Rhodium-catalyzed ortho C-H bond activation of arylamines for the synthesis of quinoline carboxylates

Article abstract of DOI:10.1039/c6ob00170j

The rhodium catalyzed annulation of anilines with alkynic esters allowing for the high-yield synthesis of quinoline carboxylates with excellent regioselectivity is described. This unprecedented reaction employs either formic acid as the C1 source and reductant or copper(ii) as the oxidant and is proposed to proceed via rhodacycle of in situ generated amide and enamine ester followed by ortho C-H activation of arylamines with rhodium as the catalyst.

Full text of DOI:10.1039/c6ob00170j

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Paper
Rhodium-Catalyzed ortho C-H Bond Activation of Arylamines for
the Synthesis of Quinoline Carboxylates
Sunita K. Gadakha, Soumen Deya and A. Sudalai*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The rhodium catalyzed annulation of anilines with alkynic esters
providing for the high yield synthesis of quinoline carboxylates
with excellent regioselectivity is described. This unprecedented
reaction employs either formic acid as C1 source and reductant or
Copper(II) as oxidant and is proposed to proceed via rhodacycle of
in situ generated amide and enamine ester followed by ortho C-H
activation of arylamines with rhodium catalyst.
Introduction
Quinoline carboxylates are ubiquitous heterocyclic units found
extensively in many natural products and pharmaceuticals and
possess anti-malarial, anti-HIV, anti-microbial and anti-TB
activities.1,2 The prevalence of quinoline units in bioactive molecules
has prompted the development of many useful methods for their
synthesis and functionalization.3 In particular, the literature related
to synthesis of quinoline 3-carboxylates found to be scarce to the
best of our knowledge.4 Despite significant advances, most of the
methods suffer from limited availability of substrates,4a,4c
complicated multi-step procedures,4b,4e and low regioselectivity,
leading to low yields of products4d in most cases. More recently,
transition metal-catalyzed functionalization of a variety of less
active C-H bonds has received substantial importance in the
construction of heterocyclic scaffolds.5 In particular, Rh(III), Ru(II),
Pd(II) and Cu(II) metal complexes have provided exciting
opportunities for the efficient synthesis of condensed heterocycles
Scheme 1 Transition metal-catalysed synthesis of heterocycles via
heteroatom-assisted chelation
Quite recent reports14 have described utilization of a directing
group that is incorporated in the product. In this context, we
reasoned that N-formyl derivative 4a generated in situ could serve
as a directing group for C-H functionalization to construct the
via chelation-assisted directing group C-H bond functionalization quinoline carboxylate units. Recently, we have reported rhodium
(e.g. indoles, pyrroles, pyridines, isoquinolones, isocoumarins, and
indolines).6-11 However, for directing group-assisted intermolecular
cyclization with alkynes, the elimination of heteroatom-assisted
chelation is often required in the early reaction stage12, 13 (Scheme
1).
catalyzed directing group assisted annulations of phenol acetates
with acrylates via ortho C-H bond activation giving coumarin
derivatives in high yields.15 In this communication, we disclose the
first efficient and direct approach to quinoline carboxylates 3 & 6
from simple and readily available anilines 1 and alkynic esters 2 by
using C-H activation via Rh catalysis with either formic acid as C1
source or Cu(OAc)2 as oxidant (Scheme 2 & 6).
aChemical Engineering
& Process Development Division, National Chemical
Results and discussion
Laboratory, Dr. Homi Bhabha Road, Pune-411008, Maharashtra, India.
We commenced our optimization study by examining reaction of
3,5-dimethoxyaniline 1a (1 mmol) with ethyl propiolate 2a (1.2
equiv) in excess of formic acid (1 mL) at various temperatures under
N2 atmosphere (Table 1). When [Rh2(OAc)4] (5 mol %) was
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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employed at 100 °C, a mixture of cyclized quinoline-3-carboxylate study, we observed that the ortho C-H bond activation was strongly
(3a, 48%) along with N-formyl derivative (4a, 45%) was obtained promoted by the electron-donating groups present at the meta to
(entry 1). In order to improve the yield of 3a, both Rh catalyst NH2 group of the substrates. For all the cases studied, the
concentration and temperature were reduced. At 70 °C, the annulated products 3a-k were indeed obtained in high yields (65-
cyclization efficiency was significantly improved to give 3a in 61% 83%) with excellent regioselectivity. However, in the case of
yield. Interestingly, on further lowering the temperature to 50 °C, a substrates with weakly electron-donating groups (aniline, 3,4-
dramatic improvement in the yield of 3a (84%) was realized (entry dimethyl or dichloroaniline), only 5-10% of the required quinoline-
3), probably due to the higher stability of rhodacycle II at lower 3-carboxylate 3 was formed (GCMS analysis) with the major product
temperature. Finally, the best result could be obtained when the being N-formyl derivative 4 (~90%). Also, in the case of internal
reaction was conducted at 50 °C with the lowered catalyst alkynes, there was no annulated product formed.
concentration (2.5 mol %; entry 5). However, further lowering of Table
2 Rh-catalyzed synthesis of quinoline-3-carboxylates:
either the temperature (35 °C) of the reaction or the catalyst substrate scopea-c
loadings (1 mol %) had a deleterious effect on the product
MeO
N
MeO
N
MeO
MeO
N
distribution (entry 4 & 7). Surprisingly, other catalysts were found
to be less effective in improving the product distribution (entry 8, 9,
11 & 13); so also with the use of other solvents such as toluene or
chlorinated solvents for the reaction. We noticed that lowering the
amount of HCO2H resulted in reduced yield of the product 3a. The
catalyst control experiment, however, gave exclusively the N-formyl
derivative 4a (91%), also in the absence of Rh catalyst, neither
coupling reaction proceeded nor deuterium exchange occurred.
CO2Me
CO2Et
CO2Et
CO2Me
3dd
OMe
3cd
3b
80%
N
75%
N
77%
MeO
MeO
N
MeO
Me
O
O
CO2Me
N
CO2Et
OMe
3g
3e
3fd
80%
72%
76%
CO2Et
Br
CO2Me
O
N
H
N
MeO
N
N
CO2Et
CO2Me
Table 1 Rh-catalyzed reaction of 3,5-dimethoxyaniline 1a with ethyl
propiolate 2a and HCO2H: optimization studiesa
OMe
3jd
3kd 67%
66%
3h 65%
3i
83%
H
catalyst
(1-5 mol %)
MeO
N
MeO
N
MeO
NH2
CHO
a
CO2Et
Arylamines (1 mmol), ethyl propiolate (1.2 mmol), Rh2(OAc)4 (2.5
CO2Et
HCO2H (1 mL)
6 h
b
mol %), HCO2H (1 mL), 50 °C, 6 h. Isolated yield after column
OMe
OMe
OMe
c
4a
2a
1a
3a
purification. 5-10% yield of N-formyl derivative 4b-k was isolated
in all the cases studied; d Methyl propiolate was used.
No.
catalyst
Catalyst
(mol %)
t (oC)
products (%)b
3a
4a
The catalytic method was successfully extended to the synthesis of
oxolinic acid 5, a quinolone antibiotic and antibacterial used in the
treatment of urinary tract infections and psoriasis. Thus, quinoline
carboxylate 3f, obtained from 3,4-methylenedioxyaniline by the
present protocol, was subjected to N-alkylation with ethyl
1
2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
[RhCOCl2]2
Rh/Al2O3
[RhCp*Cl2]2
RuCl3
5
5
100
70
50
35
50
35
50
50
50
50
50
50
50
50
48
61
84
50
85
40
41
30
10
-
45
34
11
40
10c
45
42
48
85
90
68
90
44
91
3
5
4
5
5
2.5
2.5
1
16
trifluoromethane sulfonate followed by oxidation with K3Fe(CN)6
in a single step to give oxolinic acid17 5 in 50% yield (Scheme 2).
6
7
O
8
2.5
2.5
2.5
2.5
2.5
2.5
-
ethyl trifluoromethane
CO2Et
CO2H
sulfonate, 50 0C, 2 h
O
O
O
O
9
10
11
12
13
14
N
N
followed by K3Fe(CN)6
in 20% NaOH, 8 h
22
-
5,
50%
3f
Co(NO3)2
Pd(OAc)2
No catalyst
31
Scheme 2 Short synthesis of oxolinic acid (5)
-
a Arylamines (1 mmol), ethyl propiolate (1.2 mmol), HCO2H (1 mL), 6
h. b Isolated yield after chromatographic purification. C No change in
yield of 4a was observed even after 24 h.
To gain some insight into the mechanistic details of the reaction,
the following experiments were conducted (Scheme 3): (i) when N-
formyl derivative 4a was reacted with ethyl propiolate in the
presence of Rh(II)/HCO2H combination, 3a was obtained in 70%
yield, thereby suggesting that 4a could be an intermediate in the
catalytic cycle; (ii) also, when 4a was treated with D2O in the
absence of ethyl propiolate under Rh(II)/HCO2H reaction conditions,
deuterated N-formyl derivative d3-4a was isolated in 72% yield, in
which deuterium incorporation of 43% at C-4 carbon and 57% each
at C-2 and C-6 carbons was observed (1H NMR proven). This
observed deuteration at the ortho and para positions in absence of
alkyne indicates that a reversible, electrophilic C-H metallation has
With the optimized reaction conditions established, we next
examined the reaction scope of a variety of anilines with alkynic
esters. The results are summarized in Table 2. Activated aniline
bearing bromo, methoxy, methylenedioxy, amide and methyl
groups on the aromatic nucleus including naphthyl group were well-
tolerated under the reaction conditions. In all substrate evaluation
2 | J. Name., 2012, 00, 1-3
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occurred under the reaction condition. The fact that no para C-H This metallacycle can insert an equivalent of alkyne into the Rh-C
alkynation of N-formyl derivative was observed in presence of bond of species II to generate an intermediate III, which then
alkyne, probably suggests that Rh atom is inserted in the ortho undergoes intramolecular cyclization to give intermediate IV.
position and stabilized by coordination with carbonyl of amide Subsequent reductive elimination of IV followed by H2O removal
group possibly leading to rhodacycle as intermediate;18 (iii) the UV- affords the quinoline derivatives 3 with the release of the active
visible absorptions of [Rh2(OAc)4] catalyst showed two maxima at Rh(I) catalyst for the next catalytic cycle. The catalytic cycle thus
λmax 590 nm and 445 nm which have been shifted to λmax 420 nm on consists of rhodium alternating between the Rh(I) and Rh(III)
addition of HCO2H. This blue shift may be assigned to the Rh(I) oxidation states.
species19 (see SI).
During the optimization study we observed that the
[RhCp*Cl2]2/HCO2H system was found to be inactive to afford
quinoline-3-carboxylate 3 (Table 1, entry 10). Surprisingly, by
changing to a new catalytic system [Rh(III)/Cu(II)], we observed that
3,5-dimethoxyaniline 1a underwent oxidative coupling with ethyl
propiolate 2a to afford the corresponding 2,3-disubstituted
quinoline dicarboxylate 6a in 71% yield. After several
experimentations (see SI), it was thus found that a combination of
aniline 1a (1 mmol), ethyl propiolate (2.1 equiv), [RhCp*Cl2]2 (2.5
mol %), AgSbF6 (10 mol %) and Cu(OAc)2 (20 mol %) in DCE at 50 °C
for 5 h was the best optimized condition in achieving excellent
product yields 6a-h (70-88%). Table 3 summarises the results of its
substrate scope of study.22
Scheme 3 Mechanistic studies
(iv) Cyclic voltammetry study of [Rh2OAc4] with HCO2H has shown
that there is a onset reversible reduction potential occurring at -
0.710 V attributable to Rh(II) to Rh(I) reduction process20 (Fig. 1).
Table 3 Rh(III)-catalyzed reaction of electron-rich anilines and ethyl
propiolates or phenyl acetylene: substrate scopea, b
MeO
N
MeO
NH2
CO2Et
CO2Et
[RhCp*Cl2]2
2
CO2Et
AgSbF6
OMe
OMe
Cu(OAc)2.H2O
DCE, 50 oC, 5 h
2a
MeO
1a
6a, 71% yield
MeO
N
N
N
MeO
MeO
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
MeO
CO2Et
OMe
6d
80%
6b
6e
6c
6f
88%
N
85%
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
N
CO2Et
CO2Et
81%
N
85%
6g
87%
H
N
H
N
H
N
Fig. 1 Cyclic voltammogram of [Rh2(OAc)4] in the presence of HCO2H
and 0.1 M lithium perchlorate as supporting electrolyte at 25 °C.
Scan Rate: 50 mV/sec.
MeO
MeO
Ph MeO
Ph
Me
Me
Ph
CO2Me
CO2Me
OMe Ph
7ad
Ph
Ph
6hc
75%
Based on the results presented above and literature precedence,21
we have proposed a catalytic cycle for this reaction (Scheme 4). The
first step in the catalytic cycle involves the formation of catalytically
active Rh(I) species (I), obtained from [Rh2(OAc)4] on reduction with
formic acid. Rh(I) species (I) can then undergo a reversible oxidative
addition at ortho aromatic C-H bond of N-formyl derivative 4
regioselectively to provide a six-membered rhodacycle II.
7bd
92%
7cd
87%
82%
a
Substrate 1a (1 mmol), ethyl propiolate (2.1 mmol), [RhCp*Cl2]2
(2.5 mol %), AgSbF6 (20 mol %), Cu(OAc)2·H2O (20 mol %), DCE (2
b
c
d
mL), 50 °C, 5 h. Isolated yields. Methyl propiolate was used.
Phenyl acetylene was used.
In case of internal alkynyl esters, only the Michael addition products
were produced. Additionally, when the coupling partner was
changed to simple phenylacetylene (2.1 equiv), under same
reaction conditions, 1,2-dihydroquinoline derivatives 7a-c were
obtained in high yields (82-95%). In this case, the regioselectivity
observed was remarkable and very well established in the
literature.23 This catalytic pathway can be expalained by the initial
formation of imine from aniline and phenylacetylene, its insertion
into another metal−alkynyl species followed by intramolecular
cyclization, leading to product 7. This oxidative coupling was found
to proceed via ortho C-H bond activation of arylamines (For
mechanistic and optimization studies; see SI).
A plausible mechanism for the formation of 6 via addition reaction
followed by ortho-C-H bond activation pathway is depicted in
Scheme 5. At the beginning, aniline 1 undergoes Michael addition
onto ethyl propiolate 2a to form enamine ester 8. The additive
AgSbF6 probably removes the Cl− ligand from the catalyst
Scheme 4 Rh-catalytic cycle via ortho C-H bond activation.
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[RhCp*Cl2]2 complex, giving
a cationic rhodium species I. General experimental procedure for the preparation of quinoline
Coordination of lone pair of nitrogen and double bond of imine
species 8 to a cationic species I provides the intermediate II
followed by acetate accelerated ortho-metalation affords a six-
membered rhodacycle III. The coordinative insertion of second
molecule of ethyl propiolate into the Rh-C bond of rhodacycle III
gives intermediate IV. Species IV then on intramolecular cyclization
and reductive elimination leads to the cyclized intermediate V
together with a Rh(I) species, which is reoxidized in the presence of
Cu(OAc)2 to the active rhodium species I for the next catalytic cycle.
Finally, intermediate V can be easily converted to product 6 by
oxidation with Cu(II). Cu(I) is probably reoxidized back to Cu(II) by
air.12h
3-carboxylate derivatives (3a-j):
To a mixture of substituted aniline (1a-j) (0.1 g, 1 mmol), Rh2(OAc)4
(2.5 mol %) and formic acid (1 mL) under a nitrogen atmosphere
was added followed by ethyl propiolate 2a (1.2 mmol). The
resulting brown solution was stirred at 50 °C for 6 h. After
completion of reaction (monitored by TLC), it was diluted with ethyl
acetate (10 mL), and washed with water (10 mL), 5% aqueous
sodium bicarbonate (15 mL), and brine (10 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo to give a brown solid.
On purification with flash chromatography using pet ether and ethyl
acetate (7:3), quinoline 3-carboxylic acid ester (3a-j) was eluted as a
solid.
Ethyl 5,7-dimethoxyquinoline-3-carboxylate (3a):
Yield: 85%; 0.144 g; colorless solid, mp: 122-123 °C; IR (CHCl3, cm-1):
1
υmax 1722, 1618, 1599, 1505, 1432; H NMR (200 MHz, CDCl3): δ
9.31 (s, 1H), 9.05 (s, 1H), 7.05 (s, 1H), 6.51 (s, 1H), 4.46 (q, J = 7.3 Hz,
2H), 4.00 (s, 3H), 3.96 (s, 3H), 1.46 (t, J = 7.3 Hz, 3H); 13C NMR (50
MHz, CDCl3): δ 165.5, 163.5, 156.9, 152.1, 150.9, 133.4, 120.3,
115.6, 99.8, 98.8, 61.1, 55.8, 55.7, 14.5; HRMS (ESI): calc. for
[(C14H15NO4)H] (M+Na) 284.0899, found 284.0893.
Ethyl 7-methoxyquinoline-3-carboxylate (3b):
Yield: 78%; 0.146 g; yellow solid, mp: 110-112 °C; IR (CHCl3, cm-1):
υmax 2981, 1717, 1601, 1279, 1243, 1027; 1H NMR (200 MHz, CDCl3):
δ 9.36 (d, J = 1.7 Hz, 1H), 8.73 (d, J = 1.7, 1H), 7.79 (d, J = 9.0 Hz,
1H), 7.26 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 9.0, 2.5 Hz, 1H), 4.45 (q, J =
7.1 Hz, 2H), 3.98 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); 13C NMR (50 MHz,
CDCl3): δ 165.5, 162.6, 152.0, 150.5, 138.0, 130.1, 122.1, 121.3,
120.9, 107.5, 61.2, 55.6, 14.5; HRMS (ESI): calc. for [(C13H13NO3)H]
(M+H) 232.0974, found 232.0968.
Scheme 5 Plausible mechanism for 2,3-disubstituted quinoline
carboxylates 6
Conclusion
In summary, we have presented, for the first time, a simple
annulation strategy that affords quinoline carboxylates (3a-k and
6a-h) in high yields from the corresponding substituted anilines 1a-
k via rhodium catalyzed cyclization in a single step. This cyclization
strategy involves rhodacycle as the possible intermediate formed by
the ortho C-H activation of aniline supported by deuterium
incorporation studies. We believe that this single-step cyclization
strategy will find tremendous applications in the synthesis of
bioactive heterocyclic scaffolds as demonstrated here in the high
Methyl 5,7-dimethoxyquinoline-3-carboxylate (3c):
Yield: 77%; 0.124 g; colorless solid, mp: 134-135 °C; IR (CHCl3, cm-1):
υmax 1722, 1618, 1599, 1505, 1432; 1H NMR (200 MHz, CDCl3): δ
9.31 (d, J = 1.4 Hz, 1H), 9.06 (d, J = 1.4 Hz, 1H), 7.05 (s, 1H), 6.51 (d, J
yield synthesis of oxolinic acid (5). Further exploration of the = 2.3 Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H); 13C NMR (50
reaction scope and other types of cyclizations is currently under
investigation.
MHz, CDCl3): δ 166.0, 163.6, 156.9, 152.2, 151.0, 133.5, 120.0,
115.6, 99.8, 98.8, 55.9, 55.7, 52.2; HRMS (ESI): calc. for
[(C13H13NO4)H] (M+H) 248.0845, found 248.0858.
Experimental Section:
General
Ethyl 6,7-dimethoxyquinoline-3-carboxylate (3d):
Solvents were purified and dried by standard procedures before
use; petroleum ether of boiling range 60-80 °C was used. Melting
Yield: 80%; 0.129 g; colorless solid, mp: 160-161 °C; IR (CHCl3, cm-1):
1
υmax 1722, 1618, 1599, 1505, 1432; H NMR (200 MHz, CDCl3): δ
points were uncorrected and recorded on
a Buchi B-542
instrument. H NMR and 13C NMR spectra were recorded on Bruker
AC-200 spectrometer unless mentioned otherwise. Infrared spectra
were recorded on Shimadzu FTIR-8400 spectrometer and
absorption is expressed in cm-1. ESI-MS were recorded on a Thermo
Finnigan LCQ Advantage spectrometer in ESI mode with a spray
voltage of 4.8 kV. All chemicals are purchased from Sigma-Aldrich
and used without further purification. Purification was done using
column chromatography (230-400 mesh).
1
9.20 (d, J = 1.8 Hz, 1H), 8.61 (d, J = 1.8 Hz, 1H), 7.41 (s, 1H), 7.07 (s,
1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H); 13C NMR (50 MHz, CDCl3):
δ 166.5, 154.7, 150.7, 148.3, 147.6, 136.8, 122.8, 121.6, 108.1,
106.2, 56.6, 56.4, 52.5; HRMS (ESI): calc. for [(C13H13NO4)H] (M+H)
248.0923, found 248.0924.
Ethyl 5,6,7-trimethoxyquinoline-3-carboxylate (3e):
Yield: 72%; 0.114 g; colorless solid, mp: 170-172 °C; IR (CHCl3, cm-1):
1
υmax 3000, 1718, 1607, 1479, 1278, 1020; H NMR (200 MHz, CDCl3):
δ 9.28 (s, 1H), 8.98 (s, 1H), 7.28 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 4.12
4 | J. Name., 2012, 00, 1-3
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(s, 3H), 4.04 (s, 3H), 3.97 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H); 13C NMR (50 Yield: 67%; 0.109 g; pale yellow solid, mp: 120-121 °C; IR (CHCl3, cm-
MHz, CDCl3): δ 165.8, 158.4, 149.9, 148.2, 148.0, 147.9, 141.4, 1): υmax 3330, 2940, 1720, 1650; 1H NMR (200 MHz, CDCl3/DMSO-d6
133.4, 121.5, 104.3, 61.0, 61.5, 56.5, 30.0, 14.8; HRMS (ESI): calc. (1:1)): δ 9.50 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H),
for [(C15H17NO5)H] (M+H) 292.1185, found 292.1179.
7.63 (s, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.95 (dd, J = 2.0, 8.7 Hz, 1H),
3.10 (s, 3H), 1.31 (s, 3H); 13C NMR (50 MHz, CDCl3/DMSO-d6): δ
169.0, 165.2, 150.3, 149.6, 142.3, 137.6, 129.4, 122.5, 120.9, 120.8,
115.4, 51.9, 24.0; HRMS (ESI) calcd. for C13H13N2O3[M+H]+:
245.0916, found: 245.0921.
Ethyl [1,3]dioxolo[4,5-g]quinoline-7-carboxylate (3f):
Yield: 76%; 0.128 g; colorless solid, mp: 205-206 °C; IR (CHCl3, cm-1):
υmax 1709, 1611, 1277, 1203, 1077; 1H NMR (200 MHz, CDCl3): δ
9.23 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 7.42 (s, 1H), 7.14 (s,
1H), 6.16 (s, 2H), 3.99 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 166.1,
152.7, 148.8, 148.6, 148.1, 137.0, 124.0, 121.5, 105.9, 103.6, 102.2,
52.3; HRMS (ESI): calc. for [(C12H9NO4)H] (M+H) 232.0610, found
232.0615.
Procedure for the synthesis of oxolinic acid (5):
A mixture of quinoline (0.1 g) 3f and ethyl trifluoromethane
sulfonate (0.15 g) was warmed at 50 °C for 1 h. After removal of
ethyl trifluoromethane sulfonate in vaccuo, the residue was added
to a suspension of K3Fe(CN)6 (0.25 g) in 20% NaOH (10 mL) and
stirred at room temperature for 2 h. The mixture was extracted
with ethyl acetate, and the extract was washed with brine and dried
over MgSO4. After removal of ethyl acetate, the residue was
purified by silica gel (CH2Cl2:MeOH = 50:1) to give quinolone 5
(0.053 g, 50%) as a colorless solid.
mp: 314-316 °C; lit15 mp 314-316 °C; IR (CHCl3, cm-1): υmax 3420,
1620, 1600, 1580, 1550, 1298, 1250, 1033; 1H NMR (200 MHz,
CF3CO2D): δ 9.12 (s, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 6.38 (s, 2H), 4.71
(q, J = 7.2 Hz, 2H), 1.69 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz,
CF3CO2D): δ 169.8, 158.6, 151.0, 146.3, 139.7, 123.3, 117.7, 112.0,
105.1, 101.7, 96.2, 53.5, 13.9; HRMS (ESI): calc. for [(C13H11NO5)H]
(M+H) 262.0715, found 261.0711.
Ethyl 7-methoxy-6-methylquinoline-3-carboxylate (3g):
Yield: 80%; 0.142 g; colorless solid, mp: 110-112 °C; IR (CHCl3, cm-1):
υmax 3081, 1716, 1611, 1299, 1250, 1033; 1H NMR (200 MHz, CDCl3):
δ 9.30 (s, 1H), 8.65 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 4.45 (q, J = 6.9
Hz, 2H), 4.01 (s, 3H), 2.39 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); 13C NMR
(50 MHz, CDCl3): δ 165.6, 161.6, 150.9, 149.4, 137.2, 130.5, 129.0,
121.9, 121.1, 106.2, 61.0, 55.7, 16.8, 14.4; HRMS (ESI): calc. for
[(C14H15NO3)H] (M+H) 246.1130, found 246.1125.
Ethyl 8-bromo-5,7-dimethoxyquinoline-3-carboxylate (3h):
Yield: 65%; 0.095 g; colorless solid, mp: 156-158 °C; IR (CHCl3, cm-1):
υmax 2987, 1717, 1605, 1478, 1264, 1002; 1H NMR (200 MHz, CDCl3):
δ 9.50 (d, J = 1.8 Hz, 1H), 9.13 (d, J = 1.8 Hz, 1H), 6.72 (s, 1H), 4.46
(q, J = 7.0 Hz, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H);
13C NMR (50 MHz, CDCl3): δ 165.4, 159.3, 157.1, 152.2, 148.0, 134.8,
134.0, 120.9, 115.9, 94.2, 61.4, 57.0, 56.1, 14.4; HRMS (ESI): calc.
for [(C14H14BrNO4)H] (M+H) 340.0184, found 340.0182.
General experimental procedure for the preparation of quinoline
carboxylate derivatives (6a-j), (7a-c):
A two-neck round-bottomed flask with septum was charged with
[RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2·H2O (20 mol %) and AgSbF6 (20
mol %) and evacuated, purged with nitrogen gas three times
(AgSbF6 was added inside the glove box). To the reaction mixture,
was added anilines 1a-j (1 mmol), ethyl propiolate 2a (2.1 equiv),
and 1,2-dichloroethane (2.0 mL) via syringes and again the reaction
mixture was evacuated and purged with nitrogen gas three times.
The reaction mixture was then allowed to stir at 50 °C for 5 h. It was
cooled to room temperature and diluted with CH2Cl2, filtered
through Celite. The filtrate was washed with water and the organic
layer was extracted with CH2Cl2 and dried over anhyd. Na2SO4.
Later, the solution was concentrated under reduced pressure. The
crude residue was purified through silica gel column using pet ether
and ethyl acetate (7:3) as eluent to give pure 2,3-disubstituted
quinoline carboxylates (6a-j).
Ethyl benzo[h]quinoline-3-carboxylate (3i):
Yield: 83%; 0.145 g; colorless solid, mp: 105-107 °C; lit4d mp 106-
107 °C; IR (CHCl3, cm-1): υmax 2983, 1716, 1598, 1314, 1260, 1212,
750; 1H NMR (200 MHz, CDCl3): δ 9.56 (d, J = 1.8 Hz, 1H), 9.34 (dd, J
= 7.2, 1.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H),
7.87 (d, J = 8.8 Hz, 1H), 7.76-7.80 (m, 3H), 4.48 (q, J = 7.1 Hz, 2H),
1.49 (t, J = 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 165.6, 149.0,
148.9, 137.7, 134.5, 131.1, 129.3, 128.7, 127.9, 127.4, 125.5, 125.2,
125.1, 123.9, 61.5, 14.4; HRMS (ESI): calc. for [(C16H13NO2)H] (M+H)
252.1025, found 252.1019.
Methyl benzo[h]quinoline-3-carboxylate (3j):
Yield: 66%; 0.108 g; colorless solid, mp: 124-125 °C; lit4a mp 125-
127 °C; IR (CHCl3, cm-1): υmax 2980, 1717, 1600, 1374, 1250, 1222,
750; 1H NMR (200 MHz, CDCl3): δ 9.49 (d, J = 1.8 Hz, 1H), 9.29 (dd, J
= 9.1, 2.3 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 6.9, 1.8 Hz,
1H), 7.81 (d, J = 8.7 Hz, 1H), 7.75-7.69 (m, 3H), 4.02 (s, 3H); 13C NMR
(50 MHz, CDCl3): δ 165.9, 148.9, 148.9, 137.7, 134.5, 131.1, 129.3,
128.7, 127.8, 127.4, 125.5, 125.4, 125.2, 125.6, 123.6, 52.4; HRMS
(ESI): calc. for [(C15H11NO2)H] (M+H) 238.0868, found 238.0860.
Also, the same procedure was followed for the formation of 1,2-
dihydroquinolines (7a-c) using phenyl acetylene (2.1 equiv). In case
of formation of 1,4-dihydropyridine derivatives (9i-m), an excess
amount ethyl propiolate 2a (3 equiv) was used under the same
procedure.
Ethyl
2-(2-ethoxy-2-oxoethyl)-5,7-dimethoxyquinoline-3-
carboxylate (6a):
Yield: 88%; 0.198 g; colorless solid; mp: 128-129 °C; IR (CHCl3, cm-1):
Methyl 7-acetamidoquinoline-3-carboxylate (3k):
υmax 2949, 1718, 1692, 1628, 1577, 1514, 1439, 1319, 1245, 1221,
1
1171, 1145, 993; H NMR (200 MHz, CDCl3): δ 9.05 (s, 1H), 6.97 (s,
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DOI: 10.1039/C6OB00170J
COMMUNICATION
Journal Name
1H), 6.48 (s, 1H), 4.39 (q, J = 7.0 Hz, 2H), 4.36 (s, 2H), 4.17 (q, J = 7.2 Ethyl
7-(2-ethoxy-2-oxoethyl)-2,3-dihydro-[1,4]dioxino[2,3-
Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.25 (t, J = g]quinoline-8-carboxylate (6f):
7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 170.6, 166.1, 163.6, 156.7, Yield: 85%; 0.193 g; colorless solid; mp: 110-112 °C; IR (CHCl3, cm-1):
155.7, 151.0, 135.1, 120.3, 114.9, 99.5, 98.6, 61.1, 60.6, 55.8, 55.7, υmax 2954, 1740, 1730, 1577, 1559, 1507; 1H NMR (200 MHz, CDCl3):
44.7, 14.4, 14.2; HRMS (ESI): calc. for [(C18H21NO6)H] (M+H) δ 8.64 (s, 1H); 7.48 (s, 1H), 7.27 (s, 1H), 4.41-4.31 (m, 4H), 4.17 (q, J
348.1447, found 348.1442.
= 7.2 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR
(50 MHz, CDCl3): δ 171.0, 166.1, 153.0, 148.9, 144.8, 138.9, 122.3,
121.9, 113.9, 112.7, 64.5, 64.2, 61.3, 60.7, 44.5, 29.7, 14.3, 14.2;
HRMS (ESI): calc. for [(C18H19NO6)H] (M+H) 346.1291, found
346.1290.
Ethyl 2-(2-ethoxy-2-oxoethyl)-7-methoxyquinoline-3-carboxylate
(6b):
Yield: 88%; 0.226 g; colorless solid; mp: 132-134 °C; IR (CHCl3, cm-1):
υmax 2954, 1722, 1706, 1638, 1577, 1559, 1507, 1439, 1369, 1336,
1
1284, 1224, 1179, 1147, 808; H NMR (200 MHz, CDCl3): δ 8.75 (s, Ethyl
2-(2-ethoxy-2-oxoethyl)benzo[h]quinoline-3-carboxylate
1H), 7.76 (d, J = 9.2 Hz, 1H), 7.38 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), (6g):
4.42-4.37 (m, 4H), 4.18 (q, J = 6.9 Hz, 2H), 3.96 (s, 3H), 1.42 (t, J = Yield: 87%; 0.204 g; colorless solid; mp: 174-176 °C; IR (CHCl3, cm-1):
7.2 Hz, 3H), 1.26 (t, J = 6.9 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ υmax 2980, 1740, 1729, 1570, 1589, 1507; 1H NMR (200 MHz, CDCl3):
170.7, 165.9, 162.7, 155.1, 150.6, 139.9, 129.6, 121.5, 121.3, 120.6, δ 9.39-9.22 (m, 1H), 8.81 (s, 1H), 7.89 (dd, J = 9.1, 2.8 Hz, 1H), 7.81
106.9, 61.2, 60.7, 55.6, 44.7, 14.3, 14.2; HRMS (ESI): calc. for (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.9, 2.3 Hz, 3H), 4.54 (s, 2H), 4.43 (q,
[(C17H19NO5)H] (M+H) 318.1341, found 318.1331.
J = 7.1 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.28
(t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 171.0, 166.1, 153.8,
147.5, 139.4, 134.6, 130.9, 129.1, 128.4, 127.8, 127.3, 125.4, 125.1,
124.5, 123.9, 61.4, 60.7, 44.9, 14.4, 14.3; HRMS (ESI): calc. for
[(C20H19NO4)H] (M+H) 338.1392, found 338.1387.
Ethyl
2-(2-ethoxy-2-oxoethyl)-6,7-dimethoxyquinoline-3-
carboxylate (6c):
Yield: 85%; 0.192 g; colorless solid; mp: 150-152°C; IR (CHCl3, cm-1):
υmax 2890, 1718, 1692, 1628, 1577, 1514, 1439, 1319, 1245, 1221,
1
1171, 1145, 993; H NMR (200 MHz, CDCl3): δ 8.69 (s, 1H), 7.39 (s, Methyl
7-methoxy-2-(2-methoxy-2-oxoethyl)quinoline-3-
1H), 7.11 (s, 1H), 4.48-4.33 (m, 4H), 4.18 (q, J = 7.1 Hz, 2H), 4.05 (s, carboxylate (6h):
3H), 4.02 (s, 3H), 1.47-1.39 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR Yield: 80%; 0.187 g; colorless solid; mp:107-109 °C; IR (CHCl3, cm-1):
(50 MHz, CDCl3): δ 171.0, 166.1, 154.5, 152.6, 150.3, 146.2, 138.3, υmax 2954, 1722, 1706, 1638, 1577, 1559, 1507, 1439, 1369, 1336,
1
121.9, 121.7, 107.6, 105.5, 61.2, 60.7, 56.2, 56.0, 44.5, 14.3, 14.2; 1284, 1224, 1179, 1147, 808; H NMR (200 MHz, CDCl3): δ 8.77 (s,
HRMS (ESI): calc. for [(C18H21NO6)H] (M+H) 348.1446, found 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.9,
348.1448.
2.3 Hz, 1H), 4.39 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H); 13C
NMR (50 MHz, CDCl3): δ 171.2, 166.4, 162.9, 155.0, 150.8, 140.1,
129.7, 121.5, 120.8, 107.0, 55.7, 52.3, 52.0, 44.5; HRMS (ESI): calc.
for [(C17H19NO5)H] (M+H) 290.1028, found 290.1025.
Ethyl
2-(2-ethoxy-2-oxoethyl)-5,6,7-trimethoxyquinoline-3-
carboxylate (6d):
Yield: 75%; 0.192 g; gummy liquid; IR (CHCl3, cm-1): υmax 2880, 1716,
1680, 1577, 1514, 1446, 1255, 1220, 1160; 1H NMR (200 MHz,
CDCl3): δ 9.01 (s, 1H), 7.22 (s, 1H), 4.41 (q, J = 7.0 Hz, 2H), 4.38 (s,
2H), 4.18 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 4.02 (s, 3H), 3.98 (s, 3H),
1.43 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz,
CDCl3): δ 170.8, 166.2, 158.1, 154.2, 147.5, 146.5, 140.8, 134.7,
121.2, 117.4, 103.6, 61.7, 61.2, 61.2, 60.7, 56.2, 44.6, 14.2, 14.1;
HRMS (ESI): calc. for [(C19H23NO7)H] (M+H) 378.1553, found
378.1557.
5,7-Dimethoxy-2-methyl-2,3-diphenyl-1,2-dihydroquinoline (7a):
Yield: 95%; 0.221 g; colorless solid; mp:128-130 °C; IR (CHCl3, cm-1):
υmax 3399, 2934, 2832, 1606, 1494, 1247, 699; 1H NMR (200 MHz,
CDCl3): δ 7.48 (d, J = 7.6 Hz, 2H), 7.30-7.25 (m, 2H), 7.22 (s, 4H),
7.20-7.14 (m, 2H), 5.86 (d, J = 2.2 Hz, 1H), 5.76 (d, J = 2.0 Hz, 1H),
5.50 (s, 1H), 4.31 (br. s., 1H), 3.74 (s, 3H), 3.28 (s, 3H), 1.67 (s, 3H);
13C NMR (50 MHz, CDCl3): δ 161.2, 158.0, 148.4, 146.4, 142.9,
134.9, 128.2, 127.9, 127.4, 127.1, 126.7, 126.0, 125.4, 103.9, 92.0,
89.9, 56.3, 55.0, 54.9, 29.4; HRMS (ESI): calc. for [(C24H23NO2)H]
(M+H) 358.1807, found 358.1805.
Ethyl
6-(2-ethoxy-2-oxoethyl)-[1,3]dioxolo[4,5-g]quinoline-7-
carboxylate (6e):
Yield: 81%; 0.195 g; colorless solid; mp: 168-170 °C; IR (CHCl3, cm-1):
7-Methoxy-2-methyl-2,3-diphenyl-1,2-dihydroquinoline (7b):
Yield: 87%; 0.230 g; colorless solid; mp:108-110 °C; IR (CHCl3, cm-1):
υmax 3381, 2955, 2928, 1613, 1465, 1166, 823; 1H NMR (200 MHz,
CDCl3): δ 7.51 (d, J = 7.2 Hz, 2H), 7.40-7.24 (m, 7H), 7.23-7.14 (m,
1H), 6.79 (d, J = 8.3 Hz, 1H), 6.13-6.04 (m, 2H), 5.47 (s, 1H), 4.16 (br.
s., 1H), 3.70 (s, 3H), 1.73 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 160.5,
148.8, 144.5, 139.6, 135.4, 128.9, 128.4, 128.1, 127.3, 126.8, 126.5,
125.3, 114.0, 102.5, 57.1, 98.7, 55.0, 30.1; HRMS (ESI): calc. for
[(C23H21NO)H] (M+H) 328.1701, found 328.1708.
υmax 2990, 1718, 1692, 1628, 1577, 1514, 1439, 1319, 1245, 1221,
1
1171, 1145, 993; H NMR (200 MHz, CDCl3): δ 8.63 (s, 1H), 7.34 (s,
1H), 7.11 (s, 1H), 6.15 (s, 2H), 4.38 (q, J = 7.2 Hz, 2H), 4.33 (s, 2H),
4.18 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz,
3H); 13C NMR (50 MHz, CDCl3): δ 170.9, 166.0, 152.6, 148.2, 147.4,
138.6, 123.2, 121.6, 105.4, 103.0, 102.0, 61.2, 60.6, 44.3, 14.2, 14.1;
HRMS (ESI): calc. for [(C17H17NO6)H] (M+H) 332.1134, found
332.1129.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00170J
Journal Name
2,6,7-Trimethyl-2,3-diphenyl-1,2-dihydroquinoline (7c):
COMMUNICATION
Diethyl-4-(2-ethoxy-2-oxoethyl)-1-(9H-fluoren-2-yl)-1,4-
Yield: 82%; 0.220 g; colorless solid; mp: 119-120 °C; IR (CHCl3, cm-1): dihydropyridine-3,5-dicarboxylate (9o):
1
υmax 3381, 3022, 1631, 1493, 1443, 699; H NMR (200 MHz, CDCl3): Yield: 80%; 0.209 g; gummy liquid; IR (CHCl3, cm-1): υmax 2945, 1710,
δ 7.6 (d, J = 2.0 Hz, 2H), 7.52 (d, J = 1.9 Hz, 2H), 7.51 (s, 1H), 7.39- 1590, 1510, 1430, 1211, 1084; 1H NMR (200 MHz, CDCl3): δ 7.76 (t, J
7.36 (m, 3H), 7.34-7.33 (m, 3H), 7.31-7.29 (m, 1H), 7.26 (s, 1H), 2.17 = 8.3 Hz, 2H), 7.60 (s, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.3 Hz,
(s, 6H), 1.57 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 149.0, 141.3, 132.5, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 4.28-4.24 (m,
131.5, 129.2, 128.9, 128.8, 128.8, 128.6, 128.4, 128.3, 128.2, 126.3, 5H), 4.04 (q, J = 7.2 Hz, 2H), 3.92 (s, 2H), 2.60 (d, J = 4.7 Hz, 2H), 1.33
121.9, 108.2, 81.5, 74.1, 30.1, 29.8, 29.7; HRMS (ESI): calc. for (t, J = 7.1 Hz, 6H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3):
[(C23H21NO)H] (M+H) 326.1909, found 326.1905.
δ 171.5, 166.6, 145.0, 14.3, 143.1, 142.0, 140.6, 140.3, 138.0, 127.1,
125.1, 120.8, 119.9, 117.9, 112.0, 108.2, 60.3, 60.0, 40.6, 37.0, 29.7,
14.5; HRMS (ESI): calc. for [(C28H29NO6)H] (M+H) 476.2073, found
476.2072.
Diethyl 4-(2-ethoxy-2-oxoethyl)-1-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate (9k):
Yield: 88%; 0.366 g; gummy liquid; IR (CHCl3, cm-1): υmax 2951, 1713,
1596, 1495, 1436, 1211, 1084, 755, 715, 696; 1H NMR (200 MHz,
CDCl3): δ 7.55 (s, 2H), 7.41 (s, 2H), 7.27-7.25 (m, 1H), 7.24-7.22 (m,
2H), 4.25-4.23 (m, 5H), 4.03 (q, J = 7.3 Hz, 2H), 2.57 (d, J = 4.9 Hz,
2H), 1.18 (t, J = 7.0 Hz, 3H), 1.32 (t, J = 7.0 Hz, 6H); 13C NMR (50
MHz, CDCl3): δ 171.5, 166.6, 143.2, 137.6, 129.9, 126.4, 121.1,
120.9, 108.4, 60.3, 60.0, 40.5, 29.7, 14.5, 14.3; HRMS (ESI): calc. for
[(C21H25NO6)Na] (M+Na) 410.1580, found 410.1574.
ACKNOWLEDGMENT
S.K.G. and S.D. thank CSIR, New Delhi for the award of research
fellowships and CSIR, Indus MAGIC (CSC 0123) and DST, (No.
SR/S1/OC-42/2014) New Delhi for financial support. The authors
are also thankful to Dr. V.V. Ranade, Chair, Chem. Engg. & Process
Develop. for his constant encouragement.
Diethyl-1-(3,4-dimethylphenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (9l):
Notes and references
1
(a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166-187; (b) G. Jones, In
Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees
and E. F. V. Scriven, Eds. Pergamon: Oxford, UK, 1996, 5, 167-245; (c)
A. S. Wagman and M. P. Wentland, In Comprehensive Medicinal
Chemistry II; J. B. Taylor and D. J. Eds. Triggle, Elsevier Ltd: Oxford,
UK, 2006, 7, 567-597.
Yield: 82%; 0.280 g; gummy liquid; IR (CHCl3, cm-1): υmax 2900, 1719,
1
1586, 1429, 1221, 1004, 758; H NMR (200 MHz, CDCl3): δ 7.51 (s,
2H), 7.14 (d, J = 8.2 Hz, 1H), 6.99-6.95 (m, 2H), 4.26-4.22 (m, 5H),
4.03 (q, J = 7.0 Hz, 2H), 2.56 (d, J = 4.9 Hz, 2H), 2.29 (s, 3H), 2.26 (s,
3H), 1.31 (t, J = 7.1 Hz, 6H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (50
MHz, CDCl3): δ 171.5, 166.7, 141.1, 138.3, 138.0, 134.9, 130.7,
122.2, 118.3, 107.8, 60.2, 60.0, 40.7, 29.7, 19.9, 19.2, 14.4, 14.2;
HRMS (ESI): calc. for [(C23H29NO6)H] (M+H) 416.2073, found
416.2070.
2
(a) J. E. Charris, J. N. Dominguez, N. Gamboa, J. R. Rodrigues and J. E.
Angel, Eur. J. Med. Chem., 2005, 40, 875-881; (b) R. Dayam, L. Q. Al-
Mawsawi, Z. Zawahir, M. Witvrouw, Z. Debyser and N. Neamati, J.
Med. Chem., 2008, 51, 1136-1144; (c) G. Roma, M. D. Braccio, G.
Grossi, F. Mattioli and M. Ghia, Eur. J. Med. Chem., 2000, 35, 1021-
1035; (d) M. P. Maguire, K. R. Sheets, K. McVety, A. P. Spada and A.
Zilberstein, J. Med. Chem., 1994, 37, 2129-2137.
3
For synthesis of quinoline carboxylate derivative: (a) J. N. Kim, H. J. Lee,
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Diethyl-1-(4-bromophenyl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (9m):
Yield: 85%; 0.230 g; gummy liquid; IR (CHCl3, cm-1): υmax 2947, 1728,
1696, 1638, 1438, 1362, 1337, 1259, 1238, 1196, 1177, 881; 1H
NMR (200 MHz, CDCl3): δ 7.53 (d, J = 8.6 Hz, 2H), 7.50 (s, 2H), 7.11
(d, J = 8.6 Hz, 2H), 4.26-4.21 (m, 5H), 4.02 (q, J = 7.1 Hz, 2H), 2.58 (d,
J = 4.9 Hz, 2H), 1.32 (t, J = 7.1 Hz, 6H), 1.18 (t, J = 7.1 Hz, 3H); 13C
NMR (50 MHz, CDCl3): δ 171.4, 166.4, 142.2, 137.1, 132.9, 122.3,
119.6, 108.9, 60.4, 60.0, 40.2, 29.6, 14.4, 14.3; HRMS (ESI): calc. for
[(C21H24BrNO6)H] (M+H) 466.0865, found 466.0860.
4
Diethyl-1-(2,3-dihydro-1H-inden-5-yl)-4-(2-ethoxy-2-oxoethyl)-1,4-
dihydropyridine-3,5-dicarboxylate (9n):
5
Yield: 86%; 0.276 g; gummy liquid; IR (CHCl3, cm-1): υmax 2960, 1715,
1600, 1490, 1209, 1004, 750, 710; 1H NMR (200 MHz, CDCl3): δ 7.51
(s, 2H), 7.20 (d, J = 8.0 Hz), 7.07 (s, 1H), 6.99 (dd, J = 8.0, 2.0 Hz, 2H),
4.28-4.18 (m, 5H), 4.05 (q, J = 7.1 Hz, 2H), 2.90 (q, J = 7.1 Hz, 4H),
2.55 (d, J = 4.8 Hz, 2H), 2.19-2.04 (m, 2H), 1.31 (t, J = 7.1 Hz, 6H),
1.20 (t, J = 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 171.5, 166.6,
146.1, 142.6, 141.8, 138.1, 125.2, 119.2, 117.4, 107.6, 60.1, 59.9,
40.5, 32.9, 32.3, 29.6, 25.7, 14.4, 14.2; HRMS (ESI): calc. for
[(C24H29NO6)H] (M+H) 428.2073, found 428.2070.
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