Process for preparing alkoxyphenols

A process for preparing an alkoxyphenol represented by the formula: ##STR1## wherein R is hydrogen, alkyl having 1 to 4 carbon atoms, formyl, hydroxymethyl, alkoxymethyl, dialkoxymethyl, acetoxymethyl or diacetoxymethyl, R' is alkyl having 1 to 4 carbon atoms, and n is an integer of 1 to 5, characterized in that a phenol halide represented by the formula: ##STR2## wherein R and n are as defined above, and X is chlorine or bromine is reacted, in the presence of a copper salt serving as a catalyst and of a solvent, with a product prepared by heating, in the presence of a dehydrating agent, an alkali metal hydroxide and a compound of the formula R'OH wherein R' is as defined above.

This invention relates to a process for preparing alkoxyphenols, and more 
particularly to a process for preparing alkoxyphenols from phenol halides. 
Processes are well known for preparing alkoxyphenols from phenol halides, 
in other words, for substituting alkoxyl groups for the halogen 
substituents in phenols. Usually alkoxyphenols are produced by reacting 
with heating a phenol halide with an alcoholate prepared by dissolving 
metallic sodium in an alcohol, in a suitable solvent, such as 
dimethylformamide or an amine, in the presence of a copper halide serving 
as a catalyst. Laid-Open West German Patent Application No. 2627874 and 
Chemical Abstract 86, 171074 (1974), for example, disclose a process for 
synthesizing pyrogallol in which 2,6-dibromo-4-tert-butylphenol is reacted 
with sodium methoxide with use of copper iodide as a catalyst and 
dimethylformamide as a solvent to afford 2,6-dimethoxy-4-tert-butylphenol 
in a yield of 89%. Journal of Chemical Society (C), 312 (1969) further 
discloses that several kinds of aromatic halides, including phenol 
bromide, are reacted with sodium methoxide in a mixture of methanol and 
collidine with use of copper iodide as a catlyst to give the corresponding 
methoxidated aromatic compounds in yields of 37 to 99%. 
With the conventional processes, the alcoholates used are all those 
prepared by dissolving metallic sodium in alcohols. The preparation of 
alcoholates nevertheless requires the use of expensive alkali metals, 
needs special care for handling and therefore is not always preferable. 
An object of the invention is to provide a process for preparing 
alkoxyphenols from corresponding phenol halides with use of compounds 
which are easy to handle. 
Another object of the invention is to provide a process for preparing 
alkoxyphenols from phenol halides with use of compounds which are 
inexpensive and readily available. 
These objects and other features of the invention will become apparent from 
the following description. 
The present invention provides a process for preparing an alkoxyphenol 
represented by the formula 
##STR3## 
wherein R is hydrogen, alkyl having 1 to 4 carbon atoms, formyl, 
hydroxymethyl, alkoxymethyl, dialkoxymethyl, acetoxymethyl or 
diacetoxymethyl, R' is alkyl having 1 to 4 carbon atoms, and n is an 
integer of 1 to 5, characterized in that a phenol halide represented by 
the formula 
##STR4## 
wherein R and n are as defined above, and X is chlorine or bromine is 
reacted, in the presence of a copper salt serving as a catalyst and of a 
solvent, with a product prepared by heating, in the presence of a 
dehydrating agent, an alkali metal hydroxide and a compound of the formula 
R'OH wherein R' is as defined above. 
According to the invention it is critical that a phenol halide of the 
foregoing formula be reacted with a product obtained by heating an alkali 
metal hydroxide and a compound of the formula R'OH wherein R' is as 
defined above, in the presence of a dehydrating agent. 
Thus the process of this invention is practiced with use of an alkali metal 
hydroxide which is extremely inexpensive and easy to handle, in place of 
alcoholates prepared from an alkali metal and an alcohol and heretofore 
used. The present process is therefore free of any of the drawbacks 
attributable to the use of alkali metal. It is also noteworthy that the 
yield of the desired alkoxyphenol is comparable or even superior to those 
attained with use of alcoholates of alkali metal. 
It is known that an alkali metal hydroxide and an alcohol, when heated, 
undergo the following equilibrium reaction: 
EQU MOH+R'OH.revreaction.MOR'+H.sub.2 O 
wherein M is an alkali metal, and R' is as defined above. Since this 
reaction produces MOR' in a very small amount, it is almost impossible to 
separate out only MOR' for practical use. Although removal of the 
resulting water will permit the reaction to proceed toward the right side, 
the dehydrating agents heretofore known are unable to effect dehydration 
to such an extent as to render MOR' separable for actual use. 
The present invention is based on the novel finding that the product 
obtained by heating an alkali metal hydroxide and an alcohol of the 
foregoing formula in the presence of a dehydrating agent, as separated or 
without being separated from the dehydrating agent, (hereinafter referred 
to as "first-step reaction product") is effective for preparing 
alkoxyphenols from phenol halides. In fact, we have found that the 
first-step reaction product, which is entirely different in composition 
from the pure alcoholates heretofore used, is effectively usable for the 
preparation of alkoxyphenols from phenol halides and, still more 
surprisingly, that the use, of the first-step reaction product affords the 
desired product in as high a yield as is achieved by the use of pure 
alcoholates. 
The first-step reaction product can be prepared by heating 1 to 20 moles, 
preferably 3 to 10 moles, per mole of the phenol halide of an alkali metal 
hydroxide and 1 to 50 moles, preferably 5 to 40 moles, per mole of the 
alkali metal hydroxide of a compound R'OH in the presence of a dehydrating 
agent at a temperature of 5.degree. to 200.degree. C., preferably at 
reflux temperature. The dehydrating agent is used in an amount of 0.5 to 
50 times, preferably 5 to 30 times, the amount by weight of the phenol 
halide. The heating time, although dependent on the temperature, is 
usually 0.5 to 24 hours, preferably 2 to 15 hours. At reflux temperature, 
it is about 2 to about 15 hours. Since the dehydrating agent used for the 
first-step reaction produces no adverse effect on the subsequent 
alkoxylation of the phenol halide, the agent need not be removed from the 
resulting product, but the agent may be removed. Although the first-step 
reaction product still remains to be fully clarified with respect to its 
components or composition, the product presumably is a mixture of 
alcoholate, alkali metal hydroxide, dehydrating agent, hydroxide of the 
agent, etc. The product is effectively usable for the present process 
insofar as it is prepared under the conditions described. Examples of 
alkali metal hydroxides useful for the preparation of the first-step 
reaction product are sodium hydroxide, potassium hydroxide, lithium 
hydroxide, etc. These hydroxides should not be used in the form of an 
aqueous solution. Examples of useful alcohols represented by R'OH wherein 
R' is as defined above are methyl alcohol, ethyl alcohol and n-propyl 
alcohol, and further include isopropyl alcohol and tertiary butyl alcohol. 
Examples of useful dehydrating agents are oxides of alkaline earth metals, 
such as calcium oxide and magnesium oxide, anhydrous sulfates of alkali 
metals or alkaline earth metals, such as anhydrous sodium sulfate and 
anhydrous magnesium sulfate, silica gel, molecular sieves, active alumina, 
etc. 
With this invention, the first-step reaction product is reacted with a 
phenol halide to obtain the desired alkoxyphenol. Examples of useful 
phenol halides of the foregoing formula are 2-chlorophenol, 2-bromophenol, 
2,4-dichlorophenol, 2,4-dibromophenol, 2,5-dichlorophenol, 
2,5-dibromophenol, 2,4,5-trichlorophenol, 2,4,5-tribromophenol, 
2,4,6-trichlorophenol, 2,4,6-tribromophenol, 2-chloro-4-methylphenol, 
2-bromo-4-methylphenol, 2,6-dichloro-4-methylphenol, 
2,6-dibromo-4-methylphenol, 2-chloro-4-tert-butylphenol, 
2-bromo-4-tert-butylphenol, 2,6-dichloro-4-tert-butylphenol, 
2,6-dibromo-4-tert-butylphenol, 3-methyl-4-chlorophenol, 
3-methyl-4-bromophenol, 3-methyl-4,6-dichlorophenol, 
3-methyl-4,6-dibromophenol, 3-tert-butyl-4-chlorophenol, 
3-tert-butyl-4-bromophenol, 3-tert-butyl-4,6-dichlorophenol, 
3-tert-butyl-4,6-dibromophenol, 3-chloro-4-hydroxybenzaldehyde, 
3-bromo-4-hydroxybenzaldehyde, 3-chloro-4-hydroxybenzylalcohol, 
2-chloro-4-methoxyphenol, 2-bromo-4-methoxymethylphenol, 
2-chloro-4-ethoxymethylphenol, 2-chloro-4-dimethoxymethylphenol, 
2-bromo-4-dimethoxymethylphenol, 2-chloro-4-acetoxymethylphenol, 
2-bromo-4-acetoxymethylphenol, 2-chloro-4-diacetoxymethylphenol, 
2-bromo-4-diacetoxymethylphenol. 
For the reaction of the phenol halide and the first-step reaction product 
according to the invention, 1 to 10 mole, preferably 1 to 5 mole, of the 
product is admixed with 1 mole of the phenol halide, and the mixture is 
heated usually at 50.degree. to 150.degree. C., preferably about 
100.degree. to 120.degree. C. For this reaction, suitable solvents are 
usable. Examples of useful solvents are amines, such as pyridine, 
lutidine, collidine, etc., and amides, such as dimethylformamide, 
dimethylacetamide, hexamethylsulfonamide, etc., among which amides are 
preferable to use. Such solvents are used in about 1 to 50 times, 
preferably about 10 to 30 times, the amount by weight of the phenol 
halide. Although copper salts need not always be used as catalysts in the 
present process, copper salts, if used, will result in an increased 
reaction velocity. While any of the known copper salts is usable, examples 
of preferable copper salts are mono-or di-valent copper halides, such as 
copper chloride, copper bromide and copper iodide. These copper salts are 
used in an amount of 1 to 50% by weight, preferably 20 to 30% by weight, 
based on the phenol halide. 
The process of the invention can be practiced with use of a reactor 
equipped with a usual reflux condenser, or by heating the bottom of a 
reactor with the starting mixture placed therein while recovering the 
solvent on spontaneous evaporation. 
Vanillin and other compounds useful as flavors for foods can be produced at 
a low cost and with ease from the alkoxyphenols prepared by the present 
process. 
The invention will be described in greater detail with reference to the 
following examples.

EXAMPLE 1 
Preparation of 2-methoxy-4-methoxymethylphenol 
To 1.16 g (20.7 m mol) of calcined calcium oxide were added 6 ml of dried 
methanol and 340 mg (8.5 m mol) of sodium hydroxide and then the mixture 
was refluxed for 12 hours on an oil bath. The mixture was left to stand 
and 3 ml of the supernatant was taken off from the reflux by a dried 
injection, and, the supernatant thus withdrawn, after weighing out, was 
added to 89.0 mg (0.410 m mol) of 2-bromo-4-methoxymethylphenol dried 
beforehand. To the resulting mixture were added 1.5 ml of dried 
dimethylformamide and 24 mg of anhydrous cupric chloride and the resulting 
mixture was placed in an reactor in which the air was exchanged with 
nitrogen gas. While the bottom part of the reactor was dipped in an oil 
bath heated at 110.degree. C., the mixture was stirred for 4.5 hours at 
110.degree.-118.degree. C. to evaporate the solvent. 
The remaining solvent was further distilled off from the reaction mixture 
thus obtained. Then 5 ml of 5% HCl solution was added to the above product 
and the resulting mixture was extracted with 30 ml of ether. The extract 
was washed with saturated sodium chloride solution and dried to produce 
99.0 mg of yellowish oily liquid. The liquid was developed with a mixture 
of hexane-benzene-ethyl acetate (20:1) on a silica gel column to produce 
65.9 mg (95.6% in yield) of 2-methoxy4-methoxymethylphenol. 
IR (neat): 3740, 2944, 2865, 2834, 1613, 1507, 1466, 1433, 1372, 1277, 
1240, 1154, 1086, 1032, 852, 815, 793 cm.sup.-1. 
NMR(CCl.sub.4): .delta.3.27 (S,3H, --C--OCH.sub.3), 3.81 (S,3H, 
.dbd.C--OCH.sub.3) 4.30 (S,2H, --CH.sub.2 --) 5.82 (S,1H, OH) 6.58-6.92 
(m, 3H, .dbd.CH). 
Ultimate analysis: C.sub.9 H.sub.12 O.sub.3 Calculated value: C, 64.27%; H, 
7.19%, Measured value: C, 64.30%; H, 7.25%. 
EXAMPLES 2 to 15 
Fifteen kinds of alkoxyphenols were prepared in the same manner as in 
Example 1 except that the compounds listed in Table 1 below under the 
reacting conditions specified therein are used. 
TABLE 1 
__________________________________________________________________________ 
Alkali metal 
hydroxide and 
Tem- 
Starting dewatering perature 
Time Yield 
Ex. material agent Alcohol 
(.degree.C.) 
(hr) 
Alkoxyphenol 
(%) 
__________________________________________________________________________ 
2 2-chlorophenol 
NaOH CH.sub.3 OH 
110-115 
5 2-methoxyphenol 
92 
CaO 
3 2-bromo-phenol 
NaOH CH.sub.3 OH 
110-120 
6 2-methoxyphenol 
94.5 
CaO 
4 2,4,6-tribromo- 
NaOH CH.sub.3 OH 
120-125 
5 2,4,6-trimethoxy- 
90.5 
phenol CaO phenol 
5 2-chloro-4- 
KoH CH.sub.3 OH 
110-120 
5 2-methoxy-4- 
91.4 
methylphenol 
CaO methylphenol 
6 2-bromo-4-tert- 
NaOH CH.sub.3 OH 
110-120 
5 2-methoxy-4- 
89.7 
butylphenol 
CaO tert-butylphenol 
7 2-bromo-4-tert- 
NaOH C.sub.2 H.sub.5 OH 
100-110 
6 2-ethoxy-4-tert- 
75.6 
butylphenol 
CaO butylphenol 
8 2-bromo-4-tert- 
NaOH tert- 
100-110 
6 2-tert-butoxy- 
73.5 
butylphenol 
CaO C.sub.4 H.sub.9 OH 
4-tert-butylphenol 
9 2-bromo-4- 
NaOH CH.sub.3 OH 
110-120 
3 2-methoxy-4- 
94 
formylphenol 
CaO formylphenol 
10 2-chloro-4- 
NaOH CH.sub. 3 OH 
110-120 
4 2-methoxy-4- 
92 
hydroxymethyl- 
CaO hydroxymethyl- 
phenol phenol 
11 2-bromo-4- 
NaOH CH.sub.3 OH 
110-120 
3 2-methoxy-4- 
91.5 
acetoxymethyl- 
CaO acetoxymethyl- 
phenol phenol 
12 2,6-dibromo-4- 
NaOH CH.sub.3 OH 
110-120 
4 2,4-dimethoxy-4- 
89.5 
acetoxymethyl- 
CaO acetoxymethyl- 
phenol phenol 
13 2,6-dibromo-4- 
NaOH C.sub.2 H.sub.5 OH 
110-120 
3 2,6-diethoxy-4- 
73.7 
acetoxymethyl- 
CaO acetoxymethyl- 
phenol phenol 
14 2,4,6-trichloro- 
NaOH CH.sub.3 OH 
120-125 
4 2,4,6-trimethoxy- 
88.6 
3-hydroxymethyl- 
CaO 4-hydroxymethyl- 
phenol phenol 
15 2,4,6-trichloro- 
KoH CH.sub.3 OH 
110-120 
6 2,4,6-trimethoxy- 
89.7 
phenol CaO phenol 
Comp. 
2-bromo-4-formyl- 
Na CH.sub.3 OH 
110-120 
3 2-methoxy-4- 
93.5 
Ex. phenol formylphenol 
__________________________________________________________________________ 
COMISON EXAMPLE 2 
Preparation of 2-methoxy-4-methoxymethylphenol was conducted in a similar 
manner as in Example 1 except that calcined calcium oxide (dehydrating 
agent) was not used. Sodium hydroxide (3.16 g, 79.1 m mole) was dissolved 
in 60 ml of methanol and the solution was refluxed for 12 hours. To the 30 
ml of the resulting solution, 931 mg (4.1 m mole) of 
2-bromo-4-methoxymethylphenol, 15 ml of dimethylformamide and 240 mg of 
anhydrous cupric chloride were added. The mixture was stirred at 
110.degree. to 118.degree. C. under the nitrogen stream for 4.5 hours 
while evaporating the solvent. 
The remaining solvent was further distilled off from the reaction mixture 
thus obtained. Then 5 ml of 5% HCl solution was added to the residue and 
the mixture was extracted with ether. The extract was washed with 
saturated sodium chloride solution and dried on anhydrous sodium sulfate. 
The liquid was developed with a mixture of hexane-benzene-ethyl acetate 
(20:20:1) on a silica gel column to produce 38.5 mg of 
2-methoxy-4-methoxymethylphenol. Yield: 5.6%. 
COMISON EXAMPLE 3 
Sodium hydroxide (3.16 g, 79.1 m mole) was dissolved in 60 ml of methanol 
and the solution was refluxed for 12 hours. To the solution were added 750 
mg (4.1 m mole) of 2-bromophenol and 240 mg of anhydrous cuprous chloride. 
Then the reaction was carried out in the same manner as in Comparison 
Example 2 for 5 hours while evaporating methanol. After the reaction was 
completed, 43.7 mg of 2-methoxyphenol was obtained in the same manner as 
in Comparison Example 2. Yield: 8.6%. 
COMISON EXAMPLE 4 
Sodium hydroxide (3.16 g, 79.1 m mole) was dissolved in 60 ml of methanol 
and the resulting solution was refluxed for 12 hours. To the solution were 
added 980 mg (4.1 m mole) of 2-bromo-4-t-butylphenol, 240 mg of anhydrous 
cupric chloride and 15 ml of dimethylformamide. Subsequently the reaction 
was conducted in the same manner as in Comparison Example 2 for 4.5 hours 
while heating the mixture at 110.degree. to 115.degree. C. under stirring 
to evaporate the solvent. 
After the reaction was completed, 100 mg of 2-methoxy-4-t-butylphenol was 
obtained in the same manner as in Comparison Example 2. Yield: 13.6%. 
EXAMPLE 16 
To 11.6 g of calcined calcium oxide were added 100 ml (3.12 mol) of dried 
methanol and 3.5 g (0.0875 mol) of sodium hydroxide and then the mixture 
was refluxed for 6 hours on an oil bath. The mixture was left to stand and 
50 ml of the supernatant was taken off from the reflux. The supernatant 
thus withdrawn was added to 692 mg (4 m mol) of 2 bromophenol. To the 
resulting solution were added 15 ml of dried dimethylformamide and 240 mg 
of anhydrous cupric chloride and the resulting mixture was placed in an 
reactor. While the bottom part of the reactor was dipped in an oil bath, 
the mixture was stirred for 4 hours at 110.degree.-118.degree. C. to 
evaporate the solvent. 
The remaining solvent was further distilled off from the reaction mixture 
thus obtained. Then 50 ml of 5% HCl iced solution was added to the residue 
and the resulting mixture was extracted with 300 ml of ether. The extract 
was washed with saturated sodium chloride solution and dried with 
anhydrous sodium sulfate. After removing ether, the product was distilled 
under vacuum to produce 476 mg of 2-methoxyphenol (96.0% in yield), b.p. 
53.degree.-55.degree. C./4 mmHg. 
EXAMPLE 17 
To 11.6 mg of calcined calcium oxide were added 30 ml (0.9375 mol) of dried 
methanol and 3.5 g (0.0875 mol) of sodium hydroxide and then the mixture 
was refluxed for 5 hours on an oil bath. The mixture was left to stand and 
15 ml of the supernatant was taken off from the reflux. The supernatant 
thus withdrawn was added to 890 mg (4.1 m mol) of 
2-bromo-4-methoxymethylphenol. To the reulting mixture were added 15 ml of 
dried dimethylformamide and 240 mg of anhydrous cupric chloride and the 
resulting mixture was placed in an reactor. The mixture was stirred at 
110.degree.-118.degree. C. for 4 hours on an oil bath to evaporate the 
solvent. 
The remaining solvent was further distilled off under vacuum from the 
reaction mixture. Then 50 ml of 5% HCl iced solution was added to the 
above product and the resulting mixture was extracted with 300 ml of 
ether. The extract was washed with saturated sodium chloride and dried 
with anhydrous sodium sulfate. After removing ether from the dried 
extract, the resulting liquid was developed on a silica gel column in the 
same manner as in Example 1 to produce 628 mg (91.1% in yield) of 
2-methoxy-4-methoxymethylphenol.