FIELD OF INVENTION:
The present invention relates to a process for the synthesis of 4-methoxycyclohexanone. More
particularly, the present invention relates to a process for the synthesis of 4-
methoxycyclohexanone in presence of a phase transfer catalyst.
BACKGROUND OF INVENTION:
4-Methoxycyclohexanone is an important fine chemical intermediate for the synthesis of a
variety of agrochemical and pharmaceutical active ingredients. 4-Methoxycyclohexanone is a
key intermediate mainly used for the synthesis of spirotetramat pesticide (W02012122747Al)
cis-4-methoxy-cyclohexyl-1-carbamate. Generally, 4-methoxycyclohexanone is synthesized
from different starting materials like hydroquinone, cyclohexyl methyl ether, 4-methoxycyclohexanol
and 4-methoxyphenol through various chemical transformations.
Phase-transfer catalyst or PTC is a catalyst that facilitates the migration of a reactant from one
phase into another phase where reaction occurs. By using a PTC process, one can achieve faster
reactions, obtain higher conversions or yields and make fewer byproducts.
N105152884A
CN105152884A discloses a process for the preparation of 4-methoxycyclohexanone from 4-
methoxy-cyclohexanol in which hydrogen peroxide is used as an oxidizing agent, a molecular
sieve supported phosphotungstic acid is used as a catalyst and a 4-methoxycyclohexanone
reaction solution is obtained through continuous catalytic oxidation in a tubular reactor.
WO2018037428 discloses a process for the preparation of cyclic ketones, more particularly 4-
methoxycyclohexanone using hypohalous acid.
The drawback associated with the processes as disclosed in the prior art include, reactions are
generally carried out in an acidic or basic system and requires high reaction temperature at which
4-methoxy-cyclohexanone is not stable resulting in reduction of yield of desired product.
Further, the major drawback of prior art processes is, during the hydrogenation of 4-methoxy
phenol, a major impurity 4-methoxycyclohexanol is formed in the reaction due to over3
PI EXTERNAL
hydrogenation, which is difficult to control and therefore removal of this impurity from the
desired product requires fractional distillation which results in loss of desired product yield.
Therefore, to overcome the drawbacks associated with the processes as disclosed in the prior art,
there is a need for a simple, environment friendly and cost effective process for the synthesis of
4-methoxycyclohexanone. Accordingly, the present invention provides a simple, environment
friendly process for the synthesis of 4-methoxycyclohexanone from easily available and cheap
raw materials.
OBJECTIVE OF INVENTION:
The main objective of the present invention is to provide a process for the synthesis of 4-
methoxycyclohexanone from 4-methoxyphenol in presence of a phase transfer catalyst.
SUMMARY OF INVENTION:
Accordingly, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprising the steps of:
a) hydrogenating 4-methoxyphenol in presence of a catalyst and a solvent to afford a crude
product containing 4-methoxycyclohexanone and methoxycyclohexan-1-ol;
b) oxidizing the crude product of step (a) in a solvent with an oxidizing agent in presence of
a phase transfer catalyst to afford 4-methoxycyclohexanone.
In one embodiment, the hydrogenation step (a) is carried out in presence of additive selected
from but not limited to borax, sodium carbonate, sodium acetate, sodium hydroxide, sodium
bicarbonate, potassium carbonate, potassium acetate or calcium carbonate.
In a preferred embodiment, the catalyst in hydrogenation step (a) is selected from 1 to 30% by
weight of the palladium supported on carbon or alumina.
In an another preferred embodiment, the oxidizing agent is selected from but not limited to
sodium hypochlorite, pyridinium chlorochromate (PCC), sodium bromate (NaBrO3) or
potassium dichromate (K2Cr2O7). In a more preferred embodiment, the oxidizing agent is sodium
hypochlorite.
4
PI EXTERNAL
The solvent is selected from but not limited to methyl cyclohexane, ethylene dichloride,
cyclohexane, toluene, methylene dichloride, chlorobenzene, dichlorobenzene, hexane or heptane.
The phase transfer catalyst is selected from but not limited to tetrabutylammonium bromide
(TBAB), tetramethylammonium chloride, tetrabutylphosphonium bromide,
tetrabutylphosphonium chloride or tetramethylammonium bromide.
In one embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone, wherein the yield of desired product is in the range of 87 to 96%.
In another embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprises oxidizing the mixture of 4-methoxycyclohexanone and
methoxycyclohexan-1-ol with an oxidizing agent in presence of a phase transfer catalyst to
afford 4-methoxycyclohexanone according to the reaction scheme as depicted below:
O
O
O
O
HO
O
+
.
In yet another embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprises oxidizing methoxycyclohexan-1-ol with an oxidizing agent in
presence of a phase transfer catalyst to afford 4-methoxycyclohexanone according to the reaction
scheme as depicted below:
O
O
HO
O .
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional
embodiments, so that various aspects thereof may be more fully understood and appreciated.
5
PI EXTERNAL
In line with above objectives defined, the present invention provides a process for the synthesis
of 4-methoxycyclohexanone from 4-methoxyphenol.
In an embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprising the steps of:
a) hydrogenating 4-methoxy phenol in presence of a catalyst and a solvent to afford a crude
product containing 4-methoxycyclohexanone and methoxycyclohexan-1-ol;
b) oxidizing the crude product of step (a) with an oxidizing agent in presence of a phase
transfer catalyst to afford 4-methoxycyclohexanone.
In a preferred embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprising the steps of:
a) hydrogenating 4-methoxy phenol in presence of a catalyst and a solvent at temperature in
the range of 130 to 180 oC to afford a crude product containing 4-methoxycyclohexanone
and methoxycyclohexan-1-ol;
b) oxidizing the crude product of step (a) with an oxidizing agent in presence of a phase
transfer catalyst at temperature in the range of 30 to 80 oC to afford 4-
methoxycyclohexanone.
The yield of 4-methoxycyclohexanone is in the range of 87 to 96%.
In one embodiment, the hydrogenation step (a) is carried out in presence of additive selected
from but not limited to borax, sodium carbonate, sodium acetate, sodium hydroxide, sodium
bicarbonate, potassium carbonate, potassium acetate or calcium carbonate.
The hydrogenation in step (a) is carried out at temperature in the range of 130 to 180 oC.
Preferably, the hydrogenation is carried out at temperature in 140 to 170 oC. More preferably, the
hydrogenation is carried out at temperature in 150 to 160 oC.
The hydrogenation in step (a) is carried out at pressure in the range of 4 to 7 Kg/cm2. Preferably,
the hydrogenation is carried out at pressure in the range 5 to 6 Kg/cm2.
6
PI EXTERNAL
In another embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprises oxidizing the mixture of 4-methoxycyclohexanone and
methoxycyclohexan-1-ol with an oxidizing agent in presence of a phase transfer catalyst to
afford 4-methoxycyclohexanone according to the reaction scheme as depicted below:
O
O
O
O
HO
O
+
.
In a preferred embodiment, the oxidizing agent is selected from but not limited to sodium
hypochlorite, pyridinium chlorochromate (PCC), sodium bromate (NaBrO3) or potassium
dichromate (K2Cr2O7). In a more preferred embodiment, the oxidizing agent is sodium
hypochlorite.
The oxidation in step (b) is carried out at temperature in the range of 20 to 70 oC. Preferably, the
oxidation is carried out at temperature in the range of 20 to 50 oC. More preferably, the oxidation
is carried out at temperature in 25 to 50 oC.
The oxidation in step (b) is carried out under acidic conditions. Preferably, the oxidation in step
(b) is carried in presence of acid selected from acetic acid, hydrochloric acid or sulfuric acid.
The solvent is selected from but not limited to methyl cyclohexane, ethylene dichloride,
cyclohexane, toluene, methylene dichloride, chlorobenzene, dichlorobenzene, hexane or heptane.
The phase transfer catalyst is selected from but not limited to tetrabutylammonium bromide
(TBAB), tetramethylammonium chloride, tetrabutylphosphonium bromide,
tetrabutylphosphonium chloride or tetramethylammonium bromide.
The process for the synthesis of 4-methoxycyclohexanone as disclosed in the present invention is
as depicted in scheme 1 below:
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PI EXTERNAL
Scheme: 1
O
O
HO
O
O
O
HO
O
+
The process as disclosed in the present invention is carried out in two steps. The reaction starts
with hydrogenating 4-methoxyphenol in presence of 5% palladium on carbon (Pd/C) as a
hydrogenation catalyst and borax as additive in methyl cyclohexane as a solvent at 150 oC to
obtain a crude product containing 4-methoxycyclohexanone and 4-methoxycyclohexan-1-ol. The
obtained crude product is then oxidized in presence of aqueous sodium hypochlorite solution as
an oxidizing agent and tetrabutylammonium bromide as a phase transfer catalyst at 50 oC under
acidic condition to obtain 4-methoxycyclohexanone.
In yet another embodiment, the present invention provides a process for the synthesis of 4-
methoxycyclohexanone comprises oxidizing methoxycyclohexan-1-ol with an oxidizing agent in
presence of a phase transfer catalyst to obtain 4-methoxycyclohexanone according to the reaction
scheme as depicted below:
O
O
HO
O .
Following examples are given by way of illustration and therefore should not be construed to
limit the scope of the invention.
Example 1:
4-methoxy phenol (124 g) and methyl cyclohexane (180 g) were mixed with 0.6 g borax and 1.5
g of 5% palladium on carbon (Pd/C) in an autoclave. The reaction mixture is hydrogenated at
150 oC maintaining the pressure at 5-6 Kg/cm2. After completion of the reaction, the reaction
mixture was cooled and the catalyst was separated by filtration. The solvent was removed to
obtain a crude product containing 12% of 4-methoxycyclohexan-1-ol as a by-product. This crude
product was dissolved in ethylene dichloride (150 g) and treated with 12% sodium hypochlorite
solution (90 mL) in the presence of acetic acid (9 g) and tetrabutylammonium bromide (3 g) at
8
PI EXTERNAL
40 oC for 3 h. After the conversion of 4-methoxycyclohexan-1-ol into the desired product by
oxidation was completed, the phases were separated and the organic phase was concentrated to
obtain the crude product in the yield of 96%. The crude product can be further purified by
distillation.
Example 2:
4-methoxy phenol (124 g) and methyl cyclohexane (180 g) were mixed with 0.6 g borax and 1.5
g of 5% palladium on carbon (Pd/C) in an autoclave. The reaction mixture is hydrogenated at
150 oC maintaining the pressure at 5-6 Kg/cm2. After completion of the reaction, the reaction
mixture was cooled and the catalyst was separated by filtration. The solvent was removed to
obtain a crude product containing 12% of 4-methoxycyclohexan-1-ol as a by-product. This crude
product was dissolved in ethylene dichloride (150 g) and treated with pyridinium chlorochromate
(PCC) (31 g) at 25 oC for 2 h. After the conversion of 4-methoxycyclohexan-1-ol into the desired
product by oxidation was completed, the organic phase was concentrated to obtain the crude
product in the yield of 89%.
Comparative example 1:
4-methoxy phenol (124 g) and methyl cyclohexane (180 g) were mixed with 0.6 g borax and 1.5
g of 5% palladium on carbon (Pd/C) in an autoclave. The reaction mixture is hydrogenated at
150 oC maintaining the pressure at 5-6 Kg/cm2. After completion of the reaction, the reaction
mixture was cooled and the catalyst was separated by filtration. The solvent was removed to
obtain a crude product containing 12% of 4-methoxycyclohexan-1-ol as a by-product. This crude
product was dissolved in ethylene dichloride (150 g) and treated with 30% hydrogen peroxide
(17 g) in the presence of acetic acid (9 g) and tetrabutylammonium bromide (3 g) at 40 oC. The
reaction did not complete, and after 6 h of hold period, 8% of the by-product remained in the
reaction mixture. The title compound was formed in a yield of 86%.
Comparative example 2:
4-methoxy phenol (124 g) and methyl cyclohexane (180 g) were mixed with 0.6 g borax and 1.5
g of 5% palladium on carbon (Pd/C) in an autoclave. The reaction mixture is hydrogenated at
150 oC maintaining the pressure at 5 Kg/cm2. After completion of the reaction, the reaction
9
PI EXTERNAL
mixture was cooled and the catalyst was separated by filtration. The solvent was removed to
obtain a crude product containing 12% of 4-methoxycyclohexan-1-ol as a by-product. This crude
product was dissolved in ethylene dichloride (150 g) and treated with 12% sodium hypochlorite
solution (90 mL) at 40 oC. The oxidation reaction did not complete and after 6 h of hold period,
10% of the by-product remained in the reaction mixture. The title compound was formed in a
yield of 84%.

WE CLAIM:
1. A process for the synthesis of 4-methoxycyclohexanone comprising the steps of:
a) hydrogenating 4-methoxy phenol in presence of a catalyst and a solvent to afford a
crude product containing 4-methoxycyclohexanone and methoxycyclohexan-1-ol;
b) oxidizing the crude product of step (a) in a solvent with an oxidizing agent in
presence of a phase transfer catalyst to afford 4-methoxycyclohexanone according to
the reaction scheme as depicted below:
O
O
HO
O .
2. A process for the synthesis of 4-methoxycyclohexanone comprises oxidizing the mixture
of 4-methoxycyclohexanone and methoxycyclohexan-1-ol with an oxidizing agent in
presence of a phase transfer catalyst to afford 4-methoxycyclohexanone according to the
reaction scheme as depicted below:
O
O
O
O
HO
O
+
.
3. A process for the synthesis of 4-methoxycyclohexanone comprises oxidizing
methoxycyclohexan-1-ol with an oxidizing agent in presence of a phase transfer catalyst
to afford 4-methoxycyclohexanone according to the reaction scheme as depicted below:
O
O
HO
O .
4. The process as claimed in claim 1 or 2 or 3, wherein said oxidizing agent is selected from
sodium hypochlorite, pyridinium chlorochromate (PCC), sodium bromate (NaBrO3) or
potassium dichromate (K2Cr2O7).
5. The process as claimed in claim 4, wherein said oxidizing agent is sodium hypochlorite.
6. The process as claimed in claim 2 or 3, wherein said process is carried out in the presence
or absence of a solvent.
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PI EXTERNAL
7. The process as claimed in claim 6, wherein said solvent is selected from methyl
cyclohexane, ethylene dichloride, cyclohexane, toluene, methylene dichloride,
chlorobenzene, dichlorobenzene, hexane or heptane.
8. The process as claimed in claim 1 or 2 or 3, wherein said phase transfer catalyst is
selected from tetrabutylammonium bromide, tetramethylammonium chloride,
tetrabutylphosphonium bromide, tetrabutylphosphonium chloride or
tetramethylammonium bromide.
9. The process as claimed in claim 1, 2 or 3, wherein yield of 4-methoxycyclohexanone is in
the range of 87 to 96%.