CN110002957B - Method for synthesizing homoallyl alcohol of polysubstituted olefin - Google Patents

Method for synthesizing homoallyl alcohol of polysubstituted olefin Download PDF

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CN110002957B
CN110002957B CN201910327332.3A CN201910327332A CN110002957B CN 110002957 B CN110002957 B CN 110002957B CN 201910327332 A CN201910327332 A CN 201910327332A CN 110002957 B CN110002957 B CN 110002957B
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陆晓雨
王世群
李劲松
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Chuzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Abstract

The invention belongs to the field of organic synthesis, and discloses a method for synthesizing poly-substituted olefin homoallyl alcohol. The high allyl alcohol compound of the polysubstituted olefin synthesized by the method has the advantages of short synthetic route, high reaction yield and the like, and solves the problems of difficult synthesis, low total reaction yield and the like of the conventional synthesis of the polysubstituted high allyl alcohol. Meanwhile, the reaction system has a simple feeding mode, and the reaction reagent is stable to air and water and is more convenient to operate practically. Mild reaction conditions, high regioselectivity and stereoselectivity, no by-product and convenient separation. Meanwhile, the reaction can be well compatible with some sensitive groups, and the functional group compatibility is excellent.

Description

Method for synthesizing homoallyl alcohol of polysubstituted olefin
Technical Field
The invention relates to compound preparation, and belongs to the field of organic synthesis. In particular to a method for synthesizing homoallyl alcohol of polysubstituted olefin.
Background
Alcohols are an important class of organic compounds, which are widely found in natural active molecules, drug molecules. And the alcohol is also an important organic synthesis intermediate, can be converted into organic synthons such as alkyl halide, alkyl sulfonate and the like through simple chemical reaction, and participates in cross coupling reaction catalyzed by various metals, so as to be used for constructing C-C bonds and C-miscellaneous bonds. Homoallylic alcohols are a special class of unsaturated hydrocarbon-containing alcohol compounds, which are important intermediates in organic synthesis, and require the use of homoallylic alcohol structural backbones in many types of reactions. Therefore, the research of developing a high-efficiency, convenient and easy-to-operate method for synthesizing the homoallyl alcohol is always the key point of research.
Substituted homoallylic alcohols have important applications and there are two main routes to their predecessor synthesis. The method described by formula (1) is a method reported by Sigman group et al in J.Am.chem.Soc.2012, 134, 11408-11411, respectively, in which the exposed alcoholic hydroxyl group is first protected with 4-bromoalcohol under tert-butyldimethylchlorosilane conditions, and then triphenylphosphine (PPh)3) The reaction yields a quaternary phosphonium salt intermediate which undergoes a Wittig reaction with an aldehyde at low temperature (-20 ℃ to-70 ℃), with a strong base (butyllithium), to yield the protected substituted homoallyl alcohol. Finally, the protecting group is removed under the condition of tetrabutylammonium fluoride (TBAF) to obtain the substituted homoallyl alcohol. The method for synthesizing the substituted homoallyl alcohol has long route and harsh reaction conditions, needs strong alkali and is controlled at lower temperature. Causing a certain economic waste. And only homoallyl alcohols of disubstituted olefins are obtained.
Figure BSA0000182262220000011
Long reaction route and harsh reaction conditions
Another method for synthesizing homoallylic alcohols is primarily by olefin metathesis, as is the case with the substituted homoallylic alcohols reported by Anderson in Angew. chem. int. Ed.2013, 52, 9139-one 9143, which requires the use of Grubbs' catalyst, which is expensive, as formula (2). And only homoallyl alcohols of disubstituted olefins can be synthesized by this process
Figure BSA0000182262220000021
Grubbs' catalyst is expensive and only synthesizes disubstituted olefin homoallyl alcohols
Although homoallyl alcohol can be synthesized by the above two examples, method 1 has a long route, severe reaction conditions, and a low overall yield. Method 2 catalysts are expensive. Most importantly, only homoallyl alcohol of disubstituted olefin can be synthesized by the existing method, and no method for synthesizing homoallyl alcohol of trisubstituted olefin is reported so far.
The homoallyl alcohol of polysubstituted olefin has great demand in the material, organic synthesis and medicine industries, and the existing methods for synthesizing the substituted homoallyl alcohol can only synthesize the homoallyl alcohol of disubstituted olefin. Therefore, the efficient, economical and convenient synthesis of homoallyl alcohols of polysubstituted olefins is a problem in chemical synthesis.
Disclosure of Invention
Aiming at the problems that the synthesis of the homoallyl alcohol of the polysubstituted olefin is difficult, the synthesis method is only reported so far, and the like, the invention provides the method for synthesizing the homoallyl alcohol based on the palladium-catalyzed decarboxylation for preparing the polysubstituted olefin, which has the advantages of simple and cheap palladium catalyst, wide raw material source, good functional group compatibility and short reaction route, and only needs one-step reaction.
In order to solve the technical problems, the invention adopts the following technical scheme: a method for synthesizing polysubstituted homoallyl alcohol is characterized in that: the method comprises the following steps of taking alpha, beta-unsaturated acrylic acid and an epoxy compound as raw materials, and reacting in a solvent under the action of a palladium catalyst, a ligand and alkali according to the following reaction formula to obtain a homoallyl alcohol compound of E-configuration polysubstituted olefin with a general formula (I):
Figure BSA0000182262220000022
wherein R is a plurality of types of aryl or alkenyl substituents;
the catalyst is tetratriphenylphosphine palladium;
the ligand is 1, 1' -bis (diphenylphosphino) ferrocene (dppf);
the solvent is dioxane (dioxane) or benzotrifluoride (PhCF)3) One or a mixture of two thereof;
the alpha, beta-unsaturated acrylic acid is beta-disubstituted unsaturated acrylic acid.
Preferably, the base is N-methyldicyclohexylamine.
Preferably, the amount of the substance of the base is 1.5 times the amount of the substance of the α, β -unsaturated acrylic acid.
Preferably, the amount of the substance of the epoxy is 2 times the amount of the substance of the α, β -unsaturated acrylic acid.
Preferably, the amount of the substance of the palladium catalyst is 10% of the amount of the substance of α, β -unsaturated acrylic acid.
Preferably, the amount of the substance of the ligand is 12% of the amount of the substance of α, β -unsaturated acrylic acid.
Preferably, the reaction temperature in the solvent is 90 ℃ and the reaction time is 24 h.
The former reports on homoallyl alcohols of such polysubstituted olefins, and this structure was synthesized for the first time by this method. The method for synthesizing the poly-substituted olefin homoallyl alcohol has the advantages of short reaction route, only one step, cheap catalyst, easily obtained raw materials, high synthesis economic value, wide raw material source and high reaction yield. Meanwhile, the reaction system has a simple feeding mode, does not need to use reagents sensitive to moisture and air, and is more convenient in actual use. In addition, the reaction system has mild reaction conditions, can be well compatible with some sensitive groups, is difficult to realize in the prior reaction system, and provides an efficient, convenient and economic preparation method for the homoallyl alcohol of the polysubstituted olefin.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments:
example 1, the reaction formula for this example is as follows:
Figure BSA0000182262220000031
(1) tetratriphenylphosphine palladium (Pd (PPh) under air3)410 mol%), 1, 1' -bis (diphenylphosphino) ferrocene (dppf, 12 mol%), sodium iodide (NaI, 30 mol%), beta-methylphenylacrylic acid (0.3mmol) were added to a sealed reaction tube with a branch tube containing magnetons, and the reaction tube was purged with argon three times. Under the protection of argon, 2mL of PhCF was added to the reaction tube3And 0.5mL of 1, 4-dioxoSix rings, then adding epoxy cyclohexane (2equiv.) into the reaction liquid under the protection of argon, plugging a piston, and placing the mixture in a 90 ℃ oil bath kettle to stir for reaction for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) The solvent in the organic phase obtained in step (2) was spin-dried to obtain a crude product, which was then purified by a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 85 percent, and the product purity is 100 percent.
Example 2
The reaction formula for this example is shown below:
Figure BSA0000182262220000041
(1) tetratriphenylphosphine palladium (Pd (PPh) under air3)410 mol%), 1, 1' -bis (diphenylphosphino) ferrocene (dppf, 12 mol%), sodium iodide (NaI, 30 mol%), beta-methyl-4-methylphenylacrylic acid (0.3mmol) were added to a sealed reaction tube with branch tubes containing magnetons, and the reaction tube was flushed with argon three times. Under the protection of argon, 2mL of PhCF was added to the reaction tube3And 0.5mL of 1, 4-dioxane, then adding cyclohexene oxide (2equiv.) into the reaction solution under the protection of argon, plugging a piston, and placing the mixture in a 90 ℃ oil bath kettle to stir for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) The solvent in the organic phase obtained in step (2) was spin-dried to obtain a crude product, which was then purified by a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 83 percent, and the product purity is 100 percent.
Example 3
The reaction formula for this example is shown below:
Figure BSA0000182262220000051
(1) tetratriphenylphosphine palladium (Pd (PPh) under air3)410 mol%), 1, 1' -bis (diphenylphosphino) ferrocene (dppf, 12 mol%), sodium iodide (NaI, 30 mol%), beta-methylthiophen-ylacrylic acid (0.3mmol) were added to a sealed reaction tube with branch tubes containing magnetons, and the reaction tube was flushed with argon three times. Under the protection of argon, 2mL of PhCF was added to the reaction tube3And 0.5mL1, 4-dioxane, followed by addition of cyclohexene oxide (2equiv.) to the reaction under argon, stoppering, and stirring in a 90 ℃ oil bath for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) The solvent in the organic phase obtained in step (2) was spin-dried to obtain a crude product, which was then purified by a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 87%, and the product purity is 100%.
Example 4
The reaction formula for this example is shown below:
Figure BSA0000182262220000052
(1) tetratriphenylphosphine palladium (Pd (PPh) under air3)48 mol%), 1, 1' -bis (diphenylphosphino) ferrocene (dppf, 10 mol%), sodium iodide (NaI, 30 mol%), retinoic acid (0.3mmol) were added to a sealed reaction tube with a branch tube containing magnetons, and argon gas was pumped from the reaction tube three times. Under the protection of argon, 2mL of PhCF was added to the reaction tube3And 0.5mL of 1, 4-dioxane, then adding cyclohexene oxide (2equiv.) into the reaction solution under the protection of argon, plugging a piston, and placing the mixture in a 90 ℃ oil bath kettle to stir for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) The solvent in the organic phase obtained in step (2) was spin-dried to obtain a crude product, which was then purified by a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 78 percent, and the purity of the product is 100 percent.
Example 5
The reaction formula for this example is shown below:
Figure BSA0000182262220000061
(1) tetratriphenylphosphine palladium (Pd (PPh) under air3)48 mol%), 1, 1' -bis (diphenylphosphino) ferrocene (dppf, 10 mol%), sodium iodide (NaI, 30 mol%), and acitretin (0.3mmol) were added to a sealed reaction tube with a branch tube containing magnetons, and argon gas was pumped from the reaction tube three times. Under the protection of argon, 2mL of PhCF was added to the reaction tube3And 0.5mL of 1, 4-dioxane, then adding cyclohexene oxide (2equiv.) into the reaction solution under the protection of argon, plugging a piston, and placing the mixture in a 90 ℃ oil bath kettle to stir for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) The solvent in the organic phase obtained in step (2) was spin-dried to obtain a crude product, which was then purified by a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 75 percent, and the purity of the product is 100 percent.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of homoallyl alcohol 1 of a polysubstituted olefin prepared according to the present invention;
FIG. 2 is a NMR carbon spectrum of homoallyl alcohol 1 of a polysubstituted olefin prepared according to the present invention;
table 1: the method is used to synthesize the homoallyl alcohol of polysubstituted olefin
Figure BSA0000182262220000071
Figure BSA0000182262220000081
The amounts of the substances used and the reaction conditions were experimentally expanded as in the examples to demonstrate that the technical solution of the invention has good functional group compatibility.
The present invention has been described in detail, and it should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

Claims (2)

1. A method for synthesizing a homoallyl alcohol of a polysubstituted olefin, which is characterized by comprising the following steps: the alpha, beta-unsaturated acrylic acid and epoxy compound are used as raw materials, and the reaction formula is as follows:
Figure FSB0000196173850000011
2. the process for synthesizing a homoallyl alcohol of a polysubstituted olefin according to claim 1, wherein: the amount of the substance of the epoxy is 2 times the amount of the substance of the α, β -unsaturated acrylic acid.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093167A (en) * 2010-12-10 2011-06-15 浙江大学 Method for preparing homoallylic alcohol or homopropargylic alcohol
CN112125803A (en) * 2020-09-18 2020-12-25 大连理工大学 Preparation of homoallylic alcohol compound, synthetic method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093167A (en) * 2010-12-10 2011-06-15 浙江大学 Method for preparing homoallylic alcohol or homopropargylic alcohol
CN112125803A (en) * 2020-09-18 2020-12-25 大连理工大学 Preparation of homoallylic alcohol compound, synthetic method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Photoinduced, Copper-Promoted Regio- and Stereoselective Decarboxylative Alkylation of α,β-Unsaturated Acids with Alkyl Iodides;Chao Wang等;《Org. Lett. 》;20171120;第19卷(第23期);6412-6415 *

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