1,3-Dialkynyl- and 1,3-dialkenylisobenzofurans: New π-extended congeners prepared by double nucleophilic addition of alkynyllithiums to o-phthalaldehyde

Article abstract of DOI:10.1246/cl.160884

Efficient synthetic route to 1,3-dialkynyl- and 1,3-dialkenylisobenzofurans, new π-extended congeners of isobenzofurans, was reported. A three-step protocol including double nucleophilic additions of alkynyllithiums to o-phthalaldehyde and selective oxida

Full text of DOI:10.1246/cl.160884

Received: September 27, 2016 | Accepted: October 7, 2016 | Web Released: October 21, 2016
CL-160884
1
,3-Dialkynyl- and 1,3-Dialkenylisobenzofurans:
New π-Extended Congeners Prepared by Double Nucleophilic Addition
of Alkynyllithiums to o-Phthalaldehyde
T. Hamura
Ryoji Kudo, Kei Kitamura, and Toshiyuki Hamura*
Department of Applied Chemistry for Environment, School of Science and Technology,
Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337
(E-mail: thamura@kwansei.ac.jp)
<
Previous work>
Efficient synthetic route to 1,3-dialkynyl- and 1,3-dialkenyl-
O
OH
isobenzofurans, new π-extended congeners of isobenzofurans,
was reported. A three-step protocol including double nucleo-
philic additions of alkynyllithiums to o-phthalaldehyde and
selective oxidation enables us to prepare various functionalized
π-extended isobenzofurans. The photophysical properties of
these π-extended isobenzofurans are also evaluated.
O
Ar1
Li
[O]
Ar1
Ar1
CHO
OSiR
3
OSiR
3
I
II
III
Ar1
Ar1
O
Li
Ar2
H+
O
OH
O
Keywords: 1,3-Dialkynylisobenzofuran
|
O
π-Extended congener | Three-step synthesis
A
Ar2
IV Ar2
V
Isobenzofurans are 10π electron systems with a quinoid
structure, which can serve as a useful building block for the
construction of various natural/unnatural product syntheses.
In addition, based on their unique physical properties, they have
potential utility as a component of functional materials, e.g.
fluorophores, OLEDs, and photovoltaics.4
In this context, we previously reported a one-pot synthetic
method of 1,3-diarylisobenzofurans by twofold additions of aryl
metal species to o-formyl benzoate, allowing the rapid prepa-
ration of various functionalized derivatives, including an
isobenzofuran dimer.5 Further study, however, revealed that
bis(arylethynyl)isobenzofurans V, new π-extended derivatives,
was not accessible, due to the lower reactivity of the
corresponding alkynyl metal species.6
<
This work>
R1
R1
1
­3
O
1
)
)
Li
Li
R1
[O]
O
OH
H+
H
H
OH
OH
V
2
R2
O
1
R2
R2
VI
IV
Scheme 1. Two synthetic routes to 1,3-dialkynylisobenzofurans.
Ph
Ph
Ph
O
O
Li
(2.2 equiv)
THF
78 0 °C
99%
Ph
Li
(1.1 equiv)
THF
–78 0 °C
98%
Ph
OH
OH
H
H
OH
H
O
Along these lines, an alternative approach to isobenzofurans
has been recently developed by using benzocyclobutenones I as
a masked form of intriguing species A, enabling the preparation
–
O
OH
4
a
1
2a
3a
Ph
6
,7
of various bis(arylethynyl)isobenzofurans V (Scheme 1).
However, it still has a drawback in that multistep syntheses
were required to prepare the starting material I, which hampered
an efficient way to functionalize derivatives of V. Herein we
wish to describe a new synthetic route to 1,3-dialkynylisobenzo-
furans V by using o-phthalaldehyde as a synthetic equivalent
of A. As shown in Scheme 1, double nucleophilic additions of
alkynyllithiums to o-phthalaldehyde (1), and subsequent selec-
tive mono-oxidation of diol VI efficiently gives isobenzofuran V
after acid treatment of the resulting keto-alcohol IV. Importantly,
stepwise introduction of two alkynyl groups to 1 allows for the
selective preparation of symmetrical and unsymmetrical com-
pounds V, including novel (alkenyl)ethynyl, (alkyl)ethynyl, and
Scheme 2. Successive nucleophilic additions of phenylethynyl-
lithium to o-phthalaldehyde (1).
Upon treatment of 1 with 1.1 equiv of phenylethynyllithium in
THF at ¹78 °C, nucleophilic addition occurred selectively at
one of the formyl groups in 1, affording keto-alcohol 2a and
8
lactol 3a as a mixture of products in 98% combined yield.
Importantly, the double additions to 1 did not entirely occur
at ¹78 °C in spite of the treatment of excess amount of
phenylethynyllithium (2.2 equiv). These results indicate that the
reactivity of the lithio intermediates of 2a with phenylethynyl-
lithium is lower than 1 or suppressed by the predominant
formation of the lithio intermediates of 3a in the reaction media.
Indeed, TLC analysis showed that second nucleophilic addition
occurred gradually by warming the reaction to 0 °C. Quenching
the reaction and purification by silica gel column chromatog-
(silyl)ethynyl derivatives. Moreover, dialkenylisobenzofuran, a
new π-extended congener, is also accessible by appropriate
introduction of two alkenyl groups onto the isobenzofuran core.
Scheme 2 shows the initial model study for successive
introduction of two alkynyl groups to o-phthalaldehyde (1).
9
raphy gave diol 4a in 99% yield.
Chem. Lett. 2017, 46, 25–28 | doi:10.1246/cl.160884
© 2017 The Chemical Society of Japan | 25

Table 2. Symmetrical 1,3-dialkynylisobenzofurans
Ph
Ph
Ph
R
R
MnO
toluene
°C rt
5%
2
4 M HCl
THF, rt
O
O
OH
O
O
4a
O
1) MnO2a)
H
H
Li
R
OH
OH
O
0
92%
THF
2) 4 M HClb)
9
5a
6a
7a
–78 0 °C
O
Ph
Ph
Ph
1
4
6
R
R
Scheme 3. Selective oxidation and acid-promoted cyclization to
a
Entry
1
Ar
Yield of 4/% Yield of 6/%
1
,3-bis(phenylethynyl)isobenzofuran (6a).
86 (4j)
97 (4k)
83 (6j)
82 (6k)
80 (6l)
Table 1. Symmetrical 1,3-bis(arylethynyl)isobenzofurans
Ar
Ar
2
3
O
a)
H
H
Li
Ar
OH
OH
1
) MnO
2
Si(i-Pr)3
92 (4l)
O
2) 4 M HClb)
THF
78 0 °C
–
a1.2 equiv of MnO2 in toluene at rt. THF, 0 °C.
b
O
1
4
6
Ar
Ar
group on the aromatic ring was efficiently prepared (Entry 2).
It is noted that isobenzofuran 6d, having an electron-donating
dimethylamino group on the aromatic ring, should be purified by
silica gel column chromatography under Ar atmosphere to avoid
Entry
1
Ar
Yield of 4/% Yield of 6/%
Me
99 (4b)
98 (4c)
71 (6b)
91 (6c)
58 (6d)
72 (6e)
82 (6f)
77 (6g)
71 (6h)
1
0
2
3
4
5
6
7
gradual oxidation with oxygen, affording 6d as stable solids.
OMe
NMe2
F
Halogenated derivatives 6e­6g were also prepared by using
(4-halophenyl)ethynyllithium as nucleophiles. Moreover, iso-
meric pair of alkynylisobenzofurans 6h and 6i with respect to
the connection of the naphthyl group were selectively synthe-
sized by using the corresponding naphthalenylethynyllithiums
92 (4d)
87 (4e)
(
Entries 7 and 8).
Cl
92 (4f)
Less π-conjugated (alkenyl)ethynyl-, (alkyl)ethynyl, and
silyl)ethynyl derivatives 6j­6l were also accessible (Table 2).
(
Br
91 (4g)
quant (4h)
Due to the potential instability, 1,3-dialkylisobenzofurans have
been typically used by in situ generation from appropriate
precursors or specially stabilized by steric protection, e.g.
1
1
incorporating isobenzofuran into an alicyclophane macrocycle.
Fortunately, however, isobenzofuran 6k, alkynylogous form
1
2
8
quant (4i)
71 (6i)
of the 1,3-dicyclohexylisobenzofuran, which would have an
analogous electronic effect as with 1,3-dialkylisobenzofurans,
could be carefully purified by silica gel column chromatography
a1.2 equiv of MnO2 in toluene at rt. THF, 0 °C.
b
10
under Ar atmosphere.
The unsymmetrical isobenzofurans were also efficiently
accessible (Table 3). Taking advantage of the lower reactivity
of the formyl group in monoadduct 2a in comparison with 1
(vide supra), two alkynyl groups were selectively introduced
by sequential addition of two kinds of alkynyllithiums to 1,
affording unsymmetrical diols 8a­8e. Selective mono-oxidation
of diols 8a­8e was again achieved by using MnO2 (1.2 equiv,
toluene, rt), affording keto-alcohols (structure not shown) as a
mixture of structural isomers (ca. 1:1), which were smoothly
converted to unsymmetrical isobenzofurans 9a­9e in good
yields, respectively. As for the preparation of unsymmetrical
isobenzofuran 9b, this successive protocol including one-pot
nucleophilic additions of two kinds of alkynyllithiums to 1 gave
the high yield of the desired product 9b and a very small amount
of symmetrical isobenzofuran 6a. Unfortunately, however, they
could not be separated by silica gel column chromatography.
In such a case, monoadducts 2a and 3a were purified before
performing the second nucleophilic addition to avoid the
incorporation of the symmetrical product at the final stage.
Selective mono-oxidation of diol 4a turned out to be
possible by using MnO2 as an oxidant (Scheme 3). Upon
treatment of 4a with MnO2 (1.2 equiv, MeCN, rt), the oxidation
occurred smoothly to give keto-alcohol 5a in 79% yield,
accompanied by a small amount of diketone 7a (7%). Screening
of the reaction conditions revealed that the formation of diketone
a was almost completely suppressed by using toluene as a
solvent, affording the essentially pure product 5a. Keto-alcohol
a, thus obtained, was directly converted to 1,3-bis(phenyl-
ethynyl)isobenzofuran (6a) by acid-treatment (4 M HCl, THF,
°C ¼ rt).
Various symmetrical (arylethynyl)isobenzofurans 6 were
obtained through this three-step sequence (Table 1). Upon
treatment of 1 with (4-methylphenyl)ethynyllithium, double
nucleophilic additions occurred cleanly to give diol 4b, which
was smoothly converted to isobenzofurans 6b by selective
mono-oxidation and subsequent acid-promoted cyclization
7
5
0
(
Entry 1). Isobenzofuran 6c with electron-donating methoxy
26 | Chem. Lett. 2017, 46, 25–28 | doi:10.1246/cl.160884
© 2017 The Chemical Society of Japan

3
.5
3
Table 3. Symmetrical 1,3-bis(arylethynyl)isobenzofurans
R1
R1
O
2.5
2
1
)
Li
Li
R1 a)
R2 b)
1) MnO2c)
H
H
OH
OH
O
2
)
2) 4 M HCld)
6a
6j
1
.5
1
O
6
k
1
8
9
R2
R2
11
0
.5
0
a
1
2
Entry
Ar and Ar
Yield of 8/% Yield of 9/%
㻞㻡㻜
㻟㻜㻜
㻟㻡㻜
㻠㻜㻜
㻠㻡㻜
㻡㻜㻜
㻡㻡㻜
R1
R2
=
Wavelength/nm
1
2
3
4
5
78 (8a)
85 (9a)
=
OMe
Figure 1. UV­vis absorption spectra of isobenzofuran.
R1
R2
=
=
1
78 (8b)
92 (8c)
87 (8d)
92 (8e)
89 (9b)
58 (9c)
72 (9d)
82 (9e)
Me
0
.8
R1
R2
=
=
Cl
F
0.6
0.4
6
6
6
1
a
j
k
1
0
.2
0
R1
R2
=
=
Br
㻠㻜㻜
㻠㻡㻜
㻡㻜㻜
㻡㻡㻜
㻢㻜㻜
㻢㻡㻜
㻣㻜㻜
Wavelength/nm
R1
R2
=
=
Figure 2. Fluorescence spectra of isobenzofuran.
Si(i-Pr)3
slightly red-shifted in comparison with 1,3-diphenylisobenzo-
1
4
a
THF, ¹78 °C. bTHF, ¹78 ¼ 0 °C. c1.2 equiv of MnO2 in
furan (­abs 415 nm, ­em 482 nm), indicating the small effect on
the photophysical properties by insertion of the two alkynyl
groups. The absorption and emission spectra of less π-conjugated
isobenzofuran 6k were blue-shifted to 386 and 443 nm, respec-
tively, which exhibited a lower fluorescence quantum yield than
d
toluene at rt. THF, 0 °C.
Ph
Ph
Ph
that of 6a (Φ 0.62). Cyclohexenyl-substituted isobenzofuran
6j showed a similar trend to 6a in both spectra, although the
fluorescence quantum yield was low (ΦF 0.32). In sharp contrast,
F
1
) MnO
benzene, rt
2
Red-Al®
OH
OH
OH
OH
O
Et O
2
2) 2 M HCl
–
78 °C rt
THF, 0 °C
1
6
,3-bis(phenylethenyl)isobenzofuran 11, the alkenyl congener of
a, showed a broad absorption band ranging from 380 to 530 nm,
91%
61%
4a
10
11
Ph
Ph
Ph
and peaking at 480 nm. The Stokes shift of 11 was increased
to 88 nm and the emission peak was observed at 568 nm with
a moderate fluorescence yield (ΦF 0.48). In this manner, π-
extension by ethenylation significantly affects the photophysical
properties, and thus, these newly prepared derivatives would be
Scheme 4. Synthesis of 1,3-dialkenylisobenzofuran.
Moreover, a significant point to be emphasized is that
bis(arylethenyl)isobenzofuran, a novel π-extended isobenzo-
furan, was firstly synthesized through the successive processes
1
5
promising probes for biological applications.
(
Scheme 4). Starting from propargyl alcohol 4a, double hydro-
In summary, we developed a new synthetic route to
symmetrical and unsymmetrical 1,3-dialkynylisobenzofurans
by sequential additions of o-phthalaldehyde with two identical
or different alkynyllithium. This efficient synthetic method
enables us to prepare new π-extended 1,3-dialkenylisobenzo-
furans. Further studies on synthetic applications and physical
properties of these attractive molecules are currently in progress.
1
3
μ
alumination by treatment with Red-Al (Et2O, ¹78 °C ¼ rt),
cleanly gave the high yield of bis-alcohol 10, which cannot
be straightforwardly obtained from our previous method
(Scheme 1). Subsequent two-step protocols including the selec-
tive mono-oxidation of diol 10 to keto-alcohol gave isobenzo-
furan 11 in 61% yield. As for the stability, 11 can be stored in
the solid state in a refrigerator for a several months, while it is
readily decomposed in a no degassed solution.
The absorption and fluorescence spectra of selected iso-
benzofurans were measured in chloroform (Figures 1 and 2).
This work was supported by JSPS KAKENHI Grant
Number JP15H05840 in Middle Molecular Strategy and JST
ACT-C.
1,3-Bis(phenylethynyl)isobenzofuran (6a) has its absorption
maximum at 424 nm and emission maximum at 484 nm with
excellent fluorescence quantum yield (ΦF 0.91), which are
Supporting Information is available on http://dx.doi.org/
10.1246/cl.160884.
Chem. Lett. 2017, 46, 25–28 | doi:10.1246/cl.160884
© 2017 The Chemical Society of Japan | 27

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28 | Chem. Lett. 2017, 46, 25–28 | doi:10.1246/cl.160884
© 2017 The Chemical Society of Japan