Regioselective synthesis of chromeno[4′,3′:4,5]pyrano[3,2-c][1, 8]naphthyridin-13-one derivatives by Domino Knoevenagel-Hetero-Diels-Alder reactions

Article abstract of DOI:10.1055/s-0030-1260254

Efficient synthesis of chromeno[4′,3′:4,5]pyrano[3,2-c][1,8] naphthyridin-13-one derivatives has been described by domino Knoevenagel-hetero-Diels-Alder reaction of 4-hydroxy-1-phenyl-1,8-naphthyridin- 2(1H)-one with O-allylated/propargylated salicylaldehydes. The reaction occurs in a single step and is highly regio- and stereoselective giving polycyclic heterocycles in high yields.

Full text of DOI:10.1055/s-0030-1260254

3716
PAPER
Regioselective Synthesis of Chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naph-
thyridin-13-one Derivatives by Domino Knoevenagel–Hetero-Diels–Alder
Reactions
C
hromeno[4
¢
,3
¢
:4,5
.
]pyrano[3,2
C
-
c
][1,8]naphthyri
.
din-13-onesMajumdar,*a,b Abu Taher,a Sudipta Ponraa
a
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B, India
Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, Assam, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
b
the synthesis of [6,6]-fused-annulated pyranopyran sys-
tem including natural products.15 Tietze et al. extensively
described the domino Knoevenagel–hetero-Diels–Alder
reaction (DKHDA) of unsaturated aromatic and aliphatic
Abstract: Efficient synthesis of chromeno[4¢,3¢:4,5]pyrano[3,2-
c][1,8]naphthyridin-13-one derivatives has been described by dom-
ino Knoevenagel–hetero-Diels–Alder reaction of 4-hydroxy-1-phe-
nyl-1,8-naphthyridin-2(1H)-one with O-allylated/propargylated
salicylaldehydes. The reaction occurs in a single step and is highly aldehydes with several 1,3-dicarbonyl compounds for the
synthesis of tetracycles with a pyran ring.16 During the last
regio- and stereoselective giving polycyclic heterocycles in high
yields.
few years there have been several reports of the applica-
tion of this methodology.17 Recently, we have synthesized
Key words: 1,8-naphthyridine, Knoevenagel reaction, hetero-
Diels–Alder reaction, ethylenediammonium diacetate, regioselec-
indole- and thiochromene-annulated [6,6]-fused thiopyra-
nobenzopyran derivatives using the DKHDA reaction,18
tive, stereoselective, unactivated alkenes, unactivated alkynes
which are difficult to prepare using radical cyclization and
Claisen rearrangement.13,14,19 Continuing our interest in
1,8-Naphthyridinones and their derivatives have attracted
considerable attention because this moiety is present in
many compounds that have been isolated from natural
products and found to possess medicinal and biological
activity.1 Compounds containing the 1,8-naphthyridin-
2(1H)-one skeleton are useful as antibacterials,2 anticon-
vulsants,3 antihypertensives,4 and inhibitors of both
ACAT5 and platelet aggregation.6 4-Hydroxy-1-phenyl-
1,8-naphthyridin-2(1H)-one and its derivatives act as anti-
allergic agents.7 2-Oxo-1,8-naphthyridin-3-carboxylic
acid derivatives possess potent gastric antisecretory prop-
erties and anti-inflammatory activity.8 A series of novel
imidazo[4,5-c][1,8]naphthyridine-4(5H)-ones exhibited
potent bronchodilator activity.9 There are several 1,8-
naphthyridine derivatives which were found to display
moderate cytotoxic activity against murine P388 leuke-
mia.10 Some C3 carboxamide derivatives with a spacer
have been found to show good cytotoxicity along with
anti-inflammatory activity.11 The attractive biological ac-
tivity of these 1,8-naphthyridines, for example, anti-
inflammatory, cytoprotective, and anti-allergic activity of
some 2,3-fused and 3,4-fused furo and pyrano tricyclic
compounds,12 explains the great interest in the naphthyri-
dinone moiety as a target in organic synthesis. There are
reports of the synthesis of naphthyridinone-annulated
benzofuranopyran13 and benzofuranothiopyran14 deriva-
tives, but there are no reports of the synthesis of naphthy-
ridinone-annulated benzopyranopyran derivatives.
the synthesis of annulated [6,6]-fused polycyclic
heterocycles18 and in order to explore the utility of the
DKHDA reaction, we became interested in synthesizing
potentially bioactive naphthyridinone-annulated [6,6]-
fused pyranobenzopyran derivatives using 4-hydroxy-1-
phenyl-1,8-naphthyridin-2(1H)-one and O-allylated/pro-
pargylated salicylaldehydes. Herein, we report the results
of our investigation.
The necessary precursors 2a–g were prepared by reflux-
ing various substituted salicylaldehydes 1a–g with allyl
bromide in the presence of anhydrous potassium carbon-
ate and a catalytic amount of sodium iodide in anhydrous
acetone.20 Other precursors 3a–e were prepared in high
yields and purity by the reaction of substituted salicylal-
dehydes 1a–d,f and propargyl bromide in the presence of
anhydrous potassium carbonate in anhydrous N,N-di-
methylformamide at room temperature21 (Scheme 1).
a, R1 = R2 = R3 = H
OH
O
b, R1 = H, R2 = Br, R3 = H
CHO
c, R1 = H, R2 = Cl, R3 = H
CHO
(i)
d, R1 = H, R2 = Me, R3 = H
e, R1 = H, R2 = t-Bu, R3 = H
f, R1 = Me, R2 = Cl, R3 = H
g, R1 = Me, R2 = H, R3 = Me
R3
R1
R3
R1
R2
R2
2a–g
1a–g
OH
O
a, R1 = R2 = R3 = H
b, R1 = H, R2 = Br, R3 = H
c, R1 = H, R2 = Cl, R3 = H
d, R1 = H, R2 = Me, R3 = H
e, R1 = Me, R2 = Cl, R3 = H
CHO
R1
CHO
R1
(ii)
The domino Knoevenagel–hetero-Diels–Alder reaction is
one of the most efficient and powerful synthetic route for
R3
R3
R2
R2
3a–e
1a–d,f
SYNTHESIS 2011, No. 22, pp 3716–3722
Advanced online publication: 05.10.2011
DOI: 10.1055/s-0030-1260254; Art ID: Z72411SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1
Scheme 1 Reagent and conditions: (i) allyl bromide, anhyd K2CO3,
anhyd acetone, NaI, reflux; (ii) propargyl bromide, anhyd K2CO3,
DMF, r.t.

PAPER
Chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one Derivatives
3717
O
O
CHO
CHO
H
O
O
OH
N
O
O
2a
(i)
3a
H
O
(ii)
N
N
O
N
O
N
N
Ph
Ph
Ph
6a
4
5a
Scheme 2 Reagent and conditions: (i) EDDA, chlorobenzene, reflux; (ii) EDDA, CuI, chlorobenzene, reflux.
In order to study the DKHDA reactions of 4-hydroxy-1- derivative 5b, which was confirmed by NMR experiments
phenyl-1,8-naphthyridin-2(1H)-one (4) with O-allylsali- including 2D nuclear Overhauser effect spectroscopy
cylaldehydes 2a–g and O-propargylsalicylaldehydes 3a–e, (NOESY) . The NOE correlation confirmed that the two
the O-allylsalicylaldehyde (2a) was used as a model sub- ring junction protons at 2.47 (s, 1 H) and 4.31 (t, J = 12.0
strate to optimize the reaction conditions (Scheme 2).
Hz, 1 H) interact with each other and hence they are cis to
each other as shown in Figure 1. The 13C spectra of the fi-
nal compounds 5 showed that the carbonyl carbon appear
in between d = 162.6–165.0, which is characteristic for the
carbonyl carbon of a cyclic amide. This means cyclization
occurred via the carbonyl group of the a,b-unsaturated ke-
tone and not via the carbonyl group of the cyclic amide.
We examined the influence of base and solvents on the re-
action (Table 1). Following our previous published proce-
dure,16a refluxing 4 and 2a in acetic acid medium in the
presence of triethylamine as base for ten hours gave no re-
action (entry 1). The base was changed to ethylenediam-
monium diacetate (EDDA) (10 mol%), but in this case
also the expected product was not obtained (entry 2). Us-
ing triethylamine as base and toluene as solvent with re-
flux for ten hours was also unsatisfactory (entry 3). To our
delight, when the same reaction was carried out in toluene
in the presence of ethylenediammonium diacetate instead
of triethylamine, the expected product 5a was obtained,
but in only 28% yield (entry 4); changing the solvent to
chlorobenzene increased the yield to 95%. From the opti-
mization study, it was observed that reaction of 4 and 2a
in refluxing chlorobenzene in the presence of ethylenedi-
ammonium diacetate (10 mol%) for four hours gave the
best result (entry 5).
NOE
H
O
N
O
H
N
O
Br
Figure 1
To explore this DKHDA reaction in a synthetically useful
context, we next examined the reactions of 4-hydroxy-1-
phenyl-1,8-naphthyridin-2(1H)-one (4) with O-propargy-
lated salicylaldehydes 3a–e. In a similar fashion, the reac-
tion proceeded via the domino Knoevenagel–hetero-
Diels–Alder pathway to afford chromeno[4¢,3¢:4,5]pyra-
Table 1 Effect of Base and Solvent on the DKHDA Reaction of 4
with 2a
Entry
Base
Solvent
Time (h) Yield (%)
1
2
3
4
5
6
7
Et3N
AcOH
10
10
10
10
4
–
no[3,2-c][1,8]naphthyridin-13-one
derivatives
6
EDDA
Et3N
AcOH
–
(Scheme 2).
Generally, DKHDA of alkynes requires a Lewis acid to
activate the unactivated alkyne system. In our case we
used copper(I) iodide (5 mol%) as the Lewis acid and best
yield of the final product was obtained when the reaction
was carried out in the presence of ethylenediammonium
diacetate (10 mol%) as base and copper(I) iodide (5
mol%) as Lewis acid in refluxing chlorobenzene for three
hours. In this case also, the reaction is highly regioselec-
tive giving angularly fused products; in all cases we ob-
tained angularly fused products (Table 3). Due to the mild
basic conditions and low reactivity of the amide carbonyl
group compared to a simple carbonyl functionality, no
other regioisomer was observed.
toluene
–
EDDA
EDDA
EDDA
EDDA
toluene
28
95
67
15
chlorobenzene
1,2-dichlorobenzene
benzene
4
4
Using the optimized condition, we examined the reaction
of 4 with several O-allylated aromatic aldehydes 2a–g.
The results are listed in Table 2.
The reaction is highly regio- and stereoselective. Reaction
of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (4)
with O-allylated p-bromosalicylaldehyde 2b gave exclu-
sively the cis-annulated [6,6]-fused benzopyrano pyran
The structures of the products obtained by the reaction of
4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (4) with
O-allylated p-bromosalicylaldehyde (2b) were deter-
Synthesis 2011, No. 22, 3716–3722 © Thieme Stuttgart · New York

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K. C. Majumdar et al.
PAPER
Table 2 Domino Knoevenagel–Hetero-Diels–Alder Reaction of 4 with 2a–ga
H
OH
O
O
O
CHO
R1
+
H
R3
N
N
O
N
N
R3
O
R1
5a–g
R2
Ph
Ph
R2
4
2a–g
Entry
Aromatic aldehyde
R1
H
R2
R3
H
Product
5a
Yieldb (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
95
90
88
92
93
87
84
H
Br
Cl
H
5b
H
H
5c
H
Me
t-Bu
Cl
H
5d
H
H
5e
Me
Me
H
5f
2g
H
Me
5g
a Reaction conditions: EDDA (10 mol%), chlorobenzene, reflux, 4 h.
b Isolated yields.
mined from their elemental analyses and spectroscopic or O-propargylated salicylaldehyde 3 to give the two pos-
1
data. The characteristic peaks for 6a–e in the H NMR sible heterodiene intermediates 7 and 10. Therefore, two
spectra appear as AB quartets for the OCH2 protons be- pathways can be visualized for the hetero-Diels–Alder re-
tween d = 4.67 and 4.97 ppm followed closely by singlets action. In one case, the lactam (amide) carbonyl group
for the OCH= protons at d = 6.71–6.85 ppm. The corre- could react affording the linearly fused products 8 (when
sponding carbon signals for the OCH2, OCH=, and C=O O-allylated salicylaldehyde is used) or 9 (when O-propar-
groups of the compounds in the 13C NMR spectra appear gylated salicylaldehyde is used) (Path a). In another form,
between d = 67.3–67.8, 106.0–107.1, and 163.8–164.0 the keto carbonyl group could be involved in the cycload-
ppm, respectively.
dition reaction leading to angularly fused product 5a or 11
(when O-allylated salicylaldehyde is used) and 6a (when
O-propargylated salicylaldehyde is used) (Path b). How-
ever, only angularly fused products 5a and 6a were isolat-
ed. Two important factors that may control the synthesis
The stereochemistry of the final product and the mecha-
nism of the reaction are depicted in Scheme 3. First step is
the Knoevenagel condensation between 4-hydroxy-1-
phenyl-1,8-naphthyridin-2(1H)-one (4) and O-allylated 2
Table 3 Domino Knoevenagel–Hetero-Diels–Alder Reaction of 4 with 3a–ea
O
OH
O
O
CHO
R1
+
R3
N
N
R3
N
N
O
O
R1
6a–e
R2
Ph
R2
Ph
4
3a–e
Entry
Aromatic aldehyde
R1
H
R2
R3
H
H
H
H
H
Product
6a
Yieldb (%)
1
2
3
4
5
3a
3b
3c
3d
3e
H
92
89
88
90
82
H
Br
Cl
Me
Cl
6b
H
6c
H
6d
Me
6e
a Reaction conditions: EDDA (10 mol%), CuI (5 mol%), chlorobenzene, reflux, 3 h.
b Isolated yields.
Synthesis 2011, No. 22, 3716–3722 © Thieme Stuttgart · New York

PAPER
Chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one Derivatives
3719
O
N
O
O
O
H
O
O
path a
H
or
N
O
N
N
O
N
N
O
Ph
OH
O
Ph
Ph
7
CHO
8 (not obtained)
9 (not obtained)
+
N
N
O
Ph
4
2 and 3
O
O
O
path b
O
N
N
O
N
N
O
Ph
10'
10
Ph
exo pathway
endo pathway
H
H
O
O
O
O
O
O
or
H
O
H
O
N
N
N
N
O
N
N
Ph
Ph
Ph
6a (obtained)
11 (not obtained)
5a (obtained)
Scheme 3 Probable mechanism of DKHDA reaction
of major products 5a or 6a could be classified as (a) a Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer L 120-000A
more efficient HOMO–LUMO interaction for the a,b-un-
spectrophotometer on KBr disks. 1H and 13C NMR spectra were re-
saturated ketone as a diene and alkene/alkyne as dieno-
corded on a Bruker DPX-400 spectrometer in CDCl3 with TMS as
phile in the intermediate 10 (and 10¢) compared to
internal standard. CHN was recorded on a Perkin-Elmer 2400 series
intermediate 7 and (b) more steric hindrance in the inter-
mediate 7 compared to 10 (and 10¢). The steric hindrance
is greater when the carbonyl group of the amide acts as the
heterodiene compared to the carbonyl group of the a,b-
unsaturated ketone system. In the case of the DKHDA re-
action with O-allylated salicylaldehydes, the stereochem-
istry of the final products depends on the exo- and endo-
orientation of the dienophiles in the transition states. The
intermediate 10 may undergo rotation around the single
bond to assume the structure 10¢, which may then undergo
cyclization via endo selective hetero-Diels–Alder reaction
to give the product 5a. The reaction does not proceed via
an exo pathway to give the product 11 perhaps due to the
sp2-geminal effect of 1,3-allylic strain.22
II CHN analyzer. MS were recorded on a Q-TOF microTM instru-
ment at the Indian Institute of Chemical Biology, Kolkata. Silica gel
[(60–120), Rankem, India] was used for chromatographic separa-
tion. Silica gel G [CDH, (India)] was used for TLC. Petroleum ether
(PE) refers to the fraction with bp 60–80 °C.
14-Phenyl-12b,14-dihydro-6H,7H-chromeno[4¢,3¢:4,5]pyra-
no[3,2-c][1,8]naphthyridin-13(6aH)-one (5a); Typical Proce-
dure
A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (4,
100 mg. 0.420 mmol), O-allylsalicylaldehyde (2a, 68.2 mg. 0.420
mmol), and EDDA (10 mol%) was refluxed in chlorobenzene (7
mL) for 4 h. After completion of the reaction (TLC monitoring), the
mixture was cooled and diluted with H2O (25 mL). The mixture was
extracted with EtOAc (3 × 25 mL). The combined organic extracts
were washed with brine (2 × 20 mL) and dried (Na2SO4). The re-
sulting crude product obtained after removal of the solvent was pu-
rified by column chromatography (silica gel, 60–120 mesh, PE–
EtOAc, 3:1) to give 5a as a colorless solid; yield: 95%; mp 254–256
°C.
In conclusion, we have disclosed a mild and efficient pro-
tocol for the synthesis of chromeno[4¢,3¢:4,5]pyrano[3,2-
c][1,8]naphthyridin-13-one derivatives by domino
Knoevenagel–hetero-Diels–Alder reaction of 4-hydroxy-
1-phenyl-1,8-naphthyridin-2(1H)-one with alkenes and
alkynes. The reaction is highly regio- and stereoselective
giving cis-annulated product in a single step operation.
These reactions provide a rapid route for the synthesis of
novel types of polyheterocycles containing the naphthyri-
dinone moiety.
IR (KBr): 1443, 1559, 1627, 2922 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.46–2.49 (m, 1 H), 4.37–4.48 (m,
3 H), 4.63 (d, J = 4.4 Hz, 2 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.85 (t,
J = 7.2 Hz, 1 H), 7.08–7.16 (m, 2 H), 7.31 (m, 1 H), 7.41 (d, J = 6.4
Hz, 1 H), 7.49–7.63 (m, 4 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.46 (d,
J = 4.4 Hz, 1 H).
Synthesis 2011, No. 22, 3716–3722 © Thieme Stuttgart · New York

3720
K. C. Majumdar et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 29.4, 29.7, 65.9, 66.0, 110.3,
111.2, 116.8, 118.0, 121.6, 123.2, 127.9, 128.5, 129.1, 129.4, 129.6,
130.7, 131.8, 137.4, 149.9, 150.5, 151.9, 156.0, 164.9.
HRMS: m/z [M + H]+ calcd for C24H18N2O3: 383.1395; found:
383.1407.
1H NMR (400 MHz, CDCl3): d = 1.22 (s, 9 H), 2.45–2.48 (m, 1 H),
4.36–4.43 (m, 3 H), 4.61–4.65 (m, 2 H), 6.74 (d, J = 8.8 Hz, 1 H),
7.14 (dd, J = 3.2, 4.4 Hz, 2 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.54 (d,
J = 7.2 Hz, 1 H), 7.62 (s, 3 H), 8.22 (dd, J = 3.6, 10.0 Hz, 1 H),
8.43–8.45 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 29.4, 29.6, 31.4, 34.2, 65.9, 66.0,
110.7, 111.3, 116.3, 117.9, 122.4, 125.1, 127.1, 128.5, 128.8, 129.3,
129.6, 131.8, 137.7, 144.2, 149.6, 150.0, 150.4, 155.8, 165.0.
11-Bromo-14-phenyl-12b,14-dihydro-6H,7H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13(6aH)-
one (5b)
Colorless solid; yield: 90%; mp 210–212 °C.
IR (KBr): 1449, 1585, 1641, 2910 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.48 (m, 1 H), 4.31 (t, J = 12.0 Hz,
1 H), 4.41 (s, 2 H), 4.60–4.74 (m, 2 H), 6.68 (d, J = 8.4 Hz, 1 H),
7.14–7.21 (m, 2 H), 7.26 (m, 1 H), 7.37–7.42 (m, 1 H), 7.50–7.62
(m, 4 H), 8.22 (d, J = 7.6 Hz, 1 H), 8.47 (d, J = 4.4 Hz, 1 H).
MS: m/z = 438 [M]+.
Anal. Calcd for C28H26N2O3: C, 76.69; H, 5.98; N, 6.39. Found: C,
76.85; H, 5.88; N, 6.50.
11-Chloro-12-methyl-14-phenyl-12b,14-dihydro-6H,7H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13(6aH)-
one (5f)
Colorless solid; yield: 87%; mp 288–290 °C.
IR (KBr): 1445, 1588, 1660, 2900 cm–1.
13C NMR (100 MHz, CDCl3): d = 29.0, 29.6, 65.8, 65.9, 109.6,
111.1, 113.6, 118.1, 118.6, 125.3, 128.5, 129.1, 129.3, 129.6, 131.0,
131.8, 133.2, 137.2, 150.0, 150.7, 151.1, 156.1, 164.7.
1H NMR (400 MHz, CDCl3): d = 2.51 (s, 3 H), 2.63–2.64 (m, 1 H),
4.22 (dd, J = 3.6, 7.2 Hz, 1 H), 4.32 (dd, J = 4.4, 6.8 Hz, 1 H), 4.46–
4.53 (m, 3 H), 6.65 (d, J = 8.4 Hz, 1 H), 7.10–7.19 (m, 4 H), 7.42 (t,
J = 7.2 Hz, 1 H), 7.50 (s, 2 H), 8.23 (dd, J = 1.6, 8.0 Hz, 1 H), 8.39
(dd, J = 1.6, 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 17.4, 30.8, 33.3, 66.7, 68.3, 109.5,
111.0, 115.8, 117.7, 127.3, 127.6, 128.2, 128.3, 129.2, 131.5, 137.2,
137.5, 150.0, 150.3, 153.1, 156.5, 162.6.
Anal. Calcd for C24H17BrN2O3: C, 62.49; H, 3.71; N, 6.07. Found:
C, 62.68; H, 3.60; N, 6.01.
11-Chloro-14-phenyl-12b,14-dihydro-6H,7H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13(6aH)-
one (5c)
Colorless solid; yield: 88%; mp 238–240 °C.
IR (KBr): 1449, 1586, 1638, 2896 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.45–2.48 (m, 1 H), 4.32 (t,
J = 12.0 Hz, 1 H), 4.38–4.45 (m, 2 H), 4.59–4.64 (m, 2 H), 6.74 (d,
J = 8.8 Hz, 1 H), 7.04–7.06 (m, 1 H), 7.16 (dd, J = 3.2, 4.8 Hz, 1 H),
7.30 (m, 1 H), 7.42 (m, 1 H), 7.49–7.65 (m, 4 H), 8.22 (d, J = 7.6
Hz, 1 H), 8.47–8.48 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 29.1, 29.7, 65.8, 65.9, 109.6,
111.1, 118.1, 118.1, 124.7, 126.2, 128.1, 128.5, 129.1, 129.3, 129.7,
130.2, 131.8, 137.2, 149.9, 150.6, 150.7, 156.1, 164.7.
MS: m/z = 431.17 [M + H]+.
Anal. Calcd for C25H19ClN2O3: C, 69.69; H, 4.44; N, 6.50. Found:
C, 69.56; H, 4.52; N, 6.59.
10,12-Dimethyl-14-phenyl-12b,14-dihydro-6H,7H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13(6aH)-
one (5g)
Colorless solid; yield: 84%; mp 248–250 °C.
IR (KBr): 1450, 1586, 1656, 2897 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.20 (s, 3 H), 2.38 (s, 3 H), 2.53–
2.63 (m, 1 H), 4.27–4.36 (m, 2 H), 4.51–4.56 (m, 3 H), 6.51 (s, 1 H),
6.56 (s, 1 H), 7.12 (dd, J = 4.4, 8.0 Hz, 1 H), 7.20–7.22 (m, 2 H),
7.43 (t, J = 7.6 Hz, 1 H), 7.52 (t, J = 8.4 Hz, 2 H), 8.20 (dd, J = 1.6,
7.6 Hz, 1 H), 8.40 (dd, J = 1.6, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.7, 20.9, 29.4, 32.4, 66.1, 65.6,
110.1, 111.2, 115.4, 117.8, 120.9, 125.3, 128.3, 129.1, 129.3, 129.6,
131.5, 137.3, 137.4, 139.3, 149.9, 150.2, 153.8, 156.0, 163.4.
MS: m/z = 417 [M + H]+.
Anal. Calcd for C24H17ClN2O3: C, 69.15; H, 4.11; N, 6.72. Found:
C, 69.36; H, 4.07; N, 6.60.
11-Methyl-14-phenyl-12b,14-dihydro-6H,7H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13(6aH)-
one (5d)
Colorless solid; yield: 92%; mp 280–282 °C.
IR (KBr): 1449, 1585, 1643, 2897 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.19 (s, 3 H), 2.43–2.46 (m, 1 H),
4.39 (dd, J = 9.2, 11.6 Hz, 3 H), 4.61–4.64 (m, 2 H), 6.70 (d, J = 8.4
Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 7.14 (dd, J = 3.2, 4.8 Hz, 1 H),
7.29 (s, 2 H), 7.40 (m, 1 H), 7.46–7.64 (m, 3 H), 8.22 (d, J = 7.6 Hz,
1 H), 8.45–8.46 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.8, 29.4, 29.6, 65.8, 66.0, 110.3,
111.2, 116.5, 118.0, 122.9, 128.4, 128.6, 129.1, 129.4, 130.6, 130.7,
131.7, 137.4, 149.7, 149.9, 150.4, 155.9, 164.9.
MS: m/z = 411.25 [M + H]+.
Anal. Calcd for C26H22N2O3: C, 76.08; H, 5.40; N, 6.82. Found: C,
76.32; H, 5.22; N, 6.78.
14-Phenyl-12b,14-dihydro-7H,13H-chromeno[4¢,3¢:4,5]pyra-
no[3,2-c][1,8]naphthyridin-13-one (6a); Typical Procedure
A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (4,
100 mg. 0.420 mmol), O-propargylsalicylaldehyde (2a, 67.2 mg.
0.420 mmol), EDDA (10 mol%), and CuI (5 mol%) was refluxed in
chlorobenzene (7 mL) for 3 h. After completion of the reaction
(TLC monitoring), the mixture was cooled and diluted with H2O (25
mL). The mixture was extracted with EtOAc (3 × 25 mL). The com-
bined organic extracts were washed with brine (2 × 20 mL) and
dried (Na2SO4). The resulting crude product obtained after removal
of the solvent was purified by column chromatography (silica gel,
60–120 mesh, PE–EtOAc, 3:1) to give 6a as a colorless solid; yield:
92%; mp 282–284 °C.
MS: m/z = 396 [M]+.
Anal. Calcd for C25H20N2O3: C, 75.74; H, 5.08; N, 7.07. Found: C,
75.49; H, 5.01; N, 7.13.
11-tert-Butyl-14-phenyl-12b,14-dihydro-6H,7H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13(6aH)-
one (5e)
Colorless solid; yield: 93%; mp 240–242 °C.
IR (KBr): 1449, 1585, 1653, 2954 cm–1.
IR (KBr): 1445, 1557, 1625, 2923 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.71 (d, J = 11.7 Hz, 1 H), 4.88 (d,
J = 11.7 Hz, 1 H), 4.95 (s, 1 H), 6.81 (t, J = 8.4 Hz, 3 H), 7.08–7.21
Synthesis 2011, No. 22, 3716–3722 © Thieme Stuttgart · New York

PAPER
Chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one Derivatives
3721
(m, 3 H), 7.42 (m, 1 H), 7.49–7.61 (m, 4 H), 8.22 (d, J = 7.5 Hz, 1
H), 8.50 (d, J = 3.9 Hz, 1 H).
MS: m/z = 380 [M]+.
13C NMR (100 MHz, CDCl3): d = 15.0, 31.2, 67.9, 107.2, 110.0,
115.9, 117.2, 118.4, 128.2, 128.6, 128.7, 129.2, 129.7, 131.5, 131.8,
132.4, 133.6, 136.8, 150.0, 150.9, 153.3, 154.3, 164.0.
MS: m/z = 428 [M]+.
Anal. Calcd for C24H16N2O3: C, 75.78; H, 4.24; N, 7.36. Found: C,
75.92; H, 4.12; N, 7.31.
Anal. Calcd for C25H17ClN2O3: C, 70.01; H, 4.00; N, 6.53. Found:
C, 70.13; H, 3.95; N, 6.60.
11-Bromo-14-phenyl-12b,14-dihydro-7H,13H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one (6b)
Colorless solid; yield: 89%; mp 260–262 °C.
IR (KBr): 1449, 1587, 1646, 1704, 2928 cm–1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1H NMR (400 MHz, CDCl3): d = 4.70 (d, J = 12.0 Hz, 1 H), 4.86 (d,
J = 12.0 Hz, 1 H), 4.92 (s, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 6.85 (s, 1
H), 7.19–7.23 (m, 3 H), 7.43 (m, 1 H), 7.51–7.65 (m, 4 H), 8.23 (dd,
J = 2.0, 8.0 Hz, 1 H), 8.52 (dd, J = 1.6, 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 30.4, 67.5, 106.0, 109.8, 111.3,
112.7, 118.4, 118.9, 128.7, 128.9, 129.3, 129.8, 130.9, 131.7, 135.3,
136.8, 150.0, 151.1, 152.8, 153.3, 163.8.
Acknowledgment
We thank CSIR (New Delhi) and DST (New Delhi) for financial as-
sistance. Two of us (S.P. and A.T.) is grateful to CSIR (New Delhi)
for Research Fellowships. We also thank DST (New Delhi) for pro-
viding Brüker NMR spectrometer (400 MHz), Perkin-Elmer CHN
analyzer, UV-VIS and Perkin-Elmer FT IR spectrophotometer un-
der the FIST programme.
Anal. Calcd for C24H15BrN2O3: C, 62.76; H, 3.29; N, 6.10. Found:
C, 62.92; H, 3.22; N, 6.21.
References
11-Chloro-14-phenyl-12b,14-dihydro-7H,13H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one (6c)
Colorless solid; yield: 88%; mp 272–274 °C.
(1) (a) Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ.
Chem. Rev. (Engl. Transl.) 2000, 69, 201. (b) Litvinov, V.
P. Russ. Chem. Rev. (Engl. Transl.) 2004, 73, 637.
(2) (a) Bouzard, D.; Di Cesare, P.; Essiz, M.; Jacquet, J. P.;
Ledoussal, B.; Remuzon, P.; Kessler, R. E.; Fung-Tomc, J.
J. Med. Chem. 1992, 35, 518. (b) Breault, G.; Eyermann, C.
J.; Geng, B.; Morningstar, M.; Reck, F. WO 2006134378,
2006. (c) Matsumoto, J.; Takase, Y.; Nishimura, Y. US
4,359,578, 1982.
(3) Leonard, J. T.; Gangadhar, R.; Gnanasam, S. K.;
Ramachandran, S.; Saravanan, M.; Sridhar, S. K. Biol.
Pharm. Bull. 2002, 25, 798.
(4) (a) Ferrarini, P. L.; Mori, C.; Badawneh, M.; Calderone, V.;
Calzolari, L.; Loffredo, T.; Martinotti, E.; Saccomanni, G.
Eur. J. Med. Chem. 1998, 33, 383. (b) Matsuura, A.;
Ashizawa, N.; Hase, T. WO 9412499, 1994.
IR (KBr): 1453, 1586, 1642, 1699, 2923 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.70 (d, J = 11.6 Hz, 1 H), 4.86 (d,
J = 11.6 Hz, 1 H), 4.91 (s, 1 H), 6.74 (d, J = 8.8 Hz, 1 H), 6.85 (s, 1
H), 7.04–7.07 (m, 2 H), 7.21–7.23 (m, 1 H), 7.26 (s, 1 H), 7.44 (m.
1 H), 7.50–7.56 (m, 3 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.52 (t, J = 2.0
Hz, 1 H).
MS: m/z = 414 [M]+.
Anal. Calcd for C24H15ClN2O3: C, 69.49; H, 3.64; N, 6.75. Found:
C, 69.30; H, 3.72; N, 6.81.
11-Methyl-14-phenyl-12b,14-dihydro-7H,13H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one (6d)
Colorless solid; yield: 90%; mp 268–270 °C.
IR (KBr): 1436, 1596, 1642, 2919 cm–1.
(5) Ban, H.; Muraoka, M.; Morisita, K.; Ohashi, N.
Heterocycles 2005, 65, 2763.
1H NMR (400 MHz, CDCl3): d = 2.19 (s, 3 H), 4.68 (d, J = 11. 6 Hz,
1 H), 4.85 (d, J = 11.6 Hz, 1 H), 4.91 (s, 1 H), 6.71 (d, J = 8.0 Hz, 1
H), 6.81 (s, 1 H), 6.91 (d, J = 9.6 Hz, 2 H), 7.18–7.21 (m, 1 H), 7.42
(m, 1 H), 7.52–7.63 (m, 4 H), 8.22 (d, J = 7.6 Hz, 1 H), 8.51 (d,
J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.9, 30.5, 67.3, 106.7, 110.0,
112.6, 116.8, 118.3, 126.6, 126.9, 128.7, 128.6, 129.2, 129.5, 130.0,
131.6, 134.8, 137.0, 150.0, 150.9, 151.4, 153.1, 164.0.
(6) (a) Booth, R. F. G.; Manley, P. W.; Buckham, S. P.; Hassall,
D. G.; Honey, A. C.; Lad, N.; Lunt, D. O.; Oswald, S.;
Porter, R. A.; Tuffin, D. P. Platelets 1992, 3, 129.
(b) Ferrarini, P. L.; Mori, C.; Miceli, M.; Franconi, F. Eur. J.
Med. Chem. 1994, 29, 735.
(7) Sherlock, M. H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.;
Wong, S. C.; Kreutner, W.; Bryant, R. W.; McPhail, A. T.
J. Med. Chem. 1988, 31, 2108.
(8) (a) Santilli, A. A.; Scotese, A. C.; Bauer, R. F.; Bell, S. C.
J. Med. Chem. 1987, 30, 2270. (b) Chen, K.; Kuo, S. C.;
Hsieh, M. C.; Merger, A.; Lin, C. M.; Hamel, E.; Lee, K. H.
J. Med. Chem. 1997, 40, 3049.
(9) Suzuki, F.; Kuroda, T.; Kawakita, T.; Manabe, H.; Kitamura,
S.; Ohmori, K.; Ichimura, M.; Kase, H.; Ichikawa, S. J. Med.
Chem. 1992, 35, 4866.
(10) (a) Tomita, K.; Tsuzuki, Y.; Shibamori, K.; Tashima, M.;
Kajikawa, F.; Sato, Y.; Kashimoto, S.; Chiba, K.; Hino, K.
J. Med. Chem. 2002, 45, 5564. (b) Tsuzuki, Y.; Tomita, K.;
Shibamori, K.; Sato, Y.; Kashimoto, S.; Chiba, K. J. Med.
Chem. 2004, 47, 2097.
(11) (a) Srivastava, S. K.; Jaggi, M.; Singh, A. T.; Madaan, A.;
Rani, N.; Vishnoi, M.; Agarwal, S. K.; Mukherjee, R.;
Burman, A. C. Bioorg. Med. Chem. Lett. 2007, 17, 6660.
(b) Kumar, V.; Jaggi, M.; Singh, A. T.; Madaan, A.; Sanna,
V.; Singh, P.; Sharma, P. K.; Irchhaiya, R.; Burman, A. C.
Eur. J. Med. Chem. 2009, 44, 3356.
MS: m/z = 417 [M + Na]+.
Anal. Calcd for C25H18N2O3: C, 76.13; H, 4.60; N, 7.10. Found: C,
76.31; H, 4.64; N, 6.98.
11-Chloro-12-methyl-14-phenyl-12b,14-dihydro-7H,13H-
chromeno[4¢,3¢:4,5]pyrano[3,2-c][1,8]naphthyridin-13-one (6e)
Colorless solid; yield: 82%; mp 258–260 °C.
IR (KBr): 1448, 1586, 1644, 1702, 2921 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.23 (s, 3 H), 4.67 (d, J = 12.8 Hz,
1 H), 4.88 (s, 1 H), 4.97 (d, J = 13.2 Hz, 1 H), 6.71 (s, 1 H), 6.76 (d,
J = 8.8 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 1 H), 7.21–7.23 (m, 1 H),
7.24–7.26 (m, 2 H), 7.52 (d, J = 6.4 Hz, 1 H), 7.59 (br s, 2 H), 8.25
(dd, J = 1.6, 8.0 Hz, 1 H), 8.51 (dd, J = 1.6, 4.4 Hz, 1 H).
Synthesis 2011, No. 22, 3716–3722 © Thieme Stuttgart · New York

3722
K. C. Majumdar et al.
PAPER
(12) Sherlock, M. H. US 4596809, 1986.
2008, 49, 4648. (c) Ramesh, E.; Raghunathan, R.
(13) (a) Majumdar, K. C.; Islam, R. Can. J. Chem. 2006, 84,
1632. (b) Majumdar, K. C.; Rahaman, H.; Islam, R.; Roy, B.
Tetrahedron Lett. 2006, 47, 2111. (c) Majumdar, K. C.;
Islam, R. J. Heterocycl. Chem. 2007, 44, 871.
(14) (a) Majumdar, K. C.; Islam, R. Heteroat. Chem. 2007, 18,
87. (b) Majumdar, K. C.; Islam, R.; Alam, S. Synth.
Commun. 2008, 38, 754.
(15) (a) Yadav, J. S.; Reddy, B. V. S.; Sadashiv, K.; Padmavani,
B. Adv. Synth. Catal. 2004, 346, 607. (b) Yamanaka, M.;
Nishida, A.; Nakagana, M. Org. Lett. 2000, 2, 159.
(c) Deligny, M.; Carreaux, F.; Toupet, L.; Carboni, B. Adv.
Synth. Catal. 2003, 345, 1215. (d) Berkessel, A.; Erturk, E.;
Laporte, C. Adv. Synth. Catal. 2006, 348, 223. (e)Baudelle,
R.; Melnyk, P.; Deprez, B.; Tartar, A. Tetrahedron 1998, 54,
4125.
(16) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (c) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
(d) Tietze, L. F.; Ott, C.; Gerke, K.; Buback, M. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1485.
Tetrahedron Lett. 2008, 49, 1812. (d) Lee, Y. R.; Xia, L.
Tetrahedron Lett. 2008, 49, 3283. (e) Jimenez-Alonso, S.;
Chavez, H.; Estevez-Braun, A.; Ravelo, A. G.; Feresin, G.;
Tapia, A. Tetrahedron 2008, 64, 8938. (f) Jimenez-Alonso,
S.; Estevez-Braun, A.; Ravelo, A. G.; Zarate, R.; Lopez, M.
Tetrahedron 2007, 63, 3066. (g) Manikandan, S.;
Raghunathan, R. Tetrahedron 2002, 58, 8957. (h) Yadav, J.
S.; Reddy, B. V. S.; Narsimhaswamy, D.; Lakshmi, P. N.;
Narsimulu, K.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron
Lett. 2004, 45, 3493. (i) Lee, Y. R.; Kim, Y. M.; Kim, S. H.
Tetrahedron 2009, 65, 101.
(18) (a) Majumdar, K. C.; Taher, A.; Ray, K. Tetrahedron Lett.
2009, 50, 3889. (b) Majumdar, K. C.; Taher, A.; Ponra, S.
Tetrahedron Lett. 2010, 51, 147. (c) Majumdar, K. C.;
Taher, A.; Ponra, S. Tetrahedron Lett. 2010, 51, 2297.
(d) Majumdar, K. C.; Taher, A.; Ponra, S. Synthesis 2010,
4043.
(19) (a) Majumdar, K. C.; Alam, S. J. Chem. Res. 2006, 281.
(b) Majumdar, K. C.; Alam, S. Org. Lett. 2006, 8, 4059.
(c) Majumdar, K. C.; Bandyopadhyay, A.; Biswas, A.
Tetrahedron 2003, 59, 5289.
(17) (a) Jayashankaran, J.; Manian, R. D. R. S.; Raghunathan, R.
Tetrahedron Lett. 2006, 47, 2265. (b) Matiychuk, V. S.;
Lesyk, R. B.; Obushak, M. D.; Gzella, A.; Atamanyuk, D.
V.; Ostapiuk, Y. V.; Kryshchyshyn, A. P. Tetrahedron Lett.
(20) Gazith, M.; Noys, R. M. J. Am. Chem. Soc. 1955, 77, 6091.
(21) Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J.
Tetrahedron Lett. 2004, 45, 1567.
(22) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
Synthesis 2011, No. 22, 3716–3722 © Thieme Stuttgart · New York