Process for producing .alpha.,.beta.-unsaturated aldehydes

The present invention relates to a process for producing an .alpha.,.beta.-unsaturated aldehyde which comprises subjecting an allyl-hexamethylenetetraammonium derivative to hydrolysis in water and an organic solvent homogeneously immiscible with water. The resulting .alpha.,.beta.-unsaturated aldehyde is useful as medicaments, flavorings, etc., or as raw materials for their production.

FIELD OF THE INVENTION 
The present invention relates to a process for producing .alpha., 
.beta.-unsaturated aldehydes useful as medicaments, flavorings, etc., or 
as raw materials for their production. 
BACKGROUND OF THE INVENTION 
The following processes have been known for producing .alpha., 
.beta.-unsaturated aldehydes useful as medicaments, flavorings, etc., or 
as raw materials for their production. 
##STR1## 
Each of the above processes is problematic. For example, Method No. 1 is 
environmentally unsuitable because of dimethyl sulfide responsible for the 
bad smell produced in the reaction. The yield of the Method No.2 is quite 
low. Method Nos. 3, 4 and 5 involve many reaction steps, require severe 
reaction conditions or reagents which must be handled with great care, and 
produce the desired product in low yields. 
OBJECTS OF THE INVENTION 
The main object of the present invention is to provide a process for 
readily producing .alpha., .beta.-unsaturated aldehydes in high yield and 
purity using inexpensive raw materials. 
This object as well as other objects and advantages of the present 
invention will become apparent to those skilled in the art from the 
following description. 
SUMMARY OF THE INVENTION 
The present inventors have intensively studied to achieve the above 
objects. As a result, it has been found that the above .alpha., 
.beta.-unsaturated aldehydes can be produced by hydrolyzing, in water and 
an organic solvent homogeneously immiscible with water, a quaternary 
ammonium salt composed of hexamethylenetetramine (hereinafter sometimes 
referred to as hexamine) and an optionally substituted allyl group 
attached to one nitrogen atom of the hexamine. 
In one aspect, the present invention provides a process for producing a 
compound of the formula (II): 
##STR2## 
wherein R.sup.1 and R.sup.2 are each hydrogen or an alkyl group, R.sup.3 
is hydrogen or an optionally substituted hydrocarbon group, and n is an 
integer of 1 to 10, which comprises subjecting a compound of the formula 
(I): 
##STR3## 
wherein X is halogen and the other symbols are as defined above, to 
hydrolysis in water and an organic solvent homogeneously immiscible with 
water. 
In another aspect, the present invention provides a process for producing a 
compound of the formula (II): 
##STR4## 
wherein R.sup.1 and R.sup.2 are each hydrogen or an alkyl group, R.sup.3 
is hydrogen or an optionally substituted hydrocarbon group, and n is an 
integer of 1 to 10, which comprises: 
reacting a compound of the formula (IV): 
##STR5## 
wherein X is halogen and the other symbols are as defined above, with 
hexamethylenetetramine in water and/or an organic solvent to give a 
compound of the formula (I): 
##STR6## 
wherein each symbol is as defined above and a compound of the formula 
(II): 
##STR7## 
wherein each symbol is as defined above; followed by, if necessary, adding 
water or organic solvent to the reaction mixture, and then separating the 
resultant mixture into aqueous and organic layers, and 
i) subjecting the resultant compound of the formula (I) in the aqueous 
layer to hydrolysis in the presence of an organic solvent homogeneously 
immiscible with water, while 
ii) reacting the resultant compound of the formula (II) in the organic 
layer with sodium hydrogensulfite to give a compound of the formula (III): 
##STR8## 
wherein each symbol is as defined above, and reacting the compound of the 
formula (III) with formaldehyde in water and an organic solvent 
homogeneously immiscible with water. 
Still in another aspect, the present invention provides a method of 
purifying a compound of the formula (II): 
##STR9## 
wherein R.sup.1 and R.sup.2 are each hydrogen or an alkyl group, R.sup.3 
is hydrogen or an optionally substituted hydrocarbon group, and n is an 
integer of 1 to 10, which comprises: 
reacting a compound of the formula (II) with sodium hydrogensulfite to give 
the compound of the formula (III): 
##STR10## 
wherein each symbol is as defined above, 
and reacting the compound of the formula (III) with formaldehyde in water 
and an organic solvent homogeneously immiscible with water.

DETAILED DESCRIPTION OF THE INVENTION 
The alkyl group represented by R.sup.1 or R.sup.2 includes, for example, 
straight-chain or branched alkyl groups, preferably straight-chain or 
branched alkyl groups having 1 to 6 carbon atoms. Examples of the alkyl 
group include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, 
tert-butyl, pentyl, hexyl, etc. Preferred examples are straight-chain or 
branched alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, 
propyl, isopropyl, etc. 
The hydrocarbon group of the optionally substituted hydrocarbon group 
represented by R.sup.3 includes, for example, alkyl groups, alkenyl 
groups, alkynyl groups, aryl groups, aralkyl groups, etc. Preferably, the 
hydrocarbon group is that having 1 to 20 carbon atoms. 
The alkyl group as the above hydrocarbon group includes, for example, the 
same alkyl groups as those represented by R.sup.1. The alkyl group is 
preferably a straight-chain or branched alkyl group having 1 to 6 carbon 
atoms. 
Preferred examples of the alkenyl group as the above hydrocarbon group 
include alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 
2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl, etc. 
Preferred examples of the alkynyl group as the above hydrocarbon group 
include alkynyl groups having 2 to 6 carbon atoms such as ethynyl, 
propargyl, 2-butyn-1-yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 
4-pentyn-2-yl, 3-hexyn-1-yl, etc. 
Preferred examples of the aryl group as the above hydrocarbon group include 
aryl groups having 6 to 10 carbon atoms such as phenyl, 1-naphthyl, 
2-naphthyl, etc. 
Preferred examples of the aralkyl group as the above hydrocarbon group 
include aralkyl groups having 7 to 19 carbon atoms such as benzyl, 
phenethyl, benzhydryl, 1-phenylpropyl, etc. 
The substituent of the above substituted hydrocarbon group include, for 
example, alkoxy groups, acyloxy groups, alkoxycarbonyl groups, a cyano 
group, an oxo group, a group of the formula: 
##STR11## 
wherein X is halogen. Each of these substituents may have 1 to 3 
appropriate substituents. 
Examples of the alkoxy groups as the substituent of the hydrocarbon group 
include C.sub.1-4 alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, 
etc. 
Preferred examples of the acyloxy groups as the substituent of the 
hydrocarbon group include acyloxy groups having 1 to 10 carbon atoms such 
as C.sub.1-10 alkyl-carbonyloxy groups (e.g., acetoxy, propionyloxy, 
butyryloxy, etc.), C.sub.6-10 aryl-carbonyloxy groups (e.g., benzoyloxy, 
naphthoyloxy, etc.), etc. 
Examples of the alkoxycarbonyl group as the substituent of the hydrocarbon 
group include C.sub.1-5 alkoxy-carbonyl groups such as methoxycarbony, 
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc. 
When the above hydrocarbon group is substituted, the number of the 
substituent is preferably 1 to 3. 
Examples of the halogen represented by X include chlorine, bromine, 
fluorine, iodine, etc. 
n is preferably an integer of 1 to 5, more preferably 1. 
Preferably, R.sup.1 is a methyl group. Preferably, R.sup.2 is hydrogen. 
Preferably, R.sup.3 is an acetoxymethyl group. 
In one aspect of the process of the present invention, the compound (I) 
subjected to hydrolysis in water and an organic solvent homogeneously 
immiscible with water to give the compound (II). 
Examples of the organic solvent include hydrocarbons (e.g., hexane, 
toluene, benzene, xylene, etc.), halogenated hydrocarbons (e.g., 
dichloromethane, 1,2-dichloroethane, chloroform, etc.), ethers (e.g., 
isopropyl ether, etc), esters (e.g., ethyl acetate, etc.); etc. Preferred 
examples of the organic solvent are hydrocarbons, halogenated hydrocarbons 
and ethers, more preferably toluene, dichloromethane and isopropyl ether. 
The amount of the organic solvent is preferably about 1 to about 3 times 
(v/v) the amount of the water. 
The amount of water to be,used is about 0.5 to about 2 liters per mol of 
the compound (I). 
As described above, the solvent used in the hydrolysis comprises water and 
the above organic solvent. Preferably, the hydrolysis is carried out while 
maintaining the pH of the solvent to about 4 to about 7. The pH may be 
adjusted, for example, by using an acid such as acetic acid, sulfuric 
acid, hydrochloric acid, ion-exchange resin (e.g., acidic 
resin.multidot.Na type), etc. The amount of the acid to be used is 
preferably about 0.5 to about 3 mol per mol of the compound (I). 
The reaction may be continued for about 1 to about 12 hours. The solvent 
may be separated every several hours, followed by newly adding the solvent 
for continuing the reaction. These operations may be repeated. For 
example, the solvent may newly be added about twice every 6 hours. The 
reaction temperature is room temperature (about 10.degree. C. to 
28.degree. C.) to about 100.degree. C., preferably about 60.degree. C. to 
about 80.degree. C. 
After completion of the reaction, the organic layer may be separated, the 
solvent may be evaporated, and then the residue may be distilled or 
purified by column chromatography. 
The compound (I) used as the starting material in the process can be 
obtained by reacting a compound of the formula (IV): 
##STR12## 
wherein each symbol is as defined above, with hexamine. Normally, the 
reaction is carried out in water at about 0.degree. C. to about 40.degree. 
C. to give an aqueous solution of the compound (I). The reaction time is 
about 3 to about 24 hours. The reaction may be carried out in an organic 
solvent to obtain the compound (I) in crystal form. In this case, the 
reaction temperature is about 0.degree. to about 100.degree. C., 
preferably about 20.degree. C. to about 60.degree. C. Examples of the 
solvent include halogenated hydrocarbons (e.g., dichloromethane, 
1,2-dichloroethane, chloroform, etc.), ethers (e.g., isopropyl ether, 
tetrahydrofuran, etc.), esters (e.g., ethyl acetate, etc.), amides (e.g., 
dimethylformamide, etc.), nitriles (e.g., acetonitrile, etc.), alcohols 
(e.g., methanol, ethanol, etc.), etc. In particular, chloroform, 
1,2-dichloromethane and acetonitrile are preferred. The amount of the 
solvent to be used is preferably about 0.5 to about 2 liters per mol of 
the compound (IV). The reaction time is about 3 to about 24 hours. 
In another aspect of the present invention, to purify the compound (II), 
the compound (II) containing reactants or impurities is reacted with 
sodium hydrogensulfite to give the hydrogensulfite adduct the compound 
(III), which is then reacted with formaldehyde in water and an organic 
solvent homogeneously immiscible with water to give the compound (II). 
This method gives a highly purified .alpha.,.beta.-unsaturated aldehyde in 
high yield. In particular, this method is useful for recovery of an 
.alpha.,.beta.-unsaturated aldehyde which is difficult to purify by the 
above process. 
As sodium hydrogensulfite, commercially available 35% aqueous solution 
thereof may be used as it is or after 1- to 3-fold dilution of the 
solution. The amount of the sodium hydrogensulfite to be used is 
preferably about 1 to about 2 mol per mol of the compound (II). The 
reaction giving the compound (III) is normally carried out in water, and 
the reaction temperature is preferably about 0.degree. C. to about 
50.degree. C. 
The reaction between the compound (III) and formaldehyde may be carried out 
in an organic solvent. Examples of the solvent include halogenated 
hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, chloroform, 
etc.), ethers (e.g., isopropyl ether, etc.), esters (e.g., ethyl acetate, 
etc.), etc. As the formaldehyde, a commercially available 37% aqueous 
solution thereof (i.e., formalin) can conveniently be used as it is. The 
amount of formaldehyde to be used is preferably about 1 to about 2 mol per 
mol of the compound (II). The reaction temperature is preferably about 
0.degree. C. to about 50.degree. C. The reaction time is preferably about 
0.5 to about 3 hours. 
After completion of the reaction, the reaction mixture is separated, the 
organic layer is dried over sodium sulfate, and the solvent is evaporated 
to give the desired .alpha.,.beta.-unsaturated aldehyde. 
As described above, according to the present invention, without using 
special apparatuses or reaction conditions, .alpha.,.beta.-unsaturated 
aldehydes of the formula (II) can readily be produced in high yield 
through a few steps using inexpensive raw materials and reagents which can 
easily be handled in industrial production. The process and method of the 
present invention can be used even for the production of .alpha., 
.beta.-unsaturated aldehydes having a substituent unstable to an acid or 
alkali. The .alpha.,.beta.-unsaturated aldehydes produced by the invention 
are useful as medicaments, flavorings, or raw materials for the production 
thereof. 
Further, the method or process of the present invention affords aldehydes 
in high purity which is difficult to purify by conventional purification 
techniques such as distillation, chromatography, etc. 
The following examples further illustrate the present invention in detail, 
but are not to be construed to limit the scope thereof. 
EXAMPLE 1 
1-Acetoxy-4-chloro-3-methyl-2-butene (7.8 g) was added to a suspension of 
hexamine (6.7 g) and acetonitrile (47 ml), and the mixture was stirred at 
room temperature for 16 hours. The precipitated crystals were separated by 
filtration to give crystals (12.5 g) of a quaternary ammonium salt. This 
salt (7.9 g) was dissolved in water (50 ml), and toluene (100 ml) was 
added. With stirring at 75.degree. C., acetic acid (1.5 g per addition) 
was added 30 minutes, 1 hour and 2 hours after the beginning of the 
reaction. The reaction was stopped 6 hours after the beginning of the 
reaction. The toluene layer was separated and concentrated, and the 
resulting residue was purified by column chromatography on silica gel to 
give 4-acetoxy-2-methyl-2-buten-1-al (2.6 g, 74%). 
EXAMPLE 2 
(a) Crude 1-acetoxy-4-chloro-3-methyl-2-butene (194 g, Purity: 83.8%, 1 
mol) was added to hexamine (168 g, 1.2 mol)/water (1 liter), and the 
mixture was stirred at 35.degree. C. for 4 hours and then separated into 
aqueous and organic layers. 1,2-Dichloroethane (1 liter) was added to the 
aqueous layer, and the mixture was subjected to reaction at 72.degree. C. 
for 6 hours while adjusting the pH with 1N sulfuric acid. The 
1,2-dichloroethane layer was separated, 1,2-dichloroethane (1 liter) was 
added to the aqueous layer, and the reaction was carried out again. The 
1,2-dichloroethane layers were combined and concentrated. The residue was 
distilled under reduced pressure to give 4-acetoxy-2-methyl-2-buten-1-al 
(98 g, 69%). bp..sub.0.2-0.3 mmHg: 58.degree.-66.degree. C. 
(b) Aqueous 35% sodium hydrogensulfite solution (9 g) and ice-cooled water 
(100 g) were added to the above organic layer (volume: 50 ml) containing 
4-acetoxy-2-methyl-2-buten-1-al (4.3 g, determined by gas chromatography). 
The mixture was stirred well, and the aqueous layer was separated. To the 
aqueous layer was added 1,2-dichloroethane (100 ml). To this mixture was 
added 37% aqueous formaldehyde solution (10 ml). The resulting mixture was 
stirred at 30.degree. to 40.degree. C. for 3 hours. The 1,2-dichloroethane 
layer was separated and concentrated to give 
4-acetoxy-2-methyl-2-buten-1-al (3.4 g, Recovery: 79%). Total yield 
((a)+(b)): 101.4 g (71.4% from 1-acetoxy-4-chloro-3-methyl-2-butene). 
EXAMPLE 3 
Cinnamyl chloride (8 g) was added to a suspension of hexamine (7.3 g) in 
acetonitrile (60 ml), and the mixture was stirred at room temperature for 
2 hours. The precipitated crystals were separated by filtration to give a 
quaternary ammonium salt (14.4 g). This salt (7.3 g) was dissolved in 
water (70 ml), toluene (70 ml) was added, and the mixture was treated 
according to the same manner as in Example 1 to give cinnamaldehyde (2.73 
g, 83%). 
EXAMPLE 4 
4-Bromo-1,1-dimethoxy-2-methyl-2-butene (2 g) was added to a solution of 
hexamine (1.7 g) and water (10 ml), and the mixture was stirred at room 
temperature for 14 hours. Dowex 50.times.8 (type H)(3 g) was previously 
treated with sodium chloride to convert it to type Na. Then isopropyl 
ether (20 ml) was added to the above reaction mixture, the type Na resin 
was added, and the mixture was stirred at 70.degree. C. for 6 hours. The 
isopropyl ether layer was separated, concentrated and purified by column 
chromatography to give 4,4-dimethoxy-2-methyl-2-buten-1-al (0.92 g, 64%). 
EXAMPLE 5 
Geranyl chloride (1 g) was added to a suspension of hexamine (1 g) and 
dichloromethane (10 ml), and the mixture was stirred at room temperature 
for 16 hours. The dichloromethane was evaporated, water (10 ml) and 
isopropyl ether (10 ml) were added to the residue. The mixture was stirred 
at 70.degree. C. while slowly dropping 1N sulfurinc acid (3 ml) therein. 
Treatment according the same manner as in Example 1 gave citral (0.62 g, 
80%). 
EXAMPLE 6 
1-Bromo-3-carbomethoxy-2-butene (2 g) was added to a suspension of hexamine 
(1.7 g) and dichloromethane (10 ml), and the mixture was stirred at room 
temperature for 16 hours. Then the dichloromethane was evaporated, water 
(10 ml) and isopropyl ether (10 ml) were added to the residue, acetic acid 
(1.8 ml) was added, the mixture was stirred at 70.degree. C. for 6 hours 
and treated according to the same manner as in Example 1 to give 
3-carbomethoxy-2-buten-1-al (0.83 g, 65%). 
EXAMPLE 7 
Methyl 4-bromo-3-methyl-2-butenoate (2 g) was treated according to the same 
manner as in Example 6 to give methyl 3-formyl-2-butenoate (0.98 g, 77%).