Survey of solvents for the conrad-limpach synthesis of 4-hydroxyquinolones

Article abstract of DOI:10.1080/00397910802542044

A study of the synthesis of a 4-hydroxyquinoline derivative using the Conrad-Limpach reaction led to the identification of inexpensive and user-friendly solvents for this thermal condensation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802542044

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Survey of Solvents for the
Conrad–Limpach Synthesis of 4-
Hydroxyquinolones
Jean-Cristophe Brouet a , Shen Gu a , Norton P. Peet
a & John D. Williams a
a Microbiotix, Inc , Worcester, Massachusetts, USA
Published online: 02 Apr 2009.
To cite this article: Jean-Cristophe Brouet , Shen Gu , Norton P. Peet & John
D. Williams (2009) Survey of Solvents for the Conrad–Limpach Synthesis of 4-
Hydroxyquinolones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:9, 1563-1569, DOI:
10.1080/00397910802542044
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Synthetic Communications1, 39: 1563–1569, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802542044
Survey of Solvents for the Conrad–Limpach
Synthesis of 4-Hydroxyquinolones
Jean-Cristophe Brouet, Shen Gu, Norton P. Peet,
and John D. Williams
Microbiotix, Inc., Worcester, Massachusetts, USA
Abstract: A study of the synthesis of a 4-hydroxyquinoline derivative using the
Conrad–Limpach reaction led to the identification of inexpensive and user-
friendly solvents for this thermal condensation.
Keywords: Conrad–Limpach, 4-hydroxyquinoline, thermal condensation
INTRODUCTION
Molecules containing the quinoline nucleus often display biological activ-
ity, and several quinolines are marketed drugs. Indeed, quinoline deriva-
tives have shown significant biological activity in the treatment of many
diseases including malaria,[1] arthritis,[2] diabetes,[3] HIV,[4] and heart dis-
ease.[5] The alkaloid quinine (Figure 1), once claimed as ‘‘the drug to have
relieved more human suffering than any other in history,’’ reflects the
importance of quinoline-containing compounds.[6]
The chemical synthesis of quinolines has received a substantial
amount of attention for more than a century. Many classical syntheses
have been developed, including the Skraup synthesis, the Friedlander
synthesis, and the Combes synthesis. The Conrad–Limpach synthesis,
is similarly useful for the synthesis of quinolones. These classical synth-
eses have been reviewed.[7,8] The importance attributed to the synthesis
Received August 21, 2008.
Address correspondence to John D. Williams, Microbiotix, Inc., One
Innovation Drive, Worcester, MA 01605. E-mail: jwilliams@microbiotix.com
1563

1564
J.-C. Brouet et al.
Figure 1. Quinine, a quinoline-containing natural product.
of quinolines relates to the significant biological activities of the quino-
lines and also to the challenges that these syntheses represent.
RESULTS AND DISCUSSION
In many of the classical quinoline syntheses, the formation of a
high-energy intermediate is often achieved using high boiling solvents
and=or strong acids. The Conrad–Limpach reaction, used to prepare
4-quinolones, is shown in Scheme 1. Because the ultimate substrate for
the cyclization must be in the high-energy imine-enol tautomer (4), and
because the cyclization into the hemiketal 5 breaks the aromaticity of
the phenyl ring, solvents with very high boiling points are traditionally
used for this reaction. (Alternatively, a ketene–imine intermediate formed
via direct elimination of EtOH from the imine ester 3 is an alternative
reaction pathway; the cyclization of this intermediate would also require
the breaking of aromaticity and necessitate the same high-temperature
solvents.) Indeed, mineral oil (bp > 275 ꢀC), diphenyl ether (bp ¼ 259 ꢀC),
Scheme 1. Mechanism of classical Conrad–Limpach reaction.

Synthesis of 4-Hydroxyquinolones
1565
and more recently Dowtherm A (bp ¼ 257 ꢀC) are the most widely refer-
enced solvents.[7–11] Although mineral oil is inexpensive, it is an extremely
inconvenient solvent to employ because of its physical characteristics.
Diphenyl ether is inexpensive, but it is a solid at room temperature and
has an unpleasant odor. Dowtherm A (a eutectic mixture of diphenyl
ether and biphenyl) is more convenient because it is a liquid at room
temperature, but it is more expensive and also has an unpleasant odor.
For one of our synthetic programs, we required the synthesis of large
quantities of the 4-quinolone 9. Despite literature reports of high yields
using the classical Conrad–Limpach conditions, we were unable to repli-
cate these results. A substantial improvement in the yield was seen after
substituting the traditional method for a one-pot modification in which
the usual ethyl acetoacetate was replaced by the vinyl ether 8[12]
(Scheme 2). However, we also wanted to avoid the expense and other lim-
itations of the usual solvent choices. A serendipitous discovery led to the
finding that ethyl benzoate was an adequate replacement for the usual
high-boiling solvents. Ethyl benzoate is inexpensive, can easily be
removed from the product of the reaction, and does not have the unplea-
sant odor associated with the other solvents traditionally used.
Using this information, we decided to investigate variations on the
Conrad–Limpach synthesis to improve this process by screening several
solvents of different boiling points and polarity. We began with an
exploration of different alkyl benzoates with increasing boiling points.
We then also explored a number of other high-boiling solvents that are
not traditionally used for thermal cyclization reactions.
It was confirmed that the yield of 4-hydroxyquinoline increased with
solvents of increasing boiling point and that the best yields were obtained
with solvents of boiling points greater than 250 ꢀC, as shown in Table 1.
Initially, a series of alkyl benzoates was chosen as solvents. Although
alkyl benzoates are typically considered as reagents, they behave well
as solvents in this thermal cyclization. Increasing the size of the alkyl sub-
stituent from methyl to iso-butyl improved the yield from 25% to 66%.
Unfortunately, the yield has been improved in a costly manner because
iso-butyl benzoate is 13 times more expensive than methyl benzoate.
Other high-boiling-point solvents were also screened. 2-Nitrotoluene
Scheme 2. Preparation of 4-hydroxy-2-methyl-6-nitroquinoline (9).

1566

Synthesis of 4-Hydroxyquinolones
1567
Figure 2. Yield as a function of solvent boiling point for the Conrad–Limpach
reaction.
and 1,2,4-trichlorobenzene were comparable to iso-butyl benzoate in
terms of yield but are also less expensive. Surprisingly, 2,6-di-tert-
butylphenol was found to be one of the best solvents for this reaction
because it gave a clean product in reasonable yield (65%), is significantly
less expensive than Dowtherm A, and has no unpleasant odor. Figure 2
shows a plot of solvent boiling point versus yield for several solvents used
in the Conrad–Limpach thermal cyclization, which is shown in Scheme 2.
Yields generally increase with the reaction temperature, until a maximum
value of about 65% is achieved.
CONCLUSION
A group of atypical solvents was used for the preparation of a 4-
hydroxyquinoline derivative using the Conrad–Limpach thermal
cyclization reaction. The yield of the reaction generally improved with
higher-boiling solvents. Several alternative solvents, including 1,2,4-
trichlorobenzene, 2-nitrotoluene, and 2,6-di-tert-butylphenol, could be
useful, inexpensive alternative solvents for the preparation of quinoline
derivatives on a large scale.
EXPERIMENTAL
A 1-L round-bottom flask was charged with 4-nitroaniline (7, 10.0 g,
72 mmol), ethyl 3-ethoxybut-2-enoate[12] (8, 29.0 g, 183 mmol, 2.5 eq),
and the solvent (150 mL). Concentrated sulfuric acid (two drops) was

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J.-C. Brouet et al.
added to the stirred mixture. The reaction vessel was equipped with a
short distillation apparatus to remove the ethanol produced during the
reaction. The reaction mixture was heated at reflux for 1 h (with the
exception of iso-butyl benzoate, 2,6-di-tert-butylphenol, and Dowtherm
A, which required only 35 min of heating), and the ethanol was removed
by distillation as the reaction progressed. During the reflux period,
2-methyl-6-nitro-4-quinolone (9) precipitated out of solution. Once the
reaction mixture was cooled to room temperature, the product was
collected and washed with toluene and hexanes, then dried in a vacuum
oven (60 ꢀC, 5 mmHg) to constant weight.
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