Synthesis of 5-bromopyrogallol 1,3-dimethyl ether

This invention is concerned with a method of preparing 5-bromopyrogallol 1,3-dimethyl ether by reacting equimolar amounts of pyrogallol 1,3-dimethyl ether and N-bromosuccinimide in a halogenated hydrocarbon solvent in the presence of monohydric alkyl alcohols, i.e., monohydric alkanols.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a new method of preparing 5-bromopyrogallol 
1,3-dimethyl ether. 
2. Description of the Prior Art 
M. Kohn and L. Steiner, J. Org. Chem., 12, p. 30 (1947) have described the 
preparation of 5-bromopyrogallol 1,3-dimethyl ether by debromination of 
4,5,6-tribromopyrogallol 1,3-dimethyl ether with zinc dust and acetic 
acid. Though numerous attempts have been made to synthesize the 5-bromo 
compound as the major or exclusive product directly from pyrogallol 
1,3-dimethyl ether, they have been unsuccessful. 
Because of the strong orienting influence of the methoxy groups, 
halogenation of pyrogallol 1,3-dimethyl ether occurs in the 4-position and 
only with an excess of halogenating agent sometimes occurs in the 
5-position as well. Using 1 molar equivalent of bromine as the 
halogenating agent, A. A. Levine, J. Amer. Chem. Soc., 48, p. 798 (1926) 
reported that the first bromine atom substitutes in the 4-position. D. 
Friedman and D. Ginsberg, J. Org. Chem., 23, p. 16 (1958) reported that 
bromination of pyrogallol 1,3-dimethyl ether using 1 molar equivalent of 
N-bromosuccinimide (NBS) in carbon tetrachloride yields 4-bromopyrogallol 
1,3-dimethyl ether. These authors also reported the formation of the 
4,6-dibromo compound using 2 molar equivalents of NBS and the formation of 
the 4,5,6-tribromo compound using 3 molar equivalents of NBS. Upon 
repeating the experimental procedure of D. Friedman and D. Ginsberg using 
equimolar amounts of the pyrogallol and N-bromosuccinimide in boiling 
carbon tetrachloride, it was determined by nmr analysis of the crude 
reaction mixture that the 5-bromo compound also was formed but was present 
in only very minor amounts as compared to the amount of 4-bromo compound. 
According to the present invention, it has been found that the 5-bromo 
compound can be obtained as the major product in the bromination of 
pyrogallol 1,3-dimethyl ether with NBS by conducting the reaction in the 
presence of certain alcohols. In a preferred embodiment, the bromination 
is conducted in the presence of sodium hydride in order to achieve a 
further increase in the formation of the desired 5-bromo product. 
SUMMARY OF THE INVENTION 
It is, therefore, the primary object of the present invention to provide a 
method of brominating pyrogallol 1,3-dimethyl ether with NBS to give 
5-bromopyrogallol 1,3-dimethyl ether as the major reaction product. 
Other objects of this invention will in part be obvious and will in part 
appear hereinafter. 
The invention accordingly comprises the process involving the several steps 
and the relation and order of one or more of such steps with respect to 
each of the others and the scope of the application of which will be 
indicated in the claims. 
For a fuller understanding of the nature and objects of the invention, 
reference should be had to the following detailed description. 
DETAILED DESCRIPTION OF THE INVENTION 
Specifically, the method of the present invention comprises reacting 
equimolar amounts of pyrogallol 1,3-dimethyl ether and N-bromosuccinimide 
in a halogenated hydrocarbon solvent containing a monohydric alkanol in an 
amount sufficient to give 5-bromopyrogallol 1,3-dimethyl ether as the 
major reaction product. 
The alkanol employed may be a branched or straight-chain monohydric alkanol 
and usually is a monohydric alkyl alcohol containing 1 to 6 carbon atoms, 
for example, methanol, ethanol, propanol, iso-propanol, n-hexanol, 
s-butanol and t-butanol. To achieve formation of the desired 5-bromo 
compound in a major proportion as compared to the 4-bromo compound, the 
alkanol is added to the halogenated hydrocarbon solvent in an amount 
between about 0.5% and 10.0% by volume, and usually is employed in an 
amount between about 0.5 and 1.0% by volume. 
Illustrative of the halogenated hydrocarbons that may be employed as the 
reaction solvent are carbon tetrachloride, methylene chloride, bromoform 
and chloroform. The amount of solvent is not critical, but should be 
sufficient to dissolve the reactants which amount may be readily 
determined empirically. Preferably, the reaction solvent is a chlorinated 
hydrocarbon. 
Though the reaction temperature may vary over a relatively wide range 
including reflux, it is preferred to conduct the bromination reaction at 
lower temperatures between about -70.degree. and 20.degree. C. and 
preferably below 0.degree. C., since the 5-bromo compound is obtained in 
better yields in the lower temperature range. 
To achieve further increases in the yield of the desired 5-bromo product, 
the subject bromination preferably is conducted in the presence of sodium 
hydride in addition to the monohydric alkanol. In this preferred 
embodiment, the sodium hydride is conveniently used as a 50% oil 
dispersion in an amount of about 0.01 to 0.05 mole NaH per mole of 
pyrogallol.

The following examples are given to further illustrate the present 
invention and are not intended to limit the scope thereof. 
EXAMPLE 1 
Preparaton of 5-bromopyrogallol 1,3-dimethyl ether having the formula 
##STR1## 
To a 3 liter flask equipped with a mechanical stirrer, thermometer and 
nitrogen inlet was added 154 g. (1 mole) of pyrogallol 1,3-dimethyl ether 
and 1.5 liters of CHCl.sub.3. To this solution was added 0.5 g (0.01 mole) 
of NaH (50% oil dispersion). The solution was stirred while cooling to 
-45.degree. C. with a dry-ice acetone bath and 178 g. (1 mole) of powdered 
N-bromosuccinimide was added rapidly. There was a slight exotherm. The 
reaction mixture was then stirred for 1 hour at -35.degree. C., heated to 
room temperature over the next 30 minute period, and finally refluxed for 
30 minutes. The CHCl.sub.3 was removed under reduced pressure and the 
residue solidified. The tan solid was broken up and stirred well with 2 
liters of ether. This was filtered and the residue.sup.1 washed well with 
ether. The ether was evaporated under reduced pressure to yield a tan 
solid. The solid was placed in a 10 liter flask with 6 liters of ligroin 
(boiling range 90.degree.-110.degree. C.) and heated with stirring to 
80.degree. C..sup.2. The hot solution was decanted from the brown oil and 
was filtered through a pre-heated.sup.3 celite pad, using an aspirator, 
into a pre-heated flask. The light yellow solution was allowed to cool at 
room temperature for 3 hours.sup.4. The white wooly needles were filtered 
off and dried to yield 110 g. The mother liquor was evaporated to one-half 
its original volume, reheated to dissolve any solid which precipitated and 
the hot solution worked up as in the above step. A second crop of 30 g. 
was collected to give the title compound in a total yield of 140 g. (61%) 
melting range 99.5.degree.-100.degree. C. 
FNT .sup.1 The succinimide is insoluble in ether. 
FNT .sup.2 Most of the brown oil remaining was an impurity. 
FNT .sup.3 This was accomplished by simply pouring hot ligroin through the 
celite pad under reduced pressure. 
FNT .sup.4 If a brown oil precipitates initially, then the ligroin solution is 
filtered through the celite again before cooling further. Standing for 
more than 3 hours may cause the impurity to co-precipitate. 
EXAMPLES 2-13 
In Examples 2 to 13 and the controls listed in the following Table, the 
pyrogallol 1,3-dimethyl ether and N-bromosuccinimide were reacted in 
equimolar proportions at the temperature designated using the designated % 
by volume of the specified alkanol in the specified solvent. Where 
appropriate, the amount of sodium hydride (NaH) employed also is 
specified. 
By "proportion yield" is meant the proportion of 5-bromopyrogallol 
1,3-dimethyl ether compared to 4-bromopyrogallol 1,3-dimethyl ether in % 
as measured in the crude reaction mixture by nmr analysis. 
By "crude yield" is meant the overall yield of 5-bromopyrogallol 
1,3-dimethyl ether in % as measured in the crude reaction mixture by nmr 
analysis. 
TABLE 
______________________________________ 
Pro- 
Example 
portion Crude Reaction 
Temp. *Alkanol 
NaH 
No. Yield Yield Solvent 
.degree.C. 
% by vol 
mole 
______________________________________ 
2 65.9 48 CHCl.sub.3 
+20.degree. 
EtOH 0.01 
0.75% 
3 88.1 75 " -70.degree. 
" " 
4 87.5 72 " -20.degree. 
" " 
5 82.6 73 " -20.degree. 
" -- 
6 80.0 73 " -20.degree. 
" -- 
Control 
16.8 14 " -20.degree. 
-- -- 
7 62.1 54 CH.sub.2 Cl.sub.2 
-20.degree. 
EtOH -- 
1.0% 
8 67.6 52 " -20.degree. 
EtOH -- 
2.0% 
Control 
39.3 38 " -20.degree. 
-- -- 
9 68.3 61 CCl.sub.4 
-20.degree. 
EtOH -- 
1.0% 
10 65.7 53 " -20.degree. 
EtOH -- 
10.0% 
11 73.0 63 " -20.degree. 
n-BuOH -- 
1.0% 
12 61.8 58 " -20.degree. 
iso-BuOH 
-- 
1.0% 
13 67.5 53 " -20.degree. 
t-BuOH -- 
1.0% 
Control 
22.3 21 " -20.degree. 
-- -- 
______________________________________ 
*In the alkanols listed, EtOH = ethanol; nBuOH = nbutanol; isoBuOH = 
isobutyl alcohol; and tBuOH = tertbutanol. 
Though it has been found that aromatic and substituted alkyl alcohols also 
are useful in enhancing the formation of the desired 5-bromo product, the 
proportion of 5-bromo to 4-bromo compound was not sufficient to permit 
facile isolation from the crude reaction mixture by simple crystallization 
techniques. For example, when equimolar amounts of the pyrogallol and NBS 
were reacted at -20.degree. C. in carbon tetrachloride containing 1.0% by 
volume of benzyl alcohol, the proportion yield was 43.5 (% by nmr). Under 
the same conditions but using 1.0% by volume of 2-methoxyethanol, the 
proportion yield was 41.2 (% by nmr). 
As mentioned above, the experimental procedure of D. Friedman and D. 
Ginsburg was repeated. Equimolar amounts of the pyrogallol and 
N-bromosuccinimide were reacted in carbon tetrachloride at reflux. The 
proportion yield obtained was 15.5 (% by nmr) for the 5-bromo compound and 
a crude yield of about 15.0 (% by nmr). 
The brominated compound produced by the subject method is useful, e.g., as 
a starting material for the photographic optical filter agent precursors 
forming the subject matter of copending U.S. patent application Ser. No. 
836,006 of Stanley M. Bloom et al filed Sept. 23, 1977, now U.S. Pat. No. 
4,139,381 issued Feb. 13, 1979. As discussed therein, the subject compound 
after blocking the --OH with methoxymethyl is converted to the 
corresponding Li compound, and 2 moles of the Li compound is reacted with 
saccharin pseudo-chloride to give the 3,3-disubstituted sulfamphthalein 
followed by N-acylation with ClCOO(CH.sub.2).sub.2 CN and deblocking of 
the --OH to yield the said precursor. 
Since certain changes may be made in the hereindescribed subject matter 
without departing from the scope of the invention herein involved, it is 
intended that all matter contained in the above description and examples 
be interpreted as illustrative and not in a limiting sense.