derivatives. The method has the advantages of good substrate applicability, mild reaction conditions, high regioselectivity and enantioselectivity.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing chiral 1, 3-benzoxazine derivatives.
Background
The 1, 3-benzoxazine derivative is a common organic synthesis intermediate and widely exists in natural products and various medical intermediates. Small molecule active agents such as CX-614, seclazone, etc. all have 1, 3-benzoxazine backbone units. Catalyzing asymmetric hetero [4+2] cycloaddition reaction is the most efficient and convenient method for constructing benzo heterocycle. However, only some work has been done on the synthesis of achiral 1, 3-benzoxazine derivatives through literature studies (see for details: cheng, x.; zhou, s.—j.; xu, g.—y.; wang, l.; yang, q.—q.; xuan, j.adv. Synth. Catalyst. 2020,362, 523-527.). At present, no method for synthesizing chiral 1, 3-benzoxazine derivatives through asymmetric [4+2] cycloaddition reaction exists. The hysteresis of the asymmetric synthesis method severely restricts the further research on chiral 1, 3-benzoxazine derivatives.
In view of this, on the basis of our earlier work, a method for efficiently constructing chiral 1, 3-benzoxazine compounds was developed, starting from readily available substrates, continuing to be sought. Therefore, by designing a catalytic system and screening conditions, a series of chiral 1, 3-benzoxazine derivatives are prepared by carrying out asymmetric [4+2] -cycloaddition reaction on the iridium-catalyzed racemic 2-hydroxyphenyl allyl alcohol and the 1,3, 5-triazine compound. The method has the advantages of good substrate applicability, mild reaction conditions, high regioselectivity and enantioselectivity, and the like.
Disclosure of Invention
The invention provides a method for synthesizing chiral 1, 3-benzoxazine derivatives with high regioselectivity and enantioselectivity by using easily available 2-hydroxyphenyl allyl alcohol and 1,3, 5-triazine compounds as reaction raw materials by utilizing an asymmetric [4+2] -cycloaddition strategy.
In order to achieve the purpose of the invention, the technical scheme adopted is as follows:
A method for synthesizing chiral 1, 3-benzoxazine derivatives is characterized in that: under the catalysis of iridium catalyst, racemic 2-hydroxy phenyl allyl alcohol and 1,3, 5-triazine compound take asymmetric [4+2] -cycloaddition reaction to prepare chiral 1, 3-benzoxazine derivative. The structural formula of the racemized 2-hydroxy phenyl allyl alcohol is as follows:
Wherein R can be methyl, methoxy or halogen.
Further, the method comprises the following steps: under the protection of argon, the iridium catalyst and the chiral ligand are dissolved in a solvent and placed in a sealed tube, and stirring is carried out to lead the iridium and the chiral ligand in the iridium catalyst to be fully coordinated. Then adding 2-hydroxy phenyl allyl alcohol, 1,3, 5-triazine compound and additive into the tube, replacing argon, fully reacting at 0-40 ℃ (generally about 12h, slow low-temperature reaction, fast high-temperature reaction, but excessively high temperature is unfavorable for stereoselectivity, and the most suitable temperature is 25 ℃), and purifying to obtain chiral 1, 3-benzoxazine derivatives.
Further, the structural formula of the 1,3, 5-triazine compound is as follows:
wherein Ar is phenyl or p-methoxyphenyl.
The specific reaction equation is as follows (Scheme 1):
Scheme 1 reaction equation
Further, the molar ratio of the 2-hydroxyphenyl allyl alcohol to the 1,3, 5-triazine compound is 3:1 to 1:1, wherein the yield is highest when the molar ratio is 2:1.
Further, the iridium catalyst is used in an amount of 2% to 4% (more preferably 4%) of the molar equivalent of 2-hydroxyphenylallylic alcohol.
Further, the chiral phosphoramidite ligand L is of S-configuration, and the structural formula isThe use amount is 200-400% of the iridium catalyst molar amount.
Further, the additive is trifluoroacetic acid, and the equivalent weight is 80-200% of that of 2-hydroxy phenyl allyl alcohol. The highest yields have been achieved when the catalytic amount is 100%.
Compared with the prior art, the invention has the following beneficial effects:
The method utilizes an asymmetric [4+2] -cycloaddition strategy, and provides a method for synthesizing chiral 1, 3-benzoxazine derivatives with high regio-and enantioselectivity by utilizing easily prepared 2-hydroxyphenyl allyl alcohol and 1,3, 5-triazine compounds as reaction raw materials. The method has the advantages of good substrate applicability, mild reaction conditions, high regioselectivity and high enantioselectivity.
Drawings
FIG. 1 is a hydrogen spectrum of compound 3aa prepared in the example;
FIG. 2 is a carbon spectrum of compound 3aa prepared in the example;
FIG. 3 is a high performance liquid chromatography of racemic sample 3aa prepared in the example (Racemic sample 3aa:HPLC(Daicel Chiralpak OJ-H column(hexane/iPrOH＝70:30,flow rate:1.0mL/min,λ＝215nm));
FIG. 4 is a high performance liquid chromatogram of chiral product 3 aa;
FIG. 5 is a high resolution mass spectrum of product 3 aa.
Detailed Description
The present invention will be further described with reference to examples, but is not limited thereto (mol%, eq in the following examples are the result of accounting for 2-hydroxyphenylallyl alcohol).
Implementation example 1:
Synthesis of (3 aa):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3aa (29.5 mg,93% ee, yield) :53％).1H NMR(400MHz,CDCl3)δ7.30-7.26(m,2H),7.16(ddd,J＝8.5,7.1,1.8Hz,1H),6.95(dd,J＝7.6,1.8Hz,1H),6.90-6.83(m,4H),6.02(ddd,J＝17.2,10.2,4.6Hz,1H),5.24(dt,J＝10.2,1.6Hz,1H),4.98(dt,J＝17.2,1.6Hz,1H),4.93(d,J＝10.1Hz,1H),4.67(dd,J＝10.1,1.7Hz,1H),4.17(dd,J＝4.5,2.0Hz,1H),3.96(d,J＝13.4Hz,1H),3.80(s,3H),3.78(d,J＝13.4Hz,1H).13C NMR(100MHz,CDCl3)δ159.0,154.1,140.3,130.4,130.1,129.8,128.1,120.5,120.3,117.7,116.8,113.9,78.0,58.6,55.41,55.39.HRMS(ESI)m/z calculated for C18H20NO2[M+H]+:282.1489,found:282.1496.HPLC:Daicel Chiralpak OJ-H column(hexane/iPrOH＝70:30,flow rate:1.0mL/min,λ＝215nm,tR(major)＝9.28min,tR(minor)＝11.83min.ee＝93％.
Implementation example 2:
Synthesis of (3 ab):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1b (0.2 mmol,33.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3ab (33.5 mg,94% ee, yield :57％).1H NMR(400MHz,CDCl3)δ7.31-7.26(m,2H),6.97(dd,J＝8.3,2.2Hz,1H),6.89-6.84(m,2H),6.78-6.72(m,2H),6.01(ddd,J＝17.3,10.3,4.7Hz,1H),5.22(dt,J＝10.3,1.7Hz,1H),5.00(dt,J＝17.2,1.7Hz,1H),4.89(d,J＝10.0Hz,1H),4.64(dd,J＝10.0,1.6Hz,1H),4.13(dd,J＝4.7,2.0Hz,1H),3.95(d,J＝13.4Hz,1H),3.80(s,3H),3.78(d,J＝13.5Hz,1H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ159.0,151.8,140.4,130.5,130.1,129.9,129.4,128.8,120.2,117.4,116.5,113.9,78.0,58.7,55.40,55.38,20.8.HRMS(ESI)m/z calculated for C19H22NO2[M+H]+:296.1645,found:296.1653.Optical Rotation:[α]D 25＝+36.1(c＝0.1,CHCl3).HPLC:Daicel Chiralpak OJ-H column(hexane/iPrOH＝90:10,flow rate:0.7mL/min,λ＝215nm,tR(major)＝12.54min,tR(minor)＝13.98min.ee＝94％. example 3:
Synthesis of (3 ac):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1c (0.2 mmol,46.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3ac (44.0 mg,94% ee, yield :61％).1H NMR(400MHz,CDCl3)δ7.28-7.24(m,3H),7.07(dd,J＝2.4,0.7Hz,1H),6.90-6.84(m,2H),6.74(d,J＝8.7Hz,1H),5.98(ddd,J＝17.3,10.3,4.6Hz,1H),5.26(dt,J＝10.3,1.6Hz,1H),4.97(dt,J＝17.3,1.5Hz,1H),4.89(d,J＝10.2Hz,1H),4.67(dd,J＝10.1,1.7Hz,1H),4.14(dd,J＝4.5,2.1Hz,1H),3.92(d,J＝13.3Hz,1H),3.80(s,3H),3.73(d,J＝13.3Hz,1H).13C NMR(100MHz,CDCl3)δ159.1,153.2,139.6,132.1,131.1,130.1,130.0,122.4,118.7,118.3,114.0,112.1,78.1,58.3,55.44,55.39.HRMS(ESI)m/z calculated for C18H19BrNO2[M+H]+:360.0594,found:360.0601.HPLC:Daicel Chiralpak IA column(hexane/iPrOH＝99:1,flow rate:0.7mL/min,λ＝215nm,tR(major)＝7.35min,tR(minor)＝7.74min.ee＝94％.
Implementation example 4:
Synthesis of (3 ad):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1d (0.2 mmol,46.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3ad (38.8 mg,94% ee, yield :54％).1H NMR(400MHz,CDCl3)δ7.28-7.23(m,2H),7.04-6.98(m,2H),6.89-6.84(m,2H),6.80(d,J＝8.1Hz,1H),5.98(ddd,J＝17.3,10.3,4.5Hz,1H),5.25(dt,J＝10.3,1.6Hz,1H),4.95-4.88(m,2H),4.66(dd,J＝10.1,1.7Hz,1H),4.13(dd,J＝4.5,2.0Hz,1H),3.92(d,J＝13.3Hz,1H),3.80(s,3H),3.74(d,J＝13.3Hz,1H).13C NMR(101MHz,CDCl3)δ159.1,154.9,139.8,131.0,130.1,130.0,123.4,121.0,119.9,119.2,118.2,113.9,78.2,58.2,55.41,55.38.HRMS(ESI)m/z calculated for C18H19BrNO2[M+H]+:360.0594,found:360.0598.HPLC:Daicel Chiralpak OD-H column(hexane/iPrOH＝90:10,flow rate:1.0mL/min,λ＝215nm,tR(major)＝9.22min,tR(minor)＝13.57min.ee＝92％.
Implementation example 5:
synthesis of (3 ae):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1e (0.2 mmol,44.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3ae (28.1 mg,95% ee, yield) :40％).1H NMR(400MHz,CDCl3)δ7.29-7.23(m,3H),6.91-6.84(m,3H),5.96(ddd,J＝17.3,10.4,4.5Hz,1H),5.29(ddd,J＝10.3,1.8,1.1Hz,1H),5.00(d,J＝10.1Hz,1H),4.94(ddd,J＝17.3,1.9,1.2Hz,1H),4.87(dd,J＝10.1,1.7Hz,1H),4.15(dd,J＝4.4,2.0Hz,1H),3.96(d,J＝13.4Hz,1H),3.81(s,3H),3.72(d,J＝13.5Hz,1H).13C NMR(101MHz,CDCl3)δ159.2,148.7,139.2,130.0,129.6,128.5,127.8,124.6,122.9,122.1,118.7,114.0,79.4,58.1,55.6,55.4.HRMS(ESI)m/z calculated for C18H18Cl2NO2[M+H]+:350.0709,found:30.0703.HPLC:Daicel Chiralpak OJ-H column(hexane/iPrOH＝90:10,flow rate:1.0mL/min,λ＝215nm,tR(major)＝6.74min,tR(minor)＝10.49min.ee＝95％.
Implementation example 6:
Synthesis of (3 af):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1f (0.2 mmol,41.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3ae (29.0 mg,86% ee, yield :43％).1H NMR(400MHz,CDCl3)δ7.31-7.26(m,2H),7.17(dd,J＝5.9,3.6Hz,1H),6.90-6.79(m,4H),6.05(ddd,J＝17.2,10.3,4.8Hz,1H),5.22(dt,J＝10.3,1.7Hz,1H),5.03(dt,J＝17.2,1.7Hz,1H),4.87(d,J＝10.0Hz,1H),4.68(dd,J＝10.0,1.8Hz,1H),4.18(dd,J＝4.7,2.0Hz,1H),3.91(d,J＝13.1Hz,1H),3.80(s,3H),3.76(d,J＝13.1Hz,1H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ159.0,153.0,140.7,137.6,130.5,130.3,127.7,125.1,120.3,119.4,117.2,113.9,76.8,59.6,55.4,55.3,34.9,29.7.HRMS(ESI)m/z calculated for C20H28NO2[M+H]+:338.2115,found:338.2121.HPLC:Daicel Chiralpak IB column(hexane/iPrOH＝95:5,flow rate:1.0mL/min,λ＝215nm,tR(major)＝6.60min,tR(minor)＝6.24min.ee＝86％. example 7:
synthesis of (3 ag):
1, 5-cyclooctadiene Iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,36.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3ae (32.0 mg,96% ee, yield) :63％).1H NMR(400MHz,CDCl3)δ7.40-7.17(m,5H),7.13-7.00(m,1H),6.88(dd,J＝7.6,1.8Hz,1H),6.84-6.73(m,2H),5.97(ddd,J＝17.2,10.3,4.6Hz,1H),5.18(dt,J＝10.3,1.7Hz,1H),5.01-4.83(m,2H),4.61(dd,J＝10.1,1.7Hz,1H),4.11(dd,J＝4.6,2.0Hz,1H),3.97(d,J＝13.7Hz,1H),3.78(d,J＝13.8Hz,1H).13C NMR(100MHz,CDCl3)δ152.92,139.10,137.30,128.63,127.66,127.38,127.02,126.28,119.29,119.15,116.57,115.64,77.06,57.67,54.90.
HRMS(ESI)m/z calculated for C17H18NO[M+H]+:252.1383,found:252.1386.HPLC:Daicel Chiralpak OJ-H column(hexane/iPrOH＝90:10,flow rate:0.9mL/min,λ＝215nm,tR(major)＝6.74min,tR(minor)＝10.49min.ee＝96％.
The following examples 8-12 are control variable experiments:
Example 8 (catalyst amount change):
(3 aa) Synthesis
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (2.6 mg,2 mol%) and (S) -L (8.8 mg,8 mol%) and dichloroethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,46.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 0deg.C for 24h. Work-up and purification of the crude product by TLC prep plate gave 3aa (15.1 mg,91% ee, yield: 28%).
Example 9 (reaction solvent change):
Synthesis of (3 aa):
to the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (5.3 mg,4 mol%) under argon atmosphere, (S) -L (16.6 mg,16 mol%) and methylene chloride (1.5 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work up and purification of the crude product by TLC prep plate gave 3aa (28.1 mg,92% ee, yield: 50%).
Example 10 (reaction solvent change):
Synthesis of (3 aa):
to the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and toluene (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3aa (8.1 mg,62% ee, yield: 12%).
Example 11 (reduced amount of additive):
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and toluene (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (0.5 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3aa (15.0 mg,82% ee, yield: 28%).
Example 12 (additive addition):
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (5.3 mg,4 mol%) and (S) -L (16.6 mg,16 mol%) and toluene (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 1a (0.2 mmol,30.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.5 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. The crude product was treated and purified by TLC prep plate to give 3aa (12.2 mg,86% ee, yield: 16%).
Example 13 (1 a and 2a equivalence ratio study):
Synthesis of (3 aa):
To the reaction tube was added 1, 5-cyclooctadiene iridium chloride dimer (8.0 mg,4 mol%) and (S) -L (25 mg,16 mol%) and dichloroethane (1.5 mL) under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 1a (0.3 mmol,45.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3aa (36.1 mg,85% ee, yield: 31%).
Example 14 (1 a and 2a equivalence ratio study):
Synthesis of (3 aa):
1, 5-cyclooctadiene Iridium chloride dimer (2.8 mg,4 mol%) and (S) -L (8.4 mg,16 mol%) and dichloroethane (1.5 mL) were added to the reaction tube under argon atmosphere, and stirred at room temperature for 10 minutes. Subsequently, 1a (0.1 mmol,15.0mg,1 eq.) 2a (0.1 mmol,44.6 mg) and TFA (1.0 eq.). The tube was then capped and the reaction was allowed to react at 25℃for 24h. Work-up and purification of the crude product by TLC prep plate gave 3aa (12.7 mg,70% ee, yield: 45%).
The examples are preferred embodiments of the present invention, but the present invention is not limited to the above-described embodiments, and any obvious modifications, substitutions or variations that can be made by one skilled in the art without departing from the spirit of the present invention are within the scope of the present invention.
Claims (9)
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