Synthesis of zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives

Article abstract of DOI:10.1016/j.tet.2008.02.052

Zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives were synthesized through a unique reaction of 4-hydroxy-2(1H)-quinolinone with p-benzoquinone and N-heterocyclic aromatics. The zwitterions possessed astropisomeric nature. A possible mechanism of the reaction was presented.

Full text of DOI:10.1016/j.tet.2008.02.052

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Tetrahedron 64 (2008) 4403e4407
www.elsevier.com/locate/tet
Synthesis of zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives
b
c
c
b
Sheng-Ling Zhang a,b, , Zhi-Shu Huang , Yue-Ming Li , Albert S.C. Chan , Lian-Quan Gu
*
a Department of Chemistry, Shaoguan University, Shaoguan 512005, People’s Republic of China
b School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China
c Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong
Received 26 September 2007; received in revised form 15 February 2008; accepted 18 February 2008
Available online 21 February 2008
Abstract
Zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives were synthesized through a unique reaction of 4-hydroxy-2(1H)-quinolinone with
p-benzoquinone and N-heterocyclic aromatics. The zwitterions possessed astropisomeric nature. A possible mechanism of the reaction was
presented.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 4-Hydroxy-2(1H)-quinolinone; Zwitterion; p-Benzoquinone
1. Introduction
OH
OH
N+
O
O-
A broad number of fascinating pharmacological activities
have been associated with 2-quinolinone derivatives. The qui-
nolinone alkaloids, isolated from the Rutaceae family of
plants, have been shown to exhibit a variety of biological prop-
erties1 including antibacterial, antifungal, and antiviral. 3-
Halo-2(1H)-quinolinones have been used as cardiac stimulants
and as herbicides.2 Several 2-quinolones fused to sulfur-con-
taining heterocycles have been proposed to exert cytostatic
against a broad range of malignant cell lines.3 3-Aryl-4-hy-
droxy-2(1H)-quinolinones have been found to serve as key in-
termediates in the synthesis of non-peptide GnRH receptor
antagonists.4 In addition, some 4-hydroxy-2(1H)-quinolinone
derivatives have been reported to show a broad spectrum of ac-
tivity against both wild-type HIV-1 and key NNRTI-relevant
mutant viruses.5
In a recent communication,6 we reported the synthesis of
the zwitterionic 4-hydroxycoumarin derivatives 1 (Fig. 1)
through a unique reaction of 4-hydroxycoumarins with p-ben-
zoquinone and pyridine in aqueous acetone. Apparently, the
reaction involved the nucleophilic addition of 4-hydroxycou-
marin to p-benzoquinone. 4-Hydroxy-2(1H)-quinolinone is
N
H
O
O
O
1
2
Figure 1.
similar to 4-hydroxycoumarin in the nucleophilicity of C-3.
For example, nucleophilic substitution of 4-hydroxy-2(1H)-
quinolinone and prenyl bromide in aqueous sodium hydroxide
has been carried out to generate diprenylated quinolone7 2
(Fig. 1). Thus, we envisioned that 4-hydroxy-2(1H)-quinoli-
none would also react with p-benzoquinone and pyridine to
yield the corresponding zwitterionic compound. We describe
here the synthesis of zwitterionic 4-hydroxy-2(1H)-quinoli-
none derivatives starting from 4-hydroxy-2(1H)-quinolinone
and several N-heterocyclic aromatic compounds, and the astro-
pisomeric nature of these zwitterionic compounds.
2. Results and discussion
Shah et al.8 have reported a simple and potential method to
synthesize 4-hydroxycoumarins using phenols and malonic
acid. Considering some similar chemical properties between
* Corresponding author. Tel.: þ86 751 8120118.
E-mail address: zhisland@yahoo.com.cn (S.-L. Zhang).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.052

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S.-L. Zhang et al. / Tetrahedron 64 (2008) 4403e4407
aniline and phenol, 4-hydroxy-2(1H)-quinolinone 3 would
also be synthesized following Shah’s procedure. Treating
aniline with an equimolar proportion of malonic acid in the
presence of a mixture of 2e3 mol each of anhydrous zinc
chloride and phosphorus oxychloride as the condensing agent
at 65 ꢀC for 36 h, we obtained 4-hydroxy-2(1H)-quinolinone
in 75% yield (Scheme 1).
quinolinone/p-benzoquinone/pyridine¼1:2:2, 1:2:3, 1:2:4
(mol/mol)), and (iii) solvent (methanol, ethanol), but the yield
of 4a has not been improved effectively. It was due to a exist-
ing competitive reaction, which afforded 2,3-disubstituted-1,4-
benzoquinone 5.9
The different shift of the two a-protons located on the pyr-
idine ring of 4a, at d 8.94 and 8.45 ppm, respectively,
displayed that the pyridine ring could not rotate freely along
the CeN bond. This restricted rotation made the compound
exist as atropisomers. It is worth noting that atropisomeric
compounds are of considerable interest due to their presence
in a number of biologically active natural products and their
utility as directing groups in asymmetric synthesis.10 Thus,
if other N-heterocyclic aromatics, which did not have a
C2-symmetric axis through the nitrogen atom, such as 3-meth-
ylpyridine and quinoline, were treated with 4-hydroxy-2(1H)-
quinolinone and p-benzoquinone, both cis and trans products
were obtained. The results of the reaction using 3-methylpyr-
idine, 2,4,6-trimethylpyridine, or quinoline instead of pyridine
as reactant were summarized in Table 1.
NH2
OH
CH2(COOH)2
ZnCl2, POCl3
65 °C, 36 h, 75%
N
H
O
3
Scheme 1. Synthesis of 4-hydroxy-2(1H)-quinolinone.
When the mixture of 4-hydroxy-2(1H)-quinolinone 3,
2 equiv of p-benzoquinone, and 2 equiv of pyridine in 30 ml
aqueous acetone (v/v¼1:1) was stirred at room temperature
for 24 h, the zwitterion 4a was generated in 43% yield after
column chromatography (Scheme 2). The assignment of com-
pound 4a was confirmed by 1H NMR analysis of the expected
chemical shifts and geminal coupling constants. To optimize
the yield of 4a, we studied the effect of several factors on
the outcome of this reaction, including (i) reaction temperature
(rt, 40, 50 ꢀC), (ii) the ratio of the reactants (4-hydroxy-2(1H)-
The results showed that the yield of quinoline zwitterion
(Table 1, entry 3) was much lower than that of pyridine zwit-
terion and 3-methylpyridine zwitterion (Table 1, entry 1), and
any trace of the 2,4,6-trimethylpyridine zwitterion (Table 1,
entry 2) was not detected by TLC under the similar reaction
H
O
N
O
O
OH
OH
O
O
OH
N+
pyridine
rt, 24h, 43%
O-
+
+
OH
OH
O
N
H
O
O
N
H
N
H
3
4a
Scheme 2. Synthesis of compound 4a.
5
Table 1
Reaction of 4-hydroxy-2(1H)-quinolinone with p-benzoquinone and N-heterocyclic aromatics
Entry
Heteroaromatics
Yielda (%)
Product 4
cis/transb
OH
OH
OH
N+
O-
N+
O-
1
39
1.4:1
OH
O
N
O
N
H
N
H
4b'(trans)
4b(cis)
2
3
a
0
N
OH
OH
OH
N+
O-
N+
O-
17
1:1.6
OH
N
O
N
H
O
N
H
4d'(trans)
4d(cis)
Isolated yield.
Determined by 1H NMR spectra.
b

S.-L. Zhang et al. / Tetrahedron 64 (2008) 4403e4407
4405
H
attack of quinoline and the low yield of quinoline zwitterion.
For 2,4,6-trimethylpyridine, the two methyl groups adjacent
to the nitrogen atom seriously prevented the nucleophilic at-
tack and led to no generation of 2,4,6-trimethylpyridine
zwitterion.
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
For 3-methylpyridine and quinoline zwitterions (Table 1,
entries 1 and 3), due to the restricted rotation about the
CeN bond, both cis and trans products were obtained, which
could not be separated by column chromatography (silica gel).
The assignment of the cis and trans stereochemistry and their
ratio could be determined by 1H NMR spectra (Fig. 3). For 3-
methylpyridine zwitterion, only the a-proton next to the
methyl group on the pyridine ring was predicted to show sin-
gle peak in the aromatic region. The appearance of the two ar-
omatic singlets, at d 8.94 and 8.39 ppm, respectively, implied
that both cis and trans isomers might be generated. Further-
more the two aromatic singlets had a total integrated area cor-
responding to 1H, which was consistent with the mixture of
the two isomers. The peak at d 8.79 ppm was attributed to
the a-proton (H20) adjacent to the methyl group of cis isomer,
H
H
Figure 2.
conditions. The apparent difference in the yield of these zwit-
terions disclosed that the surrounding space of the two un-
shared electrons in the N-sp2 orbital had a profound effect
on the outcome of the reaction. The larger the surrounding
space, the better yield would be obtained. Because the occu-
pied nonbonding N-sp2 orbital is parallel to C8eH bond, the
surrounding space of the nonbonding N-sp2 of quinoline is
less than that of pyridine and 3-methylpridine (Fig. 2). The
less space resulted in the difficulty of the nucleophilic
3
4
5
2
OH
8
1
N+
7
9
6
O-
20 13
10
19
18
12
11
OH
O
14
N
H
17
15
16
3''
5'
4''
4'
2''
1''
6'
OH
8
OH
8
1'
3'
N+
N+
5''
7
7
9
9
6''
2'
O-
O-
20
13
10
20 13
10
19
19
12
12
11
11
OH
18
17
OH
18
17
O
14
O
14
N
H
N
H
15
15
16
16
4b''(trans)
4b(cis)
1
Figure 3. The H NMR spectra of compounds 4a, 4b, and 4b0.

4406
S.-L. Zhang et al. / Tetrahedron 64 (2008) 4403e4407
made the 4-hydroxy-2(1H)-quinolinone ring tilt toward the
HO
OH
O
N-heterocyclic aromatic ring until the equilibration between
the ion pair attraction and the steric interaction. Conversely,
the tilting 4-hydroxy-2(1H)-quinolinone ring limited the
heterocyclic aromatic ring to rotate freely by the steric
interaction.
N+
-O
NH
Figure 4.
A possible mechanism of the formation is presented in
Figure 5. The Michael addition of 4-hydroxy-2(1H)-quinoli-
none with p-benzoquinone first gives intermediate 6, which
is subsequently autooxidized to generate quinone derivative
7. Quinone derivative 7 is attacked by pyridine at the 3-posi-
tion to form 4a, which is in a hydroquinone form due to the
electron-withdrawing effect of the pyridinium moiety.
In summary, the synthesis of the zwitterionic 4-hydroxy
2(1H)-quinolinone derivatives through a unique reaction was
in which H20 was far away from the shielding region of the
oxyanion, and came at low fields relative to H20 of the trans
isomer. Thus the area ratio of 1.4:1 of the two aromatic
singlets represented the ratio of cis and trans isomers. It was
interesting to note that there was more trans isomer than cis
isomer in the quinoline zwitterion (cis/trans¼1:1.6, Table 1,
entry 3).
1
The restricted rotation about the CeN bond was considered
to be caused from both the intramolecular ion pair attraction
and the steric interaction (Fig. 4). The ion pair attraction
described. The astropisomeric nature was determined by H
NMR spectra. A possible mechanism of the formation of zwit-
terions was presented.
O
O
OH
3. Experimental
OH
OH
OH
[O]
O
3.1. General
O
OH
N
H
O
N
H
O
N
H
O
1H NMR, 13C NMR spectra were measured on a Varian
UNITY INOVA 300 MHz spectrometer using TMS as an in-
ternal standard. For the electrospray (ESI) MS analysis, a
Finnigan LCQ Deca XP ion trap mass spectrometer equipped
with a Microsoft Windows NT data system and an ESI inter-
face was used. Elemental analysis was recorded on an
Elementar Vario EL elementary analysis device. IR absorption
was recorded on a Bruker TENSOR 37 spectrophotometer.
6
7
N
OH
OH
N+
O-
3.2. The synthesis of 4-hydroxy-2(1H)-quinolinone
O
N
H
4a
A mixture of aniline (27.9 g, 0.3 mol), malonic acid
(31.2 g, 0.3 mol), anhydrous zinc chloride (122.7 g, 0.9 mol),
Figure 5.
6'
5'
7'
3
4
4'
2
8'
OH
OH
OH
1'
3'
5
1
N+
N+
9
9
2'
6
O-
8
O-
7
10
10
14
14
11
13
13
OH
O
O
12
12
N
H
N
H
11
4b'(trans)
4b(cis)
1
Figure 6. The H NMR spectra of compounds 4d and 4d0.

S.-L. Zhang et al. / Tetrahedron 64 (2008) 4403e4407
4407
and phosphorus oxychloride (90 ml) was heated with stirring
at 65 ꢀC for 36 h, cooled and decomposed with ice and water,
and allowed to stand. The resulting crude 4-hydroxy-2(1H)-
quinolinone was collected as solid by filtration, dissolved in
10% sodium carbonate, and acidified to about the neutral
point. The collected precipitate was crystallized from metha-
nol to afford 4-hydroxy-2(1H)-quinolinone (36 g) in 75%
yield as yellow solid. 1H NMR (300 MHz, DMSO-d6)
d 11.30 (1H, s), 11.18 (1H, s), 7.75 (1H, d, J¼8.1 Hz), 7.46
(1H, t, J¼6.9 Hz), 7.24 (1H, d, J¼8.1 Hz), 7.11 (1H, t, J¼
7.8 Hz), 5.72 (1H, s) ppm; 13C NMR (DMSO-d6) d 164.10,
162.96, 139.80, 131.45, 123.29, 121.27, 115.76, 115.63,
98.94 ppm; IR (KBr) 2859, 1668, 1507, 1464, 1415,
1333 cmꢁ1; ESI-MS (m/z): 162 (Mꢁ1)þ. Anal. Calcd for
C9H7NO2: C, 67.07; H, 4.38; N, 8.69. Found: C, 66.92; H,
4.25; N, 8.81.
C21H16N2O4: C, 69.99; H, 4.48; N, 7.77. Found: C, 70.27;
H, 4.56; N, 7.87 (1H NMR spectra shown in Fig. 3).
3.3.3. Compounds 4d and 4d0
Yield 17%, yellow solid, 4d/4d0¼1:1.6. 1H NMR
(300 MHz, DMSO-d6) d 10.00 (0.64H, s), 9.84 (0.36H, s),
9.59 (1H, s) ppm; IR (Bruker) 3368, 1577, 1385 cmꢁ1
;
ESI-MS (m/z): 397 (Mꢁ1)þ. Anal. Calcd for C24H16N2O4:
C, 72.72; H, 4.07; N, 7.07. Found: C, 72.53; H, 4.11; N,
7.35 (1H NMR spectra shown in Fig. 6).
Acknowledgements
We thank the National Nature Science Foundation of China
(20672148), the Guangdong Provincial Science Foundation
(031594), and the Hong Kong Polytechnic University ASD
Fund for financial support of this study.
3.3. General procedure of the synthesis of zwitterionic
4-hydroxy-2(1H)-quinolinone derivatives
Supplementary data
A mixture of 4-hydroxy-2-(1H)-quinolinone 3 (0.82 g,
5 mmol), p-benzoquinone (1.08 g, 10 mmol), and pyridine
(0.79 g, 10 mmol) in 30 ml aqueous acetone (v/v¼1:1) was
magnetically stirred at room temperature for 24 h. The reac-
tion mixture was filtered to afford a brown crude product,
which was purified by column chromatography (silica gel,
methanol/trichloromethane¼1:10) to give the yellow
compound.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.052.
References and notes
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1169e1171.
2. Theodoridis, G. U.S. Patent 4,909,829 (Cl. 71-29; A01N43/64); Appl.
138,981, 1987.
3.3.1. Compound 4a
1
Yield 43%, yellow solid. H NMR (300 MHz, DMSO-d6)
ˇ
´
3. Koruꢀznjak, J. D.; Grdisa, M.; Slade, N.; Zamola, B.; Pavelic, K.;
Karminski-Zamola, G. J. Med. Chem. 2003, 46, 4516e4524.
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1999, 9, 2615e2620.
d 10.13 (1H, s), 8.94 (1H, d, J¼6.3 Hz), 8.45 (1H, d,
J¼6.3 Hz), 8.40 (1H, d, J¼7.8 Hz), 7.94 (1H, t, J¼6.9 Hz),
7.86 (1H, d, J¼7.5 Hz), 7.77 (1H, t, J¼7.2 Hz), 7.26 (1H, t,
J¼7.8 Hz), 6.89e6.99 (4H, m) ppm; 13C NMR (DMSO-d6)
d 173.26, 163.46, 151.83, 151.30, 147.55, 145.75, 143.05,
139.54, 131.29, 130.09, 126.40, 126.03, 125.45, 123.54,
121.68, 121.26, 120.32, 115.14, 119.94, 100.72 ppm; IR (KBr)
2931, 1628, 1581, 1348 cmꢁ1; ESI-MS (m/z): 347 (Mꢁ1)þ.
Anal. Calcd for C20H14N2O4: C, 69.36; H, 4.07; N, 8.09.
Found: C, 69.21; H, 4.03; N, 8.15.
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Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Koszalka, G. W.; Hazen,
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A. S. C.; Gu, L. Q. Org. Lett. 2004, 6, 4853e4855.
7. Shobana, N.; Yeshoda, P.; Shanmugam, P. Tetrahedron 1989, 45, 757e
762.
3.3.2. Compounds 4b and 4b0
8. Shah, V. R.; Bose, J. L.; Shah, R. C. J. Org. Chem. 1960, 25, 677e678.
9. Zhang, S. L.; Huang, Z. S.; Shen, Y. D.; Li, Y. M.; Yao, J. H.; Huang, M.;
Chan, A. S. C.; Gu, L. Q. Tetrahedron Lett. 2006, 47, 6757e6760.
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Judge, T.; Gammill, R. B. J. Org. Chem. 1999, 64, 93e100 and references
therein (atropisomeric compounds).
Yield 39%, yellow solid, 4b/4b0¼1.4:1. 1H NMR
(300 MHz, DMSO-d6) d 10.17 (0.6H, s), 10.08 (0.4H, s),
2.40 (3H, s) ppm; IR (Bruker) 2927, 1631, 1582, 1393,
1277 cmꢁ1; ESI-MS (m/z): 361 (Mꢁ1)þ. Anal. Calcd for