Metal-free synthesis of quinoline-2,4-dicarboxylate derivatives using aryl amines and acetylenedicarboxylates through a pseudo three-component reaction

Article abstract of DOI:10.1039/d1ob01188j

An efficient, useful and one-pot protocol for the synthesis of quinoline-2,4-dicarboxylate scaffolds is accomplished from aryl amines and dimethyl/diethyl acetylenedicarboxylates using 20 mol% molecular iodine as a catalyst in acetonitrile at 80 °C. In addition, the mechanistic explanation for the formation of the desired products is disclosed. The pivotal role of molecular iodine in the formation of the major products, diester quinoline derivatives, and the minor product, triesters, in two cases is described in the mechanism. The notable advantages of this method are non-involvement of a metal catalyst, avoiding of metal contamination in the final product as well as waste generation, use of a low cost and eco-friendly catalyst, ease of handling, high regioselectivity, shorter reaction time, the formation of one C-N and two C-C bonds and a broad substrate scope with good yields.

Full text of DOI:10.1039/d1ob01188j

Organic &
Biomolecular Chemistry
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Metal-free synthesis of quinoline-2,4-
dicarboxylate derivatives using aryl amines and
acetylenedicarboxylates through a pseudo three-
component reaction†
Cite this: DOI: 10.1039/d1ob01188j
Saghir Ali
and Abu T. Khan
*
An efficient, useful and one-pot protocol for the synthesis of quinoline-2,4-dicarboxylate scaffolds is
accomplished from aryl amines and dimethyl/diethyl acetylenedicarboxylates using 20 mol% molecular
iodine as a catalyst in acetonitrile at 80 °C. In addition, the mechanistic explanation for the formation of
the desired products is disclosed. The pivotal role of molecular iodine in the formation of the major pro-
ducts, diester quinoline derivatives, and the minor product, triesters, in two cases is described in the
mechanism. The notable advantages of this method are non-involvement of a metal catalyst, avoiding of
metal contamination in the final product as well as waste generation, use of a low cost and eco-friendly
catalyst, ease of handling, high regioselectivity, shorter reaction time, the formation of one C–N and two
C–C bonds and a broad substrate scope with good yields.
Received 20th June 2021,
Accepted 26th July 2021
DOI: 10.1039/d1ob01188j
rsc.li/obc
quinoline-2-carboxylate backbone is an integral part of natu-
rally occurring alkaloids, namely, ascidiathiazone A and B.6a
Introduction
Quinolines are privileged heterocyclic frameworks present in Therefore, the synthetic community has devoted considerable
numerous naturally occurring alkaloids and some of them are efforts to achieve the synthesis of quinoline mono-carboxylate
used as potent drugs.1a–c They also exhibit a broad spectrum derivatives. Wang et al. first demonstrated the synthesis of
of
biological
activities,1d
such
as
antimalarial,1e 4-aryl-quinoline-2-carboxylate derivatives from functionalized
antituberculosis,1f,g anticancer,1h,i anti-HIV,1j antiasthmatic1k glycine derivatives and olefins/alkynes under catalytic radical
and antihypertensive activities.1l Very recently, quinoline cation salt induced conditions.6b Later on, Zhang and co-
derivatives have been used for the treatment of workers reported the synthesis of 4-substituted quinoline-2-
SARS-CoV-2.1m–o Additionally, naturally occurring alkaloids, carboxylate derivatives from similar kinds of substrates invol-
namely, quinine and cinchonidine, have been exploited exten- ving a photocatalyst in the presence of blue LED light.6c,d
sively as chiral ligands for asymmetric synthesis.2 Moreover, Similarly, Balaraman and co-workers reported the synthesis of
many synthetic quinoline derivatives are marketed as antima- quinoline-3-carboxylate derivatives from aniline and alkyne in
larial drugs and some of the derivatives have been explored in the presence of a rhodium catalyst.7a
materials science.3a,b Due to their immense importance in
The Bayer Pharma Group used quinoline-2,4-carboxylate as
medicinal chemistry, materials science and organic synthesis, the key precursor for the synthesis of glucose transport inhibi-
synthetic organic chemists have put tremendous efforts to tors, namely N4-(2-(4-cyanobenzyl)-4-methylthiazol-5-yl)quino-
develop new methodologies for the synthesis of new substi- line-2,4-dicarboxylate and its derivatives.7b It reflects the
tuted quinoline derivatives. Some classical procedures are well importance of this key precursor in medicinal chemistry.
recognized for the synthesis of quinolines and their deriva- Despite the importance of quinoline-2,4-carboxylate and its
tives, such as Skraup,4a Conard–Limpach,4b Pfitzinger,4c,d derivatives, only a few methods are known so far for the syn-
Doebner–von Miller,4e Friedlaender4f and many others.5 The thesis of quinoline-2,4-dicarboxylate, as shown in Scheme 1.
Peet and co-workers8a first reported an antiallergic quinoli-
none derivative obtained in two steps using o-nitroaniline and
acetylenedicarboxylate (Scheme 1a). However, they did not
obtain quinoline-2,4-dicarboxylate. Similarly, Pitchumani and
co-workers showed the use of enamines (derived from aryl
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-
781039, Assam, India. E-mail: atk@iitg.ac.in; Fax: +91361 2582349;
Tel: +91 361 2582305
†Electronic supplementary information (ESI) available. CCDC 2053801 (5k). For
amines and dimethyl acetylenedicarboxylate) in a multi-com-
ponent reaction for the synthesis of highly functionalized pyr-
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob01188j
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tives (Scheme 1d). Dialkyl acetylenedicarboxylates are readily
available starting materials, which have been extensively used
for the synthesis of various heterocycles.13 These can act as
Michael acceptors14 as well as dienophiles15 due to the presence
of two ester groups. Our group has accomplished the synthesis
of various heterocycles using acetylenedicarboxylates.12a,16 Due
to that motivation, we are still encouraged to explore them in
our laboratory and use them for the synthesis of dimethyl/
diethyl quinoline-2,4-dicarboxylate derivatives. In continuation
of our efforts towards the synthesis of various quinolines,17
herein, we disclose the metal-free synthesis of dimethyl/diethyl
quinoline-2,4-dicarboxylate derivatives using aryl amines
and acetylenedicarboxylates in the presence of 20 mol% I2 in
acetonitrile at 80 °C (Scheme 1d). To date, there is no
literature precedent of the molecular iodine catalyzed
domino reaction of arylamines and dimethyl/diethyl
acetylenedicarboxylates.
Scheme 1 Previous reports and present work.
Results and discussion
To find out the optimum reaction conditions, p-anisidine 1a
and dimethyl acetylenedicarboxylate 2a were chosen as the
model substrates and the results are presented in Table 1. We
initiated our studies with the reaction using p-anisidine (1a,
rolidines.8b It is to be noted that none of them reported the syn-
thesis of quinoline-2,4-dicarboxylate derivatives. Pietrancosta
and co-workers9 reported a method for the synthesis of quino-
line-2,4-dicarboxylate derivatives via an improved Doebner
Miller reaction using aryl amines and an unsaturated keto-ester
(synthesized from ketoglutaric acid in three steps) (Scheme 1b).
Recently, Yi and co-workers10 disclosed a one-pot synthesis of
2,4-disubstituted quinolines through the copper(II) triflate cata-
lyzed reaction of aryl amines and acetylenedicarboxylates
(Scheme 1c). Despite the great utility of these earlier reported
methods, they have some demerits, such as the use of the
expensive metal catalyst Cu(OTf)2, the requirement of the hazar-
dous triflic acid, high reaction temperature, longer reaction
time and restricted substrate scope. In order to overcome all
these complications, the development of a straightforward pro-
tocol is still highly desirable in terms of green and sustainable
chemistry. Molecular iodine has emerged as a Lewis acid cata-
lyst that has been utilized in various organic transformations.11
Recently, our research group has shown the efficacy of mole-
cular iodine for the synthesis of various nitrogen
heterocycles,12a–e which encouraged us to develop a new meth-
odology for the synthesis of quinoline-2,4-dicarboxylate deriva-
tives using molecular iodine as a catalyst due its low cost, easy
availability, nontoxicity, versatility and environmental friendli-
ness.12f Iodine has structural features and reactivity patterns
that are similar to those of transition metals12f–h and it can be
used in place of transition metals to make the process greener
and eco-friendly. Recently, it has been utilized for several
organic transformations, such as C–N, C–O, and C–C bond for-
mations in organic compounds, which have been reviewed.12f,i
Keeping in mind the growing concerns about environment pro-
tection and waste generation, we considered that molecular
iodine can be used to develop a sustainable method for the syn-
thesis of dimethyl/diethyl quinoline-2,4-dicarboxylate deriva-
Table 1 Optimization of reaction conditionsa,b,c,d
Entry
Catalyst
Mol %
Solvent
Time
Yield 3a b (%)
1c
—
—
—
—
I2
I2
I2
I2
—
—
—
—
5
—
—
24 h
24 h
24 h
24 h
24 h
18 h
18 h
12 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
NR
NR
NR
NR
NR
28
50
68
85
83
NR
25
20
NR
NR
NR
NR
NR
NR
62
2
3c
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Dioxane
CH2Cl2
(CH2Cl)2
THF
4
5c
6
7
8
9
5
10
15
20
25
20
20
20
20
20
20
20
20
20
20
20
I2
I2
10
11
12
13
14
15d
16
17d
18
19
20d
21
PhI(OAc)2
IBr
ICl
I2
I2
I2
I2
I2
I2
I2
DMF
DMSO
MeOH
H2O
I2
48
a Reaction conditions: all the reactions were performed using p-anisi-
dine (1a, 1.0 mmol) and dimethyl acetylenedicarboxylate (2a,
2.0 mmol) in solvent (3.0 mL) at 80 °C. b Isolated yield. c Reaction per-
formed at room temperature. d Reaction performed under reflux con-
ditions. NR (no desired product).
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Table 2 Reaction of different aryl amines 1a–t with dimethyl acetyle-
nedicarboxylate 2a a,b
1.0 mmol) and dimethyl acetylenedicarboxylate (2a, 2.0 mmol)
without any solvent and catalyst (Table 1, entries 1 and 2). The
reaction did not occur at room temperature as well as upon
heating at 80 °C. The reaction did not proceed even when it
was examined in acetonitrile in the absence of a catalyst at
room temperature as well as at 80 °C (Table 1, entries 3 and 4).
The reaction did not proceed in the presence of 5 mol% I2 at
room temperature (Table 1, entry 5); however, upon heating at
80 °C for 18 h, the product 3a was isolated in 28% yield
(Table 1, entry 6). Encouraged by this successful result, we
attempted to increase the yield of the desired product 3a by
examining the different reaction parameters, such as catalyst
loading, using different catalysts and screening various sol-
vents. When the catalyst loading was increased from 5 mol%
to 10 mol%, 3a was obtained in 50% yield (Table 1, entry 7).
Upon increasing the catalyst loading from 10 mol% to
15 mol%, the reaction time was reduced to 12 h and the yield
of 3a was also further improved (Table 1, entry 8). When the
catalyst loading was further increased to 20 mol%, the reaction
was completed in 8 h and the yield of 3a was increased signifi-
cantly to 85% (Table 1, entry 9). However, a further increase in
the catalyst loading to 25 mol% did not improve the yield of 3a
(Table 1, entry 10). Next, we carried out the model reaction in
the presence of different iodine containing non-metallic cata-
lysts, such as PhI(OAc)2, IBr and ICl (Table 1, entries 11–13).
It was observed that none of them was more efficient than
I2. Next, to check the efficiency of the solvent, different sol-
vents, such as 1,4-dioxane, dichloromethane, tetrahydrofuran,
dimethyl sulfoxide, methanol and water, were tested (Table 1,
entries 14–21) using 20 mol% I2 as the catalyst. It was noted
that in all solvents, either the reaction did not occur or the
yield of 3a was low. Therefore, the best yield of 3a was obtained
in acetonitrile. From all the above observations, the optimum
reaction conditions were 20 mol% I2 in acetonitrile at 80 °C
(Table 1, entry 9) in terms of both reaction time and yield.
With the optimized reaction conditions in hand, the scope
and generality of the developed method were explored with
different aryl amines 1a–t and dimethyl acetylenedicarboxylate
2a (Table 2). The reaction of p-anisidine 1a with dimethyl acet-
ylenedicarboxylate 2a provided the desired product 3a in 85%
yield. The reaction of simple aniline 1b with 2a proceeded well
a Reaction conditions: all the reactions were performed using aryl
amines (1a–t, 1.0 mmol) and dimethyl acetylenedicarboxylate (2a,
2.0 mmol) in solvent (3.0 mL) at 80 °C. b Isolated yield. NR (no desired
product).
and gave the expected product 3b in 83% yield. Similarly, aryl aniline 1n, and 1-naphthylamine 1o, upon reaction with 2a
amine containing a hydroxyl group at the para position provided the fused quinoline derivatives 1m–o in 78–87%
afforded the corresponding product 3c in 83% yield.
yields. Interestingly, in the reaction with 5-aminoindan 1m, we
Aryl amines containing electron-donating groups, such as isolated the triester quinoline 3m′ in 8% yield along with the
4-Et and 4-Me, worked well and gave the expected quinoline desired product 3m. Gratifyingly, aryl amines containing elec-
derivatives 3d and 3e in 82% and 84% yields, respectively. tron-withdrawing groups such as 4-Cl and 2-Cl also gave the
Likewise, the reaction of aryl amines containing the 3-OMe corresponding quinolines 3p and 3q in 87% and 85% yields,
and 2-Me groups with 2a provided quinoline scaffolds 3f and respectively. In addition, 4-(methylthio)aniline 1r also provided
3g in 77% and 86% yields, respectively. The reaction of aryl the desired quinoline 3r in 86% yield. Unfortunately, aryl
amines containing the 3,5-OMe, 2,4-OMe, 3,5-Me, 2,4-Me and amines containing strong electron-withdrawing groups such as
3,4-Me groups with 2a proceeded smoothly and gave the –CO2Me and –NO2 at the para position did not give the desired
corresponding quinoline derivatives 3h–l in 80–86% yields. It products under standard conditions due to less electron
is noteworthy that the triester quinoline 3h′ was obtained in density at the ortho position with respect to the –NH2 group.
11% yield along with quinoline 3h. Notably, bicyclic aryl
Inspired by the above-discussed successful results, the
amines, such as 5-aminoindan 1m, 3,4-(methylenedioxy) scope and generality of the present protocol were extended
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further using different aryl amines 1a–o with diethyl acetylene- desired products under the standard conditions due to less
dicarboxylate 2b (Table 3). The reaction of p-anisidine 1a with electron density at the ortho-position with respect to the –NH2
diethyl acetylenedicarboxylate 2b under the standard con- group.
ditions proceeded smoothly and gave the desired quinoline 4a
We performed a scale up reaction using p-anisidine (1a,
in 86% yield. Similarly, the hydroxyl group at the para position 10 mmol) and dimethyl acetylenedicarboxylate (2a, 20 mmol)
of aryl amine 1b was well tolerated and afforded the corres- to give the desired product 3a in 86% yield (Scheme 2). All the
ponding quinoline 4b in 84% yield. The aryl amines contain- compounds were characterized using spectroscopic tech-
ing the 4-Me and 2-Me groups also worked well and provided niques, such as IR, 1H NMR, 13C NMR and HRMS. In addition,
the desired quinoline derivatives 4c and 4d in 86% and 85% the structure of compound 3k was confirmed using the single
yields, respectively. The di-substituted aryl amines containing X-ray crystallographic data (see the ESI†).
the 3,5-OMe, 2,4-Me and 3,4-Me groups upon reaction with 2b
To gain insights into the reaction mechanism, we carried
gave the expected quinoline scaffolds 4e–g in 74–88% yields. out a series of control experiments (Scheme 2). At first, we per-
Notably, the reaction of bicyclic amines, such as 3,4-(methyl- formed a reaction of p-anisidine 1a with dimethyl acetylenedi-
enedioxy)aniline 1h, 5-aminoindan 1i, and 1-naphthylamine carboxylate 2a (Scheme 3a) in the absence of molecular iodine.
1j, with 2b gave the expected quinoline derivatives 4h–j in After heating the reaction mixture for a period of 8 h, we iso-
78–83% yields. Interestingly, aryl amines having electron-with- lated hydroamination intermediate A (aza-Michael product)
drawing groups, such as 4-Cl and 2-Cl, provided the desired and it was characterized using IR, 1H NMR, 13C NMR and
quinolines 4k and 4l in 83% and 83% yields, respectively. HRMS. A similar observation has also been reported by Peet
Additionally, 4-(methylthio)aniline 1m provided the corres- and co-workers.8a Next, we carried out the reaction between
ponding quinoline 4m in 80% yield. Unfortunately, aryl intermediate A and dimethyl acetylenedicarboxylate 2a under
amines containing strong electron-withdrawing groups, such the standard conditions (Scheme 3b). The reaction was com-
as –CO2Me and –NO2, at the para position did not give the pleted in another 8 h and quinoline 3a was obtained in 83%
yield. This suggests the formation of intermediate A and its
Table 3 Reaction of different aryl amines 1a–o with diethyl acetylene-
dicarboxylate 2b a,b
Scheme 2 Gram scale synthesis.
a Reaction conditions: all the reactions were performed using aryl
amines (1a–o, 1.0 mmol) and diethyl acetylenedicarboxylate (2b,
2.0 mmol) in solvent (3.0 mL) at 80 °C. b Isolated yield. NR (no desired
product).
Scheme 3 Control experiments.
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involvement in the reaction mechanism. The reaction using amine 1a reacts with acetylenedicarboxylate 2a to give aza-
intermediate 5a with dimethyl acetylenedicarboxylate 2a under Michael product A.12i The intermediate product (A) reacts with
identical conditions did not provide the expected product the second molecule of 2a assisted by molecular iodine via the
(Scheme 3c). The reason for reaction failure might be the less Michael reaction, leading to the annulated intermediate B.
electron density at the ortho-position of the ring with respect Then intermediate B undergoes a [1,3] H shift to provide inter-
to the –NH group due to the presence of the strong electron- mediate C, which on intramolecular cyclization via the
withdrawing ester group. Next, we carried out the reactions Michael reaction promoted by molecular iodine affords reac-
using p-anisidine 1a with diphenylacetylene 2c and phenyl- tive anion species D. Next, intermediate D undergoes intra-
acetylene 2d under identical conditions, and the reactions did molecular cyclization which is also assisted by molecular
not proceed at all in both the cases (Scheme 3d and e). In both iodine to generate a four membered ring fused with tetrahy-
the cases, the formation of the four membered ring fused tet- droquinoline F through intermediate E. Due to ring strain,
rahydroquinoline intermediate was not possible. Therefore, we intermediate F undergoes cleavage to give the desired quino-
did not obtain the corresponding products using diphenylace- line 3a and reactive ketene intermediate G, which is attacked
tylene and acetylene. These two experiments suggest that the by the generated methanol in the reaction medium to give
presence of the two ester groups in acetylene is necessary for malonic ester H. Alternatively, the formation of diesters can
the formation of the product, which also supports our pro- also be explained through path II. We detected malonic ester
posed reaction mechanism.
H in the crude 1H NMR spectrum of compound 3a (see the
From the observation of control experiments and literature ESI†). In addition, malonic ester H was also detected by HRMS
precedents, the plausible mechanism for the formation of qui- (see the ESI†).
noline-2,4-dicarboxylate derivatives and triester quinoline
The formation of the minor product, triester quinoline
derivatives is shown in Scheme 4. We presumed that the reac- derivatives, occurs via two possible pathways, path III or path
tion can occur via two pathways, path I or path II, to form the IV. According to path III, intermediate L can also be formed
desired diester products. According to path I, at first, aryl from intermediate D after protonation, which undergoes C–C
Scheme 4 The plausible mechanism for the formation of quinoline derivative 3a and triester quinolines 3h’ and 3m’.
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bond cleavage with the elimination of CH3CO2Me to give the cular iodine (20 mol%, 50 mg) was added into it. The resultant
expected triester quinoline derivatives. In path IV, intermediate mixture was stirred at room temperature for 10 min and sub-
M can also be generated after protonation from intermediate I, sequently it was kept for heating at 80 °C in a pre-heated oil-
which undergoes an almost similar type of reaction like C–C bath. After completion of the reaction, it was cooled to room
bond cleavage to provide triester quinoline derivatives. Similar temperature and acetonitrile was evaporated on a rotary evap-
C–C bond cleavage has also been reported by others.10,18a,b orator. After this, a saturated solution of sodium thiosulphate
The formation of products 3h and 3h′ and 3m and 3m′ occurs was added dropwise to the reaction mixture to decolorize the
via all four possible pathways among which path I and path II iodine. Then it was extracted with ethyl acetate (3 × 5 mL). The
are more predominant; otherwise, in all other cases, path I combined organic layer was washed with water (2 × 5 mL) fol-
and path II are solely favoured for the formation of diesters.
lowed by brine solution (5 mL) and dried over anhydrous
sodium sulphate. The solvent was evaporated on a rotary evap-
orator. Finally, the crude mixture was purified using silica gel
(60–120 mesh) column chromatography.
Conclusion
Dimethyl
6-methoxyquinoline-2,4-dicarboxylate
(3a).9
(234 mg, 85%, light yellow solid); mp 152–153 °C; 1H NMR
(600 MHz, CDCl3) δ 8.72 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.23
(d, J = 9.3 Hz, 1H), 7.48 (dd, J = 9.3, 2.8 Hz, 1H), 4.09 (s, 3H),
4.05 (s, 3H), 4.00 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 166.5,
165.7, 161.3, 145.3, 144.7, 133.4, 132.9, 128.7, 124.2, 123.4,
103.2, 55.9, 53.5, 52.9; Vmax/cm−1 2926, 1745, 1640, 1478, 1336;
HRMS (ESI) calcd for C14H14NO5 276.0872 (M + H+); found
276.0872.
We have devised a simple and efficient method for the synthesis
of dimethyl/diethyl quinoline-2,4-dicarboxylate derivatives by
employing a domino reaction using readily available aryl
amines and acetylenedicarboxylates in the presence of 20 mol%
I2 under mild conditions. From the reaction mechanism, the
role of molecular iodine in the reaction for the formation of
intermediate B from product A is quite clear, i.e., the Michael
reaction as well as the other steps which are proposed in the
mechanism. This transformation occurs under metal-free con-
ditions, avoiding the use of metal catalysts with no formation of
metal waste. The important features of this protocol are its ease
of handling, use of low cost and environmentally benign cata-
lysts, high regioselectivity, use of commercially available starting
materials, no requirement for an inert atmosphere or dry
solvent, shorter reaction time, the consecutive formation of one
C–N and two C–C bonds and a broad substrate scope with good
to excellent yields. We are still exploring the synthetic appli-
cation of quinoline-2,4-dicarboxylate and studies to obtain qui-
noline-2,3,4-tricarboxylate derivatives by tuning the reaction
conditions are underway in our laboratory.
Dimethyl
6-methoxyquinoline-2,4-dicarboxylate
(3b).9
(204 mg, 83%, yellow solid); mp 128–129 °C; 1H NMR (400 MHz,
CDCl3) δ 8.85 (d, J = 8.5 Hz, 1H), 8.70 (s, 1H), 8.37 (d, J = 8.5 Hz,
1H), 7.86 (t, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 4.11 (s, 3H),
4.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 165.6, 148.8,
147.7, 136.3, 131.5, 130.8, 130.6, 126.5, 125.77, 122.5, 53.6, 53.1;
Vmax/cm−1 2956, 1721, 1507, 1434, 1355; HRMS (ESI) calcd for
C13H12NO4 246.0766 (M + H+); found 246.0766.
Dimethyl
6-hydroxyquinoline-2,4-dicarboxylate
(3c).
(217 mg, 83%, yellow solid); mp 215–216 °C; 1H NMR
(400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.44 (s, 1H), 8.12 (d, J =
9.2 Hz, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 9.2, 2.6 Hz,
1H), 3.99 (s, 3H), 3.95 (s, 3H); 13C NMR (100 MHz, DMSO-d6,) δ
165.7, 164.8, 159.5, 143.6, 143.4, 132.7, 132.7, 127.6, 123.8,
122.1, 106.2, 52.9, 52.6; Vmax/cm−1 3394, 1722, 1655, 1600,
1354; HRMS (ESI) calcd for C13H12NO5 262.0715 (M + H+);
found 262.0715.
Experimental
General information and methods
Melting points were determined on a melting point apparatus
(Buchi-540). 1H and 13C NMR spectra were recorded on 400,
500 and 600 MHz and 100, 125 and 150 MHz NMR spec-
trometers (Bruker), respectively. TMS was used as an internal
reference; chemical shifts (δ scale) are reported in parts per
million (ppm). 1H NMR spectra are reported in the order: mul-
tiplicity, coupling constant (J value) in hertz (Hz) and no. of
protons; signals are characterized as s (singlet), d (doublet), t
(triplet), m (multiplet) and bs (broad). IR spectra were recorded
on an IR spectrophotometer (PerkinElmer). HRMS spectra
were recorded using a TOF mass analyzer.
Dimethyl 6-ethylquinoline-2,4-dicarboxylate (3d). (224 mg,
86%, light yellow solid); mp 136–137 °C; H NMR (400 MHz,
CDCl3) δ 8.66 (s, 1H), 8.63 (d, J = 0.8 Hz, 1H), 8.27 (d, J = 8.7
Hz, 1H), 7.71 (dd, J = 8.7, 1.9 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H),
2.90 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.4, 165.7, 147.7, 147.4, 146.7, 135.4,
1
132.1, 131.3, 126.7, 123.3, 122.6, 53.5, 53.0, 29.7, 15.4; Vmax
/
cm−1 2964, 1725, 1649, 1498, 1333; HRMS (ESI) calcd for
C15H16NO4 274.1079 (M + H+); found 274.1093.
Dimethyl
6-methylquinoline-2,4-dicarboxylate
(3e).9
1
(218 mg, 84%, gray solid); mp 131–132 °C; H NMR (400 MHz,
CDCl3) δ 8.62 (s, 1H), 8.58 (s, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.65
(dd, J = 8.6, 1.1 Hz, 1H), 4.08 (s, 3H), 4.04 (s, 3H), 2.59 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 166.3, 165.6, 147.5, 146.6, 141.3,
General procedure for the synthesis of quinoline-2,4-
dicarboxylate derivatives
Into a 10 mL round-bottomed flask, a mixture of aryl amine (1, 135.2, 133.1, 131.1, 126.5, 124.4, 122.5, 53.5, 53.0, 22.5; Vmax
/
1.0 mmol) and acetylenedicarboxylate (2, 2.0 mmol) in 3 mL of cm−1 2962, 1721, 1633, 1500, 1352; HRMS (ESI) calcd for
acetonitrile was added. After five minutes of stirring, mole- C14H14NO4 260.0923 (M + H+); found 260.0923.
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Dimethyl 7-methoxyquinoline-2,4-dicarboxylate
Paper
(3f).
Dimethyl
6,7-dimethylquinoline-2,4-dicarboxylate
(3l).
(214 mg, 77%, light yellow solid); mp 148–149 °C; 1H NMR (231 mg, 84%, white solid); mp 139–140 °C; 1H NMR
(400 MHz, CDCl3) δ 8.75 (d, J = 9.4 Hz, 1H), 8.56 (s, 1H), 7.66 (d, (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 4.09
J = 2.5 Hz, 1H), 7.41 (dd, J = 9.4, 2.5 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 4.06 (s, 3H), 2.52 (s, 3H), 2.50 (s, 3H); 13C NMR
(s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 165.7, (100 MHz, CDCl3) δ 166.5, 165.8, 148.1, 146.6, 141.6, 141.4,
161.4, 150.9, 147.8, 135.9, 126.7, 124.2, 122.0, 120.4, 108.7, 55.9, 134.9, 132.2, 130.6, 124.8, 121.8, 53.5, 53.0, 21.0, 20.5; Vmax
/
53.6, 53.1; Vmax/cm−1 2968, 1738, 1615, 1600, 1366; HRMS (ESI) cm−1 2923, 1723, 1614, 1585, 1356; HRMS (ESI) calcd for
calcd for C14H14NO5 276.0872 (M + H+); found 276.0895.
Dimethyl 8-methylquinoline-2,4-dicarboxylate
C15H16NO4 274.1079 (M + H+); found 274.1096.
Dimethyl 7,8-dihydro-6H-cyclopenta[g]quinoline-2,4-dicar-
(3g).9
(224 mg, 86%, light yellow solid); mp 125–126 °C; 1H NMR boxylate (3m). (244 mg, 85%, yellow solid); mp 142–143 °C; H
(400 MHz, CDCl3) δ 8.64 (t, J = 3.9 Hz, 2H), 7.71–7.61 (m, 2H), NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.59 (s, 1H), 8.15 (s,
4.08 (s, 3H), 4.06 (s, 3H), 2.91 (s, 3H); 13C NMR (100 MHz, 1H), 4.09 (s, 3H), 4.06 (s, 3H), 3.14 (t, J = 7.3 Hz, 4H), 2.20
CDCl3) δ 166.6, 165.8, 148.0, 146.4, 139.53, 136.4, 130.8, 130.3, (quint, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.7,
126.5, 123.5, 122.1, 53.3, 53.1, 18.6; Vmax/cm−1 2920, 1725, 165.8, 149.4, 149.2, 148.8, 146.3, 135.5, 125.8, 125.6, 121.6,
1654, 1492, 1344; HRMS (ESI) calcd for C14H14NO4 260.0923 119.6, 53.4, 53.0, 33.4, 32.9, 26.2; Vmax/cm−1 2953, 1725, 1614,
1
(M + H+); found 260.0924.
1436, 1351; HRMS (ESI) calcd for C16H16NO4 286.1079(M +
Dimethyl 5,7-dimethoxyquinoline-2,4-dicarboxylate (3h). H+); found 286.1079.
1
(248 mg, 81%, light yellow liquid); H NMR (400 MHz, CDCl3)
Trimethyl 7,8-dihydro-6H-cyclopenta[g]quinoline-2,3,4-tri-
δ 6.86 (d, J = 2.2 Hz, 1H), 6.63 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), carboxylate (3m′). (28 mg, 8%, brown liquid); 1H NMR
4.04 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.81 (s, 1H), 4.04 (s, 3H), 4.03
(100 MHz, CDCl3) δ 169.8, 162.7, 162.1, 155.9, 149.9, 140.5, (s, 3H), 3.95 (s, 3H), 3.15–3.10 (m, 4H), 2.20 (quint, J = 7.4 Hz,
108.2, 107.7, 100.0, 97.4, 56.5, 55.8, 53.7, 52.7; Vmax/cm−1 2948, 2H); 13C NMR (100 MHz, CDCl3) δ 166.6, 166.5, 166.2, 151.4,
1739, 1621, 1596, 1348; HRMS (ESI) calcd for C15H16NO6 149.0, 147.8, 146.7, 139.6, 125.0, 123.2, 122.2, 119.7, 53.6, 53.4,
306.0978 (M + H+); found 306.0979.
53.4, 33.2, 33.1, 26.1; Vmax/cm−1 3222, 2922, 1731, 1650, 1554;
Trimethyl 5,7-dimethoxyquinoline-2,3,4-tricarboxylate (3h′). calcd for C18H18NO6 344.1134 (M + H+); found 344.1137.
1
(41 mg, 11%, yellow liquid); H NMR (400 MHz, CDCl3) δ 7.18
Dimethyl [1,3]dioxolo[4,5-g]quinoline-6,8-dicarboxylate (3n).
1
(d, J = 2.2 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 4.01 (s, 3H), 3.99 (s, (252 mg, 87%, gray solid); mp 164–165 °C; H NMR (400 MHz,
3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 8.59 (s, 1H), 8.25 (s, 1H), 7.61 (s, 1H), 6.19 (s, 2H),
CDCl3) δ 167.8, 166.4, 165.6, 163.8, 156.1, 150.8, 150.1, 139.9, 4.08 (s, 3H), 4.04 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 166.5,
118.8, 112.1, 101.9, 101.4, 57.0, 56.2, 53.5, 53.3, 52.9; Vmax
cm−1 3277, 2935, 1728, 1666, 1550; HRMS (ESI) calcd for 102.7, 101.3, 53.4, 53.0; Vmax/cm−1 2948, 1738, 1640, 1578,
C17H18NO8 364.1032 (M + H+); found 364.1059. 1367; HRMS (ESI) calcd for C14H12NO6 290.0665 (M + H+);
Dimethyl 6,8-dimethoxyquinoline-2,4-dicarboxylate (3i). found 290.668.
(245 mg, 80%, yellow solid); mp 161–162 °C; 1H NMR
Dimethyl benzo[h]quinoline-2,4-dicarboxylate (3o). (233 mg,
/
165.7, 151.7, 151.7, 147.9, 145.2, 134.2, 125.2, 121.4, 107.1,
1
(600 MHz, CDCl3) δ 8.74 (s, 1H), 7.89 (s, 1H), 6.78 (s, 1H), 4.06 78%, gray solid); mp 172–173 °C; H NMR (600 MHz, CDCl3) δ
(s, 3H), 4.05 (s, 3H), 4.03 (s, 3H), 3.99 (s, 3H); 13C NMR 9.44 (d, J = 8.1 Hz, 1H), 8.78 (s, 1H), 8.70 (d, J = 9.3 Hz, 1H),
(150 MHz, CDCl3) δ 166.5, 165.8, 162.4, 157.3, 143.2, 138.1, 8.03 (d, J = 9.3 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.82–7.77 (m,
133.3, 129.6, 124.1, 102.4, 95.2, 56.5, 56.0, 53.3, 52.9; Vmax
/
2H), 4.13 (s, 3H), 4.09 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
cm−1 2954, 1720, 1615, 1436, 1285; HRMS (ESI) calcd for 166.6, 165.8, 147.7, 146.0, 135.9, 133.5, 132.2, 131.6, 129.6,
C15H16NO6 306.0978 (M + H+); found 306.0978.
Dimethyl 5,7-dimethylquinoline-2,4-dicarboxylate
128.2, 128.0, 126.0, 125.6, 123.1, 122.2, 53.4, 53.2; Vmax/cm−1
(3j). 2965, 1739, 1642, 1600, 1368; HRMS (ESI) calcd for C17H14NO4
(225 mg, 82%, yellow solid); mp 133–134 °C; 1H NMR 296.0923(M + H+); found 296.0927.
(400 MHz, CDCl3) δ 8.09 (s, 1H), 7.99 (s, 1H), 7.36 (s, 1H), 4.07
Dimethyl 6-chloroquinoline-2,4-dicarboxylate (3p).9 (243 mg,
(s, 3H), 4.03 (s, 3H), 2.58 (s, 3H), 2.52 (s, 3H); 13C NMR 87%, light yellow solid); mp 152–153 °C; H NMR (400 MHz,
1
(100 MHz, CDCl3) δ 170.0, 165.5, 149.4, 146.7, 140.9, 139.9, CDCl3) δ 8.92 (d, J = 2.3 Hz, 1H), 8.71 (s, 1H), 8.28 (d, J = 9.1
134.7, 133.5, 128.9, 122.5, 119.2, 53.5, 53.3, 21.7, 21.0; Vmax
/
Hz, 1H), 7.78 (dd, J = 9.1, 2.3 Hz, 1H), 4.11 (s, 3H), 4.08 (s, 3H);
cm−1 2953, 1732, 1631, 1561, 1338; HRMS (ESI) calcd for 13C NMR (100 MHz, CDCl3) δ 165.7, 165.2, 147.9, 147.2, 137.2,
C15H16NO4 274.1079 (M + H+); found 274.1079.
135.1, 132.8, 131.9, 127.0, 124.9, 123.4, 53.57, 53.19; Vmax/cm−1
Dimethyl 6,8-dimethylquinoline-2,4-dicarboxylate (3k).9 2959, 1722, 1606, 1494, 1236; HRMS (ESI) calcd for
(236 mg, 86%, light yellow solid); mp 138–139 °C; 1H NMR C13H11ClNO4 280.0381 (M + H+); found 280.0391.
(600 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (s, 1H), 7.53 (s, 1H), 4.07
Dimethyl 8-chloroquinoline-2,4-dicarboxylate (3q). (239 mg,
1
(s, 3H), 4.05 (s, 3H), 2.87 (s, 3H), 2.55 (s, 3H); 13C NMR 85%, light yellow solid); mp 143–144 °C; H NMR (500 MHz,
(150 MHz, CDCl3) δ 166.7, 165.9, 146.7, 145.3, 140.9, 138.9, CDCl3) δ 8.76 (d, J = 8.7 Hz, 1H), 8.71 (s, 1H), 7.95 (d, J = 7.5
135.4, 133.3, 126.7, 122.3, 122.2, 53.3, 52.9, 22.6, 18.4; Vmax
/
Hz, 1H), 7.65 (t, J = 8.7 Hz, 1H), 4.09 (s, 3H), 4.06 (s, 3H); 13C
cm−1 2956, 1728, 1627, 1568, 1339; HRMS (ESI) calcd for NMR (125 MHz, CDCl3) δ 165.8, 165.3, 148.2, 145.2, 136.9,
C15H16NO4 274.1079 (M + H+); found 274.1079.
135.7, 130.9, 130.2, 127.9, 124.8, 123.2, 53.5, 53.2; Vmax/cm−1
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2962, 1728, 1450, 1242; HRMS (ESI) calcd for C13H11ClNO4 (quint, J = 7.1 Hz, 4H), 2.87 (s, 3H), 2.55 (s, 3H), 1.49 (td, J =
280.0381 (M + H+); found 280.0390. 7.2, 5.6 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 166.5, 165.5,
Dimethyl 6-(methylthio)quinoline-2,4-dicarboxylate (3r). 146.8, 145.7, 140.7, 139.0, 135.9, 133.1, 126.6, 122.3, 121.9,
(253 mg, 86%, light yellow solid); mp 138–139 °C; 1H NMR 62.3, 62.1, 22.5, 18.4, 14.5, 14.5; Vmax/cm−1 2983, 1717, 1619,
(400 MHz, CDCl3) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.18 (d, J = 9.0 1468, 1342; HRMS (ESI) calcd for C17H20NO4 302.1392 (M +
Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 4.08 (s, 3H), 4.05 (s, 3H), 2.63 H+); found 302.1394.
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 165.5, 147.1,
Diethyl
6,7-dimethylquinoline-2,4-dicarboxylate
(4g).
146.1, 143.9, 133.4, 131.1, 129.7, 127.2, 123.5, 118.7, 53.5, 52.9, (258 mg, 85%, light yellow solid); mp 147–148 °C; 1H NMR
15.2; Vmax/cm−1 2958, 1717, 1602, 1450, 1243; HRMS (ESI) (400 MHz, CDCl3) δ 8.57 (d, J = 2.0 Hz, 2H), 8.13 (s, 1H),
calcd for C14H14SNO4 292.0644 (M + H+); found 292.0655.
Diethyl 6-methoxyquinoline-2,4-dicarboxylate
4.60–4.55 (m, 2H), 4.52 (t, J = 7.2 Hz, 2H), 2.52 (s, 3H), 2.50 (s,
(4a).10 3H), 1.49 (td, J = 7.1, 3.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
(261 mg, 86%, yellow solid); mp 158–159 °C; 1H NMR 166.2, 165.4, 148.2, 147.1, 141.2, 141.2, 135.4, 130.7, 125.2,
(500 MHz, CDCl3) δ 8.69 (s, 1H), 8.28 (s, 1H), 8.24 (d, J = 9.3 124.8, 121.6, 62.5, 62.1, 20.9, 20.4, 14.6, 14.5; Vmax/cm−1 2981,
Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 4.55 (dq, J = 22.1, 7.0 Hz, 4H), 1721, 1464, 1230; HRMS (ESI) calcd for C17H20NO4 302.1392
4.00 (s, 3H), 1.50 (t, J = 6.9 Hz, 6H); 13C NMR (125 MHz, (M + H+); found 302.1397.
CDCl3) δ 166.2, 165.3, 161.2, 145.4, 145.2, 133.9, 133.0, 128.6,
Diethyl [1,3]dioxolo[4,5-g]quinoline-6,8-dicarboxylate (4h).
124.0, 123.2, 103.2, 62.5, 62.1, 55.9, 14.6, 14.5; Vmax/cm−1 2981, (264 mg, 83%, yellow solid); mp 175–176 °C; 1H NMR
1719, 1622, 1600, 1229; HRMS (ESI) calcd for C16H18NO5 (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.22 (s, 1H), 7.61 (s, 1H), 6.19
304.1185 (M + H+); found 304.1188.
Diethyl 6-hydroxyquinoline-2,4-dicarboxylate
(s, 2H), 4.54 (q, J = 7.1 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.48
(4b).10 (td, J = 7.1, 4.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.3,
(243 mg, 84%, light yellow solid); mp 220–221 °C; 1H NMR 159.9, 156.8, 151.5, 147.9, 145.7, 134.7, 125.1, 121.2, 107.3,
(400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 102.6, 101.3, 62.5, 62.2, 14.6, 14.5; Vmax/cm−1 2993, 1721, 1621,
8.04 (d, J = 2.6 Hz, 1H), 7.49 (dd, J = 9.2, 2.6 Hz, 1H), 4.44 (dq, J 1477, 1233; HRMS (ESI) calcd for C16H16NO6 318.0978 (M +
= 14.3, 7.1 Hz, 4H), 1.39 (dt, J = 12.1, 7.2 Hz, 6H); 13C NMR H+); found 318.0985.
(100 MHz, DMSO) δ 165.3, 164.4, 159.4, 143.7, 143.6, 133.2,
132.6, 127.5, 123.8, 121.9, 106.1, 61.8, 61.5, 14.2, 14.0; Vmax
Diethyl 7,8-dihydro-6H-cyclopenta[g]quinoline-2,4-dicarbox-
ylate (4i). (256 mg, 81%, light yellow solid); mp 150–152 °C; 1H
/
cm−1 3397, 2946, 1719, 1655, 1310; HRMS (ESI) calcd for NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.55 (s, 1H), 8.15
C15H16NO5 290.1028 (M + H+); found 290.1028.
(s, 1H), 4.60–4.55 (m, 2H), 4.54–4.49 (m, 2H), 3.14 (t, J = 7.4
Diethyl 6-methylquinoline-2,4-dicarboxylate (4c).10 (247 mg, Hz, 4H), 2.20 (p, J = 7.4 Hz, 2H), 1.49 (td, J = 7.2, 5.0 Hz, 6H);
86%, yellow solid); mp 135–136 °C; 1H NMR (400 MHz, CDCl3) 13C NMR (100 MHz, CDCl3) δ 166.4, 165.4, 149.1, 148.9, 148.9,
δ 8.62 (s, 1H), 8.59 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 146.7, 135.9, 125.7, 125.7, 121.4, 119.6, 62.5, 62.2, 33.4, 32.9,
8.7 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 4.54 (q, J = 7.2 Hz, 2H), 26.2, 14.6, 14.5; Vmax/cm−1 2979, 1719, 1454, 1369, 1232;
2.61 (s, 3H), 1.50 (td, J = 7.2, 3.9 Hz, 6H); Vmax/cm−1 2982, HRMS (ESI) calcd for C18H20NO4 314.1492 (M + H+); found
1722, 1623, 1369, 1234; HRMS (ESI) calcd for C16H18NO4 314.1495.
288.1236 (M + H+); found 288.1238.
Diethyl benzo[h]quinoline-2,4-dicarboxylate (4j). (253 mg,
Diethyl 8-methylquinoline-2,4-dicarboxylate (4d). (244 mg, 78%, yellow solid); mp 184–185 °C; 1H NMR (400 MHz, CDCl3)
1
85%, light yellow solid); mp 126–127 °C; H NMR (500 MHz, δ 9.45 (d, J = 7.7 Hz, 1H), 8.74 (s, 1H), 8.67 (d, J = 9.3 Hz, 1H),
CDCl3) δ 8.61 (d, J = 12.7 Hz, 2H), 7.68 (d, J = 7.0 Hz, 1H), 7.63 8.01 (d, J = 9.3 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.84–7.75 (m,
(t, J = 7.7 Hz, 1H), 4.54 (p, J = 7.8 Hz, 4H), 2.92 (s, 3H), 1.50 (q, 2H), 4.62–4.53 (m, 4H), 1.52 (dd, J = 14.0, 7.1 Hz, 6H); 13C
J = 7.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 166.3, 165.4, NMR (100 MHz, CDCl3) δ 166.3, 165.4, 147.6, 146.4, 136.4,
148.0, 146.8, 139.6, 136.9, 130.7, 130.1, 126.5, 123.5, 121.8, 133.5, 131.9, 131.7, 129.4, 128.1, 127.9, 125.9, 125.7, 122.8,
62.36, 62.27, 18.50, 14.53; Vmax/cm−1 2983, 1717, 1619, 1468, 122.2, 62.4, 62.4, 14.6, 14.5; Vmax/cm−1 2982, 1720, 1605, 1368,
1342; HRMS (ESI) calcd for C16H18NO4 288.1236 (M + H+); 1237; HRMS (ESI) calcd for C19H18NO4 324.1236 (M + H+);
found 288.1237.
Diethyl 5,7-dimethoxyquinoline-2,4-dicarboxylate
found 324.1236.
Diethyl 6-chloroquinoline-2,4-dicarboxylate (4k). (257 mg,
(4e).
(248 mg, 74%, light yellow liquid); H NMR (400 MHz, CDCl3) 83%, yellow solid); mp 163–164 °C; 1H NMR (400 MHz, CDCl3)
δ 6.83 (d, J = 2.3 Hz, 1H), 6.61 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), δ 8.92 (d, J = 2.3 Hz, 1H), 8.69 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H),
4.48 (q, J = 7.1 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 7.77 (dd, J = 9.1, 2.3 Hz, 1H), 4.56 (dd, J = 16.0, 7.2 Hz, 4H),
3.87 (s, 3H), 1.41 (dt, J = 9.1, 7.1 Hz, 6H); 13C NMR (100 MHz, 1.50 (q, J = 4.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.4,
CDCl3) δ 169.4, 162.5, 162.0, 155.9, 150.1, 140.8, 108.1, 107.9, 164.8, 148.3, 147.3, 137.0, 135.6, 132.9, 131.8, 127.1, 124.9,
99.9, 97.2, 62.1, 61.8, 56.2, 55.8, 14.8, 14.5; Vmax/cm−1 2938, 123.3, 62.8, 62.6, 14.6, 14.5; Vmax/cm−1 2987, 1723, 1605, 1448,
1737, 1623, 1596, 1332; HRMS (ESI) calcd for C17H20NO6 1240; HRMS (ESI) calcd for C15H15ClNO4 308.0690 (M + H+);
1
334.1291 (M + H+); found 334.1294.
Diethyl 6,8-dimethylquinoline-2,4-dicarboxylate
found 308.0697.
Diethyl 8-chloroquinoline-2,4-dicarboxylate (4l). (254 mg,
(4f).
(265 mg, 88%, light yellow solid); mp 144–145 °C; 1H NMR 82%, light yellow solid); mp 157–158 °C; H NMR (400 MHz,
1
(500 MHz, CDCl3) δ 8.56 (s, 1H), 8.38 (s, 1H), 7.52 (s, 1H), 4.53 CDCl3) δ 6.83 (d, J = 2.3 Hz, 1H), 6.61 (s, 1H), 6.41 (d, J = 2.3
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Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.91
(s, 3H), 3.87 (s, 3H), 1.41 (dt, J = 9.1, 7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 169.4, 162.5, 162.0, 155.9, 150.1, 140.8,
Notes and references
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A. S. Chan, C. Chui, J. C. Tang and K. Lam, Future Med.
Chem., 2015, 7, 947–967; (e) C. Portela, C. M. M. Afonso,
M. M. M. Pinto and M. J. Ramos, Bioorg. Med. Chem., 2004,
12, 3313–3321; (f) A. Nayyar, A. Malde, R. Jain and
E. Coutinho, Bioorg. Med. Chem., 2006, 14, 847–856;
(g) S. Vangapamdu, M. Jain, R. Jain, S. Kaur and
P. P. Singh, Bioorg. Med. Chem., 2004, 12, 2501–2508;
(h) J. Charris, P. Martinez, J. Dominguez, S. Lopez, J. Angel
and G. Espinoza, Heterocycl. Commun., 2003, 9, 251–256;
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108.1, 107.9, 99.9, 97.2, 62.1, 61.8, 56.2, 55.8, 14.8, 14.5; Vmax
/
cm−1 2983, 1722, 1446, 1370, 1239; HRMS (ESI) calcd for
C15H15ClNO4 308.0690 (M + H+); found 309.0709.
Diethyl 6-(methylthio)quinoline-2,4-dicarboxylate (4m).
(258 mg, 80%, light yellow solid); mp 152–153 °C; 1H NMR
(500 MHz, CDCl3) δ 8.67 (s, 1H), 8.63 (s, 1H), 8.21 (d, J = 9.1
Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 4.55 (dq, J = 22.6, 7.1 Hz, 4H),
2.64 (s, 3H), 1.50 (td, J = 7.1, 2.7 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 165.9, 165.2, 147.2, 146.6, 143.6, 134.0, 131.3, 129.7,
127.2, 123.4, 118.8, 62.6, 62.2, 15.2, 14.6, 14.5; Vmax/cm−1 2924,
1719, 1602, 1448, 1234; HRMS (ESI) calcd for C16H18NO4S
320.0957 (M + H+); found 320.0985.
Dimethyl 2-(4-methoxyphenylamino)maleate (A). (240 mg,
1
90%, yellow liquid); H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H),
6.85 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.9 Hz, 2H), 5.27 (s, 1H),
3.74 (s, 3H), 3.69 (s, 3H), 3.63 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.1, 164.9, 157.0, 149.1, 133.5, 123.1, 114.5, 91.7,
55.5, 52.7, 51.1; Vmax/cm−1 3287, 2952, 1739, 1669, 1277;
HRMS (ESI) calcd for C13H16NO5 266.1028 (M + H+); found
266.1041.
Dimethyl 2-(4-(methoxycarbonyl)phenylamino)maleate (5a).
(232 mg, 79%, yellow liquid); 1H NMR (500 MHz, CDCl3) δ 9.71
(s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.52 (s,
1H), 3.86 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.6, 166.6, 164.6, 146.5, 144.6, 131.0, 125.3, 119.2,
96.9, 53.1, 52.1, 51.5; Vmax/cm−1 3286, 2949, 1716, 1597, 1268;
HRMS (ESI) calcd for C14H16NO6 294.0978 (M + H+); found
294.0982.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
SA thanks IIT Guwahati for his research fellowship. We also
thank the Central Instruments Facility (CIF), IIT Guwahati for
instrument facilities. We are thankful to the Department of
Science and Technology, New Delhi for financial support
(Research Grant No.: CRG/2018/002120/OC) to Professor
A. T. Khan. We also thank the MHRD for the 400 MHz NMR
facility under the COE-FAST programme (Sanction No. 5-5/
2014-TS VII) and the DST for providing the 500 MHz NMR
facility under the DST-FIST programme (Sanction No. SR/FST/
CS-II/2017/23C). We would like to express our deep sense of
gratitude to Professor Bhisma K. Patel for proposing the prob-
able reaction mechanism for the formation of the diester
product. We are grateful to Prof S. S. Bag for the discussion on
the proposed mechanism. We are also thankful to the referees
for their valuable comments as well as the editor for his criti-
cal evaluation of our manuscript.
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