Strategy to Construct Stair-Shaped Partially Reduced Naphtho[1,2-b]pyrano[2,3-d]oxepines and Dinaphtho[1,2-b,d]oxepines

Article abstract of DOI:10.1002/jhet.2342

A concise and efficient base-induced synthesis of stair-shaped, 4-methylthio-2-oxo-5,6-dihydro-2H-naphtho[1,2-b]pyran[2,3-d]oxepine-3-carbonitriles (3) has been delineated by the reaction of 3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-one (1) and methyl 2-cyano-3,3-dimethylthioacrylate in DMSO using powdered KOH as a base at room temperature. Amination of 3 has been achieved by reaction with secondary amine in ethanol at reflux temperature to yield 4-sec-amino-2-oxo-5,6-dihydro-2H-naphtho[1,2-b]pyran[2,3-d]oxepine-3-carbonitriles (4). Reaction of 3 with aryl methyl ketone (5) in DMSO at room temperature using powdered KOH as a base produced stair-shaped 5-aryl-7,8-dihydro-1,4-dioxa-2,3-dioxodinaphtho[1,2-b,d]oxepine (6) in good yields. However, reaction of 6-aryl-2H-pyran-2-one-3-carbonitrile (8) with 3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-one (1) did not give similar product, but in lieu 4-aryl-5,6-dihydronaphtho[1,2-b]oxepino[4,5-b]pyran-2-ylidene)acetonitrile (9) was isolated and characterized.

Full text of DOI:10.1002/jhet.2342

2070
Strategy to Construct Stair-Shaped Partially Reduced Naphtho[1,2-b]
pyrano[2,3-d]oxepines and Dinaphtho[1,2-b,d]oxepines
Vol 53
Sanjay K. Gautam,a Hardesh K. Maurya,b Ramendra Pratap,c Brijesh Kumar,d Abhinav Kumar,a
a
a
*
*
Vishnu K. Tandon, and Vishnu Ji Ram
aDepartment of Chemistry, Lucknow University, Lucknow 226007, India
bMedicinal Chemistry Department, CSIR-Central Institute of Aromatic Plants, Kukrail Road, Lucknow 226015, India
cDepartment of Chemistry, Delhi University, North Campus, New Delhi 1100074, India
dDivision of SAIF, Central Drug Research Institute, Lucknow 226001, India
*
E-mail: vishnutandon@yahoo.co.in; vjiram@yahoo.com
Received May 26, 2014
DOI 10.1002/jhet.2342
Published online 16 September 2016 in Wiley Online Library (wileyonlinelibrary.com).
A concise and efficient base-induced synthesis of stair-shaped, 4-methylthio-2-oxo-5,6-dihydro-2H-
naphtho[1,2-b]pyran[2,3-d]oxepine-3-carbonitriles (3) has been delineated by the reaction of 3,4-dihydronaphtho
[1,2-b]oxepin-5(2H)-one (1) and methyl 2-cyano-3,3-dimethylthioacrylate in DMSO using powdered KOH as a
base at room temperature. Amination of 3 has been achieved by reaction with secondary amine in ethanol at reflux
temperature to yield 4-sec-amino-2-oxo-5,6-dihydro-2H-naphtho[1,2-b]pyran[2,3-d]oxepine-3-carbonitriles (4).
Reaction of 3 with aryl methyl ketone (5) in DMSO at room temperature using powdered KOH as a base produced
stair-shaped 5-aryl-7,8-dihydro-1,4-dioxa-2,3-dioxodinaphtho[1,2-b,d]oxepine (6) in good yields. However,
reaction of 6-aryl-2H-pyran-2-one-3-carbonitrile (8) with 3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-one (1) did
not give similar product, but in lieu 4-aryl-5,6-dihydronaphtho[1,2-b]oxepino[4,5-b]pyran-2-ylidene)acetonitrile
(9) was isolated and characterized.
J. Heterocyclic Chem., 53, 2070 (2016).
INTRODUCTION
naphtho[b]oxepine (IV) (Fig. 1) [6] fused 2-pyranone system
are meagerly developed. However, extensive literature survey
revealed that the chemistry of 2-oxo-5,6-dihydro-2H-naphtho
[1,2-b]pyrano[2,3-d]oxepine-5-carbonitrile (IV) is not devel-
oped so far. Dibenzoxepine [7] fused with heterocyclic
system is known to display diverse pharmacological activities,
and some of them are highly effective in the treatment of
anxiety, depression and schizophrenia [8,9]. The therapeutic
importance of this ring system aroused considerable interest
to develop the chemistry of 2-pyranone fused naphtho[1,2-b]
oxepine and other heterocyclic ring system through base-
catalyzed ring transformation and framework rearrangement.
2H-pyran-2-one ring system is widely present in various
natural products derived from marine organism, animals
and plant kingdom in the form of either isolated or substruc-
ture. Natural products (I, IIa–c) of naphthoxepine skeleton
display diverse pharmacological activities. Luffalactone (I)
[1] isolated from Liffariella variabilis and various other
chiral naphthoxepine derivatives (IIa–c) isolated from
Sinningia aggregate display anti-inflammatory, phospholi-
pase A2 inhibitory [2] and antimicrobial [3] activities (Fig. 1).
Despite diverse pharmacological activities, they are also
useful as synthon for the construction of newer entities to
generate molecular diversity through ring transformation
and stated framework rearrangement.
RESULTS AND DISCUSSION
Although the chemistry of 2-pyranone is well devel-
oped and plenty of literature is available [4], the synthesis
and ring transformation studies of partially reduced
suitably functionalized benzo[b]oxepine (III) [5,6] and
Herein, we report an elegant regioselective approach to
the synthesis of stair-shaped tetracyclic and pentacyclic
heteroarenes. Our primary strategy to synthesize stair-shaped
© 2016 Wiley Periodicals, Inc.

November 2016 A Concise and an Efficient Base Induced Synthesis of Stair Shaped 5,6-Dihydronaphtho[1,2-b]oxepino 2071
[4,5-b]pyran, Dioxodinaphtho[1,2-b,d]oxepine and Naphtho[1,2-b]pyran[2,3-d]oxepine has been Reported
Table 1
Structure, Mp and yields of naphtho[1,2-b]pyrano[2,3-d]oxepines
(4) (Scheme 1).
Comp.
Structure
Mp (°C)
Yield (%)
4a
254–256
52
Figure 1. Naturally occurring naphthoxepine (I, II) analogs and synthetic
analogs (III, IV).
4b
306–308
63
oxa-aza- and oxa-aza-thia-heterocycles is based on the
selection of right precursor. For this purpose, we
selected 3,4-dihydro-2H-naphtho[1,2-b]oxepin-5-one (1)
[10] as a substrate which on reaction with methyl 2-
cyano-3,3-dimethylthioacrylate (2) [11] in DMSO in the
presence of powdered KOH at room temperature pro-
vided 4-methylthio-2-oxo-5,6-diydro-2H-naphtho[1,2-b]
pyrano[2,3-d]oxepine-3-carbonitrile (3) and was aminated
with sec-amine in boiling ethanol to yield 4-sec-amino-2-
oxo-5,6-diydro-2H-naphtho[1,2-b]pyrano[2,3-d]oxepine-
3-carbonitrile (4) (Scheme 1). Numerous compounds prepared
are listed in Table 1.
The intermediate 3 was used as a precursor for the
carbanion-induced ring transformation and framework
rearrangement. Thus, a base-induced ring transformation
of 3 by in situ generated carbanion from aryl methyl ketone
(5) at room temperature in DMSO led to provide regioselective
stair-shaped 5-aryl-7,8-dihydro-1,4-dioxa-2,3-dioxodinaphtho
[1,2-b,d]oxepine (6) following path A. Mechanistically, there
is also a possibility for the formation of (2-aryl-5,6-
dihydronaphtho[1,2-b]oxepino[4,5-c]pyran-2-ylidene)acetoni-
trile (7). However, this reaction regioselectively gave product 6
only. The regioselectivity of product 6 over 7 is possibly
because of steric hindrance at bridged carbon adjacent to ring
oxygen of lactone (3) and also the presence of a better leaving
group (SMe), and charge density calculation at C-4 position of
4c
310–312
130–132
53
61
4d
4e
138–140
228–230
262–264
53
65
70
4f
Scheme 1. Synthesis of naphtho[1,2-b]pyrano[2,3-d]oxepines (3,4) (Table 1).
4g
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S. K. Gautam, H. K. Maurya, R. Pratap, B. Kumar, A. Kumar, V. K. Tandon, and V. J. Ram
Vol 53
3 favors nucleophilic attack and directs the reaction to follow
path A to give product 6 (Scheme 2). The reaction is initiated
through substitution at C-4 followed by cyclization and hydro-
lysis of imine intermediate to yield 6. All the compounds thus
prepared are listed in Table 2.
and recyclization with liberation of methylmercaptan to yield
9 (Scheme 3).
All the compounds prepared are listed in Table 3. It is
noteworthy that the precursor 6-aryl-2H-pyran-2-one-3-
carbonitrile (8) were synthesized from the reaction of methyl
2-cyano-3,3-dimethylthioacrylate (2) with aryl methyl
ketone (5) in the presence of base (KOH or NaOH) at room
temperature in DMSO [4,11].
In order to ascertain the nature of the reactive orbitals
involved in reaction, density functional theory (DFT) cal-
culations were performed of the representative compounds
5 and 8. Optimized molecular geometries were calculated
using the B3LYP [13] exchange-correlation functional. The
spin-restricted DFT method was employed to model the
closed shell-oxidized species. The 6-31G** basis set was
used for all the atoms. The optimized structures of the com-
pounds were used for molecular orbital analyses. Atomic
charges were calculated using natural population analyses
(NPA) [14] as implemented in Gaussian 03 program [15].
The natural charges over various atoms of interest are
displayed in Figure 2. The natural charges on methyl carbon
in 5 and unsaturated carbon center attached to phenyl ring in
It was conspicuous that when similar reaction was
carried out using 6-aryl-4-methylthio-2H-pyran-2-one-3-
acetonitriles (8), an isolated lactone with 3,4-dihydro-2H-
naphtho[1,2-b]oxepin-5-one (1) as a source of carbanion in
DMSO using powdered KOH as a base at room temperature
did not follow the path B (Scheme 3) to give 6. However, the
reaction product isolated and characterized was 4-aryl-5,6-
dihydronaphtho[1,2-b]oxepino[4,5-b]pyran-2-ylidene) ace-
tonitrile (9). The chemical shift for CH–CN proton in
1H NMR of 9 and ortep diagram from X-ray diffraction of
a analogous compound reported [5c,12] earlier revealed
that the compound 9 exists as a Z isomer. The formation
of this product is only possible if reaction follows path A
(Scheme 3). The reaction is possibly initiated by Michael
addition of 3,4-dihydro-2H-naphtho[1,2-b]oxepin-5-one
(1) [10] to the 6-aryl-2H-pyran-2-one-3-carbonitrile (8)4,11
by attacking at C-6 followed by elimination of carbon dioxide
Scheme 2. Synthesis and proposed mechanism of 5-aryl-7,8-dihydro-1,4-dioxa-2,3-dioxodinaphtho[1,2-b,d]oxepine (6) (Table 2).
Journal of Heterocyclic Chemistry
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November 2016 A Concise and an Efficient Base Induced Synthesis of Stair Shaped 5,6-Dihydronaphtho[1,2-b]oxepino 2073
[4,5-b]pyran, Dioxodinaphtho[1,2-b,d]oxepine and Naphtho[1,2-b]pyran[2,3-d]oxepine has been Reported
Table 2
Table 2
(Continued)
Structure, Mp and yields of 5-aryl-7,8-dihydro-1,4-dioxa-2,3-
dioxodinaphtho[1,2-b,d]oxepine (6) (Scheme 2).
Comp.
Structure
Mp (°C)
Yield (%)
Comp.
Structure
Mp (°C)
Yield (%)
6g
154–156
42
6a
300–302
42
6h
108–110
51
6b
309–311
59
8 that are À0.77989 and +0.41418esu respectively indicates
that the nature of both the carbon centers is different and
therefore their reactivity towards electrophiles and nucleo-
philes also differs.
6c
305–307
58
CONCLUSION
A concise and efficient base-induced synthesis of stair-
shaped, 4-methylthio-2-oxo-5,6-dihydro-2H-naphtho[1,2-b]
pyran[2,3-d]oxepine-3-carbonitriles (3) has been delineated
by the reaction of 3,4-dihydronaphtho[1,2-b]oxepin-5(2H)-
one (1) and methyl 2-cyano-3,3-dimethylthioacrylate in
DMSO using powdered KOH as a base at room temperature.
Amination of 3 has been achieved by reaction with secondary
amine in ethanol at reflux temperature to yield 4-sec-amino-2-
oxo-5,6-dihydro-2H-naphtho[1,2-b]pyran[2,3-d]oxepine-
3-carbonitriles (4). Reaction of 3 with aryl methyl ketone
in DMSO at room temperature using powdered KOH as
a base produced stair-shaped 5-aryl-7,8-dihydro-1,4-
dioxa-2,3-dioxodinaphtho[1,2-b,d]oxepine (6) in good
yields. However, reaction of 6-aryl-2H-pyran-2-one-3-
carbonitrile (8) with 3,4-dihydronaphtho[1,2-b]oxepin-5
(2H)-one (1) did not give analogous product, but in lieu
4-aryl-5,6-dihydronaphtho[1,2-b]oxepino[4,5-b]pyran-2-
ylidene)acetonitrile (9) was isolated and characterized.
6d
6e
162–164
214–216
47
48
6f
144–146
64
EXPERIMENTAL
Materials and equipments. The reagents and the solvents
used in this study were of analytical grade and were used
without further purification. The melting points were determined
on an electrically heated Townson Mercer melting point
apparatus and are uncorrected. Commercial reagents were used
without purification. 1H and 13C NMR spectra were measured
on a Bruker WM-300 (300 MHz)/Jeol-400, using CDCl3 and
(Continued)
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Vol 53
Table 3
(Continued)
Scheme 3. Synthesis and proposed mechanism of (z) 4-aryl-5,6-dihydro-
naphtho[1,2-b]oxepino[4,5-b]pyran-2-ylidene)acetonitrile (9) (Table 3).
Comp.
Structure
Mp (°C)
Yield (%)
9c
278–280
85
9d
9e
9f
290–292
248–250
216–218
75
62
68
9 g
268–270
56
Table 3
Structure, Mp and yields of 4-aryl-5,6-dihydro-naphtho[1,2-b]oxepino
[4,5-b]pyran-2-ylidene)acetonitrile (9) (Scheme 3).
Comp.
Structure
Mp (°C)
Yield (%)
67
9a
280–282
9 h
242–244
58
9b
266–268
87
9i
252–254
52
(Continued)
Journal of Heterocyclic Chemistry
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November 2016 A Concise and an Efficient Base Induced Synthesis of Stair Shaped 5,6-Dihydronaphtho[1,2-b]oxepino 2075
[4,5-b]pyran, Dioxodinaphtho[1,2-b,d]oxepine and Naphtho[1,2-b]pyran[2,3-d]oxepine has been Reported
Figure 2. Electrostatic potentials surfaces for the compounds 5 and 8 calculated at the B3LYP level of theory (red/green/blue denotes areas of
high/medium/low charge densities) and computed natural charges on atom centers of interest. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com]
DMSO-d6 as the solvents. Chemical shift are reported in parts per
million shift (δ value) from Me4Si (δ 0 ppm for 1H NMR) or
based on the middle peak of the solvent (CDCl3), δ 77.00 ppm
for 13C NMR) as the internal standard. Signal patterns are
indicated as s, singlet; bs, broad singlet; d, doublet; dd, double
doublet; t, triplet; m, multiplet; bh, broad hump. Coupling
constant (J) are given in hertz. Infrared (IR) spectra were
recorded on a Perkin-Elmer AX-1 spectrophotometer in KBr
disc and reported in wave number (cmÀ1). Electrospray
ionization mass spectrometry spectrometers were used for mass
spectra analysis. 13C NMR spectra of compounds could not be
reported because of their very poor solubility in deuterated
solvents (DMSO-d6 and CDCl3) used.
[1,2-b]-pyrano-[2,3-d]-oxepine-5-carbonitrile (3, 1 mmol) and
secondary amines (1.2 mmol) in methanol (40 mL) was refluxed
for 5 h. The resulting solid was filtered and washed with EtOH.
The product was purified by silica gel (60–120 mesh) column
chromatography using CHCl3–MeOH as eluent (if required).
6-Oxo-4-(piperidin-1-yl)-3,6-dihydro-2H-naphtho[1,2-b]-pyrano
[2,3-d]oxepine-5-carbonitrile (4a). Pale yellow solid; yield: 52%;
Mp 254–256°C; IR (KBr): 2250 (CN); 1691 (C = O); 1467, 1216,
1
1099, 909 cmÀ1; H NMR (400 MHz, DMSO-d6): δ 2.53 (m, 6H,
3×CH2), 2.74 (m, 4H, 2×CH2), 3.63 (t, 2H, CH2), 4.84 (t, 2H,
OCH2), 7.32 (s, 1H, Ar-H), 7.66 (m, 2H, Ar-H), 7.72 (s, 1H, Ar-H),
7.95 (d, 1H, Ar-H), 8.24 (d, 1H, Ar-H); HRMS (ESI) calcd for
C23H20N2O3: 372.1474 (M+), Found: 372.1463; Anal. Calcd. for
C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 74.29; H, 5.39;
Synthesis and characterization
N, 7.48.
General procedure for the synthesis of 6-oxo-4-methylthio-3,6-
dihydro-2H-naphtho[1,2-b]pyrano[2,3-d]oxepine-5-carbonitriles
(3). A mixture of 3,4-dihydro-2H-naphtho[1,2-b]oxepin-5-one (1,
212 mg, 1 mmol), methyl 2-cyano-3,3-dimethylthioacrylate (2,
203 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in 20 mL
DMSO stirred at room temperature for 2.5 h. Thereafter, the
reaction mixture was poured onto crushed ice with vigorous
stirring for 1 h. The pale yellow colored solid was filtered, dried
and crystallized with CHCl3-hexane as 4-methylthio-2-oxo-5,6-
diydro-2H-naphtho[1,2-b]pyrano[2,3-d]oxepine-3-carbonitrile (3)
as needles, yield 302 mg (90%); Mp 148–150°C; IR (KBr): 2213
(CN); 1701 (C = O); 1578; 1285; 1205; 1118; 1063; 969; 892;
808; 753; 562 cmÀ1; 1H NMR (300 MHz, CDCl3+ DMSO-d6): δ
1.57 (s, 3H, CH3), 3.03 (t, 2H, CH2), 4.76 (t, 2H, OCH2), 7.59
(m, 3H, Ar-H), 7.83 (d, 1H, Ar-H), 7.92 (d, 1H, Ar-H), 8.31 (d,
1H, Ar-H); HRMS (ESI) calcd for C19H13NO3S: 336.0616
(MH+), found: 336.0610; Anal. Calcd. for C19H13NO3S: C,
6-Oxo-4-(pyrrolidin-1-yl)-3,6-dihydro-2H-naphtho[1,2-b]-pyrano
[2,3-d]oxepine-5-carbonitrile (4b).
Light cream-colored solid;
yield 63%; Mp 306–308°C; IR (KBr): 2239 (CN); 1702 (C = O),
1
1452, 1221, 1113, 1026, 765 cmÀ1; H NMR (400 MHz, DMSO-
d6): δ 2.49 (m, 4H, 2×CH2), 2.74 (m, 4H, 2×CH2), 3.63 (t, 2H,
CH2), 4.84 (t, 2H, OCH2), 7.64 (m, 4H, Ar-H), 7.94 (d, 1H, Ar-H),
8.23 (d, 1H, Ar-H); HRMS (ESI) calcd for C22H18N2O3: 358.1317
(M+), Found: 358.1309; Anal. Calcd. for C22H18N2O3: C, 73.73; H,
5.06; N, 7.82. Found: C, 73.54; H, 5.01; N, 7.78.
4-Morpholino-6-oxo-3,6-dihydro-2H-naphtho[1,2-b]pyrano-
[2,3-d]oxepine-5-carbonitrile (4c).
Pale yellow crystalline
solid; yield 53%; Mp 310–312°C; IR (KBr): 2221 (CN), 1709
(C= O), 1460, 1021, 763cmÀ1; 1HNMR (400 MHz, DMSO-d6): δ
2.65 (m, 4H, 2xNCH2), 3.47 (t, 2H, CH2), 3.53 (m, 4H,
2xOCH2); 4.76 (t, 2H, OCH2), 7.25 (s, 1H, Ar-H), 7.64 (m, 3H,
Ar-H), 7.86 (d, 1H, Ar-H), 8.19 (d, 1H, Ar-H); HRMS (ESI)
calcd for C22H18N2O4: 375.1267 (MH+), Found: 375.1256; Anal.
Calcd. for C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C,
68.04; H, 3.91; N, 4.18. Found: C, 67.91; H, 3.89; N, 4.06.
General procedure for the synthesis of 6-oxo-4-(sec-amino)-3,6-
dihydro-2H-naphtho[1,2-b]pyrano[2,3-d]oxepine-5-carbonitriles
(4). A mixture of 4-(methylthio)-6-oxo-3,6-dihydro-2H-naphtho
70.40; H, 4.81; N, 7.43.
4-(4-Methylpipridin-1-yl)-6-oxo-3,6-dihydro-2H-naphtho[1,2-b]
pyrano[2,3-d]oxepine-5-carbonitrile (4d). Brown-colored powder;
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Vol 53
yield 61%; Mp 130–132°C; IR (KBr): 2235 (CN), 1698 (C = O),
1451, 1113, 1026, 765cmÀ1 1H NMR (400MHz, DMSO-d6):
OCH2), 6.54 (s, 1H, CH), 7.58 (m, 6H, Ar-H), 7.81 (d, 1H, Ar-H),
;
7.89 (d, 1H, Ar-H), 7.92 (d, 2H, Ar-H), 8.34 (d, 1H, Ar-H);
HRMS (ESI) calcd for C26H15ClO5: 442.0608 (M+); Found:
442.0599; Anal. Calcd. for C26H15ClO5: C, 75.52; H, 3.41.
Found: C, 75.31; H, 3.29.
δ 1.20 (s, 3H, CH3), 2.55 (m, 4H, CH2), 2.74 (t, 2H, CH2),
3.63 (m, 4H, 2xCH2), 4.84 (t, 2H, OCH2), 7.65 (m, 4H,
Ar-H), 7.95 (d, 1H, Ar-H), 8.24 (d, 1H, Ar-H); HRMS (ESI)
calcd for C24H22N2O3: 386.1630 (M+), Found: 386.1621; Anal.
Calcd. for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25. Found: C,
74.42; H, 5.69; N, 7.20.
4-(4-Benzylpiperazin-1-yl)-6-oxo-3,6-dihydro-2H-naphtho[1,2-b]
pyrano[2,3-d]oxepine-5-carbonitrile (4e). Light buff-colored solid;
yield 53%; Mp 138–140°C; IR (KBr): 2216 (CN), 1697 (C = O),
1113, 1021, 763, 686, 643 cmÀ1; 1H NMR (400 MHz, DMSO-d6): δ
2.41 (bs, 4H, 2×NCH2), 2.49 (bs, 4H, 2×CH2), 3.47 (t, 2H, CH2),
3.53 (t, 2H, CH2), 4.76 (t, 2H, OCH2), 7.25 (m, 6H, Ar-H), 7.64
(m, 3H, Ar-H), 7.86 (d, 1H, Ar-H), 8.18 (d, 1H, Ar-H); HRMS
(ESI) calcd for C29H25N3O3: 464.1974 (MH+), Found: 464.1964;
Anal. Calcd. for C29H25N3O3: C, 75.14; H, 5.44; N, 9.07. Found:
C, 75.28; H, 5.41; N, 7.16.
4-(4-Methylpiprazin-1-yl)-6-oxo-3,4-dihydro-2H-naphtho[1,2-b]
pyrano[2,3-d]oxepine-5-carbonitrile (4f). Yellow-colored powder;
yield 65%; Mp 228–230°C; IR (KBr): 2228 (CN), 1709 (C = O),
1450, 1200, 1121, 1026, 765 cmÀ1; 1H NMR (400 MHz, DMSO-d6):
δ 2.23 (s, 4H, 2×CH2), 2.49 (s, 3H, NCH3), 2.73 (t, 4H, 2×CH2),
3.59 (t, 2H, CH2), 4.84 (t, 2H, OCH2), 7.64 (m, 4H, Ar-H), 7.95
(d, 1H, Ar-H), 8.25 (d, 1H, Ar-H), HRMS (ESI) calcd for
C23H21N3O3: 388.1661 (MH+), Found: 388.1653; Anal. Calcd.
for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85. Found: C, 71.11;
5-Pyridyl-7,8-dihydro-1,4,9-trioxa-2,3-dioxanaphtho[b]oxepine
[4,5-b]naphthalene (6c).
305–307°C; IR (KBr): 1765 (C = O), 1708, 1630, 1575, 1490, 1402,
1257, 1104, 1003, 879, 813, 769, 718, 673 cmÀ1 1H NMR
Light brown powder; yield 58%; Mp
;
(300 MHz, CDCl3): δ 3.16 (t, 2H, CH2); 4.78 (t, 2H, OCH2); 6.87
(s, 1H, CH); 7.58 (m, 6H, Ar-H); 7.82 (d, 1H, Ar-H); 7.97 (d, 1H,
Ar-H); 8.18 (d, 1H, Ar-H); 8.34 (d, 1H, Ar-H); HRMS (ESI) calcd
for C25H15NO5 410.0950 (MH+); Found: 410.0940; Anal. Calcd.
for C25H15NO5: C, 73.35; H, 3.69; N, 3.42. Found: C, 73.19; H,
3.62; N, 3.39.
5-(4-Methoxyphenyl)-7,8-dihydro-1,4,9-trioxa-2,3-dioxa naphtho
[b]oxepine[4,5-b]naphthalene (6d). Brown-colored solid; yield
47%; Mp 162–164°C; IR (KBr): 1775 (C = O), 1718, 1680, 1572,
1
1496, 1404, 1257, 1104, 1003, 879, 814, 769, 718, 673 cmÀ1; H
NMR: (300 MHz, CDCl3): δ 3.00 (t, 2H, CH2), 3.86 (s, 3H, CH),
4.46 (t, 2H, OCH2), 6.86 (s, 1H, CH), 7.56 (m, 6H, Ar-H), 7.81
(d, 2H, Ar-H), 8.38 (d, 2H, Ar-H); HRMS (ESI) calcd for
C27H18O6: 438.1103 (M+), Found: 438.1097; Anal. Calcd. for
C27H18O6: C, 73.97; H, 4.14. Found: C, 73.79; H, 4.02.
5-(1-Naphthyl)-7,8-dihydro-1,4,9-trioxa-2,3-dioxanaphtho[b]oxe-
pine[4,5-b]naphthalene (6e).
Light reddish brown solid; yield
48%; Mp 214–216°C; IR (KBr): 1765 (C = O), 1699, 1625, 1575,
1490, 1334, 1111, 1001, 767, 683, 484 cmÀ1; 1H NMR (300 MHz,
CDCl3): δ 3.16 (t, 2H, CH2), 4.78 (t, 2H, OCH2), 7.11 (s, 1H, CH),
7.70 (m, 7H, Ar-H), 7.90 (d, 2H, Ar-H), 8.30 (m, 3H, Ar-H), 8.28
(d, 1H, Ar-H), HRMS (ESI) calcd for C30H18O5: 458.1154 (M+),
Found: 458.1142; Anal. Calcd. for C30H18O5: C, 78.59; H, 3.96.
H, 5.41; N, 10.79.
6-Oxo-4(4-methylpiprazin-1-yl)-3,6-dihydro-2H-naphtho[1,2-b]
pyrano[2,3-d]oxepine-5-carbonitrile (4g).
Buff-colored powder;
yield 70%; Mp 262–264°C; IR (KBr): 2242 (CN), 1707 (C = O),
1
1113, 1021, 763 cmÀ1; H NMR (400 MHz, DMSO-d6): δ 2.88
Found: C, 78.40; H, 3.75.
(m, 8H, 4×CH2), 3.75 (t, 2H, CH2), 4.86 (t, 2H, OCH2), 7.00
(d, 2H, Ar-H), 7.27 (d, 2H, Ar-H), 7.66 (m, 3H, Ar-H), 7.74
(d, 1H, Ar-H), 7.96 (d, 1H, Ar-H), 8.27 (d, 1H, Ar-H);
HRMS (ESI) calcd for C28H22ClN3O3: 484.1428 (MH+),
Found: 484.1417; Anal. Calcd. for C28H22ClN3O3: C, 69.49;
5-(4-Methylphenyl)-7,8-dihydro-1,4,9-trioxa-2,3-dioxa naphtho
[b]oxepine[4,5-b]naphthalene (6f). Brown solid; yield 64%; Mp
144–146°C; IR (KBr): 1775 (C = O), 1704, 1580, 1490, 1437,
1341, 1251, 1094, 1012, 956, 911, 823, 774, 670, 625, 507 cmÀ1
;
1H NMR: (300 MHz, CDCl3 +DMSO-d6): δ 2.19 (s, 3H, CH3),
3.14 (t, 2H, CH2), 4.78 (t, 2H, OCH2), 6.54 (s, 1H, CH), 7.58 (m,
6H, Ar-H), 7.85 (dd, 2H, Ar-H), 7.92 (d, 1H, Ar-H), 8.35 (d, 1H,
Ar-H); HRMS (ESI) calcd for C27H18O5: 422.1154 (M+), Found:
422.1147; Anal. Calcd. for C27H18O5: C, 76.77; H, 4.29. Found: C,
H, 4.58; N, 8.68. Found: C, 69.38; H, 4.54; N, 8.67.
General procedure for the synthesis of 5-aryl-7,8-dihydro-
1,4,9-trioxa-2,3-dioxonaphtho[b]oxepin[4,5-b]naphthalene (6).
A mixiture of 4-methylthio-2-oxo-5,6-dihydro-2H-naphtho[1,2-
b]pyran[2,3-d]oxepine-3-carbonitriles (3, 1 mmol), aryl methyl
ketone (5, 1 mmol) and powdered KOH (1.2 mmol) in DMSO
(10 mL) was stirred at room temperature for 3 h. The reaction
mixture was poured onto crushed ice and neutralized with 5%
aqueous HCl with stirring at room temperature. The resulting
solution was filtered, washed with water and dried. The product
was purified by silica gel (60–120 mesh) column chromatography
using EtOAc-hexane as eluent.
5-Phenyl-7,8-dihydro-1,4,9-trioxa-2,3-dioxonaphtho[b]oxepin
[4,5-b]naphthalene (6a). Yellow powder; yield 42%; Mp 300–302°C;
IR (KBr): 1775 (C = O), 1718, 1575, 1496, 1404, 1257, 1104, 1003, 814,
796, 718, 673 cmÀ1; 1H NMR (300 MHz, CDCl3): δ 3.16 (t, 2H, CH2),
4.78 (t, 2H, OCH2), 6.87 (s, 1H, CH), 7.58 (m, 6H, Ar-H), 7.84 (d, 1H,
Ar-H), 7.98 (d, 2H, Ar-H), 8.18 (d, 1H, Ar-H), 8.34 (d, 1H, Ar-H);
HRMS (ESI) calcd for C26H16O5: 408.0998 (M+), Found: 408.0988;
Anal. Calcd.forC26H16O5:C,76.46;H,3.95.Found:C,76.30;H,3.91.
5-(4-Chlorophenyl)-7,8-dihydro-1,4,9-trioxa-2,3-dioxanaphtho
76.64; H, 4.14.
5-Theinyl-7,8-dihydro-1,4,9-trioxa-2,3-dioxanaphtho[b]oxe-
pine[4,5-b]naphthalene (6g).
52%; Mp 154–156°C; IR (KBr) 1718 (C = O) 1611, 1447, 1363,
1186, 1071, 929, 761, 667 cmÀ1 1H NMR (300 MHz, CDCl3
Black-colored powder; yield
;
+ DMSO-d6): δ 3.03 (t, 2H, CH2), 4.76 (t, 2H, OCH2), 6.57
(s, 1H, CH), 7.57 (m, 6H, Ar-H), 7.91 (d, 1H, Ar-H), 8.13
(d, 1H, Ar-H), 8.31 (d, 1H, Ar-H); HRMS (ESI) calcd for
C24H14O5S: 415.0640 (MH+), Found: 415.0631; Anal. Calcd.
for C24H14O5S: C, 69.56; H, 3.40. Found: C, 69.69; H, 3.44.
5-Furyl-7,8-dihydro-1,4,9-trioxa-2,3-dioxanaphtho[b]oxepine
[4,5-b]naphthalene (6h). Dark brown-colored solid; yield 51%;
Mp 108–110°C; IR (KBr): 1733 (C = O) 1616, 1459, 1327, 1197,
1092, 943, 769, 662 cmÀ1; 1H NMR ( 300 MHz, CDCl3 +DMSO-
d6): δ 3.14 (t, 2H, CH2), 4.78 (t, 2H, OCH2), 6.54 (s, 1H, CH),
7.55 (m, 6H, Ar-H), 7.91 (d, 1H, Ar-H), 8.15 (d, 1H, Ar-H), 8.35
(d, 1H, Ar-H); HRMS (ESI) calcd for C24H14O6: 398.0790 (M+),
Found: 398.0779; Anal. Calcd. for C24H14O6: C, 72.36; H, 3.54.
[b]oxepine[4,5-b]naphthalene (6b).
59%; Mp 309–311°C; IR (KBr): 1775 (C = O), 1718, 1572, 1496,
1404, 1257, 1104, 1003, 814, 769, 718, 673 cmÀ1 1H NMR
(300 MHz, CDCl3 +DMSO-d6): δ 3.14 (t, 2H, CH2), 4.78 (t, 2H,
Pale yellow powder; yield
Found: C, 72.49; H, 3.58.
;
General procedure for the synthesis of 2-(4-aryl)-2H-
naphtho[1,2-b]pyrano[2,3-d]oxepine-6(3H)ylidene)acetonitriles(9).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2016 A Concise and an Efficient Base Induced Synthesis of Stair Shaped 5,6-Dihydronaphtho[1,2-b]oxepino 2077
[4,5-b]pyran, Dioxodinaphtho[1,2-b,d]oxepine and Naphtho[1,2-b]pyran[2,3-d]oxepine has been Reported
A mixiture of 6-aryl-2H-pyran-2-one-3-carbonitrile (8, 1 mmol),
3,4-dihydro-2H-naphtho[1,2-b]oxepin-5-one (1, 1 mmol) and
powdered KOH (1.2 mmol) in DMSO (20 mL) was stirred at
room temperature for 3 h, and the reaction mixture was poured
onto crushed ice and neutralized with 5% aqueous HCl (if
required) with stirring at room temperature. The resulting
solution was filtered, washed with water and dried. The solid
product obtained was crystallized with suitable solvent to
yield 9.
Found: 393.1344; Anal. Calcd. for C26H19NO3: C, 79.37; H, 4.87;
N, 3.56. Found: C, 79.25; H, 4.84; N, 3.54.
(Z)2-(4-(Pyridin-4-yl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-6
(3H)-ylidene)acetonitrile (9g). Buff-colored powder; yield 56%;
Mp 268–270°C; IR (KBr): 2201 (CN), 1657, 1411, 1112, 1023,
766, 708, 648 cmÀ1; 1H NMR (300 MHz, DMSO-d6): δ 2.87 (t, 2H,
CH2), 4.76 (t, 2H, OCH2), 5.11 (s, 1H, CH), 6.75 (s, 1H, CH), 7.68
(m, 6H, Ar-H), 7.91 (d, 1H, Ar-H), 8.12 (m, 2H, Ar-H), 8.40 (d, 1H,
Ar-H); HRMS (ESI) calcd for C24H16N2O2: 364.1212 (M+), Found
364.1202; Anal. Calcd. for C24H16N2O2: C, 79.11; H, 4.43; N, 7.69.
(Z)2-(4-Phenyl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-6(3H)-
ylidene)acetonitrile (9a). Scarlet-colored powder; yield 67%; Mp
280–282°C; IR (KBr): 2198 (CN), 1655, 1556, 1415, 1251, 1112,
Found: C, 79.23; H, 4.47; N, 7.71
(Z)2-(4-(Furan-2-yl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-
1
6(3H)-ylidene)acetonitrile (9h). Brown-colored powder; yield
54%; Mp 242–244°C; IR (KBr): 2204 (CN), 1660, 1475, 1421,
1015, 764, 676 cmÀ1; H NMR (300 MHz, DMSO-d6 +CDCl3): δ
2.64 (t, 2H, CH2), 4.42 (s, 1H, CH), 4.66 (dt, 2H, OCH2), 6.37 (s,
1H, Ar-H), 7.48 (m, 9H, Ar-H), 8.12 (d, 1H, Ar-H), 8.21 (d, 1H,
Ar-H); HRMS (ESI) calcd for C25H17NO2: 363.1259 (M+), Found:
363.1251; Anal. Calcd. for C25H17NO2: C, 82.63; H, 4.72; N, 3.85.
Found: C, 82.51; H, 4.69; N, 3.81.
(Z)2-(4-(4-Chlorophenyl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-
6(3H)-ylidene)acetonitrile (9b). Scarlet-colored powder; yield
87%; Mp 266–268°C; IR (KBr): 2194 (CN), 1655, 1543, 1340,
1250, 1102, 1015, 764, 676 cmÀ1; 1H NMR (300 MHz, DMSO-d6):
δ 3.31 (dt, 2H, CH2), 5.11 (s, 1H, CH), 5.51 (dt, 2H, OCH2), 6.48
(s, 1H, CH), 7.64 (m, 8H, Ar-H), 7.92 (d, 1H, Ar-H), 8.08 (d, 1H,
Ar-H); HRMS (ESI) calcd for C25H16ClNO2: 398.0948 (MH+)
Found: 398.0929 (MH+); Anal. Calcd. for C25H16ClNO2: C,
1
1253, 1026, 814, 747 cmÀ1; H NMR (300MHz, DMSO-d6): δ
3.18 (t, 2H, CH2), 4.55 (s, 1H, CH), 4.78 (t, 2H, OCH2), 6.88 (s,
1H, CH), 7.56 (m, 5H, Ar-H), 7.82 (d, 1H, Ar-H), 7.97 (d, 1H,
Ar-H); 8.16 (d, 1H, Ar-H); 8.34 (d, 1H, Ar-H); HRMS (ESI) calcd
for C23H15NO3: 353.1052 (M+), Found 353.1044; Anal. Calcd. for
C23H15NO3: C, 78.17; H, 4.28; N, 3.96. Found: C, 78.05; H, 4.26;
N, 3.92.
(Z)2-(4-(Thiophen-2-yl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-
6(3H)-ylidene)acetonitrile (9i). Brown-colored powder; yield 52%;
Mp 252–254°C; IR (KBr): 2190 (CN), 1633, 1450, 1114, 1021, 769,
1
680 cmÀ1; H NMR (300 MHz, DMSO-d6): δ 3.16 (t, 2H, CH2),
4.79 (t, 2H, OCH2), 5.45 (s, 1H, CH), 6.88 (s, 1H, CH), 7.56 (m, 5H,
Ar-H), 7.82 (d, 1H, Ar-H), 7.97 (d, 1H, Ar-H), 8.16 (d, 1H, Ar-H),
8.34 (d, 1H, Ar-H); HRMS (ESI) calcd for C23H15NO2S: 369.0823
(M+), Found: 369.0814; Anal. Calcd. for C23H15NO2S: C, 74.78; H,
4.09; N, 3.79. Found: C, 74.70; H, 4.06; N, 3.76.
75.47; H, 4.05; N, 3.52. Found: C, 75.36; H, 4.01; N, 3.49.
(Z)2-(4-(4-Bromophenyl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-
6(3H)-ylidene)acetonitrile (9c). Scarlet-colored powder; yield
85%; Mp 278–280°C; IR (KBr): 2195 (CN), 1653, 1536, 1343,
1
1102, 1012, 764, 676 cmÀ1; H NMR (300 MHz, DMSO-d6): δ
3.30 (dt, 2H, CH2), 5.11 (s, 1H, CH), 5.52 (dt, 2H, OCH2), 6.48
(s, 1H, CH), 7.59 (m, 8H, Ar-H), 7.95 (d, 1H, Ar-H), 8.08 (d, 1H,
Ar-H); HRMS (ESI) calcd for C25H16BrNO2: 441.0364 (M+),
Found: 441.0352; Anal. Calcd. for C25H16BrNO2: C, 67.89; H,
Acknowledgments. HKM is thankful to DST, New Delhi, India,
for DST Fast Track Young Scientist Fellowship. VJR is thankful
to UGC, New Delhi, India, for Emeritus fellowship.
3.65; N, 3.17. Found: C, 67.77; H, 3.52; N, 3.06.
(Z)2-(4-Naphthyl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-
6(3H)-ylidene)acetonitrile (9d).
Brick red-colored powder;
REFERENCES AND NOTES
yield 75%; Mp 290–292°C; IR (KBr): 2190 (CN), 1655, 1343,
1102, 1018, 844, 764, 676 cmÀ1; 1H NMR (300 MHz, DMSO-d6):
δ 2.87 (t, 2H, CH2), 4.76 (t, 2H, OCH2), 5.11 (s, 1H, CH), 6.75 (s,
1H, CH), 7.71 (m, 7H, Ar-H), 7.91 (d, 2H, Ar-H), 8.13 (m, 3H,
Ar-H), 8.28 (d, 1H, Ar-H); HRMS (ESI) calcd for C29H19NO2:
413.1416 (M+), Found: 413.1410; Anal. Calcd. for C29H19NO2:
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(Z)2-(4-Methylphenyl)-2H-naphtho[1,2-b]pyrano[2,3-d]oxepin-
6(3H)-ylidene)acetonitrile (9e). Brick red-colored powder; yield
62%; Mp 248–250°C; IR (KBr): 2210 (CN), 1636, 1461, 1284,
1087, 886, 769, 703 cmÀ1; 1H NMR (300 MHz, DMSO-d6): δ 1.23 (s,
3H, CH3), 2.87 (t, 2H, CH2), 4.76 (t, 2H, OCH2), 5.11 (s, 1H, CH),
6.75 (s, 1H, CH), 7.66 (m, 6H, Ar-H), 7.95 (d, 1H, Ar-H), 8.14 (m,
2H, Ar-H), 8.24 (d, 1H, Ar-H); HRMS (ESI) calcd for C26H19NO2:
377.1416 (M+), Found: 377.1408; Anal. Calcd. for C26H19NO2:
C, 82.74; H, 5.07; N, 3.71. Found: C, 82.80; H, 5.10; N, 3.74.
(Z)2-(4-(4-Methoxyphenyl)-2H-naphtho[1,2-b]pyrano[2,3-d]
oxepin-6(3H)-ylidene)acetonitrile (9f).
powder; yield 68%; Mp 216–218°C; IR (KBr): 2190 (CN), 1805,
1655, 1546, 1343, 1102, 1018, 764, 676 cmÀ1 1H NMR
Dark brown-colored
;
(300 MHz, DMSO-d6): δ 2.77 (t, 2H, CH2), 4.33 (s, 3H, OCH3),
4.77 (t, 2H, OCH2), 5.21 (s, 1H, CH), 6.76 (s, 1H, CH), 7.68 (m,
6H, Ar-H), 7.89 (d, 1H, Ar-H), 8.13 (m, 2H, Ar-H), 8.28 (d, 1H,
Ar-H); HRMS (ESI) calcd for C26H19NO3: 393.1365 (M+),
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. K. Gautam, H. K. Maurya, R. Pratap, B. Kumar, A. Kumar, V. K. Tandon, and V. J. Ram
Vol 53
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet