Chemistry Reference
In-Depth Information
OCH
3
CH
2
COCl
O
100ºC / 8h
+
EPZG
/cyclohexane
CH
3
O
Scheme 13.3
O
O
Cl
N
140ºC / 5h
+
ClCH
2
COCl
EPZG
Ph
CC
Ph
Scheme 13.5
Et
7.3 Benzylations
Scheme 13.4
Diphenylmethanes are the basic building block for a
wide variety of pharmaceutical products. Although
anhydrous AlCl
3
can be used in catalytic quantities
(provided that there are no functional groups that
can complex with this reagent), it is unselective,
giving rise to a high concentration of polybenzylated
products. It will scramble substituents that may be
present already in the molecule, further reducing the
selectivity of the reaction. Furthermore, the catalyst
must be washed out of the reaction mixture prior to
isolation of the product, so AlCl
3
cannot be reused.
Envirocat EPZ10, however, can be used under
very similar conditions to those used for AlCl
3
.
Unlike the homogeneous reagent, it will not scram-
ble substituents, it can give lower concentrations of
unwanted polybenzylated products and it can be
reused. This has been demonstrated in the benzyla-
tion of benzene (see Scheme 13.6), where four uses
were obtained from the catalyst. The reactions were
performed using a 10 : 1 molar ratio of benzene to
benzyl chloride (BzCl) and the reaction time reflects
the rate of addition of BzCl to the suspension. At the
end of each reaction the catalyst was filtered off
and, washed with and resuspended in benzene. With
each use, little or no decrease in activity was
observed and the isolated yields of diphenyl methane
remained at 70-75%.
cations is limited to activated aromatics and/or
activated alkyl chlorides. The most commonly used
aromatics are anisole and mesitylene. Acylation of
less-activated aromatic substrates, e.g. xylene,
toluene, etc. with acetyl chloride cannot be catalysed
by EPZG. However, if the aliphatic chloride is
activated by the presence of an electron-releasing
group, e.g. alkyl chain or phenyl, some very useful
intermediates can be produced using Envirocat
technology.
The acylation of anisole with phenylacetyl chlo-
ride to produce 4-methoxydeoxybenzoin is a reac-
tion that is catalysed efficiently and selectively by
EPZG (see Scheme 13.3). This particular ketone is
the intermediate to the anti-cancer drug Tamoxifen
[32] (see Scheme 13.4). The reaction is performed at
100°C in the presence of cyclohexane in an excess
of anisole over 8 h to give 100% conversion of the
acid chloride. Once the catalyst has been filtered off
and unreacted anisole recovered, the product is puri-
fied by treating the crude with cyclohexane to give
a yield of 85%, with a GC assay of >99% for the
para
isomer.
a-Chloroacetophenones are very useful interme-
diates in the production of agrochemicals. With
2,4,6-trimethyl-a-chloroacetophenone, the reaction
is performed at 140°C in the presence of cyclohexane
and 100% conversion is achieved over 5 h. Again,
treatment of the isolated crude with cyclohexane
results in an isolated yield of 85% (see Scheme 13.5).
7.4 Olefin alkylation
Olefin alkylation of aromatics results in a range of
intermediates that are used to produce surfactants.
