Facile and practical synthesis of π-extended oxepins by benzannulation and intramolecular cyclization

Article abstract of DOI:10.1016/j.tetlet.2018.12.008

π-Extended oxepins 1 and dimer 8 were synthesized by the benzannulation of the corresponding asymmetric diarylacetylene derivatives and 2-(phenylethynyl)benzaldehyde followed by the Cu-catalyzed intramolecular cyclization. The optical properties of the π-extended oxepins 1 and 8 are also investigated.

Full text of DOI:10.1016/j.tetlet.2018.12.008

Accepted Manuscript
Facile and practical synthesis of π-extended oxepins by benzannulation and in-
tramolecular cyclization
Rui Umeda, Yuji Shimizu, Yuta Ida, Masahiro Ikeshita, Shuichi Suzuki, Takeshi
Naota, Yutaka Nishiyama
PII:
S0040-4039(18)31440-0
https://doi.org/10.1016/j.tetlet.2018.12.008
TETL 50471
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 November 2018
28 November 2018
3 December 2018
Please cite this article as: Umeda, R., Shimizu, Y., Ida, Y., Ikeshita, M., Suzuki, S., Naota, T., Nishiyama, Y., Facile
and practical synthesis of π-extended oxepins by benzannulation and intramolecular cyclization, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.008
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Facile and practical synthesis of π-extended
oxepins by benzannulation and
intramolecular cyclization
Leave this area blank for abstract info.
Rui Umeda,* Yuji Shimizu, Yuta Ida, Masahiro Ikeshita, Shuichi Suzuki, Takeshi Naota, and Yutaka
Nishiyama

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Facile and practical synthesis of π-extended oxepins by benzannulation and
intramolecular cyclization
Rui Umeda,a ,* Yuji Shimizua , Yuta Idaa , Masahiro Ikeshitab , Shuichi Suzukib , Takeshi Naotab and
Yutaka Nishiyamaa
aFaculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho Suita, Osaka 564-8680, Japan
bGraduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka 560-8531, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
π-Extended oxepins 1 and dimer 8 were synthesized by the benzannulation of the corresponding
asymmetric diarylacetylene derivatives and 2-(phenylethynyl)benzaldehyde followed by the Cu-
catalyzed intramolecular cyclization. The optical properties of the π- extended oxepins 1 and 8
are also investigated.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Oxepin
Benzannulation
Intramolecular cyclization
Copper catalyst
The dibenzo[b,f]oxepin derivative are known to display a wide
range of biological activity and pharmaceutical properties and are
expected to be used as broad pharmacological application such as
antipsychotic, antidepressant, therapeutic agents, and so on.1
Therefore, the synthesis of their derivatives has been intensively
investigated.2,3 On the other hand, it has been recently reported
that a derivative having a tribenzo[b,d,f ]oxepine skeleton can be
used as an organic EL device, and further utilization of the π-
extended oxepin derivatives would be expected.4,5
We now plan to synthesize the dibenzo[b,f]naphth[2,3-
d]oxepin derivatives 1 by the demethylation and intramolecular
cyclization of 2, which could be prepared by the Asao and
Yamamoto benzannulation reaction9,10 of asymmetric
diarylacetylene
(Scheme 1).
3
and 2-(phenylethynyl)benzaldehyde (4)
Demethylation
and
Cyclization
Benzannulation
OMe
Ar
CHO
+
Ar
Br
Ar
Br
Ph
O
OMe
4
2
1
3
O
O
O
Scheme 1
dibenzo[b,f]naphth[2,3-d]oxepin
dibenz[b,f]oxepin
tribenz[b,d,f]oxepin
The synthesis of π-extended oxepins 1 is shown in Scheme 2.
First, 1-iodo-2-methoxybenzene derivatives 5a-c and 1-iodo-2-
methoxynathpthlene (5d) as starting materials can be easily
prepared by direct iodination of the corresponding aromatic
compounds with iodine and periodic acid.11 The Sonogashira
coupling of 1-iodo-2-methoxybenzene derivatives 5a-c or 1-iodo-
2-methoxynathpthlene (5d) and 1-bromo-2-ethynylbenzene (6)
gave the corresponding asymmetric diarylacetylene derivatives
3a-d in excellent yields. The Cu-catalyzed benzannulation of 2-
(phenylethynyl)benzaldehyde (4) and 3a-c in the presence of the
trichloroacetic acid afforded 2a-c in good yields. In the case of
sterically bulky 2d, the yield of 2d was slightly lower than those
of 2a-c and 2d was obtained as an inseparable mixture of
rotamers (3:2). Finally, the demethylation of 2a-d by the
treatment with BBr3 under -78 ˚C occurred to form 7a-d followed
by the Cu-catalyzed intramolecular cyclization to give the π-
Compared to derivatives of dibenzo[b,f]oxepin and
tribenzo[b,d,f]oxepin, examples of the synthetic methods of
dibenzo[b,f]naphth[2,3-d]oxepin and its derivatives are still rare.
Ila and coworker have accomplished the first synthesis of
dibenzo[b,f]naphth[2,3-d]oxepin
from
10,11-
dihydrodibenzoxepin-10-one as starting material, though this
synthetic method required multiple steps.6 Very recently,
Korean5b and Japanese7 groups reported independently the
synthesis of dibenzo[b,f]naphth[2,3-d]oxepin derivative by the
Pd-catalyzed annulative two-fold cross-coupling of dibromo
diphenylether derivative and diborylnaphthalene derivative or
dibromonaphthalene derivative and cyclic diarylborinic acid,
respectively. 8

2
Tetrahedron
extended oxepins 1a-d in moderate to excellent yields. The
1c substituted with a chlorine group exhibited almost the same as
that of 1a. In the absorption spectra of 1d having two
naphthalene rings, a new broad absorption was observed at 277
nm and at 331 nm. On the other hand, in the UV-vis absorption
spectra of the dimer 8, the absorption wavelength was not shifted
as compared with that of the monomer 1a, and the molar
absorption coefficient at 265 nm was only increased. This result
suggests that no effective conjugation is working between the
two oxepin units. Although the fluorescence spectra of π-
extended oxepin derivatives 1a-d and 8 were measured, no
fluorescence emission was observed.
yield of 1b having methoxy group, electron donor group, is lower
than those of 1a and 1c. These results are probably due to the
acidity of hydroxy groups of 7.
4
cat.Cu(OTf)2
cat.Pd(PPh3)4
Cul
Br
I
CCl3COOH
Br
Ar
Ar
+
ClCH2CH2Cl
80 °C
Et3N, THF
r.t.
OMe
OMe
3a (90%), 3b (98%),
3c (93%), 3d (96%)
5a-d
6
OMe
Ar
OH
Ar
cat.CuI, 1-butylimidazole
K2CO3
BBr3
Ar
O
Br
Br
CH2Cl2
-78 °C to r.t.
toluene
120 °C
1a (83% in two steps),
1b (46% in two steps),
1c (98% in two steps),
1d (51% in two steps)
7a-d
2a (62%), 2b (68%),
2c (77%), 2d (52%)
Me
Cl
O
O
O
O
1a
1b
1c
1d
Scheme 2
Next, the dibenzo[b,f]naphth[2,3-d]oxepin dimer 8 was also
prepared in same manner as described for 1 (Scheme 3). First, the
double iodination of 4,4’-dimethoxybiphenyl gave 3,3’-diiodo-
4,4’-dimethoxybiphenyl (9). Sonogashira coupling of 9 and 1-
bromo-2-ethynylbenzene (6) afforded 10 and then Cu-catalyzed
benzannulation with 2-(phenylethynyl)benzaldehyde (4) gave 11
in 91% yield. The dibenzonaphthoxepin dimer 8 was obtained by
demethylation and intramolecular cyclization.
6
cat.Pd(PPh3)4
CuI
H5IO6
I2
MeO
MeO
I
I
MeOH
THF, Et3N
r.t.
OMe
OMe
70 °C, 4 h
48%
97%
9
Figure 1. UV-vis absorption spectra of π-extended oxepin
derivatives 1a-d and 8 in CH2Cl2.
Br
4
Br
cat.Cu(OTf)2
MeO
Br
RO
CCl3COOH
ClCH2CH2Cl
80 °C
OMe
OR
Table 1. Optical properties of π-extended oxepin
91%
Br
derivatives 1 and 8 in CH2Cl2
10
Absorptiona
11 (R = Me)
12 (R = H)
BBr3, CH2Cl2
-78 °C to r.t.

abs / nm ( / M-1cm-1)
cat.CuI
O
1a
1b
1c
1d
8
265 (77500), 290 (sh, 22600)
266 (95000), 290 (sh, 53600)
265 (78600), 290 (sh, 27800)
261 (76700), 277 (75300), 331 (7100)
265 (144100), 290 (sh, 36000)
1-butylimidazole
K2CO3
toluene
120 °C
O
66%
8 (63% in two steps)
Scheme 3
a[c] = ~10-5 M.
In order to investigate the photophysical properties of π-
extended oxepin derivatives 1a-d and 8, we measured the UV-vis
spectra in dichloromethane solvent and their results are shown in
Figure 1 and Table 1. When UV-vis absorption spectra of 1a was
measured, a strong broad and shoulder peaks were observed 265
nm and around 290 nm, respectively, and the absorption of 1a
was observed up to 330 nm. In the case of 1b substituted with a
methyl group, the absorption wavelength did not change greatly,
though the molar extinction coefficient of 1b observed
significantly larger than that of 1a. UV-vis absorption spectra of
In conclusion, we succeeded in the synthesis of π-extended
oxepin derivatives 1a-d and
8
by the Cu-catalyzed
benzannulation and intramolecular cyclization. The preparation
of various substituted π-extended oxepin derivatives using this
methodology is being undertaken in our laboratories. Also,
further study will be focused on the computational analysis of
them and progress will be reported in due course.

3
Z. P.; Cui, D.-M.; Zhang, C. Org. Biomol. Chem. 2018, 16, 832-
837.
References and notes
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Highlights
A copper catalyzed seven-membered ring system is
described.
A new synthetic method of the π-extended oxepins
is developed.
Photophysical properties of π-extended oxepins are
disclosed.