Method for the preparation of a , /3-unsaturated ketones

Technical Field:

This invention relates to a method for the preparation of a , β-unsaturated ketones represented by general formula (II)

(where R is a heterocyclic group with nitrogen atom in the ring or a phenyl group with electron donative substituents) (hereinafter referred to as Compound II). Compound (II) is extremely important as an intermediate for pharmaceuticals and agricultural chemicals.

Background Art:

Conventionally known methods for the preparation of Comound I include a synthetic method by aldol condensation of aldehyde and acetone (described in such documents as Ber. 353569 (1902)) and a method that aldehyde and acetoacetate are Knovenagel condensed, hydrolyzed and decarboxylated (described in such documents as J. Org. Chem. 22 1451 (1957) 3 . The methods are not applicable to industrial manufacturing since the yield is generally low.

An object of this invention is to provide methods for the preparation of a , β -unsaturated ketones which are excellent as industrial manufacturing methods.

Disclosure of Invention:

The inventors carried out varaious studies to accomplish the above purpose, and found that Coumpound (II) can be obtained with good yield by reacting specific

aldehydes with acetone, in a water solvent, using specific catalysts, while heating, and thus have accomplished this invention.

That is, this invention is a method for the preparation of a , β-unsaturated ketones represented by general formula (II)

(where R is a heterocyclic group with nitrogen atom in the ring or a phenyl group with electron donative substituents) which comprises reacting aldehydes represented by general formula (I)

RCHO (I)

(where R is as defined above) with acetone, in the presence as a catalyst of one or two or more compounds selected from the group consisting of perhydroisoindole and pyrrolidine which may have substituents, in a water solvent, at 20°C to 40°C, and

« then reacting at the reflux temperature.

Aldehydes represented by general formula (I)

RCHO (I)

(where R is as defined above) (hereinafter referred to as Compound II) and used in this invention include benzaldehydes with electron donative substituents such as p- (N,N-dimethylamino) benzaldehyde and 2,4, 6-trimethylbenzaldehyde. and heterocyclic aldehydes with nirogen atom in the ring such as 2-pyridine carbaldehyde, 3-pyridine carbaldehyde and 4-pyridine carbaldehyde.

Compounds used as catalyst include perhydroisoindole and pyrrolidine represented by the following formula which may be substituted.

(where Ri, R ₂ , R ₃ and R . are hydrogen or lower al iphatic groups).

Their concrete examp les are pyrrol idine and pyrrol idines subst i tuted at the 3 and/or 4 pos i t i ons such as 3-methy l pyrro l ϊ d ine, 3-e thy l pyrro l i d i ne, 3, 3-

diraethylpyrrolidine, 3, 3-diethylρyrrolidine, 3, 4-dimethylpyrrolidine and 3,4- dϊethylpyrrolidine.

Two or more of these catalysts can be used by mixing. Water is indispensable as a catalyst. A reaction in an organic solvent results in extremely low yield.

(1) RCHO + CH»CCHs ^ RCHCH ₂ CCH ₃

II I II

0 OH 0

(2) RCHCH2CCH3 ~∑∑L RCH=CHCCH ₃ + H ₂ 0

I II II

OH 0 0

The reaction proceeds according to the above reaction equations (1) and (2). If R is a heterocyclic group containing N in the ring such as pyridyl group, Reaction (2) proceeds more, and , β-unsaturated ketones are formed from β - hydroxyketones during the addition reaction or post treatment. Therefore, it is difficult to isolate £-hydroxyketones. , β-unsaturated ketones may be formed by addition reaction at room temperature followed by dehydration with strong acid. However it is rather preferable to convert from S-hydroxyketones to a , β - unsaturated ketones by heating during the addition reaction.

If R is a phenyl group with electron donative substituents such as N- dimethylamino group or trimethyl group, the equilibrium of (1) shifts to the aldehyde side, and the reaction does not proceed. Therefore Rection (2) is advanced by heating and the equilibrium is shifted to synthesize a , #-unsaturated ketones.

A way of implementing the preparation method for compound I is described in detail in the following.

1.5 to 20 times moles, preferably 3 to 10 times moles, to a mole of Compound II, of acetone; 50 to 2000ml, prefeerably 200 to 500ml, to a mole of Compound II, of water; and 0.002 to 0.1 moles, preferably 0.01 to 0.05 moles, to a mole of Compound II, of catalyst are mixed. Into the resulting mixture is dropped a mole of Compound II at 20 to 40°C over 0.5 to 5 hours, then the mixture is kept stirring under reflux for 0.5 to 7 hours.

After the reaction is completed, the reaction solution is neutralized with acid such as hydrochloric acid to pH 1 to 6, acetone is distilled and recovered. Then the residue is extracted with water-insoluble organic solvent such as chloroform or toluene. The extract is concentrated and distilled under vacuum to give the intended Compound I.

Best Mode for carrying Out the Invention:

This invention is further described in detail by reference to the following examples. The range of this invention is not limited at all by the following examples.

Example 1

Into a reaction vessel of li in inside volume were placed 290.5g (5 moles) of acetone, 300ml of water and 3.6g (0.05 moles) of pyrrolidine, to which 149.2g (1 mole) of p-(N,N-dimethylamino) benzaldehyde was dropped over an hour while keeping at 30 °C. Then the resulting solution was stirred under reflux for 9 hours.

The solution was neutralized with concentrated hydrochloric acid up to pH 4.5, and heated to distill up to the distillation temperature of 100 °C. Then 300ml of chloroform was added, and the solution was neutralized with 28% NaOH aqueous solution to pH 12 and separated.

Furthermore, the aqueous layer was extracted with 200ml of chloroform twice. The obtained chloroform layers were combined to the previous chloroform layer to concentrate. The obtained crystal was recrystal1ized from a mixture solvent of benzene and hexane to give 113.6g (crude yield: 60.0%) of yellow crystal with melting point of 137.5 to 140.5 °C.

The crystal was analyzed by gas chromatography to find that the intended product, 4- (ρ-(N,N-dimethylamino) phenyl) -3-butene-2-one, was 97.8% in purity. (Yield: 58.7% to ρ-(N,N-dimethylamino) benzaldehyde)

Example 2

Into a reaction vessel of 300ml in inside volume were placed 87.2g (1.5 moles) of acetone, 90ml of water and 2.Og (0.02 moles) of 3, 3-dimethylpyrrolidine, to which 29.6g (0.2 mole) of 2, 4, 6-trimethylbenzaldehyde was dropped over an hour while keeping at 30 °C. Then the resulting solution was stirred under reflux for 7 hours.

The solution was adjusted the pH to 4.5 with concentrated hydrochloric acid, and heated to distill up to the distillation temperature of 100 °C. Then 80ml of chloroform was added to the resulting solution to extract and the solution was separaated. The toluene layer was concentrated. The obtained extract was distilled under reduced pressure to give distillate with boiling point of 94 to 96°C at 0.02mmHg. This distillate crystallized after the distillation to give 27. lg of yellow crystal with boiling point of 64 to 69 °C (crude yield: 72.0%).

The crystal was analyzed by gas chromatography to find that the intended product, 4-(2, 4, 6-trimethylphenyl)-3-butene-2-one, was 94.8% in purity. (Yield: 68.3% to 2,4, 6-trimethylbenzaldehyde)

Example 3

Into a reaction vessel of 1 £ in inside volume were placed 290.5g (5 moles) of acetone, 300ml of water and 3.6g (0.05 moles) of pyrrolidine, to which 107. lg (1 mole) of 3-pyridine carbaldehyde was dropped over an hour while keeping at 30°C. Then the resulting solution was stirred under reflux for 8 hours.

After the reaction was completed, concentrated hydrochloric acid was dropped to make the pH 4.5, and the solution was heated to distill up to the distillation temperature of 100°C. Then 300ml of chloroform was added, and the solution was neutralized with 28% NaOH aqueous solution to pH 12 and separated. Furthermore, the aqueous layer was extracted with 200ml of chloroform twice.

The obtained chloroform layers were combined to the previous chloroform layer to concentrate. The obtained extract was distilled under reduced pressure to give 122.8g (crude yield: 83.4%) of yellow extract with boiling point of 113. °C at

1. lmmHg and n^ ⁸ 1.5941.

The extract was analyzed by gas chromatography to find that the intended product, 4-(3-ρyridyl)-3-butene-2-one, was 94.9% in purity. (Yield: 79.1% to 3- pyridine carbaldehyde)

Industrial Applicability:

This invention is to provide methods for the preparation of a, /3-unsaturated ketones having heterocyclic groups with nitrogen atom in the ring or phenyl groups with electron donative substituents, which are difficult to synthesize, from corresponding aldehydes andacetone, with good yield. The invention is greatly significant in industry.