Process for producing 1-(p-prenylphenyl)ethanol

A process for producing 1-(p-prenylphenyl)ethanol, which comprises reacting p-chloroprenylbenzene with magnesium at a temperature between 100.degree. C. and 150.degree. C. to form a Grignard reagent, and then reacting it with acetaldehyde.

This invention relates to a novel and improved process for producing 
1-(p-prenylphenyl)ethanol. 
1-(p-Prenylphenyl)ethanol is a known compound useful as a synthesis 
intermediate for 2-(p-prenylphenyl) propionic acid which has excellent 
anti-inflammatory and analgesic activities and reduced gastrointestinal 
action. It is known that 1-(p-prenylphenyl)ethanol can be produced by 
reacting a starting p-haloacetophenone ketal such as 
2-(p-bromophenyl)-2-methyl-1,3-dioxolane with magnesium in accordance with 
the following scheme to prepare a Grignard reagent, reacting it with a 
prenyl halide, subjecting the resulting 
2-methyl-2-(p-prenylphenyl)-1,3-dioxolane to acid hydrolysis to form 
p-prenylacetophenone, and reducing it with a metal hydride such as sodium 
borohydride or lithium aluminum hydride (see U.S. Pat. No. 4,251,543). 
##STR1## 
The method for producing 1-(p-prenylphenyl)ethanol shown above has the 
defect that the starting 2-(p-bromophenyl)-2-methyl-1,3-dioxolane is 
expensive because it is produced through acetylation of bromobenzene and 
ketalization, and that the operation is complex because a large amount of 
a crystalline by-product forms during the Grignard reaction. 
We studied a useful method of producing 1-(p-prenylphenyl)ethanol from an 
industrially more easily available material through a shorter route. As a 
result, we hit upon an idea of reacting a Grignard reagent, obtained by 
the reaction of p-chloroprenylbenzene reagent with metallic magnesium, 
with acetaldehyde, and experimentally performed this reaction. 
As regards the preparation of a Grignard reagent from p-chloroprenylbenzene 
with metallic magnesium, Lee B. Jones et al. reported that they prepared 
the Grignard reagent in tetrahydrofuran in the same way as in the 
preparation of a Grignard reagent from bromobenzene and metallic magnesium 
(by reacting bromobenzene with 1 atomic equivalent of metallic magnesium 
in the ether solvent in accordance with a customary method). [J. Org. 
Chem., Vol. 35, No. 6, 1777-1781 (1970)]. 
Our investigations have shown however that when p-chloroprenylbenzene is 
reacted with 1 atomic equivalent of metallic magnesium in accordance with 
an ordinary Grignard reagent preparing method in tetrahydrofuran solvent 
under reflux at about 70.degree. C., the rate of the reaction is very 
slow, and the conversion of p-chloroprenylbenzene to the Grignard reagent 
is extremely low (see Comparative Example 1 given hereinafter). 
Further investigations we conducted in order to solve the aforesaid problem 
have led to the discovery that when p-chloroprenylbenzene and metallic 
magnesium are heated together at a temperature between 100.degree. C. and 
150.degree. C., preferably at a temperature between 110.degree. C. and 
130.degree. C., the reaction between them proceeds very smoothly and 
effectively and the Grignard reagent is formed with good selectivity, and 
that the reaction of the Grignard reagent with acetaldehyde gives 
1-(p-prenylphenyl)ethanol in good yields. 
According to this invention, there is provided a novel and industrially 
advantageous process for producing 1-(p-prenylphenyl)ethanol, which 
comprises reacting p-chloroprenylbenzene with magnesium at a temperature 
between 100.degree. C. and 150.degree. C. to form a Grignard reagent, and 
then reacting it with acetaldehyde. 
The reaction of preparing the Grignard reagent from p-chloroprenylbenzene 
and metallic magnesium is carried out preferably in a solvent. Suitable 
solvents are those which are usually employed in the preparation of 
Grignard reagents, and examples include ethers such as tetrahydrofuran, 
tetrahydropyran, diethyl ether, diisopropyl ether and 1,2-dimethoxyethane. 
Tetrahydrofuran is especially preferred. This reaction is carried out by 
using 0.8 to 1.5 atomic equivalents, preferably 1.0 to 1.4 atomic 
equivalents, of metallic magnesium based on p-chloroprenylbenzene as in 
the usual preparation of Grignard reagents. 
In order to perform the reaction of p-chloroprenylbenzene and magnesium in 
such proportions smoothly with a high conversion and selectivity, it is 
critical to use such higher reaction temperatures (i.e., at least 
100.degree. C.) than the reaction temperatures heretofore used in Grignard 
reagent preparation. Lower temperatures have been found to be unable to 
give feasible rates of reaction. On the other hand, temperatures exceeding 
150.degree. C. may increase side-reactions and are not desirable. From the 
molecular structure of p-chloroprenylbenzene, it is unexpected that it 
will react with metallic magnesium at a temperature of 100.degree. C. to 
150.degree. C. to give the corresponding Grignard reagent with a good 
selectivity without substantially causing undesirable side-reactions such 
as the isomerization of the double bond at the side chain of 
p-chloroprenylbenzene. 
In starting the reaction of p-chloroprenylbenzene with magnesium, it is 
preferred to activate magnesium by adding a small amount of at least one 
of iodine, ethyl bromide, ethylenedibromide, etc. In order to perform the 
Grignard reagent-forming reaction at the aforesaid reaction temperatures, 
i.e., 100.degree. C. to 150.degree. C., preferably 110.degree. C. to 
130.degree. C., there can be used, for example, a method which comprises 
performing the reaction under pressure in an autoclave, or a method which 
comprises performing the reaction in a very much reduced amount of the 
solvent, for example using tetrahydrofuran in an amount of about 0.1 to 
1.0 part by weight per part by weight of p-chloroprenylbenzene. 
The Grignard reagent thus prepared from p-chloroprenylbenzene and metallic 
magnesium is then reacted with acetaldehyde. Prior to this reaction, the 
Grignard reagent needs not to be isolated from the reaction mixture, but 
can be reacted as such with acetaldehyde. The reaction of the Grignard 
reagent with acetaldehyde is carried out at a temperature of generally 
between about -40.degree. C. and about 20.degree. C., preferably between 
about 0.degree. C. and about 10.degree. C. The amount of acetaldehyde is 
generally about 1 mole or slightly larger, preferably up to about 1.5 
moles, per mole of p-chloroprenylbenzene used in the preparation of the 
Grignard reagent. Under these conditions, the reaction between the 
Grignard reagent and acetaldehyde proceeds very rapidly, and so long as 
temperature control is possible, the reaction can be terminated almost 
instantaneously, for example, in less than several minutes. In industrial 
practice, a suitable length of time is selected from periods of, for 
example, up to about 24 hours by considering the ease of removing the 
heat. After the above-mentioned reaction with acetaldehyde, the reaction 
mixture is treated in a customary manner, for example treated with an 
acidic aqueous solution such as an aqueous solution of acetic acid, dilute 
sulfuric acid or dilute hydrochloric acid or an aqueous solution of 
ammonium chloride, thereby giving 1-(p-prenylphenyl)ethanol. 
The resulting 1-(p-prenylphenyl)ethanol can be separated from the reaction 
mixture, and purified, by methods known per se, for example extraction, 
distillation and chromatography. 
The p-chloroprenylbenzene used as a starting material in the process of 
this invention can be easily obtained in high yields by, for example, 
reacting p-dichlorobenzene with metallic magnesium to form a Grignard 
reagent and reacting it with a prenyl halide. 
Since p-dichlorobenzene is produced industrially in quantities at low cost 
in order to use it for production of insecticides, etc., the process of 
this invention which can give 1-(p-prenylphenyl)ethanol substantially in 
two steps starting from p-dichlorobenzene is very significant from an 
industrial viewpoint. 
The reaction of preparing the Grignard reagent from p-dichlorobenzene and 
metallic magnesium can be effected by methods known per se, preferably in 
a solvent. Suitable solvents used in the reaction are ethers such as 
tetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether and 
1,2-dimethoxyethane. Tetrahydrofuran is especially preferred. The reaction 
temperature is not critical, but generally temperatures of about 
40.degree. C. to about 90.degree. C., especially 50.degree. C. to 
70.degree. C., are suitable. In starting the reaction, magnesium can be 
effectively activated by adding a small amount of at least one of iodine, 
ethyl bromide, ethylenedibromide, etc. The amount of metallic magnesium is 
generally from about 1 atomic equivalent to a slightly larger amount, for 
example up to about 1.5 atomic equivalents, based on p-dichlorobenzene. 
By coupling the resulting Grignard reagent with a prenyl halide, 
p-chloroprenylbenzene can be obtained. The coupling reaction is carried 
out at about 0.degree. C. to about 40.degree. C., preferably about 
10.degree. C. to about 30.degree. C. Prenyl chloride and prenyl bromide 
are preferred as the prenyl halide. The amount of the prenyl halide is 
generally from 1 mole to a slightly larger amount (usually up to about 1.5 
moles) per mole of p-dichlorobenzene used to prepare the Grignard reagent. 
The resulting p-chloroprenylbenzene can be separated from the reaction 
mixture by any separating method generally employed, such as extraction, 
distillation or chromatography. 
The p-chloroprenylbenzene can also be produced by preparing a Grignard 
reagent from metallic magnesium and p-bromochlorobenzene instead of 
p-dichlorobenzene, and reacting it with a prenyl halide in accordance with 
the above-mentioned method. In view of availability and cost, the use of 
p-dichlorobenzene is advantageous in commercial practice. When 
p-bromochlorobenzene is used instead of p-dichlorobenzene, it can be 
reacted with metallic magnesium to form a Grignard reagent and then the 
Grignard reagent can be reacted with a prenyl halide in the same way as in 
the case of using p-dichlorobenzene except that preferably the Grignard 
reagent is prepared at a temperature of about 10.degree. C. to about 
90.degree. C., particularly 20.degree. C. to 70.degree. C. 
As described in the above-cited U.S. Pat. No. 4,251,543, the 
1-(p-prenylphenyl)ethanol produced by the process of this invention can be 
converted to 2-(p-prenylphenyl)propionic acid useful as an analgesic 
anti-inflammatory agent by treating it with a halogenating agent such as 
thionyl chloride, phosphorus trichloride and phosphorus tribromide to form 
a 1-halo-1-(p-prenylphenyl)ethane, cyanating it with a metal cyanide such 
as sodium cyanide or copper cyanide to form 
2-(p-prenylphenyl)-propionitrile, and then hydrolyzing it, or reacting the 
1-halo-1-(p-prenylphenyl)ethane with metallic magnesium to form a Grignard 
reagent and then reacting it with carbon dioxide.

The following examples illustrate the present invention in greater detail. 
EXAMPLE 1 
##STR2## 
(A) Under a nitrogen atmosphere, 58.3 g of magnesium turnings, 800 ml of 
tetrahydrofuran and about 0.1 g of iodine were put in a flask. When 2 ml 
of ethyl bromide was added while stirring the above materials, coloration 
by iodine disappeared and the temperature of the contents of the flask 
rose. While tetrahydrofuran was refluxed, a solution of 294 g of 
p-dichlorobenzene in 2 liters of tetrahydrofuran was added dropwise over 
the course of about 4 hours. After the addition, the mixture was stirred 
for 2 hours, and cooled to room temperature. Then, a solution of 271.7 g 
of prenyl chloride in 800 ml of tetrahydrofuran was added dropwise at 
15.degree. C. to 20.degree. C. over about 4 hours. After the addition, the 
reaction mixture was left to stand overnight at room temperature. Then, 2 
liters of a 10% by weight aqueous solution of ammonium chloride was added, 
and the mixture was separated into an organic layer and an aqueous layer. 
The aqueous layer was extracted with 300 ml of diethyl ether. The diethyl 
ether layer was combined with the organic layer previously separated, and 
washed with water, dried, concentrated and distilled to give 222.3 g 
(yield 61.6%) of p-chloroprenylbenzene having a boiling point of 
64.degree. C. to 65.5.degree. C./0.38 mmHg. The nuclear magnetic resonance 
spectrum of the product was as follows. (The chemical shifts are expressed 
in .delta. (ppm) when hexamethylsiloxane (HMS) is used as a standard.) 
.sup.1 H NMR (CDCl.sub.3): .delta. 1.66 (6H, s), 3.23 (2H, d, J=7.5 Hz), 
5.21 (1H, t, J=7.5 Hz), and 6.94-7.26 (4H, m). 
(B) Under a nitrogen atmosphere, 9.6 g of magnesium turnings, 30 ml of 
tetrahydrofuran and about 50 mg of iodine were put in a flask. With 
stirring, 2 ml of ethyl bromide was added, whereupon coloration by iodine 
disappeared. With stirring, the mixture was heated and maintained at 
110.degree. C. to 120.degree. C., and 60 g of p-chloroprenylbenzene was 
added. During the reaction, 20 ml of tetrahydrofuran was further added. 
After continuing the reaction for 4.5 hours, the reaction mixture was 
cooled to room temperature, and 200 ml of tetrahydrofuran was added. A 
solution of 22.0 g of acetaldehyde in 30 ml of tetrahydrofuran was added 
at 5.degree. C. to 10.degree. C. over the course of about 2 hours. After 
the addition, the mixture was stirred for 1 hour, and then 400 ml of a 10% 
by weight aqueous solution of ammonium chloride was added. The mixture was 
separated into an organic layer and an aqueous layer. The aqueous layer 
was extracted with 30 ml of diethyl ether. The diethyl ether layer was 
combined with the organic layer previously separated and washed with 
water, dried, concentrated and distilled to give 47.3 g (yield 74.9%) of 
1-(p-prenylphenyl)ethanol having a boiling point of 108.degree. C. to 
110.degree. C./0.5 mmHg. The nuclear magnetic resonance spectrum of the 
product was as follows. (The chemical shifts are expressed in .delta. 
(ppm) when hexamethylsiloxane is used as a standard.) 
.sup.1 H NMR (CDCl.sub.3): .delta. 1.36 (3H, d, J=6.5 Hz), 1.67 (6H, s), 
2.26 (1H, s), 3.25 (2H, d, J=7.5 Hz), 4.73 (1H, q, J=6.5 Hz), 5.25 (1H, t, 
J=7.5 Hz), and 7.0-7.3 (4H, m). 
EXAMPLE 2 
Magnesium turnings (9.6 g), 250 ml of tetrahydrofuran and about 50 mg of 
iodine were put in an autoclave purged with nitrogen. With stirring, 2 ml 
of ethyl bromide was added, and then, 60 g of p-chloroprenylbenzene was 
added. The mixture was heated and maintained at 110.degree. C. to 
120.degree. C. for 5 hours. The reaction mixture was cooled to room 
temperature, and transferred to a 500 ml three-necked flask. In an 
atmosphere of nitrogen, a solution of 22.0 g of acetaldehyde in 30 ml of 
tetrahydrofuran was added dropwise at 5.degree. C. to 10.degree. C. over 
the course of about 2 hours. After the addition, the mixture was stirred 
for 1 hour, and then 400 ml of a 10% by weight aqueous solution of 
ammonium chloride was added. The mixture was separated into an organic 
layer and an aqueous layer. The aqueous layer was extracted with 30 ml of 
diethyl ether. The diethyl ether was combined with the organic layer 
previously separated, and washed with water, dried, concentrated and 
distilled to give 45.2 g (yield 71.6%) of 1-(p-prenylphenyl)ethanol. 
EXAMPLE 3 
p-Chloroprenylbenzene was produced in the same way as in Example 1 except 
that 413.4 g of prenyl bromide was used instead of 271.7 g of prenyl 
chloride. The amount of p-chloroprenylbenzene obtained was 245.8 g (yield 
68.1%). Using 60 g of the resultant p-chloroprenylbenzene, 
1-(p-prenylphenyl)ethanol was produced in the same way as in Example 1. 
The amount of 1-(p-prenylphenyl)ethanol obtained was 47.5 g (yield 75.2%). 
EXAMPLE 4 
##STR3## 
Under nitrogen atmosphere, 55.1 g of magnesium turnings, 800 ml of 
tetrahydrofuran, and about 0.1 g of several pieces of iodine were put in a 
flask. With stirring, 2 ml of ethyl bromide was added, whereupon 
coloration by iodine disappeared. Then, a solution of 361.7 g of 
p-bromochlorobenzene in 2 liters of tetrahydrofuran was added dropwise at 
such a speed that the reaction temperature was maintained at 25.degree. C. 
to 30.degree. C. After the addition, the mixture was further stirred for 1 
hour, and cooled to about 20.degree. C. A solution of 256.8 g of prenyl 
chloride in 800 ml of tetrahydrofuran was added dropwise at 15.degree. C. 
to 20.degree. C. over the course of about 4 hours. After the addition, the 
mixture was left to stand overnight at room temperature. Two liters of a 
10% by weight aqueous solution of ammonium chloride were added, and the 
mixture was separated into an organic layer and an aqueous layer. The 
aqueous layer was extracted with 300 ml of diethyl ether. The diethyl 
ether layer was combined with the organic layer previously separated, and 
washed with water, dried, concentrated, and distilled to give 218.3 g 
(yield 64.0%) of p-chloroprenylbenzene. 
COMATIVE EXAMPLE 1 
##STR4## 
The following comparative experiment was conducted in order to demonstrate 
the superiority (high conversion) of the Grignard reagent preparation in 
accordance with the process of this invention from p-chloroprenylbenzene 
and magnesium to a conventional process. 
(A) Conventional process (reaction temperature. the refluxing temperature 
of tetrahydrofuran, i.e. about 70.degree. C.): 
Under nitrogen atmosphere, 0.8 g of magnesium turnings, 10 ml of 
tetrahydrofuran and about 5 mg of iodine were put in a flask. With 
stirring, 0.2 ml of ethyl bromide was added, whereupon coloration by 
iodine disappeared. While tetrahydrofuran was refluxed with stirring, a 
solution of 6 g of p-chloroprenylbenzene in 20 ml of tetrahydrofuran was 
added, and the reaction was carried out for 5 hours. After the reaction, 
the reaction mixture was cooled to room temperature, and poured into 40 ml 
of a 10% aqueous solution of ammonium chloride to hydrolyze the Grignard 
reagent. The product was analyzed by gas chromatography. It was found that 
in the above Grignard reagent producing reaction, the conversion of 
p-chloroprenylbenzene was 9.0%. 
(B) Process of the invention (reaction temperature: 110.degree. 
C.-130.degree. C.): 
Under nitrogen atmosphere, 0.8 g of magnesium turnings, 3 ml of 
tetrahydrofuran and about 5 mg of iodine were put in a flask. With 
stirring, 0.2 ml of ethyl bromide was added, whereupon coloration by 
iodine disappeared. While tetrahydrofuran was refluxed with stirring, a 
solution of 6 g of p-chloroprenylbenzene in 2 ml of tetrahydrofuran was 
added, and the reaction was carried out at 110.degree. C. to 130.degree. 
C. for 5 hours. After the reaction, the reaction mixture was cooled to 
room temperature, and poured into 40 ml of a 10% by weight aqueous 
solution of ammonium chloride to hydrolyze the Grignard reagent. Analysis 
of the product by gas chromatography showed that in the Grignard reagent 
producing reaction, the conversion of p-chloroprenylbenzene was 95.6%. 
REFERENTIAL EXAMPLE 
##STR5## 
166 g of 1-(p-prenylphenyl)ethanol was dissolved in a mixture of 870 ml of 
acetone and 34.5 g of pyridine. While the solution was maintained at 
0.degree. C., 60.1 of phosphorus trichloride was added over the course of 
about 2 hours. The mixture was stirred at room temperature for 2 hours. 
Acetone was distilled off, and n-hexane and cold water were added to the 
mixture. The n-hexane layer was washed successively with a 1.6% aqueous 
solution of sodium hydroxide and water, dried and concentrated to give 
174.6 g of 1-chloro-1-(p-prenylphenyl)ethane. 
In an atmosphere of nitrogen, 81.3 g of magnesium turnings, 983 ml of 
tetrahydrofuran and about 0.2 g of iodine were mixed, and 2 ml of ethyl 
bromide was added to activate magnesium. A solution of 174.6 g of the 
1-chloro-1-(p-prenylphenyl)ethane obtained as above in 170 ml of 
tetrahydrofuran was added dropwise at a reaction temperature of 20.degree. 
C. to 25.degree. C. over the course of 4 hours. After the addition, the 
mixture was stirred at the same temperature for 1 hour. The reaction 
mixture was then cooled to a temperature between -20.degree. C. and 
-10.degree. C., and carbon dioxide gas was blown into it at the same 
temperature until no exotherm was noted. The reaction mixture was warmed 
to room temperature, and poured into dilute hydrochloric acid, followed by 
extraction with diisopropyl ether. A 2 N aqueous solution of sodium 
hydroxide was added to the diisopropyl ether extract, and the mixture was 
stirred and allowed to stand and separate. The resulting aqueous layer was 
washed three times with n-hexane, and then acidified with 2 N hydrochloric 
acid. The resulting mixture was then extracted with diisopropyl ether. The 
extract was washed with water and a small amount of an aqueous solution of 
sodium bicarbonate, dried, concentrated and then subjected to molecular 
distillation to give 100 g of 2-(p-prenylphenyl)propionic acid.