阅读说明：本技术 一种无合成气的高效合成α,β-不饱和醛的方法 (Method for efficiently synthesizing alpha, beta-unsaturated aldehyde without synthesis gas ) 是由 游劲松 谭光映 吴祎民 师洋 兰静波 高戈 杨宇东 于 2019-04-15 设计创作，主要内容包括：本发明涉及一种高效合成α,β-不饱和醛的方法。本专利所述的简单烷基醛与炔烃之间的氢甲酰基转移反应,利用廉价易得的正丁醛作为氢甲酰基的供体,能将一系列炔烃高效快速地转化为α,β-不饱和醛。与传统的氢甲酰化反应体系相比,该方法无需使用易燃易爆的合成气,无需使用特制装置容纳合成气,采用商业可得的催化剂和配体,操作简便,条件温和,成本低廉,饱和醛和炔烃氢化产物等副反应产物被彻底抑制,具有专一的化学选择性以及优良的区域选择性和立体选择性,存在巨大的应用潜力。(The invention relates to a method for efficiently synthesizing alpha, beta-unsaturated aldehyde. According to the hydrogen formyl transfer reaction between simple alkyl aldehyde and alkyne, n-butyl aldehyde which is cheap and easy to obtain is used as a donor of hydrogen formyl, and a series of alkyne can be efficiently and quickly converted into alpha, beta-unsaturated aldehyde. Compared with the traditional hydroformylation reaction system, the method does not need to use flammable and explosive synthesis gas, does not need to use a special device to contain the synthesis gas, adopts commercially available catalysts and ligands, has simple and convenient operation, mild conditions and low cost, thoroughly inhibits side reaction products such as saturated aldehyde and alkyne hydrogenation products, has specific chemical selectivity, excellent regioselectivity and stereoselectivity, and has huge application potential.)

1. a process for producing an α, β -unsaturated aldehyde compound, characterized by comprising the steps of:

(1) adding a catalyst, a phosphine ligand, an additive, an internal alkyne derivative, aldehyde and a solvent into a clean and dry reactor, uniformly mixing at room temperature, and then reacting at-40-160 ℃ for 0.1-720 hours under anhydrous and anaerobic conditions;

(2) after the reaction, the reaction tube was cooled to room temperature, dichloromethane was added to dilute the reaction system, and the reaction system was further filtered through celite, washed with dichloromethane, the filtrates were combined, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography.

2. The synthesis method according to claim 1, wherein the general structural formula of the alkynes derivatives in the step (1) is:

R¹，R²are each alkyl, aryl, steroid or R¹And R²The carbon chain of the alkyl is a straight chain, a branched chain or a cyclic chain with the carbon number of 0-40.

3. The method of claim 1, wherein the aldehyde in step (1) has the general structural formula of one of:

R-CHO

r is alkyl, wherein the carbon chain of the alkyl is a straight chain, a branched chain or a cyclic chain with the carbon number of 0-40.

4. The process according to claim 1, wherein the catalyst in the step (1) is palladium on carbon, tetrakis (triphenylphosphine) palladium, palladium acetate, palladium chloride, bis (acetonitrile) palladium dichloride, bis (benzonitrile) palladium dichloride, 1' -bis (diphenylphosphino) ferrocene palladium dichloride, bis (triphenylphosphine) palladium dichloride, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, allylpalladium (II) chloride dimer, (1, 5-cyclooctadiene) palladium (II) dichloride, rhodium on carbon, rhodium trichloride, rhodium acetate, acetylacetonatocarbonyltriphenylphosphine rhodium, bicyclooctenylrhodium chloride dimer, cyclopentadienylmethoxyrhodium dimer, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, triphenylphosphine rhodium chloride, ruthenium trichloride, triphenylphosphine ruthenium chloride, dichlorodicarbonylbis (triphenylphosphine) ruthenium, One or more of bis (2-methylallyl) (1, 5-cyclooctadiene) ruthenium (II) and p-cymene ruthenium dichloride dimer.

5. The production process according to claim 1, wherein the phosphine ligand in the step (1) is S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, triethyl phosphonoacetate, R-binaphthol phosphate, 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl, diphenylphosphorylazide, R- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, 2-chloro-2-oxo-1, 3, 2-dioxaphospholane, 1-propylphosphoric anhydride, S-binaphthol phosphate, 2-dicyclohexylphosphorus-2 ' -methylbiphenyl, 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1, 1 '-biphenyl, tetraethyl p-xylylenediphosphate, 2- (1, 3-dioxane-2-yl) ethyltriphenylphosphonium bromide, 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, 2- (di-t-butylphosphine) -1,1' -binaphthyl, 1, 2-bis (dimethylphosphine) ethane, one or more of diethyl cyanophosphate, isopropenyl-2, 3-dihydroxy-1, 4-bis-diphenylphosphinobutane, (1-pentyl) triphenyl phosphonium bromide, 2- (diphenylhydroxyphosphinylene) ethyltriethoxysilane, - (-) - (3, 5-dioxo-4-phosph-cyclohepta [2,1-A:3,4-A' ] dinaphthalen-4-yl) dimethylamine.

6. The production process according to claim 1, wherein the additive in the step (1) is pyridine, 2' -bipyridine, 1, 10-o-phenanthroline, triphenylphosphine, tri-tert-butylphosphine tetrafluoroborate, tricyclohexylphosphine tetrafluoroborate, 1' -binaphthyl-2, 2' -bisdiphenylphosphine, 2- (di-tert-butylphosphine) -1,1' -binaphthyl, 1, 2-bis (dimethylphosphine) ethane, bis (2-diphenylphosphinoethyl) phenylphosphine, n-butyl-bis (1-adamantyl) phosphorus, 1' -bis (diphenylphosphine) ferrocene, 1,2,3,4, 5-pentaphenyl-1 ' - (di-tert-butylphosphine) ferrocene, 2' -bis (di-3, 5-methylphenylphosphine) -1,1 '-binaphthyl, N-dimethyl-1- (2-diphenylphosphino) ferroceneethylamine, 1' - (diphenylphosphino) propane, 4-nitrobenzoic acid, diphenyl (2,4, 6-trimethylbenzoyl) phosphine oxide, silver hexafluoroantimonate, L-proline, pivalic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, sodium carbonate, potassium hydrogencarbonate, sodium bicarbonate, potassium carbonate, cesium pivalate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, dipotassium hydrogen phosphate, sodium acetate, potassium acetate, diethylamine, triethylamine, diisopropylamine, cyclohexanediamine, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, hexamethylenetetramine, tetramethyldiethylamine, dimethyldiethylamine.

7. The method according to claim 1, wherein the solvent in step (1) is one or more selected from methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, diethyl ether, dimethyl sulfoxide, benzene, o-dichlorobenzene, chlorobenzene, toluene, xylene, mesitylene, cyclohexane, petroleum ether, t-amyl alcohol, 1, 4-dioxane, 1, 2-dichloroethane, N-dimethylformamide, and N, N-dimethylacetamide.

8. The method according to claim 1, wherein the molar ratio of the alkynes derivative, n-butyraldehyde, the catalyst, the ligand and the additive in the step (1) is 1 (0.01-50): 0.01-10): 0.01-100): 0.01-200.

9. The method according to claim 1, wherein the reaction concentration of the acetylenic derivative in the step (1) is 0.0001-10 mol/L.

Technical Field

The invention relates to a method for efficiently synthesizing alpha, beta-unsaturated aldehyde without synthesis gas.

Background

α, β -unsaturated aldehydes are an important class of synthetic intermediates in the field of organic synthesis, and are often used in the synthesis of pesticides, pharmaceuticals, bioactive molecules and fine chemicals [ see: (a) G.Glorius in Science of Synthesis, Vol.25(Ed.: R.Bruckner), Georg Thieme, Stuttgart,2007, p.733; (b) d.j.rowe, perfum.flavour.2000, 25,1 ].

Among many methods for synthesizing α, β -unsaturated aldehydes, hydroformylation of alkynes is considered to be one of the most efficient and rapid synthetic strategies for constructing unsaturated aldehydes, and has received great attention from synthetic chemists. In the last decades, a series of catalytic systems for synthesizing α, β -unsaturated aldehydes by means of alkyne hydroformylation have been reported, wherein Buchwald, Hidai, Alper, Beller, Breit, zhang, etc. have conducted pioneering research [ see: (a) j.r.johnson, g.d.cuny, s.l.buchwald, angelw.chem.1995, 107, 1877; angew.chem.int.ed.engl.1995,34,1760; (b) y.ishii, k.miyashita, k.kamita, m.hidai, j.am.chem.soc.1997,119, 6448; (c) g.vanden Hoven, h.alper, j.org.chem.1999,64,3964; (d) g.van den Hoven, h.alper, j.org.chem.1999,64,9640; (e) x.fang, m.zhang, r.jackstell, m.beller, angelw.chem.2013, 125, 4743; angew.chem.int.ed.2013,52,4645; (f) v. agabekov, w.seiche, b.breit, chem.sci.2013,4,2418; (g) z.zhang, q.wang, c.chen, z.han, x. -q.dong, x.zhang, org.lett.2016,18,3290.]All of these methods involve alkyne and CO, H₂And reacting together to produce the aldehyde compound. Despite the great success in the related art, two important factors seriously affect the further application of hydroformylation reactions: first, despite the synthesis gas (CO: H)₂1: 1) the catalyst is cheap and abundant, but has high toxicity, flammability and explosiveness, and the reaction process needs high-pressure synthesis gas, so special equipment is needed to contain the high-pressure synthesis gas; in addition, compared to the hydroformylation of olefins, the hydroformylation of alkynes is more challenging, the regioselectivity of the reaction is difficult to control, and the production of side reaction products, such as hydrogenation products of alkynes and saturated aldehydes, is difficult to suppress [ see: (a) natta, P.Pino, The 12th International Congress of Pure and Applied Chemistry, New York, September 1951; (b) greenfield, j.h.wotiz, i.wender, j.org.chem.1957,22,542; (c) b.fell, m.beutler,Tetrahedron Lett.1972,13,3455；(d)C.Botteghi,C.Salomon,TetrahedronLett.1974,15,4285；(e)K.Doyama,T.Joh,T.Shiohara,S.Takahashi,Bull.Chem.Soc.Jpn.1988,61,4353；(f)P.G.M.Wuts,A.R.Ritter,J.Org.Chem.1989,54,5180；(g)E.M.Campi,W.R.Jackson,Y.Nilsson,Tetrahedron Lett.1991,32,1093；(h)P.Nombel,N.Lugan,F.Mulla,G.Lavigne,Organometallics 1994,13,4673.]. In view of the importance of hydroformylation in the fields of experimental research and industrial application, as one of the most challenging issues in the field of synthetic chemistry, it is of great significance to develop hydroformylation reactions with controllable selectivity and without the participation of synthesis gas.

The method realizes the hydrogen formyl transfer reaction between simple alkyl aldehyde and alkyne, the reaction uses cheap and easily obtained n-butyl aldehyde as the donor of hydrogen formyl, synthesis gas is not required to be used as the source of hydrogen formyl, a special device is not required to contain the synthesis gas, commercially available catalysts and ligands are adopted, the operation is simple and convenient, the condition is mild, the cost is low, side reaction products such as saturated aldehyde and alkyne hydrogenation products are thoroughly inhibited, a series of alkyne can be efficiently and quickly converted into alpha, beta-unsaturated aldehyde, the method has excellent chemical selectivity, regioselectivity and Z/E selectivity, and has huge application potential.

Disclosure of Invention

The invention aims to develop a method for catalyzing alkyne hydroformylation reaction by rhodium, which is efficient and does not need synthesis gas.

The second purpose of the invention is to rapidly construct alpha, beta-unsaturated aldehyde compounds.

The technical scheme for solving the problem is to adopt the following raw materials and preparation routes.

(1) Adding a catalyst, a phosphine ligand, an additive, internal alkyne, aldehyde and a solvent into a clean and dry reactor, uniformly mixing at room temperature, and then reacting at-40-160 ℃ for 0.1-720 hours under anhydrous and oxygen-free conditions;

(2) after the reaction, the reaction tube was cooled to room temperature, dichloromethane was added to dilute the reaction system, and the reaction system was further filtered through celite, washed with dichloromethane, the filtrates were combined, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography.

Wherein the general structural formula of the internal alkyne is as follows:

R¹，R²are each alkyl, aryl, steroid or R¹And R²A linked macrocycle. Wherein the carbon chain of the alkyl is a straight chain, a branched chain or a cyclic chain with the carbon number of 0-40.

Wherein the aldehyde has the structural general formula:

R-CHO

r is alkyl. Wherein the carbon chain of the alkyl is a straight chain, a branched chain or a cyclic chain with the carbon number of 0-40.

In the step (1), the catalyst is palladium carbon, tetrakis (triphenylphosphine) palladium, palladium acetate, palladium chloride, bis (acetonitrile) palladium dichloride, bis (benzonitrile) palladium dichloride, 1' -bis (diphenylphosphino) ferrocene palladium dichloride, bis (triphenylphosphine) palladium dichloride, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, allylpalladium (II) chloride dimer, (1, 5-cyclooctadiene) palladium (II) dichloride, rhodium carbon, rhodium trichloride, rhodium acetate, acetylacetonatocarbonyltriphenylphosphine rhodium, dicyclooctenylrhodium chloride dimer, cyclopentadienylmethoxyrhodium dimer, dichloropentamethylcyclopentadienyl rhodium (III) dimer, triphenylphosphine rhodium chloride, ruthenium trichloride, triphenylphosphine ruthenium chloride, dichlorodicarbonylbis (triphenylphosphine) ruthenium, bis (2-methylallyl) (1, 5-cyclooctadiene) ruthenium (II) and p-cymene ruthenium dichloride dimer.

In the step (1), the phosphine ligand is S- (-) -1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, triethyl phosphorylacetate, R-binaphthol phosphate, 2-dicyclohexyl-2, 4, 6-triisopropyl-biphenyl, diphenyl azide phosphate, R- (+) -1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, 2-chloro-2-oxo-1, 3, 2-dioxaphospholane, 1-propyl phosphoric anhydride, S-binaphthol phosphate, 2-dicyclohexyl-2 '-methyl-biphenyl, 2-dicyclohexyl-2', 6 '-diisopropoxy-1, 1' -biphenyl, tetraethyl p-xylene diphosphate, ethyl phosphate, ethyl, 2- (1, 3-dioxane-2-yl) ethyltriphenylphosphonium bromide, 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, 2- (di-tert-butylphosphino) -1,1 '-binaphthyl, 1, 2-bis (dimethylphosphino) ethane, diethyl cyanophosphate, isopropenyl-2, 3-dihydroxy-1, 4-bisdiphenylphosphinobutane, (1-pentyl) triphenylphosphonium bromide, 2- (diphenylphosphineoyl) ethyltriethoxysilane, - (-) - (3, 5-dioxo-4-phosph-cyclohepta [2,1-A:3,4-A' ] dinaphthalene-4-yl) dimethylamine.

In the step (1), the additives are pyridine, 2 '-bipyridine, 1, 10-o-phenanthroline, triphenylphosphine, tri-tert-butylphosphine tetrafluoroborate, tricyclohexylphosphine tetrafluoroborate, 1' -binaphthyl-2, 2 '-bisdiphenylphosphine, 2- (di-tert-butylphosphino) -1,1' -binaphthyl, 1, 2-bis (dimethylphosphino) ethane, bis (2-diphenylphosphinoethyl) phenylphosphine, N-butyl-bis (1-adamantyl) phosphorus, 1 '-bis (diphenylphosphino) ferrocene, 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene, 2 '-bis (di-3, 5-methylphenylphosphine) -1,1' -binaphthyl, N-dimethyl-1- (2-diphenylphosphino) ferrocene ethylamine, N-methyl-ethyl ether, N-methyl ether, 1,1' - (diphenylphosphino) propane, 4-nitrobenzoic acid, diphenyl (2,4, 6-trimethylbenzoyl) phosphine oxide, silver hexafluoroantimonate, L-proline, pivalic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium carbonate, cesium pivalate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, dipotassium hydrogen phosphate, sodium acetate, potassium acetate, diethylamine, triethylamine, diisopropylamine, cyclohexanediamine, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, hexa (methylene) tetramine, tetramethyldiethylamine, dimethyldiethylamine.

In the step (1), the solvent is one or more of methanol, ethanol, tetrahydrofuran, dichloromethane, trichloromethane, diethyl ether, dimethyl sulfoxide, benzene, o-dichlorobenzene, chlorobenzene, toluene, xylene, mesitylene, cyclohexane, petroleum ether, tert-amyl alcohol, 1, 4-dioxane, 1, 2-dichloroethane, N-dimethylformamide and N, N-dimethylacetamide.

In the step (1), the molar ratio of the internal alkyne, the n-butyraldehyde, the catalyst, the ligand and the additive is 1 (0.01-50), 0.01-10, (0.01-100) and (0.01-200).

In the step (1), the reaction concentration of the internal alkyne is 0.0001-10 mol/L.

By nuclear magnetic resonance hydrogen spectroscopy (¹H NMR), carbon spectrum (¹³C NMR) and high resolution mass spectroscopy confirmed the structure of the α, β -unsaturated aldehyde compound (see figure 3). The detection instrument is as follows: agilent 400-MR DD2spectrometer, wherein TMS is internal standard, CDCl₃Is a solvent; shimadzu LCMS-IT-TOF (ESI) model high resolution mass spectrometer.

Compared with the existing alkyne hydroformylation reaction, the synthesis route used by the invention is simpler, more efficient and environment-friendly, and is embodied as follows:

1. the synthetic route of the invention avoids the use of synthesis gas, and the reaction operation is simpler and safer.

2. The synthetic route of the invention has specific chemoselectivity and excellent regioselectivity and stereoselectivity.

3. The synthetic route of the invention avoids alkyne hydrogenation and saturated aldehyde by-products in the traditional route.

Drawings

FIG. 1 is a drawing of an abstract;

FIG. 2 is a structural formula of an α, β -unsaturated aldehyde derivative provided by the present invention;

FIG. 3 is a chemical reaction formula for preparing an α, β -unsaturated aldehyde derivative;

FIG. 4 is a nuclear magnetic hydrogen spectrum of the compound (E) -2-heptyldec-2-enal of the present invention.

Detailed Description

The invention will be further described with reference to specific embodiments, which will aid in the understanding of the invention. It is not intended that the scope of the invention be limited thereby, but rather that the invention be defined by the claims appended hereto.