Regioselective synthesis of pentacyclic polyheterocycles: Sequential [3,3] sigmatropic rearrangement of 4-(4′-aryloxybut-2′-ynyloxy)-1-phenyl- 1,8-naphthyridin-2(1H)-ones

Article abstract of DOI:10.1002/jhet.5570440420

(Chemical Equation Presented) A number of 4-aryloxymethyl-6-phenyl-2H- pyrano[3,2-c][1,8]naphthyridin-5(6H)-ones (4a-f) are regioselectively synthesized in 72-78% yield by the Claisen rearrangement of 4-(4′- aryloxybut-2′-ynyloxy)-1-phenyl-1,8-naphthyridi

Full text of DOI:10.1002/jhet.5570440420

Jul-Aug 2007
871
Regioselective Synthesis of Pentacyclic Polyheterocycles:
Sequential [3,3] Sigmatropic Rearrangement of 4-(4'-Aryloxybut-2'-
ynyloxy)-1-phenyl-1,8-naphthyridin-2(1H)-ones
Krishna C. Majumdar* and Rafique-ul-Islam
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B. India.
E-mail: kcm_ku@yahoo.co.in
Received September 1, 2006
H
R
O
O
O
OAr
OAr
O
CH3
N
N
O
N
N
O
N
N
O
Ph
3
Ph
4
Ph
5
A number of 4-aryloxymethyl-6-phenyl-2H-pyrano[3,2-c][1,8]naphthyridin-5(6H)-ones (4a-f) are
regioselectively synthesized in 72-78% yield by the Claisen rearrangement of 4-(4'-aryloxybut-2'-
ynyloxy)-1-phenyl-1,8-naphthyridin-2(1H)-ones (3a-f) in refluxing chlorobenzene for 4-6 h. These
products are then subjected to a second Claisen rearrangement catalyzed by anhydrous AlCl3 at room
temperature for 2 h to give hitherto unreported pentacyclic heterocycles (5a-f) in 78-85% yield.
J. Heterocyclic Chem., 44, 871 (2007).
(3a-f) were synthesized in 50-55% yield by the reaction of
4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1) with
different 1-aryloxy-4-chlorobut-2-ynes (2a-f) in refluxing
dry acetone in the presence of anhydrous potassium
carbonate. Compound (1) was prepared as described by
Sherlock et al. [4]. Compounds 3(a-f) were characterized
from their elemental analyses and spectroscopic data
(Scheme 1).
INTRODUCTION
1,8-Naphthyridin-2(1H)-ones and their derivatives are
known to possess anti-inflammatory, anti-allergic, potent
antisecretary, antitumor, broncodilator properties [1-3].
4-Hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one and its
derivatives have been used as antiallergic agent [4].
2-Oxo-1,8-naphthyridin-3-carboxylic acid derivatives
possess potent gastric antisecretary properties and anti-
inflammatory activities [5,6]. A series of novel imidazo-
[4,5-c][1,8]naphthyridin-4(5H)-ones exhibited potent
bronchodilator activity [7]. Earlier, we reported the
sequential [3,3] sigmatropic rearrangement of suitably
substituted but-2-ynes to give interesting results [8]. Few
pyrano[3,2-c][1,8]naphthyridin-5-one derivatives possess
antiallergic, antiinflammatory and cytoprotective activity
[9]. In view of the medicinal importance of 1,8-naphthyri-
dinone and its derivatives, this prompted us to undertake a
study to synthesize a number of polyheterocycles derived
from 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one by
the application of Claisen rearrangement of 4-(4'-aryl-
oxybut-2'-ynyl-1-yloxy)-1-phenyl-1,8-naphthyridin-
2(1H)-ones. These substrates are chosen as they may provide
additional scope for further [3,3] sigmatropic rearrangement
to give polyheterocycles. They are also unique for comparing
the relative ease of [3,3] sigmatropic rearrangement of
aryloxy-propynyl moieties with those of naphthyridinyloxy-
propynyl moieties suitably tailored in the same molecule.
Here, we report the result of this investigation.
Scheme 1
OH Cl
+
O
dry acetone,
anhydrous K2CO3
OAr
reflux, 22-24 h
N
N
O
N
N
O
Ph
1
Ph
OAr
3a-f
2a-f
Ar
Yield (%)
54
a
b
c
d
e
f
4-ClC6H4
4-OMeC6H4 55
2-MeC6H4
4-MeC6H4
C6H5
3
51
55
50
50
2-ClC6H4
The substrate 3a was refluxed in chlorobenzene
(132°C) for 4 h to give a solid compound 4a mp-224-
226°C in 78% yield. Compound 4a was characterized
1
from its elemental analysis and spectroscopic data. Its H
NMR spectrum (400 MHz) showed two proton doublets
at ꢀ 5.05 (J = 2Hz, -OCH2), 5.20 (J = 2 Hz, -OCH2)
respectively, one proton multiplet at ꢀ 5.93-5.95 (m, 1H,
=CH) and a multiplet for twelve aromatic proton at ꢀ
6.89-8.47. The other substrates 3(b-f) were also treated
similarly to give products 4(b-f) (Scheme 2).
RESULTS AND DISCUSSION
In our present study, the starting materials 4-(4'-
aryloxybut-2'-ynyloxy)-1-phenyl-1,8-naphthyridin-2-ones

872
K. C. Majumdar and R. Islam
Vol 44
Scheme 2
-OCH2) and ꢀ 6.83-8.44 (m, 11H, ArH). Substrates 4b-f
were similarly treated to give products 5b-f. The
stereochemistry of the ring junction of products 5 can
only be surmised from the molecular model (Dreiding
model), which shows a strain free cis-arrangement
(Scheme 4).
O
OAr
O
N
Chlorobenzene,
reflux, 4-6 h
OAr
N
N
O
Ph
N
O
Ph
4a-f
3a-f
Ar
Yield (%)
4
a
b
c
d
e
f
4-ClC6H4
4-OMeC6H4
2-MeC6H4
4-MeC6H4
C6H5
78
78
72
74
75
75
R 3
Scheme 4
R4
H
R2
O
O
2-ClC6H4
Anhydrous AlCl3
dry DCM, rt., 2h
OAr
R1
O
CH3
O
Although substrates 3(a-f) possess two potential sites
for [3,3] sigmatropic rearrangement aryl-propargyl ether
moiety and a vinyl-propargyl ether moiety, all the
substrate underwent [3,3] sigmatropic rearrangement at
the vinyl-propargyl ether moiety to give compounds 4(a-
f). The formation of 4(a-f) from 3(a-f) may be easily
explained by the initial [3,3] sigmatropic rearrangement
of 3(a-f) to 6 and rapid enolization to form 7 followed by
[1,5] hydrogen shift and electrocyclic ring closure to give
the products 4(a-f) (Scheme 3).
N
N
O
N
N
Ph
4a-f
Ph
R1
R2 R3
R4 Yield (%)
5a-f
5
a
b
c
d
e
f
H
H
CH3
H
H
H
H
H
H
H
H
Cl
OCH3
H
CH3
H
H
H
H
H
H
H
H
82
84
80
78
82
85
Cl
The formation of products 5a-f from 4a-f can be
mechanistically rationalized by series of steps
a
involving an initial charge-accelerated [3,3] sigmatropic
rearrangement. Substrates 4 form an ether-oxygen-
AlCl3 complex that may undergo [3,3] sigmatropic
rearrangement through a charge delocalized transition
state to give intermediate 9 followed by rapid tautomer-
ization and proton exchange to give intermediate phenol
11 which on 5-exo-cyclization afford the products 5
(Scheme 5).
Scheme 3
H
O
O
O
OAr
OAr
OAr
H
[3,3]
N
N
O
N
N
O
N
N
Ph
7
O
Ph
Ph
3a-f
6
1,5 H shift
Scheme 5
O
O
OAr
OAr
ECR
R
H
R
N
N
O
O
N
N
O
O
N
Ph
Ph
O
+
:
O
4a-f
8
AlCl3
-
AlCl3
[3,3]
N
N
O
N
O
Ph
A close examination of the structure of products 4(a-f)
revealed that these still contain an allyl-aryl ether moiety
well suited for a second Claisen rearrangement.
Therefore, substrate 4a was treated with anhydrous AlCl3
in dry dichloromethane solution, as AlCl3 is a versatile
catalyst for the catalytic Claisen rearrangement [10]. After
two hours of stirring at room temperature a new
compound was obtained. This was characterized as 8-
chloro-11a-methyl-13-phenyl-6a,11a,12,13-tetrahydro-6H-
benzo[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naphtha-yridin-
12-one (5a) from its elemental analysis and spectroscopic
data.
Ph
9
4a-f
R
OAlCl2
R
O
O
OH
:
N
N
O
N
N
O
Ph
Ph
11
10
H
O
R
1
O
Its H NMR (400 MHz) spectrum displayed a three
CH3
O
proton singlet at ꢀ 2.01 (-CH3), ꢀ 3.54-3.57 (dd, 1H, J = 4
Hz, 8 Hz, ring juncture H), ꢀ 4.23-4.28 (dd, 1H, J = 8 Hz,
11 Hz, -OCH2), ꢀ 4.49-4.53 (dd, 1H, J = 4 Hz, 11 Hz,
N
N
Ph
5

Jul-Aug 2007
Regioselective Synthesis of Pentacyclic Polyheterocycles
873
(m, 2H, ArH), 6.90-6.92 (m, 2H, ArH), 7.14-7.16 (dd, 1H, J =
4.7 Hz, 7.8 Hz, ArH), 7.26-7.29 (m, 2H, ArH), 7.47-7.50 (t, 1H,
J = 7.4 Hz, ArH), 7.55-7.58 (t, 2H, J = 7.8 Hz, ArH), 8.25-8.26
(dd, 1H, J = 1.7 Hz, 7.8 Hz, ArH), 8.46-8.47 (dd, 1H, J = 1.7 Hz,
4.6 Hz, ArH); ms: m/z 413 (M++H), 435 (M++Na); Anal. Calcd
for C25H20N2O4: C, 72.80; H, 4.89; N, 6.79%; Found C, 72.68;
H, 5.04; N, 6.87%.
In conclusion, we have executed the sequential Claisen
rearrangement, an oxy-Claisen rearrangement of
propynyl-vinyl ether followed by another oxy-Claisen
rearrangement of allyl-aryl ether. This methodology
represents a straightforward approach for the construction
of the furopyran ring system. The synthesis of pentacyclic
heterocycles has been achieved in three steps starting
from 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one.
4-[4-(2-Methylphenoxy)-2-butynyl]oxy-1-phenyl-1,2-dihydro-
[1,8]naphthyridin-2-one 3c. Yield: 2.01 g (51 %), solid, mp
146-148°; ir (KBr): ꢀmax 2922, 2226 (CꢃC), 1667 (C=O), 1585,
1448 cm–1; uv (EtOH): ꢁmax 240 (log ꢄ 4.03), 272 (log ꢄ 3.69), 278
EXPERIMENTAL
1
(log ꢄ 3.67), 321 (log ꢄ 3.96), 333 (log ꢄ 3.85) nm; H nmr (400
MHz, CDCl3): ꢂH 2.27 (s, 3H, -CH3) 4.72 (s, 2H, -OCH2), 4.90 (s,
2H, -OCH2), 6.20 (s, 1H, =CH), 6.83-6.87 (m, 2H, ArH), 6.90-
6.92 (m, 2H, ArH), 7.14-7.16 (dd, 1H, J = 4.7 Hz, 7.8 Hz, ArH),
7.26-7.29 (m, 2H, ArH), 7.47-7.50 (t, 1H, J = 7.4 Hz, ArH), 7.55-
7.58 (t, 2H, J = 7.8 Hz, ArH), 8.25-8.26 (dd, 1H, J = 1.7 Hz, 7.8
Hz, ArH), 8.46-8.47 (dd, 1H, J = 1.7 Hz, 4.6 Hz, ArH); ms: (m/z)
397 (M++H), 419 (M++Na); Anal. Calcd for C25H20N2O3: C, 75.74;
H, 5.08; N, 7.07%; Found C, 75.93; H, 5.18; N, 7.19 %.
4-[4-(4-Methylphenoxy)-2-butynyl]oxy-1-phenyl-1,2-dihydro-
[1,8]naphthyridin-2-one 3d. Yield: 2.17 g (55 %), solid, mp 146-
148°; ir (KBr): ꢀmax 2926, 2226 (CꢃC), 1661 (C=O), 1584, 1510
cm–1; uv (EtOH): ꢁmax 240 (log ꢄ 4.02), 270 (log ꢄ 3.68), 278 (log
ꢄ 3.65), 321 (log ꢄ 4.00), 333 (log ꢄ 3.90) nm; 1H nmr (400 MHz,
CDCl3): ꢂH 2.27 (s, 3H, -CH3), 4.73 (s, 2H, -OCH2), 4.91 (s, 2H, -
OCH2), 6.21 (s, 1H, =CH), 6.84-6.86 (d, 2H, J = 8.2 Hz, ArH),
7.07-7.09 (d, 2H, J = 8 Hz, ArH), 7.12-7.15 (dd, 1H, J = 4.7 Hz,
7.6 Hz, ArH), 7.24-7.27 (m, 2H, ArH), 7.46-7.50 (t, 1H, J = 7.2
Hz, ArH), 7.54-7.58 (t, 2H, J = 7.2 Hz, ArH), 8.23-8.25 (d, 1H, J =
7.6 Hz, ArH), 8.45 (d, 1H, J = 3 Hz, ArH); ms: (m/z) 397 (M++H),
419 (M++Na); Anal. Calcd for C25H20N2O3: C, 75.74; H, 5.08; N,
7.07%; Found C, 75.95; H, 5.11; N, 7.14%.
Melting points were determined in an open capillary and are
uncorrected. IR spectra were recorded on a Perkin-Elmer L 120-
000A spectrometer (ꢀmax in cm-1) on KBr disks. UV absorption
spectra were recorded in EtOH on a Shimadzu UV-2401PC
1
spectrophotometer (ꢁmax in nm). H NMR (400 MHz, 500 MHz)
and 13C NMR (125.7 MHz) spectra were recorded on a Vaian-
400 MHz FT NMR and Bruker DPX-500 spectrometers in
CDCl3 (chemical shifts in ꢂ) with TMS as internal standard.
Elemental analyses and mass spectra were recorded on a Leco
932 CHNS analyzer and on a QTOF Micromass (Waters)
1
instrument respectively. H NMR and 13C NMR spectra were
recorded at the Indian Institute of Chemical Biology, Kolkata
and Bose Institute, Kolkata. Silica gel [(60-120 mesh),
Spectrochem, India] was used for chromatographic separation.
Silica gel G [E-Merck (India)] was used for TLC. Petroleum
ether refers to the fraction boiling between 60° and 80°C.
The 1-aryloxy-4-chlorobut-2-ynes 2(a-f) were prepared
according to the earlier published procedure [11].
General procedure for the preparation of compounds 3a-f.
A mixture of 1-aryloxy-4-chlorobut-2-ynes (2a-f) (10 mmol),
4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1) (2.38 g, 10
mmol), anhydrous K2CO3 (3 g) was refluxed in dry acetone for
22-24 h. The reaction mixture was cooled, filtered and washed
with acetone. The solvent was removed from the combined
filtrate and the residual mass extracted with chloroform (3 X 25
ml). The extract washed with brine (2 X 25 ml) and dried
(Na2SO4). The residual crude mass was then purified by column
chromatography over silica gel. Elution of the column with
petroleum ether: ethyl acetate (2:1) furnished compounds 3(a-f).
4-[4-(4-Chlorophenoxy)-2-butynyl]oxy-1-phenyl-1,2-dihydro-
[1,8]naphthyridin-2-one 3a. Yield: 2.24 g (54 %), white solid,
mp 136-138°; ir (KBr): ꢀmax 2935, 2226 (CꢃC), 1658 (C=O),
1585, 1448 cm–1; uv (EtOH): ꢁmax 240 (log ꢄ 4.01), 270 (log ꢄ
3.68), 278 (log ꢄ 3.65), 320 (log ꢄ 3.94), 333 (log ꢄ 3.89) nm; 1H
nmr (400 MHz, CDCl3): ꢂH 4.74 (t, 2H, J = 2 Hz, -OCH2), 4.91
(t, 2H, J = 2 Hz, -OCH2), 6.22 (s, 1H, =CH), 6.88-6.90 (dd, 2 H,
J = 2 Hz, 7 Hz, ArH), 7.13-7.17 (dd, 1H, J = 4.8 Hz, 8 Hz, ArH),
7.23-7.28 (m, 4H, ArH), 7.49-7.59 (m, 3H, ArH), 8.23-8.25 (dd,
1H, J = 1.6 Hz, 8 Hz, ArH), 8.45-8.47 (dd, 1H, J = 1.6 Hz, 4.8
Hz, ArH); ms: m/z 417 (M++H), 439 (M++Na); Anal. Calcd for
C24H17N2O3Cl: C, 69.15; H, 4.11; N, 6.72%; Found C, 69.24; H,
4.17; N, 6.68%.
4-[(4-Phenoxy-2-butynyl)oxy]-1-phenyl-1,2-dihydro[1,8]-
naphthyridin-2-one 3e. Yield: 1.91 g (50 %), solid, mp 132-
134°; ir (KBr): ꢀmax 2921, 2226 (CꢃC), 1663 (C=O), 1584, 1448
cm–1; uv (EtOH): ꢁmax 241 (log ꢄ 4.04), 264 (log ꢄ 3.73), 271
(log ꢄ 3.74), 278 (log ꢄ 3.72), 321 (log ꢄ 4.01), 333 (log ꢄ 3.90)
1
nm; H nmr (500 MHz, CDCl3): 4.77 (s, 2H, -OCH2), 4.92 (s,
2H, -OCH2), 6.22 (s, 1H, =CH), 6.95-7.00 (m, 3H, ArH), 7.13-
7.15 (dd, 1H, J = 4.7 Hz, 7.8 Hz, ArH), 7.25-7.31 (m, 4H, ArH),
7.46-7.49 (t, 1H, J = 7.4 Hz, ArH), 7.55-7.58 (t, 2H, J = 7.8 Hz,
ArH), 8.23-8.5 (dd, 1H, J = 1.7 Hz, 7.8 Hz, ArH), 8.45-8.46 (dd,
1H, J = 1.7 Hz, 4.6 Hz, ArH); ms: (m/z) 383 (M++H), 405
(M++Na); Anal. Calcd for C24H18N2O3: C, 75.38; H, 4.74; N,
7.33%; Found C, 75.64; H, 4.69; N, 7.48%.
4-[4-(2-Chlorophenoxy)-2-butynyl]oxy-1-phenyl-1,2-dihydro-
[1,8]naphthyridin-2-one 3f. Yield: 2.08 g (50 %), solid,
mp142-144°; ir (KBr): ꢀmax 2919, 2226 (CꢃC), 1663 (C=O),
1583, 1448 cm–1; uv (EtOH): ꢁmax 240 (log ꢄ 3.99), 275 (log ꢄ
3.68), 281 (log ꢄ 3.65), 321 (log ꢄ 3.96), 333 (log ꢄ 3.85) nm; 1H
nmr (400 MHz, CDCl3): ꢂH 4.73 (s, 2H, -OCH2), 4.92 (s, 2H, -
OCH2), 6.22 (s, 1H, =CH), 6.98-7.01 (d, 1H, J = 8.7 Hz, ArH),
7.15-7.17 (dd, 2H, J = 4.7 Hz, 7.7 Hz, ArH), 7.20-7.29 (m, 4H,
ArH), 7.48-7.51 (t, 1H, J = 7.3 Hz, ArH), 7.56-7.59 (t, 2H, J =
7.5 Hz, ArH), 8.23-8.25 (d, 1H, J = 7.7 Hz, ArH), 8.47-8.48 (d,
1H, J = 3.4 Hz, ArH); ms: (m/z) 417 (M++H), 439 (M++Na);
Anal. Calcd for C24H17N2O3Cl: C, 69.15; H, 4.11; N, 6.72%;
Found C, 69.13; H, 4.21; N, 6.89%.
4-[4-(4-Methoxyphenoxy)-2-butynyl]oxy-1-phenyl-1,2-
dihydro[1,8]naphthyridin-2-one 3b. Yield: 2.26 g (55 %),
solid, mp 122-124°; ir (KBr): ꢀmax 2948, 2226 (CꢃC), 1660
(C=O), 1585, 1508 cm–1; uv (EtOH): ꢁmax 240 (log ꢄ 4.00), 270
(log ꢄ 3.73), 279 (log ꢄ 3.68), 321 (log ꢄ 3.96), 331 (log ꢄ 3.87)
nm; 1H nmr (500 MHz, CDCl3): ꢂH 3.76 (s, 3H, -OCH3), 4.72 (s,
2H, -OCH2), 4.92 (s, 2H, -OCH2), 6.22 (s, 1H, =CH), 6.83-6.87
General procedure for the preparation of compounds 4a-f.
Compounds 3(a-f) (1 mmol) were refluxed in chlorobenzene (5
ml) for 4-6 h. The reaction was monitored by TLC. The

874
K. C. Majumdar and R. Islam
Vol 44
chlorobenzene was removed at reduced pressure and the residual
mass was chromatographed over silica gel. Elution of the
column with petroleum ether removed residual chlorobenzene
and the rearranged products (4a-f) were obtained by eluting the
column with petroleum ether: ethyl acetate (4:1).
Calcd for C25H20N2O3: C, 75.74; H, 5.08; N, 7.07%; Found C,
75.82; H, 5.04; N, 7.20%.
3-(Phenoxymethyl)-6-phenyl-5,6-dihydro-4H-pyrano[3,2-c]-
[1,8]naphthyridin-5-one 4e. Yield: 0.28 g (75 %), solid, mp
222-224°; ir (KBr): ꢀmax 2919, 1663 (C=O), 1644, 1583 cm–1; uv
(EtOH): ꢀmax 240 (log ꢁ 3.96), 344 (log ꢁ 3.88), 357 (log ꢁ 3.83)
3-[(4-Chlorophenoxy)methyl]-6-phenyl-5,6-dihydro-4H-
pyrano[3,2-c][1,8]naphthyridin-5-one 4a. Yield: 0.32 g (78
%), solid, mp 224-226°; ir (KBr): ꢀmax 2918, 1662 (C=O), 1641,
1582 cm–1; uv (EtOH): ꢀmax 240 (log ꢁ 4.11), 344 (log ꢁ 3.88),
353 (log ꢁ 3.89) nm; 1H nmr (500 MHz, CDCl3): ꢂH 5.05 (d, 2H,
J = 2 Hz, -OCH2), 5.20 (d, 2H, J = 2 Hz, -OCH2), 5.93-5.95 (m,
1H, =CH), 6.89-6.91 (d, 2H, J = 8.9 Hz, ArH), 7.14-7.16 (dd,
1H, J = 4.6 Hz, 7.9 Hz, ArH), 7.18-7.20 (d, 2H, J = 8.9 Hz,
ArH), 7.25-7.28 (m, 2H, ArH), 7.47-7.50 (t, 1H, J = 7.4 Hz,
ArH), 7.56-7.59 (t, 2H, J = 7.5 Hz, ArH), 8.22-8.24 (dd, 1H, J =
1.6 Hz, 7.8 Hz, ArH), 8.44-8.47 (dd, 1H, J = 1.6 Hz, 4.6 Hz,
ArH); 13C NMR (125 MHz, CDCl3): 67.20, 67.96, 108.43,
111.15, 113.99, 116.58, 118.60, 118.90, 126.03, 128.98, 129.37,
129.52, 129.66, 129.99, 130.01, 130.95, 132.29, 137.41, 150.70,
151.50, 157.50, 158.16, 162.17; ms: (m/z) 417 (M++H), 439
(M++Na); Anal. Calcd for C24H17N2O3Cl: C, 69.15; H, 4.11; N,
6.72%; Found C, 69.30; H, 4.24; N, 6.81%.
1
nm; H nmr (500 MHz, CDCl3): ꢂH 5.06 (d, 2H, J = 2 Hz,
-OCH2), 5.23 (d, 2H, J = 2 Hz, -OCH2), 5.98-6.00 (m, 1H,
=CH), 6.91-6.93 (t, 1H, J = 7.3 Hz, ArH), 6.98-6.99 (d, 2H, J =
7.9 Hz, ArH), 7.13-7.16 (dd, 1H, J = 4.6 Hz, 7.8 Hz, ArH), 7.23-
7.28 (m, 4H, ArH), 7.47-7.50 (t, 1H, J = 7.4 Hz, ArH), 7.56-7.59
(t, 2H, J = 7.5 Hz, ArH), 8.23-8.25 (dd, 1H, J = 1.7 Hz, 7.8 Hz,
ArH), 8.44-8.45 (dd, 1H, J = 1.7 Hz, 4.6 Hz, ArH); ms: (m/z)
383 (M+ + H), 405 (M+ + Na); Anal. Calcd for C24H18N2O3: C,
75.38; H, 4.74; N, 7.33%; Found C, 75.56; H, 4.96; N, 7.37%.
3-[(2-Chlorophenoxy)methyl]-6-phenyl-5,6-dihydro-4H-
pyrano[3,2-c][1,8]naphthyridin-5-one 4f. Yield: 0.31 g (75
%), solid, mp 218-220°; ir (KBr): ꢀmax 2921, 1663 (C=O), 1644,
1583 cm–1; uv (EtOH): ꢀmax 240 (log ꢁ 4.06), 347 (log ꢁ 3.83),
357 (log ꢁ 3.87) nm; 1H nmr (500 MHz, CDCl3): ꢂH 5.07 (d, 2H,
J = 2 Hz, -OCH2), 5.19 (d, 2H, J = 2 Hz, -OCH2), 6.00-6.02 (m,
1H, =CH), 6.96-6.98 (m, 1H, ArH), 7.11-7.17 (m, 2H, ArH),
7.25-7.28 (m, 4H, ArH), 7.48-7.51 (t, 1H, J = 7.5 Hz, ArH),
7.56-7.59 (t, 2H, J = 7.4 Hz, ArH), 8.24-8.25 (dd, 1H, J = 1.6
Hz, 7.8 Hz, ArH), 8.44-8.46 (dd, 1H, J = 1.7 Hz, 4.6 Hz, ArH);
ms: (m/z) 417 (M++H), 439 (M++Na); Anal. Calcd for
C24H17N2O3Cl: C, 69.15; H, 4.11; N, 6.72%; Found C, 69.28; H,
4.16; N, 6.80%.
General procedure for the preparation of 5a-f. Compounds
(4a-f) (0.5 mmol) were dissolved in dry dichloromethane (10
ml) and anhydrous AlCl3 (0.06 g, 0.5 mmol) was added to it.
The reaction mixture was stirred at room temperature for 0.5-2.0
h. Crushed ice was added to the reaction mixture after which the
mixture was extracted with dichloromethane. The combined
extracts were washed with water (20 ml), brine (20 ml) and
dried (Na2SO4). The solvent was removed and the residual
viscous mass was chromatographed over silica gel using
petroleum ether: ethyl acetate (3:1) as eluant to afford the
products 5(a-f).
3-[(4-Methoxyphenoxy)methyl]-6-phenyl-5,6-dihydro-4H-
pyrano[3,2-c][1,8]naphthyridin-5-one 4b. Yield: 0.32 g (78
%), solid, mp 222-224°; ir (KBr): ꢀmax 2922, 1662 (C=O), 1638,
1583 cm–1; uv (EtOH): ꢀmax 240 (log ꢁ 4.10), 341 (log ꢁ 3.87),
1
357 (log ꢁ 3.92) nm; H nmr (400MHz, CDCl3): ꢂH 3.74 (s, 3H,
-OCH3), 5.05 (d, 2H, J = 2 Hz, -OCH2), 5.16 (d, 2H, J = 2 Hz,
-OCH2), 5.98-6.00 (m, 1H, =CH), 6.77-6.79 (m, 2H, ArH), 6.89-
6.92 (m, 2H, ArH), 7.13-7.16 (dd, 2H, J = 4.6 Hz, 7.8 Hz, ArH),
7.25-7.27 (m, 1H, ArH), 7.46-7.50 (t, 1H, J = 7.4 Hz, ArH),
7.55-7.59 (t, 2H, J = 7.3 Hz, ArH), 8.22-8.24 (dd, 1H, J = 1.5
Hz, 7.8 Hz, ArH), 8.43-8.44 (dd, 1H, J = 1.6 Hz, 4.5 Hz, ArH);
ms: (m/z) 413 (M++H), 435 (M++Na); Anal. Calcd for
C25H20N2O4: C, 72.80; H, 4.89; N, 6.79%; Found C, 72.98; H,
4.97; N, 6.91%.
3-[(2-Methylphenoxy)methyl]-6-phenyl-5,6-dihydro-4H-
pyrano[3,2-c][1,8]naphthyridin-5-one 4c. Yield: 0.28 g (72
%), solid, mp 224-226°; ir (KBr): ꢀmax 2918, 1662 (C=O), 1641,
1582 cm–1; uv (EtOH): ꢀmax 240 (log ꢁ 4.08), 343 (log ꢁ 3.87),
357 (log ꢁ 3.91) nm; 1H nmr (500 MHz, CDCl3): ꢂH 2.29 (s, 3H,
-CH3), 5.08 (d, 2H, J = 2 Hz, -OCH2), 5.22 (d, 2H, J = 2 Hz,
-OCH2), 6.03-6.05 (m, 1H, =CH), 6.82-6.85 (t, 1H, J = 7.2 Hz,
ArH), 6.92-6.94 (t, 1H, J = 8 Hz, ArH), 7.04-7.16 (m, 3H, ArH),
7.27-7.29 (m, 2H, ArH), 7.48-7.51 (t, 1H, J = 7.4 Hz, ArH),
7.56-7.59 (t, 2H, J = 7.4 Hz, ArH), 8.24-8.25 (dd, 1H, J = 1.7
Hz, 7.8 Hz, ArH), 8.44-8.45 (dd, 1H, J = 1.7 Hz, 4.6 Hz, ArH);
ms: (m/z) 397 (M++H), 419 (M++Na); Anal. Calcd for
C25H20N2O3: C, 75.74; H, 5.08; N, 7.07%; Found C, 75.99; H,
5.21; N, 7.12 %.
8-Chloro-11a-methyl-13-phenyl-6a,11a,12,13-tetrahydro-
6H-benzo[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naphthyridin-
12-one 5a. Yield: 0.17
g (82 %), solid, mp 145-147°
(decomposed); ir (KBr): ꢀmax 2923, 1657 (C=O), 1623, 1589,
1475 cm–1; uv (EtOH): ꢀmax 240 (log ꢁ 3.99), 282 (log ꢁ 3.67),
325 (log ꢁ 3.85), 337 (log ꢁ 3.81) nm; 1H nmr (400 MHz, CDCl3):
ꢂH 2.01 (s, 3H, -CH3) 3.54-3.57 (dd, 1H, J = 4 Hz, 8 Hz, ring
juncture H), 4.23-4.28 (dd, 1H, J = 8 Hz, 11 Hz, -OCH2), 4.49-
4.53 (dd, 1H, J = 4 Hz, 11 Hz, -OCH2), 6.83-6.85 (d, 1H, J = 8.4
Hz, ArH), 7.11-7.14 (m, 2H, ArH), 7.23-7.28 (m, 3H, ArH),
7.43-7.47 (t, 1H, J = 7.2 Hz, ArH), 7.49- 7.53 (m, 2H, ArH),
8.21-8.23 (dd, 1H, J = 1.3 Hz, 7.8 Hz, ArH), 8.44 (d, 1H, J = 3
Hz, ArH); 13C NMR (125 MHz, CDCl3): 24.24, 49.13, 66.56,
84.21, 110.31, 111.03, 112.68, 118.36, 124.83, 125.72, 127.56,
128.75, 129.70, 129.77, 132.86, 137.20, 150.71, 151.69, 157.97,
158.50, 162.55; ms: (m/z) 417 (M++H), 439 (M++Na); Anal.
Calcd for C24H17N2O3Cl: C, 69.15; H, 4.11; N, 6.72%; Found C,
69.11; H, 4.19; N, 6.77%.
3-[(4-Methylphenoxy)methyl]-6-phenyl-5,6-dihydro-4H-
pyrano[3,2-c][1,8]naphthyridin-5-one 4d. Yield: 0.29 g (74
%), solid, mp 216-218°; ir (KBr): ꢀmax 2923, 1665 (C=O), 1644,
1583 cm–1; uv (EtOH): ꢀmax 242 (log ꢁ 4.06), 344 (log ꢁ 3.92),
354 (log ꢁ 3.90) nm; 1H nmr (400 MHz, CDCl3): ꢂH 2.26 (s, 3H,
-CH3) 5.04 (d, 2H, J = 2 Hz, -OCH2), 5.19 (d, 2H, J = 2 Hz,
-OCH2), 5.97-5.99 (m, 1H, =CH), 6.86-6.88 (d, 2H, J = 8.4 Hz,
ArH), 7.03-7.05 (d, 2H, J = 8.4 Hz, ArH), 7.13-7.16 (dd, 1H, J =
4.8 Hz, 8.4 Hz, ArH), 7.25-7.29 (m, 2H, ArH), 7.36-7.50 (t, 1H,
J = 7.6 Hz, ArH), 7.55-7.59 (t, 2H, J = 7.6 Hz, ArH), 8.22-8.24
(dd, 1H, J = 1.6 Hz, 7.6 Hz, ArH), 8.43-8.44 (dd, 1H, J = 1.6
Hz, 4.4 Hz, ArH). ms: (m/z) 397 (M++H), 419 (M++Na); Anal.
8-Methoxy-11a-methyl-13-phenyl-6a,11a,12,13-tetra-
hydro-6H-benzo[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naph-
thyridin-12-one 5b. Yield: 0.17 g (84%), solid, mp 148-150°
(decomposed); ir (KBr): ꢀmax 2921, 1655 (C=O), 1587, 1486
cm-1; uv (EtOH): ꢀmax 240 (log ꢁ 4.00), 282 (log ꢁ 3.61), 325

Jul-Aug 2007
Regioselective Synthesis of Pentacyclic Polyheterocycles
875
1
(log ꢀ 3.90), 337 (log ꢀ 3.77) nm; H nmr (500 MHz, CDCl3):
ꢁH 1.99 (s, 3H, -CH3) 3.51-3.54 (dd, 1H, J = 4 Hz, 8 Hz, ring
juncture H) 3.77 (s, 3H, -OCH3) 4.24-4.28 (dd, 1H, J = 8 Hz,
11 Hz, -OCH2), 4.50-4.54 (dd, 1H, J = 4 Hz, 11 Hz, -OCH2),
6.71-6.72 (d, 1H, J = 8.3 Hz, ArH), 6.83-6.85 (m, 2H, ArH),
7.10-7.13 (dd, 1H, J = 4.7 Hz, 7.5 Hz, ArH), 7.25-7.36 (m, 2H,
ArH), 7.44-7.47 (t, 1H, J = 7.1 Hz, ArH), 7.53-7.55 (m, 2H,
ArH), 8.21-8.23 (d, 1H, J = 7.6 Hz, ArH), 8.43-8.44 (d, 1H, J
= 3.2 Hz, ArH); ms: (m/z) 413 (M++H), 435 (M++Na); Anal.
Calcd for C25H20N2O4: C, 72.80; H, 4.89; N, 6.79%; Found C,
72.87; H, 5.10; N, 6.70 %.
10-Chloro-11a-methyl-13-phenyl-6a,11a,12,13-tetrahydro-
6H-benzo[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naphthyr-
idin-12-one 5f. Yield: 0.17 g (85%), solid, mp 250-252°; ir
(KBr): ꢀmax 2923, 1659 (C=O), 1622, 1588, 1455 cm–1; uv
(EtOH): ꢂmax 240 (log ꢀ 3.97), 282 (log ꢀ 3.67), 325 (log ꢀ 3.90),
337 (log ꢀ 3.82) nm; 1H nmr (500 MHz, CDCl3): ꢁH 2.04 (s, 3H,
-CH3), 3.59-3.62 (dd, 1H, J = 4 Hz, 8 Hz, ring juncture H), 4.23-
4.27 (dd, 1H, J = 8Hz, 11 Hz, -OCH2), 4.51-4.54 (dd, 1H, J = 4
Hz, 11 Hz, -OCH2), 6.82-6.85 (t, 1H, J = 7.7 Hz, ArH), 7.10-
7.12 (dd, 1H, J = 4.6 Hz, 7.8 Hz, ArH), 7.14-7.20 (m, 2H, ArH),
7.28-7.30 (d, 2H, J = 7.3 Hz, ArH), 7.44-7.47 (t, 1H, J = 7.4 Hz,
ArH), 7.53-7.58 (t, 2H, J = 7.5 Hz, ArH), 8.20-8.22 (dd, 1H, J =
1.7 Hz,7.8 Hz, ArH), 8.43-8.45 (dd, 1H, J = 1.7 Hz, 4.6 Hz,
ArH); ms: (m/z) 417 (M++H), 439 (M++Na); Anal. Calcd for
C24H17N2O3Cl: C, 69.15; H, 4.11; N, 6.72%; Found C,
69.31; H, 4.09; N, 6.83%.
10,11a-Dimethyl-13-phenyl-6a,11a,12,13-tetrahydro-6H-
benzo[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naphthyridin-12-
one 5c. Yield: 0.15 g (80%), solid, mp 238-240°; ir (KBr): ꢀmax
2925, 1655 (C=O), 1622, 1588, 1475 cm–1; uv (EtOH): ꢂmax 240
(log ꢀ 4.00), 280 (log ꢀ 3.67), 325 (log ꢀ 3.88), 337 (log ꢀ 3.76)
1
nm; H nmr (500 MHz, CDCl3): ꢁH 1.99 (s, 3H, -CH3) 2.21 (s,
Acknowledgement. We thank the CSIR (New Delhi) for
financial assistance. Mr. R.I. is thankful to CSIR (New Delhi)
for a Senior Research Fellowship. We also thank the DST (New
Delhi) for providing UV-VIS spectrophotometer and FT-IR
spectrometer under DST-FIST program.
3H, -CH3) 3.51-3.54(dd, 1H, J= 4 Hz, 8 Hz, ring juncture H)
4.20-4.24 (dd, 1H, J = 8 Hz, 11 Hz, -OCH2) 4.50-4.54 (dd, 1H, J
= 4 Hz, 11 Hz, -OCH2), 6.79-6.82 (t, 1H, J = 7.4 Hz, ArH), 6.99-
7.01 (d, 1H, J = 7.4 Hz, ArH), 7.09-7.11 (m, 2H, ArH), 7.25-
7.29 (m, 2H, ArH), 7.44-7.47 (t, 1H, J = 7.4 Hz, ArH), 7.54-7.57
(t, 2H, J = 7.6 Hz, ArH), 8.21-8.22 (dd, 1H, J = 1.2 Hz, 7.7 Hz,
ArH), 8.42-8.43 (d, 1H, J = 3.1 Hz, ArH); ms: (m/z) 397
(M++H), 419 (M++Na); Anal. Calcd for C25H20N2O3: C, 75.74;
H, 5.08; N, 7.07%; Found C, 75.80; H, 4.98; N, 7.10%.
REFERENCES
ꢃ
Corresponding author. Tel.: +91-33-2582-7521, fax: +91-33-
25828282; e-mail: kcm_ku@yahoo.co.in
8,11a-Dimethyl-13-phenyl-6a,11a,12,13-tetrahydro-6H-
benzo[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naphthyridin-
12-one 5d. Yield: 0.15 g (78%), solid, mp 200-202°; ir (KBr):
ꢀmax 2924, 1656 (C=O), 1620, 1586, 1488 cm–1; uv (EtOH):
ꢂmax 240 (log ꢀ 4.03), 286 (log ꢀ 3.64), 296 (log ꢀ 3.62), 325
[1] Chen, K.; Kuo, S. C.; Hsieh, M. C.; Merger, A.; Lin, C. M.;
Hamel, E.; Lee,K. H. J. Med. Chem. 1997, 40, 3049-3055.
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1
(log ꢀ 3.89), 337 (log ꢀ 3.80) nm; H nmr (500 MHz, CDCl3):
ꢁH 1.99 (s, 3H, -CH3), 2.30 (s, 3H, -CH3), 3.50-3.52 (dd, 1H, J
= 4 Hz, 8 Hz, ring juncture H) 4.21-4.25 (dd, 1H, J = 8Hz, 11
Hz), 4.50-4.53 (dd, 1H, J = 4 Hz, 11 Hz), 6.81-6.83 (d, 1H, J =
8.1 Hz, ArH), 6.96-6.97 (d, 1H, J = 3.2 Hz, ArH), 7.07 (s, 1H,
ArH), 7.10-7.12 (dd, 1H, J = 4.8 Hz, 7.8 Hz, ArH), 7.25-7.29
(m, 2H, ArH), 7.44-7.47 (t, 1H, J = 7.4 Hz, ArH), 7.48-7.54
(m, 2H, ArH), 8.21-8.23 (d, 1H, J = 7.8 Hz, ArH), 8.43-8.44
(d, 1H, J = 4 Hz, ArH); ms: (m/z) 397 (M++H), 419 (M++Na);
Anal. Calcd for C25H20N2O3: C, 75.74; H, 5.08; N, 7.07%;
Found C, 76.01; H, 5.22; N, 7.15%.
11a-Methyl-13-phenyl-6a,11a,12,13-tetrahydro-6H-benzo-
[4',5']furo[2',3':4,5]pyrano[3,2-c][1,8]naphthyridin-12-one
5e. Yield: 0.15 g (82%), solid, mp 242-244°; ir (KBr): ꢀmax 2927,
1654 (C=O), 1621, 1587, 1477 cm–1; uv (EtOH): ꢂmax 240 (log ꢀ
3.79), 281 (log ꢀ 3.43), 325 (log ꢀ 3.65), 337 (log ꢀ 3.56) nm; 1H
nmr (400 MHz, CDCl3): ꢁH 1.99 (s, 3H, -CH3) 3.54-3.57 (dd,
1H, J = 4 Hz, 8Hz, ring juncture H), 4.21-4.26 (dd, 1H, J = 8
Hz, 11 Hz, -OCH2), 4.51-4.55 (dd, 1H, J = 4 Hz, 11 Hz, -OCH2),
6.89-6.94 (m, 2H, ArH), 7.09-7.12 (m, 1H, ArH), 7.15-7.19 (t,
1H, J = 7.6 Hz, ArH), 7.24-7.29 (m, 3H, ArH), 7.45-7.53 (m,
3H, ArH), 8.20-8.23 (dd, 1H, J = 1.4 Hz, 7.8 Hz, ArH), 8.42-
8.44 (dd, 1H, J = 1.4 Hz, 4.4 Hz, ArH); ms: (m/z) 383 (M++H),
405 (M++Na); Anal. Calcd for C24H18N2O3: C, 75.38; H, 4.74; N,
7.33%; Found C, 75.44; H, 4.85; N, 7.40%.
[7] Suzuki, F.; Kuroda, T.; Kawakita, T.; Manabe, H.; Kitamura,
S.; Ohmori, K.; Ichimura, M.; Kase, H.; Ichikawa, S. J. Med. Chem.
1992, 35, 4866.
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