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CN108727179A - A kind of alpha, beta-unsaturated ketone of α-allyl substitution, the synthetic method of ester or nitrile compound - Google Patents

A kind of alpha, beta-unsaturated ketone of α-allyl substitution, the synthetic method of ester or nitrile compound Download PDF

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CN108727179A
CN108727179A CN201810788951.8A CN201810788951A CN108727179A CN 108727179 A CN108727179 A CN 108727179A CN 201810788951 A CN201810788951 A CN 201810788951A CN 108727179 A CN108727179 A CN 108727179A
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allyl
synthetic method
ester
beta
alpha
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CN108727179B (en
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马献涛
于静
江梦园
燕然
唐林
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Xinyang Normal University
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
    • C07C49/796—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/34—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/213—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C49/217—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom

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Abstract

The present invention provides the synthetic methods of a kind of alpha, beta-unsaturated ketone of α-allyl substitution, ester or nitrile compound.This method is alkylating reagent using allyl alcohol, with phosphorus ylide under allyl palladium chloride (II) dimer, the effect of biphosphine ligand catalyst system and catalyzing, it is stirred to react in reaction dissolvent 6~24 hours under the conditions of 20~100 DEG C, it is reacted using the Wittig of one kettle way, prepare the α of α-allyl substitution, alpha, beta-unsaturated ketone, ester or nitrile compound.This method is simple, raw material is easily obtained, reaction condition is mild.Requirement of this method to reaction condition is relatively low, using aryl, heteroaryl and lard type allyl alcohols as alkylating reagent, realize that ketone group, ester group and cyano stablize the one kettle way allylation-Wittig reactions of phosphorus ylide, with the wider scope of application, should also have certain research and prospects for commercial application.

Description

A kind of synthesis of the alpha, beta-unsaturated ketone, ester or nitrile compound of α-allyl substitution Method
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of α of α-allyl substitution, alpha, beta-unsaturated ketone, ester or nitrile The synthetic method of compound.
Background technology
α, alpha, beta-unsaturated ketone, ester and nitrile are important synthetic intermediate, are widely used in organic synthesis.Permitted simultaneously There is also the α of alpha-substituted, alpha, beta-unsaturated ketone, ester or nitrile structural units in drug bioactive molecule, therefore carry out α-allyl and take The study on the synthesis of the alpha, beta-unsaturated ketone in generation, ester or nitrile compound has important value.
Synthetic method reported in the literature mainly has：1) allyl acetic acid ester occurs with alpha, beta-unsaturated ketone under palladium chtalyst MBH reacts, but this method needs palladium chtalyst dosage larger (10mol%), while needing that excessive phosphorus reagent, acetic acid is added (more than 1.0 equivalents) etc. come promote reaction progress；2) stablize the allylation-Wittig reactions of phosphorus ylide, but in document The allylation reagent of use is mainly commercially difficult to the allyl carbonate, the allyamine compounds that obtain, and in reaction It needs that additive (acid or alkali) is added to promote to react, and reaction temperature is higher (>=100 DEG C).Above method is usually still needed in height It carries out, therefore, still has disadvantages that, it would be highly desirable to improve in malicious, readily volatilized organic solvent.
Invention content
Present invention is primarily aimed at provide a kind of catalysis process：Using derive from a wealth of sources, it is cheap and easy to get, stablize low toxicity alkene Propyl alcohols is alkylating reagent, in a mild condition, the phosphorus ylide one kettle way allyl stablized with ketone group, ester group and cyano Change-Wittig reactions prepare alpha, beta-unsaturated ketone, ester or the nitrile compound of α-allyl substitution.
The present invention uses following technical scheme：
A kind of α of α-allyl substitution, alpha, beta-unsaturated ketone, ester or nitrile compound synthetic method, it is vertical with allyl alcohol and phosphorus leaf Moral is reaction substrate, under allyl palladium chloride (II) dimer and the effect of biphosphine ligand catalyst system and catalyzing, one kettle way allylation- Wittig reactions prepare alpha, beta-unsaturated ketone, ester or the nitrile compound of α-allyl substitution.
Further, the dosage of allyl palladium chloride (II) dimer is 0.5~10mol%.
Further, the dosage of allyl palladium chloride (II) dimer is 1~2.5mol%.
Further, which is characterized in that the biphosphine ligand is bis- (diphenyl phosphine) ethane (dppe) of 1,2-, Isosorbide-5-Nitrae-bis- (two Phosphniline) butane (dppb), bis- (diphenyl phosphine) pentanes (dppp) of 1,5- or 1, bis- (diphenylphosphine) ferrocene (dppf) of 1'-, double phosphines The dosage of ligand is 2~40mol%.
Further, the biphosphine ligand is bis- (diphenylphosphine) ferrocene (dppf) of 1,1'-, dosage for 4~ 10mol%.
Further, it is as follows：
Allyl alcohol, phosphorus ylide, allyl palladium chloride (II) dimer and biphosphine ligand are added in reaction dissolvent, in nitrogen It is stirred to react under the conditions of 20~100 DEG C 6~24 hours in atmosphere, formalin is then added, is stirred to react 6~12 at room temperature Hour, obtain the α of α-allyl substitution, alpha, beta-unsaturated ketone, ester or nitrile compound,
Reaction equation is：
Wherein：
R1It is-H, phenyl, heteroaryl or alkyl；
R2It is-H, alkyl or phenyl；
R3It is-H, alkyl or phenyl；
R4It is ketone group, ester group or cyano；
The reaction dissolvent is the aqueous solution of alcohol, water or alcohol.
Further, the reaction dissolvent is methanol, ethyl alcohol or water.
Further, Wittig reactions carry out under nitrogen or air.
Further, the reaction temperature of diastereoselective allylation is 30~60 DEG C, and the reaction time is 6~12 hours.
Further, the formalin is 37% formalin.
The beneficial effects of the present invention are：
1, the reagents such as allyl alcohol, catalyst, ligand used in the present invention are generally commercialized, and can directly be commercially available.
2, this method can be used it is cheap and easy to get, derive from a wealth of sources, stablize low toxicity, green allyl alcohols compound be alkylation try Agent, under more mild reaction temperature, under conditions of relatively low catalyst amount, using the aqueous solution of alcohol, water or alcohol as reaction Solvent realizes the efficient preparation of the alpha, beta-unsaturated ketone, ester or nitrile compound of α-allyl substitution.This method is to reaction condition It is required that it is relatively low, the scope of application is wider, with the obvious advantage compared with known method, have and potential be widely applied foreground.
Specific implementation mode
Following embodiment is not used to limit protection scope of the present invention for illustrating the present invention.Unless otherwise specified, real Apply the conventional means that technological means used in example is well known to those skilled in the art.
1 cinnamyl alcohol of embodiment and benzoyl phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=30/1), separation yield 86%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.78-7.75(m,2H),7.55-7.50(m,1H), 7.46-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.21-7.17 (m, 1H), 6.51 (d, J= 16.0Hz, 1H), 6.29 (dt, J=16.0,7.2Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.69 (d, J=0.8Hz, 1H), 3.35 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ198.0,146.7,137.9,137.5,132.5, 132.3,129.6,128.7,128.3,127.4,126.7,126.6,126.3,35.6。
The present embodiment reaction equation is as follows：
2 cinnamyl alcohol of embodiment and benzoyl phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with water (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.The reaction was complete for TLC monitorings Afterwards, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product is purified with pillar layer separation (solvent petrol ether/ethyl acetate=30/1), separation yield 96%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.78-7.75(m,2H),7.55-7.50(m,1H), 7.46-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.21-7.17 (m, 1H), 6.51 (d, J= 16.0Hz, 1H), 6.29 (dt, J=16.0,7.2Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.69 (d, J=0.8Hz, 1H), 3.35 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ198.0,146.7,137.9,137.5,132.5, 132.3,129.6,128.7,128.3,127.4,126.7,126.6,126.3,35.6。
The reaction equation of the present embodiment is as follows：
3 cinnamyl alcohol of embodiment and benzoyl phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (10.9mg, 10mol%), dppf (66.5mg, 40mol%) with water (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.The reaction was complete for TLC monitorings Afterwards, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product is purified with pillar layer separation (solvent petrol ether/ethyl acetate=30/1), separation yield 96%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.78-7.75(m,2H),7.55-7.50(m,1H), 7.46-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.21-7.17 (m, 1H), 6.51 (d, J= 16.0Hz, 1H), 6.29 (dt, J=16.0,7.2Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.69 (d, J=0.8Hz, 1H), 3.35 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ198.0,146.7,137.9,137.5,132.5, 132.3,129.6,128.7,128.3,127.4,126.7,126.6,126.3,35.6。
The reaction equation of the present embodiment is as follows：
4 cinnamyl alcohol of embodiment and benzoyl phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (1.1mg, 1mol%), dppf (6.6mg, 4mol%) and Water (0.5mL), then vacuumizes, nitrogen protection, reacts 12h under the conditions of 60 DEG C.TLC monitorings are added 37% after the reaction was complete Formalin (0.068mL, 0.90mmol), is stirred to react 6h at room temperature.Product purifies (solvent oil with pillar layer separation Ether/ethyl acetate=30/1), separation yield 45%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.78-7.75(m,2H),7.55-7.50(m,1H), 7.46-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.21-7.17 (m, 1H), 6.51 (d, J= 16.0Hz, 1H), 6.29 (dt, J=16.0,7.2Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.69 (d, J=0.8Hz, 1H), 3.35 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ198.0,146.7,137.9,137.5,132.5, 132.3,129.6,128.7,128.3,127.4,126.7,126.6,126.3,35.6。
The reaction equation of the present embodiment is as follows：
5 cinnamyl alcohol of embodiment and benzoyl phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (0.55mg, 0.5mol%), dppf (3.3mg, 2mol%) It with water (0.5mL), then vacuumizes, nitrogen protection, reacts 12h under the conditions of 60 DEG C.TLC monitorings are added after the reaction was complete 37% formalin (0.068mL, 0.90mmol), is stirred to react 6h at room temperature.Product purifies (solvent with pillar layer separation Petrol ether/ethyl acetate=30/1), separation yield 39%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.78-7.75(m,2H),7.55-7.50(m,1H), 7.46-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.21-7.17 (m, 1H), 6.51 (d, J= 16.0Hz, 1H), 6.29 (dt, J=16.0,7.2Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.69 (d, J=0.8Hz, 1H), 3.35 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ198.0,146.7,137.9,137.5,132.5, 132.3,129.6,128.7,128.3,127.4,126.7,126.6,126.3,35.6。
The reaction equation of the present embodiment is as follows：
6 1- phenyl allyl alcohols of embodiment and benzoyl phosphorus ylide prepare the α, β-unsaturation of α-allyl substitution Ketone
1- phenyl allyl alcohols (48.2mg, 0.36mmol, 1.2equiv.), benzoyl are sequentially added into tubular reactor Phosphorus ylide (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) and water (0.5mL), then vacuumizes, nitrogen protection, reacts 12h under the conditions of 60 DEG C.TLC monitorings are anti- After answering completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product column chromatography point From purification (solvent petrol ether/ethyl acetate=30/1), separation yield 93%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.78-7.75(m,2H),7.55-7.50(m,1H), 7.46-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.21-7.17 (m, 1H), 6.51 (d, J= 16.0Hz, 1H), 6.29 (dt, J=16.0,7.2Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.69 (d, J=0.8Hz, 1H), (3.35 dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ198.0,146.7,137.9,137.5,132.5, 132.3,129.6,128.7,128.3,127.4,126.7,126.6,126.3,35.6。
The reaction equation of the present embodiment is as follows：
7 4- methoxycinnamates alcohol of embodiment and benzoyl phosphorus ylide prepare the α, β-unsaturation of α-allyl substitution Ketone
4- methoxycinnamates alcohol (59.0mg, 0.36mmol, 1.2equiv.), benzoyl are sequentially added into tubular reactor Phosphorus ylide (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) and water (0.5mL), then vacuumizes, nitrogen protection, reacts 12h under the conditions of 60 DEG C.TLC monitorings are anti- After answering completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product column chromatography point From purification (solvent petrol ether/ethyl acetate=10/1), separation yield 92%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.78 (dd, J=8.0,1.6Hz, 2H), 7.54-7.50 (m, 1H), 7.43-7.39 (m, 2H), 7.31-7.26 (m, 2H), 6.86-6.81 (m, 2H), 6.46 (d, J=15.6Hz, 1H), 6.16 (dt, J=15.6,6.8Hz, 1H), 5.90 (d, J=0.8Hz, 1H), 5.68 (d, J=0.8Hz, 1H), 3.76 (s, 3H), 3.33 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ197.5,159.0,146.7,137.5,132.0, 131.7,130.0,129.4,128.0,127.0,126.3,124.1,114.0,55.1,35.2。
The reaction equation of the present embodiment is as follows：
8 4- trifluoromethyls cinnamyl alcohol of embodiment and benzoyl phosphorus ylide prepare the α, β-insatiable hunger of α-allyl substitution And ketone
4- trifluoromethyls cinnamyl alcohol (72.7mg, 0.36mmol, 1.2equiv.), benzoyl are sequentially added into tubular reactor Base phosphorus ylide (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) and water (0.5mL), then vacuumizes, nitrogen protection, reacts 12h under the conditions of 60 DEG C.TLC monitorings are anti- After answering completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product column chromatography point From purification (solvent petrol ether/ethyl acetate=30/1), separation yield 83%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.73 (dd, J=7.6,2.4Hz, 2H), 7.58-7.40 (m, 7H), 6.51 (d, J=16.0Hz, 1H), 6.37 (dt, J=16.0,6.4Hz, 1H), 5.92 (d, J=0.8Hz, 1H), 5.72 (d, J=0.8Hz, 1H), 3.40 (dd, J=6.4,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ197.8, 146.2,140.9,137.8,132.5,131.2,129.7,129.6,128.3,127.2,12 6.1,125.2 (q, J= 7.2Hz),35.1。
The reaction equation of the present embodiment is as follows：
9 3- pyridyl groups allyl alcohol of embodiment and benzoyl phosphorus ylide prepare the α, β-unsaturation of α-allyl substitution Ketone
3- pyridyl groups allyl alcohol (48.6mg, 0.36mmol, 1.2equiv.), benzoyl are sequentially added into tubular reactor Phosphorus ylide (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) and water (0.5mL), then vacuumizes, nitrogen protection, reacts 12h under the conditions of 60 DEG C.TLC monitorings are anti- After answering completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product column chromatography point From purification (solvent petrol ether/ethyl acetate=10/1), separation yield 80%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 8.60 (s, 1H), 8.45 (d, J=4.0Hz, 1H), 7.79–7.74(m,2H),7.72–7.68(m,1H),7.59–7.55(m,1H),7.48–7.44(m,2H),7.26–7.20(m, 1H), 6.51 (d, J=16.0Hz, 1H), 6.40 (dt, J=16.0,6.8Hz, 1H), 5.97 (d, J=0.8Hz, 1H), 5.75 (d, J=0.8Hz, 1H), 3.43 (dd, J=6.8,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ197.5,148.4, 148.2,146.2,137.8,133.0,132.5,129.5,129.4,129.1,128.9,128.4,127.1,123.3,35.4。
The reaction equation of the present embodiment is：
10 E-2- hexene 1- alcohol of embodiment and benzoyl phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
E-2- hexene 1- alcohol (36.0mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus are sequentially added into tubular reactor Ylide (114.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=30/1), separation yield 82%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.77 (d, J=6.8Hz, 2H), 7.56-7.51 (m, 1H), 7.47-7.41 (m, 2H), 5.89 (d, J=0.8Hz, 1H), 5.63 (d, J=0.8Hz, 1H), 5.59-5.43 (m, 2H), 3.17 (dd, J=6.4,0.8Hz, 2H), 2.03 (dt, J=12.8,6.4Hz, 2H), 1.45-1.37 (m, 2H), 0.89 (t, J= 7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ198.0,147.5,138.0,133.7,132.3,129.8,128.3, 126.5,125.6,35.3,34.8,22.9,13.8。
The reaction equation of the present embodiment is as follows：
11 cinnamyl alcohol of embodiment and 4- methoxybenzoyl base phosphorus ylides prepare the α, β-unsaturation of α-allyl substitution Ketone
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (123.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with water (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.The reaction was complete for TLC monitorings Afterwards, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product is purified with pillar layer separation (solvent petrol ether/ethyl acetate=10/1), separation yield 86%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.82–7.77(m,2H),7.35–7.30(m,2H), 7.29-7.25 (m, 2H), 7.20-7.17 (m, 1H), 6.95-6.87 (m, 2H), 6.46 (d, J=15.6Hz, 1H), 6.25 (dt, J=15.6,6.8Hz, 1H), 5.80 (d, J=0.8Hz, 1H), 5.60 (d, J=0.8Hz, 1H), 3.81 (s, 3H), 3.35 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ196.2,163.0,146.5,137.2,132.2,132.0, 130.0,128.4,127.0,126.6,126.1,124.4,113.4,55.3,35.6。
The reaction equation of the present embodiment is as follows：
12 cinnamyl alcohol of embodiment and 4- chlorobenzene formacyl phosphorus ylides prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (124.2mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=30/1), separation yield 90%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3)δ7.75–7.66(m,2H),7.45–7.25(m,6H), 7.24-7.18 (m, 1H), 6.52 (d, J=16.0Hz, 1H), 6.27 (dt, J=16.0,7.2Hz, 1H), 5.95 (d, J= 0.8Hz, 1H), 5.67 (d, J=0.8Hz, 1H), 3.38 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ 196.5,146.2,138.8,137.5,135.7,132.6,130.8,128.5,128.6,127.5,126.7,126.4, 126.3,35.4。
The reaction equation of the present embodiment is as follows：
13 cinnamyl alcohol of embodiment and 2- furanylcarbonyl phosphorus ylides prepare the alpha, beta-unsaturated ketone 1h of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (111.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=30/1), separation yield 85%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.60 (dd, J=1.2,0.8Hz, 1H), 7.36-7.33 (m, 2H), 7.30-7.26 (m, 2H), 7.22-7.15 (m, 2H), 6.52 (dd, J=3.2,1.2Hz, 1H), 6.48 (d, J= 16.0Hz, 1H), 6.24 (dt, J=16.0,7.2Hz, 1H), 6.08 (d, J=0.8Hz, 1H), 5.85 (d, J=0.8Hz, 1H), 3.36 (dd, J=7.2,0.8Hz, 2H)；13C NMR(100MHz,CDCl3)δ183.0,151.5,146.7,146.0,136.8, 132.0,128.0,126.9,126.0,125.8,124.3,119.4,111.6,35.0。
The reaction equation of the present embodiment is as follows：
14 cinnamyl alcohol of embodiment and tertiary butyl acyl group phosphorus ylide prepare the alpha, beta-unsaturated ketone of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (108.0mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=30/1), separation yield 88%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.40-7.18 (m, 5H), 6.40 (d, J=16.0Hz, 1H), 6.16 (dt, J=16.0,7.2Hz, 1H), 5.50 (s, 1H), 5.46 (s, 1H), 3.12 (dd, J=7.2,1.2Hz, 2H), 1.20(s,9H)；13C NMR(100MHz,CDCl3)δ210.3,146.5,137.0,132.1,128.2,126.8,126.2, 125.7,117.9,43.6,37.1,27.4。
The reaction equation of the present embodiment is as follows：
15 cinnamyl alcohol of embodiment and ethoxycarbonyl phosphorus ylide prepare the α of α-allyl substitution, beta-unsaturated esters
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (104.4mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=20/1), separation yield 76%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.40-7.20 (m, 5H), 6.46 (d, J=16.0Hz, 1H), 6.25 (dt, J=16.0,7.2Hz, 1H), 6.24 (s, 1H), 5.62 (d, J=0.8Hz, 1H), 4.23 (q, J=7.2Hz, 2H), 3.23 (dd, J=7.2,0.8Hz, 2H), 1.31 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ166.9, 139.5,137.3,132.1,128.6,127.2,126.9,126.0,125.5,60.9,35.2,14.5。
The reaction equation of the present embodiment is as follows：
16 cinnamyl alcohol of embodiment and cyano phosphorus ylide prepare the 'alpha ', ' bela '-unsaturated nitrile of α-allyl substitution
Cinnamyl alcohol (48.2mg, 0.36mmol, 1.2equiv.), benzoyl phosphorus ylide are sequentially added into tubular reactor (90.3mg, 0.30mmol), allyl palladium chloride (II) dimer (2.8mg, 2.5mol%), dppf (16.6mg, 10mol%) with absolute methanol (0.5mL), then vacuumizes, nitrogen protection, react 12h under the conditions of 60 DEG C.TLC monitoring reactions After completely, 37% formalin (0.068mL, 0.90mmol) is added, is stirred to react 6h at room temperature.Product pillar layer separation It purifies (solvent petrol ether/ethyl acetate=30/1), separation yield 66%.
The nuclear-magnetism of product is composed：1H NMR(400MHz,CDCl3) δ 7.40-7.25 (m, 5H), 6.55 (d, J=16.0Hz, 1H), 6.16 (dt, J=16.0,7.2Hz, 1H), 5.93 (s, 1H), 5.82 (s, 1H), 3.16 (d, J=6.8,2H)；13C NMR (100MHz,CDCl3)δ136.9,134.4,131.0,128.9,128.0,126.7,123.4,121.9,118.7,37.9。
The reaction equation of the present embodiment is as follows：
The embodiment of the above is only used to explain the present invention, the scope of the present invention is not limited, for this technology It, certainly can be according to technology contents disclosed in this specification, by way of replacing or changing for the technical staff in field Other embodiments are made easily, therefore all changes and improvements etc. done in the principle of the present invention and process conditions, it should all wrap It includes in scope of the present invention patent.

Claims (10)

1. a kind of α-α of allyl substitution, alpha, beta-unsaturated ketone, ester or nitrile compound synthetic method, which is characterized in that with allyl Base alcohol is reaction substrate with phosphorus ylide, under allyl palladium chloride (II) dimer and the effect of biphosphine ligand catalyst system and catalyzing, one - Wittig the reactions of pot method allylation prepare alpha, beta-unsaturated ketone, ester or the nitrile compound of α-allyl substitution.
2. synthetic method according to claim 1, which is characterized in that the dosage of allyl palladium chloride (II) dimer For 0.5~10mol%.
3. synthetic method according to claim 1, which is characterized in that the dosage of allyl palladium chloride (II) dimer For 1~2.5mol%.
4. synthetic method according to claim 1, which is characterized in that the biphosphine ligand is bis- (diphenyl phosphine) second of 1,2- Bis- (diphenyl phosphine) butane of alkane, Isosorbide-5-Nitrae-, bis- (diphenyl phosphine) pentanes of 1,5- or 1, bis- (diphenylphosphine) ferrocene of 1'-, biphosphine ligand Dosage is 2~40mol%.
5. synthetic method according to claim 1, which is characterized in that the biphosphine ligand is 1,1'- bis- (diphenylphosphines) Ferrocene, dosage are 4~10mol%.
6. synthetic method according to claim 1, which is characterized in that be as follows：
Allyl alcohol, phosphorus ylide, allyl palladium chloride (II) dimer and biphosphine ligand are added in reaction dissolvent, in nitrogen Stirring carries out diastereoselective allylation 6~24 hours under the conditions of 20~100 DEG C in atmosphere, and formalin is then added, stirs at room temperature It mixes and carries out Wittig and react 6~12 hours, obtain the α of α-allyl substitution, alpha, beta-unsaturated ketone, ester or nitrile compound,
Reaction equation is：
Wherein：
R1It is-H, phenyl, heteroaryl or alkyl；
R2It is-H, alkyl or phenyl；
R3It is-H, alkyl or phenyl；
R4It is ketone group, ester group or cyano；
The reaction dissolvent is the aqueous solution of alcohol, water or alcohol.
7. synthetic method according to claim 6, which is characterized in that the reaction dissolvent is methanol, ethyl alcohol or water.
8. synthetic method according to claim 6, which is characterized in that Wittig reactions carry out under nitrogen or air.
9. synthetic method according to claim 6, which is characterized in that the reaction temperature of diastereoselective allylation is 30~60 DEG C, Reaction time is 6~12 hours.
10. synthetic method according to claim 6, which is characterized in that the formalin is 37% formalin.
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