CN108610271A - A kind of Alpha-Methyl ketenes and its synthetic method - Google Patents
A kind of Alpha-Methyl ketenes and its synthetic method Download PDFInfo
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- CN108610271A CN108610271A CN201611127575.5A CN201611127575A CN108610271A CN 108610271 A CN108610271 A CN 108610271A CN 201611127575 A CN201611127575 A CN 201611127575A CN 108610271 A CN108610271 A CN 108610271A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Abstract
The invention discloses a kind of synthetic methods of α methyl ketenes.3 easily to prepare, with structure diversity and more reaction centers, 3 two alkylthio group, 2 propylene, 1 ketone and organic peroxide are raw material, and a step realizes methylating for ketenes α, and gained α methyl ketenes can further be converted into functionalization product.This method raw material is easy to get, is easy to operate, and synthetic reaction condition is mild, reaction efficiency is high, and functional group has diversity.
Description
Technical field
The invention discloses a kind of methods that ketenes is alpha-methylated.With bis- alkylthio group -2- propylene -1- ketone of 3,3- and organic mistake
Oxide is starting material, FeCl3For catalyst, in a heated condition, a step generates Alpha-Methyl ketenes.
Compared with the synthetic method alpha-methylated with the ketenes reported, raw material of the present invention is easy to get, is easy to operate, synthesis is anti-
Mild condition, efficient is answered, yield is in 50%-90%, and product has good stereoselectivity and functional group's diversity.
In the Alpha-Methyl ketenes skeleton structure that the present invention synthesizes alkylthio group be can further function dough group, can be with
As drug and the intermediate of chemical products structure.
Background technology
Methyl group is widely present in natural products and bioactive molecule, and can be converted into a series of important
Organic intermediate, such as ketone, ester, amide, nitrile (Angew.Chem.Int.Ed., 2013,52,12256；Chem.Rev., 2011,
111,5215).Therefore, the ring that methyl group is important in organic chemistry is introduced into different molecules.
Traditional methylation method be utilize electrophilic methylating reagent, as dimethyl suflfate, dimethyl carbonate, iodomethane,
Diazomethane etc., to O, S, C, the atoms such as N methylate.But it wherein generally requires that excessive highly basic is added, and methylates
Reagent toxicity is strong, big to human body and environmental hazard.Either utilize precious metal, such as ruthenium, rhodium, palladium.The present invention is with 3,3- bis-
Alkylthio group -2- propylene -1- ketone and organic peroxide are starting material, under molysite catalysis, one-step synthesis Alpha-Methyl ketenes.It is logical
Cross R in regulation and control 11、R2、R3、R4Substituent group synthesizes a series of Alpha-Methyl ketenes derivative of different structures.
Invention content
The purpose of the present invention is to provide a kind of raw materials to be easy to get, reaction condition is mild, wide adaptability, can simply and easily close
At the method for Alpha-Methyl ketenes 1.
To achieve the goals above, technical scheme is as follows：
It is that raw material is in organic solvent with molysite with 3,3-, bis- alkylthio group -2- propylene -1- ketone 2 and organic peroxide
Catalyst, 120 DEG C are reacted 1-48 hours.Routinely isolation and purification method carries out product separation and characterization after reaction, obtains
Alpha-Methyl ketenes derivative 1.
Technical solution is characterized in that：
1. bis- alkylthio group -2- propylene -1- ketone of 3,3- and organic peroxide are raw material
R1Selected from following group：R1Selected from following group：Acetyl group, ethoxy acyl group, cyano, methyl, contains pivaloyl group
The aryl-acyl of different substituents (one or two or more kinds in such as hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl),
2- naphthalenes acyl group, 2- furyls acyl group, 2- thienyls acyl group or 2- pyridyl group acyl groups；R2For carbon atom number be 1-4 alkyl or
Aryl；
2. organic peroxide is di-tert-butyl peroxide (DTBP), peroxidized t-butyl perbenzoate (TBPB), uncle
One or two or more kinds in butylhydroperoxide (TBHP)；
2. metallic catalyst is CuCl2、Cu(OH)2、CuCl、Cu2O、FeCl3、FeCl2、Fe(OAc)2、Fe(OTf)2、
FeBr2、FeSO4·H2O or Ag2CO3；Wherein, FeCl3It is best as catalyst effect.
3. reaction dissolvent is n,N-Dimethylformamide (DMF), n,N-dimethylacetamide (DMA), N- crassitudes
One or both of ketone (NMP), 1,2- dichloroethanes (DCE), methanol, chlorobenzene and 1,4- dioxane mixture；Wherein, instead
Should in aprotic polar solvent N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or chlorobenzene effect it is best.
4. the molar concentration of synthon 3 is 0.05-1.0M.
5. the reaction time is 0.1-48 hours.Wherein, optimum reacting time is 1-48 hours.
6. reaction temperature is 30-150 DEG C.Wherein, optimal reaction temperature is 60-150 DEG C.
The present invention has the following advantages：
1) synthon 3, bis- alkylthio group -2- propylene -1- ketone 2 of 3- have structure diversity, can be used for synthesizing different type
With the Alpha-Methyl ketenes derivative 1 of structure.
2) synthon 3, bis- alkylthio group -2- propylene -1- ketone 2 of 3- are easy to prepare, and it is cheap and easily-available to prepare raw material, of low cost,
It is easy to industrialized production.
3) synthetic reaction of Alpha-Methyl ketenes derivative 1 uses the FeX of the relatively low relative nontoxic of price2It is right as catalyst
It is environmental-friendly.
4) stereoselectivity and functional group's diversity that 1 product of Alpha-Methyl ketenes derivative has had, have a wide range of applications
Property.
6) in 1 skeleton structure of Alpha-Methyl ketenes derivative alkylthio group and carbonyl, ester group etc. be all can further functional group
The group of change, this structure can be as drug and the intermediates of chemical products structure.
In short, the present invention is next high using the structure diversity of 3,3-, bis- alkylthio group -2- propylene -1- ketone 2 and more reaction centers
The Alpha-Methyl ketenes derivative 1 of effect synthesis different type and structure, raw material is cheap and easily-available, obtains the furans containing multiple substituent groups
Ring structure, easy to operate, target product yield is high, and can further function dough.
Specific implementation mode
The present invention with 3,3-, bis- alkylthio group -2- propylene -1- ketone 2 and organic peroxide for raw material (synthon), with molysite
It is reacted under heating condition in organic solvent for catalyst, generates Alpha-Methyl ketenes derivative 1 (reaction equation 1).
Detailed process is：In 25mL schlenk pipes, 3,3-, bis- alkylthio group -2- propylene -1- ketone 2 is sequentially added under argon gas
(0.5mmol), molysite (relative to substrate 10mol%), organic peroxide (1.0mmol) and 2.0mL solvents, 120 DEG C of stirrings
20 hours.Lower removing Volatile Colstituent is depressurized after being cooled to room temperature, then (eluent is petroleum ether (60-90 with silica gel column chromatography separation
DEG C)/ethyl acetate, v/v=70:1) target product 1, is obtained.Target product is measured by nuclear magnetic resoance spectrum and high resolution mass spectrum
It is confirmed.
Contribute to further understand the present invention by following embodiments, but present disclosure is not limited to that.
Embodiment 1
In 25mL schlenk pipes, sequentially added under argon gas 3,3- dimethyl sulphur-based -2- propylene -1- ketone 2a (0.5mmol),
Ferric trichloride (10mol%), peroxidized t-butyl perbenzoate (1.0mmol) and 2.0mL n,N-Dimethylformamide, 120 DEG C are stirred
It mixes 20 hours.Lower removing Volatile Colstituent is depressurized after being cooled to room temperature, then (eluent is petroleum ether (60- with silica gel column chromatography separation
90 DEG C)/ethyl acetate, v/v=70:1) target product 1a (84mg, yield 70%), is obtained.Target product passes through nuclear magnetic resonance
Spectrum and high resolution mass spectrum measurement are confirmed.
Embodiment 2
In 25mL schlenk pipes, sequentially added under argon gas 3,3- dimethyl sulphur-based -2- propylene -1- ketone 2b (0.5mmol),
Ferric trichloride (10mol%), peroxidized t-butyl perbenzoate (1.0mmol) and 2.0mLN, dinethylformamide, 120 DEG C are stirred
It mixes 20 hours.Lower removing Volatile Colstituent is depressurized after being cooled to room temperature, then (eluent is petroleum ether (60- with silica gel column chromatography separation
90 DEG C)/ethyl acetate, v/v=70:1) target product 1b (53mg, yield 60%), is obtained.Target product passes through nuclear magnetic resonance
Spectrum and high resolution mass spectrum measurement are confirmed.
Embodiment 3
Reaction step is with operation with embodiment 2, and difference from Example 2 is, 3,3- dimethyl sulphur-based -2- propylene -1-
Ketone is 2c.Stop reaction, it is post-treated to obtain target product 1c (80mg, yield 60%).
Embodiment 4
Reaction step is with operation with embodiment 2, and difference from Example 2 is, 3,3- dimethyl sulphur-based -2- propylene -1-
Ketone is 2d.Stop reaction, it is post-treated to obtain target product 1d (89mg, yield 65%).
Embodiment 5
In 25mL schlenk pipes, Alpha-Methyl ketenes 1b (0.3mmol), hydrazine hydrate are sequentially added under nitrogen
(1.5mmol) and 2.0mL acetonitriles, 82 DEG C of stirring 20h.Lower removing Volatile Colstituent is depressurized after being cooled to room temperature, then uses silica gel column layer
(eluent is petroleum ether (60-90 DEG C)/ethyl acetate, v/v=5 for analysis separation:1) target product 3a (34mg, yield, are obtained
80%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measurement.
Embodiment 6
In 25mL schlenk pipes, Alpha-Methyl ketenes 1b (0.3mmol), guanidine nitrate (0.6mmol), hydrogen-oxygen are sequentially added
Change potassium (1.8mmol) and 2mL ethyl alcohol, 80 DEG C of stirring 22h.Lower removing Volatile Colstituent is depressurized after being cooled to room temperature, then uses silicagel column
(eluent is petroleum ether (60-90 DEG C)/ethyl acetate, v/v=5 to chromatography:1) target product 3a (36mg, yield, are obtained
70%).Target product is confirmed by nuclear magnetic resoance spectrum and high resolution mass spectrum measurement.
Claims (9)
1. a kind of Alpha-Methyl ketenes, molecular structural formula are as follows：
R1Selected from following group：Acetyl group, ethoxy acyl group, cyano, methyl, contains different substituents (on aryl at pivaloyl group
Substituent group is the one or two or more kinds in hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl etc.) aryl-acyl, 2- naphthalenes
Base acyl group, 2- furyls acyl group, 2- thienyls acyl group or 2- pyridyl group acyl groups；R2The alkyl or aryl for being 1-4 for carbon atom number.
2. the synthetic method of Alpha-Methyl ketenes described in a kind of claim 1, it is characterised in that：With bis- alkylthio group -2- propylene of 3,3- -
1- ketone 2 and organic peroxide are starting material, and molysite is catalyst, and under heating condition, a step generates Alpha-Methyl ketenes 1；
The molecular structural formula of 3,3- bis- alkylthio group -2- propylene -1- ketone 2 is as follows,
R1Selected from following group：Cyano, ethoxy acyl group, cyano, contains the different substituents (substituent group on aryl at second pivaloyl group
For the one or two or more kinds in hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl etc.) aryl-acyl, 2- naphthalenes acyl group,
2- furyls acyl group, 2- thienyls acyl group and 2- pyridyl group acyl groups；R2The alkyl or aryl for being 1-4 for carbon atom number；
Synthetic route as shown in following reaction equations,
3. synthetic method according to claim 2, it is characterised in that：
Wherein：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- and the molar ratio of organic peroxide are 1:1-1:5；
Metallic catalyst is CuCl2、Cu(OH)2、CuCl、Cu2O、FeCl3、FeCl2、Fe(OAc)2、Fe(OTf)2、FeBr2、
FeSO4·H2O or Ag2CO3In one or two or more kinds, 3,3- bis- alkylthio group -2- propylene -1- ketone 2 rub with metallic catalyst
You are than being 1:0.01-1:0.1；
Organic peroxide is di-tert-butyl peroxide (DTBP), peroxidized t-butyl perbenzoate (TBPB), t-butyl peroxy
Change the one or two or more kinds in hydrogen (TBHP)；
Reaction dissolvent is n,N-Dimethylformamide (DMF), n,N-Dimethylformamide (DMA), N-Methyl pyrrolidone
(NMP), one or more of 1,2- dichloroethanes (DCE), methanol, chlorobenzene and 1,4- dioxane mixture；3,3-
Molar concentration of the two alkylthio group -2- propylene -1- ketone in reaction dissolvent is 0.05-1.0M；
Reaction atmosphere is the one or two or more kinds in air, oxygen, nitrogen or argon gas；Reaction time is 0.1-48 hours；Instead
It is 30-150 DEG C to answer temperature.
4. synthetic method described in accordance with the claim 3, it is characterised in that：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- generates 1
Metallic catalyst is preferably FeCl in reaction3。
5. synthetic method described in accordance with the claim 3, it is characterised in that：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- generates 1
2 and the preferred molar ratio of metallic catalyst are 1 in reaction:0.02-1:0.1.
6. synthetic method described in accordance with the claim 3, it is characterised in that：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- generates 1
2 and the preferred molar ratio of organic peroxide are 1 in reaction:1.5-1:3.
7. synthetic method described in accordance with the claim 3, it is characterised in that：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- generates 1
Reaction preferably carries out in polar non-solute N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or chlorobenzene.
8. synthetic method described in accordance with the claim 3, it is characterised in that：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- generates 1
It is 1-48 hours to react optimum reacting time.
9. synthetic method described in accordance with the claim 3, it is characterised in that：Bis- alkylthio group -2- propylene -1- ketone 2 of 3,3- generates 1
It is 60-150 DEG C to react optimal reaction temperature.
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| CN113121438A (en) * | 2020-01-10 | 2021-07-16 | 安礼特（上海）医药科技有限公司 | Preparation method of isoquinolone compound |
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| CN113121438A (en) * | 2020-01-10 | 2021-07-16 | 安礼特（上海）医药科技有限公司 | Preparation method of isoquinolone compound |
| CN113121438B (en) * | 2020-01-10 | 2023-05-23 | 江苏希迪制药有限公司 | Preparation method of isoquinolinones compound |
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