Copper(ii) triflate-catalyzed reactions for the synthesis of novel and diverse quinoline carboxylates

Article abstract of DOI:10.1039/c3ra44943b

An efficient one-pot synthesis of a variety of quinoline carboxylates was accomplished by Cu(OTf)₂-catalyzed reactions of Michael addition/cyclization/aromatization between 2-aminoaryl carbonyls and alkynyl carboxylates. This methodology offers

Full text of DOI:10.1039/c3ra44943b

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Copper(II) triflate-catalyzed reactions for the synthesis
of novel and diverse quinoline carboxylates†
Cite this: DOI: 10.1039/c3ra44943b
*
Rameshwar Prasad Pandit and Yong Rok Lee
An efficient one-pot synthesis of a variety of quinoline carboxylates was accomplished by Cu(OTf)2-
catalyzed reactions of Michael addition/cyclization/aromatization between 2-aminoaryl carbonyls and
alkynyl carboxylates. This methodology offers several significant advantages, namely, ease of handling,
mild reaction conditions, enhanced reaction rates, and use of an effective and non-toxic catalyst. The
synthesized compounds were further transformed into highly functionalized novel quinoline
carboxylates bearing aromatic rings on the quinoline skeleton using the Suzuki reaction.
Received 11th July 2013
Accepted 13th September 2013
DOI: 10.1039/c3ra44943b
www.rsc.org/advances
reduction of nitro compounds (path b),10b and b-keto esters in
the presence of various catalysts lead to the formation of 3-
Introduction
Quinolines and their derivatives are prevalent structural motifs
and are found in a wide variety of natural products with
important pharmacological activities.1 These compounds have
been shown to possess various biological properties, such as
antimalarial, antimicrobial, antitumor, anti-inammatory,
antiasthmatic, and antihypertensive activities.2 In addition,
some isolated from marine organisms have been shown to have
other properties, such as, the inhibitions of phosphoinositide-
dependent protein 1 (PDK-1), which is involved in the
progression of some cancers,3 and tyro-kinase PDGF-RTK.4 Due
to their interesting activities, a number of classical methods,
including the Skraup,5 Doebner-von Miller,6 Doebner,7
quinolinecarboxylic esters via cyclocondensation. The useful-
ness of quinoline moiety has driven the attention of synthetic
chemists towards the discovery of exceptionally convenient
strategies in designing and synthesis of exclusive quinoline
skeleton. Consequently numerous methods dealing with cata-
lytic activity of Brønsted acids (polyphosphoric sulfamic or
p-TsOH)11 and Lewis acids (AuCl3, Y(OTf)3, ZnCl2, Ag3PW12O40
,
FeCl3, Mg(ClO4)2, RuCl2(dmso)4, CuI or Ag(OTf))12 has been
explored.
Other useful methods have been described for the synthesis
of quinoline carboxylates, such as, cycloaddition between 2-
amino carbonyl compounds and dialkyl acetylenedicarboxylates
or alkyl acetylenecarboxylates, in which AuCl(PPh3)/AgOTf,13 b-
cyclodextrin (b-CD),14 or pyridine15 were used as catalysts, and
PPh3 (ref. 16) as a promoter (Scheme 2).
Recently, other methods of synthesizing quinoline dicar-
boxylate were reported based on the photo-Fries rearrangement
of p-substituted anilides17 and the [Cp*Fe(CO2)]2-catalyzed
reductive cyclization of o-nitro Baylis–Hillman acetates.18
Despite a few methods devised to synthesize quinoline dicar-
boxylate,13–16 which is limited in the use of propiolates, there is
still a demand for simpler, less toxic, more effective, milder
catalysts. In particular, the reported methods have been widely
used for the synthesis of quinoline methylcarboxylates and
ethylcarboxylates.
8
9
10
¨
Combes, Ptzinger, and Friedlander protocols, have been
used to synthesize the quinoline core. Among these,
¨
Friedlander annulation has been widely used to synthesize
substituted 3-quinolinecarboxylic esters (Scheme 1).10 Reac-
tions between 2-aminoaryl carbonyl compounds, generated in
situ by oxidation of 2-aminobenzylic alcohols (path a)10a or by
Development of new methods for functionalized quinoline
has always been a challenge since the installation of particular
Scheme 1 Typical method for the synthesis of quinoline carboxylates from
aminocarbonyls and 1,3-ketoesters.
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic
of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631; Tel: +82-53-810-2529
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra44943b
Scheme 2 General methods for the synthesis of quinoline carboxylates from
aminocarbonyls and dialkyl acetylene dicarboxylates.
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functionality in the moiety oen requires tactful handling of exhibited at d 8.60 ppm as a singlet. In order to compare with
vulnerable function in the reaction. Our on-going studies on reported work, further reactions were carried out. For exam-
mild and efficient synthetic methods for producing function- ples, reaction of 1a with 2a in the presence of 10 mol% of
alized quinoline carboxylates and dicarboxylates led to examine pyridine in reuxing 1,2-dichloroethane for 12 h provided 3a in
potentially more convenient and safe catalysts. Of those exam- 68% yield, whereas that in 10 mol% of PPh3 for 12 h afforded
ined, Cu(OTf)2 was found to provide a viable alternative, 3a in 50% yield.
because of its availability, ease of handling, enhanced reaction
Several methods for the synthesis of quinoline carboxylates
rates, greater selectivity, and simple requirements.19 Here, we starting from 2-amino carbonyl compounds have been repor-
describe the copper triate-catalyzed synthesis of biologically ted.13–16 These known methods mostly employed internal
interesting novel and diverse quinoline carboxylates bearing acetylene carboxylates such as dialkyl acetylenedicarboxylates
methyl, ethyl, prenyl, phenylpropyl, phenoxyethyl, benzyl, 1- and ethyl 3-phenylpropiolate as reactants, which provided
naphthyl, and phenyl groups. We also report on the synthesis of quinoline dicarboxylates.13–16 To explore the generality and
functionalized quinoline dicarboxylates with various substitu- scope of our method, additional reactions between 2-aminoaryl
ents such as dibromo, methyl, phenyl, and 4-bromophenyl on carbonyl compounds 1a–1d and various internal/terminal
the quinoline ring.
acetylene carboxylates 2b–2l were carried out in the presence of
10 mol% of Cu(OTf)2 under optimized reaction conditions. In
particular, a number of synthesized terminal alkylpropiolates
bearing prenyl, 3-phenylpropyl, 2-phenoxyethyl, benzyl, naph-
thalen-1-ylmethyl, and phenyl group were used. Results are
summarized in Table 2. Reaction between 2-amino-3,5-dibro-
mobenzaldehyde (1a) and diethyl acetylenedicarboxylate (2b)
in the presence of 10 mol% of Cu(OTf)2 in 1,2-dichloroethane
under reux for 6 h furnished 6,8-dibromo-2,3-diethylquino-
line dicarboxylate (3b) in 85% yield (Table 2, entry 1). Treat-
ment of 1a with methyl propiolate (2c) or ethyl propiolate (2d)
afforded the expected products 3c and 3d at yields of 92 and
90%, respectively (Table 2, entries 2–3). Further reactions
between 1a and other propiolates 2e–2j were also successful.
Treatment of 1a with propiolates 2e–2g bearing a prenyl,
3-phenylpropyl, or 2-phenoxyethyl group provided the desired
products 3e–3g at yields of 86, 80, and 73%, respectively
(entries 4–6), whereas treatment of 1a with 2h–2j bearing
benzyl, naphthalene-1-yl methyl, or phenyl group afforded
products 3h–3j in 80, 78, and 81% yield (entries 7–9). Impor-
tantly, all terminal acetylenic carboxylates 2e–2j provided the
directionality to afford 3-quinoline carboxylates as single
isomers and no regioisomeric 2-substituted quinoline carbox-
ylates were observed in the process. The reactions of 2-amino
acetophenone (1b), 2-amino benzophenone (1c), and 2-amino-
40-bromobenzophenone (1d) were also successful. Conversion
of 1b–1d into the corresponding products 3k–3p took slightly
more time (12 h), but at satisfactory yields of 75–82% (entries
10–15). In addition, treatment of 1a with ethyl 3-phenyl-
propiolate (2k) for 12 h afforded 3q in 30% yield and starting
material 1a (50%) was recovered (entry 16). However, reaction
with ethyl 3-methylpropiolate (2l) for 12 h did not provide the
desired product 3r, instead almost of starting material was
recovered (entry 17).
Results and discussion
To synthesize 6,8-dibromo-2,3-dimethylquinoline dicarboxylate
(3a), we rst investigated reactions between 2-amino-3,5-dibro-
mobenzaldehyde (1a) and dimethyl acetylenedicarboxylate
(DMAD, 2a) using different catalysts and solvents. Results are
depicted in Table 1. Reaction between 1a and 2a in the pres-
ence of InCl3 (10 mol%) or Yb(OTf)3 (both Lewis catalysts) in
reuxing methylene chloride for 12 h provided the desired
product 3a in 78 and 81% yield, respectively. When CuCl (10
mol%) was used, 3a was obtained in 66% yield. Interestingly,
when Cu(OTf)2 was used as a catalyst, a signicant increase in
yield occurred. Treatment of 1a with 2a in the presence of 10
mol% of Cu(OTf)2 in reuxing methylene for 12 h afforded 3a
ꢀ
in 90% yield. When the temperature was raised to 83 C using
1,2-dichloroethane, the yield improved to 96%. Despite the use
of high boiling solvents at their reux, reactions in toluene,
ethanol, and water did not improve the yield. Compound 3a
was easily separated by column chromatography and identied
by analyzing spectroscopic data. In the 1H NMR spectrum of
3a, the two m-protons on the benzene ring appeared at d 8.21
(d, J ¼ 2.0 Hz) and d 7.99 (d, J ¼ 2.0 Hz) ppm due to a long
range coupling, whereas one proton on the pyridinyl ring
Table 1 Effects of catalysts and solvents for the synthesis of 2,3-quinoline
dicarboxylate 3a
The formation of 3k could be explained by the putative
mechanism shown in Scheme 3. Dimethyl acetylenedicarbox-
ylate forms a carbonyl–copper complex in the presence of
Cu(OTf)2, and this complex is attacked by 2-amino acetophe-
none (1b) to produce intermediate 4 via Michael reaction.
Proton transfer of 4 followed by isomerization of 5 gives inter-
mediate 6, which then forms a complex with Cu(OTf)2 to afford
7. Intramolecular cyclization of 7 furnishes 8, which on
aromatization yields the nal product 3k. As an evidence of this
Catalyst
Solvent
Condition
Yield (%)
InCl3 (10 mol%)
Yb(OTf)3 (10 mol%)
CuCl (10 mol%)
Cu(OTf)2 (10 mol%)
Cu(OTf)2 (10 mol%)
Cu(OTf)2 (10 mol%)
Cu(OTf)2 (20 mol%)
Cu(OTf)2 (20 mol%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
Toluene
EtOH
Reux, 12 h
Reux, 12 h
Reux, 12 h
Reux, 12 h
Reux, 6 h
Reux, 12 h
Reux, 12 h
Reux, 12 h
78
81
66
90
96
89
82
75
H2O
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Table 2 Cu(OTf)2-catalyzed synthesis of a variety of quinoline carboxylates in refluxing 1,2-dichloroethane
Entry
1
Starting material
Acetylene carboxylate
Time (h)
6
Product
Yield (%)
85
2
3
6
6
92
90
4
5
6
7
7
7
7
7
86
80
73
80
8
9
7
7
78
81
10
11
12
12
76
75
12
13
12
12
80
76
14
15
12
12
82
80
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Table 2 (Contd. )
Entry
Starting material
Acetylene carboxylate
Time (h)
12
Product
Yield (%)
30
16
17
12
0
Conclusions
In summary, we have synthesized a variety of quinoline
carboxylates through reactions between 2-aminoaryl carbonyl
compounds and acetylene dicarboxylates or propiolates. The
key strategy involves Cu(OTf)2-catalyzed cascade reactions via
Michael addition/cyclization/aromatization. The synthesized
compounds were further transformed into novel and inter-
esting polysubstituted quinoline carboxylates bearing aromatic
rings on the quinoline skeleton using Suzuki reactions.
Scheme 3 The possible mechanism for the formation of 3k.
mechanism, the Michael adduct 6 was isolated from a reaction
mixture aer 5 h and characterized by NMR spectroscopy, but
underwent complete conversion into the nal product in a
prolonged reaction time (12 h).
Experimental
All the experiments were carried out under nitrogen atmo-
sphere. Merck precoated silica gel plates (Art. 5554) with uo-
rescent indicator were used for analytical TLC. Flash column
chromatography was performed using silica gel 9385 (Merck).
1H NMR and 13C NMR spectra were recorded on a Varian VNS
(300 and 75 or 150 MHz, respectively) spectrometer in CDCl3
using d ¼ 7.24 and 77.0 ppm as solvent chemical shis.
Multiplicities were abbreviated as s ¼ singlet, d ¼ doublet, t ¼
triplet, m ¼ multiplet, dd ¼ doublet of doublets, dt ¼ doublet of
triplets. IR spectra were recorded on a FTIR (BIO-RAD), and
HRMS were carried out at the Korean Basic Science Institute.
As an application of this methodology, we attempted the
conversion of synthesized compound 3a to other interesting
novel molecules using Suzuki reactions, as shown in Scheme 4.
Reaction of 3a with phenylboronic acid in the presence of
Pd(PPh3)4 in reuxing aqueous THF for 5 h gave 9 in 71% yield,
whereas reaction with 3-methoxyphenylboronic acid for 3 h
provided 10 in 87% yield. Similarly, the Suzuki coupling of ethyl
6,8-dibromoquinoline-3-carboxylate (3d) with phenylboronic
acid or 3-methoxyphenylboronic acid furnished 11 and 12 in 79
and 85% yield, respectively. We expect that these synthetic
routes will be widely used to synthesize novel and diverse pol-
ysubstituted quinoline carboxylates bearing aromatic rings on
the quinoline skeleton.
General procedure for the synthesis of quinoline carboxylates
To a solution of 2-aminoaryl carbonyl (0.5 mmol) and acetylene
carboxylate (0.6 mmol) in 1,2-dichloroethane (5 mL) was added
Cu(OTf)2 (18 mg, 10 mol%) and the reaction mixture was
reuxed for 6–12 h. Aer completion of reaction as indicated by
TLC, the solvent was removed under reduced pressure. The
residue was puried by column chromatography on silica gel
using hexane–EtOAc (10 : 1) to give the product.
Dimethyl
6,8-dibromoquinoline-2,3-dicarboxylate
(3a).
White solid, (192 mg, 96%), mp 165–166 ꢀC; 1H NMR (300 MHz,
CDCl3): d 8.60 (s, 1H), 8.21 (d, J ¼ 2.0 Hz, 1H), 7.99 (d, J ¼ 2.0 Hz,
1H), 3.99 (s, 3H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3): d 166.6,
164.8, 151.5, 144.3, 139.1, 138.9, 130.4, 129.0, 126.6, 124.0,
122.4, 53.4, 53.3; FT-IR (KBr) 3069, 1727, 1272, 1144 cmꢁ1
;
HRMS (EI) m/z (M+) calcd for C13H9Br2NO4: 400.8898. Found:
400.8897.
Diethyl 6,8-dibromoquinoline-2,3-dicarboxylate (3b). White
solid, (182 mg, 85%), mp 160–162 ꢀC; 1H NMR (300 MHz,
CDCl3): d 8.65 (s, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 4.50 (q, J ¼ 7.5
Scheme 4 Transformation to poly substituted quinoline carboxylates using
Suzuki coupling.
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Hz, 2H), 4.42 (q, J ¼ 7.2 Hz, 2H), 1.44–1.37 (m, 6H); 13C NMR (75
MHz, CDCl3): d 166.1, 164.3, 151.8, 144.1, 139.0, 138.6, 130.3,
128.8, 126.4, 124.0, 122.1, 62.5, 62.4, 14.2, 14.1; FT-IR (KBr)
2982, 1732, 1275, 1063 cmꢁ1; HRMS (EI) m/z (M+) calcd for
Naphthalen-1-ylmethyl 6,8-dibromoquinoline-3-carboxylate
(3i). White solid, (183 mg, 78%), mp 181–182 ꢀC; 1H NMR
(300 MHz, CDCl3): d 9.53 (d, J ¼ 1.5 Hz, 1H), 8.68 (d, J ¼ 1.5 Hz,
1H), 8.21 (d, J ¼ 1.5 Hz, 1H), 8.12 (d, J ¼ 8.1 Hz, 1H), 7.99 (d, J ¼
1.8 Hz, 1H), 7.91–7.87 (m, 2H), 7.65 (d, J ¼ 6.9 Hz, 1H), 7.60–7.45
(m, 3H), 5.90 (s, 2H); 13C NMR (150 MHz, CDCl3): d 164.3, 151.0,
145.5, 138.2, 138.0, 133.7, 131.7, 130.7, 130.6, 129.8, 128.8,
128.7, 127.9, 126.8, 126.1, 125.9, 125.2, 124.5, 123.3, 120.8, 65.9;
FT-IR (KBr) 3058, 2928, 1716, 1251, 1108, 784 cmꢁ1; HRMS (EI)
m/z (M+) calcd for C21H13Br2NO2: 468.9313; found: 468.9314.
Phenyl 6,8-dibromoquinoline-3-carboxylate (3j). White solid,
(164 mg, 81%), mp 193–195 C; H NMR (300 MHz, CDCl3): d
9.60 (s, 1H), 8.84 (d, J ¼ 1.5 Hz, 1H), 8.22 (d, J ¼ 1.5 Hz, 1H), 8.04
(s, 1H), 7.44–7.38 (m, 2H), 7.28–7.21 (m, 3H); 13C NMR (75 MHz,
CDCl3): d 163.2, 151.2, 150.6, 146.0, 139.0, 138.6, 131.0, 129.8,
129.8, 128.9, 126.6, 126.3, 124.4, 121.6, 121.6, 121.3; FT-IR (KBr)
3053, 1725, 1473, 1207, 1095 cmꢁ1; HRMS (EI) m/z (M+) calcd for
C
15H13Br2NO4: 428.9211. Found: 428.9211.
Methyl 6,8-dibromoquinoline-3-carboxylate (3c). White
solid, (157 mg, 92%), mp 124–126 ꢀC; 1H NMR (300 MHz,
CDCl3): d 9.52 (s, 1H), 8.74 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 4.03
(s, 3H); 13C NMR (75 MHz, CDCl3): d 165.1, 151.1, 145.7, 138.3,
138.2, 130.9, 128.9, 126.1, 124.7, 121.1, 53.0; FT-IR (KBr) 3074,
1713, 1276, 1108 cmꢁ1
;
HRMS (EI) m/z (M+) calcd for
1
ꢀ
C
11H7Br2NO2: 342.8844. Found: 342.8842.
Ethyl 6,8-dibromoquinoline-3-carboxylate (3d). White solid,
1
ꢀ
(160 mg, 90%), mp 121–123 C; H NMR (300 MHz, CDCl3): d
9.49 (s, 1H), 8.69 (s, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 4.46 (q, J ¼ 7.2
Hz, 2H), 1.43 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
164.5, 151.1, 145.6, 138.1, 138.0, 130.8, 128.8, 126.1, 125.0,
120.9, 62.0, 14.4; FT-IR (KBr) 2985, 1721, 1261, 1109 cmꢁ1
;
C
16H9Br2NO2: 404.9000. Found: 404.8998.
Dimethyl 4-methylquinoline-2,3-dicarboxylate (3k).17 Yellow
HRMS (EI) m/z (M+) calcd for C12H9Br2NO2: 356.9000. Found:
356.8997.
solid, (99 mg, 76%), mp 80 ꢀC; 1H NMR (300 MHz, CDCl3): d 8.24
(d, J ¼ 8.1 Hz, 1H), 8.06 (d, J ¼ 8.1 Hz, 1H), 7.79 (dd, J ¼ 9.3,
7.2 Hz, 1H), 7.67 (dd, J ¼ 6.9, 6.9 Hz, 1H), 4.02 (s, 3H), 3.98
(s, 3H), 2.71 (s, 3H); 13C NMR (150 MHz, CDCl3): d 168.2, 165.4,
146.1, 144.7, 143.7, 130.9, 130.7, 128.9, 127.8, 127.0, 123.9, 53.2,
52.7, 15.4; FT-IR (KBr) 3007, 2953, 1726, 1568, 1443, 1244, 1058,
3-Methylbut-2-enyl 6,8-dibromoquinoline-3-carboxylate (3e).
White solid, (170 mg, 86%), mp 98–100 ꢀC; 1H NMR (300 MHz,
CDCl3): d 9.51 (d, J ¼ 1.5 Hz, 1H), 8.71 (d, J ¼ 1.5 Hz, 1H), 8.22 (d,
J ¼ 2.1 Hz, 1H), 8.04 (d, J ¼ 2.1 Hz, 1H), 5.48 (t, J ¼ 7.2 Hz, 1H),
4.90 (d, J ¼ 7.2 Hz, 2H), 1.79 (s, 6H); 13C NMR (75 MHz, CDCl3): d
164.5, 151.1, 145.5, 140.3, 138.0, 137.9, 130.8, 128.8, 126.0,
125.0, 120.8, 118.1, 62.8, 25.9, 18.3; FT-IR (KBr) 2972, 1713,
770 cmꢁ1
.
Diethyl 4-methylquinoline-2,3-dicarboxylate (3l). Yellow
solid, (107 mg, 75%), mp 63–64 ꢀC; 1H NMR (300 MHz, CDCl3): d
8.23 (d, J ¼ 8.1 Hz, 1H), 8.06 (d, J ¼ 8.1 Hz, 1H), 7.77 (dd, J ¼ 8.1,
6.9 Hz, 1H), 7.66 (dd, J ¼ 7.5, 7.1 Hz, 1H), 4.52–4.41 (m, 4H), 2.72
(s, 3H), 1.45–1.36 (m, 6H); 13C NMR (75 MHz, CDCl3): d 167.9,
165.4, 146.4, 145.9, 143.9, 131.1, 130.8, 129.0, 128.0, 127.1.
124.1, 62.5, 62.0, 15.5, 14.2, 14.1; FT-IR (KBr) 2982, 1730, 1239,
1182 cmꢁ1; HRMS (EI) m/z (M+) calcd for C16H17NO4: 287.1158.
Found: 287.1157.
1245, 1106, 926 cmꢁ1
;
HRMS (EI) m/z (M+) calcd for
C
15H13Br2NO2: 396.9313. Found: 396.9312.
3-Phenylpropyl 6,8-dibromoquinoline-3-carboxylate (3f).
1
ꢀ
White solid, (178 mg, 80%), mp 75–76 C; H NMR (300 MHz,
CDCl3): d 9.53 (s, 1H), 8.64 (d, J ¼ 2.0 Hz, 1H), 8.25 (d, J ¼ 2.0 Hz,
1H), 8.06 (d, J ¼ 1.5 Hz, 1H), 7.31–7.18 (m, 5H), 4.43 (t, J ¼ 6.3
Hz, 2H), 2.80 (t, J ¼ 7.8 Hz, 2H), 2.20–2.10 (m, 2H); 13C NMR
(150 MHz, CDCl3): d 164.2, 150.7, 145.3, 140.6, 137.9, 137.8,
130.5, 128.6, 128.3, 128.3, 128.2, 128.2, 125.9, 125.7, 124.5,
Dimethyl 4-phenylquinoline-2,3-dicarboxylate (3m).16 Yellow
solid, (128 mg, 80%), mp 79–80 ꢀC; 1H NMR (300 MHz, CDCl3): d
8.30 (d, J ¼ 8.4 Hz, 1H), 7.82–7.76 (m, 1H), 7.62–7.52 (m, 2H),
120.6, 65.0, 32.1, 29.8; FT-IR (KBr) 3055, 1720, 1240, 1100 cmꢁ1
;
HRMS (EI) m/z (M+) calcd for C19H15Br2NO2: 446.9470. Found:
446.9469.
7.48–7.46 (m, 3H), 7.34–7.31 (m, 2H), 4.04 (s, 3H), 3.60 (s, 3H); 13
C
2-Phenoxyethyl 6,8-dibromoquinoline-3-carboxylate (3g).
White solid, (164 mg, 73%), mp 100–102 ꢀC; 1H NMR (300 MHz,
CDCl3): d 9.53 (d, J ¼ 2.0 Hz, 1H), 8.71 (d, J ¼ 2.0 Hz, 1H), 8.24 (d,
J ¼ 2.1 Hz, 1H), 8.05 (d, J ¼ 2.1 Hz, 1H), 7.32–7.27 (m, 2H), 7.00–
NMR (75 MHz, CDCl3): d 167.6, 165.5, 148.0, 147.0, 144.8, 134.4,
131.0, 130.6, 129.3, 129.3, 129.2, 128.8, 128.3, 128.3, 127.5, 127.2,
126.6, 53.4, 52.4; FT-IR (KBr) 3050, 2995, 1725, 1245, 1180 cmꢁ1
.
Diethyl 4-phenylquinoline-2,3-dicarboxylate (3n).16 Yellow
solid, (133 mg, 76%), mp 60–61 ꢀC; 1H NMR (300 MHz, CDCl3): d
8.30 (d, J ¼ 7.8 Hz, 1H), 7.81–7.76 (m, 1H), 7.62–7.52 (m, 2H),
7.48–7.46 (m, 3H), 7.35–7.32 (m, 2H), 4.51 (q, J ¼ 7.2 Hz, 2H),
4.09 (q, J ¼ 7.2 Hz, 2H), 1.43 (t, J ¼ 7.2 Hz, 3H), 0.96 (t, J ¼ 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 167.1, 165.2, 147.9, 147.0,
145.8, 134.7, 130.9, 130.6, 129.4. 129.4, 129.1, 128.7, 128.2,
128.2, 127.5, 127.0, 126.6, 62.6, 61.5, 14.2, 13.6; FT-IR (KBr)
6.95 (m, 3H), 4.76 (t, J ¼ 4.5 Hz, 2H), 4.35 (t, J ¼ 4.5 Hz, 2H); 13
C
NMR (150 MHz, CDCl3): d 164.4, 158.3, 151.0, 145.7, 138.3,
138.1, 130.8, 129.6, 129.6, 128.7, 126.0, 124.3, 121.4, 120.9,
114.6, 114.6, 65.6, 64.2; FT-IR (KBr) 3060, 1715, 1247, 1105
cmꢁ1; HRMS (EI) m/z (M+) calcd for C18H13Br2NO3: 448.9262.
Found: 448.9262.
Benzyl 6,8-dibromoquinoline-3-carboxylate (3h). White
solid, (167 mg, 80%), mp 145–146 ꢀC; 1H NMR (300 MHz,
CDCl3): d 9.55 (s, 1H), 8.73 (d, J ¼ 2.0 Hz, 1H), 8.23 (d, J ¼ 2.0 Hz,
1H), 8.04 (s, 1H), 7.45–7.38 (m, 5H), 5.44 (s, 2H); 13C NMR (75
MHz, CDCl3): d 164.3, 151.1, 145.7, 138.2, 138.1, 135.4, 130.8,
128.9, 128.9, 128.9, 128.8, 128.5, 128.5, 126.1, 124.7, 121.0, 67.6;
FT-IR (KBr) 3066, 1713, 1245, 1109 cmꢁ1; HRMS (EI) m/z (M+)
calcd for C17H11Br2NO2: 418.9157. Found: 418.9156.
3030, 1985, 1728, 1240, 1179 cmꢁ1
Dimethyl 4-(4-bromophenyl)quinoline-2,3-dicarboxylate
.
(3o). White solid, (164 mg, 82%), mp 162–163 ꢀC; 1H NMR
(300 MHz, CDCl3): d 8.28 (d, J ¼ 8.4 Hz, 1H), 7.80–7.74 (m, 1H),
7.60–7.50 (m, 4H), 7.18 (d, J ¼ 7.8 Hz, 2H), 4.00 (s, 3H), 3.61 (s,
3H); 13C NMR (75 MHz, CDCl3): d 167.3, 165.4, 147.0, 146.7,
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144.9, 133.37, 131.6, 131.6, 131.2, 131.0, 131.0, 130.7, 129.5, mmol) in THF–H2O (1 : 1) (5 mL) was added Pd(PPh3)4 (29 mg,
127.2, 127.0, 126.2, 123.4, 53.5, 52.6; FT-IR (KBr) 3066, 2948, 5 mol%) under N2 and the mixture was heated at 60 ꢀC for 3 h.
1731, 1231, 1052, 774 cmꢁ1; HRMS (EI) m/z (M+) calcd for The reaction mixture was quenched with saturated NH4Cl
C
19H14BrNO4: 399.0106. Found: 399.0105.
Diethyl 4-(4-bromophenyl)quinoline-2,3-dicarboxylate (3p). The combined layers were washed with water (10 mL), dried
solution (10 mL) and extracted with ethyl acetate (3 ꢂ 10 mL).
White solid, (170 mg, 80%), mp 100–101 ꢀC; 1H NMR (300 MHz, (MgSO4), and evaporated under reduced pressure. Flash chro-
CDCl3): d 8.25 (d, J ¼ 8.4 Hz, 1H), 7.77–7.72 (m, 1H), 7.59–7.48 matography on silica gel using hexane–ethyl acetate (4 : 1)
(m, 4H), 7.18 (d, J ¼ 8.4 Hz, 2H), 4.46 (q, J ¼ 7.2 Hz, 2H), 4.06 (q, afforded 10 (397 mg, 87%) as an oil; 1H NMR (300 MHz, CDCl3):
J ¼ 7.2 Hz, 2H), 1.38 (t, J ¼ 7.2 Hz, 3H), 0.99 (t, J ¼ 7.2 Hz, 3H); d 8.69 (s, 1H), 8.05 (d, J ¼ 2.1 Hz, 1H), 7.92 (d, J ¼ 2.1 Hz, 1H),
13C NMR (75 MHz, CDCl3): d 167.0, 165.3, 147.2, 146.8, 146.1, 7.31–7.30 (m, 1H), 7.28 (d, J ¼ 2.7 Hz, 1H), 7.26 (d, J ¼ 2.4 Hz,
133.8, 131.7, 131.7, 131.3, 131.3, 131.2, 130.9, 129.4, 127.3, 1H), 7.24–7.23 (m, 1H), 7.21–7.16 (m, 1H), 7.14–7.12 (m, 1H),
127.1, 126.4, 123.4, 62.8, 61.8, 14.3, 13.8; FT-IR (KBr) 2978, 1725, 6.89–6.83 (m, 2H), 3.86 (s, 6H), 3.76 (s, 6H); 13C NMR (75 MHz,
1213, 1044, 771 cmꢁ1
;
HRMS (EI) m/z (M+) calcd for CDCl3): d 167.0, 165.4, 160.0, 159.0, 149.7, 144.8, 141.0, 140.8,
140.7, 139.7, 139.2, 132.6, 130.0, 128.8, 127.7, 125.5, 123.0,
C
21H18BrNO4: 427.0419. Found: 427.0422.
Ethyl 6,8-dibromo-2-phenylquinoline-3-carboxylate (3q). 122.2, 119.8, 116.2, 114.0, 113.5, 113.1, 55.2, 55.1, 52.7, 52.7; FT-
1
ꢀ
White solid, (129 mg, 30%), mp 80–82 C; H NMR (300 MHz, IR (neat) 2951, 2838, 1732, 1594, 1449, 1391, 1284, 1143, 1049,
CDCl3): d 8.44 (s, 1H), 8.19 (d, J ¼ 1.8 Hz, 1H), 7.99 (d, J ¼ 1.8 Hz, 785, 697 cmꢁ1; HRMS m/z (M+) calcd for C27H23NO6: 457.1525.
1H), 7.74–7.71 (m, 2H), 7.46–7.44 (m, 3H), 4.20 (q, J ¼ 7.2 Hz, Found: 457.1522.
2H), 1.08 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 167.6,
Ethyl 6,8-diphenylquinoline-3-carboxylate (11). To a mixture
158.4, 143.9, 139.4, 138.1, 137.5, 129.7, 129.2, 129.0, 129.0, of phenylboronic acid (181 mg, 1.5 mmol), 3d (180 mg, 0.5
128.2, 128.2, 127.4, 127.2, 126.2, 120.2, 61.9, 13.6; FT-IR (KBr) mmol), and K2CO3 (207 mg, 1.5 mmol) in THF–H2O (1 : 1)
3060, 1710, 1583, 1438, 1250, 1105, 696 cmꢁ1; HRMS (EI) m/z (5 mL) was added Pd(PPh3)4 (29 mg, 5 mol%) under N2 and the
(M+) calcd for C18H13Br2NO2: 432.9313. Found: 432.9315.
mixture was heated at 60 C for 3 h. The reaction mixture was
ꢀ
Dimethyl 2-(2-acetylphenylamino)maleate (6). Yellow solid, quenched with saturated NH4Cl solution (10 mL) and extracted
1
ꢀ
mp 82–84 C; H NMR (300 MHz, CDCl3): d 11.92 (s, NH, 1H), with ethyl acetate (3 ꢂ 10 mL). The combined layers were
7.80 (d, J ¼ 9.6 Hz, 1H), 7.36–7.24 (m, 1H), 7.01–6.96 (m, 1H), washed with water (10 mL), dried (MgSO4), and evaporated
6.62 (d, J ¼ 8.4 Hz, 1H), 5.59 (s, 1H), 3.76 (s, 3H), 3.72 (s, 3H), under reduced pressure. Flash chromatography on silica gel
2.63 (s, 3H); 13C NMR (75 MHz, CDCl3): d 200.6, 167.9, 165.5, using hexane–ethyl acetate (5 : 1) afforded 11 (278 mg, 79%) as
1
ꢀ
144.3, 142.0, 133.4, 131.7, 124.0, 121.3, 118.6, 100.3, 53.0, 51.6, an off-white solid, mp 60–62 C; H NMR (300 MHz, CDCl3): d
28.3; FT-IR (KBr) 3455, 3290, 1733, 1669, 1594, 1440, 1272, 1199, 9.34 (d, J ¼ 2.1 Hz, 1H), 8.79 (d, J ¼ 2.1 Hz, 1H), 7.98 (d, J ¼ 2.0
768 cmꢁ1; HRMS (EI) m/z (M+) calcd for C14H15NO5: 277.0950. Hz, 1H), 7.96 (d, J ¼ 2.0 Hz, 1H), 7.63–7.62 (m, 2H), 7.61–7.59
Found: 277.0947.
(m, 2H), 7.41–7.35 (m, 4H), 7.33–7.29 (m, 2H), 4.36 (q, J ¼ 6.9
Hz, 2H), 1.33 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
165.3, 156.0, 149.5, 146.6, 141.3, 139.7, 139.5, 139.1, 138.7,
132.3, 130.5, 129.3, 128.9, 128.0, 128.0, 127.7, 127.6, 127.3,
General procedure for Suzuki coupling
Dimethyl 6,8-diphenylquinoline-2,3-dicarboxylate (9). To a 126.0, 123.3, 120.0, 115.2, 61.5, 14.2; FT-IR (KBr) 3049, 2983,
mixture of phenylboronic acid (181 mg, 1.5 mmol), 3a (200 mg, 1717, 1599, 1478, 1256, 1107, 1020, 762, 695 cmꢁ1; HRMS m/z
0.5 mmol), and K2CO3 (207 mg, 1.5 mmol) in THF–H2O (1 : 1) (M+) calcd for C24H19NO2: 353.1416. Found: 353.1414.
(5 mL) was added Pd(PPh3)4 (29 mg, 5 mol%) under N2 and the
Ethyl 6,8-bis(3-methoxyphenyl)quinoline-3-carboxylate (12).
ꢀ
mixture was heated at 60 C for 5 h. The reaction mixture was To a mixture of 3-methoxyphenylboronic acid (226 mg, 1.5
quenched with saturated NH4Cl solution (10 mL) and extracted mmol), 3d (180 mg, 0.5 mmol), and K2CO3 (207 mg, 1.5 mmol)
with ethyl acetate (3 ꢂ 10 mL). The combined layers were in THF–H2O (1 : 1) (5 mL) was added Pd(PPh3)4 (29 mg, 5 mol%)
washed with water (10 mL), dried (MgSO4), and evaporated under N2 and the mixture was heated at 60 ꢀC for 3 h. The
under reduced pressure. Flash chromatography on silica gel reaction mixture was quenched with saturated NH4Cl solution
using hexane–ethyl acetate (5 : 1) afforded 9 (281 mg, 71%) as (10 mL) and extracted with ethyl acetate (3 ꢂ 10 mL). The
yellow solid, mp 115–117 ꢀC; 1H NMR (300 MHz, CDCl3): d 8.82 combined layers were washed with water (10 mL), dried
(s, 1H), 8.15 (d, J ¼ 2.0 Hz, 1H), 8.05 (d, J ¼ 2.0 Hz, 1H), 7.80– (MgSO4), and evaporated under reduced pressure. Flash chro-
7.71 (m, 4H), 7.52–7.39 (m, 6H), 3.97 (s, 3H), 3.96 (s, 3H); 13C matography on silica gel using hexane–ethyl acetate (3 : 1)
NMR (75 MHz, CDCl3): d 167.1, 165.4, 149.8, 144.8, 141.3, 140.9, afforded 12 (351 mg, 85%) as an off-white solid, mp 123–125 ꢀC;
139.7, 139.2, 138.0, 132.7, 130.8, 130.8, 129.0, 129.0, 128.2, 1H NMR (300 MHz, CDCl3): d 9.46 (d, J ¼ 2.1 Hz, 1H), 8.89 (d, J ¼
127.8, 127.8, 127.7, 127.6, 127.3, 127.3, 125.4, 122.0, 52.8, 52.7; 2.1 Hz, 1H), 8.09 (d, J ¼ 2.1 Hz, 1H), 8.07 (d, J ¼ 2.1 Hz, 1H),
FT-IR (KBr) 2952, 2919, 1728, 1574, 1265, 1194, 1142, 1061, 762, 7.45–7.37 (m, 2H), 7.32–7.25 (m, 4H), 7.01–6.93 (m, 2H), 4.47 (q,
695 cmꢁ1; HRMS m/z (M+) calcd for C25H19NO4: 397.1314. J ¼ 7.2 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 1.45 (t, J ¼ 7.2 Hz, 3H);
Found: 397.1312.
13C NMR (75 MHz, CDCl3): d 165.2, 160.0, 159.2, 149.6, 146.8,
Dimethyl 6,8-bis(3-methoxyphenyl)quinoline-2,3-dicarbox- 141.1, 141.0, 140.1, 139.5, 138.8, 132.1, 130.0, 128.9, 127.5,
ylate (10). To a mixture of 3-methoxyphenylboronic acid (226 126.1, 123.3, 123.0, 119.8, 116.3, 113.3, 113.2, 113.0, 61.4, 55.2,
mg, 1.5 mmol), 3a (200 mg, 0.5 mmol), and K2CO3 (207 mg, 1.5 55.2, 14.2; FT-IR (KBr) 3055, 2975, 1713, 1594, 1481, 1373, 1232,
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1034, 782, 696 cmꢁ1; HRMS m/z (M+) calcd for C26H23NO4:
413.1627. Found: 413.1624.
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Acknowledgements
This research was supported by the Nano Material Technology
Development Program of the Korean National Research Foun-
dation (NRF) funded by the Ministry of Education, Science and
Technology (2012M3A7B4049675).
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