Didehydroisobenzofuran: A New Reactive Intermediate for Construction of Isoacenofuran

Article abstract of DOI:10.1002/chem.201804655

An efficient generation method of didehydroisobenzofuran, a new heteroaryne species, was developed by bromine/lithium exchange of the dibromoisobenzofuran. The reactive intermediate, thus generated, was trapped by appropriate arynophile to give the [2+2], [2+3], and [2+4] cycloadducts, respectively. Moreover, the reaction could be applied to the syntheses of isoanthracenofurans (anthra[2,3-c]furans), a new class of heteroacenes, with isoelectoronic structure to the corresponding acenoheteroles (anthra[2,3-b]furans).

Full text of DOI:10.1002/chem.201804655

A Journal of
Accepted Article
Title: Didehydroisobenzofuran: a new reactive intermediate for
construction of isoacenofuran
Authors: Toshiyuki Hamura, Suguru Matsuoka, Sunna Jung, Kaoru
Miyakawa, Yu Chuda, and Ryo Sugimoto
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To be cited as: Chem. Eur. J. 10.1002/chem.201804655
Link to VoR: http://dx.doi.org/10.1002/chem.201804655
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COMMUNICATION
Didehydroisobenzofuran: a new reactive intermediate for
construction of isoacenofuran
Suguru Matsuoka, Sunna Jung, Kaoru Miyakawa, Yu Chuda, Ryo Sugimoto, and Toshiyuki Hamura*
Dedication ((optional))
Abstract: An efficient generation method of didehydroisobenzofuran, dibromoisobenzofuran 2 served as a synthetic equivalent to 1,
a new heteroaryne species, was developed by bromine–lithium
exchange of the dibromoisobenzofuran. The reactive intermediate,
thus generated, was trapped by appropriate arynophile to give the
allowing expeditious assembly of polycycle 5 by two directional
[
3–5]
[2+4] cycloadditions.
Further study on developing the
synthetic utility of dibromoisobenzofuran 2 revealed that the
direct generation of didehydroisobenzofuran 1 was feasible by
two-step protocol including the bromine–lithium exchange of
dibromoisobenzofuran 2 (Eq. 3). This new heteroaryne, thus
generated, was trapped with arynophile to give functionalized
[
2+2], [2+3], and [2+4] cycloadducts, respectively. Moreover, the
reaction could be applied to the syntheses of isoanthracenofurans
anthra[2,3-c]furans), novel class of heteroacenes, with
isoelectoronic structure to the corresponding acenoheteroles
anthra[2,3-b]furans).
(
a
[
6,7]
(
isobenzofuran with various synthetic potential.
Moreover, the
[
2+4] cycloadduct was converted to isoanthracenofuran, a novel
class of heteroacenes with isoelectoronic structure to the
corresponding anthra[2,3-b]furans, which is described in this
communication.
Design and generation of a reactive intermediate is an important
subject in organic chemistry, because discovery of a novel
reactivity inherent in its unique structure would lead to develop a
Table
1 shows the initial study for the generation of
new reaction, which opens
a
way to access to various
[8,9]
didehydroisobenzofuran, which was trapped with arynophile.
Upon treatment of dibromodiphenyisobenzofuran 8, a model
substrate, with n-BuLi (2.0 equiv) in the presence of
diphenylisobenzofuran 9 (1.5 equiv, THF, 0 °C → r.t., 3 h), [2+4]
cycloaddition occurred to give the cycloadduct 10 in 40% yield
[
1]
functionalized organic molecules.
•
•
Direct synthetic use
(
entry 1). The structure of 10 was determined by NMR analysis.
6
5
Br
Br
O
O
(1)
O
O
Screening of the reaction conditions revealed that toluene was a
choice of solvent to produce the desired product in better yield
1
5
1
2
(
entry 3). Moreover, s-BuLi and PhLi were also available for the
Formal synthetic use (previous work)
generation of didehydroisobenzofuran, giving the cycloadduct 10
in moderate yield (entries 4 and 5). These results were contrary
to the poor results using t-BuLi, i-PrMgBr, and i-PrMgCl•LiCl
Br
Br
Br
Br
O
O
O
O
(2)
(
entries 6–8).
2
3
4
5
•
Two-step generation of didehydroisobenzofuran and its trapping (this work)
Table 1. Generation and trapping of didehydroisobenzofuran.
Br
Br
Met
Br
R-Met
RBr
O
O
O
O
(3)
Ph
O
Ph
O
Ph
O
Ph
O
Br
Br
conditions1)
2
6
Met-Br
1
7
0
°C → r.t.
Ph
Ph
Ph
Ph
Scheme 1. Didehydroisobenzofuran,
a
new reactive intermediate for
8
9
10
construction of polycyclic structure.
Entry
R-Met
n-BuLi
Solvent
THF
Yield (%)
1
2
3
4
5
6
7
8
40
42
57
38
41
In this context, we previously reported a formal synthetic use of
didehydroisobenzofuran 1, possessing a highly strained 1,2-
n-BuLi
2
Et O
n-BuLi
toluene
THF
didehydroarene structure at the C
5 6
–C position, enabling rapid
construction of polycyclic structures through the successive
s-BuLi
[
2]
cycloadditions (Eqs.
1
and 2).
In this process,
PhLi
THF
2
)
t-BuLi
THF
–
–
3
)
[a]
Mr. S. Matsuoka, Dr. S. Jung, Mr. K. Miyakawa, Mr. Y. Chuda, Mr.
R. Sugimoto, Prof. Dr. T. Hamura
i-PrMgBr
i-PrMgBr•LiCl
THF
THF
19
Department of Applied Chemistry for Environment, Kwansei Gakuin
University
1
)
R-Met (2.0 equiv) and diphenylisobenzofuran 9 (1.5 equiv) were used.
2
-1 Gakuen, Sanda 669-1337, Japan
2)
The reduced 5-bromo-1,3-diphenylisobenzofuran was produced in
E-mail: thamura@kwansei.ac.jp
3
4% yield. The starting materials were recovered.
)
1
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
In these reactions, one plausible structure of byproducts
was the dual-cycloadduct (structure not shown) by further
reaction with the initially formed cycloadduct 10, which was
worked well as a trapping agent to give the [2+2] cycloadduct 19
in 79% yield. In addition, the [2+3] cycloaddition was realized by
reaction of didehydroisobenzofuran B and nitrone 20 to produce
[
10]
[14]
detected by MALDI-TOF mass spectrometry (Figure S1).
the cycloadduct 21, albeit in low yield.
This competing reaction with didehydroisobenzofuran was
due to the similar reactivity of the furan moiety in 10
compared with that of diphenylisobenzofuran 9.
R
O
To suppress the formation of the above-mentioned
[
11]
multiple-cycloadducts,
possessing sterically crowded 2,6-xylyl groups in the furan
moiety was tested as another precursor of
didehydroisobenzofuran. In addition, to gain the precise
behavior regarding the two-step generation of
dibromoisobenzofuran
11
O
R
R
O
R
Ar
O
Ar
O
9a: R = Ph
9b: R =
C
1
5
CPh
O
n-BuLi, THF
n-BuLi or PhLi
toluene
–
40 °C, 5 h
Ar
Ar
–40 °C
1
6 (81%)
(79%)3)
17a (94%)
17b (86%)
Ar
O
didehydroisobenzofuran, the reaction was conducted at
lower temperature: upon treatment of 11 with 1.2 equiv of n-
BuLi (1.60 M in hexane) in the presence of dimethyl furan
Br
Br
Ar
11,2)
1
1
2 (6.0 equiv, THF, –95 → –78 °C, 5 min), the [2+4]
Ph
O
EtO
H
OTBS
H
cycloadduct 14 was obtained only in 4% yield, and the
major product was bromoisobenzofuran 13 lacking one
bromine atom (88%). This result implies that aryllithium
species A generated by the Br/Li exchange of 11 has a
Ar
O
N
Ar
O
Ph
OTBS
OEt
t-Bu
18
20
N
O
t-Bu
PhLi, toluene
–40 ºC, 1.5 h
n-BuLi, toluene
–40 → –20 ºC
40 min
Ar
Ar
1
9 (79%)
21 (25%)
[
12,13]
finite lifetime at –78 °C.
60%)4)
(
On the other hand, if the same reaction was performed
initially at –78 °C followed by warming to –50 °C, [2+4]
cycloadduct 14 was obtained as a major product in 53%
yield. At –50 °C, lithio species A undergoes 1,2-elimination
of LiBr to generate the didehydroisobenzofuran B. These
behaviors provided us with the handle to control generation
of the two reactive species A and B.
Scheme 3. [2+4], [2+3], and [2+2] cycloadditions of didehydroisobenzofuran.
) Ar: 2,6-dimethylphenyl. 2) Arynophile (1.2~5.0 equiv) and R-Li (1.5~2.5
equiv) were used. 3) n-BuLi, toluene, –78 ºC → rt. 4) n-BuLi, toluene, –40 °C.
1
As one of the synthetic application, the high-ordered polyacene
framework could be efficiently synthesized by two-directional
[
15]
annulation of didehydroisobenzofuran (Scheme 4).
Me
Me
Me
Me
Me
O
Ph
Ph
Me
O
Me
Me
Me
Me
Me
Me
Br
Br
H
n-BuLi
O
O
O
O
O
Ph
O
Ph
O
THF
Ph
O
Br
Br
Br
Me
Me
Ph
Ph
n-BuLi
Me
Me
10
1
2
toluene
1
1
13
14
Br
Br
Br
–40 → 0 °C
Ph
Ph
Ph
6
9%
23
9
–
98 → –78 °C
88%
4
%
Ar
Ar
Br
–
78 → –50 °C 35%
Li
53%
2
2
O
O
–40 °C
16%
27%
6
3%
0%
n-BuLi, toluene
–40 → 0 °C
Br
–
40 → 0 °C
Ph
4
Ar
Ar
Br
Br
A
B
5
3%
O
Ar: 2,6-dimethylphenyl
Ph
Ph
O
Ph
Ph
C
D
Scheme
didehydroisobenzofuran.
2.
[2+4]
Cycloaddition
of
sterically
congested
Ph
O
Ph
O
O
O
Ph
Ph
Ph
2
4
Ph
Ph
E
By using various arynophiles, functionalized isobenzofurans
were accessible via the [2+4], [2+3], and [2+2] cycloadditions
Scheme 4. Efficient synthetic access to high-ordered polyacene framework via
two-directional annulations of didehydroisobenzofuran C.
(
Scheme 3). Typical experimental procedure is represented by
furan cycloaddition: To a mixture of dibromide 11 and furan 15
5.0 equiv) in THF was slowly added n-BuLi (1.5 equiv in
(
hexane) at –40 °C. After 5 h, the reaction was stopped by
adding water. Extractive workup followed by purification by
silica-gel column chromatography gave the cycloadduct 16 in
In
the
first
step,
the
[2+4]
cycloaddition
of
didehydroisobenzofuran
C
and diphenylisobenzofuran
9
described in Table 1 (entry 3) was conducted to give the mono-
8
1% yield.
Similarly, diphenylisobenzofuran 9a and
cycloadduct 10, which was directly used as an arynophile by
dialkynylisobenzofuran 9b prove to be applicable for the [2+4]
cycloaddition, affording pentacycles 17a and 17b in 94% yield
and 86% yield, respectively. Moreover, ketene silyl acetal 18
reaction with dibromobenzyne D, selectively generated from
[16]
tetrabromobenzene (22)
(n-BuLi, toluene, –40 → 0 °C),
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COMMUNICATION
affording the diepoxypentacene 23.
Subsequent third
cycloaddition of heptacyclic aryne E, generated from 23, and
isobenzofuran occurred cleanly to produce the highly
9
1
7a
6a
6b
condensed polycycle 24 as a mixture of stereoisomers.
2
Scheme 5 shows the conversion of the [2+4] cycloadduct 17a
to the isoanthracenofuran 26a by two-step sequences including
the reductive aromatization of the ring opened diol derivative.
Interestingly, the first ring opening of the substrate 17a with 4 M
2
H
2
SO
5a in high yield without producing the isomeric diol 25a’.
Subsequent reductive aromatization of 25a occurred cleanly by
treatment with 3.0 equiv of SnCl (toluene, 25 °C). Evaporation
4 N
(THF, 50 °C) proceeded in S 2’ manner to give the diol
2
2
of the solvent, followed by washing the crude product with
MeOH gave essentially pure isoanthracenofuran 26a as a blue
solid.
Importantly, the product 26a is a novel class of
2 2
in CH Cl
heteroacene in that an o-quinoidal structure is only drawn in the
closed-shell resonance form, and therefore, it would show
unique physyical properties as well as high reactivities
compared to the corresponding isoelectronic acene analogues
0
2
50 300 350 400 450 500 550 600 650 700 750 800 850 900
Wavelength (nm)
[
17]
Figure 1. UV-vis absorption spectra of isobenzofuran 17a, and
(
e.g. diphenyltetracene).
Indeed, NMR analysis showed that
was readily oxidized
isoanthracenofurans 26a and 26b (in CH
2
Cl
2
).
isoanthracenofuran 26a dissolved in CDCl
3
to the endoperoxide 27a (Figure S2), although 26a was
relatively stable in the solid-state and could be stored under Ar
atomospher for several months.
In summary,
an
efficient
generation
method
of
didehydroisobenzofurans, a new heteroaryne species, was
developed by bromine–metal exchange of the
dibromoisobenzofurans. The reactive intermediates, thus
In a similar two-step sequence, the isobenzofuran 17b could
also be converted to the dialkynylated isoanthracenofuran 26b,
which was more stable than diaryl derivative 26a. In this case,
the formation of endoperoxide 27b occurred gradually after 1 h
generated, were efficiently trapped by appropriate arynophiles
to give the various cycloadducts, and some of them could be
(
Figure S4).
converted to anthra[2,3-c]furans,
heteroacenes, with isoelectoronic
corresponding (anthra[2,3-b]furans).
a
novel class of
structure to the
Further synthetic
OH Ph
Ph
Ph
Ar
O
SnCl2
Ar
O
4
M H2SO4
cat. 4 M H2SO4
applications are under active investigation in our laboratory.
1
7a
THF, 50 ºC
toluene, 25 ºC
82%
9
1% Ar
Ar
OH Ph
2
5a
26a
Ar: 2,6-dimethylphenyl
Acknowledgements
Ar
O
Ph OH
Ar
O
R
Ar
Ph
This work was supported by JSPS KAKENHI Grant Number
JP15H05840 in Middle Molecular Strategy and JST ACT-C
Grant Number JPMJCR12YY, Japan.
O
O
O
Ar
Ph OH
5a'
Ar
Ar
R
Ph
2
26b (R:
C
CPh)
27a
Keywords: reactive intermediate • didehydroisobenzofuran •
isoacenofuran • polycycle • π-conjugated molecule
Scheme 5. Syntheses of isoanthracenofurans 26a and 26b.
[
1]
a) R. A. Moss, M. S. Platz, M. Jones, Jr., Eds. Reactive Intermediate
Chemistry; Wiley: Hoboken, NJ, 2004; b) M. S. Singh, Reactive
Intermediates in Organic Chemistry; Wiley-VCH: Weinheim, Germany,
2014.
The absorption spectra of 26a and 26b in CH
Figure 1, together with that of 1,3-diarylisobenzofuran 17a for
comparison. Isoanthracenofuran 26a has its absorption
2 2
Cl are shown in
maximum at 647 nm, which is largely red-shifted compared to
isobenzofuran 17a (λabs = 358 nm). This result clearly shows the
significant effect by introducing butadiene units on to the
isobenzofuran core, which makes the structure more quinoidal.
In addition, the introduction of phenylethynyl groups into the
acene core significantly affects the photophysical property: the
alkynyl derivative 26b exhibits an absorption in the near-infrared
[2]
a) S. Eda, T. Hamura, Molecules 2015, 20, 19449–19462; b) H.
Haneda, S. Eda, M. Aratani, T. Hamura, Org. Lett. 2014, 16, 286–289.
For selected reviews on isobenzofurans: a) W. Friedrichsen, Adv.
Heterocyl. Chem. 1980, 26, 135–241; b) W. Friedrichsen, Adv.
Heterocyl. Chem. 1999, 73, 1–96.
[
[
3]
4]
For selective synthetic examples of isobenzofuans, see: a) P. Binger, P.
Wedemann, R. Goddard, U. H. Brinker, J. Org. Chem. 1996, 61, 6462–
6464; b) R. Rodrigo, Tetrahedron, 1988, 44, 2093–2135; c) H. N. C.
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Mak, H. N. C. Wong, J. Org. Chem. 1990, 55, 3214–3221; e) S.-H.
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J. E. Rainbolt, G. P. Miller, J. Org. Chem. 2007, 72, 3020–3030.
(
NIR) region with the maximum at 720 nm, which is red-shifted
about 73 nm in comparison with that of 26a, revealing its quite
narrow bandgap electronic structure.
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Chemistry - A European Journal
10.1002/chem.201804655
COMMUNICATION
[
5]
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Chem. Soc. 1971, 93, 2346–2348; b) R. N. Warrener, M. Shang, D. N.
Butler, Chem. Commun. 2001, 1550–1551; c) A. Sygula, R. Sygula, P.
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3420–3425; c) C. Nájera, J. M. Sansano, M. Yus, Tetrahedron, 2003,
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Serwatowski, Tetrahedron 2005, 61, 6590–6595.
[
6]
Recently, we developed one-pot synthetic method of 1,3-
diarylisobenzofurans by sequential reaction of methyl 2-formylbenzoate
with two identical or different aryl metal species, see: T. Hamura, R.
Nakayama, Chem. Lett. 2013, 42, 1013–1015. See also: K. Asahina, S.
Matsuoka, R. Nakayama, T. Hamura, Org. Biomol. Chem. 2014, 12,
[13] For selected reactions of o-dihalobenzenes with n-BuLi, see: a) H.
Gilman, R. D. Gorsich, J. Am. Chem. Soc. 1956, 78, 2217–2222; b) L.
S. Chen, G. J. Chen, C. Tamborski, J. Organomet. Chem. 1980, 193,
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Org. Lett. 2004, 6, 1589–1592.
9
773–9776.
[
[
7]
8]
For our synthetic application of isobenzofurans to polyacene derivatives,
[14] As for the solvent choice used in these cycloadditions, the suitable
conditions are dependent on the substrate combination and
organolithium reagents.
see: a) R. Akita, K. Kawanishi, T. Hamura, Org. Lett. 2015, 17, 3094–
3
097; b) S. Eda, F. Eguchi, H. Haneda, T. Hamura, Chem. Commun.
015, 51, 5963–5966. See also ref 2.
2
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Bettinger, Pure Appl. Chem. 2010, 82, 905–915.
For selected reviews on arynes: a) R. W. Hoffmann, Dehydrobenzene
and Cycloalkynes, Academic, New York, 1967; b) S. V. Kessar, In
Comprehensive Organic Synthesis; Trost, B. M. Ed., Pergamon: Oxford,
U. K., 1991, Vol. 4, pp. 483–515; c) H. Pellissier, M. Santelli,
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Markina, R. C. Larock, Org. Biomol. Chem. 2013, 11, 191–218.
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See also ref 2b.
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pioneering studies by Hart on the generation and trapping of 1,4-
benzdiyne equivalents, see: a) H. Hart, D. Ok, J. Org. Chem. 1986, 51,
979–986. (b) H. Hart, C.-Y. Lai, G. Nwokogu, S. Shamouilian, A.
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Yamada, F. Wudl, Org. Lett. 2003, 5, 4433–4436.
[
9]
[
[
10] For details, see supporting information.
11] The dibromoisobenzofuran 11 was efficiently prepared in four steps
including the sequential reactions of methyl 2-formylbenzoate with two
identical aryl Grignard reagent. For details, see supporting information.
12] For selected examples of halogen–lithium exchange of functionalized
arenes, see: a) J. Clayden, Organolithiums: Selectivity for Synthesis,
[17] Recently, a synthetic method of isoacenothiophenes, non-classical S-
heteroacenes, was developed, see: X. Shi, T. Y. Gopalakrishna, Q.
Wang, C. Chi, Chem. Eur. J. 2017, 23, 8525–8531.
[
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Chemistry - A European Journal
10.1002/chem.201804655
COMMUNICATION
COMMUNICATION
Suguru Matsuoka, Sunna Jung, Kaoru
Miyakawa, Yu Chuda, Ryo Sugimoto,
and Toshiyuki Hamura*
R
R
Ar
O
Br
n-BuLi
O
O
O
Br
Page No. – Page No.
new heteroaryne
Ar
Didehydroisobenzofuran:
a
new
reactive intermediate for construction
of isoacenofuran
An efficient generation method of didehydroisobenzofuran, a new heteroaryne
species, was developed by bromine–lithium exchange of the
dibromoisobenzofuran. The reactive intermediate, thus generated, was trapped by
arynophiles to give various cycloadducts, one of which could be converted to
isoanthracenofurans, a novel class of heteroacenes, possessing unique physical
properties.
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