CN109879830A - A kind of oxaza heptane derivative and preparation method thereof containing exocyclic double bond - Google Patents
A kind of oxaza heptane derivative and preparation method thereof containing exocyclic double bond Download PDFInfo
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- CN109879830A CN109879830A CN201910237249.7A CN201910237249A CN109879830A CN 109879830 A CN109879830 A CN 109879830A CN 201910237249 A CN201910237249 A CN 201910237249A CN 109879830 A CN109879830 A CN 109879830A
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Abstract
The present invention provides a kind of oxaza heptane derivative and preparation method thereof containing exocyclic double bond, the preparation method comprises the following steps: by four acetylene compounds with 2 in toluene solvant, 4, the heating reaction of 4- trimethyl -2- oxazoline, after reaction, cooled to room temperature separates product purification, obtains the oxaza heptane derivative containing exocyclic double bond.Compared with prior art, the present invention provides a series of preparation methods of new oxaza heptane derivatives containing exocyclic double bond.Relative to common Hete rocyclic derivatives, the oxaza heptane derivative prepared by the present invention containing exocyclic double bond has the presence of exocyclic double bond and oxygen nitrogen heteroatom, and obtains rare seven-members ring structure, the more complicated novelty of structure.Substance of the present invention may can also have wide application in medical industry, and preparation method provided by the invention is easy, efficient, and the reaction time is short, high-efficient.
Description
Technical field
The invention belongs to organic compound field, more particularly to a kind of oxaza heptane derivative containing exocyclic double bond and
Preparation method.
Background technique
Heterocyclic compound is comprising one or more heteroatomic cyclic compounds.The number and type of heterocyclic compound are numerous
It is more, it is the important component of organic compound, the mostly several compounds for being distributed in nature are all containing heterocyclic system.It is miscellaneous
Cycle compound has certain physiological activity and pharmacology value mostly, has in fields such as natural products, pharmaceutical molecules, functional materials
Important application.
Developing the method for efficiently synthesizing novel heterocyclic compounds is always the research hotspot in Synthetic Organic Chemistry.Tradition is closed
The condensation reaction that carbonyls and amine, alcohol or mercaptan etc. are mainly used at the method for heterocyclic compound, as Paal-Knorr contracts
Close reaction, Hantzsch condensation reaction etc..But conventional synthesis route, there are severe reaction conditions, substrate universality is not high to ask
Topic.In recent years, the extensive concern of chemist, but transition are caused based on transition metal-catalyzed cyclization synthesizing heterocyclic compound
Metal price is higher, and be easy to cause metal residual.
Therefore, it is more important to develop the method for efficiently synthesizing novel heterocyclic compounds participated in without transition metal.
Summary of the invention
The preparation method of the purpose of the present invention is to provide a kind of oxaza heptane derivative containing exocyclic double bond, preparation
Method is easy, efficient, and the reaction time is short, high-efficient.
Another object of the present invention is to provide a kind of oxaza heptane derivative containing exocyclic double bond have multifunctional
Change, structure is more complicated, has broad application prospects.
Specific technical solution of the present invention is as follows:
A kind of preparation method of the oxaza heptane derivative containing exocyclic double bond, comprising the following steps:
By four acetylene compounds with 2 in toluene solvant, the heating reaction of 4,4- trimethyl -2- oxazolines, after reaction, from
It is so cooled to room temperature, product purification is separated, obtain the oxaza heptane derivative containing exocyclic double bond.
Further, the molar ratio of four acetylene compound, 2,4,4- trimethyl -2- oxazolines and toluene is 1:1:28-
66；
The heating reaction refers to be carried out under conditions of being heated to 100-110 DEG C, reaction time at least 12h.
The purifies and separates specifically: products therefrom is washed with water, ethyl acetate extraction, decompression is spin-dried for, and uses volume ratio
The ethyl acetate of 1:80: the column chromatography for separation of petroleum ether obtains white solid, i.e., the oxaza heptane containing exocyclic double bond is derivative
Object.
The four acetylene compounds structural formulaR is straight chained alkyl, branched alkyl or unsaturation
Hydrocarbon；R1For hydrogen, halogen, straight chained alkyl, branched alkyl, ester group or alkoxy.
Further, four acetylene compound the preparation method comprises the following steps:
1) using sodium hydride as catalyst, malonate and propargyl bromide are added in anhydrous acetonitrile, under the conditions of ice-water bath
Reaction, then purifies and separates, obtain compound 1；
2) compound 1 of step 1) preparation and phenylacetylene bromide or substituted phenylacetylene bromide are blended in Pd (PPh3)2Cl2In the anhydrous and oxygen-free catalyst system of/CuI, alkali is made with triethylamine, using anhydrous acetonitrile as solvent, is stirred to react at room temperature, is purified
After separation, four acetylene compounds are obtained.
Further, the molar ratio of sodium hydride described in step 1), malonate, propargyl bromide and anhydrous acetonitrile is 4-5:
1:2.2-3.2:20-23；The malonate is selected from diethyl malonate or dimethyl malenate.
In step 1) under the conditions of ice-water bath reaction temperature at 0-5 DEG C；Reaction time was at 5 hours or more；
Purifies and separates described in step 1) specifically: product adds water washing, is extracted with ethyl acetate, decompression be spin-dried for get
Compound 1.
The structural formula of compound 1 described in step 1)R is straight chained alkyl, branched alkyl or not
Saturated hydrocarbons；
Compound 1 and phenylacetylene bromide or substituted phenylacetylene bromide, Pd (PPh in step 2)3)2Cl2/ CuI, triethylamine
The mass ratio of the material with anhydrous acetonitrile is 1:2.2-3.2:0.03-0.04:4-5:30-45；
Step 2) is described to be stirred to react, and the reaction time was at 10 hours or more；
Step 2) the substituted phenylacetylene bromide is selected to fluorophenylethynyl bromine；
Purifies and separates described in step 2) specifically: product is washed with water, and is extracted with ethyl acetate, and decompression is spin-dried for, and uses body
Product is than the ethyl acetate for 1:60: petroleum ether column chromatography for separation obtains four acetylene compounds.
Pd (PPh described in step 2)3)2Cl2The anhydrous and oxygen-free catalyst system of/CuI, molar ratio Pd (PPh3)2Cl2: CuI=
3:1。
A kind of oxaza heptane derivative containing exocyclic double bond provided by the invention, is prepared using the above method,
Its structural formula are as follows:
Wherein E1And E2It is identical, it is CO2R1, R1For straight chained alkyl, branched alkyl or unsaturated hydrocarbon-based；R be hydrogen, halogen,
Straight chained alkyl, branched alkyl, ester group or alkoxy.
Preferably, the structural formula of the oxaza heptane derivative containing exocyclic double bond is
The preparation method of oxaza heptane derivative provided by the invention containing exocyclic double bond, is in no catalyst, nothing
In the state of additive, unprotect, using toluene as solvent, at 100-110 DEG C by four alkynes substrates and 2,4,4- trimethyl -2- oxazolines
Reaction, reaction process by four alkynes substrate recirculations, react by HDDA first and generate benzyne intermediate, and then height is active
2+2 cycloaddition, shape occur for benzyne intermediate and 2, the reaction of 4,4- trimethyl -2- oxazolines, the triple carbon-carbon bonds and carbon-to-nitrogen double bon of benzyne
At unstable four-membered ring, subsequent four-membered ring open loop due to biggish ring strain, carbon nitrogen singly-bound fracture is formed negatively charged on nitrogen
Positively charged resonant on lotus, carbon, the methyl being then connected with carbonium ion loses under the nitrogen anion effect of another molecule
Active hydrogen is removed, forms carbon-carbon double bond with carbonium ion, and negatively charged nitrogen equally captures the active hydrogen on another molecule methyl,
Finally obtain the oxaza heptane derivative containing exocyclic double bond.
Compared with prior art, the present invention provides a series of new oxaza heptane derivatives containing exocyclic double bond
Preparation method.Relative to common Hete rocyclic derivatives, the oxaza heptane derivative prepared by the present invention containing exocyclic double bond has ring
The presence of external double bond and oxygen nitrogen heteroatom, and rare seven-members ring structure is obtained, the more complicated novelty of structure.The present invention
Substance may can also have wide application in medical industry, and preparation method provided by the invention is easy, efficient, reaction
Time is short, high-efficient.
Detailed description of the invention
Fig. 1 is the structural formula of the oxaza heptane derivative prepared by the present invention containing exocyclic double bond；
Fig. 2 is the structural formula of the oxaza heptane derivative containing exocyclic double bond prepared by embodiment 1；
Fig. 3 is the structural formula of the oxaza heptane derivative containing exocyclic double bond prepared by embodiment 2；
Fig. 4 is the nuclear magnetic resonance spectroscopy of the oxaza heptane derivative containing exocyclic double bond prepared by embodiment 1；
Fig. 5 is the carbon-13 nmr spectra of the oxaza heptane derivative containing exocyclic double bond prepared by embodiment 1；
Fig. 6 is the nuclear magnetic resonance spectroscopy of the oxaza heptane derivative containing exocyclic double bond prepared by embodiment 2；
Fig. 7 is the carbon-13 nmr spectra of the oxaza heptane derivative containing exocyclic double bond prepared by embodiment 2；
Fig. 8 is the reaction mechanism schematic diagram of 1 step 3) of embodiment；
Fig. 9 is 1 preparation process reaction equation of embodiment；
Figure 10 is 2 preparation process reaction equation of embodiment.
Specific embodiment
Embodiment 1
A kind of oxaza heptane derivative containing exocyclic double bond, structural formula are as follows:
The preparation method of the above-mentioned oxaza heptane derivative containing exocyclic double bond, comprising the following steps:
(1) using 830mmol sodium hydride as catalyst, 200mmol diethyl malonate and 440mmol propargyl bromide are added
The ice-water bath into 210mL anhydrous acetonitrile is stirred to react 8 hours, and product adds water washing, is extracted with ethyl acetate, and decompression is spin-dried for, and obtains
To product, i.e. compound 1, structural formula
(2) compound 1 of 80mmol step (1) preparation and 200mmol phenylacetylene bromide are blended in Pd (PPh3)2Cl2/
In the anhydrous and oxygen-free catalyst system of CuI (2.56mmol/0.85mmol), molar ratio Pd (PPh3)2Cl2: CuI=3:1, with
336mmol triethylamine makees alkali, using 150mL anhydrous acetonitrile as solvent, is stirred to react at room temperature 12 hours, and product is washed with water, and uses
Ethyl acetate extraction, decompression are spin-dried for, and the ethyl acetate for being 1:60 with volume ratio: petroleum ether column chromatography for separation obtains product precursor
Compound 2, i.e. four acetylene compounds, structural formula are
(3) under conditions of 108 DEG C, take 2mmol precursor compound 2 prepared by step (2) 10mL toluene solvant with
2mmol2,4,4- trimethyl -2- oxazolines are reacted 12 hours, and compound 3, i.e. the oxaza heptane derivative containing exocyclic double bond are obtained
Crude product；The crude product with water of the oxaza heptane derivative containing exocyclic double bond of preparation is washed, ethyl acetate extraction,
Decompression is spin-dried for, with volume ratio ethyl acetate: petroleum ether=1:80 column chromatography for separation obtains white solid product, i.e., outer double containing ring
The oxaza heptane derivative of key, structural formulaIt is about 75% that column, which chromatographs yield,.
White solid product structure passes through；1H NMR；13C NMR is measured.
White solid product:
1H NMR(400MHz,C6D6) δ 7.54-7.52 (d, J=8Hz, 2H), 7.26-7.24 (m, 5H), 6.95-6.89
(m,3H),4.73(s,1H),4.30(s,2H),4.01–3.91(m,4H),3.87(s,1H),3.62(s,2H),3.52(s,
2H), 2.79 (s, 1H), 0.97 (s, 6H), 0.91-0.88 (t, J=6Hz, 6H).
13C NMR(101MHz,C6D6)δ171.07,158.60,145.02,144.12,141.47,140.89,131.24,
130.68,126.79,124.73,124.15,112.39,95.91,95.13,88.41,72.26,61.57,59.73,56.60,
41.87,38.39,27.17,13.65。
Embodiment 2
A kind of oxaza heptane derivative containing exocyclic double bond, structural formula are as follows:
The preparation method of the above-mentioned oxaza heptane derivative containing exocyclic double bond, comprising the following steps:
(1) using 830mmol sodium hydride as catalyst, 200mmol dimethyl malenate and 440mmol propargyl bromide are added
The ice-water bath into 210mL anhydrous acetonitrile is stirred to react 8 hours, and product adds water washing, is extracted with ethyl acetate, and decompression is spin-dried for, and obtains
To product, i.e. compound 1, structural formula
(2) compound 1 of 80mmol step (1) preparation and 200mmol are blended in Pd (PPh to fluorophenylethynyl bromine3)2Cl2In the anhydrous and oxygen-free catalyst system of/CuI (2.56mmol/0.85mmol), molar ratio
Pd(PPh3)2Cl2: CuI=3:1 makees alkali with 336mmol triethylamine, using 150mL anhydrous acetonitrile as solvent, at room temperature
It is stirred to react 12 hours, product is washed with water, and is extracted with ethyl acetate, and decompression is spin-dried for, the ethyl acetate for being 1:60 with volume ratio:
Petroleum ether column chromatography for separation obtains product precursor compounds 2, i.e. four acetylene compounds, structural formula
(3) under conditions of 108 DEG C, take 2mmol precursor compound 2 prepared by step (2) 10mL toluene solvant with
2mmol2,4,4- trimethyl -2- oxazolines are reacted 12 hours, and compound 3, i.e. the oxaza heptane derivative containing exocyclic double bond are obtained
Crude product；The crude product with water of the oxaza heptane derivative containing exocyclic double bond of preparation is washed, ethyl acetate extraction,
Decompression is spin-dried for, with volume ratio ethyl acetate: petroleum ether=1:80 column chromatography for separation obtains white solid product, i.e., outer double containing ring
The oxaza heptane derivative of key, structural formulaIt is about 75% that column, which chromatographs yield,.
White solid product structure passes through；1H NMR；13C NMR is measured.
White solid product:
1H NMR(400MHz,C6D6) δ 7.32-7.29 (m, 2H), 6.98-6.94 (m, 2H), 6.90-6.86 (t, J=8
Hz, 2H), 6.55-6.51 (t, J=8Hz, 2H), 4.74 (s, 1H), 4.21 (s, 2H), 3.78 (s, 1H), 3.58 (s, 2H),
3.44(s,2H),3.30(s,6H),2.79(s,1H),0.97(s,6H)。
13C NMR(126MHz,C6D6)δ171.78,163.63,163.59,161.68,161.61,158.83,144.35,
144.09,141.97,137.07,133.37,133.31,132.66,132.60,124.94,120.26,115.87,115.69,
114.84,114.67,112.35,96.55,94.48,88.03,72.68,59.87,56.99,52.81,42.23,38.76,
27.57。
Claims (10)
1. a kind of preparation method of the oxaza heptane derivative containing exocyclic double bond, which is characterized in that the preparation method packet
Include following steps:
By four acetylene compounds with 2 in toluene solvant, the heating reaction of 4,4- trimethyl -2- oxazolines is after reaction, naturally cold
But to room temperature, product purification is separated, obtains the oxaza heptane derivative containing exocyclic double bond.
2. preparation method according to claim 1, which is characterized in that four acetylene compound, 2,4,4- trimethyl -2-
Oxazoline and the molar ratio of toluene are 1:1:28-66.
3. according to right want 1 or 2 described in preparation method, which is characterized in that heating reaction, which refers to, is being heated to 100-110
It is carried out under conditions of DEG C, reaction time at least 12h.
4. preparation method according to claim 1, which is characterized in that the four acetylene compounds structural formulaR is straight chained alkyl, branched alkyl or unsaturated hydrocarbons；R1For hydrogen, halogen, straight chained alkyl, branched alkane
Base, ester group or alkoxy.
5. preparation method according to claim 1 or 4, which is characterized in that four acetylene compound the preparation method comprises the following steps:
1) using sodium hydride as catalyst, malonate and propargyl bromide is added in anhydrous acetonitrile, reacted under the conditions of ice-water bath,
Then purifies and separates obtain compound 1；
2) compound 1 of step 1) preparation and phenylacetylene bromide or substituted phenylacetylene bromide are blended in Pd (PPh3)2Cl2/
In the anhydrous and oxygen-free catalyst system of CuI, alkali is made with triethylamine, using anhydrous acetonitrile as solvent, is stirred to react at room temperature, purifies and separates
Afterwards, four acetylene compounds are obtained.
6. preparation method according to claim 5, which is characterized in that sodium hydride described in step 1), malonate, alkynes third
Bromide and the molar ratio of anhydrous acetonitrile are 4-5:1:2.2-3.2:20-23.
7. the structural formula of compound 1 described in step 1)R is straight chained alkyl, branched alkyl or insatiable hunger
And hydrocarbon.
8. preparation method according to claim 5, which is characterized in that compound 1 and phenylacetylene bromide or taken in step 2)
The phenylacetylene bromide in generation, Pd (PPh3)2Cl2The mass ratio of the material of/CuI, triethylamine and anhydrous acetonitrile are 1:2.2-3.2:0.03-
0.04:4-5:30-45.
9. a kind of oxaza heptane derivative containing exocyclic double bond of any one of claim 1-9 the method preparation, special
Sign is, the oxaza heptane derivative structural formula containing exocyclic double bond are as follows:
Wherein E1And E2It is identical, it is CO2R1, R1For straight chained alkyl, branched alkyl or unsaturated hydrocarbon-based；R is hydrogen, halogen, straight chain
Alkyl, branched alkyl, ester group or alkoxy.
10. the oxaza heptane derivative according to claim 9 containing exocyclic double bond, which is characterized in that described to contain ring
The structural formula of the oxaza heptane derivative of external double bond is
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045586A (en) * | 2021-03-26 | 2021-06-29 | 安徽师范大学 | Synthetic method of benzoxazole alkane derivative |
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| CN103857659A (en) * | 2011-07-01 | 2014-06-11 | 吉利德科学公司 | Fused benzoxazepinones as ion channel modulators |
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