CN106905162B - A kind of preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene - Google Patents
A kind of preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene, the 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formoxyl cyclohexene general formula is as shown in I:R is a substitution, two substitutions, three substitutions and quaternary halogen, nitro, amino, 1-10 carbon alkyl or 1-10 alkoxy in formula；Preparation method includes the following: to mix 3- benzyloxy propionic aldehyde, (E)-(2- nitroethylene) aromatic compound with secondary amine and solvent; in 0~25 DEG C after reaction 1-24 hours; washed, extraction, separation, obtain 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene；
Description
Technical field
The present invention relates to a kind of preparation methods of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene, belong to
In compound synthesis technical field.
Background technique
Polysubstituted hexamethylene olefine aldehydr be widely present in the structure of biologically active natural products and drug.They are also
Very useful organic synthesis intermediate.Its newest synthetic method is to synthesize such complexity by the more meters of Lip rivers reaction of organic catalysis
Structure.Enders etc. is more by three components that secondary amine is catalyzed alpha, beta-unsaturated aldehyde, nitro compds hydrocarbon compound and simple aldehyde
The reaction of rice Lip river has synthesized three substitutions and quaternary hexamethylene olefine aldehydr (Adv.Synth.Catal.2008,350,267-279)；Gong
Three substitutions have been synthesized Deng reacting by secondary amine catalysis simple alcohols, crotonaldehyde with more meters of Lip rivers of four components of nitro compds hydrocarbon compound
Hexamethylene olefine aldehydr (Chem.Eur.J.2009,15,6815-6818)；Chen etc. is catalyzed alpha, beta-unsaturated aldehyde and 2- by secondary amine
The α of nitro allyl acetate, γ-regioselectivity [3+3] cycloaddition reaction synthesize such polysubstituted hexamethylene olefine aldehydr
(Org.Lett.2016,18,116-119)。
However, the disadvantages of these synthetic method yields are not high, and the reaction time is long, and some reaction raw materials are complicated, this nothing
It doubts and limits its application.
Summary of the invention
It is an object of the invention to solve the deficiencies in the prior art, a kind of 3- benzyloxymethyl -4- aromatic radical -5- nitre is provided
The preparation method of base -1- formyl cyclohexene.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene,
3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formoxyl cyclohexene the general formula is as shown in I:
R is a substitution, two substitutions, three substitutions and quaternary halogen, nitro, amino, 1-10 carbon alkyl or 1-10 alcoxyl in formula
Base；
Preparation method include the following: by 3- benzyloxy propionic aldehyde, (E)-(2- nitroethylene) aromatic compound and secondary amine and
Solvent mixing, it is washed, extract, separate in 0~25 DEG C after reaction 1-24 hour, obtain 3- benzyloxymethyl -4- aromatic radical -5-
Nitro -1- formyl cyclohexene；
Preferably, the mol ratio of 3- benzyloxy propionic aldehyde and (E)-(2- nitroethylene) aromatic compound is 2~5:1；
Secondary amine is α, the α-diphenylprolinol that racemization, R configuration and S configuration oxygen are trimethyl silane protection, respectively such as
Shown in formula C1, C2 and C3, dosage is the 1~100% of (E)-(2- nitroethylene) aromatic compound mole dosage；
Organic solvent is methylene chloride, chloroform, ether, tetrahydrofuran, toluene, ethyl alcohol, n-hexane, petroleum ether or different
Propyl alcohol, consumption of organic solvent are 3~20 times of substrate total weight, and reaction temperature is -20 DEG C~40 DEG C,
Preferably, secondary amine dosage is 1~30%, the You Jirong of (E)-(2- nitroethylene) aromatic compound mole dosage
Agent dosage is 3~10 times of substrate total weight.
Preferably, the 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene is individual isomer.
The beneficial effects of the present invention are: synthetic method provided by the invention is easy to operate, reaction condition is mild, nothing is not needed
Water, anaerobic processing, do not need cryogenic refrigeration yet.Target product yield is high, and gained target product is individual isomer, in optics
The enantioselectivity reacted under pure catalyst is greater than 99%ee.
Specific embodiment
Below by specific embodiment, technical scheme of the present invention will be further explained in detail.
Technical solution of the present invention described in detail below.The embodiment of the present invention only for illustrating specific method, this method its
Scale should not be limited by the examples.
Embodiment 1:3- benzyloxymethyl -4- phenyl -5- nitro -1- formyl cyclohexene
3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol), (E)-(2- nitroethylene) benzene are added in 100mL reaction flask
(29.8mg, 0.2mmol), catalyst C1 (13mg, 0.04mmol) and 10mL n-hexane are placed in 0 DEG C and stir 24 hours, TLC inspection
Survey fully reacting.Reaction solution concentration rear pillar chromatography (leacheate: petrol ether/ethyl acetate=10/1 to 5/1) obtains target production
Object 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene 53mg, yield 75%.
Embodiment 2:(3S, 4S, 5S) -3- benzyloxymethyl -4- phenyl -5- nitro -1- formyl cyclohexene
Method similar to Example 1: in 100mL reaction flask be added 3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol),
(E)-(2- nitroethylene) benzene (29.8mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL n-hexane, are placed in 0
DEG C stirring 24 hours, TLC detect fully reacting.Reaction solution is concentrated rear pillar and chromatographs (leacheate: petrol ether/ethyl acetate=10/1
To 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene
53.5mg, yield 76%, > 99%ee.
Embodiment 3:(3R, 4R, 5R) -3- benzyloxymethyl -4- phenyl -5- nitro -1- formyl cyclohexene
Method similar to Example 1: in 100mL reaction flask be added 3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol),
(E)-(2- nitroethylene) benzene (29.8mg, 0.2mmol), catalyst C3 (13mg, 0.04mmol) and 10mL n-hexane, are placed in 0
DEG C stirring 24 hours, TLC detect fully reacting.Reaction solution is concentrated rear pillar and chromatographs (leacheate: petrol ether/ethyl acetate=10/1
To 5/1) obtain target product (3R, 4R, 5R) -3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene
53.4mg, yield 76%, > 99%ee.
Embodiment 4:(3S, 4S, 5S) -3- benzyloxymethyl -4- (p-fluorophenyl) -5- nitro -1- formyl cyclohexene
Method similar to Example 1: in 100mL reaction flask be added 3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol),
(E) the fluoro- 4- of -1- (2- nitroethylene) benzene (33.4mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane is placed in 0 DEG C and stirs 24 hours, and TLC detects fully reacting.Reaction solution is concentrated rear pillar and chromatographs (leacheate: petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyl -4- (p-fluorophenyl) -5- nitro -1- formyl
Cyclohexene 57.6mg, yield 78%, > 99%ee.
Embodiment 5:(3S, 4S, 5S) -3- benzyloxymethyl -4- (rubigan) -5- nitro -1- formyl cyclohexene
Method similar to Example 1: in 100mL reaction flask be added 3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol),
(E) the chloro- 4- of -1- (2- nitroethylene) benzene (36.7mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane is placed in 0 DEG C and stirs 24 hours, and TLC detects fully reacting.Reaction solution is concentrated rear pillar and chromatographs (leacheate: petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyl -4- (rubigan) -5- nitro -1- formyl
Cyclohexene 56.3mg, yield 73%, > 99%ee.
Embodiment 6:(3S, 4S, 5S) -3- benzyloxymethyl -4- (aminomethyl phenyl) -5- nitro -1- formyl cyclohexene
Method similar to Example 1: in 100mL reaction flask be added 3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol),
(E) -1- methyl -3- (2- nitroethylene) benzene (32.6mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane is placed in 0 DEG C and stirs 24 hours, and TLC detects fully reacting.Reaction solution is concentrated rear pillar and chromatographs (leacheate: petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyl -4- (aminomethyl phenyl) -5- nitro -1- first
Acyl group cyclohexene 51.2mg, yield 70%, > 99%ee.
Embodiment 7:(3S, 4S, 5S) -3- benzyloxymethyl -4- (m-bromophenyl) -5- nitro -1- formyl cyclohexene
Method similar to Example 1: in 100mL reaction flask be added 3- benzyloxy propionic aldehyde (82.1mg, 0.5mmol),
(E) the bromo- 3- of -1- (2- nitroethylene) benzene (45.6mg, 0.2mmol), catalyst C2 (13mg, 0.04mmol) and 10mL just oneself
Alkane is placed in 0 DEG C and stirs 24 hours, and TLC detects fully reacting.Reaction solution is concentrated rear pillar and chromatographs (leacheate: petroleum ether/acetic acid second
Ester=10/1 to 5/1) obtain target product (3S, 4S, 5S) -3- benzyloxymethyl -4- (m-bromophenyl) -5- nitro -1- formyl
Cyclohexene 57.6mg, yield 67%, > 99%ee.
The present invention is not limited to the above embodiments, and what is described in the above embodiment and the description is only in order to illustrate this hair
Bright principle, without departing from the spirit and scope of the present invention, the present invention also have the variation of various unsubstantialities and change
Into these both fall in the scope of protection of present invention.
Claims (4)
1. a kind of preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene, it is characterised in that:
3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formoxyl cyclohexene the general formula is as shown in I:
R is a substitution, two substitutions, three substitutions and quaternary halogen, nitro, amino, 1-10 carbon alkyl or 1-10 alcoxyl in formula
Base；
Preparation method includes the following: by 3- benzyloxy propionic aldehyde, (E)-(2- nitroethylene) aromatic compound and secondary amine and solvent
Mixing, it is washed, extract, separate in 0~25 DEG C after reaction 1-24 hour, obtain 3- benzyloxymethyl -4- aromatic radical -5- nitro -
1- formyl cyclohexene；
Wherein, the secondary amine is α, the α-diphenylprolinol that racemization, R configuration and S configuration oxygen are trimethyl silane protection, point
Not as shown in formula C1, C2 and C3,
2. the preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene according to claim 1,
It is characterized in that:
The mol ratio of the 3- benzyloxy propionic aldehyde and (E)-(2- nitroethylene) aromatic compound is 2~5:1；
The secondary amine dosage is the 1~100% of (E)-(2- nitroethylene) aromatic compound mole dosage；
The solvent is methylene chloride, chloroform, ether, tetrahydrofuran, toluene, ethyl alcohol, n-hexane, petroleum ether or isopropyl
Alcohol, the solvent usage are 3~20 times of substrate total weight.
3. the preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene according to claim 2,
It is characterized in that, the secondary amine dosage is the 1~30% of (E)-(2- nitroethylene) aromatic compound mole dosage, the solvent
Dosage is 3~10 times of substrate total weight.
4. the preparation method of 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene according to claim 1,
It is characterized in that, the 3- benzyloxymethyl -4- aromatic radical -5- nitro -1- formyl cyclohexene is individual isomer.
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Effective date of registration: 20190725 Address after: 310000 Room 311, Building No. 688, Bin'an Road, Changhe Street, Binjiang District, Hangzhou City, Zhejiang Province Patentee after: Hangzhou Li'an Biological Technology Co., Ltd. Address before: 324000 North Road, Quzhou, Zhejiang, No. 78, No. nine Patentee before: Quzhou University |