Water-soluble 1,3-diarylisobenzoheteroles: Syntheses and characterization

Article abstract of DOI:10.1246/cl.170137

Efficient synthetic route to water-soluble 1,3-diarylisobenzoheteroles, including isobenzofuran, isobenzothiophene, and isobenzoselenophene, was developed. Based on our one-pot synthetic method for diarylisobenzofurans, novel D-π-D and A-π-A types of diarylisobenzoheteroles became accessible, and they could be smoothly converted to the water-soluble isobenzoheteroles. The photophysical properties of newly prepared isobenzoheteroles are also evaluated.

Full text of DOI:10.1246/cl.170137

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Water-soluble 1,3-Diarylisobenzoheteroles: Syntheses and Characterization
Hitoshi Tozawa, Kei Kitamura, and Toshiyuki Hamura*
Advance Publication on the web February 23, 2017
doi:10.1246/cl.170137
© 2017 The Chemical Society of Japan
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1
Water-soluble 1,3-Diarylisobenzoheteroles: Syntheses and Characterization
Hitoshi Tozawa, 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)
Efficient synthetic route to water-soluble 1,3-
The photophysical properties of these newly prepared
diarylisobenzoheteroles are also evaluated, which is described
in this communication.
On the basis of our previous protocol, the D-π-D type of
diarylisobenzofuran 1a was prepared via double nucleophilic
additions of (4-dimethylaminophenyl)magnesium bromide 6
(3.3 equiv) to o-formyl benzoate 5 (Scheme 1). In this
reaction, the selective nucleophile attack of the Grignard
diarylisobenzoheteroles, including isobenzofuran, isobenzo-
thiophene, and isobenzoselenophene, was developed. Based
on our one-pot synthetic method of diarylisobenzofurans,
novel D-π-D and A-π-A types of diarylisobenzoheteroles
became accessible, and they could be smoothly converted to
the water-soluble isobenzoheteroles.
The photophysical
properties of newly prepared isobenzoheteroles are also
evaluated.
reagent to the formyl group in
transesterification of the resulting adduct gave 3-
phenylphthalide 7, which, in turn, accepted second
nucleophile, affording adduct 8. Final acid-promoted
dehydrative aromatization of 8 (CF3CO2H, r.t.) efficiently
produced the diarylisobenzofuran 1a.
5
and subsequent
Keywords: isobenzoheteroles | water-soluble materials |
divergent synthesis
a
Isobenzoheteroles,
such
as
isobenzofuran,
isobenzothiophene, and isobenzoselenophene, have unique
π-conjugated systems with a quinoid structure, which can
serve as a component in functional materials.1 However,
the chemistry of these molecules is still not fully explored,
presumably due to the scarce availability of various
substituted derivatives.2,3
In this context, we recently reported an efficient
synthetic access to 1,3-diarylisobenzofurans by sequential
reactions of methyl 2-formylbenzoate with two aryl
Grignard reagents.4 Notably, this process allowed us to
prepare various functionalized diarylisobenzofurans, e.g.
the D-π-D congener possessing two electron donating
dimethylaminophenyl groups onto the isobenzofuran core,
which exhibited an interesting electrochromic behavior.5
Based on this knowledge, we now developed facile
syntheses of novel D-π-D and A-π-A types of
NMe2
NMe2
O
BrMgO
TFA
r.t.
ArMgBr (6)
OMe
CHO
O
O
THF
–40 → 0 ºC
63%
5
8
1a
NMe2
NMe2
ArMgBr (6)
Lawesson's
reagent
toluene, 80 ºC
THF, –40 → 0 ºC
then sat. NH4Cl aq.
47%
NMe2
NMe2
NMe2
Lawesson's
reagent
diarylisobenzoheteroles 1 and 2.
Importantly, these
TPAP, NMO
O
O
O
S
OH
CH2Cl2, r.t.
toluene, r.t.
47%
functionally attractive isobenzoheteroles were smoothly
converted to water-soluble isobenzoheteroles 3 and 4
containing doubly substituted quaternary ammonium salts
or potassium carboxylates, which would have potential
utility for in vivo fluorescence imaging and singlet oxygen
acceptors (Figure 1).6,7
58%
(2 steps)
9
1b
10
NMe2
NMe2
NMe2
Lawesson's reagent
CH2Cl2, r.t.
44% (2 steps)
NMe3 I–
CO2K
NMe2
CO2H
O
O
Ar
S
S
S
P
Ar
P
BrMg
NMe2
S
(Ar = p-OMeC6H4)
Ar
6
X
X
X
X
Lawesson's reagent
7 (Ar = p-NMe2C6H4)
Scheme 1. Efficient synthetic route to D-π-D type of isobenzofuran 1a
and isobenzothiophene 1b
NMe2
CO2H
X = O (2a), S (2b)
NMe3 I–
CO2K
X = O (4a), S (4b)
X = O (1a), S (1b),
Se (1c)
X = O (3a), S (3b),
Se (3c)
Further study on this successive process revealed that
ring opened keto-alcohol 9 was selectively produced by
treatment of adduct 8 under milder acidic conditions (sat. aq.
NH4Cl).3f This finding allowed the divergent syntheses of
isobenzoheteroles from a single starting material 5. Thus,
Figure 1. D-π-D and A-π-A types of 1,3-diarylisobenzoheteroles, and
water-soluble 1,3-diarylisobenzoheteroles

2
keto-alcohol 9,8 obtained by the reaction of 5 with Grignard
reagent 6 and sat. aq. NH4Cl quench, was oxidized (TPAP,
NMO, CH2Cl2, r.t.)9 to give diketone 10, which was treated
with Lawesson’s reagent (CH2Cl2, r.t.),10 affording the D-π-D
type of isobenzothiophene 1b in 47% yield as bright orange
solids. The formation of 1b might be explained by the
conversion of diketone to dithioketone by reaction with
Lawesson’s reagent and its cyclization.1a,11
1a
1b
1c
Aside from the reaction mechanism, it is interesting to
note that keto-alcohol 9 and isobenzofuran 1a, which
corresponded to the reduced form of the diketone 10, could
also be directly converted to the isobenzothiophene 1b by
using Lawesson’s reagent. In these cases, no oxidizing agents
were required to obtain the isobenzothiophene 1b.
Moreover, isobenzoselenophene 1c with dimethyl-
aminophenyl groups on each aromatic ring could be accessed
from isobenzofuran 1a by treatment with Woollins’ reagent
(toluene, 100 °C),12 where the formal exchange of oxygen to
selenium on the central heterocyclic ring in 1a was observed
to give the isobenzoselenophene 1c in 32% yield as bright
orange solids (Scheme 2).13 In contrast, similar reaction of
diketone 10 with Woollins’ reagent (toluene, 100 °C) gave the
desired product 1c in quite low yield (3%).
Figure 3. Fluorescence spectra of isobenzoheteroles 1a–1c in CH3CN
We next examined the conversion of these D-π-D types
of isobenzoheteroles 1a–1c to water-soluble π-congeners by
N-methylation. Upon treatment of 1a with MeI (acetone, r.t.),
double methylation occurred cleanly, and the quaternary
ammonium salt 3a was gradually precipitated from the
reaction mixture, affording essentially pure product 3a after
filtration. Similar reactions of isobenzoheteroles 1b and 1c
also gave quaternary ammonium salts 3b and 3c in good
yields, respectively. These quaternary ammonium salts, thus
obtained, have been extensively characterized by
spectroscopic means, and as one of the characteristic features,
they were highly soluble in water, MeOH, CH3CN, and
DMSO.
NMe2
NMe2
Woollins' reagent
toluene, 100 ºC
N+Me3I–
NMe2
O
Se
Ph
Se
Se Se
P
Se Ph
32%
P
1a
1c
MeI
X
X
Woollins' reagent
NMe2
NMe2
acetone, r.t.
Scheme 2. D-π-D type of isobenzoselenophene 1c
N+Me3I–
NMe2
The absorption and fluorescence spectra of D-π-D type
of isobenzoheteroles were measured in acetonitrile (Figures 2
and 3).14 The isobenzofuran 1a has its absorption maximum
at 459 nm and emission maximum at 573 nm, and it exhibited
highly fluorescent (ΦF 0.76). On the other hand, the
absorption maximum of isobenzothiophene 1b and
isobenzoselenophene 1c was slightly blue-shifted (1b: 434 nm,
1c: 448 nm). The emission peaks of these dyes were
observed at 592 and 605 nm, respectively, which resulted in
the larger Stokes shift in comparison with 1a. Moreover,
isobenzothiophene 1b exhibited high fluorescent quantum
yield (ΦF 0.88) as same as 1a, whereas isobenzoselenophene
1c showed much lower yield (ΦF 0.34).
1a: X = O
1b: X = S
1c: X = Se
3a: 58% (X = O)
3b: 94% (X = S)
3c: 84% (X = Se)
Scheme 3. N-Methylation of 1,3-diarylisobenzoheteroles 1 to
water-soluble isobenzoheteroles 3
Another water-soluble isobenzoheteroles
4 having
potassium carboxylates at each aromatic ring could also be
synthesized. When diarylisobenzofuran 12, prepared by the
sequential reactions of methyl 2-formylbenzoate 5 with (4-
bromophenyl)magnesium bromide, was treated with n-BuLi
(THF, –78 °C), bromine–lithium exchange occurred quickly,
and subsequent trapping of the dilithio-intermediate with CO2
efficiently gave the A-π-A type of diarylisobenzofuran 2a in
87% yield. Conversion of the dicarboxylic acid 2a to
potassium salt 4a was realized by treatment with K2CO3 in
1a
1b
1c
refluxing
EtOH,15
leading
to
the
water-soluble
diarylisobenzofuran 4a as orange solids.
In addition, A-π-A type of diarylisobenzothiophene 2b
was prepared from the same starting material 5. Double
nucleophilic additions of Grignard reagent 11 to 5, and
selective oxidation of the resulting diol gave diketone 13,
which was treated with Lawesson’s reagent, affording
isobenzothiophene 2b after carboxylation of the dibromide
14.16 As for the formation of the diarylisobenzothiophene 2b,
isobenzofuran 2a was also a suitable substrate, and the
isobenzothiophene 2b was obtained in good yield. As
Figure 2. UV–Vis absorption spectra of isobenzoheteroles 1a–
1c in CH3CN

3
described for the synthesis of 4a, the A-π-A congener 2b was
converted to the potassium carboxylate 4b by treatment with
K2CO3.17
3a
3b
3c
CO2R
Br
O
n-BuLi
BrMg
Br
11
OMe
THF, –78 ºC
O
O
then CO2
THF, –40 → 0 °C;
then TFA
CHO
87%
5
49%
12
ArMgBr (11)
CO2R
K2CO3
EtOH, reflux
87%
Br
THF, –40 → 0 °C;
sat. aq. NH4Cl;
then MnO2
Lawesson's reagent
R = H (2a)
= K (4a)
Figure 5. Fluorescence spectra of isobenzoheteroles 3a–3c in H2O
CH2Cl2, r.t.
69%
72%
Br
CO2R
Br
n-BuLi
Lawesson's reagent
toluene, reflux
THF, –78 ºC
O
O
4a
4b
S
S
then CO2
92%
69%
13
14
CO2R
K2CO3
EtOH, reflux
93%
Br
Br
R = H (2b)
= K (4b)
Scheme 4. Efficient synthetic route to A-π-A type of isobenzoheterole 2
and water-soluble isobenzoheterole 4
Figure 6. UV–Vis absorption spectra of isobenzoheteroles 4a and 4b in
H2O
Finally, photophysical properties of water-soluble
isobenzoheteroles 3 and 4 were studied, and the absorption
and fluorescence spectra in H2O are shown in Figures 4–7.14
Water-soluble isobenzofuran 3a has its absorption maximum
at 412 nm and emission maximum at 476 nm with excellent
4a
4b
fluorescence quantum yield (ΦF 0.91).
Slightly lower
absorption maximum was observed for isobenzothiophene 3b,
which also showed excellent fluorescence quantum yield in
MeCN (ΦF 0.88), albeit moderate in H2O (ΦF 0.46).18 In
contrast,
the
fluorescence
quantum
yield
of
isobenzoselenophene 3c was only 0.09, although the
absorption maximum of 3c was similar to 3a.19
Figure 7. Fluorescence spectra of isobenzoheteroles 4a and 4b in H2O
Similar trend of the properties was observed for the
potassium carboxylates 4 as in the case of quaternary
ammonium salts 3, where isobenzofuran 4a showed red-
shifted absorption from isobenzothiophene 4b about 22 nm,
thus indicating a more quinoidal structure of 4a. Moreover,
they exhibited moderate to high fluorescence quantum yield
photophysical properties, and thus they would be a promising
component for biological applications and water-soluble π-
materials for electronic devices.15c
In summary, we developed a divergent process that is
capable of converting the same starting material, methyl 2-
formylbenzoate, into diarylisobenzofurans, diarylisobenzo-
in H2O (4a: ΦF 0.83, 4b: 0.54).
In this manner,
thiophens,
and
diarylisobenzoselenophenes
including
isobenzoheteroles acquired water-solubility exhibited typical
functionally attractive water-soluble isobenzoheteroles. The
application of these novel π-conjugated molecules for singlet
oxygen acceptors and fluorescent probes are currently
underway in our laboratory.
3a
3b
3c
This work was supported by JSPS KAKENHI Grant
Number JP15H05840 in Middle Molecular Strategy and JST
ACT-C.
Supporting
Information
is
available
on
http://dx.doi.org/10.1246/cl.******.
Figure 4. UV–Vis absorption spectra of isobenzoheteroles 3a–
3c in H2O
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15
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In contrast to the conversion of keto-alcohol 9 to isobenzothiphene
1b with Lawesson’s reagent, the similar reaction of the keto-
alcohol, obtained by the reaction of 5 with Grignard reagent 11, did
not give the isobenzothiophene 14. In this case, isobenzofuran 12
was produced as a major product.
16
17
At present, the synthesis of isobenzoselenophene from the expected
precursor 12 and 13 was unsuccessful, although the reason was not
clear.
18
19
The absorption and emission spectra of 3a, 3b, and 3c were also
measured in acetonitrile, see the Supporting Information.
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