Subject:      Phenyl acetones by electrolytic oxidation
From:         "guest" <guest@webshack-cafe.com>
Date:         1997/11/08

Electrolytic Oxidation.
=================
If electrolytic reduction then why not electrolytic oxidation?

See Appendix 5 for a general method of preparing Phenyl acetones by
electrolytic oxidation. [European Patent Application 0247526]. Why do they
always use those funny electrodes. Do carbon, lead, silver electrodes not
work or do they just give lower yields?


Appendix - Phenyl acetones by electrolytic oxidation.
=========================================
Process for 3,4-dimethoxyphenyl-acetone preparation. European Patent
Application 0247526, Filed: 02.12.87; to LARK S.p.a. Milan.

A process for preparing 3,4-dimethoxyphenylacetone is disclosed, which
consists in electrolytically epoxidating isoeugenol-methylether in a
mixture consisting of water and of a dipolar aprotic solvent, in the
presence of Br- ions, and in isomerizing the so-obtained epoxide, in an
inert organic solvent, in the presence of catalytic amounts of lithium
salts, by means of a heating at temperatures comprised within the range of
from 50° C up to the solvent refluxing temperatures.
The present invention relates to a process for the preparation of
3,4-dimethoxyphenylacetone by means of the electrochemical epoxidation of
isoeugenol-methylether and subsequent catalytic isomerization of the
so-obtained epoxide.
3,4-dimethoxyphenyl acetone is a useful intermediate for the synthesis of
Methyldopa, (-methyl-(-(3,4-dihydroxyphenyl)-alanine, an important
antihypertensive agent (U.S. Pat. 2,868,818).

State Of The Prior Art
------------------------------
The preparation of 3,4-dimethoxyphenylacetone by means of the oxidation of
isoeugenol-methylether by organic peracids (performic acid or peracetic
acid), to yield an intermediate diol which is subsequently converted into a
ketone by acidic hydrolysis is known (C.A. 82, 72640, 1975; and C.A. 69,
106243, 1968).
Such methods show however the drawback of requiring the use or organic
peracids, the dangerousness of which is known.

Furthermore, the preparation is known of 3,4-dimethoxyphenylacetone by
starting from veratraldehyde via the Darzens reaction (C.A. 101, 152292,
1984), or by starting from 3,4-dimethoxyphenylacetic acid by condensation
with acetic anhydride and ketene (C.A. 102, 24290, 1985).
Such methods, however, do not result economically valid, and they are
difficulty accomplishable on an industrial basis, mainly due to the high
cost and the not easy availability of the starting products.

Purpose of the present invention is preparing 3,4-dimethoxyphenylacetone by
means of a simple, cheap, highly selective and high-yield process, which
can be easily accomplished on an industrial scale by using non-dangerous
reactants and low-cost, easily available starting products.
It has been found now that the above purpose, and still other purposes, are
achieved by means of a process which comprises the electrochemical
epoxidation of isoeugenol-methylether and the subsequent catalytic
isomerization of the obtained epoxide into 3,4-dimethoxyphenylacetone.

Description Of The Invention
Therefore, the object of the present invention is a process for preparing
3,4-dimethoxyphenylacetone, characterised in that:
(a) isoeugenol-methylether, having the formula: 3,4-(MeO)2.C6H3.CH=CH.Me I
is submitted to an electrolysis in a not-partitioned electrochemical cell,
in a medium comprising a dipolar aprotic solvent and an aqueous solution
containing an alkali metal bromide or an alkali-earth metal bromide or a
quaternary ammonium bromide, in such an amount as to have at least 0.6 mol
of Br- ions per water litre, with graphite anodes or anodes constituted by
titanium, coated with oxides of precious metals of the VIII group or with
mixed oxides thereof with valve metals selected from Ti, Nb, Ta and Zr, and
that: (b) the epoxide II having the formula:

[begin non-proportional font]

MeO    //\
   \  //  \
    \//    \       O
     |     ||     / \
     |     ||    /   \
     |     ||---CH---CH--Me
    /\\    /
   /  \\  /
MeO    \\/

[end non-proportional font]

isolated from the reaction mixture resulting from (a) step is submitted to
an isomerization, in an inert organic solvent and in the presence of
catalytic amounts of a lithium salt selected from lithium iodide, bromide
and perchlorate, by being heated at temperatures comprised within the range
of from 50° C to the solvent refluxing temperature, to produce a methyl
ketone III.
The electrolysis reaction (a), leading to the formation of the epoxide, can
be carried out both batch-wise and continuously, at temperatures comprised
within the range of from 0° C to 50° C, preferably of from 10° C to 30° C,
with current intensities higher than 100 A/m2 being used, and with the
reaction mixture being kept stirred, by a stirring of mechanical type, or
obtained by exploiting the turbulence as generated by the gases formed
during the electrochemical reaction.
As the dipolar aprotic solvents, e.g., acetonitrile, dimethylformamide,
dimethylsulphoxide, sulpholane, N-methylpyrrolidone and dimethylacetamide,
preferably acetonitrile and dimethylformamide, can be used.

Generally, a volume ratio of the dipolar aprotic solvent to water comprised
within the range of from 1:1 to 10:1 and a concentration of
isoeugenol-methylether (I) in the mixture constituted by the solvent and
water higher than 10 g/L is used.

In order to be able to obtain high selectivities and high yields of epoxide
(II), it was found in particular that using is necessary, in the
electrolysis reaction (a), both a high concentration of Br- ions, higher
than 0.6 mol/water litre, up to the concentration corresponding to the
maximum solubility in H2O of the used bromide, and anodes constituted by
graphite or titanium coated with oxides of precious metals of the VIII
Group of the Periodic System, e.g., with Ru oxides or with mixed oxides of
the same metals with such valve metals as Ti, Zr, Nb and Ta. In fact, the
use of low concentrations of Br- ions and of common Pt anode leads to the
formation of substantial amounts of by-products, mainly constituted by
dimerization products. The high concentration of bromides in the reaction
mixture, besides favouring the yield of epoxide, renders easier the end
separation of the epoxide from the organic reaction phase and allows
furthermore high current efficiencies to be achieved.
The reaction (b) of isomerization of epoxide (II) to ketone (III), in the
presence of catalytic amounts of a lithium salt, takes place with high
yields and in a regioselective way. Generally, amounts of lithium salt
comprised within the range of from 0.05 to 0.4 mol per mol of epoxide (II),
and concentrations of epoxide in the organic solvent comprised within the
range of from 5 to 50 g/100 ml of solvent are used. 

As the inert organic solvents, e.g., acetonitrile and (C1-C4)-alkyl
acetates, preferably ethyl acetate, can be used. The duration of the
isomerization reaction can range from 2 up to 10 hours, according to the
adopted experimental parameters.

According to a practical operating way, to a not-partitioned
electrochemical cell the aqueous solution of alkali-metal bromide is
charged, and to it the organic solution of olefin (I) is added; then, with
the temperature being kept at a prefixed value comprised within the range
of from 10° C to 30° C, a current amount comprised within the range of from
2 to 2.6 Faradays per olefin mole is passed, until the starting olefin has
disappeared.

After the reaction has been completed, the epoxide (II) is separated from
the aqueous phase containing the alkali-metal bromides.
The so-obtained epoxide is dissolved in the organic solvent selected for
the subsequent isomerization step, e.g., in an alkyl acetate, to it a
catalytic amount of lithium salt is added and the reaction mass is heated
at the reflux temperature for the necessary time for isomerization to be
completed.
The lithium salt is then separated from the organic phase by means of
aqueous washes, or by the addition of a suitable non-solvent and subsequent
filtration.
The ketone (III) is finally obtained by evaporating its organic solution to
dryness, and shows, at a chromatographic analysis, a purity of (90%.
Then, if necessary, a further purification thereof may be performed by
means of the common techniques, e.g., of distillation, liquid
chromatography.
Some non-limitative examples are now supplied to the purpose of
illustrating the invention.

Example 1.
6.27 g of NaBr is dissolved in 25 ml of H2O and 125 ml of CH3CN, the
mixture is then strongly stirred by means of magnetic stirring, and to it
3.76 g of isoeugenol-methylether (I) is then added.
The obtained mixture is then electrolysed in a 250-ml not-partitioned
electrochemical cell, with a constant current of 850 mA, with two graphite
anodes with a total surface of about 17 cm2, and a central stainless-steel
cathode having a surface of about 25 cm2 being used, with a distance
between electrodes of about 1 cm. 5,200 Coulombs are passed, with the
reaction mixture being kept at a temperature of 20° C.
From the reaction mixture, discharged from the electrochemical cell, two
phases, i.e., the aqueous phase, containing Br- ions, and the organic
phase, containing acetonitrile and the reaction product, are separated.
From the organic phase acetonitrile is evaporated off under reduced
pressure, and to the resulting reaction product 40 ml of ethyl acetate is
added.
The gas-chromatographic analysis of the organic phase shows the presence of
epoxide (II) with a >90% purity.
The reaction mixture in ethyl acetate is then transferred to a 100-ml
reactor, purged under a nitrogen atmosphere, 340 mg of LiI is added, and
the whole mass is then heated, with mechanical stirring, on an oil bath, up
to ethyl acetate reflux temperature. The heating is continued for 5 hours,
until the disappearance of the epoxide (II), as evidenced by the thin-layer
chromatography.
The reaction product is cooled to room temperature, is washed with 10 ml of
H2O to the purpose of removing lithium iodide and is then dehydrated over
Na2SO4.
3.57 g is obtained of dimethoxy-phenylacetone (III), as determined by
gas-chromatographic analysis with an inner standard of
4,4'-dimethoxybenzophenone. The yield of ketone (III) relative to the
olefin (I) used as the starting material is of 87.1%.

Example 2
Example 1 is repeated in exactly the same way, with the exception that in
the isomerization step 250 mg of LiBr instead of 340 mg of LiI is used, and
that the reaction time results to be of 10 hours, instead of 5 hours. In
this way, a yield of ketone (III) of 86% relatively to the olefin (I) used
as the starting material is obtained.

Example 3
To a 250-ml not-partitioned electrochemical cell, 125 ml of CH3CN, 25 ml of
H2O, 6.47 g of NaBr and 2.78 g of isoeugenol-methylether (I) is added. The
mixture is electrolysed at a constant current of 350 mA, with a titanium
anode coated with a mixed Ru-Ti oxide (50:50 by weight), with a total
surface of about 7 cm2, and a central stainless-steel cathode having a
surface of about 15 cm2 being used, with a distance between electrodes of
about 1 cm. Through the cell 4,000 Coulombs are passed, with the reaction
mixture being kept at the temperature of 20° C.
The reaction mixture is then processed according to such modalities as
reported in Example 1, until the solution of the reaction product in ethyl
acetate is obtained; to such solution, 337 mg of LiI is added.
The mixture is then refluxed (at ethyl acetate refluxing temperature) for 5
hours, and the process is continued as described in Example 1, until 2.795
g is obtained of ketone (III), with a yield of 92.2% relatively to the
olefin (I) used as the starting material.

Example 4
To a 250-ml not-partitioned electrochemical cell, 125 ml of CH3CN, 25 ml of
H2O, 6.40 g of NaBr and 2.675 g of isoeugenol-methylether (I) is added.
The mixture, kept at 20° C, is electrolysed, with the same constant current
density and the same set of electrodes as of Example 1 being used, through
the cell 3,625 Coulombs, equalling 2.5 Faradays/mol, being passed. The
reaction mixture is then transferred to a rotary evaporator, for CH3CN to
be stripped under vacuum. The resulting reaction product is then extracted
three times with 30 ml of ethyl acetate, and is then dried over Na2SO4.
The organic extract, concentrated to a volume of 25 ml, and with 160 mg of
added LiI, is refluxed (at ethyl acetate refluxing temperature) for 6
hours.
The process is continued as described in Example 1, and 2.54 g is obtained
of ketone (III), with a yield of 86.5% relatively to the olefin (I) used as
the starting material.

Example 5
To a 250-ml not-partitioned electrochemical cell, 135 ml of CH3CN, 15 ml of
H2O, 6.20 g of NaBr and 2.82 g of olefin (I) is added.
The mixture, kept at 20° C, is electrolysed by using the same electrodes as
of Example 1, but with a constant current density of 1.7 A being used,
until through the cell 4,000 Coulombs have been passed.  The reaction
mixture is then processed as described in Example 4.
2.56 g is obtained of ketone (III), with a yield of 83.2%, as computed
relatively to the olefin (I) used as the starting material.

Examples 6-9
To a 250-ml not-partitioned electrochemical cell, 100 ml of DMF, 50 ml of
H2O, 6.72 g of NaBr and 4.25 g of isoeugenol-methylether (I) is charged.
The mixture is then electrolysed under the same conditions, and by using
the same set of electrodes as used in Example 1, with a total of 5,670
Coulombs being passed.
At reaction end, the mixture is discharged, to it 250 ml is added of 20%
aqueous NaCl solution, and it is then extracted four times with 50 ml of
ethyl acetate. The extract is washed twice with 50 ml of 20% aqueous NaCl
solution, and is then dried.
The organic extract is concentrated to a volume of 100 ml by the solvent
being evaporated off.
On three aliquots, of 20 ml each, of said extract, the isomerization
reactions are carried out at the ethyl acetate reflux temperature, by using
the same lithium salts and reaction times as shown in Table 1.
From the fourth aliquot of 20 ml of above said extract, ethyl acetate is
evaporated off and replaced with the same amount of acetonitrile.
The isomerization of the reaction product is then carried out at
acetonitrile refluxing temperature, with the lithium salt and the reaction
time being used as shown in Table 1.
In Table 1 also the conversions and the yields of ketone (III), as computed
relatively to olefin (I) used as the starting material, are reported for
each example.
Table 1

                             Lithium Salt
Eg.     Solvent         Type    mg      Time    Con %   Yield %
6       Ethyl Acetate   LiI     180     6 h     100     91.4
7       Ethyl Acetate   LiBr    140     10 h    100     87.7
8       Ethyl Acetate   LiClO4  160     10 h    60      45.8
9       Aceto-nitrile   LiI     185     6 h     100     77.1    

Claims
1.      Process for preparing 3,4-dimethoxyphenylacetone, characterised in that:
(a) isoeugenol-methylether is submitted to an electrolysis in a
not-partitioned electrochemical cell, in a medium comprising a dipolar
aprotic solvent and an aqueous solution containing an alkali metal bromide
or an alkali-earth metal bromide or a quaternary ammonium bromide, in such
an amount as to have at least 0.6 mol of Br- ions per water litre, with
graphite anodes or anodes constituted by titanium, coated with oxides of
precious metals of the VIII group or with mixed oxides thereof with valve
metals selected from Ti, Nb, Ta and Zr.
and that: (b) the epoxide isolated from the reaction mixture resulting from
(a) step is submitted to an isomerization, in an inert organic solvent and
in the presence of catalytic amounts of a lithium salt selected from
lithium iodide, bromide and perchlorate, by being heated at temperatures
comprised within the range of from 50° C to the solvent refluxing
temperature.
2.      Process according to claim 1, characterised in that the electrolysis is
carried out at temperatures comprised within the range of from 0° C to 50°
C, using a current density higher than 100 A/m2
3.      Process according to one or both of the claims 1-2, characterised in
that the ratio by volume of the dipolar aprotic solvent to water is
comprised within the range of from 1:1 to 10:1 and that the concentration
of isoeugenol-methylether in the mixture constituted by the dipolar aprotic
solvent and water is higher than 10
4.      Process according to claim 3, wherein the dipolar aprotic solvent is
selected from acetonitrile and dimethylformamide.
5.      Process according to one or more of the claims 1-4, wherein in (b)
isomerization reaction an amount of lithium salt comprised within th range
of from 0.05 to 0.4 mol/mol of epoxide (II), and a concentration of epoxide
in the inert organic solvent comprised within the range of from 5 to 50
g/100 ml of solvent is used.
6.      Process according to claim 5, characterised in that the inert organic
solvent is selected from acetonitrile and ethyl acetate.


