An improved protocol for the synthesis of quinoline-2,3-dicarboxylates under neutral conditions via biomimetic approach

Article abstract of DOI:10.1002/hlca.200900254

A mild and efficient protocol for synthesis of quinoline derivatives in aqueous medium under neutral conditions is described. The reaction proceeded smoothly in H₂O catalyzed by supramolecular catalyst β-CD. By this protocol, various quinoline derivatives were synthesized in excellent yields.

Full text of DOI:10.1002/hlca.200900254

Helvetica Chimica Acta – Vol. 93 (2010)
257
An Improved Protocol for the Synthesis of Quinoline-2,3-dicarboxylates
under Neutral Conditions via Biomimetic Approach
by Bandaru Madhav, Sabbavarapu Narayana Murthy, Kakulapati Rama Rao, and
Yadavalli Venkata Durga Nageswar*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road,
Hyderabad 500-607, India (phone: þ 914027160512; e-mail: dryvdnageswar@gmail.com)
A mild and efficient protocol for synthesis of quinoline derivatives in aqueous medium under neutral
conditions is described. The reaction proceeded smoothly in H2O catalyzed by supramolecular catalyst b-
CD. By this protocol, various quinoline derivatives were synthesized in excellent yields.
Introduction. – As part of our program to explore biomimetic approaches through
supramolecular catalysis in promoting various organic transformations [1], we
attempted to prepare biologically active heterocycles using b-cyclodextrin (b-CD) as
a catalyst and H2O as a reaction medium. However, the fundamental problem in
performing organic reactions in H2O is that many organic substrates are hydrophobic
and are insoluble in H2O. The aqueous reactions can be rendered more ꢀsophisticatedꢁ if
they can be performed under supramolecular catalysis. Cyclodextrins are cyclic
oligosaccharides possessing hydrophobic cavities. They are torus-like macro-rings
made up of glucopyranose units. They bind substrates selectively and catalyze chemical
reactions by supramolecular catalysis involving the reversible formation of host – guest
complexes with the substrates by noncovalent bonding as seen in enzyme-complexation
processes [2]. The complexation depends on the size, shape, and hydrophobicity of the
guest molecule. These attractive features of cyclodextrins in the biomimetic modeling
of chemical reactions prompted us to investigate the synthesis of 4-substituted
quinoline-2,3-dicarboxylates.
Results and Discussions. – Initially, the reaction between 2-aminobenzophenone
and dimethyl acetylenedicarboxylate was carried out in H2O catalyzed by b-CD
resulting in the formation of dimethyl 4-phenylquinoline-2,3-dicarboxylate in one pot
at 758 in 85% yield. When 50% of b-CD was used as the catalyst, the desired quinoline
derivative was obtained in an almost quantitative yield, and reaction time was
significantly short. In the absence of b-CD, the reaction did not take place. To check the
generality of the reaction, various 2-amino carbonyl compounds were used as
substrates, and all of the reactions proceeded to give the desired quinoline derivatives
in yields, generally, > 80%. 5-Nitro-2-aminobenzophenone did not react, but traces of
the product were isolated after longer reaction times. All these reactions also
proceeded with diethyl acetylenedicarboxylate, but di(tert-butyl) acetylenedicarbox-
ylate did not react under the present experimental conditions.
ꢂ 2010 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Helvetica Chimica Acta – Vol. 93 (2010)
Table 1. Synthesis of 4-Substituted Quinoline-2,3-dicarboxylatesa) by Using b-Cyclodextrin (b-CD) under
Neutral Conditions in Aqueous Medium
Entry
R
R1
R2
R3
Yieldb) [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Me
Me
Ph
Ph
Ph
Ph
H
H
Ph
Ph
Me
Me
2-ClꢀC6H4
2-ClꢀC6H4
Me
H
H
H
H
H
H
H
H
Br
Br
MeO
MeO
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
MeO
MeO
Cl
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
92
89
85
82
83
81
94
91
83
80
89
85
82
78
88
85
H
Cl
OꢀCH2ꢀO
Me
OꢀCH2ꢀO
a) Structures of the products were confirmed by 1H- and 13C-NMR spectroscopy, and direct comparison
with authentic samples. b) Yields of isolated products.
In general, all of the reactions were very clean. The compounds were purified by
just passing them through a small silica-gel column. The results showed that the
substitution played a significant role in governing the reactivity of the substrate. In
general, reactions with 2-aminobenzophenones led to lower yields compared to 2-
aminoacetophenones. However, 2-aminoacetophenones led to products in lower yields
when compared to 2-amino-5-chlorobenzaldehyde. Among the 2-aminoacetophenones,
unsubstituted 2-aminoacetophenone (Table 1, Entries 1 and 2) afforded good yields,
and 4,5-methylenedioxy-2-aminoacetophenone (Table 1, Entries 15 and 16) resulted in
lower yields. Similarly, reactions with substituted 2-aminobenzophenones gave lower
yields compared to unsubstituted 2-aminobenzophenones. Finally, reactions of 2-
aminophenones with dimethyl acetylenedicarboxylate (DMAD) resulted in higher
yields when compared to those with diethyl acetylenedicarboxylates.
b-CD, being a supramolecular catalyst, catalyzes the reaction by forming inclusion
complex with the substrates due to its hydrophobic cavity. Evidence for complexation
1
between the 2-aminobenzophenone (A) and cyclodextrin is provided by H-NMR
spectroscopy as the most important technique for the characterization of inclusion
complexes. Although all of the reactions were carried out with 0.5 equiv. of b-CD,
complexation studies were undertaken with b-CD/2-aminobenzophenone 1:1 complex
as a representative example. A comparative study of the shifts in cyclodextrin H-atoms

Helvetica Chimica Acta – Vol. 93 (2010)
259
(host H-atoms) indicated that there is a downfield shift of HꢀC(3) (0.075) and
HꢀC(5) (0.073) of cyclodextrin in the b-CD – A and b-CD – A-DMAD complex,
respectively, compared to b-CD, indicating the formation of an inclusion complex of A
with b-CD. This clearly demonstrates that 2-aminobenzophenone (A) is activated by b-
CD, which promotes the reaction. b-Cyclodextrin was recovered in good quantity and
reused for four times successively with sustained yields (Table 2).
Table 2. Catalyst Recyclability
Cycles
Yield [%]
Catalyst recovered [%]
Native
92
87
85
82
92
90
87
83
1
2
3
Conclusions. – We have presented an elegant, simple, and ꢀecofriendlyꢁ protocol for
the synthesis of quinoline derivatives in H2O. This methodology under mild and neutral
conditions overcomes the drawbacks of unwanted by-products, low yields, high
temperatures, and problematic organic solvents.
We thank CSIR, New Delhi, India, for fellowships to B. M. and S. N. M.
Experimental Part
General. All reactions were carried out without any special precautions in an atmosphere of air.
Chemicals were purchased from Fluka and S. D. Fine Chemicals. TLC: precoated silica-gel plates (60
F254, 0.2-mm layer; E. Merk). M.p.: Fischer– Johns and Barnstead Electrothermal apparatus; uncor-
1
rected. H-NMR Spectra: Varian 200 or Bruker 300 spectrometer; in CDCl3; d in ppm, J in Hz. MS:
QSTAR XL, LCQ-Ion Trap spectrometer in m/z.
Typical Procedure for the Synthesis of Dimethyl 4-Phenylquinoline-2,3-dicarboxylate. b-CD (0.567 g,
0.5 mmol) was dissolved in H2O (10 ml) by warming to 508 until a clear soln. was formed. Then, 2-
aminobenzophenone (0.197 g, 1 mmol), was added dropwise, followed by dimethyl acetylenedicarbox-
ylate (0.170 g, 1.2 mmol). The mixture was stirred at 758 until the reaction was complete (as monitored by
TLC). The mixture was extracted with AcOEt, and the extract was filtered. The aq. layer was cooled to 58
to recover b-CD by filtration. The org. layer was dried (Na2SO4). The solvent was removed under
reduced pressure, and the resulting product was further purified by column chromatography; yield 85%
1
(Table 1, Entry 3). Bright yellow solid., M.p. 128 – 1298 (lit. 129 – 1308). H-NMR (300 MHz, CDCl3):
8.39 (d, J ¼ 8.5, 1 arom. H); 7.86 – 7.81 (m, 1 arom. H); 7.67 – 7.57 (m, 2 arom. H); 7.52 – 7.50 (m, 3 arom.
H); 7.38 – 7.35 (m, 2 arom. H); 4.08 (s, COOMe); 3.64 (s, COOMe). 13C-NMR (75 MHz, CDCl3): 167.46;
165.34; 165.27; 148.30; 148.19; 146.84; 146.74; 144.70; 134.36; 131.12; 131.09; 130.42; 130.34; 129.23;
128.81; 128.22; 127.60; 127.13; 126.59; 53.44; 52.42. ESI-MS: 322 ([M þ H]þ).
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Received July 3, 2009