Synthesis of a Quinolone Derivative

Pinaki Bose* and Carl Lovely

700 Planetarium Place
Arlington, TX 76010
Date: October 17, 2011

ABSTRACT: The antibiotic precursor 6-bromo-4-oxo-

4H-quinoline was successfully synthesized from 4-
bromoaniline. The product was generated with reason-
able purity and yield from condensation of the aniline
with Meldrum's Acid, followed by thermal rearrange-
ment. The identity and purity of the product was veri-
fied using infrared spectroscopy and melting point
comparisons.

Quinolones are a class of heterocyclic compounds

containing a 4-oxo-4H-quinoline motif. These mole-
cules and their derivatives, such as fluoroquinolones,
are bioactive and are often used as potent antibiotics.
(1) Due to their importance in pharmaceuticals, there is
significant interest in the synthesis of quinolone deriva-
tives.
In this study, we demonstrate the synthesis of 6-
bromo-4-oxo-4H-quinoline (4) from 4-bromoaniline
via condensation with Meldrum's Acid followed by
thermal rearrangement of the intermediate. Our target
of synthesis is shown in Figure 1.
Scheme 1. Condensation of Meldrum's Acid and
4-bromoaniline
EXPERIMENTAL
4.6 g (31.9 mmol) of Meldrum's Acid was dissolved in
60 mL of methyl orthoformate and heated for two
hours under reflux in an inert nitrogen atmosphere. At
the end of two hours, the acid solution was allowed to
cool before the addition of 4-bromoaniline (3.8 g,
22.1 mmol). The resulting reaction mixture was heated
again using the same reflux and neutral atmosphere
conditions for two periods of four hours, during which
a yellow precipitate was formed. This precipitate was
collected using suction filtration and then purified by
recrystallization from methanol. 6.216 g (87%) yield;
m.p. 135-137 °C; infrared spectrum in Figure 2;
1H NMR in Figure 3.

2.00 g (6.12 mmol) of 3 was then added to hot di-

Figure 1. 6-bromo-4-oxo-4H-quinoline (4), the intended phenyl ether (31 mL) and heated under reflux for sev-
synthesis product. eral hours until gas evolution ceased. The mixture was
then cooled to room temperature and 31 mL of petrole-
The process begins with the condensation of 4-
um ether was added and swirled to yield a murky mix-
bromoaniline (1) with Meldrum's Acid (2), catalyzed by
ture from which the product was allowed to precipitate
methyl orthoformate in an inert nitrogen atmosphere.
for 48 hours. The solid product was collected using suc-
The reaction yields the stable yellow solid 2,2-dimethyl-
tion filtration and washed with petroleum ether.
5-(4-bromopehnylaminomethylene)-1,3-dioxan-4,6-
0.913 g (67%) yield; m.p. >250 °C; infrared spectrum in
dione (3). Scheme 1 illustrates the reaction leading to 3.
Figure 4; 1H NMR in Figure 5.
Thermal rearrangement of 3 gives rise to the final
product, 4, shown in Figure 1. A full mechanism for the
rearrangement is provided in Scheme 2.

RESULTS AND DISCUSSION
The quinolone derivative pictured in Figure 1 was
successfully synthesized with 67% yield from 1 (4-
bromoaniline) and 2 (Meldrum's Acid), and the identity
of the product was verified using infrared spectroscopy
and 1H NMR data.
While the first step of the reaction proceeded with
good yield (87%), the drop in yield in the second is at-
tributed to overheating and lack of agitation, which led
to the formation of a hard, black residue on the bottom
inner surface of the flask. Almost 0.3 g of this residue
was recovered, but was discarded as the infrared spec-
trum did not match that of the remaining product.
However, the yield of the second step compares favora-
bly with the literature-reported yield of 72% despite this
loss. (2)
Both the infrared and NMR data for 3 are in close
agreement with literature. (2) The presence of peaks
between 3000 and 3300 cm-1 in the infrared spectrum
of the yellow intermediate 3 indicates the presence of
aromatic hydrogens in the benzene ring. Furthermore,
the peak at 1714 cm-1 is believed to arise from C=O
stretching of the esters in Meldrum's Acid ring.
The 1H NMR of 3 reveals a clear 1:4:6 ratio between
peak areas. The single sharp peak of area 6H at 1.2 ppm
is believed to be representative of the six equivalent
methyl protons. The two doublet peaks near 6.7 ppm
with a collective area of 4H are indicative of para sub-
stitution on an aromatic ring, and likely are a result of
the four aromatic protons. The remaining two 1H dou-
blet peaks at 6.7 and 8.0 ppm are likely the nitrogen
proton and the proton on the adjacent carbon, respec-
tively. These two adjacent protons likely cause splitting,
resulting in doublet peaks.
The final product was a brown solid whose melting
point exceeded the thermometer maximum of 250 °C;
the true melting point is expected to lie at 282-284 °C.
(3) Though the product failed to melt, it seemed to sub-
limate to some extent above 217 °C. A similar phenom-
enon was observed and exploited for product purifica-
tion in the literature. (2)
The infrared data for the final product 4 shown in
Figure 4 features several peaks in the aromatic region
between 3000 and 3300 cm-1, as well as a strong peak
at 1604 cm-1 due to the carbonyl group. The N-H stretch
was identified as the peak at 3422 cm-1. The infrared
spectrum of the product is in close agreement with the
literature. (2)
Data from 1H NMR of the product features a sharp,
unsplit peak at 4.8 ppm, identified as the nitrogen pro-
ton, and a group of peaks between 6.0 and 7.2 ppm,
identified as the remaining aromatic protons. The ratio
between peak areas was 10:1. However, the low signal-
to-noise ratio in the reading suggests that the integra-
tion may not be very accurate. The reason for the noise
in the reading is believed to be due to the insolubility of
the product in the solvent, CDCl3.
Despite the possibly faulty NMR reading of the prod-
uct, the IR data and melting point suggest that the tar-
get quinolone was successfully synthesized and suffi-
ciently purified for characterization with a reasonable
yield.
ACKNOWLEDGMENTS
We acknowledge the help and direction provided by Dr.
Carl Lovely and the technical support provided by Dr. Su-
mit Bhawal.
REFERENCES
(1) Nelson, JM; Chiller, TM; Powers, JH; Angulo, FJ.
Fluoroquinolone-resistant Campylobacter species and
the withdrawal of fluoroquinolones from use in poultry:
a public health success story. Clin. Infect. Dis. 2007,
44(7), 977-80.
(2) Beifuss, U; Schniske, U; Feder, G. Efficient allyla-
tion of 4-silyloxyquinolinium triflates and other posi-
tively charged heteroaromatic systems. Tetrahedron.
2001, 57(6), 1005-1013.
(3) Huang, X and Liu, Z. Solid-Phase Synthesis of
4(1H)-Quinolone and Pyrimidine Derivatives Based on
a New Scaffold-Polymer-Bound Cyclic Malonic Acid
Ester. J. Org. Chem. 2002, 67(19), 6731-6737.
Figure 2. Infrared spectrum of yellow intermediate 3

Figure 3. 1H NMR of yellow intermediate 3

3
Figure 4. Infrared spectrum of the final product 4

Figure 5. 1H NMR of the final product 4

4
Scheme 2. Mechanism of thermal rearrangement from intermediate to final product

Lab Question: The base molecule of the product is quinoline, which is a fully aro-
matic double heterocyclic ring. The 4H is used to indicate ring saturation at carbon 4.
Though double bonded to oxygen, carbon 4 has no double bonds in the ring structure,
and so is a point of unsaturation, a deviation from the base quinoline structure that
must be indicated and specified using 4H.