CN101525291A - Green asymmetric synthesis method of chiral bicyclics compound - Google Patents
Green asymmetric synthesis method of chiral bicyclics compound Download PDFInfo
- Publication number
- CN101525291A CN101525291A CN 200910097515 CN200910097515A CN101525291A CN 101525291 A CN101525291 A CN 101525291A CN 200910097515 CN200910097515 CN 200910097515 CN 200910097515 A CN200910097515 A CN 200910097515A CN 101525291 A CN101525291 A CN 101525291A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- acid
- formula
- chiral
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 bicyclics compound Chemical class 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000003054 catalyst Substances 0.000 claims abstract description 35
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- FBRJYBGLCHWYOE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(F)(F)F FBRJYBGLCHWYOE-UHFFFAOYSA-N 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 238000004440 column chromatography Methods 0.000 claims description 22
- 238000004821 distillation Methods 0.000 claims description 22
- 239000003480 eluent Substances 0.000 claims description 22
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 22
- 239000012044 organic layer Substances 0.000 claims description 22
- 238000000926 separation method Methods 0.000 claims description 22
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 9
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims description 7
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 claims description 5
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000003147 proline derivatives Chemical class 0.000 claims description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 claims description 2
- FQXQBFUUVCDIRK-UHFFFAOYSA-N 3-trifluoromethylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=C1 FQXQBFUUVCDIRK-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 23
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000008346 aqueous phase Substances 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 abstract 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 238000006555 catalytic reaction Methods 0.000 description 23
- 238000000338 in vitro Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 18
- 238000000746 purification Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000005698 Diels-Alder reaction Methods 0.000 description 8
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001993 dienes Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a green asymmetric synthesis method of chiral bicyclics compound as shown in formula (I): taking cyclohexene ketone derivative as shown in formula (II) and nitroolefin derivative as shown in formula (III) as raw materials; in the existence of chiral secondary amine catalyst, protonic acid and water, reacting for 3-72 hours at a temperature of -20-40 DEG C; after the completion of the reaction, processing the obtained reaction liquid to obtain the chiral bicyclics compound as shown in the formula (I); the chiral secondary amine catalyst is the praline derivative as shown in formula (IV); quantity relative ratio of the nitroolefin derivative as shown in formula (III) to the cyclohexene ketone derivative as shown in formula (II) is 1:1-3. The chiral bicyclics compound provided in the invention is a new chiral compound, the synthesized compound synthesized by aqueous phase in a green way demonstrates fine reactive characteristics, thus being capable of being used in the field of organic synthesis, material and the like.
Description
(1) technical field
The present invention relates to a kind of green method of asymmetric synthesis of chiral bicyclics compound.
(2) background technology
Asymmetric synthesis has become the important research direction of 21 century chemistry, is an indispensable integral part in fields such as Synthetic Organic Chemistry, biological chemistry, medical chemistry and chemistry of pesticide.Usually, asymmetric catalysis synthesis is realized by using chiral auxiliary(reagent), chiral reagent and chiral catalyst.The catalysis asymmetric synthesis is optimal method of asymmetric synthesis, and it only uses a spot of chiral catalyst just to obtain a large amount of chiral product.
Chiral bicyclics compound is the very important compound of a class, is the precursor of a lot of medicines and a very important class synthetic intermediate.Wherein, the catalytic Diels-Alder reaction of chirality secondary amine is the important reaction of synthesis of chiral bicyclics compound one class.MacMillan group in 2000 utilization catalyzer (1) reacts (J.Am.Chem.Soc., 2000,122,4243) by the Diels-Alder of imines catalytic olefine and diene first, synthesized the chiral bicyclics compound that a class contains aldehyde radical.Barbas group utilizes the Diels-Alder reaction (Terahedron Lett., 2002,43,3817) of catalyzer (2) by enamine catalysis ketenes and nitroolefin first.C ó rdova group utilizes the Diels-Alder reaction of catalyzer (2) catalysis cyclonene and nitroolefin first, synthesized the chiral bicyclics compound that a class contains nitro.Through reaction in four days, the yield of product reached 61%, and diastereomer ratio is＞25: 1, and ee value (enantiomeric excess value) can reach 67% (Adv.Synth.Catal., 2007,349,2549).
Water is synthetic except the cost cheapness, and outside the factors such as environmental friendliness, water react can have good promoter action to the reactive behavior and the selectivity of substrate.Recently, the Asymmetric Diels-Alder Reaction research of carrying out at aqueous phase also has report.Ogilvie group is by self-designed catalyzer (3), and in the Diels-Alder of aqueous phase success catalytic olefine and diene reaction, the yield that reaction finishes after product reaches 88%, ee value (enantiomeric excess value) can reach 94% (Org.Lett., 2005,7,4141).The Diels-Alder of Hayashi group utilization catalyzer (4) catalytic olefine and diene reacts, and finds to have promoted at aqueous phase the carrying out of this reaction, and speed and the optical selective that reacts all had good promoter action.Yield through 11 hours reaction after products reaches 93%, and ee value (enantiomeric excess value) can reach 94% (Angew.Chem.Int.Ed., 2008,47,6634).
These achievements in research have been enriched the kind of aqueous phase Diels-Alder reaction, for green synthesis of chiral bicyclics compound provides multiple synthetic method.But, the research work in this field just just begins, further explore new catalyzer and reaction type, synthetic new chiral bicyclics compound, and then research and develop it in Application for Field such as asymmetric organic synthesis and medicines, and final obtain to have good asymmetric induction effect, be easy to the reaction system that recovery set such as uses at characteristic, will be important emerging research field in the modern Green Chemistry.
(3) summary of the invention
The object of the present invention is to provide a kind of green method of asymmetric synthesis of chiral bicyclics compound.
The technical solution used in the present invention is:
A kind of green method of asymmetric synthesis suc as formula the chiral bicyclics compound shown in (I), described method is: being raw material suc as formula the cyclohexenone derivates shown in (II) with suc as formula the nitroolefin derivative shown in (III), in the presence of chirality secondary amine catalyst, protonic acid and water, under-20～40 ℃ of temperature, reacted 3～72 hours, after reaction finished, the reaction solution separating treatment obtained suc as formula the chiral bicyclics compound shown in (I); Described chirality secondary amine catalyst is suc as formula the proline derivative shown in (IV); Described is 1: 1～3 suc as formula the nitroolefin derivative shown in (III) with suc as formula the amount of substance ratio of the cyclohexenone derivates shown in (II); Described amount of substance ratio suc as formula the nitroolefin derivative shown in (III), chirality secondary amine catalyst, protonic acid, water is 1: 0.05～0.3: 0.05～0.3: 30～40;
In formula (I), formula (II), formula (III) or the formula (IV), R
1, R
2, R
3Independent separately is the alkyl of H or C1～C20; R
4Be H, the alkyl of C1～C20, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, the fluorine-based phenyl of 2-, the fluorine-based phenyl of 3-, the fluorine-based phenyl of 4-, 2-chloro phenyl, 3-chloro phenyl, 4-chloro phenyl, 2-bromo phenyl, 3-bromo phenyl, 4-bromo phenyl, the 2-nitrophenyl, the 3-nitrophenyl, the 4-nitrophenyl, the 2-trifluoromethyl, the 3-trifluoromethyl, the 4-trifluoromethyl, furyl or thienyl; R
5Be one of following formula:
Reaction equation is as follows:
Comparatively preferred, in formula (I), formula (II), formula (III) or the formula (IV), described R
1, R
2, R
3Independent separately is hydrogen or methyl; Described R
4Be preferably 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 4-aminomethyl phenyl, phenyl, the fluorine-based phenyl of 4-, 4-chloro phenyl, 3-bromo phenyl, 4-bromo phenyl, 3-nitrophenyl, 4-trifluoromethyl or furyl; Described R
5Be preferably following formula:
More specifically, described chiral bicyclics compound is: (1) (1S, 4S, 5S, 6R) 6-(2-p-methoxy-phenyl)-5-nitro two rings [2,2,2] octane-2-ketone, (2) (1S, 4S, 5S, 6R) 6-(3-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone, (3) (1S, 4S, 5S, 6R) 6-(4-p-methoxy-phenyl)-5-nitro two rings [2,2,2] octane-2-ketone, (4) (1S, 4S, 5S, 6R) 6-(4-aminomethyl phenyl)-5-nitro two rings [2,2,2] octane-2-ketone, (5) (1S, 4S, 5S, 6R) 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone, (6) (1S, 4S, 5S, 6R) 6-(the fluorine-based phenyl of 4-)-5-nitro two rings [2,2,2] octane-2-ketone, (7) (1S, 4S, 5S, 6R) 6-(4-chloro phenyl)-5-nitro two rings [2,2,2] octane-2-ketone, (8) (1S, 4S, 5S, 6R) 6-(3-bromo phenyl)-5-nitro two rings [2,2,2] octane-2-ketone, (9) (1S, 4S, 5S, 6R) 6-(4-bromo phenyl)-5-nitro two ring [2,2,2] octane-2-ketone, (10) (1S, 4S, 5S, 6R) 6-(3-nitrophenyl)-5-nitro two rings [2,2,2] octane-2-ketone, (11) (1S, 4S, 5S, 6R) 6-(4-trifluoromethyl)-5-nitro two rings [2,2,2] octane-2-ketone, (12) (1S, 4S, 5S, 6R) 6-furans-5-nitro two rings [2,2,2] octane-2-ketone, (13) (1S, 4S, 5S, 6R) 6-phenyl-4-methyl-5-nitro two ring [2,2,2] octane-2-ketone, (14) (1S, 2R, 3S, 4R) 2-phenyl-5,5-dimethyl-3-nitro two rings [2,2,2] octane-7-ketone.
Described is 1: 1～3 suc as formula the nitroolefin derivative shown in (III) with suc as formula the amount of substance ratio of the cyclohexenone derivates shown in (II), is preferably 1: 1.2.
Described chirality secondary amine catalyst is a proline derivative, and its general structure is formula (IV), preferably shown in formula V;
It is one of following that the present invention recommends described protonic acid: HCl, HBr, H
2SO
4, HBF
4, HPF
6, CH3COOH, CF
3COOH, CF
3SO
3H, phenylformic acid, o-fluorobenzoic acid, a fluorobenzoic acid, parafluorobenzoic acid, toluylic acid, p-methylbenzoic acid, o-Carboxynitrobenzene, M-NITROBENZOIC ACID, p-nitrobenzoic acid, o-trifluoromethyl phenylformic acid, m-trifluoromethylbenzoic acid, to trifluoromethylbenzoic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, to Witco 1298 Soft Acid, α-Nai Huangsuan, beta-naphthalenesulfonic-acid, α-Nai Yisuan, oleic acid, stearic acid, dodecyl sulfonic acid or methacrylic acid.
The preferred described protonic acid of the present invention is organic protonic acid, and it is one of following that described organic protonic acid is preferably: phenylformic acid, parafluorobenzoic acid, p-nitrobenzoic acid, o-trifluoromethyl phenylformic acid or to trifluoromethylbenzoic acid; Most preferably be trifluoromethylbenzoic acid, structure is suc as formula shown in (VI):
Described amount of substance ratio suc as formula the nitroolefin derivative shown in (III), chirality secondary amine catalyst, protonic acid, water is 1: 0.05～0.3: 0.05～0.3: 30～40, is preferably 1: 0.2: 0.2: 34.
Described temperature of reaction is 15～40 ℃, is preferably 25 ℃; The described reaction times is 3～72 hours, is preferably 12～36 hours.
Reaction solution method for separating and processing of the present invention is: after reaction finishes, the reaction solution ethyl acetate extraction, standing demix, get the organic layer distillation except that the residuum after desolvating, with the volume ratio of sherwood oil and ether is that 7: 3 elutriant is an eluent, carries out column chromatography for separation and purifies and obtain the chiral bicyclics compound product.
Comparatively concrete, recommend the green method of asymmetric synthesis of chiral bicyclics compound of the present invention to carry out: being raw material suc as formula the cyclohexenone derivates shown in (II) with suc as formula the nitroolefin derivative shown in (III) according to following steps, in the chirality secondary amine catalyst shown in formula V, under the existence shown in (VI) to trifluoromethylbenzoic acid and water, under 25 ℃ of temperature, reacted 12～36 hours, after reaction finishes, the reaction solution ethyl acetate extraction, standing demix, getting the residuum that organic layer distillation removes after desolvating is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carries out column chromatography for separation and purifies and obtain the chiral bicyclics compound product; In described formula (II) or the formula (III), R
1, R
2, R
3Independent separately is hydrogen or methyl; R
4Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 4-aminomethyl phenyl, phenyl, the fluorine-based phenyl of 4-, 4-chloro phenyl, 3-bromo phenyl, 4-bromo phenyl, 3-nitrophenyl, 4-trifluoromethyl or furyl; Described is 1: 1.2 suc as formula the nitroolefin derivative shown in (III) with suc as formula the amount of substance ratio of the cyclohexenone derivates shown in (II); Described is 1: 0.2: 0.2 suc as formula the nitroolefin derivative shown in (III), chirality secondary amine catalyst, to the amount of substance ratio of trifluoromethylbenzoic acid, water: 34.
The present invention compared with prior art, its beneficial effect is: chiral bicyclics compound of the present invention has chirality; Green synthetic this compounds of water shows good response characteristic, can be applied to fields such as organic synthesis, material.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this.
Comprise in the specific embodiments of the invention:
(1S, 4S, 5S, 6R) 6-(2-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(3-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-aminomethyl phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(the fluorine-based phenyl of 4-)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-chloro phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(3-bromo phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-bromo phenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(3-nitrophenyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-trifluoromethyl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-furans-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-phenyl-4-methyl-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 2R, 3S, 4R) 2-phenyl-5,5-dimethyl-3-nitro two ring [2,2,2] octane-7-ketones;
Embodiment 1:(1S, 4S, 5S, 6R) 6-(2-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 2-p-methoxy-phenyl nitroolefin (0.134g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.124g, yield 60%, Ee value are 90%), wherein
1H NMR (500MHz, CDCl3): δ=7.25-7.23 (m, 1H), 7.16-7.14 (m, 1H), 6.90-6.88 (m, 1H), 6.86-6.84 (m, 1H), 4.96-4.94 (m, 1H), 4.19-4.18 (m, 1H), 3.7 (s, 3H), 2.87-2.85 (m, 1H), 2.71-2.70 (m, 1H), 2.42-2.41 (m, 2H), 2.31-2.24 (m, 1H), 1.99-1.88 (m, 2H), 1.68-1.61 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=212.1,156.7,128.9 (* 2), 128.0,120.8,110.7,90.0,54.4,46.1,42.1,41.9,34.8,24.0,18.6ppm.
Embodiment 2:(1S, 4S, 5S, 6R) preparation of 6-(3-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 3-p-methoxy-phenyl nitroolefin (0.134g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 12h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.165g, yield 80%, Ee value are 96%), wherein
1H NMR (500MHz, CDCl3): δ=7.24-7.21 (m, 1H), 6.80-6.78 (m, 1H), 6.67-6.65 (s, 2H), 4.82-4.80 (m, 1H), 4.13-4.11 (m, 1H), 3.77 (s, 3H), 2.97-2.95 (m, 1H), 2.69-2.68 (m, 1H), 2.50-2.48 (m, 2H), 2.24-2.18 (m, 1H), 1.97-1.90 (m, 2H), 1.73-1.68 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.7,160.0,142.6,130.3,118.8,112.9,112.8,91.1,55.2,47.4,44.9,42.2,34.3,23.3,18.2ppm.
Embodiment 3:(1S, 4S, 5S, 6R) preparation of 6-(4-p-methoxy-phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-p-methoxy-phenyl nitroolefin (0.134g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.202g, yield 98%, Ee value are 93%), wherein
1H NMR (500MHz, CDCl3): δ=7.02-7.00 (d, J=10Hz, 2H), 6.84-6.82 (d, J=10Hz, 2H), 4.78-4.77 (d, J=5Hz, 1H), 4.08-4.07 (d, J=5Hz, 1H), 3.76 (s, 3H), 2.94 (s, 1H), 2.63 (s, 1H), 2.52-2.44 (m, 2H), 2.22-2.17 (m, 1H), 1.95-1.90 (m, 2H), 1.71-1.66 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.9,158.8,133.1,127.9 (* 2), 114.4 (* 2), 91.4,55.2,47.8,44.2,42.2,34.2,23.2,18.1ppm.
Embodiment 4:(1S, 4S, 5S, 6R) preparation of 6-(4-aminomethyl phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-aminomethyl phenyl nitroolefin (0.122g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.188g, yield 97%, Ee value are 93%), wherein
1H NMR (500MHz, CDCl3): δ=7.12-7.10 (d, J=10Hz, 2H), 6.99-6.97 (d, J=10Hz, 2H), 4.81-4.79 (m, 1H), 4.11-4.09 (m, 1H), 2.96-2.94 (m, 1H), 2.65-2.64 (m, 1H), 2.53-2.44 (m, 2H), 2.30 (s, 3H), 2.24-2.17 (m, 1H), 1.97-1.89 (m, 2H), 1.72-1.67 (m, 1H) ppm;
13CNMR (125MHz, CDCl3): δ=211.9,138.1,137.4,129.8 (* 2), 126.7 (* 2), 91.3,47.8,44.7,42.3,34.4,23.3,20.9,18.2ppm.
Embodiment 5:(1S, 4S, 5S, 6R) preparation of 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds phenyl nitroolefin (0.112g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.180g, yield 98%, Ee value are 95%), wherein
1H NMR (500MHz, CDCl3): δ=7.33-7.24 (m, 3H), 7.11-7.09 (d, J=10Hz, 2H), 4.83-4.81 (m, 1H), 4.16-4.15 (m, 1H), 2.98-2.96 (m, 1H), 2.69-2.68 (m, 1H), 2.55-2.45 (m, 2H), 2.26-2.19 (m, 1H), 1.99-1.90 (m, 2H), 1.74-1.68 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.8,141.1,129.2 (* 2), 127.7,126.8 (* 2), 91.2,47.6,45.0,42.3,34.4,23.4,18.3ppm.
Embodiment 6:(1S, 4S, 5S, 6R) preparation of 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro add the phenyl nitroolefin (0.112g, 0.75mmol), cyclonene (0.096g, 1mmol) and 0.5mL water, in the chirality secondary amine catalyst
(0.029g, 0.15mmol) and phenylformic acid (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 24h, (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent with ethyl acetate extraction, residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (the Ee value is 82% for 0.165g, yield 90%).
Embodiment 7:(1S, 4S, 5S, 6R) preparation of 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro add the phenyl nitroolefin (0.112g, 0.75mmol), cyclonene (0.072g, 0.75mmol) and 0.5mL water, in the chirality secondary amine catalyst
(0.0087g, 0.0375mmol) and phenylformic acid (0.0046g, 0.0375mmol) common catalysis following 40 ℃ the reaction 3h, (2 * 20mL), standing demix is got after organic layer distillation takes off most extraction solvent with ethyl acetate extraction, residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (the Ee value is 75% for 0.147g, yield 80%).
Embodiment 8:(1S, 4S, 5S, 6R) preparation of 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds phenyl nitroolefin (0.112g, 0.75mmol), cyclonene (0.192g, 2mmol) with 0.4mL water, at chirality secondary amine catalyst (V) (0.0436g, 0.225mmol) and parafluorobenzoic acid (0.0315g, 0.225mmol) common catalysis under-20 ℃ the reaction 72h, with ethyl acetate extraction (2 * 20mL), standing demix, get after organic layer distillation takes off most extraction solvent, residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carries out column chromatography for separation and purifies and obtain target compound (0.180g, yield 98%, Ee value are 93%).
Embodiment 9:(1S, 4S, 5S, 6R) preparation of 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds phenyl nitroolefin (0.112g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and p-nitrobenzoic acid (0.025g, 0.15mmol) common catalysis following 25 ℃ the reaction 30h, with ethyl acetate extraction (2 * 20mL), standing demix, get after organic layer distillation takes off most extraction solvent, residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carries out column chromatography for separation and purifies and obtain target compound (0.180g, yield 98%, Ee value are 90%).
Embodiment 10:(1S, 4S, 5S, 6R) preparation of 6-phenyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds phenyl nitroolefin (0.112g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and o-trifluoromethyl phenylformic acid (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 30h, with ethyl acetate extraction (2 * 20mL), standing demix, get after organic layer distillation takes off most extraction solvent, residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carries out column chromatography for separation and purifies and obtain target compound (0.180g, yield 98%, Ee value are 89%).
Embodiment 11:(1S, 4S, 5S, 6R) preparation of 6-(the fluorine-based phenyl of 4-)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-fluorophenyl nitroolefin (0.125g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.191g, yield 97%, Ee value are 95%), wherein
1H NMR (500MHz, CDCl3): δ=7.09-7.06 (m, 2H), 7.02-6.99 (m, 2H), and 4.76-4.73 (m, 1H), 4.14-4.12 (m, 1H), and 2.98-2.97 (m, 1H), 2.66-2.65 (m, 1H), and 2.52-2.48 (m, 2H), 2.24-2.18 (m, 1H), 1.98-1.93 (m, 2H), 1.76-1.70 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.7,162.0 (d,
1J
C-F=245.8Hz), and 136.9,128.6,128.5,116.2,116.0,91.3,47.6,44.3,42.3,34.3,23.3,18.1ppm.
Embodiment 12:(1S, 4S, 5S, 6R) preparation of 6-(4-chloro phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-chloro-phenyl-nitroolefin (0.137g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.207g, yield 99%, Ee value are 94%), wherein
1H NMR (500MHz, CDCl3): δ=7.30-7.28 (d, J=7.5Hz, 2H), 7.05-7.04 (d, J=7.5Hz, 2H), 4.73-4.72 (m, 1H), and 4.13-4.11 (m, 1H), 3.03-2.96 (m, 1H), and 2.66-2.65 (m, 1H), 2.55-2.44 (m, 2H), and 2.24-2.18 (m, 1H), 1.99-1.89 (m, 2H), 1.75-1.69 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.5,139.5,133.7,129.4 (* 2), 128.2 (* 2), 91.0,47.4,44.4,42.3,34.3,23.2,18.1ppm.
Embodiment 13:(1S, 4S, 5S, 6R) preparation of 6-(3-bromo phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 3-bromophenyl nitroolefin (0.170g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 12h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.133g, yield 55%, Ee value are 88%), wherein
1H NMR (500MHz, CDCl3): δ=7.41-7.40 (m, 1H), 7.27-7.26 (m, 1H), 7.21-7.18 (m, 1H), 7.03-7.02 (m, 1H), 4.77-4.75 (m, 1H), 4.13-4.12 (m, 1H), 3.00-2.99 (m, 1H), 2.67-2.65 (m, 1H), 2.52-2.50 (m, 2H), 2.21-2.18 (m, 1H), 1.98-1.90 (m, 2H), 1.76-1.70 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.2,143.2,130.9,130.8,130.2,125.3,123.2,90.7,47.3,44.6,42.2,34.2,23.2,18.1ppm.
Embodiment 14:(1S, 4S, 5S, 6R) preparation of 6-(4-bromo phenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-bromophenyl nitroolefin (0.170g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 12h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.222g, yield 92%, Ee value are 92%), wherein
1H NMR (500MHz, CDCl3): δ=7.45-7.43 (d, J=10Hz, 2H), 7.00-6.98 (d, J=10Hz, 2H), 4.73-4.71 (m, 1H), and 4.12-4.10 (m, 1H), 2.99-2.97 (m, 1H), and 2.66-2.64 (m, 1H), 2.55-2.43 (m, 2H), and 2.24-2.17 (m, 1H), 1.96-1.92 (m, 2H), 1.75-1.70 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.5,140.0,132.3 (* 2), 128.6 (* 2), 121.8,90.9,47.4,44.5,42.3,34.3,23.2,18.1ppm.
Embodiment 15:(1S, 4S, 5S, 6R) preparation of 6-(3-nitrophenyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 3-nitrophenyl nitroolefin (0.146g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 12h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.152g, yield 70%, Ee value are 93%), wherein
1H NMR (500MHz, CDCl3): δ=8.51-8.50 (m, 1H), 8.32-8.30 (m, 1H), and 7.95-7.94 (m, 1H), 7.69-7.66 (m, 1H), and 3.72-3.69 (m, 1H), 3.64-3.63 (m, 1H), and 2.67-2.63 (m, 2H), 2.51-2.47 (m, 1H), and 2.36-2.31 (m, 1H), 1.90-1.83 (m, 2H), 1.75-1.69 (m, 2H) ppm;
13C NMR (125MHz, CDCl3): δ=211.0,149.6,139.9,132.8,130.3,124.6,122.0,93.0,41.6,40.1,35.7,34.6,21.7,20.3ppm.
Embodiment 16:(1S, 4S, 5S, 6R) preparation of 6-(4-trifluoromethyl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-trifluoromethyl nitroolefin (0.163g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 12h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.230g, yield 98%, Ee value are 90%), wherein
1HNMR (500MHz, CDCl3): δ=7.65-7.55 (m, 2H), 7.26-7.20 (m, 2H), and 4.79-4.75 (m, 1H), 4.23-4.22 (m, 1H), and 3.03-3.00 (m, 1H), 2.72-2.68 (m, 1H), and 2.59-2.46 (m, 2H), 2.27-2.18 (m, 1H), 1.99-1.94 (m, 2H), 1.77-1.75 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=211.4,144.9,130.5,128.5,127.4 (* 2), 126.2 (* 2), 90.6,47.2,44.7,42.2,34.2,23.1,18.1ppm.
Embodiment 17:(1S, 4S, 5S, 6R) preparation of 6-furans-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds furans nitroolefin (0.104g, 0.75mmol), cyclonene (0.096g, 1mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.029g, 0.15mmol) and to trifluoromethylbenzoic acid (VI) (0.0285g, 0.15mmol) common catalysis following 25 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.169g, yield 96%, Ee value are 92%), wherein
1H NMR (500MHz, CDCl3): δ=7.32-7.31 (d, J=5Hz, 1H), 6.28-6.27 (m, 1H), and 6.13-6.12 (d, J=5Hz, 1H), 4.94-4.92 (m, 1H), 4.28-4.26 (m, 1H), 3.00-2.96 (m, 1H), 2.70-2.69 (m, 1H), 2.48-2.45 (m, 2H), 2.20-2.13 (m, 1H), 2.01-1.94 (m, 2H), 1.70-1.63 (m, 1H) ppm;
13C NMR (125MHz, CDCl3): δ=210.7,152.9,142.7,110.4,106.6,87.7,46.0,41.8,38.8,34.3,22.4,18.4ppm.
Embodiment 18:(1S, 4S, 5S, 6R) preparation of 6-phenyl-4-methyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds phenyl nitroolefin (0.112g, 0.75mmol), 3-methyl cyclohexane ketenes (0.220g, 2mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.048g, 0.25mmol) and to trifluoromethylbenzoic acid (VI) (0.0475g, 0.25mmol) common catalysis following 30 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix is got after organic layer distillation takes off most solvent, and residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carry out the column chromatography for separation purification and obtain target compound (0.184g, yield 95%, Ee value are 83%), wherein
1H NMR (500MHz, CDCl3): 7.32-7.25 (m, 3H), 7.06-7.05 (d, J=5Hz, 2H), and 4.69-4.68 (d, J=5Hz, 1H), 3.96-3.95 (d, J=5Hz, 1H), 2.74-2.73 (d, J=5Hz, 1H), 2.38-2.30 (m, 2H), 2.26-2.18 (m, 2H), 2.01-1.93 (m, 1H), 1.51-1.42 (m, 1H), 1.09 (s, 3H) ppm;
13CNMR (125MHz, CDCl3): δ=211.9,140.8,129.3 (* 2), 127.8,126.6 (* 2), 96.9,49.5,47.5,46.9,37.7,24.8,24.1,23.1ppm.
Embodiment 19:(1S, 2R, 3S, 4R) 2-phenyl-5, the preparation of 5-dimethyl-3-nitro two ring [2,2,2] octane-7-ketones
25mL in vitro adds phenyl nitroolefin (0.112g, 0.75mmol), 4,4-dimethyl cyclonene (0.248g, 2mmol) with 0.5mL water, at chirality secondary amine catalyst (V) (0.039g, 0.20mmol) and to trifluoromethylbenzoic acid (VI) (0.038g, 0.20mmol) common catalysis following 15 ℃ the reaction 20h, with ethyl acetate extraction (2 * 20mL), standing demix, get after organic layer distillation takes off most solvent, residuum is that 7: 3 elutriant is an eluent with the volume ratio of sherwood oil and ether, carries out column chromatography for separation and purifies and obtain target compound (0.196g, yield 96%, the Ee value is 93%), wherein
1HNMR (500MHz, CDCl3): δ=7.33-7.24 (m, 3H), 7.17-7.15 (d, J=10Hz, 2H), and 4.60-4.58 (d, J=10Hz, 1H), 4.22-4.20 (d, J=10Hz, 1H), 2.97 (s, 1H), 2.88-2.84 (m, 1H), 2.61 (s, 1H), 2.37-2.33 (m, 1H), 2.02-1.99 (m, 1H), 1.76-1.73 (m, 1H), 1.13 (s, 3H), 1.12 (s, 3H) ppm;
13C NMR (125MHz, CDCl3): δ=211.9,141.3,129.1 (* 2), 127.6 (* 2), 127.2,90.1,51.0,44.3,43.2,40.9,40.3,30.9,30.6,29.5ppm.
Claims (10)
1. green method of asymmetric synthesis suc as formula the chiral bicyclics compound shown in (I), it is characterized in that described method is: being raw material suc as formula the cyclohexenone derivates shown in (II) with suc as formula the nitroolefin derivative shown in (III), in the presence of chirality secondary amine catalyst, protonic acid and water, under-20～40 ℃ of temperature, reacted 3～72 hours, after reaction finished, the reaction solution separating treatment obtained suc as formula the chiral bicyclics compound shown in (I); Described chirality secondary amine catalyst is suc as formula the proline derivative shown in (IV); Described is 1: 1～3 suc as formula the nitroolefin derivative shown in (III) with suc as formula the amount of substance ratio of the cyclohexenone derivates shown in (II); Described amount of substance ratio suc as formula the nitroolefin derivative shown in (III), chirality secondary amine catalyst, protonic acid, water is 1: 0-05～0-3: 0-05～0-3: 30～40;
In formula (I), formula (II), formula (III) or the formula (IV), R
1, R
2, R
3Independent separately is the alkyl of H or C1～C20; R
4Be H, the alkyl of C1～C20, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, the fluorine-based phenyl of 2-, the fluorine-based phenyl of 3-, the fluorine-based phenyl of 4-, 2-chloro phenyl, 3-chloro phenyl, 4-chloro phenyl, 2-bromo phenyl, 3-bromo phenyl, 4-bromo phenyl, the 2-nitrophenyl, the 3-nitrophenyl, the 4-nitrophenyl, the 2-trifluoromethyl, the 3-trifluoromethyl, the 4-trifluoromethyl, furyl or thienyl; R
5Be one of following formula:
2. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 is characterized in that described R
1, R
2, R
3Independent separately is hydrogen or methyl.
3. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 is characterized in that described R
4Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 4-aminomethyl phenyl, phenyl, the fluorine-based phenyl of 4-, 4-chloro phenyl, 3-bromo phenyl, 4-bromo phenyl, 3-nitrophenyl, 4-trifluoromethyl or furyl.
4. as the green method of asymmetric synthesis of the described chiral bicyclics compound of one of claim 1～3, it is characterized in that described chirality secondary amine catalyst is shown in formula V;
5. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 is characterized in that described protonic acid is one of following: HCl, HBr, H
28O
4, HBF
4, HPF
6, CH3COOH, CF
3COOH, CF
3SO
3H, phenylformic acid, o-fluorobenzoic acid, a fluorobenzoic acid, parafluorobenzoic acid, toluylic acid, p-methylbenzoic acid, o-Carboxynitrobenzene, M-NITROBENZOIC ACID, p-nitrobenzoic acid, o-trifluoromethyl phenylformic acid, m-trifluoromethylbenzoic acid, to trifluoromethylbenzoic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, to Witco 1298 Soft Acid, α-Nai Huangsuan, beta-naphthalenesulfonic-acid, α-Nai Yisuan, oleic acid, stearic acid, dodecyl sulfonic acid or methacrylic acid.
6. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 is characterized in that described protonic acid is organic protonic acid.
7. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 6 is characterized in that described organic protonic acid is one of following: phenylformic acid, parafluorobenzoic acid, p-nitrobenzoic acid, o-trifluoromethyl phenylformic acid or to trifluoromethylbenzoic acid.
8. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 is characterized in that described amount of substance ratio suc as formula the nitroolefin derivative shown in (III), chirality secondary amine catalyst, protonic acid, water is 1: 0.2: 0.2: 34.
9. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 is characterized in that described temperature of reaction is 25 ℃, and the reaction times is 12～36 hours.
10. the green method of asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, it is characterized in that described reaction solution method for separating and processing is: after reaction finishes, the reaction solution ethyl acetate extraction, standing demix, get the organic layer distillation except that the residuum after desolvating, with the volume ratio of sherwood oil and ether is that 7: 3 elutriant is an eluent, carries out column chromatography for separation and purifies and obtain the chiral bicyclics compound product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910097515 CN101525291B (en) | 2009-04-03 | 2009-04-03 | Green asymmetric synthesis method of chiral bicyclics compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910097515 CN101525291B (en) | 2009-04-03 | 2009-04-03 | Green asymmetric synthesis method of chiral bicyclics compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101525291A true CN101525291A (en) | 2009-09-09 |
| CN101525291B CN101525291B (en) | 2012-12-12 |
Family
ID=41093390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910097515 Expired - Fee Related CN101525291B (en) | 2009-04-03 | 2009-04-03 | Green asymmetric synthesis method of chiral bicyclics compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101525291B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531911A (en) * | 2011-12-22 | 2012-07-04 | 浙江工业大学 | Chiral dicyclic compound and asymmetric syntheses method thereof |
| CN114426323A (en) * | 2020-09-21 | 2022-05-03 | 中国石油化工股份有限公司 | Oil field polymer bactericidal flocculant and preparation method and application thereof |
| CN116024083A (en) * | 2023-02-22 | 2023-04-28 | 凯莱英生命科学技术(天津)有限公司 | Device and method for preparing chiral amine compound by continuous flow reaction |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101041638B (en) * | 2007-04-29 | 2010-05-26 | 浙江工业大学 | Chirality amine containing imidazole sulfur ether structure and preparation method and usage thereof |
-
2009
- 2009-04-03 CN CN 200910097515 patent/CN101525291B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531911A (en) * | 2011-12-22 | 2012-07-04 | 浙江工业大学 | Chiral dicyclic compound and asymmetric syntheses method thereof |
| CN102531911B (en) * | 2011-12-22 | 2016-02-17 | 浙江工业大学 | Chiral bicyclics compound and method of asymmetric synthesis thereof |
| CN114426323A (en) * | 2020-09-21 | 2022-05-03 | 中国石油化工股份有限公司 | Oil field polymer bactericidal flocculant and preparation method and application thereof |
| CN114426323B (en) * | 2020-09-21 | 2022-11-04 | 中国石油化工股份有限公司 | Oil field polymer sterilization flocculant and preparation method and application thereof |
| CN116024083A (en) * | 2023-02-22 | 2023-04-28 | 凯莱英生命科学技术(天津)有限公司 | Device and method for preparing chiral amine compound by continuous flow reaction |
| CN116024083B (en) * | 2023-02-22 | 2023-06-13 | 凯莱英生命科学技术(天津)有限公司 | Device and method for preparing chiral amine compound by continuous flow reaction |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101525291B (en) | 2012-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101099408B1 (en) | Subsidiary urea compound and subsidiary conjugated addition using the catalyst as a method for producing a subsidiary compound by reaction | |
| CN104447725A (en) | Chiral compound comprising iminopyridyl oxazoline and preparation method thereof | |
| CN101525291B (en) | Green asymmetric synthesis method of chiral bicyclics compound | |
| CN104447451A (en) | New preparation method of oseltamivir intermediate | |
| KR102261108B1 (en) | Highly enantioselective bifunctional chiral organocatalytic compound, method for preparing the same, and method for preparing non-natural gamma-amino acid from nitrocompound using thereof | |
| CN101781222A (en) | Method for preparing enamine ketone compound | |
| Das et al. | Sulfonic acid functionalized silica: an efficient heterogeneous catalyst for a three-component synthesis of 1, 4-dihydropyridines under solvent-free conditions | |
| CN102906064A (en) | Method for producing (1r, 2s)-1-amino-2-vinyl cyclopropane carboxylic acid ester that has improved optical purity | |
| CN112812033B (en) | Novel synthesis method of oseltamivir | |
| CN110698426B (en) | Method for preparing 1, 3-benzothiazole derivative by efficient catalysis of potassium tert-butoxide | |
| CN101845011B (en) | (S)-prolineamide type derivative, preparation method and application thereof | |
| CN102140071A (en) | Method for synthesizing 2-(4-tert-butyl-phenyl) malonic mononitrile (2-methoxyl) ethyl ester | |
| CN105481715A (en) | Camphor Schiff base, and preparation method and application thereof | |
| CN102627571B (en) | Preparation and synthesis method for chiral ammonium salt | |
| CN102060754A (en) | Method for preparing polysubstituted tetrahydropyridine | |
| CN101372458A (en) | Method for synthesizing acylated enamine without catalyst or solvent | |
| CN109575041B (en) | Polycyclic pyridine compound and preparation method thereof | |
| CN111018771B (en) | Method for synthesizing 3- (2-cyanovinyl) indole derivative | |
| CN101863815A (en) | Synthesis method of cis 3-phenyl substituted s-proline derivative | |
| JP5179430B2 (en) | Method for producing optically active alcohol | |
| KR100616276B1 (en) | Process for producing 2,n-dimethyl-n-(3,3-diphenylpropyl)-1-amino-2-propanol | |
| CN112824411A (en) | Bridged ring isoindolinone derivatives, and preparation method and application thereof | |
| CN101863805B (en) | (S)-N-(2(3-(trifluoromethyl) phenyl) methyl)-tertiary butyl-2-sulfinamide and synthesis method thereof | |
| Shen et al. | An efficient synthesis of enantiomerically pure trans-N1, N2-dimethylcyclohexane-1, 2-diamine | |
| CN113861072A (en) | Preparation method of aryl cyclopropane compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121212 |