CN107513050B - A kind of preparation method that olefin(e) acid bromine lactonizes - Google Patents
A kind of preparation method that olefin(e) acid bromine lactonizes Download PDFInfo
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- CN107513050B CN107513050B CN201710732759.2A CN201710732759A CN107513050B CN 107513050 B CN107513050 B CN 107513050B CN 201710732759 A CN201710732759 A CN 201710732759A CN 107513050 B CN107513050 B CN 107513050B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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Abstract
The present invention relates to the preparation methods that structural formula olefin(e) acid bromine as follows lactonizes:
Description
The present invention relates to a kind of preparation methods that olefin(e) acid bromine lactonizes.
Bromine lactonization reaction refers to alkene acid compounds under the action of reagent containing bromine, and intramolecular cyclization occurs and obtains
Bromine lactone compound.In this reaction process, one step of ethylene linkage for being related to reaction generates two miscellaneous (O-C-C- of new carbon
Br) singly-bound.For generating the olefin(e) acid substrate of two chiral centres simultaneously, bromine lactonization reaction shows stereocpecificity.This is anti-
It answers and has just been occupied an important position in Synthetic Organic Chemistry since self-discovery, be widely used in the fully synthetic research of natural products
In, it is a kind of very effective synthetic method.
In view of the importance of bromine lactonization reaction, synthetic method receives more and more attention in recent years.Olefin(e) acid and bromine
The reaction of simple substance is to be most widely used at present and method that the most common bromine lactonizes.But since bromine simple substance is that one kind has
Poison is corrosive, volatile liquid, not easy to operate, and the application of the method is restricted.Then more and more researchs exist
It is improved in conventional method, finds the brominated reagent of alternative bromine.Current main synthetic method has following two: (1)
Bromine of the olefin(e) acid under N- bromo-succinimide (NBS) and the like effect lactonizes；(2) olefin(e) acid is in oxidant and metal bromate
Bromine under compound effect lactonizes.These improved methods provide safe optional approach abundant for bromine lactonization reaction,
But have the defects that different: reagent price is expensive, and yield is not high, and regioselectivity is bad.
The object of the present invention is to provide a kind of preparation methods that new olefin(e) acid bromine lactonizes.It is characterized in that with olefin(e) acid (3- alkene
Acid, obtusilic acid, 5- olefin(e) acid) it is that raw material under the action of dimethyl sulfoxide/oxalyl bromine composite reagent, is obtained using methylene chloride as solvent
It lactonizes product to corresponding bromine.Preparation method of the invention is with reagent is cheap and easy to get, easy to operate, yield is high, selectivity
Good advantage.Reaction equation is as follows:
The present invention relates to the preparation methods that structural formula olefin(e) acid bromine as follows lactonizes:
Its main process is: the dichloromethane solution of dimethyl sulfoxide (1.5eq) being first added dropwise to oxalyl bromine at -78 DEG C
In the dichloromethane solution of (1.5eq), then raw material olefin(e) acid is added dropwise, is then back to 0 DEG C of reaction, obtains corresponding bromine and lactonize production
Object, 3- olefin(e) acid and obtusilic acid obtain gamma lactone product, and 5- olefin(e) acid then obtains delta-lactone product, and yield is 45~85%.
The lactonize structure of product of the olefin(e) acid bromine prepared in the method for the present invention all passes through nuclear magnetic resonance and is confirmed.Analysis
As a result after being attached to embodiment.
Specific embodiment
(1)(4R*, 5S*) preparation of the bromo- 5- phenyl of -4--dihydrofuran -2 (3H) -one
Nitrogen protection, in the 100mL three-necked flask equipped with thermometer, addition oxalyl bromine (7.5mmol, 1.1mL,
1.5eq) and anhydrous methylene chloride (10mL).At liquid nitrogen--78 DEG C of ethanol bath, dimethyl sulfoxide is slowly added dropwise with constant pressure funnel
Anhydrous methylene chloride (10mL) solution of (7.5mmol, 0.53mL, 1.5eq).After being added dropwise, continue to stir at -78 DEG C
10min, then (E) -4- phenyl -3-butenoic acid (5mmol, 810mg, 1.0eq) anhydrous methylene chloride (10mL) solution is added dropwise.Drop
After adding, continues to stir 10min at -78 DEG C, be then back to 0 DEG C of reaction 2h.At 0 DEG C of ice bath, 30mL sodium bicarbonate water is added
Solution (5%), liquid separation take organic phase, are washed with saturated sodium-chloride water solution (50mL), and anhydrous sodium sulfate is dry.Filtering, revolving
Solvent afforded crude material is removed, is purified through column chromatography for separation and (petrol ether/ethyl acetate=15: 1), obtains (4R*, 5S*) the bromo- 5- benzene of -4-
Base-dihydrofuran -2 (3H) -one 915mg, yield 76%.1H NMR (300MHz, CDCl3) δ 7.46-7.36 (m, 5H), 5.66
(d, J=5.1Hz, 1H), 4.37 (ddd, J=7.2,6.3,5.1Hz, 1H), 3.24 (dd, J=18.3,7.5Hz, 1H), 2.97
(dd, J=18.3,6.6Hz, 1H).13C NMR (75MHz, CDCl3) δ 173.08,135.98,129.48,129.18,125.52,
87.99,45.70,38.94.
(2) 5- (bromomethyl) -3,3- dimethyl-dihydrofuran -2 (3H) -one preparation
Nitrogen protection, in the 100mL three-necked flask equipped with thermometer, addition oxalyl bromine (7.5mmol, 1.1mL,
1.5eq) and anhydrous methylene chloride (10mL).At liquid nitrogen--78 DEG C of ethanol bath, dimethyl sulfoxide is slowly added dropwise with constant pressure funnel
Anhydrous methylene chloride (10mL) solution of (7.5mmol, 0.53mL, 1.5eq).After being added dropwise, continue to stir at -78 DEG C
10min, then 2 are added dropwise, anhydrous methylene chloride (10mL) solution of 2- dimethyl -4- penetenoic acid (5mmol, 640mg, 1.0eq).Drop
After adding, continues to stir 10min at -78 DEG C, be then back to 0 DEG C of reaction 2h.At 0 DEG C of ice bath, 30mL sodium bicarbonate water is added
Solution (5%), liquid separation take organic phase, are washed with saturated sodium-chloride water solution (50mL), and anhydrous sodium sulfate is dry.Filtering, revolving
Solvent afforded crude material is removed, is purified through column chromatography for separation and (petrol ether/ethyl acetate=10: 1), obtains 5- (bromomethyl) -3,3- bis-
Methyl-dihydro furans -2 (3H) -one 880mg, yield 85%.1H NMR (300MHz, CDCl3) δ 4.66-4.57 (m, 1H),
3.54 (dd, J=10.8,5.1Hz, 1H), 3.47 (dd, J=10.8,6.0Hz, 1H), 2.25 (dd, J=12.9,6.3Hz,
1H), 1.91 (dd, J=12.9,9.3Hz, 1H), 1.28 (s, 3H), 1.26 (s, 3H).13C NMR (75MHz, CDCl3)δ
180.97,74.74,41.87,40.61,33.74,24.96,24.91.
(3) 6- (bromomethyl)-oxinane -2- ketone preparation
Nitrogen protection, in the 100mL three-necked flask equipped with thermometer, addition oxalyl bromine (7.5mmol, 1.1mL,
1.5eq) and anhydrous methylene chloride (10mL).At liquid nitrogen--78 DEG C of ethanol bath, dimethyl sulfoxide is slowly added dropwise with constant pressure funnel
Anhydrous methylene chloride (10mL) solution of (7.5mmol, 1.52g, 1.5eq).After being added dropwise, continue to stir at -78 DEG C
10min, then anhydrous methylene chloride (10mL) solution of 5- hexenoic acid (5mmol, 570mg, 1.0eq) is added dropwise.After being added dropwise ,-
Continue to stir 10min at 78 DEG C, be added potassium carbonate (25mmol, 3.45g, 5.0eq) and 18- crown ether -6 (0.25mmol, 66mg,
0.05eq), room temperature reaction 5h is then returned.It filters, 30mL distilled water is added in filtrate, liquid separation takes organic phase, uses saturated sodium-chloride
Aqueous solution (50mL) washing, anhydrous sodium sulfate are dry.Filtering, revolving remove solvent afforded crude material, purify (petroleum through column chromatography for separation
Ether/ethyl acetate=10: 1) 6- (bromomethyl)-oxinane -2- ketone 435mg, yield 45% are obtained,.1H NMR
(600MHz, CDCl3) δ 4.52-4.47 (m, 1H), 3.52 (dd, J=10.8,4.2Hz, 1H), 3.47 (dd, J=10.8,
6.0Hz, 1H), 2.60 (dddd, J=18.0,6.6,4.8,1.2Hz, 1H), 2.46 (ddd, J=17.4,9.6,7.2Hz, 1H),
2.14-2.08 (m, 1H), 1.97 (ddq, J=13.8,7.2,4.8Hz, 1H), 1.91-1.83 (m, 1H), 1.70 (dtd, J=
13.8,11.4,5.4Hz, 1H).13C NMR (150MHz, CDCl3) δ 170.45,78.70,33.89,29.50,26.42,
18.27。
Claims (1)
- The preparation method of product 1. olefin(e) acid bromine described in a kind of Formula II lactonizes, it is characterised in that with 3- olefin(e) acid shown in Formulas I, 4- Olefin(e) acid, 5- alkene acid compounds are raw material, using methylene chloride as solvent, in the effect of dimethyl sulfoxide and oxalyl bromine composite reagent Under, it obtains bromine shown in corresponding Formula II and lactonizes product, main process is: at -78 DEG C first by the dichloromethane of dimethyl sulfoxide Alkane solution is added dropwise in the dichloromethane solution of oxalyl bromine, then alkene acid compounds shown in Formulas I are added dropwise, and is then back to 0 DEG C of reaction, Reaction equation is as follows:R=H, Ph or CmH2m+1, m=1-5.
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| CN108383812A (en) * | 2018-04-25 | 2018-08-10 | 北京工商大学 | A kind of α, the preparation method of β-unsaturation-gamma lactone |
| CN108383708A (en) * | 2018-04-25 | 2018-08-10 | 北京工商大学 | A kind of preparation method of alpha-brominated ketone |
| CN113372310A (en) * | 2021-07-12 | 2021-09-10 | 江苏弘和药物研发有限公司 | Synthesis method of 4-n-octyl butenolide |
| CN113754616B (en) * | 2021-09-27 | 2023-07-18 | 北京工商大学 | Preparation method of trans-3-phenylthio-gamma-lactone |
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Non-Patent Citations (3)
| Title |
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| Enantioselective synthesis of 4-alkenoic acids via Pd-catalyzed allylic alkylation: stereocontrolled construction of c and d-lactones;Isabel Alvarado-Beltran 等;《Tetrahedron: Asymmetry》;20150708;第26卷;802-809 * |
| Hypervalent Iodine(III)-Mediated Decarboxylative Ritter-Type Amination Leading to the Production of α‑Tertiary Amine Derivatives;Kensuke Kiyokawa 等;《J. Org. Chem.》;20170612;第82卷;11711-11720 * |
| 烯酸在碘化铵催化作用下的卤代内酯化反应;朱敏 等;《高等学校化学学报》;20140228;第35卷;286-291 * |
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