Process development of the synthesis of 3,4,5-trimethoxytoluene

Article abstract of DOI:10.1021/op0502248

3,4,5-Trimethoxytoluene (TMT) was synthesized, starting from p-cresol, through bromination followed by methylation to give 3,5-dibromo-4-methoxytoluene (DBMT). The methoxylation of the latter with sodium methoxide in methanol was studied under pressure and by continuous distillation of the solvent, methanol. The O-methylation reaction preceding the methoxylation was advantageous from the point of view of separation, purification, and isolation of the desired product and also in reducing the tar formation. The residue obtained was minimized to 0.6-0.7 wt % of the DBMT. The methoxylation reaction with distillative removal of methanol gave a conversion of 98% of DBMT to the mixture of methoxylated products, and the conversion to TMT was 86.5% as compared to 93% and 70.81%, respectively, when the reaction was carried out under pressure in a sealed reactor. However, the overall conversion to TMT based on p-cresol is 64.27% for the methoxylation reaction under pressure and 78.46% for the reaction by continuous removal of methanol calculated as isolated yield. The advantages of the methoxylation of the DBMT over the published literature procedures involving direct methoxylation of 3,5-dibromo-p-cresol followed by methylation of the dimethoxy-p-cresol are the ease of separation, purification, and isolation by vacuum fractionation of the desired product TMT.

Full text of DOI:10.1021/op0502248

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Organic Process Research & Development 2006, 10, 487−492
Process Development of the Synthesis of 3,4,5-Trimethoxytoluene
Ananthakrishnan Sankaranarayanan* and S. B. Chandalia
Chemical Engineering DiVision, UniVersity Institute of Chemical Technology, UniVersity of Mumbai, Matunga,
Mumbai - 400 019, India
Abstract:
p-cresol is usually carried out in a semi-batch mode due to
the high exothermicity of the reaction. Since two moles of
hydrogen bromide are liberated during the bromination
reaction, the recovery of bromine from the liberated hydrogen
bromide is an integral part of the process scheme for
economic reasons. During the synthesis of 2,6-dibromo-p-
cresol (DBC), a small amount of 2-bromo-p-cresol is formed.
Another alternative for the bromination of p-cresol is by
oxidative bromination with two moles each of hydrobromic
acid and hydrogen peroxide respectively in a liquid-liquid
two-phase system.5,6
The methoxylation of unactivated substituted aryl halides
is generally carried out in high boiling solvents such as N,N-
dimethylformamide (DMF) in the presence of copper powder
or cuprous halides as catalyst via ipso substitution. The
methoxylation reaction is a nucleophilic substitution reaction,
and it generally exhibits second-order kinetics. During the
methoxylation of aryl halides with sodium methoxide,
copper-catalyzed competitive hydrodehalogenation reaction
of aryl halide has been reported by Bacon and co-workers.7-9
The authors found that the amount of reduction increased
when methoxy substituents were present ortho to the halogen
atom and, further, that the aryl iodides were more responsive
to reduction than bromides. The mechanism of the copper-
catalyzed nucleophilic substitution of aryl halides was studied
extensively by Derek Van Allen10 et al. The authors reported
that the nucleophilic substitution reaction takes place via a
four-center mechanism involving interaction between the
cuprous methoxide complex and the aryl bromide. The four-
center mechanism, σ-bond metathesis, however, does not
explain the hydrodehalogenation reaction observed in ortho-
substituted aryl halides which according to Bacon et al.7-9
involved a copper-mediated hydride ion transfer from the
methoxide to the aryl halide.
3,4,5-Trimethoxytoluene (TMT) was synthesized, starting from
p-cresol, through bromination followed by methylation to give
3,5-dibromo-4-methoxytoluene (DBMT). The methoxylation of
the latter with sodium methoxide in methanol was studied under
pressure and by continuous distillation of the solvent, methanol.
The O-methylation reaction preceding the methoxylation was
advantageous from the point of view of separation, purification,
and isolation of the desired product and also in reducing the
tar formation. The residue obtained was minimized to 0.6-0.7
wt % of the DBMT. The methoxylation reaction with distillative
removal of methanol gave a conversion of 98% of DBMT to
the mixture of methoxylated products, and the conversion to
TMT was 86.5% as compared to 93% and 70.81%, respectively,
when the reaction was carried out under pressure in a sealed
reactor. However, the overall conversion to TMT based on
p-cresol is 64.27% for the methoxylation reaction under
pressure and 78.46% for the reaction by continuous removal
of methanol calculated as isolated yield. The advantages of the
methoxylation of the DBMT over the published literature
procedures involving direct methoxylation of 3,5-dibromo-p-
cresol followed by methylation of the dimethoxy-p-cresol are
the ease of separation, purification, and isolation by vacuum
fractionation of the desired product TMT.
Introduction
Fine chemicals based on p-cresol have gained significant
importance as starting materials in the food and pharmaceuti-
cal industry in recent past. One of the industrially important
intermediates, 3,4,5-trimethoxytoluene (TMT), obtained from
p-cresol, on oxidation by air to yield 3,4,5-trimethoxyben-
zaldehyde, an intermediate for the well-known antibacterial,
trimethoprim and on oxidation by peracid to yield 2,3-
dimethoxy-5-methyl-2,5-cyclohexadiene-1,4-dione,1-3 an in-
termediate for the synthesis of the cardiovascular agent,
Coenzyme-Q10 (ubiquinone).4
The effective reducing agents in these reactions comprised
primary, secondary, and tertiary alkoxides in which one or
more aliphatic-type hydrogen atoms were attached to the
carbon, either R or â to the oxygen. Products from tertiary
alkoxides included tar. During methoxylation of the aryl
halide, competing reduction of the aryl halide takes place
via copper-mediated hydride ion transfer from the methoxide
The general process scheme for the synthesis of TMT
from p-cresol involves the unit processes such as bromina-
tion, methoxylation, and O-methylation. The bromination of
* Corresponding author. Present address: Medical Pharmacology and Toxi-
cology, Genome & Biomedical Facility, 451 East Health Sciences Drive,
University of California, Davis, CA. 95616. E-mail: asandaranarayanan@
ucdavis.edu. Telephone: (530) 754-7400 (Lab). Fax: (530) 752-7710.
(1) Murakami, K.; Tsuji, M. Japan Kokai Tokkyo Koho JP 0710800, 1993.
(2) Terao, S.; Kawamatsu, Y. Japan Kokai Tokkyo Koho JP 79106440, 1978.
(3) Orieto, H.; Shimizu, M.; Hayakawa, T.; Takehira, K. Japan Kokai Tokkyo
Koho JP 79106440, 1988.
(5) Seikel, M. K. Org. Synth. 1944, 24, 47-53.
(6) Mukhopadhyay, S.; Ananthakrishnan, S.; Chandalia, S. B. Org. Process
Res. DeV. 1999, 3, 451-454.
(7) Bacon, R. G. R.; Stewart, O. J. J. Chem. Soc., Chem. Commun. 1969, 301.
(8) Bacon, R. G. R.; Rennison, S. C. J. Chem. Soc., Chem. Commun. 1969,
308, 312.
(9) Aalten, H. L.; Gerad van Koten; Grove, D. M.; Kuilman, T.; Piekstra, O.
G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565-5578.
(10) Van Allen, D. Methodology and Mechanism: ReinVestigating the Ullmann
Reaction; Thesis, University Massachusetts, Amherst, MA, 2004.
(4) Murakami, K.; Tsujii, M. (Eisai Kagaku Kk, Japan.). Japan Kokai Tokkyo
Koho JP 07010800, 1995.
10.1021/op0502248 CCC: $33.50 © 2006 American Chemical Society
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to the aryl halide to obtain the arene and formaldehyde.7
Scheme 1. Synthesis of 3,4,5-Trimethoxytoluene
CuX
Ar-Br + CH3ONa CH OH8 Ar-H + NaBr + H-CHO (1)
3
Formaldehyde could not be isolated in this case due to its
loss by volatilization or alkoxide-catalyzed condensation
processes.
The process scheme reported in the patented literature11,12
for the synthesis of TMT involved the use of cuprous iodide
as catalyst and DMF as solvent for the methoxylation of
DBC, making it an economically unviable process for scale-
up. The direct methoxylation of DBC requires at least three
moles of sodium methoxide stoichiometrically, of which one
mole of the methoxide is consumed by the relatively more
acidic phenolic proton, and the remaining two moles, for
the substitution reaction. The resulting oxygen-anion charge
delocalizes into the aromatic nucleus, thereby deactivating
the ring to further substitution reaction. Since bromide is a
better leaving group due to its larger atomic radius, a
concerted four-center mechanism involving copper methox-
ide and the carbon-halogen bond can be envisaged. Under
these conditions the simultaneous formation of the C-OCH3
bond and of NaBr is facilitated.
The formation of excessive amounts of residue probably
could be due to the condensation reaction between DBC and
the methoxylated cresols (either mono or di) wherein the
sodium methoxide acts as base. Further, the separation and
purification of 3,5-dimethoxy-p-cresol (DMC) by vacuum
fractionation is cumbersome. The fractionation step of cresols
could be avoided by O-methylating the crude mixture of
methoxylated cresols with DMS under alkaline conditions
and then separating and purifying the TMT by vacuum
fractionation. An alternative to this problem would be to
O-methylate the DBC with dimethyl sulfate (DMS) under
alkaline conditions and then methoxylate the resulting DBMT
with 2.2-2.5 mol of sodium methoxide. Under these
conditions the methoxylation takes place in an uncharged
aromatic system. The synthesis of TMT starting from p-cresol
involves bromination and methylation followed by meth-
oxylation as key steps. There is little information available
on the byproducts and the intermediates such as the mono-
methoxylated derivatives formed during direct methoxylation
of DBC or DBMT. Therefore, an alternative process scheme
with the O-methylation step preceding the methoxylation step
was considered. (Scheme 1). The methoxylation of DBMT
was studied with methanol as solvent under pressure in a
sealed system, as well as by continuous distillation of the
solvent methanol at atmospheric pressure. The effect of
process parameters such as period of reaction, temperature,
and the reactant concentration were studied for the pressure
reaction. The reaction carried out by continuous distillation
of methanol is superior to the reaction under pressure from
the point of view of separation and purification of TMT.
The methoxylation of DBMT by continuous distillation of
methanol is superior to the direct methoxylation of DBC in
terms of conversion, selectivity, isolation, and residue
formation.
Experimental Section
Bromination. Experimental Procedure. The experiments
were carried out in a 1.0-L borosilicate glass reactor equipped
with a six-bladed turbine impeller, four baffles, an addition
funnel, and a reflux condenser. The outgoing gases were
passed through a caustic scrubber. The assembly was kept
in a constant-temperature bath. For large-scale industrial
bromination reactions the use of a glass-lined reaction vessel
can be considered to avoid corrosion.
One mole of p-cresol dissolved in 272 mL of 1,2-
dichloroethane was cooled to 20 °C. Liquid bromine (2.07
mol) was added continuously over a period of 5.0 h to the
reaction mixture. The reaction temperature was maintained
at 20-25 °C during the addition of bromine and for an
additional 2.0 h to ensure completion of reaction. The
reaction mixture was diluted with water and was extracted
with 1,2-dichloroethane to recover product. The organic layer
was washed with sodium metabisulfite solution to remove
the dissolved bromine and then washed with water to remove
the dissolved hydrobromic acid. The organic phase was
distilled under reduced pressure to remove 1,2-dichloroethane
from the crude product mixture. The conversion of p-cresol
was 100%, and the conversion to DBC was 0.964 mol
(96.4%). The conversion to the side product, 2-bromo-p-
cresol (MBC), was 0.028 mol (2.8%). On commercial scale
the organic phase containing the bromo derivatives can be
directly taken for the methylation reaction.
Purification of 2,6-Dibromo-p-cresol. The residual prod-
uct mixture after 1,2-dichloroethane recovery was distilled
under reduced pressure to separate the MBC (bp, 109-114
°C at 29-31 mm). The residue was then crystallized from
aqueous methanol to obtain DBC (yield: 0.9 mol, 90%;
purity: 99.5%).
Analytical Procedure. Five to ten milliliters of the organic
layer was evaporated to dryness under vacuum to obtain a
solid product. The melting point of the solid was determined
to be 46-48 °C. The organic layer was analyzed by gas
chromatography on Chemito 8510 equipped with a flame
ionization detector and connected to an integrator. The
(11) Mitsui Petrochemical Industries Ltd. Japan Kokai Tokkyo Koho JP 8168635,
1979.
(12) Gu, L.; Zhong, Y. Faming Zhuangli Shenqing Gongkai Shuomingshu CN
86100772, 1986.
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quantitation of the isolated DBC was calculated by external
calibration against purified industrial standard.
and the volume was measured. Freshly distilled dry methanol
was added to make up the volume to 400 mL. Before heating
the reaction mixture under pressure we ensured that all the
sodium metal had reacted completely. The presence of high
excess of methanol ensured complete conversion of sodium
metal to the methoxide. To the above solution, 0.1212 mol
of freshly prepared dry cuprous chloride was added, and the
reaction mixture was heated to 140 °C for a period of 8.0 h.
After 8.0 h the reaction mixture was cooled to 27-30 °C
and distilled under reduced pressure to recover methanol.
Five hundred milliliters of water was added to the product
mixture and then acidified to pH 3 with 40% sulfuric acid.
The solution was filtered under vacuum to remove the
insoluble cuprous salts, and the product mixture was
extracted into toluene. The toluene layer was washed with
water to neutral pH and then was distilled under reduced
pressure to remove the solvent toluene. The residual crude
mixture was fractionated under vacuum to separate the tar.
The fraction collected as distillate was analyzed by gas
chromatography to quantitate TMT and other mono- and
dimethoxylated toluenes by external calibration against
industrial standards. Retention times of the methoxylated
toluenes are as follows: 3,4-DMT 4.25 min, BDMT 8.75
min, TMT, 7.25 min.
(b) Methoxylation by Continuous Distillation of Metha-
nol. Experimental Procedure. The reactions were carried out
in a 2-liter, three-necked, round-bottomed flask fitted with
a thermo-well and a 0.16-m long Vigruex column to which
a condenser was attached in the downward direction for
continuous removal of solvent. The reaction mixture was
stirred with a Teflon paddle-type stirrer connected to an
overhead motor with a speed regulator. The whole assembly
was kept in an oil bath heated with an electric heater.
In a typical reaction, 2.0 mol of DBMT, 5 mol of sodium
methoxide (27% w/v solution in methanol), and 0.5198 mol
DMF were added to a clean, dry, three-neck flask, and the
volume was measured. Freshly distilled dry methanol was
added to make up the volume to 1200 mL and was stirred
to obtain a homogeneous solution. Freshly prepared dry
cuprous chloride (0.3839 mol) was added, and the reaction
mixture was heated. The temperature of the reaction mixture
was raised progressively from 70 to 105 °C by continuous
distillation of methanol over a period of 5.0 h. The final
temperature of the reaction mixture, after distillation of most
of the methanol, was maintained at 105 °C for an additional
2.0 h. The reaction mixture was cooled to 27-30 °C. Water
(1200 mL) was added to the reaction mixture and stirred for
15-20 min. Further purification was carried out as described
above for the pressure reaction.
Conditions. Column used was a 2-m long, 0.003-m
diameter stainless steel column packed with 10% SE-30 on
chromosorb-W; carrier gas, nitrogen; flow rate, 20 mL/min;
injector temperature, 300 °C; detector temperature, 300 °C;
oven temperature, 150 °C, ramp rate: 10 °C/min, 280 °C.
Methylation. Experimental Procedure. The experiments
were carried out in a 1.0-L borosilicate glass reactor equipped
with a six-bladed turbine impeller, four baffles, an addition
funnel, and a reflux condenser. The outgoing gases were
passed through a caustic scrubber. The assembly was kept
in a constant-temperature bath. The reaction was carried out
in a semi-batch mode due to high exothermicity of the
reaction.
One mole of DBC (purity: 99.5%) and 1.2 mol of DMS
were dissolved in 335 mL of 1,2-dichloroethane, and the
temperature of the solution was maintained at 30-35 °C.
Sodium hydroxide (1.25 mol, 50%w/w aqueous solution) was
added continuously over a period of 4.0 h to the above
mixture, maintaining the reaction temperature at 30-35 °C.
After complete addition of sodium hydroxide, the reaction
mixture was stirred for an additional 1.0 h at the same
temperature to ensure completion of reaction. The aqueous
and organic layers were separated. The organic phase was
washed with water to neutral pH and distilled under reduced
pressure to recover the 1,2-dichloroethane. The crude 3,5-
dibromo-4-methoxytoluene (DBMT) was distilled under
vacuum to obtain the pure compound (yield:0.93 mol, 93%;
purity: 99%). The aqueous phase was acidified with 40%
sulphuric acid to recover the unreacted DBC, which can be
recycled.
An alternative to this mode of carrying out the methylation
reaction could be to add DMS in a continuous mode,
maintaining a moderately alkaline pH. This mode of addition
of both the DMS and alkali could be very useful to optimize
the quantity of methylating agent during scale-up.
Analytical Procedure. The organic layer was analyzed by
gas chromatography, and the column conditions were the
same as those mentioned in the bromination step. The
quantitation of the isolated DBMT was calculated by external
calibration against purified industrial standard (retention
time: 10.5 min.).
Methoxylation. The reaction was carried out in two
different modes, (a) under pressure in a sealed reactor and
(b) at atmospheric pressure with distillative removal of
methanol.
(a) Methoxylation under Pressure. Experimental Pro-
cedure. Experiments were carried out in a stainless steel
autoclave of 600 mL capacity. The autoclave was equipped
with a multiple four-bladed, magnetically driven impeller
and an internal cooling coil. A solenoid valve controlled the
flow of coolant (water) in the coil. The autoclave was heated
externally by a heating element, and the temperature of the
reaction was maintained within (1 °C of the desired value.
In a typical reaction, 0.4286 mol of DBMT, 1.072 mol
of sodium methoxide (27% w/v solution in methanol), and
0.164 mol of DMF were added to a clean, dry autoclave,
The product mixture containing the methoxylated toluenes
after separating from the residue was fractionated under
vacuum. Pure TMT was collected as a fraction distilling at
117-118 °C at 5 mmHg (yield: 1.62 gmol, 81%; purity:
99%). The residue obtained was 0.6 wt % of DBMT taken
initially.
Analytical Procedure. The conversion of DBMT was
determined by estimating the amount of sodium bromide
formed in the reaction by Volhard’s method13 to get an initial
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Table 1. Bromination of p-cresola
Table 2. Methylation of DBC
components
gmol
%
components
gmol
1.0
%
p-cresol
liquid bromine
% overall conversion
% conversion to DBC
% conversion to 2-bromo-p-cresol
% selectivity to DBC
1.0
DBC
2.07
1.00
0.964
0.028
0.964
dimethyl sulfate
1.2
100
96.40
2.80
% conversion of DBC
% converson to DBMT
% residue (by weight of DBC)
0.9621
0.9410
0.0190
96.21
94.10
1.90
96.40
a Reaction conditions: DBC, 1.0 mole; dimethyl sulfate, 1.2 mol; sodium
hydroxide (50% w/w aqueous solution), 1.25 mol; mode of addition of aqueous
sodium hydroxide, semi-batch; temperature, 30-35 °C; solvent, 1,2-dichloro-
ethane, 335 mL; addition time of aqueous sodium hydroxide, 4.0 h; time for
completion of reaction, 1.0 h.
a Reaction conditions: p-cresol, 1.0 mol; mode of addition of bromine, semi-
batch; temperature, 20-25 °C; solvent, 1,2-dichloroethane, 272 mL; addition
time of bromine, 5.0 h; time for completion of reaction, 2.0 h.
estimate of the progress of the reaction. Since cuprous
chloride was used as catalyst in the reaction, the actual
amount of sodium bromide formed was calculated by
subtracting the number of moles of cuprous chloride from
the total moles obtained by titration. The actual conversion
of DBMT was calculated based on the GC analysis.
The crude product mixture after separating from the
residue was analyzed by gas chromatography, and the column
conditions were the same as those mentioned in the bromi-
nation step to estimate the amount of TMT and other
byproducts formed.
Table 3. Material balance: methoxylation of DBMT under
pressurea
components
mol taken
0.4286
mol recovered
%
DBMT
DBMT
TMT
92.93
7.07
70.86
5.99
10.75
0.7
0.0303
0.3035
0.0257
0.04606
DMT
BDMT
% Residue
Total
0.4286
0.4056
a Reaction conditions: DBMT, 0.4286 mol; sodium methoxide (27% w/v
methanol solution), 1.072 mol; DMF, 0.164 mol; CuCl, 0.1212 mol; temperature,
140 °C; solvent, methanol; time of reaction, 8.0 h; speed of agitation, 1000 rpm;
volume of reaction mixture, 400 mL.
The purity of the isolated product was determined by
external calibration against industrial standards.
Results and Discussion
of aqueous sodium hydroxide to a solution of DBC and
dimethyl sulfate in 1,2-dichloroethane. The overall conver-
sion of DBC was 96.21%, and the conversion to DBMT was
94.1%. The residue, calculated based on the weight of DBC,
was 1.9% (Table 2).
Definitions. ConVersion. The conversion is defined as the
ratio of the moles of the reactant reacted to the moles of the
reactant taken initially.
SelectiVity. The selectivity to a particular product is
defined as the ratio of moles of the reactant reacted for the
formation of that particular product to the moles of the
reactant reacted.
ConVersion to Product. The conversion to any given
product is defined as ratio of the moles of the reactant
consumed for the formation of that product to the moles of
the reactant taken initially.
Bromination. The bromination of p-cresol with liquid
bromine is an electrophillic substitution reaction. The hy-
droxyl group, being electron donating in nature, activates
the ring, and hence, the reaction does not require a halogen
carrier. The continuous addition of bromine prevents its
accumulation in the reaction mixture at any given point of
time, thereby preventing localized heat generation. The
overall conversion of p-cresol was 100%, and the selectivity
to DBC was 96.4%. The side product, 2-bromo-p-cresol was
2.8% (Table 1).
Methylation. At high temperature, the methylation of
DBC with dimethyl sulfate under alkaline conditions results
in the formation of significant amount of residue of unknown
composition. We suspect that the formation of residue at high
temperature, could be due to a self-condensation reaction of
DBC.14 To reduce the formation of residue, the reaction was
carried out in a semi-batch mode by the continuous addition
Methoxylation. Methanol was used as solvent in the
reaction due to the easy availability of solution of sodium
methoxide in methanol. The rate of the reaction is increased
significantly in the presence of cuprous chloride as catalyst
and DMF as cosolvent. The formation of dimethylamino
derivatives is possible at 140 °C due to the decomposition
of DMF and the further competing condensation of di-
methylamine with the aryl halide. However, the absence of
these derivatives in the final product mixture indicates their
loss in the aqueous phase as hydrogen sulfates during acid
extraction. Further, there were no uncontrolled reactions with
DMF even during scale-up up to 1 kg mol of p-cresol, and
no exothermicity was observed.
Since the reaction requires higher temperatures, it was
carried out in two different modes.
Methoxylation under Pressure. Material Balance. In the
methoxylation reaction 94.7% of the DBMT has been
accounted for. Since the composition of the residue was
unknown, it was calculated based on the weight of DBMT
taken initially (Table 3).
Effect of Period of Reaction. The time versus conversion
data indicates an increase in the conversion of DBMT to
93% with time estimated on the basis of the amount of
unconverted DBMT as analysed by GC. The conversion to
the side products formed was calculated by gas chromato-
graphic analysis of the crude mixture by external calibration
using industrial standards before further purification. The
(13) Beckett, A. H.; Stenlake, J. B. Practical Pharmaceutical Chemistry, Part
I, 3rd ed.; Athelon Press: London, 1975-76.
(14) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. ReV. 1974, 43, 679.
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