CN115477631B - Synthesis method of compound containing dimethyl enol group - Google Patents

Synthesis method of compound containing dimethyl enol group Download PDF

Info

Publication number
CN115477631B
CN115477631B CN202211226668.9A CN202211226668A CN115477631B CN 115477631 B CN115477631 B CN 115477631B CN 202211226668 A CN202211226668 A CN 202211226668A CN 115477631 B CN115477631 B CN 115477631B
Authority
CN
China
Prior art keywords
reaction
ethyl acetate
bis
compound
subenol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202211226668.9A
Other languages
Chinese (zh)
Other versions
CN115477631A (en
Inventor
江世智
雷婷
吴珍珍
杨斌全
鹿贵东
白梦娇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dali University
Original Assignee
Dali University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dali University filed Critical Dali University
Priority to CN202211226668.9A priority Critical patent/CN115477631B/en
Publication of CN115477631A publication Critical patent/CN115477631A/en
Application granted granted Critical
Publication of CN115477631B publication Critical patent/CN115477631B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • 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
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • 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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Abstract

The invention discloses the technical field of synthesis of compounds containing dimethyl enol groups, in particular to a method for synthesizing compounds containing dimethyl enol groups; under the protection of nitrogen, adding a magneton and a condenser into a double-neck round bottom flask, and adding a bromosubstrate 1, bis (tri-tertiary butyl phosphine) palladium (0), toluene, triethylamine and an olefin compound 2; then the reaction flask was sealed and placed in a 90 ℃ oil bath; after the reaction was completed (monitored by TLC, about 12 minutes), the reaction mixture was cooled to room temperature and NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; insoluble solids were removed by transfer through a short column of silica gel with ethyl acetate and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted 3 times with water; the patent has the advantages of simple synthetic route, simple and easily obtained raw materials, simple and convenient operation, less catalyst usage, low cost, easy obtainment and better derivative yield.

Description

Synthesis method of compound containing dimethyl enol group
Technical Field
The invention relates to the technical field of synthesis of compounds containing a dimethyl enol group, in particular to a method for synthesizing compounds containing a dimethyl enol group.
Background
At present: total synthesis work of (E) -Suberenol is reported (J.Am.chem.Soc., 2018,140 (8): 3156-3169.; https:// doi.org/10.1021/jacs.8b00665). For the synthesis of Suberenol, guthertz group starts from 7-methoxy coumarin (6), and is firstly subjected to cleavage to obtain coumarate (7), then iodine atoms are introduced to obtain a compound (10), cyclization is carried out to obtain 6-iodo-7-methoxy coumarin (11), 6-iodo-7-methoxy coumarin (11) and 2-methyl-3-butyn-2-ol (12) generate 6-alkynyl coumarin (13) under the catalysis of Pd/Cu, and finally (E) -Suberenol (5) is obtained through reduction reaction catalyzed by [ Cp-RuCl ] 4. The synthetic route uses highly active iodides. In addition, 6-iodo-7-methoxycoumarin (11) is difficult to obtain and the conversion rate of the reaction is very low, so that 7-hydroxycoumarin with high structural similarity needs to be used to obtain the required iodide with low yield; the Guthertz group has relatively lengthy synthetic routes and low total yields, and few reports of mild and efficient enol compound synthesis from simple raw materials are available at present. Such as the use of highly reactive iodides which are difficult to prepare, requiring severe reaction conditions at high temperatures. And the existing route has complicated steps, the starting materials are not universal, the reaction time is long, the atom economy is poor, the preparation cost is high, and the total yield is low. In view of this, it is important to develop a simple and economical synthesis method for synthesizing various dimethyl enols. .
Based on this, the present invention devised a method for synthesizing a compound containing a dimethylenol group to solve the above-mentioned problems.
Disclosure of Invention
The present invention is directed to a method for synthesizing compounds containing a dimethylenol group, which solves the problems set forth in the background art.
In order to achieve the above purpose, the present invention provides the following technical solutions: a method for synthesizing a compound containing a dimethyl enol group, the method comprising the steps of:
step one: preparation of E-subenol (5)
Under the protection of nitrogen, adding a magneton and a condenser into a double-neck round bottom flask, and adding a bromosubstrate 1, bis (tri-tertiary butyl phosphine) palladium (0), toluene, triethylamine and an olefin compound 2; then the reaction flask was sealed and placed in a 90 ℃ oil bath; after the reaction was completed (monitored by TLC, about 12 minutes), the reaction mixture was cooled to room temperature and NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; insoluble solids were removed by transfer through a short column of silica gel with ethyl acetate and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted 3 times with water, 1 time with saturated sodium chloride; the combined organic layers were treated with anhydrous Na 2 SO 4 Drying, filtering the organic phase, and concentrating to obtain a crude product; obtaining a compound E-subenol after wet sample loading column chromatography purification;
step two: (E) Preparation of-2-methyl-4- (2, 4, 6-trimethoxyphenyl) but-3-en-2-ol (5-1):
the two-necked round bottom flask was charged with magneton and condenser, 2-bromo-1, 3, 5-trimethoxybenzene, bis (tri-t-butylphosphine) palladium (0) and toluene under nitrogen protection, et 3 N, olefinic compound 2 (1, 1-dimethylallyl alcohol); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after the reaction was complete (monitored by TLC, about 1 hour), the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction product was then filtered through celite and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted with water and brine; combining the organic phases with anhydrous Na 2 SO 4 Drying, filtering the organic phase and heating to 30 DEG CConcentrating in vacuo to provide a crude product; after purification by flash column chromatography, the target compound was obtained;
step three: (E) Preparation of-4- (4- (ethoxymethoxy) phenyl) -2-methylbut-3-en-2-ol (5-2):
under the protection of nitrogen, a two-necked round bottom flask was charged with magneton and condenser, 1-bromo-4- (ethoxymethoxymethyl) benzene, bis (tri-t-butylphosphine) palladium (0), toluene, et 3 N, olefinic compound 2 (1, 1-dimethylallyl alcohol); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after the reaction was complete (monitored by TLC, about 30 minutes), the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction product was then filtered through celite and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted with water and brine; combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography, the target compound was obtained;
step four: (E) Preparation of 1- (2-hydroxy-5- (3-hydroxy-3-methylbut-1-en-1-yl) -4-methoxyphenyl) ethan-1-one (5-3):
under the protection of nitrogen, a two-necked round bottom flask was charged with magneton and a condenser, 1- (5-bromo-2-hydroxy-4-methoxybenzene) ethan-1-one, bis (tri-t-butylphosphine) palladium (0), toluene, et 3 N, olefinic compound 2 (1, 1-dimethylallyl alcohol); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after the reaction was complete (monitored by TLC, about 1 hour), the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction product was then filtered through celite and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted with water and brine; combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography, the target compound was obtained;
step five: (E) Preparation of-4- (benzofuran-5-yl) -2-methylbut-3-en-2-ol (5-4):
under the protection of nitrogen, a two-necked round bottom flask was charged with magneton and condenser, 5-bromobenzofuran, bis (tri-t-butylphosphine) palladium (0), toluene, et 3 N, olefinic compound 2 (1, 1-dimethylallyl alcohol); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after 30 minutes of reaction, the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction product was then filtered through celite and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted with water and brine; combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; purifying by flash column chromatography to obtain the target compound;
step six: (E) Preparation of-4- (1H-indol-5-yl) -2-methylbut-3-en-2-ol (5-5):
to a two-necked round bottom flask was added magneton and condenser, 5-bromo-1H-indole, bis (tri-t-butylphosphine) palladium (0), toluene, et3N (82 μl,0.6mmol,1.5 eq.) and olefinic compound 2 (1, 1-dimethylallyl alcohol) under nitrogen; then the reaction flask was sealed and placed in a 100 ℃ oil bath; after 30 minutes of reaction, the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction product was then filtered through celite and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted with water and brine; combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography, the target compound was obtained;
step seven: (E) Preparation of 2-methyl-4- (thiophen-3-yl) but-3-en-2-ol (5-6):
under the protection of nitrogen, a two-necked round bottom flask was charged with magneton and condenser, 3-bromothiophene, bis (tri-t-butylphosphine) palladium (0), toluene, et 3 N, olefinic compound 2 (1, 1-dimethylallyl alcohol); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after 30 minutes of reaction, the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 Aqueous solution, howeverStirring for 5 minutes; the crude reaction product was then filtered through celite and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted with water and brine; combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography, the target compound was obtained.
As a further aspect of the present invention, the saturated sodium bicarbonate solution may be replaced with potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, calcium phosphate.
As a further aspect of the present invention, the tri-t-butylphosphine may be replaced with triphenylphosphine, trimethylphosphine, tris (o-methylphenyl) phosphine, tricyclohexylphosphine, tricyclohexylfluoroborate, tri-N-butylphosphine, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, bis (2-diphenylphosphinophenyl) ether, tris (2-furyl) phosphine, tri-t-butylphosphine tetrafluoroborate, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 2- (di-t-butylphosphine) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ' - (N, N-dimethylamine) -biphenyl, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, N-butylbis (1-adamantyl) phosphine, 1' -bis (diisopropylphosphine) ferrocene, R- (+) -1,1' -bis (diphenylphosphine), 2' -bis (diphenylphosphine) biphenyl, 2' -bis (diphenylphosphine), 1, 4' -bis (diphenylphosphine, 2' -bis (diphenylphosphine) biphenyl, 2' -dicyclohexylphosphine-2 ' - (N, N-dimethylamine) -biphenyl, 2' -dicyclohexylphosphine-4 ' -diphenyl phosphine, 4' -diphenyl ether, 4',6' -triisopropylbiphenyl, tetraphenylphosphine palladium chloride, bis (tri-t-butylphosphine) palladium, [1,1' -bis (di-t-butylphosphine) ferrocene ] palladium (II) dichloride or no ligand added.
As a further scheme of the invention, the triethylamine can be replaced by tri-N-propylamine, N-diisopropylethylamine, N-diethylaniline, tri-N-octylamine and N, N-cyclohexylmethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylenediamine, N-methyldicyclohexylamine, tetrabutylammonium hydroxide, potassium acetate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, calcium phosphate, or no base is added.
As a further scheme of the invention, the toluene can replace tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, benzene, xylene, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, 1, 2-dichloroethane, polyethylene glycol, acetonitrile, chlorobenzene, dimethyl sulfoxide or no solvent is added.
As a further scheme of the invention, the reaction temperature in the synthesis process is between 40 ℃ and 145 ℃.
As a further aspect of the present invention, the bromosubstrate is:
or other similar bromosubstrates.
As a further aspect of the present invention, the olefinic compound is:
or other olefinic compounds.
Compared with the prior art, the invention has the beneficial effects that:
1. the synthetic route of the patent uses a simple and easy-to-prepare brominated substrate as a starting material, and the dimethylenols compound is obtained with higher yield and is synthesized for the first time. The patent route overcomes the problems of environmental hazard, complex operation, low yield and the like, simultaneously avoids the use of high-activity iodides which are difficult to prepare, uses different bromine-substituted compounds and also obtains enol compounds in high to medium yield by using different bromine-substituted compounds; in general, the patent has the advantages of simple and quick synthetic route, simple and easily obtained raw materials, simple and convenient operation, less catalyst usage, low price and easy obtaining, and better derivative yield, thereby providing a new method for synthesizing enol compounds, and providing more possibility for mass production of products and improvement of production efficiency. The prepared dimethyl enol compound is a compound with potential physiological activity; at the same time, the use of high-activity iodides which are difficult to prepare is avoided; using electron-rich, large-steric-hindrance deactivated brominated compounds as intermediates; solves the problems of low purity, complex operation, low yield and incapability of mass production in the prior art; the atom economy of the reaction is improved; the preparation method of the enol compound has the advantages of stable process, simple and convenient operation and high synthesis efficiency.
2. The method has the advantages of simple and quick synthetic route, simple and easily obtained raw materials, simple and convenient operation, less catalyst usage, low price and easy obtaining, and better derivative yield, thereby not only providing a new method for synthesizing the dimethyl enols compound, but also providing more possibility for large-scale production of products and improving the production efficiency.
Drawings
FIG. 1 is a schematic diagram of the hydrogen nuclear magnetic resonance spectrum of E-subenol (5) of the present invention;
FIG. 2 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-subenol (5) of the present invention;
FIG. 3 is a schematic representation of the nuclear magnetic resonance hydrogen spectrum of E-subenol (5) derivative 1 of the present invention;
FIG. 4 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-subenol (5) derivative 1 of the present invention;
FIG. 5 is a schematic representation of the nuclear magnetic resonance hydrogen spectrum of E-subenol (5) derivative 2 of the present invention;
FIG. 6 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-subenol (5) derivative 2 of the present invention;
FIG. 7 is a schematic representation of the nuclear magnetic resonance hydrogen spectrum of E-subenol (5) derivative 3 of the present invention;
FIG. 8 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-subenol (5) derivative 3 of the present invention;
FIG. 9 is a schematic representation of the nuclear magnetic resonance hydrogen spectrum of E-subenol (5) derivative 4 of the present invention;
FIG. 10 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-subenol (5) derivative 4 of the present invention;
FIG. 11 is a schematic diagram of the nuclear magnetic resonance hydrogen spectrum of E-subenol (5) derivative 5 of the present invention;
FIG. 12 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-suberol (5) derivative 5 of the present invention;
FIG. 13 is a schematic representation of the nuclear magnetic resonance hydrogen spectrum of E-subenol (5) derivative 6 of the present invention;
FIG. 14 is a schematic representation of the nuclear magnetic resonance carbon spectrum of E-subenol (5) derivative 6 of the present invention.
Detailed Description
Referring to fig. 1-14, the present invention provides a technical solution: a method for synthesizing a compound containing a dimethyl enol group, the method comprising the steps of:
step one: : preparation of E-subenol (5)
To a two-necked round bottom flask was added magneton and condenser under nitrogen protection, 6-bromo-7-methoxycoumarin (1.02 g,4.0mmol,1.0 eq.) bis (tri-t-butylphosphine) palladium (0) (164 mg,0.032mmol,0.08 eq.) toluene (15 mL), triethylamine (834 μl,6.0mmol,1.5 eq.) 1, 1-dimethylallyl alcohol (1.88 mL,18.0mmol,4.5 eq.); then the reaction flask was sealed and placed in a 90 ℃ oil bath; after the reaction was completed (monitored by TLC, about 12 minutes), the reaction mixture was cooled to room temperature and NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; insoluble solids were removed by transfer through a short column of silica gel with ethyl acetate and washed with ethyl acetate (100 mL); the filtrate was diluted with ethyl acetate and extracted 3 times with water, 1 time with saturated sodium chloride; the combined organic layers were treated with anhydrous Na 2 SO 4 Drying, filtering the organic phase, and concentrating to obtain a crude product; after wet-loading column chromatography (eluent, PE: ea=8:1 to 2:1) purificationCompound E-subenol is obtained: (1.02 g,98% yield);
compound E-subenol structural characterization data:
1 H NMR(400MHz,CDCl 3 )δ7.63(d,1H,J＝9.4Hz),7.48(s,1H),6.85(d,1H,J＝16.2Hz),6.78(s,1H),6.36(d,1H,J＝16.2Hz),6.26(d,1H,J＝9.4Hz),3.90(s,3H),1.44(s,6H)；
13 C NMR(100MHz,CDCl 3 )δ161.20,159.93,155.11,143.49,139.20,125.33,123.78,119.74,113.39,112.20,98.94,71.26,56.00,29.91；
IR(KBr):3838.15,3732.92,3433.47,2932.10,2345.14,1728.08,1611.93,1356.06,1210.07,1020.71,830.13,675.92cm -1 ；
HRMS(EI)calcd for C 15 H 16 O 4 [M+Na] + 283.0940,found 283.0941.
step two: (E) Preparation of-2-methyl-4- (2, 4, 6-trimethoxyphenyl) but-3-en-2-ol (5-1):
to a two-necked round bottom flask was added magneton and condenser, 2-bromo-1, 3, 5-trimethoxybenzene (98.4 mg,0.4mmol,1.0 eq.) bis (tri-t-butylphosphine) palladium (0) (16.4 mg,0.032mmol,0.08 eq.) and toluene (3 mL, 10min sparged with nitrogen before addition), et3N (82 μl,0.6mmol,1.5 eq.) 1, 1-dimethylallyl alcohol (184 μl,1.8mmol,4.5 eq.) were added; then the reaction flask was sealed and placed in a 100 ℃ oil bath; after the reaction was complete (monitored by TLC, about 1 hour), the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction was then filtered through celite and washed with ethyl acetate (30 mL); the filtrate was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL) and brine (10 mL); combining the organic phases with anhydrous Na 2 SO 4 Drying above, filtering the organic phase, and concentrating in vacuum at 30 ℃ to provide a crude product; after purification by flash column chromatography (PE: ea=15:1 to 2:1), the target compound was obtained (40.5 mg, yield 41%; recovered starting material, 49.2mg,50%; yield 91% based on recovered starting material);
(E) -structural data characterization of 2-methyl-4- (2, 4, 6-trimethoxyphenyl) but-3-en-2-ol:
1 H NMR(400MHz,CDCl 3 )δ6.81(d,J＝16.5Hz,1H),6.70(d,J＝16.5Hz,1H),6.13(s,2H),3.82(s,6H),3.81(s,3H),1.42(s,7H)；
13 C NMR(100MHz,CDCl 3 )δ159.94,159.25,138.88,116.41,107.13,90.67,71.75,55.68,55.29,30.00；
IR(KBr):3881.16,3657.04,3509.77,3370.59,3315.668,3256.67,3000.69,2856.29,1614.78,1411.74,1240.71,1004.91,787.98,689.26,565.10cm -1 .
step three: (E) Preparation of-4- (4- (ethoxymethoxy) phenyl) -2-methylbut-3-en-2-ol (5-2):
to a two-necked round bottom flask under nitrogen protection was added magneton and condenser, 1-bromo-4- (ethoxymethoxymethyl) benzene (92 mg,0.4mmol,1.0 eq.) bis (tri-t-butylphosphine) palladium (0) (16.4 mg,0.032mmol,0.08 eq.) toluene (3 mL, sparged with nitrogen for 10min before addition), et3N (82 μl,0.6mmol,1.5 eq.) 1, 1-dimethylallyl alcohol (184 μl,1.8mmol,4.5 eq.); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after the reaction was complete (monitored by TLC, about 30 minutes), the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction was then filtered through celite and washed with ethyl acetate (30 mL); the filtrate was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL) and brine (10 mL); combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography (PE: ea=8:1 to 2:1), the target compound was obtained (74 mg, yield 80%, recovered starting material, 10.1mg,11%; yield 91% based on recovered starting material);
(E) -characterization of structural data of 4- (4- (ethoxymethoxy) phenyl) -2-methylbut-3-en-2-ol:
1 H NMR(400MHz,CDCl 3 )δ7.31(d,J＝2.1Hz,1H),7.30(d,J＝2.1Hz,1H),7.00(d,J＝2.1Hz,1H),6.98(d,J＝2.1Hz,1H),6.53(d,J＝16.1Hz,1H),6.23(d,J＝16.1Hz,1H),5.22(s,2H),3.72(q,J＝7.1Hz,2H),1.41(s,6H),1.22(t,J＝7.1Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ156.83,135.83,130.67,127.50,125.74,116.32,93.10,71.05,64.24,29.93,15.13；
IR(KBr):3478.96,3380.26,3267.86,2869.52,1681.96,1619.20,1370.58,1295.80,1114.74,1079.85,856.23,701.95,573.31cm -1 .
step four: (E) Preparation of 1- (2-hydroxy-5- (3-hydroxy-3-methylbut-1-en-1-yl) -4-methoxyphenyl) ethan-1-one (5-3):
to a two-necked round bottom flask under nitrogen protection was added magneton and condenser, 1- (5-bromo-2-hydroxy-4-methoxybenzene) ethan-1-one (97.6 mg,0.4mmol,1.0 eq.) bis (tri-tert-butylphosphine) palladium (0) (16.4 mg,0.032mmol,0.08 eq.) toluene (3 mL, sparged with nitrogen for 10min before addition), et3N (82 μl,0.6mmol,1.5 eq.) 1, 1-dimethylallyl alcohol (184 μl,1.8mmol,4.5 eq.); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after the reaction was complete (monitored by TLC, about 1 hour), the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction was then filtered through celite and washed with ethyl acetate (30 mL); the filtrate was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL) and brine (10 mL); combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography (PE: ea=8:1 to 2:1), the target compound was obtained (45 mg,45%; recovered starting material, 52.7mg,54%; 99% yield based on recovered starting material);
(E) -1- (2-hydroxy-5- (3-hydroxy-3-methylbut-1-en-1-yl) -4-methoxyphenyl) ethan-1-one structural data characterization:
1 H NMR(400MHz,CDCl 3 )δ12.76(s,1H),7.73(s,1H),6.76(d,J＝16.2Hz,1H),6.41(s,1H),6.30(d,J＝16.2Hz,1H),3.88(s,3H),2.61(s,3H),1.45(s,6H)；
13 C NMR(100MHz,CDCl 3 )δ202.85,164.56,163.30,137.11,129.07,120.30,118.37,113.51,99.36,77.24,71.28,55.83,29.97,26.40；
IR(KBr):3464.50,2964.65,1616.85,1440.76,1379.93,1238.21,1183.45,1122.80,881.32,814.28,588.64,517.14cm -1 .
step five: (E) Preparation of-4- (benzofuran-5-yl) -2-methylbut-3-en-2-ol (5-4):
to a two-necked round bottom flask under nitrogen protection was added a magnet and a condenser, 5-bromobenzofuran (78.4 mg,0.4mmol,1.0 eq.) bis (tri-t-butylphosphine) palladium (0) (16.4 mg,0.032mmol,0.08 eq.) toluene (3 mL, sparged with nitrogen for 10min before addition), et3N (82 μl,0.6mmol,1.5 eq.), 1-dimethylallyl alcohol (184 μl,1.8mmol,4.5 eq.); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after 30 minutes of reaction, the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction was then filtered through celite and washed with ethyl acetate (30 mL); the filtrate was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL) and brine (10 mL); combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography (PE: ea=8:1 to 2:1), the title compound was obtained (72.9 mg,92% yield);
(E) -4- (benzofuran-5-yl) -2-methylbut-3-en-2-ol structural data characterization:
1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝2.2Hz,1H),7.58(d,J＝1.7Hz,1H),7.44(d,J＝8.5Hz,1H),7.35(dd,J＝8.6,1.8Hz,1H),6.73(dd,J＝2.2,0.9Hz,1H),6.68(d,J＝16.1Hz,1H),6.34(d,J＝16.1Hz,1H),1.45(s,6H).
13 C NMR(100MHz,CDCl 3 )δ154.55,145.45,136.46,132.00,127.76,126.53,122.86,119.09,111.39,106.64,71.11,29.97；
IR(KBr):3818.95,3613.46,3548.05,3361.82,3224.16,2907.54,2711.24,2441.15,1943.73,1756.19,1550.36,1343.00,1063.84,779.27,685.71,585.70,507.96cm -1 .
step six: (E) Preparation of-4- (1H-indol-5-yl) -2-methylbut-3-en-2-ol (5-5):
to a two-necked round bottom flask under nitrogen protection was added magneton and condenser, 5-bromo-1H-indole (78 mg,0.4mmol,1.0 eq.) bis (tri-t-butylphosphine) palladium (0) (16.4 mg,0.032mmol,0.08 eq.) toluene (3 mL, sparged with nitrogen for 10min before addition), et3N (82 μl,0.6mmol,1.5 eq.), 1-dimethylallyl alcohol (184 μl,1.8mmol,4.5 eq.); then the reaction flask was sealed and placed in a 100 ℃ oil bath; after 30 minutes of reaction, the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction was then filtered through celite and washed with ethyl acetate (30 mL); the filtrate was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL) and brine (10 mL); combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography (PE: ea=8:1 to 2:1), the title compound was obtained (73.3 mg,93% yield);
(E) -characterization of structural data of 4- (1H-indol-5-yl) -2-methylbut-3-en-2-ol:
1 H NMR(400MHz,CDCl 3 )δ8.35(s,1H),7.64(s,1H),7.31(d,J＝1.5Hz,2H),7.20–7.12(m,1H),6.70(d,J＝16.1Hz,1H),6.57–6.47(m,1H),6.33(d,J＝16.1Hz,1H),1.46(s,6H)；
13 C NMR(100MHz,CDCl 3 )δ135.49,134.71,128.87,128.14,127.50,124.80,120.46,119.21,111.27,102.72,71.28,31.02,29.97；
IR(KBr):3517.70,3362.91,3271.93,2953.63,1335.48,1115.94,969.39,800.64,732.30,471.72cm -1 .
step seven: (E) Preparation of 2-methyl-4- (thiophen-3-yl) but-3-en-2-ol (5-6):
to a two-necked round bottom flask under nitrogen protection was added a magnet and condenser, 3-bromothiophene (65 mg,0.4mmol,1.0 eq.), bis (tri-t-butylphosphine) palladium (0) (16.4 mg,0.032mmol,0.08 eq.), toluene (3 mL, sparged with nitrogen for 10min before addition), et3N (82 μl,0.6mmol,1.5 eq.), 1-dimethylallyl alcohol (184 μl,1.8mmol,4.5 eq.); however, the method is thatThen sealing the reaction bottle and placing the reaction bottle in an oil bath at 100 ℃; after 30 minutes of reaction, the reaction mixture was cooled to room temperature and 1mL of saturated NaHCO was added 3 The aqueous solution was then stirred for 5 minutes; the crude reaction was then filtered through celite and washed with ethyl acetate (30 mL); the filtrate was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL) and brine (10 mL); combining the organic phases with anhydrous Na 2 SO 4 The organic phase was dried, filtered and concentrated in vacuo at 30 ℃ to afford the crude product; after purification by flash column chromatography (PE: ea=8:1 to 2:1), the title compound was obtained (58.7 mg,92% yield).
(E) -2-methyl-4- (thiophen-3-yl) but-3-en-2-ol structural data characterization:
1 H NMR(400MHz,CDCl 3 )δ7.27(dd,J＝5.1,2.9Hz,1H),7.21(dd,J＝5.1,1.2Hz,1H),7.14(dd,J＝3.0,1.2Hz,1H),6.60(d,J＝16.1Hz,1H),6.22(d,J＝16.0Hz,1H),1.41(s,6H)；
13 C NMR(100MHz,CDCl 3 )δ139.49,137.40,126.09,124.95,121.94,120.72,70.98,29.87；
IR(KBr):3855.32,3512.80,3288.92,3194.79,3047.73,2837.25,2638.89,2348.34,1402.00,1141.69,982.26,832.22,724.20,656.28,521.57cm -1 .
as a further aspect of the present invention, the saturated sodium bicarbonate solution may be replaced with potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, calcium phosphate.
As a further aspect of the present invention, the tri-t-butylphosphine may be replaced with triphenylphosphine, trimethylphosphine, tris (o-methylphenyl) phosphine, tricyclohexylphosphine, tricyclohexylfluoroborate, tri-N-butylphosphine, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, bis (2-diphenylphosphinophenyl) ether, tris (2-furyl) phosphine, tri-t-butylphosphine tetrafluoroborate, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 2- (di-t-butylphosphine) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ' - (N, N-dimethylamine) -biphenyl, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, N-butylbis (1-adamantyl) phosphine, 1' -bis (diisopropylphosphine) ferrocene, R- (+) -1,1' -bis (diphenylphosphine), 2' -bis (diphenylphosphine) biphenyl, 2' -bis (diphenylphosphine), 1, 4' -bis (diphenylphosphine, 2' -bis (diphenylphosphine) biphenyl, 2' -dicyclohexylphosphine-2 ' - (N, N-dimethylamine) -biphenyl, 2' -dicyclohexylphosphine-4 ' -diphenyl phosphine, 4' -diphenyl ether, 4',6' -triisopropylbiphenyl, tetraphenylphosphine palladium chloride, bis (tri-t-butylphosphine) palladium, [1,1' -bis (di-t-butylphosphine) ferrocene ] palladium (II) dichloride or no ligand added.
As a further scheme of the invention, the triethylamine can be replaced by tri-N-propylamine, N-diisopropylethylamine, N-diethylaniline, tri-N-octylamine and N, N-cyclohexylmethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylenediamine, N-methyldicyclohexylamine, tetrabutylammonium hydroxide, potassium acetate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, calcium phosphate, or no base is added.
As a further scheme of the invention, the toluene can replace tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, benzene, xylene, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, 1, 2-dichloroethane, polyethylene glycol, acetonitrile, chlorobenzene, dimethyl sulfoxide or no solvent is added.
As a further scheme of the invention, the reaction temperature in the synthesis process is between 40 ℃ and 145 ℃.
As a further aspect of the present invention, the bromosubstrate is:
or other similar bromosubstrates.
As a further aspect of the present invention, the olefinic compound is:
or other olefinic compounds.

Claims (2)

1. The synthesis method of the compound E-subenol containing dimethyl enol group is characterized by comprising the following steps:
preparation of E-subenol
Under the protection of nitrogen, adding a magneton and a condenser into a double-neck round bottom flask, and adding a bromosubstrate 3, bis (tri-tertiary butyl phosphine) palladium (0), toluene, triethylamine and an olefin compound 4; then sealing the reaction bottle and placing the reaction bottle in an oil bath at 40-90 ℃; after the reaction was completed, the reaction mixture was cooled to room temperature and NaHCO was added thereto 3 The aqueous solution was then stirred for 5 minutes; insoluble solids were removed by transfer through a short column of silica gel with ethyl acetate and washed with ethyl acetate; the filtrate was diluted with ethyl acetate and extracted 3 times with water, 1 time with saturated sodium chloride; the combined organic layers were treated with anhydrous Na 2 SO 4 Drying, filtering the organic phase, and concentrating to obtain a crude product; and (3) carrying out column chromatography purification by a wet method to obtain the compound E-subenol.
2. The method for synthesizing a compound E-subenol containing a dimethyl enol group according to claim 1, wherein: the reaction temperature during the synthesis was 90 ℃.
CN202211226668.9A 2022-10-09 2022-10-09 Synthesis method of compound containing dimethyl enol group Active CN115477631B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211226668.9A CN115477631B (en) 2022-10-09 2022-10-09 Synthesis method of compound containing dimethyl enol group

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211226668.9A CN115477631B (en) 2022-10-09 2022-10-09 Synthesis method of compound containing dimethyl enol group

Publications (2)

Publication Number Publication Date
CN115477631A CN115477631A (en) 2022-12-16
CN115477631B true CN115477631B (en) 2024-02-09

Family

ID=84393773

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211226668.9A Active CN115477631B (en) 2022-10-09 2022-10-09 Synthesis method of compound containing dimethyl enol group

Country Status (1)

Country Link
CN (1) CN115477631B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111825537A (en) * 2019-04-15 2020-10-27 四川大学 Method for efficiently synthesizing alpha, beta-unsaturated aldehyde without synthesis gas
CN114539123A (en) * 2022-02-28 2022-05-27 大理大学 Method for synthesizing TMC-205 in one step

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111825537A (en) * 2019-04-15 2020-10-27 四川大学 Method for efficiently synthesizing alpha, beta-unsaturated aldehyde without synthesis gas
CN114539123A (en) * 2022-02-28 2022-05-27 大理大学 Method for synthesizing TMC-205 in one step

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors";Mark W. Irvine et al;Neurochemistry International;第61卷;第593–600 页 *
"Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes";Alexandre Guthertz et al;J. Am.Chem. Soc.;第140卷;第3156-3169页 *

Also Published As

Publication number Publication date
CN115477631A (en) 2022-12-16

Similar Documents

Publication Publication Date Title
Hermeke et al. Phosphonium ion tagged chiral phosphoric acids and their application in Friedel–Crafts reactions of indoles
Xie et al. Aza-Michael addition reactions between nitroolefins and benzotriazole catalyzed by MCM-41 immobilized heteropoly acids in water
Li et al. Phosphine-containing Lewis base catalyzed cyclization of benzofuranone type electron-deficient alkenes with allenoates: a facile synthesis of spirocyclic benzofuranones
Srivastava et al. Direct sulfonylation of Baylis–Hillman alcohols and diarylmethanols with TosMIC in ionic liquid-[Hmim] HSO4: an unexpected reaction
CN109265475B (en) Preparation method of polysubstituted aryl ethylene boronic acid pinacol ester derivative
CN104892614A (en) Synthesis method of 6H-isoindolo[2, 1-alpha]indol-6-one derivative
CN111592507A (en) Novel green and simple method for preparing polysubstituted furan
CN115477631B (en) Synthesis method of compound containing dimethyl enol group
Prasad et al. Synthesis of functionalized carbamates and quinones via sequential oxidation of salicylaldehydes using TBHP as the oxidant
CN111484436A (en) Method for introducing isopentenyl group to C3 position of indole
CN104710417B (en) Azaindole derivatives and synthesis method thereof
CN115477630B (en) Coumarin derivatives and preparation method thereof
Xu et al. Gallium trichloride-catalyzed conjugate addition of indole and pyrrole to α, β-unsaturated ketones in aqueous media
Shelke et al. Cellulose sulphuric acid as a biodegradable and reusable catalyst for the Knoevenagel condensation
Muthyala et al. Cu (OTf) 2 Catalyzed Synthesis of Bis (5‐methyl‐2‐furyl) methanes by Condensation of 2‐Methylfuran with Carbonyl Compounds under Solvent Free Conditions
CN113004233B (en) Compound for preparing PRC2 inhibitor, preparation method and application thereof
CN111018899B (en) Method for preparing 1, 1-boron alkyne compound by metal catalysis of terminal olefin
CN104803907B (en) A kind of indoles goes the method that aromatization is combined to substituted cyclopropane compound
CN106631887B (en) A kind of preparation technology of (1R, 2S) 1 cyano group 2 (3,4 difluorophenyl) cyclopropane
CN105001163A (en) Tetra-substituted imidazole synthesis method
CN111233616A (en) Pyrenyl [4] helicene and synthesis method and application thereof
Achari et al. Conformationally rigid chiral ferrocene derivative: Synthesis, resolution and stereochemical assignment
Morikawa et al. Sc (OTf) 3-catalyzed cyclooligomerization of 2, 4-dialkoxybenzyl alcohols. Formation of resorcin [n] arene peralkyl ethers
CN110668960A (en) Preparation method of alpha-aryl alpha-aminoketone compound
Yang et al. Synthesis and separation of the atropisomers of 2-(5-benzo [b] fluorenyl)-2′-hydroxy-1, 1′-binaphthyl and related compounds

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant