Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives: A new facile synthesis of substituted 2,3-dihydrobenzoxepine-4-carboxylates

Article abstract of DOI:10.1016/j.tet.2012.05.047

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives 2a-t with (ethoxycarbonylmethylene)triphenylphosphorane provided the 2-oxoethylidene-2,3-dihydrobenzoxepine-4-carboxy-lates 3a-t with Z (cis) selectivity. Various basic catalysts were studied for the reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with the combination of Wittig reagent to provide compound 3b. The reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with other Wittig reagents, such as methylene(triphenylene)phosphorane and (1-ethoxycarbonylethylidene)triphenylphosphorane provided ketone derivative 4a rather 2-oxoethylidene derivative 3b. The ketone derivative 4a was reacted with Wittig reagent (ethoxycarbonylmethylene)triphenylphosphorane to give 2,3-dihydrobenzoxepine-4-carboxylate 3b. The present approach is novel, straight forward and being reported for the first time.

Full text of DOI:10.1016/j.tet.2012.05.047

Tetrahedron 68 (2012) 6289e6297
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Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives: a new
facile synthesis of substituted 2,3-dihydrobenzoxepine-4-carboxylates
*
Bhimapaka China Raju , Gannerla Saidachary, Jaladi Ashok Kumar
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives 2aet with (ethoxycarbonyl-
methylene)triphenylphosphorane provided the 2-oxoethylidene-2,3-dihydrobenzoxepine-4-carboxy-
lates 3aet with Z (cis) selectivity. Various basic catalysts were studied for the reaction of 2-(chlor-
omethyl)-2H-chromen-2-ol 2a with the combination of Wittig reagent to provide compound 3b. The
reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with other Wittig reagents, such as methylene(-
Received 29 December 2011
Received in revised form 10 May 2012
Accepted 14 May 2012
Available online 24 May 2012
triphenylene)phosphorane
and
(1-ethoxycarbonylethylidene)triphenylphosphorane
provided
Keywords:
ketone derivative 4a rather 2-oxoethylidene derivative 3b. The ketone derivative 4a was reacted with
Wittig reagent (ethoxycarbonylmethylene)triphenylphosphorane to give 2,3-dihydrobenzoxepine-4-
carboxylate 3b. The present approach is novel, straight forward and being reported for the first time.
Ó 2012 Elsevier Ltd. All rights reserved.
CeO bond formation
CeC bond formation
Wittig reaction
2-(Chloromethyl)-2H-chromen-2-ol
2,3-Dihydrobenzoxepines
1. Introduction
there is no method available for the synthesis of substituted 2-
oxoethylidene-2,3-dihydrobenzoxepine-4-carboxylates.
Benzoxepines and their derivatives are important benzo-fused
heterocyclic compounds with various biological applications in
drugs, pharmaceuticals, and agrochemicals.1 Pterulones ((E/Z-I), 6-
hydroxypterulone (II), pterulinic acid (E/Z-III)) and pterulone-B (E-
IV) are novel monochlorinated 2,3-dihydrobenzoxepine natural
products isolated from Pterula species (Fig. 1) and are effective in-
hibitors of eukaryotic respiratory chain at the NADH site of the
ubiquinone oxidoreductase (complex I).2 Pterulones displayed po-
tent antifungal, and in vitro week cytotoxic activity toward mam-
malian cells and their synthesis are well reported in the literature.3
2,3-Dihydro-1-benzoxepine synthesis constitutes an important
objective and RCM reaction of allyloxy biphenyl thioacetals with
titanocene species,4 and palladium catalyzed [5þ2] annulation of
2-aroylmethoxyarylboronic acids with alkynes5 are available
methods in the literature. However, to the best of our knowledge
2. Results and discussion
As a part of our research interest in design and synthesis of bi-
ologically active heterocyclic compounds6 with potential activities,
herein we report the synthesis of 2-oxoethylidene-2,3-
dihydrobenzoxepine-4-carboxylate derivatives by the Wittig7 ho-
mologation of 2,2,3-trisubstituted 2H-chromenes for the first time.
b-Ketoester having chloro substituent at 4th position has an impact
on their reactivity and therefore we studied the reactivity of sali-
cylaldehyde 1a with ethyl 4-chloro-3-oxobutanoate under basic
conditions to provide 2-(chloromethyl)-2H-chromen-2-ol 2a.8a
Thus obtained 2-(chloromethyl)-2H-chromen-2-ol derivative 2a
(1 equiv) is initially taken up for the Wittig reaction with (ethox-
ycarbonylmethylene)triphenylphosphorane9
(2.5
equiv)
in
dichloromethane (DCM) at room temperature for 24 h (Scheme 1)
and to provide (3Z,4E)-ethyl-(2-ethoxy-2-oxoethylidene)-2,3-
dihydrobenzo[b]oxepine-4-carboxylate 3b in 46% yield preferen-
tially with Z (cis) configuration10 (1H NMR experiment) as colorless
solid. The IR spectrum of 3b has shown absorption bands at
nmax¼1712, 1616 and 1554 cmꢀ1 corresponding to two carbonyl
group and an olefin double bond. The 1H NMR spectrum showed
two separate signals corresponds to ethoxy groups, one methylene
Fig. 1. Structures of pterulones.
singlet, and other characteristic singlet at
to C-5 of benzoxepine, another singlet at
oxoethylidene, and four protons corresponds to aromatic ring.
d
¼7.58 ppm corresponds
d
¼6.52 ppm of 2-
* Corresponding author. Tel.: þ91 40 27191725; fax: þ91 40 27160512; e-mail
address: chinarajuiict@yahoo.co.in (B. China Raju).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.047

6290
B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
Compound 3b was further analyzed by 13C NMR spectroscopy,
where the characteristic two quaternary signals at
EtNiPr2 in DCM was found to be better when compared to other
bases, such as pyridine, Et3N, DABCO, DBU and DMAP (Scheme 2,
Table 1, entries 12e20), where the primary and secondary amines
were not effective under these conditions. A plausible mechanism
is shown in Scheme 3, 2H-chromene 2a upon Wittig reaction/basic
conditions rearranging ðSN2Þ to (E)-ethyl 3-oxo-2,3-dihydrobenzo
[b]oxepine-4-carboxylate 4a (1H NMR experiment) with the elim-
ination of HCl. Thus formed (ketone derivative) 4a readily un-
dergoes in situ homologation with Wittig reagent afford 3b with
the elimination of Ph3PO (see Supplementary data). Under similar
conditions 3a & 3c were synthesized in very good yields. Com-
pound 3d is prepared by the reaction of 2a with (cyanomethylene)
triphenylphosphorane generated in situ with t-BuOK11 under ni-
trogen atmosphere in benzene at 0 ꢁC to room temperature
(Scheme 1).
d¼160.9 and
d
¼131.1 ppm correspond to C-3 and C-4 of the oxepine part. The
signal at
signal at
d
¼66.4 ppm corresponds to C-2 of the OCH2 carbon. The
d¼165.9, 166.0 ppm corresponds to ester carbonyls and
122.2 to oxoethylidene carbon. Compound 3b showed molecular
ion MS (ESI) m/z 325 [MþNa]þ, and further confirmed by HRMS
(m/z calcd for C17H18O5Na [MþNa]þ: 325.1046 and found:
325.1073).
Scheme 1. Synthesis of 2,3-dihydrobenzoxepinecarboxylate derivatives 3aed.
The result encouraged us to search for the optimization of re-
action conditions for the formation of compound 3b. We have ex-
amined the reaction of 2a (1 equiv) with Wittig reagent
(ethoxycarbonylmethylene)triphenylphosphorane (1.5 equiv) in
DCM at room temperature, the product 3b was isolated in 32% yield
after 24 h, however under reflux conditions, the yield was im-
proved to 65% with 2 equiv of Wittig reagent. The effect of solvents
THF, MeCN, MeOH, EtOH, CHCl3, benzene, toluene, and H2O was
studied with 3 equiv of Wittig reagent and found that DCM, and
benzene were the solvent of choice in terms of yield (96%) and
reaction time (Table 1, entries 1e11). One equivalent of Wittig re-
agent is utilized as a base to trap the HCl formed during the reaction
and another equivalent utilized for the homologation to provide 3b.
Since the Wittig reagent used in excess (3 equiv), next we have
modified the reaction conditions in combination of tertiary amines
(1.2 equiv) and Wittig reagent (1.4 equiv) to minimize excess Wittig
reagent to provide 3b in good yield (96%). Accordingly, we have
taken up study on the reaction of 2a with the various bases in which
Scheme 2. Synthesis of benzoxepine derivative 3b.
CO2C2H5
O
CO2C2H5
OH
CO2C2H5
Ylide
-BHCl
O
or
O
2a
OH
Cl
tert.amine
Cl
O
4a
Ph3P=CH-CO2C2H5
-Ph3PO
CO2C2H5
H
CO2C2H5
O
3b
Scheme 3. Plausible mechanism.
In order to evaluate the efficiency of the methodology, various
substituted 2-(chloromethyl)-2H-chromen-2-ol derivatives having
electron withdrawing and donating substituents at various posi-
tions on aromatic ring fluoro (entry 2e), bromo (entry 2f), chloro
(entry 2g), 6,8-dichloro (entry 2h), 6-chloro-8-bromo (entry 2i),
methoxy (entry 2j), methyl (entry 2k), C-allyl (entry 2l), O-alkyl
derivatives (entry 2meo), phenyl (entry 2p) and pyrimidinyl (entry
2q), naphthyl (entry 2r, 2s) and pyran (entry 2t) were studied with
(ethoxycarbonylmethylene)triphenylphosphorane to form series of
new (3Z,4E)-ethyl-(2-ethoxy-2-oxoethylidene)-2,3-dihydrobenzo
[b]oxepine-4-carboxylates 3aet in very good yields (Table 2).
Electron withdrawing groups afforded high yields compared to
electron donating groups. 2-(chloromethyl)-2H-chromen-2-ol 2e,
2i, 2k, 2m, 2r, 2s and 2t are new, and prepared from the corre-
sponding salicylaldehydes with ethyl 4-chloro-3-oxobutanoate in
good yields.8a Compounds 2p and 2q are prepared by Suzuki cou-
pling8a of 5-bromosalicylaldehyde with phenylboronic acid and
pyrimidin-2-ylboronic acid in presence of Pd(PPh3)4.
Having achieved the preparation of substituted 2,3-
dihydrobenzo[b]oxepine-4-carboxylates 3aet; next we examined
the reaction of 2-(chloromethyl)-2H-chromen-2-ol derivative 2a
with other Wittig reagent, such as methylene(triphenylene)phos-
phorane under optimized conditions (Scheme 4),11 however the
reaction could not provide the corresponding oxepine derivative 3,
but yielded (E)-Ethyl 3-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate 4a in 60% yield, this may be due to methylene(-
triphenylene)phosphorane could presumably acting as a base on
ketone 4a rather than nucleophile. The reaction of 2a with another
Wittig reagent (1-ethoxycarbonylethylidene)triphenylphosphor-
ane,9f,12 in DCM at room temperature, and on reflux conditions
Table 1
Optimization of the reaction conditions for the synthesis of 3b
Entry
Ylide [equiv]
Basea
Solvent
Time [h]
Yieldd [%]
1
2
3
4
5
6
7
8
1.5
2.5
3.0
1.5
3.0
3.0
2.5
2.5
3.0
3.0
3.0
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
d
DCMb
24
24
24
24
6
12
24
24
6
32
46
96
30
90
60
20
10
58
70
60
26
20
60
68
96
90
84
90
70
d
DCMb
d
DCMc
d
Benzeneb
Benzenec
Toluenec
EtOHb
d
d
d
d
MeOHb
H2Oc
9
d
10
11
12
13
14
15
16
17
18
19
20
d
MeCNb
THFc
24
2
d
Pyridine
Pyridine
DABCO
DBU
EtNiPr2
EtNiPr2
DMAP
DMAP
Et3N
DCMc
24
24
12
12
12
8
12
8
12
Benzenec
DCMc
DCMc
DCMc
Benzenec
DCMc
Benzenec
DCMc
a
1.2 equiv
b
c
Room temperature.
Reflux conditions.
Isolated.
d

B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
6291
Table 2
Synthesis of 2,3-dihydrobenzoxepine-4-carboxylates
Entry
a
2H-Chromenes (2)
Oxepines (3)
Time (h)
12
Yielda (%)
94
b
c
12
14
96
82
d
e
14
8
60
93
f
10
10
8
92
88
88
90
82
80
90
88
92
g
h
i
8
j
14
14
16
16
14
14
k
l
m
n
o
89
(continued on next page)

6292
B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
Oxepines (3)
Table 2 (continued )
Entry
2H-Chromenes (2)
Time (h)
16
Yielda (%)
p
q
78
16
18
72
88
r
s
t
18
18
63
60
a
Isolated yields.
Further we attempted an effort for one-pot synthesis of 3b,
accordingly salicylaldehyde 1a is reacted with ethyl 4-chloro-3-
oxobutanoate under basic condition (30 mol % piperidine in
DCM) provided 2-(chloromethyl)-2H-chromen-2-ol derivative 2a
(TLC). The Wittig reagent (ethoxycarbonylmethylene)triphenyl-
phosphorane (3 equiv) is added to 2a at room temperature and the
contents were refluxed for 24 h, after usual work up and column
chromatography the products obtained were 3b (40%) and 4a (20%,
Scheme 6). The one-pot reaction is also carried out with EtNiPr2
(2.5 equiv), but the 2-(chloromethyl)-2H-chromen-2-ol derivative
2a obtained in low yield. In general, we found that the piperidine
(30 mol %) and Wittig reagent (3 equiv) is essential to provide 2,3-
dihydrobenzoxepine derivatives 3aet in one-pot reaction. Under
these conditions, the electron withdrawing groups were an ad-
vantage over donating present on salicylaldehydes to provide cor-
responding benzoxepines in good yields.
Scheme 4. Wittig homologation of 4a.
(benzene/toluene were also studied), the reaction could not give
the corresponding -methyl derivative 3, but 4a was exclusively
a
formed (Scheme 5) in very good yield (80%). This may be due to
steric congestion between ketone derivative 4a and Wittig reagent
Ph3P]C(CH3)COOC2H5, the fact that the tetra substituted double
bond would suffer from allylic strain. Synthesis of substituted
benzo[b]oxepin-3(2H)-ones recently reported by Chan et al. by the
gold catalyzed intramolecular heterocyclization/PetasiseFerrier
rearrangement of 2-(prop-2-ynyloxy) aromatic aldehydes.13 In-
terestingly for the first time we observed the formation of 4a by the
reaction of 2a with (1-ethoxycarbonylethylidene)triphenylphos-
phorane in DCM at room temperature in very good yield. The
generality of this reaction was then tested with electron donating
and withdrawing groups present on 2-(chloromethyl)-2H-chro-
men-2-ol. Electron donating substituent methoxy 2j and the elec-
tron withdrawing substituents bromo (2f), chloro (2g) afforded
ketone derivatives 4j, 4f, & 4g (crude products 1H NMR experi-
ment). Thus obtained ketone derivatives 4a, 4f, 4g & 4j were sub-
jected to Wittig homologation with (ethoxycarbonylmethylene)
triphenylphosphorane in DCM solvent under reflux conditions to
Scheme 6. One-pot synthesis of 3b.
3. Conclusion
afford
its
corresponding
2,3-dihydrobenzo[b]oxepine-4-
carboxylate derivatives 3b (96%), 3f (90%), 3g (86%) & 3j (80%,
Scheme 5).
In conclusion, we have developed a new approach for the syn-
thesis of substituted 2-oxoethylidene-2,3-dihydrobenzoxepine-4-
carboxylates 3aet with Z (cis) selectivity by Wittig homologation
of 2-(chloromethyl)-2H-chromen-2-ol derivatives 2aet using
commercially available chemicals for the first time. Rearrangement
of 2-(chloromethyl)-2H-chromen-2-ol to ketone derivatives upon
Wittig/basic conditions and in situ Wittig homologation to provide
2,3-dihydrobenzoxepines is the new aspect. The results
Scheme 5. Wittig reactions of 4a, 4f, 4g & 4j.

B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
6293
summarized in Table 2 indicate the scope and generality of the
reaction with respect to the examples described therein. All the
J¼6.8 Hz, 3H, OCH2CH3), 4.18 (d, J¼11.3 Hz, 1H, CH2Cl), 4.32 (d,
J¼11.3 Hz, 1H, CH2Cl), 4.34 (q, J¼6.8 Hz, 2H, OCH2CH3), 7.22 (d,
J¼2.26 Hz, 1H, Ar), 7.56 (d, J¼2.26 Hz, 1H, Ar), 7.62 (s, 1H, CHAr)
compounds 3aet were characterized by spectral data (1H NMR, 13
C
NMR, IR and mass). The ketone derivatives 4 are important syn-
thons and presently utilizing in our laboratory for the synthesis of
heterocyclic compounds, biological applications and will be
reported in due course.
ppm. 13C NMR (75 MHz, CDCl3):
d 14.1, 49.0, 61.8, 98.9, 111.1, 120.1,
123.9, 127.2, 127.3, 134.8, 135.0, 147.8, 164.1 ppm. IR (KBr) 3413,
2981, 1712, 1662, 1632, 1448, 1278, 1210, 1017 cmꢀ1. MS (ESI): 363,
365 [MꢀOH]þ.
4. Experimental section
4.1. General
4.2.4. Ethyl 2-(chloromethyl)-2-hydroxy-8-methyl-2H-chromene-3-
carboxylate (2k). Yield 174 mg (62%); yellow liquid; Rf (20%
EtOAc/hexane) 0.50; 1H NMR (300 MHz, CDCl3):
d
1.38 (t, J¼7.0 Hz,
3H, OCH2CH3), 2.28 (s, 3H, CH3), 4.06 (d, J¼11.3 Hz, 1H, CH2Cl), 4.18
(d, J¼11.3 Hz, 1H, CH2Cl), 4.29 (q, J¼7.0 Hz, 2H, OCH2CH3), 6.86 (t,
J¼7.2 Hz, 1H, Ar), 7.04 (d, J¼7.5 Hz, 1H, Ar), 7.16 (d, J¼7.3 Hz, 1H, Ar)
The chemicals, salicylaldehydes (SigmaeAldrich), piperidine,
and all the solvents were obtained commercially. Wittig reagents
were prepared as per the literature procedures. The 2-(chlor-
omethyl)-2H-chromen-2-ol derivatives were synthesized accord-
ing to our earlier reported method.8a All the melting points were
determined on a Mettler-Temp apparatus and are uncorrected. IR
was recorded with a Thermo Nicolet Nexus 670 spectrometer. 1H
NMR and 13C NMR spectra were recorded on a Gemini 200 MHz,
7.64 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.1, 15.3, 49.2,
61.3, 97.6, 117.5, 121.3, 121.5, 125.9, 126.5, 134.2, 137.1, 150.3,
165.1 ppm. IR (KBr) 3446, 2923, 1705, 1635, 1467, 1375, 1288, 1248,
1209, 1066, 1025 cmꢀ1. MS (ESI): 305, 307 [MþNa]þ.
4.2.5. Ethyl 2-(chloromethyl)-2-hydroxy-7-(methoxymethoxy)-2H-
Bruker Avance 300 MHz spectrometers. Chemical shifts (
d
) are
chromene-3-carboxylate (2m). Yield 183 mg (56%); yellow liquid; Rf
quoted in parts per million and are referenced to tetramethylsilane
(TMS) as internal standard. EIMS obtained on 7070H spectrometers
operating at 70 eV using a direct inlet system. HRMS were carried
out on Agilent 6510 Q-TOF LC/MS instrument. All reactions were
monitored by thin layer chromatography (TLC) on pre-coated silica
gel 60 F254 (mesh); spots were visualized under UV light. Column
chromatographic separations were carried out on silica gel
(60e120 mesh).
(20% EtOAc/hexane) 0.48; 1H NMR (300 MHz, CDCl3):
d 1.38 (t,
J¼7.2 Hz, 3H, OCH2CH3), 3.46 (s, 3H, CH3), 4.02 (d, J¼11.1 Hz, 1H,
CH2Cl), 4.22 (d, J¼11.1 Hz, 1H, CH2Cl), 4.29 (q, J¼7.2 Hz, 2H,
OCH2CH3), 5.15 (s, 2H, OCH2), 6.60e6.69 (m, 2H, Ar), 7.12 (d,
J¼8.3 Hz, 1H, Ar), 7.62 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d
14.1, 49.1, 56.2, 61.2, 94.1, 98.3, 103.8, 110.6, 112.3, 119.0, 129.9,
136.6, 153.7, 161.1, 165.2 ppm. IR (KBr) 3423, 2975, 1705, 1614, 1501,
1375, 1281, 1212, 1157, 1076, 1003 cmꢀ1. MS (ESI): 351, 353
[MþNa]þ.
4.2. Typical procedure for the synthesis of substituted 2-
(chloromethyl)-2H-chromen-2-ol (2e, 2h, 2i, 2k, 2m, 2r, 2s, 2t)
4.2.6. Ethyl 2-(chloromethyl)-3-hydroxy-3H-benzo[f]chromene-2-
carboxylate (2r). Yield 196 mg (62%); yellow liquid; Rf (20%
Ethyl 4-chloro-3-oxobutanoate (164 mg, 1 mmol) was added to
the mixture of a stirred solution of 5-fluoro-2-hydroxybenzaldehyde
(140 mg, 1 mmol) and piperidine (30 mol %) in DCM (2 mL) at room
temperature over a period of 15 min. The mixture was stirred for
another 8 h at the same temperature. After completion of the re-
action (TLC), the crude product was subjected to column chroma-
tography purification (hexane/ethyl acetate 95:5) to give 2e (183 mg,
64% yield) as yellow liquid.
EtOAc/hexane) 0.30; 1H NMR (300 MHz, CDCl3):
d
1.42 (t, J¼7.2 Hz,
3H, OCH2CH3), 4.06 (d, J¼11.3 Hz, 1H, CH2Cl), 4.32 (d, J¼11.3 Hz, 1H,
CH2Cl), 4.34 (q, J¼7.2 Hz, 2H, OCH2CH3), 7.2 (d, J¼9.1 Hz, 1H, Ar),
7.34e7.40 (m, 1H, Ar) 7.48e7.56 (m, 1H, Ar), 7.72 (d, J¼8.1 Hz, 1H,
Ar), 7.78 (d, J¼8.9 Hz, 1H, Ar), 8.05 (d, J¼8.3 Hz, 1H, Ar), 8.39 (s, 1H,
CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.1, 48.8, 61.3, 98.3, 110.8,
117.5, 119.6, 120.8, 124.5, 127.7, 128.7, 129.2, 130.0, 132.3, 133.5, 151.5,
165.2 ppm. IR (KBr) 3401, 2982, 1707, 1636, 1465, 1398, 1262, 1220,
1054 cmꢀ1. MS (ESI): 301 [MꢀOH]þ.
4.2.1. Ethyl 2-(chloromethyl)-6-fluoro-2-hydroxy-2H-chromene-3-
carboxylate (2e). Yellow liquid; Rf (20% EtOAc/hexane) 0.48; 1H
4.2.7. Ethyl 2-(chloromethyl)-2-hydroxy-2H-benzo[h]chromene-3-
NMR (300 MHz, CDCl3):
d
1.40 (t, J¼7.0 Hz, 3H, OCH2CH3), 4.06 (d,
carboxylate (2s). Yield 134 mg (42%); yellow liquid; Rf (20%
J¼11.3 Hz, 1H, CH2Cl), 4.28 (d, J¼11.3 Hz, 1H, CH2Cl), 4.32 (q,
J¼7.0 Hz, 2H, OCH2CH3), 6.94 (d, J¼8.9 Hz,1H, Ar), 7.24e7.32 (m, 2H,
EtOAc/hexane) 0.28; 1H NMR (300 MHz, CDCl3):
d
1.41 (t, J¼7.2 Hz,
3H, OCH2CH3), 4.30 (d, J¼11.3 Hz, 1H, CH2Cl), 4.34 (d, J¼11.1 Hz, 1H,
CH2Cl), 4.36 (q, J¼7.5 Hz, 2H, OCH2CH3), 7.30 (d, J¼8.3 Hz, 1H, Ar),
7.46 (d, J¼8.3, 1H, Ar), 7.52e7.62 (m, 2H, Ar), 7.76e7.82 (m, 1H, Ar),
7.87 (s, 1H, CHAr), 8.32e8.38 (m, 1H, Ar) ppm. 13C NMR (75 MHz,
Ar), 7.64 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.1, 49.1,
61.7, 98.2, 117.9, 119.2, 123.1, 127.0, 128.1, 132.4, 135.3, 150.8,
164.7 ppm. IR (KBr) 3404, 2981, 2927, 1710, 1633, 1478, 1272, 1210,
1019 cmꢀ1. MS (ESI): 285, 287 [MþH]þ.
CDCl3): d 14.2, 49.4, 61.3, 98.6, 112.4, 119.9, 121.7, 122.7, 123.9, 124.8,
126.3,127.7,128.3,136.1,137.3,149.1,165.1 ppm. IR (KBr) 3410, 3049,
2980, 1690, 1630, 1570, 1374, 1341, 1297, 1218, 1056, 1017 cmꢀ1. MS
(ESI): 319 [MþH]þ.
4.2.2. Ethyl 6,8-dichloro-2-(chloromethyl)-2-hydroxy-2H-chromene-
3-carboxylate (2h). Yield 220 mg (66%); yellow liquid; Rf (20%
EtOAc/hexane) 0.36; 1H NMR (300 MHz, CDCl3):
d 1.39 (t,
J¼6.8 Hz, 3H, OCH2CH3), 4.16 (d, J¼11.3 Hz, 1H, CH2Cl), 4.32 (d,
J¼11.3 Hz, 1H, CH2Cl), 4.35 (q, J¼6.8 Hz, 2H, OCH2CH3), 7.19 (d,
J¼2.26 Hz, 1H, Ar), 7.41 (d, J¼2.26 Hz, 1H, Ar), 7.64 (s, 1H, CHAr)
4.2.8. Ethyl 2-(chloromethyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-
2H,6H-pyrano[3,2-g]chromene-3-carboxylate (2t). Yield 133 mg
(38%); yellow liquid; Rf (20% EtOAc/hexane) 0.30; 1H NMR
ppm. 13C NMR (75 MHz, CDCl3):
d
14.0, 48.7, 61.7, 98.9, 120.1,
(300 MHz, CDCl3):
d
1.33 (s, 6H, 2CH3), 1.36 (t, J¼6.8 Hz, 3H,
123.9, 126.5, 128.9, 130.6, 132.1, 134.7, 164.1, 167.0 ppm. IR (KBr)
3417, 2923, 1712, 1634, 1457, 1375, 1281, 1221, 1019 cmꢀ1. MS
(ESI): 319, 321 [MꢀOH]þ.
OCH2CH3), 1.80 (t, J¼6.8 Hz, 2H, CH2), 2.71 (t, J¼6.8 Hz, 2H, CH2),
4.00 (d, J¼10.6 Hz, 1H, CH2Cl), 4.22 (d, J¼10.6 Hz, 1H, CH2Cl),
4.30 (q, J¼6.8 Hz, 2H, OCH2CH3), 6.42 (s, 1H, Ar), 6.95 (s, 1H, Ar),
7.65 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.2, 21.6,
4.2.3. Ethyl,8-bromo-6-chloro-2-(chloromethyl)-2-hydroxy-2H-
26.8, 32.5, 49.2, 61.1, 75.4, 98.1, 104.6, 111.2, 115.4, 118.2, 129.8,
136.9, 152.2, 158.6, 165.6 ppm. IR (KBr) 3441, 2927, 1711, 1617,
1394, 1271, 1200, 1093 cmꢀ1. MS (ESI): 335, 337 [MꢀOH]þ.
chromene-3-carboxylate (2i). Yield 242 mg (64%); yellow liquid; Rf
(20% EtOAc/hexane) 0.38; 1H NMR (300 MHz, CDCl3):
d 1.38 (t,

6294
B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
HRMS-ESI calcd for C18H21ClO5Na [MþNa]þ 375.09697; found
1252, 1223, 1146, 1057, 1009 cmꢀ1. MS (ESI): 331 [MþH]þ, 353
[MþNa]þ. HRMS-ESI calcd for C19H22O5 Na [MþNa]þ 353.13594;
found 353.13514.
375.09655.
4.3. Method-A: typical procedure for the synthesis of
substituted 2-oxoethylidene-2,3-dihydrobenzoxepine-4-
carboxylates (3aec & 3eet)
4.4.4. Typical procedure for the synthesis of (3Z,4E)-ethyl 3-(cyano-
methylene)-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3d). In an
oven dried round bottom flask, the triphenyl(cyanomethyl)phos-
phonium bromide (840 mg, 2.2 mmol) in dry benzene (1 mL) is
transferred under nitrogen atmosphere. The reaction flask is
cooled to 0 ꢁC, the potassium tert-butoxide (246 mg, 2.2 mmol)
was added at a time and the contents were stirred for 1 h. After
the mixture becomes light yellow color, the ethyl 2-(chlor-
omethyl)-2-hydroxy-2H-chromene-3-carboxylate 2a (268 mg,
1 mmol) in benzene (1 mL) was added slowly at the same tem-
perature. The contents were slowly brought to room temperature
(6 h), after completion of the reaction (TLC), the reaction mixture
was quenched with aqueous NH4Cl solution, and extracted with
ether (3ꢂ10 mL). The organic layer was dried over Na2SO4, solvent
removed under reduced pressure and crude product was purified
by column chromatography (hexane/ethyl acetate 9:1) to give 3d
(150 mg, 60% yield) as colorless solid; mp 43e44 ꢁC. 1H NMR
A mixture of ethyl 2-(chloromethyl)-2-hydroxy-2H-chromene-3-
carboxylate 2a (268 mg, 1.0 mmol) and [(ethoxycarbonylmethylene)
triphenylphosphorane (1.04 g, 3 mmol) in DCM (4 mL) were stirred
under reflux conditions for 24 h. After completion of the reaction
(TLC), solvent was removed under reduced pressure, and crude
product was purified by column chromatography (hexane/ethyl ac-
etate 9.5:0.5) provide (3Z,4E)-ethyl-(2-ethoxy-2-oxoethylidene)-
2,3-dihydrobenzo[b]oxepine-4-carboxylate 3b (290 mg, 96% yield)
as colorless solid.
4.4. Method-B: typical procedure for the synthesis of
substituted 2-oxoethylidene-2,3-dihydrobenzoxepine-4-
carboxylates (3aec & 3eet)
Phosphonium ylide [(ethoxycarbonylmethylene)triphenylphos-
phorane, (487 mg, 1.4 mmol) was added to a stirred solution of
ethyl 2-(chloromethyl)-2-hydroxy-2H-chromene-3-carboxylate 2a
(268 mg, 1.0 mmol) and EtNiPr2 (154 mg, 1.2 mmol) in DCM (4 mL)
and the contents were refluxed for 12 h. After completion of the
reaction (TLC), the solvent was removed under reduced pressure,
and crude product was purified by column chromatography (hex-
ane/ethyl acetate 9.5:0.5) provide (3Z,4E)-ethyl-(2-ethoxy-2-
(300 MHz, CDCl3):
d
1.38 (t, J¼7.0 Hz, 3H, OCH2CH3), 4.32 (q,
J¼7.0 Hz, 2H, OCH2CH3), 4.89 (s, 2H, OCH2), 6.54 (s, 1H, C]CH),
7.04e7.10 (m, 2H, Ar), 7.33e7.42 (m, 2H, Ar), 7.74 (s, 1H, CHAr)
ppm. 13C NMR (75 MHz, CDCl3):
d 14.4, 61.6, 70.4, 102.7, 116.3,
119.8, 123.0, 123.3, 127.2, 133.2, 136.3, 142.8, 148.7, 160.8,
165.4 ppm. IR (KBr) 3091, 2923, 2853, 2208, 1707, 1602, 1483, 1290,
1255, 1226, 1170, 1010 cmꢀ1. MS (ESI): 255 [M ]þ.
oxoethylidene)-2,3-dihydrobenzo[b]oxepine-4-carboxylate
(290 mg, 96% yield) as colorless solid.
3b
4.4.5. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-7-fluoro-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3e). Yellow solid; Rf (20%
EtOAc/hexane) 0.50; mp 84e85 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.1. (3Z,4E)-Ethyl 3-(2-methoxy-2-oxoethylidene)-2,3-
d
1.32 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.39 (t, J¼6.9 Hz, 3H, OCH2CH3),
dihydrobenzo[b]oxepine-4-carboxylate (3a). Yellow solid; Rf (20%
4.22 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q, J¼6.9 Hz, 2H, OCH2CH3),
5.22 (s, 2H, OCH2), 6.54 (s, 1H, C]CH), 6.99 (d, J¼8.6 Hz, 1H, Ar),
7.20e7.26 (m, 1H, Ar), 7.36 (d, J¼2.3 Hz, 1H, Ar), 7.48 (s, 1H, CHAr)
EtOAc/hexane) 0.52; mp 68e69 ꢁC.1H NMR (300 MHz, CDCl3):
d 1.40
(t, J¼7.2 Hz, 3H, OCH2CH3), 3.77 (s, 3H, OCH3), 4.32 (q, J¼7.2 Hz, 2H,
OCH2CH3), 5.24 (s, 2H, OCH2), 6.54 (s, 1H, C]CH), 6.96e7.06 (m, 2H,
Ar), 7.24e7.38 (m, 2H, Ar), 7.60 (s,1H, CHAr) ppm. 13C NMR (75 MHz,
ppm. 13C NMR (75 MHz, CDCl3):
d 14.1, 14.2, 60.6, 61.6, 66.6, 121.1,
122.8, 124.4, 127.1, 131.7, 132.3, 134.3, 139.1, 143.3, 159.1, 166.1,
166.9 ppm. IR (KBr) 2983, 2922, 1709, 1619, 1589, 1478, 1385, 1279,
1247, 1160 cmꢀ1. MS (ESI): 359 [MþK]þ.
CDCl3): d 14.2, 51.4, 61.3, 66.3, 119.8, 121.7, 122.3, 123.3, 131.0, 132.2,
135.7,141.0,144.2,160.9,165.9,166.4 ppm. IR (KBr) 2986, 2928,1710,
1615,1556,1480, 1439,1386,1338, 1290, 1257,1217,1150, 1113,1058,
1006 cmꢀ1. MS (ESI): 289 [MþH]þ, 311 [MþNa]þ. HRMS-ESI calcd for
C16H17O5 [MþH]þ 289.10705; found 289.10649.
4.4.6. (3Z,4E)-Ethyl 7-bromo-3-(2-ethoxy-2-oxoethylidene)-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3f). Colorless solid; Rf (20%
EtOAc/hexane) 0.48; mp 101e102 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.2. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-2,3-dihydrobenzo
d
1.33 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.39 (t, J¼6.9 Hz, 3H, OCH2CH3),
[b]oxepine-4-carboxylate (3b). Colorless solid; Rf (20% EtOAc/hex-
4.22 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q, J¼7.2 Hz, 2H, OCH2CH3),
5.21 (s, 2H, OCH2), 6.54 (s, 1H, C]CH), 6.94 (d, J¼8.7 Hz, 1H, Ar) 7.37
(dd, J¼2.5, 8.7 Hz, 1H, Ar), 7.48 (s, 1H, CHAr), 7.51 (d, J¼2.3 Hz, 1H,
ane) 0.62; mp 63e64 ꢁC. 1H NMR (300 MHz, CDCl3):
d 1.33 (t,
J¼7.2 Hz, 3H, OCH2CH3), 1.39 (t, J¼6.9 Hz, 3H, OCH2CH3), 4.22 (q,
J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q, J¼6.9 Hz, 2H, OCH2CH3), 5.24 (s,
2H, OCH2), 6.53 (s, 1H, C]CH), 6.96e7.06 (m, 2H, Ar), 7.24e7.38 (m,
Ar) ppm. 13C NMR (75 MHz, CDCl3):
d 14.2, 14.3, 60.6, 61.6, 66.7,
114.4, 121.8, 122.9, 124.9, 132.3, 134.7, 137.4, 139.1, 143.3, 159.6, 166.1,
166.2 ppm. IR (KBr) 2984, 1707, 1620, 1587, 1551, 1477, 1384, 1278,
1248, 1210, 1160, 1127 cmꢀ1. MS (ESI): 381, 383 [MþH]þ, 403, 405
[MþNa]þ. HRMS-ESI calcd for C17H17BrO5Na [MþNa]þ 403.01516;
found 403.01468.
2H, Ar), 7.59 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.4,
14.5, 60.3, 61.3, 66.4, 119.8, 122.2, 123.3, 131.1, 132.2, 135.7, 140.9,
144.0, 160.9, 165.9, 166.0 ppm. IR (KBr) 2981, 2927, 1712, 1616, 1554,
1479, 1446, 1286, 1255, 1220, 1192, 1153, 1112, 1059, 1000 cmꢀ1. MS
(ESI): 325 [MþNa]þ; HRMS-ESI calcd for C17H18O5Na [MþNa]þ
325.1046; found 325.1073.
4.4.7. (3Z,4E)-Ethyl-7-chloro-3-(2-ethoxy-2-oxoethylidene)-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3g). Colorless solid; Rf (20%
EtOAc/hexane) 0.46; mp 92e93 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.3. (3Z,4E)-Ethyl 3-(2-tert-butoxy-2-oxoethylidene)-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3c). Yellow liquid; Rf (20%
d
1.32 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.39 (t, J¼6.9 Hz, 3H, OCH2CH3),
EtOAc/hexane) 0.62; 1H NMR (300 MHz, CDCl3):
d
1.38 (t,
4.22 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q, J¼6.9 Hz, 2H, OCH2CH3),
5.22 (s, 2H, OCH2), 6.54 (s, 1H, C]CH), 6.99 (d, J¼8.7 Hz, 1H, Ar),
7.20e7.26 (m, 1H, Ar), 7.36 (d, J¼2.3 Hz, 1H, Ar), 7.48 (s, 1H, CHAr)
J¼7.2 Hz, 3H, OCH2CH3), 1.52 (s, 9H, 3ꢂ CH3), 4.32 (q, J¼7.2 Hz,
2H, OCH2CH3), 5.19 (s, 2H, OCH2), 6.44 (s, 1H, C]CH), 6.96e7.06
(m, 2H, Ar), 7.24e7.34 (m, 2H, Ar), 7.54 (s, 1H, CHAr) ppm. 13C
ppm. 13C NMR (75 MHz, CDCl3):
d 14.1, 14.2, 60.5, 61.6, 66.6, 121.2,
NMR (75 MHz, CDCl3):
123.3, 124.1, 131.3, 131.9, 135.7, 140.4, 143.0, 160.9, 165.4,
166.1 ppm. IR (KBr) 2978, 2931, 1709, 1603, 1449, 1371, 1285,
d
14.6, 28.4, 61.2, 66.4, 80.6, 119.8, 122.3,
122.8, 124.4, 127.1, 131.7, 132.3, 134.3, 139.1, 143.3, 159.1, 166.0,
166.1 ppm. IR (KBr) 2983, 2920, 1708, 1619, 1589, 1478, 1385, 1279,
1246, 1209, 1159, 1125 cmꢀ1. MS (ESI): 337 [MþH]þ, 359, 361

B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
6295
[MþNa]þ; HRMS-ESI calcd for C17H17ClO5Na [MþNa]þ 359.0675;
1055, 1010 cmꢀ1. MS (ESI): 343 [MþH]þ, 365 [MþNa]þ. HRMS-ESI
calcd for C20H22O5 Na [MþNa]þ 365.13594; found 365.13513.
found 359.0678.
4.4.13. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-8-(methoxymeth
oxy)-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3m). Yellow solid;
Rf (20%EtOAc/hexane) 0.62; mp 81e82 ꢁC.1H NMR (300 MHz, CDCl3):
4.4.8. (3Z,4E)-Ethyl-7,9-dichloro-3-(2-ethoxy-2-oxoethylidene)-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3h). Colorless solid; Rf (20%
EtOAc/hexane) 0.40; mp 121e122 ꢁC. 1H NMR (300 MHz, CDCl3):
d
1.33 (t, J¼7.2 Hz, 3H, OCH2CH3),1.38 (t, J¼7.2 Hz, 3H, OCH2CH3), 3.48
d
1.34 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.40 (t, J¼6.9 Hz, 3H, OCH2CH3),
(s, 3H, OCH3), 4.22 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.30 (q, J¼7.2 Hz, 2H,
OCH2CH3), 5.15 (s, 2H, OCH2), 5.23 (s, 2H, OCH2), 6.54 (s, 1H, C]CH),
6.62e6.74 (m, 2H, Ar), 7.26 (d, J¼8.7 Hz, 1H, Ar), 7.58 (s, 1H, CHAr)
4.24 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q, J¼6.9 Hz, 2H, OCH2CH3),
5.32 (s, 2H, OCH2), 6.54 (s,1H, C]CH), 7.26 (d, J¼2.6 Hz,1H, Ar), 7.39
(d, J¼2.2 Hz, 1H, Ar), 7.42 (s, 1H, CHAr) ppm. 13C NMR (75 MHz,
ppm.13C NMR (75 MHz, CDCl3):
d 14.2,14.3, 56.2, 60.4, 61.3, 66.4, 94.1,
CDCl3):
d 14.2, 14.3, 60.6, 61.7, 67.9, 123.4, 126.0, 126.1, 127.1, 131.6,
106.2, 110.9, 117.3, 121.5, 128.2, 137.2, 141.0, 143.9, 160.5, 162.1, 166.0,
166.5 ppm. IR (KBr) 2982, 1704, 1610, 1579, 1548, 1283, 1217, 1162,
1112, 1024 cmꢀ1. MS (ESI): 363 [MþH]þ, 385 [MþNa]þ. HRMS-ESI
calcd for C19H22O7Na [MþNa]þ 385.12577; found 385.12631.
132.6, 133.5, 137.9, 143.1, 154.9, 165.7, 165.8 ppm. IR (KBr) 2985,
1709, 1627, 1589, 1467, 1384, 1334, 1276, 1225, 1156, 1059 cmꢀ1. MS
(ESI): 388 [MþNH4]þ. HRMS-ESI calcd for C17H16Cl2O5Na [MþNa]þ
393.02670; found 393.02694.
4.4.14. (3Z,4E)-Ethyl 8-(allyloxy)-3-(2-ethoxy-2-oxoethylidene)-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3n). Yellow solid; Rf (20%
EtOAc/hexane) 0.58; mp 114e115 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.9. (3Z,4E)-Ethyl 9-bromo-7-chloro-3-(2-ethoxy-2-
oxoethylidene)-2,3-dihydrobenzo[b]oxepine-4-carboxylate
(3i). Colorless solid; Rf (20% EtOAc/hexane) 0.42; mp 129e130 ꢁC.
d
1.32 (t, J¼6.9 Hz, 3H, OCH2CH3), 1.38 (t, J¼7.2 Hz, 3H, OCH2CH3),
1H NMR (300 MHz, CDCl3):
d
1.34 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.40 (t,
4.21 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.29 (q, J¼7.2 Hz, 2H, OCH2CH3),
4.53 (d, J¼5.1 Hz, 2H, OCH2CH]CH2), 5.23 (s, 2H, OCH2), 5.26e5.46
(m, 2H, CH]CH2), 5.92e6.08 (m, 1H, CH]CH2), 6.54 (s, 1H, C]CH),
6.54e6.62 (m, 2H, Ar), 7.20e7.30 (m,1H, Ar), 7.58 (s,1H, CHAr) ppm.
J¼6.9 Hz, 3H, OCH2CH3), 4.24 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q,
J¼6.9 Hz, 2H, OCH2CH3), 5.32 (s, 2H, OCH2), 6.53 (s, 1H, C]CH), 7.31
(d, J¼2.3 Hz, 1H, Ar), 7.40 (s, 1H, CHAr), 7.55 (d, J¼2.3 Hz, 1H, Ar)
ppm. 13C NMR (75 MHz, CDCl3):
d 14.3, 14.3, 60.6, 61.7, 68.0, 115.1,
13C NMR (75 MHz, CDCl3):
d 14.2, 14.3, 60.4, 61.2, 66.4, 68.9, 104.3,
123. 3, 125.9, 127.6, 133.3, 133.5, 134.6, 137.9, 143.1, 155.8, 165.7,
165.8 ppm. IR (KBr) 2984, 2929, 1715, 1626, 1459, 1382, 1286, 1234,
1157, 1055 cmꢀ1. MS (ESI): 432, 434 [MþNH4]þ.
110.5, 116.4, 118.2, 121.3, 127.7, 132.4, 137.2, 141.2, 143.9, 162.1, 162.3,
166.4, 166.5 ppm. IR (KBr) 2981, 1703, 1612, 1580, 1548, 1362, 1282,
1218, 1167, 1115, 1055 cmꢀ1. MS (ESI): 359 [MþH]þ, 381 [MþNa]þ;
HRMS-ESI calcd for C20H23O6 [MþH]þ 359.1416; found 359.1499.
4.4.10. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-7-methoxy-2,3-
dihydrobeno[b]oxepine-4-carboxylate (3j). Yellow solid; Rf (20%
EtOAc/hexane) 0.52; mp 65e66 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.15. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-8-(3-methylbut-
2-enyloxy)-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3o). Yellow
solid; Rf (20% EtOAc/hexane) 0.58; mp 83e84 ꢁC. 1H NMR
d
1.32 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.40 (t, J¼6.9 Hz, 3H, OCH2CH3),
3.82 (s, 3H, OCH3), 4.21 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q,
J¼6.9 Hz, 2H, OCH2CH3), 5.19 (s, 2H, OCH2), 6.47 (s, 1H, C]CH), 6.80
(d, J¼3.2 Hz, 1H, Ar), 6.84e6.88 (dd, J¼2.7, 8.7 Hz, 1H, Ar), 6.96 (d,
J¼8.7 Hz, 2H, Ar), 7.49 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
(300 MHz, CDCl3):
d
1.32 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.38 (t,
J¼7.2 Hz, 3H, OCH2CH3), 1.74 (s, 3H, CH3), 1.80 (s, 3H, CH3), 4.21 (q,
J¼7.2 Hz, 2H, OCH2CH3), 4.29 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.49 (d,
J¼6.6 Hz, 2H, OCH2), 5.23 (s, 2H, OCH2), 5.38e5.48 (m, 1H,
OCH2CH]C), 6.50e6.58 (m, 2H, Ar), 6.54 (s, 1H, C]CH), 7.24 (d,
J¼8.7 Hz, 1H, Ar), 7.59 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d
14.2, 14.3, 55.6, 60.4, 61.4, 67.7, 118.1, 119.0, 120.6, 121.8, 123.8,
131.5, 140.4, 144.6, 154.5, 154.9, 166.1, 166.5 ppm. IR (KBr) 2982,
2920, 1706, 1620, 1560, 1493, 1457, 1390, 1346, 1251, 1215, 1160,
1036 cmꢀ1. MS (ESI): 333 [MþH]þ, 355 [MþNa]þ. HRMS-ESI calcd
for C18H21O6 [MþH]þ 333.1333; found 333.1358.
d
14.3, 14.4, 18.2, 25.7, 59.9, 60.7, 64.9, 66.2, 104.0, 110.4, 116.1, 119.4,
121.2, 127.4, 136.9, 137.8, 141.2, 143.9, 162.4, 162.5, 165.8, 166.0 ppm.
IR (KBr) 2979, 2917, 1702, 1611, 1546, 1380, 1281, 1216, 1163, 1111,
1023 cmꢀ1. MS (ESI): 387 [MþH]þ, 409 [MþNa]þ. HRMS-ESI calcd
for C22H26O6Na [MþNa]þ 409.16216; found 409.16141.
4.4.11. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-9-methyl-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3k). Pale yellow solid; Rf
(20% EtOAc/hexane) 0.72; mp 71e72 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.16. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-7-phenyl-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (3p). Yellow solid; Rf (20%
EtOAc/hexane) 0.62; mp 51e52 ꢁC. 1H NMR (300 MHz, CDCl3):
d
1.33 (t, J¼6.8 Hz, 3H, OCH2CH3),1.39 (t, J¼7.7 Hz, 3H, OCH2CH3), 2.35
(s, 3H, CH3), 4.22 (q, J¼7.7 Hz, 2H, OCH2CH3), 4.31 (q, J¼6.8 Hz, 2H,
OCH2CH3), 5.28(s, 2H, OCH2), 6.54(s,1H, C]CH), 6.90(t, J¼7.7 Hz,1H,
Ar), 7.16 (d, J¼6.8 Hz, 1H, Ar), 7.19 (d, J¼7.7 Hz, 1H, Ar), 7.56 (s, 1H,
d
1.33 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.40 (t, J¼7.2 Hz, 3H, OCH2CH3),
4.23 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.32 (q, J¼7.2 Hz, 2H, OCH2CH3),
5.27 (s, 2H, OCH2), 6.56 (s, 1H, C]CH), 7.11 (d, J¼8.3 Hz, 1H, Ar),
7.24e7.34 (m, 1H, Ar), 7.38 (t, J¼8.3 Hz, 1H, Ar), 7.48e7.58 (m, 4H,
CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.3, 14.4, 16.5, 60.3, 61.3,
66.9, 121.4, 122.0, 123.4, 128.8, 130.6, 133.5, 133.6, 141.3, 144.7, 159.0,
166.0, 166.4 ppm. IR (KBr) 2926, 2856, 1707, 1619, 1464, 1377, 1332,
1264, 1201, 1149, 1096, 1050, 1008 cmꢀ1. MS (ESI): 317 [MþH]þ;
HRMS-ESI calcd for C18H21O5 [MþH]þ 317.1311; found 317.1393.
Ar), 7.66 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.2, 14.3,
60.5, 61.5, 66.6, 120.1, 122.3, 123.3, 126.7, 127.3, 128.8, 130.9, 131.3,
134.1, 135.5, 139.6, 140.9, 143.84, 160.0, 166.3, 166.4 ppm. IR (KBr)
2984,1710, 1618, 1478, 1377, 1290, 1219,1150, 1124,1061, 1006 cmꢀ1
.
MS (ESI): 379 [MþH]þ, 401 [MþNa]þ. HRMS-ESI calcd for
4.4.12. (3Z,4E)-Ethyl 9-allyl-3-(2-ethoxy-2-oxoethylidene)-2,3-
C23H22O5Na [MþNa]þ 401.13594; found 401.13558.
dihydrobenzo[b]oxepine-4-carboxylate (3l). Colorless solid; Rf (20%
EtOAc/hexane) 0.68; mp 81e82 ꢁC.1H NMR (300 MHz, CDCl3):
d 1.33 (t,
4.4.17. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-7-(pyrimidin-2-
yl)-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3q). Brown solid; Rf
(20% EtOAc/hexane) 0.38; mp 141e142 ꢁC. 1H NMR (300 MHz,
J¼6.9 Hz, 3H, OCH2CH3), 1.39 (t, J¼7.2 Hz, 3H, OCH2CH3), 3.44 (d,
J¼6.6 Hz, 2H, CH2Ar), 4.22 (q, J¼6.9 Hz, 2H, OCH2CH3), 4.32 (q,
J¼6.9 Hz, 2H, OCH2CH3), 5.00e5.08 (m, 2H, CH]CH2), 5.26 (s, 2H,
OCH2), 5.86e6.02 (m,1H, CH2CH]CH2), 6.52 (s,1H, C]CH), 6.92e6.98
(m, 1H, Ar), 7.14e7.24 (m, 2H, Ar), 7.55 (s, 1H, CHAr) ppm. 13C NMR
CDCl3):
d
1.34 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.41 (t, J¼7.2 Hz, 3H,
OCH2CH3), 4.24 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.34 (q, J¼7.2 Hz, 2H,
OCH2CH3), 5.29 (s, 2H, OCH2), 6.58 (s, 1H, C]CH), 7.20 (d, J¼8.3 Hz,
1H, Ar), 7.48e7.60 (m, 2H, Ar), 7.64 (s, 1H, CHAr), 8.90 (br s, 2H, Ar),
(75 MHz, CDCl3):
d 14.3, 14.4, 34.4, 60.4, 61.3, 67.2, 115.9, 121.3, 122.3,
123.9, 130.9, 132.8, 133.8, 136.5, 141.0, 144.9, 158.8, 166.2, 166.5,
166.6 ppm. IR (KBr) 2980, 2927,1710,1612,1455,1380,1280,1201,1152,
9.15 (s,1H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
d 14.2,14.3, 60.7, 61.7,

6296
B. China Raju et al. / Tetrahedron 68 (2012) 6289e6297
66.6,121.2,123.0,123.8,128.4,130.3,132.3,133.0,134.0,139.8,143.2,
154.5, 157.4, 161.1, 166.1, 166.3 ppm. IR (KBr) 2924, 2854, 1711, 1615,
1459, 1376, 1262, 1212, 1150, 1052 cmꢀ1. MS (ESI): 381 [MþH]þ.
159.4, 165.3, 191.5 ppm. IR (KBr) 3451, 2981, 2925, 1728, 1675, 1605,
1565, 1482, 1447, 1394, 1284, 1250, 1189, 1115, 1041 cmꢀ1. MS (ESI):
233 [MþH]þ, 255 [MþNa]þ. HRMS-ESI calcd for C13H13O4 [MþH]þ
233.08084; found 233.08117.
4.4.18. (1E,3Z)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-3,4-
dihydronaphtho[2,1-b]oxepine-2-carboxylate
solid; Rf (20% EtOAc/hexane) 0.46; mp 53e54 ꢁC. 1H NMR
(300 MHz, CDCl3):
(3r). Pale
yellow
4.5.2. (E)-Ethyl 7-bromo-3-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate (4f). Yield 226 mg (73%); colorless solid; Rf (20%
EtOAc/hexane) 0.42; mp 68e69 ꢁC. 1H NMR (300 MHz, CDCl3):
d
1.32 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.44 (t,
J¼6.9 Hz, 3H, OCH2CH3), 4.24 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.38 (q,
J¼6.9 Hz, 2H, OCH2CH3), 5.47 (s, 2H, OCH2), 6.50 (s, 1H, C]CH), 7.22
(d, J¼8.9 Hz, 1H, Ar), 7.41 (t, J¼7.9 Hz, 1H, Ar), 7.57 (t, J¼7.4 Hz, 1H,
Ar), 7.76 (s, 1H, Ar), 7.78 (d, J¼2.5 Hz, 1H, Ar), 8.13 (d, J¼8.8 Hz, 1H,
d
1.38 (t, J¼7.0 Hz, 3H, OCH2CH3), 4.33 (q, J¼7.0 Hz, 2H, OCH2CH3),
4.57 (s, 2H, OCH2), 7.05 (d, J¼8.7 Hz, 1H, Ar), 7.50 (dd, J¼2.5, 8.7 Hz,
1H, Ar), 7.63 (d, J¼2.0 Hz, 1H, Ar), 7.77 (s, 1H, CHAr) ppm. 13C NMR
(75 MHz, CDCl3):
d 14.2, 61.9, 78.5, 116.9, 122.5, 127.4, 131.7, 136.4,
Ar), 8.42 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.2, 14.3,
136.8, 144.0, 158.4, 165.2, 192.1 ppm. IR (KBr) 2923, 2854, 2854,
1711, 1680, 1605, 1474, 1379, 1285, 1255, 1224, 1191, 1115, 1038 cmꢀ1
.
60.4, 61.5, 70.9, 117.8, 119.7, 120.3, 122.7, 124.8, 127.7, 128.8, 130.2,
131.5, 133.2, 133.6, 135.1, 146.3, 161.4, 166.6, 167.2 ppm. IR (KBr)
2976, 2926, 1712, 1609, 1555, 1461, 1388, 1279, 1216, 1151, 1056,
1014 cmꢀ1. MS (ESI): 353 [MþH]þ, 375 [MþNa]þ; HRMS-ESI calcd
for C21H20O5 Na [MþNa]þ 375.1203; found 375.1215.
MS (ESI): 333, 335 [MþNa]þ. HRMS-ESI calcd for C13H11BrO4Na
[MþNa]þ 332.97329; found 332.97411.
4.5.3. (E)-Ethyl 7-chloro-3-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate (4g). Yield 234 mg (88%); colorless solid; Rf (20%
EtOAc/hexane) 0.38; mp 54e55 ꢁC. 1H NMR (300 MHz, CDCl3):
4.4.19. (3Z,4E)-Ethyl 3-(2-ethoxy-2-oxoethylidene)-2,3-
dihydronaphtho[1,2-b]oxepine-4-carboxylate (3s). Yellow liquid. Rf
d
1.37 (t, J¼7.3 Hz, 3H, OCH2CH3), 4.32 (q, J¼7.3 Hz, 2H, OCH2CH3),
(20% EtOAc/hexane) 0.46; 1H NMR (300 MHz, CDCl3):
d 1.32 (t,
4.56 (s, 2H, OCH2), 7.09 (d, J¼8.5 Hz, 1H, Ar), 7.35 (d, J¼8.5 Hz, 1H,
J¼6.8 Hz, 3H, OCH2CH3), 1.44 (t, J¼6.8 Hz, 3H, OCH2CH3), 4.21 (q,
J¼6.8 Hz, 2H, OCH2CH3), 4.38 (q, J¼6.8 Hz, 2H, OCH2CH3), 5.47 (s,
2H, OCH2), 6.50 (s, 1H, C]CH), 7.22 (d, J¼9.0 Hz, 2H, Ar), 7.42 (t,
J¼7.6 Hz, 1H, Ar), 7.57 (t, J¼7.6 Hz, 1H, Ar), 7.77 (d, J¼9.0 Hz, 1H,
Ar), 8.13 (d, J¼8.3 Hz, 1H, Ar), 8.42 (s, 1H, CHAr) ppm. 13C NMR
Ar), 7.47 (s, 1H, Ar), 7.76 (s, 1H, CHAr) ppm. 13C NMR (75 MHz,
CDCl3):
d 14.2, 61.8, 78.4, 122.1, 126.8, 129.6, 130.5, 133.3, 133.8,
143.7, 157.9, 165.0, 191.8 ppm. IR (KBr) 2922, 1714, 1681, 1607, 1477,
1384, 1274, 1193, 1105, 1033 cmꢀ1. MS (ESI): 267, 269 [MþH]þ, 289,
291 [MþNa]þ. HRMS-ESI calcd for C13H11ClO4Na [MþNa]þ
289.02381; found 289.02356.
(75 MHz, CDCl3):
d 14.2, 14.3, 60.5, 61.4, 67.0, 117.2, 120.5, 121.9,
123.7, 126.2, 127.2, 128.3, 128.5, 130.6, 131.2, 133.1, 135.4, 141.4,
158.3, 166.6, 167.0 ppm. IR (KBr) 2974, 2922, 1718, 1603, 1548,
1452, 1372, 1260, 1222, 1156, 1043, 1014 cmꢀ1. MS (ESI): 353
[MþH]þ, 375 [MþNa]þ.
4.5.4. (E)-Ethyl
carboxylate (4j). Yield 210 mg (80%); yellow liquid; Rf (20% EtOAc/
hexane) 0.50; 1H NMR (300 MHz, CDCl3):
7-methoxy-3-oxo-2,3-dihydrobenzo[b]oxepine-4-
d
1.38 (t, J¼7.0 Hz, 3H,
OCH2CH3), 3.81 (s, 3H, OCH3), 4.32 (q, J¼7.0 Hz, 2H, OCH2CH3),
4.4.20. (6E,8Z)-Ethyl
8-(2-ethoxy-2-oxoethylidene)-2,2-dimethyl-
4.54 (s, 2H, OCH2), 6.91e6.98 (m, 2H, Ar), 7.06 (d, J¼8.8 Hz, 1H,
3,4,8,9-tetrahydro-2H-oxepino[3,2-g]chromene-7-carboxylate
Ar), 7.80 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
d 14.3, 55.7,
(3t). Yellow liquid; Rf (20% EtOAc/hexane) 0.40; 1H NMR (300 MHz,
61.6, 79.2, 117.6, 120.0, 121.6, 126.4, 128.1, 132.6, 145.2, 153.5, 155.9,
165.5 ppm. IR (KBr) 2924, 1729, 1675, 1607, 1571, 1496, 1464, 1389,
CDCl3):
d
1.32 (t, J¼7.2 Hz, 3H, OCH2CH3),1.34 (s, 6H, 2ꢂCH3), 1.38 (t,
J¼7.2 Hz, 3H, OCH2CH3), 1.80 (t, J¼6.8 Hz, 2H, CH2), 2.72 (t, J¼6.8 Hz,
2H, CH2Ar), 4.21 (q, J¼7.2 Hz, 2H, OCH2CH3), 4.29 (q, J¼7.2 Hz, 2H,
OCH2CH3), 5.19 (s, 2H, OCH2), 6.40 (s, 1H, Ar), 6.52 (s, 1H, C]CH),
7.05 (s, 1H, Ar), 7.55 (s, 1H, CHAr) ppm. 13C NMR (75 MHz, CDCl3):
1244, 1209, 1164, 1039 cmꢀ1
.
MS (ESI): 263 [MþH]þ, 285
[MþNa]þ. HRMS-ESI calcd for C14H14O5Na [MþNa]þ 285.07334;
found 285.07257.
d
14.2, 14.3, 21.5, 26.9, 32.6, 60.3, 61.1, 66.4, 75.6, 107.0, 115.8, 116.4,
Acknowledgements
120.8, 127.1, 136.9, 141.5, 144.6, 158.1, 160.6, 166.6, 166.8 ppm. IR
(KBr) 3451, 2923, 2852, 1709, 1616, 1552, 1495, 1458, 1207, 1126,
1058 cmꢀ1. MS (ESI): 387 [MþH]þ, 409 [MþNa]þ. HRMS-ESI calcd
for C22H26O6Na [MþNa]þ 409.16216; found 409.16175.
The authors thank Dr. J.S. Yadav, Director and Dr. J. Madhusu-
dana Rao, former HOD, Organic Chemistry Division-1, CSIR-IICT for
their constant encouragement. The authors thank Dr. V. Jayathirtha
Rao, Chief Scientist, CSIR-IICT for useful discussions. Financial as-
sistance to G.S. from CSIR and J.A.K. from UGC, New Delhi is
gratefully acknowledged.
4.5. Typical procedure for the synthesis of (E)-ethyl 3-oxo-2,3-
dihydrobenzo[b]oxepine-4-carboxylates (4a, 4f, 4g & 4j)
Supplementary data
A mixture of ethyl 2-(chloromethyl)-2-hydroxy-2H-chromene-
3-carboxylate
ethoxycarbonylethylidene)triphenylphosphorane
2a,
(268
mg,
1.0
mmol)
and
(506
(1-
mg,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.05.047.
1.4 mmol) in DCM (4 mL) were stirred at the room temperature for
6 h (TLC) under nitrogen atmosphere. After the completion of the
reaction, the solvent was evaporated under reduced pressure, crude
residue was purified by column chromatography (hexane/ethyl
acetate 9:1) afford (E)-ethyl 3-oxo-2,3-dihydrobenzo[b]oxepine-4-
carboxylate 4a (190 mg, 82% yield) as yellow liquid.
References and notes
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