choice.6 Here we report a very simple and highly efficient
method for the synthesis of aromatic and cyclic ketones using
carboxylic acids in the presence of cyanuric chloride and
AlCl3 under mild conditions.
Table 1. Intermolecular Friedel-Crafts Acylations of
Carboxylic Acids with Toluene in the Presence of Cyanuric
Chloride/AlCl3 at Room Temperature
Cyanuric chloride is useful for the synthesis of alcohols,
diazocarbonyl, acyl azides, and hydroxamic acids as well as
acyl chlorides from carboxylic acids.7,8 Use of a 1:1:1 molar
ratio of carboxylic acid-cyanuric chloride-amine is known
to provide the acid chloride at room temperature.8b We
hypothesized that an acyl chloride formed in such a way
could be used in the same pot for direct synthesis of ketones
via the Friedel-Crafts reaction, and at the same time the
HCl byproduct from AlCl3 could be buffered by an amine
base. We found this to be true, plus we were pleasantly
surprised to find that the acylation occurred rapidly and at
room temperature.
Mixing cyanuric chloride with carboxylic acids gave no
reaction with toluene under a variety of attempted conditions.
However, mild and expedient formation of the activated form
of the acid in less than 15 min was achieved by adding
pyridine dropwise to the mixture of cyanuric chloride and
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carboxylic acid in CH2Cl2 at room temperature. Typically,
the carboxylic acid (0.43 mmol, 1 mol equiv) and cyanuric
chloride (0.69 mmol, 1.6 mol equiv) were dissolved in
CH2Cl2 (5 mL) in an open test tube, and then pyridine (0.43
mmol, 1 mol equiv) was added dropwise at room tempera-
ture. The suspension that formed was occasionally agitated
on a vortex mixer. After 15 min at room temperature, AlCl3
(0.52 mmol, 1.2 mol equiv) was added portion-wise, followed
by addition of excess toluene. The reaction mixture was
occasionally shaken on a vortex mixer at room temperature
for 5-20 min until conversion to the ketone was complete
(monitored by TLC and GC-MS analyses).
Interestingly, in all cases, very high regioselective carbony-
lation took place at the para position. Encouraged by the
remarkable activity of the cyanuric chloride/pyridine/AlCl3
system as a means to achieve acylation, we examined the scope
and limitations of its use in intermolecular Friedel-
Crafts reactions of toluene with various aliphatic as well as
aromatic carboxylic acids (Table 1). Aliphatic carboxylic acids
and aromatic carboxylic acids bearing either electron-donating
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