Exploration of C5-C6-Unsubstituted 1,4-Dihydropyridines for the Construction of exo -Hexahydro-1 H -chromeno[3,4- h ][1,6]naphthyridine-3-carboxylates Using a Stereoselective Povarov Reaction

Article abstract of DOI:10.1055/s-0034-1380431

A wide variety of substituted exo-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxylate derivatives have been synthesized from 3-aminocoumarins, aldehydes, and 5,6-unsubstituted 1,4-dihydropyridine derivatives in the presence of 10 mol% of ytterbiu

Full text of DOI:10.1055/s-0034-1380431

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2745–2755
2745
special topic
K. Islam et al.
Special Topic
Synthesis
Exploration of C5–C6-Unsubstituted 1,4-Dihydropyridines for the
Construction of exo-Hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylates Using a Stereoselective Povarov Reaction
Kobirul Islama
Deb K. Dasa
Ejaz Akrama
Abu T. Khan*a,b
R5
O
R4
R3
Ph
H
Ph
O
R1
H
NH2
O
R5
N
R1
Yb(OTf)3 (10 mol%)
R2
+
+
CHO
H
a Department of Chemistry, Indian Institute of Technology
Guwahati, Guwahati 781039, India
b Aliah University, IIA/27, New Town, Kolkata 700 156, West
Bengal, India
NH
O
N
R3
R4
MeCN, r.t.
69–91%
O
R2
O
atk@iitg.ernet.in
25 examples
This work is dedicated to my mentor, retired Professor Dr.
R. R. Schmidt, Department of Chemistry, University of
Konstanz, Germany, on the occasion of his 80th birthday.
Received: 04.04.2015
Accepted after revision 12.05.2015
Published online: 02.07.2015
quinoline derivatives with poor stereoselectivity. Therefore,
a major task is to improve the stereoselectivity of the Po-
varov reaction; moreover, the one-pot synthesis of a single
diastereomer is still a key challenge.6 Apart from vinyl
ethers and vinyl sulfides, an extensive literature survey re-
veals that various other dienophiles such as cyclopentadi-
ene,7a indene,7b silyl enol ethers,7c methylenecyclopro-
panes,3d vinylidenecyclopropanes,7d norbornenes,7e ketene
dithioacetals,3c triacetylglucal,3e N-acetyl-2-azetidine,7f α,β-
unsaturated hydrazones,7g and indoles7h have been exploit-
ed in the Povarov reaction.
DOI: 10.1055/s-0034-1380431; Art ID: ss-2015-c0223-st
Abstract A wide variety of substituted exo-hexahydro-1H-chrome-
no[3,4-h][1,6]naphthyridine-3-carboxylate derivatives have been syn-
thesized from 3-aminocoumarins, aldehydes, and 5,6-unsubstituted
1,4-dihydropyridine derivatives in the presence of 10 mol% of ytterbi-
um(III) triflate in acetonitrile at room temperature using a one-pot Po-
varov reaction. Some of the salient features of this protocol are: good
yields and no need for an aqueous workup procedure or chromato-
graphic separation.
1,4-Dihydropyridines are considered as privileged scaf-
folds in medicinal chemistry as they possess manifold phar-
macological activity.8 They are also important because of
their wide application in synthesis9 and as organic scaffolds
for the preparation of libraries of alkaloid-like compounds
and related heterocyclic systems.10 Among them, C5–C6-
unsubstituted 1,4-dihydropyridines are particularly signifi-
cant because of their substitution pattern, which enables
the use of dihydropyridines as the dienophile component in
the imino-Diels–Alder reaction for the synthesis of substi-
tuted naphthyridine derivatives.11
In recent years, 3-aminocoumarin has been a key inter-
mediate for the construction of various heterocyclic com-
pounds.12 3-Aminocoumarins have also been used as the
amine component in the Povarov reaction for the construc-
tion of tetrahydropyrido[2,3-c]coumarins13a,b and pyri-
do[2,3-c]coumarins13c,d by our research group and others.
These successful results encouraged us to investigate
whether the Povarov reaction could be exploited further for
the synthesis of hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylates using 3-aminocoumarins, alde-
Key words aromatic aldehydes, 1,4-dihydropyridines, 3-aminocouma-
rin, Povarov reaction, ytterbium(III) triflate
Multicomponent reactions1 have emerged as an import-
ant synthetic strategy, as they have several features of an
ideal synthesis. The one-pot Povarov reaction,2 or the hetero-
Diels–Alder reaction, is recognized as a potential synthetic
strategy for the construction of natural and unnatural poly-
heterocycles owing to its rich synthetic diversity. Lewis acid
mediated [4 +2] hetero-Diels–Alder reaction between the
azadiene moiety of an N-arylimine and a dienophile, such
as an activated electron-enriched alkene (vinyl ethers, alkyl
vinyl sulfides, etc.) is an established route to tetrahydro-
quinolines.3 The presence of tetrahydroquinolines (or oxi-
dized derivatives) in natural products, bioactive com-
pounds, and drugs has received much interest in the syn-
thetic community.4 Over the years, tremendous effort has
been made in the development of the Povarov reaction for
the synthesis of complex enantioenriched bioactive azahet-
erocycles and valuable intermediates for the total synthesis
of natural products.5 However, the known examples of the
Povarov reaction generally produce both endo- and exo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

2746
K. Islam et al.
Special Topic
Synthesis
hydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxyl-
ate derivatives involving ytterbium(III) triflate via an imi-
no-Diels–Alder reaction using aldehydes, 3-aminocouma-
rins, and 1,4-dihydropyridines as shown in Scheme 1.
Various 5,6-unsubstituted 1,4-dihydropyridines 3 were
synthesized by three-component cyclization of α,β-unsatu-
rated aldehydes, amines, and 1,3-dicarbonyl compounds
using 5 mol% hydrated iron(III) sulfate as the catalyst in
methanol at room temperature.15 For the present study, op-
timization began using an equimolar mixture of 4-nitro-
benzaldehyde (1a), 3-aminocoumarin (2a), and 5,6-unsub-
stituted 1,4-dihydropyridine 3a in acetonitrile (2 mL) in the
presence of 5 mol% ytterbium(III) triflate. The mixture was
stirred at room temperature and purification gave exo-
hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-car-
boxylate 4a as the product in 54% overall yield (Table 1, en-
try 1). 1H NMR spectra of the crude reaction mixture
showed the presence of only a single diastereomeric prod-
uct, which was further confirmed by X-ray diffraction anal-
ysis.
R5
N
O
R5
O
R4
R3
Ph
R4
R3
Ph
H
Yb(OTf)3
(10 mol%)
R1
H
3a–g
N
H
NH2
R1
+
R2
OHC
MeCN, r.t.
NH
O
O
O
2a–g
R2
1
O
4a–y
Scheme 1 Synthesis of exo-hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylate derivatives
hydes, and C5–C6-unsubstituted 1,4-dihydropyridines.
Ytterbium(III) triflate is a useful catalyst for the aza-Diels–
Alder reaction and it has also been used widely for many
other organic transformations.14 In this paper, we wish to
report the simple and rapid one-pot synthesis of exo-hexa-
Table 1 Optimization of the Reaction Conditions for the Synthesis of exo-Hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxylate 4aa
O
MeO
Me
MeO
Me
O
Ph
NO2
Ph
H
N
N
H
3a
catalyst (mol%)
solvent, r.t.
H
+
CHO
NH
O
NH2
O
O2N
O
O
1a
2a
4a
Entry
Catalyst (mol%)
Solvent
Time (h)
Yieldb (%)
1
2
Yb(OTf)3 (5)
Yb(OTf)3 (10)
Yb(OTf)3 (15)
Yb(OTf)3 (20)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
In(OTf)3 (10)
Cu(OTf)2 (10)
AgOTf (10)
MeCN
MeCN
MeCN
MeCN
CH2Cl2
DMF
6.0
2.0
54
82
77
74
70
–
3
2.0
4
2.0
5
3.5
6
12.0
12.0
6.0
7
THF
56
71
44
72
33
–
8
EtOH
9
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
6.0
10
11
12
13
14
15
3.5
12.0
12.0
12.0
12.0
12.0
I2 (10)
32
–
Fe2(SO4)3·xH2O (10)
–
–
a Reaction conditions: 4-nitrobenzaldehyde (1a), 3-aminocoumarin (2a), 1,4-dihydropyridine 3a (ratio 1:1:1), r.t.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

2747
K. Islam et al.
Special Topic
Synthesis
To find the optimized conditions the model reaction
was carried out using 10, 15, and 20 mol% of the catalyst yt-
terbium(III) triflate (Table 1, entries 2–4) and the desired
product 4a was obtained in 82%, 77% and 74% yields, re-
spectively. It was observed that the yield of the product in-
creased significantly by increasing the amount of catalyst
from 5 mol% to 10 mol%. However, no further improvement
in the yield of 4a was observed, even when the amount of
catalyst increased to 20 mol% (entry 4). Suitable solvent
systems were also examined, dichloromethane, N,N-di-
methylformamide, tetrahydrofuran, ethanol, and toluene
were used for the model reaction (entries 5–9). The reac-
tion process was restrained in terms of reaction time and
yields when performed in dichloromethane, tetrahydrofu-
ran, ethanol, or toluene (entries 5 and 7–9). The reaction
did not occur in N,N-dimethylformamide and unreacted
starting materials were recovered (entry 6). It was noted
that the shortest reaction time and the best yield were ob-
tained in acetonitrile (entry 2) at room temperature. To ex-
amine the efficacy of ytterbium(III) triflate compared to
other catalysts, the model reaction was performed using
tions. It is worthwhile to mention that the products were
isolated simply by filtration and further purification was by
recrystallization (MeCN–hexane).
Table 2 Synthesis of Substituted exo-Hexahydro-1H-chromeno[3,4-
h][1,6]naphthyridine-3-carboxylate Derivatives Using the Povarov Reac-
tiona
O
MeO
Me
O
MeO
Me
Ph
Ph
H
R1
H
N
H
N
Yb(OTf)3
(10 mol%)
NH
O
NH2
O
+
R2
R2
R1CHO
MeCN, r.t.
O
O
1
2a–g
4a–r
2a R2 = H
2d R2 = 6-OMe
2e R2 = 8-OMe
2f R2 = 8-OEt
2g:
2b R2 = 6-Br
NH2
2c R2 = 6-NO2
O
O
other
catalysts
[In(OTf)3,
Cu(OTf)2,
AgOTf,
I2,
Entry
R1
2
4
Time (h) Yieldb (%)
Fe2(SO4)3·xH2O] (entries 10–14). Indium(III) triflate also
promoted the tandem reactions smoothly, albeit the yield
of 4a decreased to 72% (entry 10). Using copper(II) triflate
or iodine as the catalyst (entries 11 and 13) provided lower
yields. Catalysts, such as silver(I) triflate and iron(III) sulfate
hydrate did not promote the reaction (entries 12 and 14).
The reaction did not take place in the absence of a catalyst
(entry 15). Hence, the best yields for the Povarov reaction
employed ytterbium(III) triflate as the catalyst (entries 2)
with acetonitrile as solvent at room temperature.
After optimization of the reaction conditions, the reac-
tion was performed with a mixture of benzaldehyde (1b),
3-aminocoumarin (2a), and 1,4-dihydropyridine 3a under
identical conditions and the desired product 4b was ob-
tained in 79% yield (Table 2, entry 2). To explore the syn-
thetic scope and the generality of this protocol further, var-
ious reactions were examined with a wide variety of aro-
matic aldehydes 1 containing different substituents in the
aromatic ring, such as Me, OMe, Cl, Br, F and CN, with 3-
aminocoumarin (2a) and 1,4-dihydropyridine 3a, respec-
tively. The reaction time and percentage yield of the prod-
ucts 4c–i are shown in Table 2 (entries 3–9). Among the ex-
amined aldehydes, aromatic aldehydes with containing a
strong electron-withdrawing group on the benzene ring
(R1 = 4-O2NC6H4 and R1 = 4-NCC6H4) gave the desired prod-
ucts in higher yields in shorter reaction times (entries 1 and
9). Reactions with other aldehydes, such as 4-methylbenz-
aldehyde (1c) and 4-methoxybenzaldehyde (1d), gave the
corresponding product 4 in lower yields (entries 3–5). It
should be noted that functional groups such as fluoro,
chloro, bromo, nitro, and methoxy, are well tolerated and
the reactions preceded smoothly under these mild condi-
1
2
4-O2NC6H4
Ph
2a
4a
2
6
5
5
5
6
6
5
2
8
7
7
6
3
3
4
4
4
12
91
79
76
82
86
77
81
87
88
72
74
69
72
79
84
81
79
76
–
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
4b
4c
4d
4e
4f
3
4-MeC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
4-ClC6H4
4-BrC6H4
4-FC6H4
4-NCC6H4
2-furyl
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
4j
2-thienyl
1H-indol-3-yl
cyclohexyl
4-O2NC6H4
4-O2NC6H4
Ph
4k
4l
4m
4n
4o
4p
4q
4r
Ph
Ph
Ph
2g
4s
a Reaction conditions: aldehyde 1 (0.5 mmol), 3-aminocoumarin 2 (0.5
mmol), 1,4-dihydropyridine 3a (0.5 mmol), Yb(OTf)3 (10 mol%), MeCN (2
mL), r.t.
b Isolated yields.
The same methodology was further extended with al-
dehydes bearing a heteroaromatic substituent, such as fu-
ran-2-carbaldehyde (R1 = 2-furyl), thiophene-2-carbalde-
hyde (R1 = 2-thienyl), and 1H-indole-3-carbaldehyde (R1 =
1H-indol-3-yl), and the desired products 4j–l were isolated
in moderate to good yields (entries 10–12). Additionally,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

2748
K. Islam et al.
Special Topic
Synthesis
our protocol was further verified with an aliphatic alde-
hyde, namely cyclohexanecarbaldehyde, and the desired
product 4m was obtained in 72% yield (entry 13).
1718, and 1681 cm–1 due to the NH and two ester carbonyl
group in 4b. The H NMR spectrum of 4b showed a broad
1
singlets at δ = 5.30 due to the NH proton, and two singlets
at δ = 2.70 and 3.46 due to the Me and OMe groups in hexa-
hydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxyl-
ate 4b. The stereochemistry of the fused ring junctions and
other positions was established from the value of their cou-
pling constants. The protons H11, H12, and H10 appear as
doublets at δ = 2.13, 4.50, and 4.62. The coupling constant
between H11 and H10 (J11,10) was found to be 2.8 Hz indi-
cating a cis ring junction between the two dihydropyridine
rings in 4b. Similarly, the coupling constant value between
H11 and H12 (J11,12) was found to be 11.6 Hz in 4b indicat-
ing the trans diaxial relationship between these protons as
shown in Figure 1. The exo structure of 4b is also confirmed
by X-ray diffraction analysis, and its crystal structure is
shown in Figure 1.
A plausible mechanism for the formation of substituted
exo-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-
carboxylate derivatives 4 is shown in Scheme 2. We believe
that the condensation reaction between aromatic aldehyde
1 and 3-aminocoumarin 2 leads to the formation of inter-
mediate imine A, which undergoes a concerted [4+2]-cyc-
loaddition reaction with the dienophile, C5–C6-unsubsti-
tuted 1,4-dihydropyridine, to afford the final product exo-
hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-car-
boxylate 4.
To verifying the generality of this method, other substi-
tuted 3-aminocoumarins such as 3-amino-6-bromocouma-
rin (2b), 3-amino-6-nitrocoumarin (2c), and 3-amino-6-
methoxycoumarin (2d), 3-amino-8-methoxycoumarin (2e),
and 3-amino-8-ethoxycoumarin (2f) were also tested with
4-nitrobenzaldehyde (1a) or benzaldehyde (1b) and 1,4-di-
hydropyridine 3a under the optimized conditions and the
anticipated exo-hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylate derivatives 4n–r were obtained in
good yields (entries 14–18). However, the 3-aminocouma-
rin derivative containing a naphthyl ring 2g failed to give
the desired product when allowed to react with benzalde-
hyde and 1,4-dihydropyridine 3a (entry 19), which may be
accounted for by the inability of the dienophile, 1,4-substi-
tuted dihydropyridine, to approach the diene in the [4+2]-
cycloaddition manner due to steric hindrance caused by the
bulkiness of the diene formed. Furthermore, the same reac-
tions were also executed with different substituted 1,4-di-
hydropyridines 3b–g with aromatic aldehydes and 3-ami-
nocoumarin to give desired products 4t–y in good yields
(Table 3).
The product 4b was characterized by IR spectroscopy,
1H and 13C NMR spectroscopy, and mass spectrometry. In its
IR spectrum, it showed characteristic absorptions at 3347,
Table 3 Synthesis of Various Substituted exo-Hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxylate 4 Using the Povarov Reactiona
R5
R5
O
O
R4
R3
R4
Ph
H
Ph
R1
H
N
N
H
R3
Yb(OTf)3
(10 mol%)
+
NH
O
NH2
R1CHO
MeCN, r.t.
O
O
O
2a
1
4a–y
3b R3 = Bn, R4 = Me, R5 = OEt
3c R3 = 4-MeC6H4CH2, R4 = Me, R5 = OMe
3d R3 = 4-MeOC6H4CH2, R4 = Me, R5 = OMe
3e R3 = n-Bu, R4 = Me, R5 = OMe
3f R3 = Bn, R4 = Me, R5 = Me
3g R3 = Bn, R4 = Me, R5 = Ph
Entry
R1
4-O2NC6H4
3
4
Time (h)
Yieldb (%)
1
2
3
4
5
6
3b
3c
3d
3e
3f
4t
5
3
3
4
4
4
88
91
84
78
76
73
4-O2NC6H4
Ph
4u
4v
4w
4x
4y
Ph
4-O2NC6H4
4-O2NC6H4
3g
a Reaction conditions: aldehyde 1 (0.5 mmol), 3-aminocoumarin 2a (0.5 mmol), 1,4-dihydropyridine 3 (0.5 mmol), Yb(OTf)3 (10 mol%), MeCN (2 mL), r.t.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

2749
K. Islam et al.
Special Topic
Synthesis
Figure 1 X-ray crystal structure of 4b
Based on literature reports,11a,b it is also possible that
the reactions may proceed via a stepwise Mannich-like pro-
cess where the first step is the electrophilic interaction of
the dihydropyridine with in situ formed imine A [probably
activated by coordination with the Lewis acid, ytterbi-
um(III) triflate], to form an intermediate B, which would
then undergo ring closure in anti-mode via an intramolecu-
lar attack by the position 4 of the coumarin ring via reactive
intermediate B, to the desired product 4 as shown in
Scheme 2. The stereochemical outcome can be rationalized
by considering the preferential attack of the dihydropyri-
dine from its less hindered face and the final cyclization B
taking place in a stereocontrolled manner to yield exo-
hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-car-
boxylate derivative 4.
In conclusion, we have developed a simple and efficient
protocol for the synthesis of hitherto unreported exo-hexa-
hydro-1H-chromeno[3,4-h][1,6] naphthyridine-3-carbox-
ylate derivatives using 10 mol% of ytterbium(III) triflate in
acetonitrile at ambient temperature using 5,6-unsubstitut-
ed 1,4-dihydropyridines and 3-aminocoumarin as primary
building blocks. The reaction conditions are simple and the
NH2
R2
R1CHO
+
O
O
R5
N
O
1
2
R4
R3
Ph
LA
R1
R1
δ+
stepwise
mechanism
N
O
3
δ–
LA
N
O
R2
R2
O
O
A
A
concerted
mechanism
R5
O
R5
N
O
R5
O
R4
Ph
R4
R3
Ph
R4
Ph
H
R1
R1
R1
N
3
N
H
R3
R3
H
δ–
LA
NH
NH
O
N
R2
R2
R2
A
O
O
O
O
O
4
B
Scheme 2 Plausible mechanism for the formation of hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxylate derivatives using the Povarov
reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

2750
K. Islam et al.
Special Topic
Synthesis
transformation is effective for a wide range of aldehydes, 3-
aminocoumarins, and 5,6-unsubstituted 1,4-dihydropyri-
dines. The products are easily isolable in good to excellent
yields without aqueous workup or chromatographic sepa-
ration.
13C NMR (100 MHz, CDCl3): δ = 169.60, 157.82, 153.86, 147.27,
146.55, 141.05, 138.90, 129.58, 129.06 (2 C), 128.83, 128.49 (3 C),
128.44 (2 C), 127.97 (2 C), 127.73 (2 C), 127.00, 126.29, 125.43, 125.08
(2 C), 124.28, 121.46, 120.89, 116.55, 109.99, 94.25, 55.74, 50.79,
46.72, 42.98, 39.36, 17.70.
HRMS (ESI): m/z [M + H]+ calcd for C37H33N2O4: 569.2440; found:
569.2445.
Melting points were determined on a Büchi melting point apparatus
and are uncorrected. IR spectra were recorded on IR spectrophotome-
ter. 1H and 13C NMR spectra were recorded on Varian 400 & Bruker
600 spectrometer using TMS as an internal reference. HRMS spec-
trometry data was collected on Q-TOF LC/MS. X-ray crystal structures
were determined with a Siemens P-4 diffractometer.16
Methyl 1-Benzyl-2-methyl-7-oxo-4-phenyl-5-(p-tolyl)-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4c)
White solid; yield: 0.442 g (76%); mp 154–155 °C; Rf = 0.44 (10%
EtOAc–hexane).
IR (KBr): 3348, 1717, 1681 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.0 Hz, 2 H), 7.29–7.25 (m, 4
H), 7.22–7.08 (m, 6 H), 7.03 (d, J = 7.6 Hz, 2 H), 6.95–6.88 (m, 2 H),
6.84 (d, J = 7.2 Hz, 2 H), 5.27 (s, 1 H), 4.61 (d, J = 2.8 Hz, 1 H), 4.56 (s, 2
H), 4.61 (d, J = 11.6 Hz, 1 H), 3.84 (s, 1 H), 3.46 (s, 3 H), 2.69 (s, 3 H),
2.43 (s, 3 H), 2.10 (d, J = 16.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.56, 157.77, 153.82, 147.18,
146.62, 138.88, 138.43, 137.92, 129.68 (2 C), 129.56, 128.43 (2 C),
128.37 (2 C), 127.80 (2 C), 127.72 (2 C), 126.92, 126.20, 125.28, 125.03
(2 C), 124.20, 121.45, 120.81, 116.46, 109.76, 94.21, 55.39, 50.73 (2 C),
46.71, 42.90, 39.34, 21.26, 17.65.
exo-Hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carbox-
ylate Derivatives 4a–y; General Procedure
Aromatic aldehyde 1 (0.5 mmol), 3-aminocoumarin 2 (0.5 mmol), and
Yb(OTf)3 (10 mol%) in MeCN (2 mL) were added to a 25-mL round-
bottomed flask and the mixture was stirred at r.t. for 10 min. Then,
dihydropyridine 3 (0.5 mmol) was added to the mixture and it was
stirred at r.t. for a further 2–8 h until the reaction was complete (TLC
monitoring). When the reaction was almost complete (Tables 2 and
3), a solid precipitate appeared slowly. The solid precipitate was fil-
tered off through a Büchner funnel and it was washed with cold hex-
ane–EtOH (1:1, 10 mL) to remove unreacted starting materials. Finally
it was dried with a vacuum pump and recrystallized (MeCN–hexane)
to give pure 4a–y (69–91%).
HRMS (ESI): m/z [M + H]+ calcd for C38H35N2O4: 583.2597; found:
583.2598.
Methyl 1-Benzyl-5-(4-methoxyphenyl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4d)
Methyl 1-Benzyl-2-methyl-5-(4-nitrophenyl)-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4a)
White solid; yield: 0.490 g (82%); mp 245–247 °C; Rf = 0.28 (20%
EtOAc–hexane).
Yellow solid; yield: 0.558 g (91%); mp 277–279 °C; Rf = 0.31 (20%
EtOAc–hexane).
IR (KBr): 3343, 1718, 1678 cm–1
.
IR (KBr): 3336 (NH), 1716 (C=O), 1683 (C=O), 1519 (NO2), 1345 cm–1
(NO2).
1H NMR (400 MHz, CDCl3): δ = 8.32 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.4
Hz, 2 H), 7.28–7.22 (m, 2 H), 7.21–7.11 (m, 6 H), 6.97–6.93 (m, 4 H),
6.78 (d, J = 6.0 Hz, 2 H), 5.26 (s, 1 H), 4.63 (d, J = 2.8 Hz, 1 H), 4.62 (s, 1
H), 4.53 (d, J = 8.8 Hz, 2 H), 3.73 (s, 1 H), 3.46 (s, 3 H), 2.68 (s, 3 H), 2.10
(d, J = 11.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.31, 157.59, 153.83, 148.80,
148.23, 147.36, 145.76, 128.63, 129.13 (2 C), 129.02 (2 C), 128.57 (3
C), 127.66 (2 C), 127.09, 126.60, 125.93, 124.98 (2 C), 124.40, 124.19
(2 C), 120.99 (2 C), 116.55, 110.85, 93.94, 55.24, 50.94, 50.78, 46.43,
43.04, 39.38, 17.71.
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 8.8 Hz, 2 H), 7.29–7.25 (m, 2
H), 7.24–7.14 (m, 4 H), 7.12–7.08 (m, 2 H), 7.03 (d, J = 7.6 Hz, 2 H),
6.99 (d, J = 8.8 Hz, 2 H), 6.94–6.92 (m, 2 H), 6.84 (d, J = 6.8 Hz, 2 H),
5.26 (s, 1 H), 4.61 (d, J = 2.4 Hz, 1 H), 4.56 (s, 2 H), 4.45 (d, J = 12.0 Hz,
1 H), 3.88 (s, 3 H), 3.86 (s, 1 H), 3.46 (s, 3 H), 2.69 (s, 3 H), 2.08 (d, J =
11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.65, 159.94, 157.87, 153.85,
147.24, 146.60, 138.94, 132.85, 129.61, 129.07 (2 C), 128.50 (2 C),
128.44 (2 C), 127.76 (2 C), 126.99, 126.27, 125.36, 125.10 (2 C),
124.28, 121.51, 120.89, 116.55, 114.43 (2 C), 109.87, 94.26, 55.39,
55.13, 50.80 (2 C), 46.79, 43.01, 39.42, 17.71.
HRMS (ESI): m/z [M + H]+ calcd for C38H35N2O5: 599.2546; found:
599.2546.
HRMS (ESI): m/z [M + H]+ calcd for C37H32N3O6: 614.2291; found:
614.2291.
Methyl 1-Benzyl-2-methyl-7-oxo-4-phenyl-5-(3,4,5-trimethoxy-
phenyl)-4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylate (4e)
Methyl 1-Benzyl-2-methyl-7-oxo-4,5-diphenyl-4,4a,5,6,7,12c-
hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxyl-
ate (4b)
Off-white solid; yield: 0.566 g (86%); mp 178–180 °C; Rf = 0.15 (20%
EtOAc–hexane).
Off-white solid; yield: 0.449 g (79%); mp 188–190 °C; Rf = 0.39 (20%
EtOAc–hexane).
IR (KBr): 3347 (NH), 1718 (C=O), 1681 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): δ = 7.50–7.40 (m, 5 H), 7.29–7.24 (m, 2 H),
7.22–7.09 (m, 6 H), 7.02 (d, J = 7.2 Hz, 2 H), 6.94–6.89 (m, 2 H), 6.85
(d, J = 6.4 Hz, 2 H), 5.30 (s, 1 H), 4.62 (d, J = 2.8 Hz, 1 H), 4.57 (s, 2 H),
4.50 (d, J = 11.6 Hz, 1 H), 3.83 (s, 1 H), 3.46 (s, 3 H), 2.70 (s, 3 H), 2.13
(d, J = 11.6 Hz, 1 H).
IR (KBr): 3350, 1716, 1682 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.19 (m, 2 H), 7.16–7.08 (m, 4 H),
7.06–7.01 (m, 2 H), 6.97 (d, J = 7.2 Hz, 2 H), 6.88–6.82 (m, 2 H), 6.76
(d, J = 6.4 Hz, 2 H), 6.58 (s, 2 H), 5.24 (s, 1 H), 4.53 (d, J = 2.8 Hz, 1 H),
4.49 ( d, J = 6.4 Hz, 2 H), 4.37 ( d, J = 11.6 Hz, 1 H), 3.87–3.78 (m, 10 H),
3.38 (s, 3 H), 2.63 (s, 3 H), 2.01 (d, J = 11.6 Hz, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 169.44, 157.50, 153.71, 153.52,
147.00, 146.31, 138.68, 137.94, 136.55, 129.33, 128.33 (4 C), 127.66
(3 C), 126.79, 126.21, 125.20, 124.85 (3 C), 124.08, 121.16, 120.64,
116.20, 109.68, 104.55, 93.80, 60.80, 56.15 (3 C), 55.92, 50.61, 46.47,
42.73, 39.21, 17.52.
13C NMR (100 MHz, CDCl3): δ = 169.51, 157.77, 153.82, 147.30,
146.37, 138.84, 136.85, 129.68 (2 C), 129.59, 129.47, 128.50 (4 C),
127.72 (2 C), 127.03, 126.39, 125.57, 125.06 (2 C), 124.31, 121.35,
120.93, 116.55, 116.12, 115.90, 110.19, 94.13, 55.07, 50.83, 50.78,
46.66, 43.06, 39.37, 17.69.
HRMS (ESI): m/z [M + H]+ calcd for C40H39N2O7: 659.2757; found:
HRMS (ESI): m/z [M + H]+ calcd for C37H32FN2O4: 587.2346; found:
659.2813.
587.2349.
Methyl 1-Benzyl-5-(4-chlorophenyl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4f)
Methyl 1-Benzyl-5-(4-cyanophenyl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4i)
White solid; yield: 0.464 g (77%); mp 238–239 °C; Rf = 0.39 (20%
Pale-yellow solid; yield: 0.522 g (88%); mp 245–246 °C; Rf =0.24 (20%
EtOAc–hexane).
EtOAc–hexane).
IR (KBr): 3358, 1718, 1678 cm–1
.
IR (KBr): 3345, 2227, 1717, 1682 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.39 (m, 4 H), 7.30–7.26 (m, 2 H),
7.22–7.10 (m, 6 H), 7.03 (d, J = 7.6 Hz, 2 H), 6.94–6.88 (m, 2 H), 6.83
(d, J = 7.2 Hz, 2 H), 5.26 (s, 1 H), 4.62–4.55 (m, 3 H), 4.50 (d, J = 11.2 Hz,
1 H), 3.80 (s, 1 H), 3.47 (s, 3 H), 2.70 (s, 3 H), 2.09 (d, J = 11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.39, 157.63, 153.75, 147.23,
146.23, 139.66, 138.75, 134.43, 129.35 (2 C), 129.30 (2 C), 129.17 (2
C), 128.45 (3 C), 127.69 (2 C), 126.97, 126.37, 125.52, 124.98 (2 C),
124.24, 121.23, 120.86, 116.47, 110.19, 94.06, 55.09, 50.79, 50.72,
46.55, 42.92, 39.32, 17.64.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.0
Hz, 2 H), 7.23–7.19 (m, 2 H), 7.15–7.04 (m, 6 H), 6.91 (d, J = 7.6 Hz, 2
H), 6.9–6.82 (m, 2 H), 6.73 (d, J = 6.4 Hz, 2 H), 5.19 (s, 1 H), 4.56 (d, J =
2.4 Hz, 1 H), 4.52–4.46 (m, 3 H), 3.67 (s, 1 H), 3.41 (s, 3 H), 2.62 (s, 3
H), 2.03 (d, J = 11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.42, 157.73, 153.85, 147.48,
146.78, 145.85, 138.69, 132.90 (2 C), 129.26, 128.89 (2 C), 128.65 (2
C), 128.60 (2 C), 127.70 (2 C), 127.18, 126.66, 126.03, 125.05 (2 C),
124.48, 121.13, 121.04, 118.56, 116.71, 112.88, 110.88, 94.10, 55.59,
51.01, 50.86, 46.53, 43.09, 39.43, 17.77.
HRMS (ESI): m/z [M + H]+ calcd for C37H32ClN2O4: 603.2051; found:
603.2062.
HRMS (ESI): m/z [M + H]+ calcd for C38H32N3O4: 594.2393; found:
594.2394.
Methyl 1-Benzyl-5-(4-bromophenyl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4g)
Methyl 1-Benzyl-5-(furan-2-yl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4j)
White solid; yield: 0.524 g (81%); mp 251–252 °C; Rf = 0.41 (20%
EtOAc–hexane).
Light-brown solid; yield: 0.423 g (72%); mp 126–128 °C; Rf = 0.36
(20% EtOAc–hexane).
IR (KBr): 3347, 1718, 1676 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.26 (t, J = 7.6 Hz, 1 H),
7.20–7.03 (m, 9 H), 6.96–6.82 (m, 2 H), 6.77 (d, J = 6.8 Hz, 2 H), 6.46 (s,
1 H), 6.40 (s, 1 H), 5.14 (s, 1 H), 4.58–4.47 (m, 4 H), 3.84 (s, 1 H), 3.40
(s, 3 H), 2.60 (s, 3 H), 2.03 (d, J = 11.6 Hz, 1 H).
IR (KBr): 3347, 1716, 1681 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.4
Hz, 2 H), 7.30–7.26 (m, 2 H), 7.22–7.10 (m, 6 H), 7.02 (d, J = 7.6 Hz, 2
H), 6.96–6.92 (m, 2 H), 6.82 (d, J = 6.8 Hz, 2 H), 5.24 (s, 1 H), 4.61 (d, J =
2.4 Hz, 1 H), 4.55 (d, J = 4.0 Hz, 2 H), 4.48 (d, J = 11.6 Hz, 1 H), 3.80 (s, 1
H), 3.47 (s, 3 H), 2.69 (s, 3 H), 2.07 (d, J = 11.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.46, 157.70, 153.80, 147.30,
146.22, 140.22, 138.77, 132.19 (2 C), 129.66 (2 C), 129.30, 128.50 (4
C), 127.72 (2 C), 127.04, 126.42, 125.62, 125.03 (2 C), 124.31, 122.69,
121.26, 120.91, 116.56, 110.28, 94.10, 55.21, 50.88, 50.77, 46.58,
42.93, 39.35, 17.70.
13C NMR (100 MHz, CDCl3): δ = 169.45, 157.56, 153.62, 152.57,
147.23, 146.44, 143.01 (2 C), 138.70, 129.02, 128.41 (3 C), 127.70 (2
C), 126.90, 126.27, 125.46, 124.95 (2 C), 124.16, 121.09, 120.77,
116.39, 110.62, 110.24, 109.76, 94.52, 50.70, 50.65, 49.31 (2 C), 46.38,
39.96, 17.61.
HRMS (ESI): m/z [M + H]+ calcd for C37H32BrN2O4: 647.1545 and
HRMS (ESI): m/z [M + H]+ calcd for C35H31N2O5: 559.2233; found:
649.1525; found: 647.1558 and 649.1534.
559.2228.
Methyl 1-Benzyl-5-(4-fluorophenyl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4h)
Methyl 1-Benzyl-2-methyl-7-oxo-4-phenyl-5-(thiophen-2-yl)-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4k)
White solid; yield: 0.510 g (87%); mp 159–160 °C; Rf = 0.37 (20%
White solid; yield: 0.425 g (74%); mp 187–188 °C; Rf = 0.22 (20%
EtOAc–hexane).
EtOAc–hexane).
IR (KBr): 3351, 1721, 1682 cm–1
.
IR (KBr): 3343, 1716, 1681 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.36 (dd, J = 5.2, 3.6 Hz, 2 H), 7.24–7.18
(m, 2 H), 7.16–7.05 (m, 6 H), 7.05–7.02 (m, 2 H), 6.94 (d, J = 7.6 Hz, 2
H), 6.89–6.82 (m, 2 H), 6.76 (d, J = 6.8 Hz, 2 H), 5.18 (s, 1 H), 4.54 (d, J =
2.4 Hz, 1 H), 4.48 (d, J = 4.0 Hz, 2 H), 4.42 (d, J = 12.0 Hz, 1 H), 3.71 (s, 1
H), 3.39 (s, 3 H), 2.61 (s, 3 H), 2.00 (d, J = 12 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 4.8 Hz, 1 H), 7.30 (t, J = 7.6
Hz, 2 H), 7.22–7.06 (m, 10 H), 6.91 (d, J = 7.2 Hz, 2 H), 6.83 ( d, J = 6.8
Hz, 2 H), 5.37 (s, 1 H), 4.83 (d, J = 11.6 Hz, 1 H), 4.62 (d, J = 2.0 Hz, 1 H),
4.54 (s, 2 H), 3.97 (s, 1 H), 3.46 (s, 3 H), 2.68 (s, 3 H), 2.18 (d, J = 11.6
Hz, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 169.64, 157.71, 153.84, 147.43,
146.43, 144.47, 138.85, 129.00, 128.56 (4 C), 127.86 (2 C), 127.56,
127.10 (2 C), 126.44, 126.19, 125.74, 125.11 (2 C), 124.36, 121.28,
121.01, 116.62, 110.40, 94.33, 51.54, 50.90, 50.77, 46.65, 43.94, 39.71,
17.74.
13C NMR (100 MHz, CD2Cl2): δ = 169.56, 157.58, 154.05, 149.03,
148.92, 146.72, 146.26, 139.14, 130.45, 129.61 (2 C), 129.18 (2 C),
129.11 (2 C), 129.02, 128.21 (2 C), 127.78, 127.12, 125.41 (2 C), 124.73
(2 C), 124.00, 123.63, 118.64, 117.94, 110.00, 94.64, 55.80, 53.46,
51.23, 47.01, 43.59, 39.86, 17.98.
HRMS (ESI): m/z [M + H]+ calcd for C35H31N2O4S: 575.2005; found:
HRMS (ESI): m/z [M + H]+ calcd for C37H31BrN3O6: 694.1371; found:
575.1998.
694.1366.
Methyl 1-Benzyl-5-(1H-indol-3-yl)-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4l)
Methyl 1-Benzyl-2-methyl-11-nitro-5-(4-nitrophenyl)-7-oxo-4-
phenyl-4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylate (4o)
Off-white solid; yield: 0.419 g (69%); mp 244–246 °C; Rf = 0.52 (20%
Yellow solid; yield: 0.554 g (84%); mp 276–279 °C; Rf = 0.23 (20% EtO-
EtOAc–hexane).
Ac–hexane).
IR (KBr): 3339, 1716, 1680 cm–1
.
IR (KBr): 3355, 1734, 1675, 1522, 1341 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H),
7.47 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.26–7.17 (m, 7 H),
7.14–7.08 (m, 3 H), 6.97 ( d, J = 7.2 Hz, 3 H), 6.88 (d, J = 6.8 Hz, 3 H),
5.39 (s, 1 H), 4.83 (d, J = 11.6 Hz, 1 H), 4.67 (d, J = 2.0 Hz, 1 H), 4.60 (s,
2 H), 3.93 (s, 1 H), 3.39 (s, 3 H), 2.72 (s, 3 H), 2.50 (d, J = 11.2 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 8.8 Hz, 2 H), 7.94 (dd, J = 8.8,
2.8 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.34–7.28 (m, 3 H), 7.22–7.14 (m,
4 H), 7.03 (d, J = 7.6 Hz, 2 H), 6.83 (d, J = 7.2 Hz, 3 H), 5.58 (s, 1 H), 4.68
(d, J = 11.6 Hz, 1 H), 4.64 (d, J = 2.4 Hz, 1 H), 4.53 (s, 2 H), 3.77 (s, 1 H),
3.47 (s, 3 H), 2.70 (s, 3 H), 2.17 (d, J = 11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.04, 158.09, 154.28, 147.39,
146.92, 139.09, 137.13, 129.86, 128.67 (2 C), 128.51 (2 C), 127.97 (2
C), 127.14, 126.25, 125.71, 125.46, 125.26 (2 C), 124.42, 124.13,
122.78, 121.78, 121.02, 120.20, 119.76, 116.74, 115.12, 111.87,
110.06, 94.45, 50.99, 50.89, 49.21, 47.16, 41.25, 40.13, 17.89.
13C NMR (100 MHz, CDCl3 + TFA): δ = 192.25, 169.41, 157.30, 150.44,
148.91, 145.46, 142.54, 137.03, 133.89, 130.77, 130.23 (3 C), 130.00,
129.61 (2 C), 129.27, 127.50 (2 C), 127.44 (3 C), 124.59 (3 C), 122.73,
120.99, 118.86, 117.63, 101.71, 59.77, 57.91, 57.67, 56.44, 54.44,
44.86, 23.92.
HRMS (ESI): m/z [M + H]+ calcd for C39H34N3O4: 608.2549; found:
HRMS (ESI): m/z [M + H]+ calcd for C37H31N4O8: 659.2142; found:
608.2544.
659.2158.
Methyl 1-Benzyl-5-cyclohexyl-2-methyl-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4m)
Methyl 1-Benzyl-11-methoxy-2-methyl-7-oxo-4,5-diphenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4p)
White solid; yield: 0.413 g (72%); mp 213–214 °C; Rf = 0.32 (20%
Off-white solid; yield: 0.484 g (81%); mp 164–166 °C; Rf = 0.25 (20%
EtOAc–hexane).
EtOAc–hexane).
IR (KBr): 3338, 1718, 1684 cm–1
.
IR (KBr): 3345, 1714, 1684 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.22 (m, 5 H), 7.21–7.08 (m, 4 H),
7.10–7.02 (m, 1 H), 6.92–6.73 (m, 4 H), 5.29 (s, 1 H), 5.04 (s, 1 H), ),
4.59 (s, 1 H), 4.47 (s, 2 H), 4.27 (s, 1 H), ), 3.55 (s, 3 H), 3.39 (d, J = 10.4
Hz, 1 H), 2.62 (s, 3 H), 2.01–1.87 (m, 4 H), 1.85–1.68 (m, 3 H), 1.54–
1.42 (m, 3 H), 1.24–1.20 (m, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.54–7.42 (m, 5 H), 7.28–7.18 (m, 6 H),
7.11 (d, J = 8.4 Hz, 1 H), 7.06–7.04 (m, 2 H), 7.02–6.94 (m, 2 H), 6.67
(d, J = 7.2 Hz, 1 H), 6.34 (s, 1 H), 5.38 (s, 1 H), 4.67–4.56 (m, 3 H), 4.49
(d, J = 11.2 Hz, 1 H), 3.84 (s, 1 H), 3.46 (s, 3 H), 3.31 (s, 3 H), 2.68 (s, 3
H), 2.16 (d, J = 10.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.83, 158.21, 154.57, 147.27,
146.98, 138.92, 130.20, 128.72, 128.55 (2 C), 128.03 (2 C), 127.10,
126.51, 125.31 (2 C), 125.22, 124.38, 121.60, 120.75, 116.65, 110.02,
94.18, 54.01, 51.09, 50.85, 47.09, 39.54, 38.97, 37.32, 31.17, 29.87,
26.97, 26.54, 26.39, 25.08, 17.87.
13C NMR (100 MHz, CDCl3): δ = 169.76, 158.15, 156.22, 154.12,
146.42, 141.74, 141.02, 138.27, 129.92, 129.20 (2 C), 128.99, 128.83
(2 C), 128.53 (2 C), 128.07 (2 C), 127.85 (2 C), 127.17, 126.48, 125.18
(2 C), 122.37, 117.66, 112.62, 109.96, 104.44, 94.43, 55.79, 55.38,
50.96, 50.74, 47.16, 43.09, 39.36, 17.63.
HRMS (ESI): m/z [M + H]+ calcd for C37H39N2O4: 575.2910; found:
HRMS (ESI): m/z [M + H]+ calcd for C38H35N2O5: 599.2546; found:
575.2912.
599.2547.
Methyl 1-Benzyl-11-bromo-2-methyl-5-(4-nitrophenyl)-7-oxo-4-
phenyl-4,4a,5,6,7,12c-hexahydro-1I-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylate (4n)
Methyl 1-Benzyl-9-methoxy-2-methyl-7-oxo-4,5-diphenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4q)
Yellow solid; yield: 0.547 g (79%); mp 243–245 °C; Rf = 0.31 (20%
White solid; yield: 0.472 g (79%); mp 215–217 °C; Rf = 0.23 (20%
EtOAc–hexane).
EtOAc–hexane).
IR (KBr): 3362, 1718, 1678 cm–1
.
IR (KBr): 3347, 1716, 1684 cm–1
.
1H NMR (400 MHz, CD2Cl2): δ = 8.35 (d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.8
Hz, 2 H), 7.32–7.18 (m, 7 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.98 (d, J = 7.6 Hz,
3 H), 6.85 (d, J = 6.8 Hz, 2 H), 5.34 (s, 1 H), 4.63 (d, J = 11.6 Hz, 1 H),
4.55 (s, 2 H), 4.53 (d, J = 2.8 Hz, 1 H), 3.75 (s, 1 H), 3.48 (s, 3 H), 2.71 (s,
3 H), 2.13 (d, J = 12 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.46–7.38 (m, 5 H), 7.35–7.10 (m, 6 H),
7.01 (d, J = 5.2 Hz, 2 H), 6.90–6.78 (m, 3 H), 6.70 (d, J = 7.2, 1 H), 6.59–
6.48 (m, 1 H), 5.32 (s, 1 H), 4.62–4.54 (m, 3 H), 4.48 (d, J = 10.8, 1 H),
3.88 (s, 3 H), 3.82 (s, 1 H), 3.44 (s, 3 H), 2.68 (s, 3 H), 2.12 (d, J = 11.6
Hz, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 169.77, 157.47, 154.09, 147.42,
146.67, 141.05, 139.09, 136.88, 129.91, 129.18 (2 C), 128.95, 128.62
(2 C), 128.54 (2 C), 128.09 (2 C), 127.85 (2 C), 127.12, 126.38, 125.21
(2 C), 124.18, 122.45, 113.04, 110.15, 108.27, 94.32, 56.33, 55.82,
50.93, 50.90, 47.14, 43.05, 39.44, 17.83.
13C NMR (100 MHz, CDCl3): δ = 169.49, 157.85, 154.13, 148.87,
148.43, 147.56, 145.83, 136.89, 135.59, 129.35 (2 C), 129.23, 129.09
(2 C), 128.72 (2 C), 127.75 (2 C), 126.73, 126.17, 125.09 (2 C), 124.59,
124.39 (2 C), 121.20 (2 C), 116.82, 111.18, 93.90, 55.35, 51.13, 50.68,
46.53, 43.27, 39.46, 21.15, 17.83.
HRMS (ESI): m/z [M + H]+ calcd for C38H35N2O5: 599.2546; found:
HRMS (ESI): m/z [M + H]+ calcd for C38H34N3O6: 628.2448; found:
599.2544.
628.2446.
Methyl 1-Benzyl-9-ethoxy-2-methyl-7-oxo-4,5-diphenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4r)
Methyl 1-(4-Methoxybenzyl)-2-methyl-7-oxo-4,5-diphenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4v)
White solid; yield: 0.465 g (76%); mp 169–170 °C; Rf = 0.22 (20%
White solid; yield: 0.502 g (84%); mp 230–231 °C; Rf = 0.24 (20%
EtOAc–hexane).
EtOAc–hexane).
IR (KBr): 3347, 1716, 1684 cm–1
.
IR (KBr): 3340, 1717, 1679 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.37 (m, 5 H), 7.23 (t, J =7.4 Hz, 2
H), 7.20–7.12 (m, 4 H), 7.0 (d, J = 7.4 Hz, 2 H), 6.85 (d, J = 7.5 Hz, 2 H),
6.78 (t, J = 7.4 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H), 6.52 (d, J = 7.4 Hz, 1 H),
5.31 (s, 1 H), 4.52–4.50 (m, 3 H), 4.47 (d, J = 11.2 Hz, 1 H), 4.24–4.12
(m, 2 H), 3.80 (s, 3 H), 3.79 (s, 1 H), 2.66 (s, 3 H), 2.11 (d, J = 11.2 Hz, 1
H), 1.43 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.78, 157.67, 154.13, 146.74,
146.69, 141.11, 139.13, 137.21, 129.85, 129.18 (2 C), 128.94, 128.63
(2 C), 128.54 (2 C), 128.10 (2 C), 127.85 (2 C), 127.11, 126.38, 125.23
(2 C), 124.16, 122.52, 112.99, 110.27, 109.73, 94.33, 65.04, 55.82,
50.93, 50.89, 47.14, 43.09, 39.46, 17.83, 14.98.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.39 (m, 5 H), 7.31–7.22 (m, 2 H),
7.14 (t, J = 8.4 Hz, 2 H), 7.12 (d, J = 7.2 Hz, 1 H), 7.01 (d, J = 7.2 Hz, 2 H),
6.96–6.88 (m, 2 H), 6.82–6.70 (m, 4 H), 5.31 (s, 1 H), 4.60 (s, 1 H),
4.56–4.40 (m, 3 H), 3.81 (s, 1 H), 3.77 (s, 3 H), 3.44 (s, 3 H), 2.69 (s, 3
H), 2.12 (d, J = 11.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.73, 158.64, 158.05, 154.11,
147.34, 146.62, 141.09, 130.87, 129.57, 129.15, 128.91 (2 C), 128.50
(2C), 128.04 (2 C), 127.79 (2 C), 126.36 (2 C), 125.55, 124.38, 121.54,
121.06, 116.66 (2 C), 114.07 (2 C), 110.24, 94.25, 55.80, 55.49, 50.88,
50.30, 46.76, 43.06, 39.39, 17.45.
HRMS (ESI): m/z [M + H]+ calcd for C38H35N2O5: 599.2546; found:
599.2517.
HRMS (ESI): m/z [M + H]+ calcd for C39H37N2O5: 613.2702; found:
613.2702.
Methyl 1-Butyl-2-methyl-7-oxo-4,5-diphenyl-4,4a,5,6,7,12c-hexa-
Ethyl 1-Benzyl-2-methyl-5-(4-nitrophenyl)-7-oxo-4-phenyl-
4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naphthyridine-
3-carboxylate (4t)
hydro-1H-chromeno[3,4-h][1,6]naphthyridine-3-carboxylate (4w)
White solid; yield: 0.417 g (78%); mp 216–217 °C; Rf = 0.26 (20%
EtOAc–hexane).
Orange solid; yield: 0.552 g (88%); mp 227–228 °C; Rf = 0.32 (20%
EtOAc–hexane).
IR (KBr): 3351, 1720, 1679 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.38 (m, 5 H), 7.36–7.20 (m, 6 H),
7.16–7.12 (m, 1 H), 6.92 (d, J = 6.8 Hz, 2 H), 5.39 (s, 1 H), 4.53 (s, 1 H),
4.32 (d, J = 11.6 Hz, 1 H), 3.69 (s, 1 H), 3.40 (s, 3 H), 3.28–3.12 (m, 2 H),
2.68 (s, 3 H), 2.02 (d, J = 12.0 Hz, 1 H), 1.69–1.60 (m, 2 H), 1.08–0.94
(m, 2 H), 0.69–0.65 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.71, 158.42, 154.01, 147.46,
147.01, 141.01, 129.78, 129.19 (2 C), 128.94, 128.48 (2 C), 128.08 (2
C), 127.76 (2 C), 126.31, 125.86, 124.93, 122.09, 120.79, 117.08,
110.89, 94.62, 55.73, 55.79, 47.41, 46.28, 43.12, 39.39, 32.89, 19.89,
17.29, 13.54.
IR (KBr): 3347, 1716, 1680, 1519, 1345 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.4
Hz, 2 H), 7.29–7.24 (m, 2 H), 7.22–7.12 (m, 6 H), 6.97 (d, J = 7.2 Hz, 4
H), 6.81 (d, J = 6.4 Hz, 2 H), 5.29 (s, 1 H), 4.67–4.62 (m, 2 H), 4.56 (d, J =
2.8 Hz, 2 H), 4.02–3.90 (m, 2 H), 3.78 (s, 1 H), 2.70 (s, 3 H), 2.12 (d, J =
11.2 Hz, 1 H), 0.94 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.86, 157.74, 153.62, 148.96,
148.36, 147.51, 145.95, 138.78, 129.21, 129.11 (2 C), 128.62 (4 C),
127.74 (2 C), 127.20, 126.63, 126.09, 125.08 (2 C), 124.52, 124.23 (2
C), 121.11 (2 C), 116.72, 111.06, 94.56, 59.29, 55.37, 50.83, 46.46,
43.20, 39.54, 17.73, 14.39.
HRMS (ESI): m/z [M + H]+ calcd for C34H35N2O4: 535.2597; found:
535.2597.
HRMS (ESI): m/z [M + H]+ calcd for C38H34N3O6: 628.2448; found:
628.2439.
3-Acetyl-1-benzyl-2-methyl-5-(4-nitrophenyl)-4-phenyl-
1,4,4a,5,6,12c-hexahydro-7H-chromeno[3,4-h][1,6]naphthyridin-
7-one (4x)
Methyl 2-Methyl-1-(4-methylbenzyl)-5-(4-nitrophenyl)-7-oxo-4-
phenyl-4,4a,5,6,7,12c-hexahydro-1H-chromeno[3,4-h][1,6]naph-
thyridine-3-carboxylate (4u)
Brown solid; yield: 0.454 g (76%); mp 167–170 °C; Rf = 0.12 (20%
EtOAc–hexane).
Yellow solid; yield: 0.571 g (91%); mp 226–228 °C; Rf = 0.29 (20%
EtOAc–hexane).
IR (KBr): 3345, 1718, 1624, 1520, 1344 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.8 Hz, 2 H), 7.70 (d, J = 8.8
Hz, 2 H), 7.33 (t, J = 7.6, 2 H), 7.27–7.16 (m, 6 H), 7.02–6.97 (m, 4 H),
6.97 (d, J = 6.8 Hz, 2 H), 5.33 (s, 1 H), 4.67–4.57 (m, 4 H), 3.51 (s, 1 H),
2.71 (s, 3 H), 2.21 (d, J = 11.2 Hz, 1 H), 1.84 (s, 3 H).
IR (KBr): 3343, 1718, 1684, 1514, 1344 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 8.4
Hz, 2 H), 7.27 (d, J = 7.2 Hz, 2 H), 7.18 (t, J = 8.0 Hz, 3 H), 7.12–6.84 (m,
6 H), 6.71 (d, J = 7.2 Hz, 2 H), 5.29 (s, 1 H), 4.65–4.61 (s, 2 H), 4.52 (s, 2
H), 3.74 (s, 1 H), 3.48 (s, 3 H), 2.70 (s, 3 H), 2.29 (s, 3 H), 2.16 (d, J =
11.2 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

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13C NMR (100 MHz, CDCl3): δ = 197.56, 157.61, 154.56, 148.64,
148.56, 147.55, 145.07, 138.30, 129.34, 129.09 (2 C), 129.02 (2 C),
128.66 (2 C), 128.00 (2 C), 127.32 (2 C), 126.24, 125.05 (2 C), 124.59,
124.52 (2 C), 121.06, 121.01, 116.80, 110.67, 103.53, 55.24, 50.95,
46.66, 43.43, 41.20, 29.66, 18.52.
HRMS (ESI): m/z [M + H]+ calcd for C37H32N3O5: 598.2342; found:
598.2374.
(4) (a) Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev.
2011, 111, 7157. (b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002,
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Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41, 1668.
(b) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913. (c) Xia, C.;
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Sarma, R.; Prajapati, D. Tetrahedron Lett. 2012, 53, 6460.
(c) Kouznetsov, V. V.; Gómez, C. M. M.; Ruíz, F. A. R.; del Olmo, E.
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3-Benzoyl-1-benzyl-2-methyl-5-(4-nitrophenyl)-4-phenyl-
1,4,4a,5,6,12c-hexahydro-7H-chromeno[3,4-h][1,6]naphthyridin-
7-one (4y)
Pale-yellow solid; yield: 0.481 g (73%); mp 295–297 °C; Rf = 0.19 (20%
(7) (a) Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855.
(b) Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M. J. Hetero-
cycl. Chem. 1988, 25, 1831. (c) Makioka, Y.; Shindo, T.;
Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthesis 1995, 801. (d) Lu,
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J. I.; Lough, A. J.; Batey, R. A. J. Org. Chem. 2010, 75, 702.
(f) Stevenson, P. J.; Nieuwenhuyzen, M.; Osborne, D. Chem.
Commun. 2002, 444. (g) Sridharan, V.; Perumal, P. T.; Avendaño,
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R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A.
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(c) Williams, D. A.; Lemke, T. L.; Foye, W. O. In Foye’s Principles
of Medicinal Chemistry; Lippincott Williamsand Wilkins: Balti-
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Knaus, E. E. Bioorg. Med. Chem. 2005, 13, 4085.
EtOAc–hexane).
IR (KBr): 3339, 1715, 1622, 1517, 1346 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.4
Hz, 2 H), 7.51 (d, J = 7.2 Hz, 2 H), 7.28–7.32 (m, 1 H), 7.28–7.09 (m, 11
H), 6.99 (d, J = 7.6 Hz, 3 H), 6.88 (d, J = 6.8 Hz, 2 H), 5.27 (s, 1 H), 4.87
(s, 1 H), 4.67–4.49 (m, 3 H), 3.90 (s, 1 H), 2.23–2.16 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 197.34, 157.73, 152.34, 148.46,
147.65, 145.63, 142.77, 138.82, 130.78, 129.37 (2 C), 128.84 (4 C),
128.28 (4 C), 128.09 (4 C), 127.47, 126.94, 126.28 (2 C), 125.14 (2 C),
124.71, 124.51 (2 C), 121.10, 116.94, 110.79, 106.94, 55.44, 50.83,
46.88, 43.60, 40.85, 20.70.
HRMS (ESI): m/z [M + H]+ calcd for C42H34N3O5: 660.2498; found:
660.2492.
(9) (a) Lavilla, R. J. Chem. Soc., Perkin Trans.
1 2002, 1141.
Acknowledgment
(b) Carranco, I.; Díaz, J. L.; Jiménez, O.; Lavilla, R. Tetrahedron
Lett. 2003, 44, 8449. (c) Masdeu, C.; Gómez, E.; Williams, N. A.
O.; Lavilla, R. Angew. Chem. Int. Ed. 2007, 46, 3043.
K.I. thanks UGC for his research fellowship. D.K.D. acknowledges CSIR,
New Delhi for financial support for a S.R.F. The authors are grateful to
the Director, IIT Guwahati for providing general facilities to carry out
the research work and they thank DST for providing the XRD facility
under the FIST programme.
(10) (a) Charette, A. B.; Mathieu, S.; Martel, J. Org. Lett. 2005, 7, 5401.
(b) Chai, L.; Zhao, Y.; Sheng, Q.; Liu, Z.-Q. Tetrahedron Lett. 2006,
47, 9283. (c) Chen, J.; McNeil, A. J. J. Am. Chem. Soc. 2008, 130,
16496. (d) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642. (e) Verendel, J. J.; Zhou, T.; Li, J.-Q.;
Paptchikhine, A.; Lebedev, O.; Andersson, P. G. J. Am. Chem. Soc.
2010, 132, 8880.
(11) (a) Lavilla, R.; Bernabeu, M. C.; Carranco, I.; Diaz, J. L. Org. Lett.
2003, 5, 717. (b) Carranco, I.; Diaz, J. L.; Jimenez, O.; Vendrell,
M.; Albericio, F.; Royo, M.; Lavilla, R. J. Comb. Chem. 2005, 7, 33.
(c) Vicente-Garcia, E.; Catti, F.; Ramon, R.; Lavilla, R. Org. Lett.
2010, 12, 860. (d) Maiti, S.; Sridharan, V.; Menéndez, J. C.
J. Comb. Chem. 2010, 12, 713. (e) Lavilla, R.; Carranco, I.; Díaz, J.
L.; Bernabeu, M. C.; de la Rosa, G. Mol. Diversity 2003, 6, 171.
(f) Di Pietro, O.; Viayna, E.; Vicente-García, E.; Bartolini, M.;
Ramón, R.; Juárez-Jiménez, J.; Clos, M. V.; Pérez, B.; Andrisano,
V.; Luque, F. J.; Lavilla, R.; Muñoz-Torrero, D. Eur. J. Med. Chem.
2014, 73, 141.
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(b) Soman, S. S.; Thaker, T. H.; Rajput, R. A. Chem. Heterocycl.
Compd. 2011, 46, 1514. (c) Khan, A. T.; Das, D. K. Tetrahedron
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Adv. 2014, 4, 3581. (b) Kudale, A. A.; Kendall, J.; Miller, D. O.;
Collins, J. L.; Bodwell, G. J. J. Org. Chem. 2008, 73, 8437. (c) Khan,
A. T.; Das, D. K.; Islam, K.; Das, P. Tetrahedron Lett. 2012, 53,
6418. (d) Kudale, A. A.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J.
Org. Biomol. Chem. 2011, 9, 7196.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380431.
S
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p
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755

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K. Islam et al.
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(16) Complete crystallographic data of 4b have been deposited with
the Cambridge Crystallographic Data Centre, CCDC No. 997069.
Copy of this information may be obtained free of charge from
the Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK, [fax: +44(1223)336033, e-mail:
deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2745–2755