Hepatitis C.8 A variety of synthetic methods exist which allow
access to highly functionalized 4-hydroxyquinolinone esters,
facilitating library synthesis and drug discovery (Figure 1). For
example, substituted anilines 2 can be directly converted into
4-hydroxyquinolinone esters 1 by heating in the presence of
methanetricarboxylates (Route A).9 Difluorobenzonitriles 3 can
be elaborated to 4-hydroxyquinolinone esters via a double SN-
Ar pathway (Route B).7a Anthranilic esters 4 can be acylated
with malonyl chlorides and cyclized to the 4-hydroxyquinoli-
none esters under acidic conditions (Route C).10 Anthranilic
acids react with phosgene to form 2H-3,1-benzoxazine-2,4(1H)-
diones 5 (isatoic anhydrides),11 which can then be transformed
into 4-hydroxyquinolinone esters via reaction with malonates
(Route D).12 Although each of these methods offers certain
advantages, the high reaction temperatures (>200 °C) for the
conversion of 2 to 1 (Route A), the limited availability of a
broad range of suitably substituted starting materials (Route B),
and the need to isolate the acylated intermediate prior to
cyclization to 1 (Route C) have limited the widespread applica-
tion of these methods. Route D is perhaps the most general
protocol for the preparation of 1 starting from an isatoic
anhydride 5 and involves an N-alkylation-malonate addition-
intramolecular cyclization sequence.
A Practical Method for Preparation of
4-Hydroxyquinolinone Esters
Gregory L. Beutner,* Jeffrey T. Kuethe, and
Nobuyoshi Yasuda
Department of Process Research, Merck and Company, Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
ReceiVed June 6, 2007
4-Hydroxyquinolinone esters are a common motif for many
medicinal agents. Several methods exist for preparation of
these compounds, generally involving the use of sodium
hydride, which raises significant safety issues and limits their
application to large-scale synthesis. In this note a practical,
safe, and general method that employs a combination of
diisopropylethylamine and sodium tert-butoxide is described.
This allows for the synthesis of 4-hydroxyquinolinone esters
and amides in good yields.
4-Hydroxyquinolinone esters of type 1 represent the core
structure of several natural products1 and are the central
pharmacophore found in a number of medicinal agents. Com-
pounds of general subclass 1 have found numerous applications
as antimicrobial agents,2 antiangiogenics,3 antimalarial agents,4
aldose reductase inhibitors,5 anticonvulsants,6 multiple sclerosis
therapies,7 and RNA polymerase inhibitors for the treatment of
FIGURE 1. Synthesis of 4-hydroxyquinolinone esters.
The most commonly employed base to effect both the
N-alkylation of the isatoic anhydride and the subsequent
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10.1021/jo071200x CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/04/2007
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