A concise synthesis of tunable fluorescent 1,3-dihydroisobenzofuran derivatives as new fluorophores

Article abstract of DOI:10.1016/j.dyepig.2014.10.013

A convenient potassium tert-butoxide catalyzed addition-elimination reaction has been achieved using exo-cyclic enol ethers and aryl aldehydes as the starting materials. The transition-metal free reaction proceeded smoothly to afford 1,3-dihydroisobenzofuran derivatives with good to excellent yields. More importantly, the resulting products were discovered as novel fluorophores with good fluorescence properties and remarkable Stokes shifts. Changing the nature of the substituents in 1,3-dihydroisobenzofurans derivatives allowed the maximum emission wavelengths to be tuned between 438 and 597 nm and the Stokes shifts varied between 63 and 166 nm. In particular, derivative C27 containing a piperidyl and a cyano group showed the maximum emission wavelength of 597 nm and a Stokes shift of 166 nm.

Full text of DOI:10.1016/j.dyepig.2014.10.013

Accepted Manuscript
A concise synthesis of tunable fluorescent 1,3-dihydroisobenzofuran derivatives as
new fluorophores
Xue Song Shang, Deng Yuan Li, Nian Tai Li, Pei Nian Liu
PII:
S0143-7208(14)00410-0
10.1016/j.dyepig.2014.10.013
DYPI 4564
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 8 August 2014
Revised Date: 17 October 2014
Accepted Date: 20 October 2014
Please cite this article as: Shang XS, Li DY, Li NT, Liu PN, A concise synthesis of tunable fluorescent
1,3-dihydroisobenzofuran derivatives as new fluorophores, Dyes and Pigments (2014), doi: 10.1016/
j.dyepig.2014.10.013.
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ACCEPTED MANUSCRIPT
Graphical Abstract
R3
R1
O
t-BuOK (20 mol %)
3
R1
+
R CHO
O
o
DMF, 18-crown-6, 110 C
R2
R2
Novel fluorophores
E-max: 438 to 597 nm;
Stokes shift: up to 166 nm

ACCEPTED MANUSCRIPT
A concise synthesis of tunable fluorescent 1,3-dihydroisobenzofuran
derivatives as new fluorophores
Xue Song Shang, Deng Yuan Li, Nian Tai Li and Pei Nian Liu*
Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab for Advanced
Materials and Institute of Fine Chemicals, East China University of Science and Technology,
Meilong Road 130, Shanghai, China
*
Corresponding author. E-mail: liupn@ecust.edu.cn
1

ACCEPTED MANUSCRIPT
Abstract: A convenient potassium tert-butoxide catalyzed addition-elimination reaction has
been achieved using exo-cyclic enol ethers and aryl aldehydes as the starting materials. The
transition-metal free reaction proceeded smoothly to afford 1,3-dihydroisobenzofuran
derivatives with good to excellent yields. More importantly, the resulting products were
discovered as novel fluorophores with good fluorescence properties and remarkable Stokes
shifts. Changing the nature of the substituents in 1,3-dihydroisobenzofurans derivatives
allowed the maximum emission wavelengths to be tuned between 438 and 597 nm and the
Stokes shifts varied between 63 and 166 nm. In particular, derivative C27 containing a
piperidyl and a cyano group showed the maximum emission wavelength of 597 nm and a
Stokes shift of 166 nm.
Keywords: Addition-elimination, 1,3-dihydroisobenzofuran, fluorescence, Stokes shift,
tunable
2

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1
. Introduction
Fluorescent molecules have recently attracted significant attention because of their
extensive applications in the dyeing industry and in various fields of research [1-3]. Efficient,
high-yield strategies to synthesize fluorescent scaffolds are therefore quite desirable [4-7],
particularly methods of generating "smart" fluorophores with tunable fluorescent emission
[
8-24]. These fluorescent scaffolds typically have a core with extended π-conjugated
aryl-(hetero)aryl motifs. Extending such π-conjugated systems by introducing a vinyl or
aromatic group can yield high-emission fluorophores that are particularly useful for
bioimaging [25-32].
Despite significant progress in this area, efficiently generating small useful organic
fluorophores in biological applications remains a challenge. One class of compounds with
substantial potential as tunable fluorophores are 1,3-dihydroisobenzofuran derivatives, a new
type of vinylogous analogues of benzalphthalide [33], which can be served as a potential
medical intermediate. Little is known about how the structure of these derivatives influences
their fluorescence, which is a crucial question since it is possible that substituting the
1
,3-dihydroisobenzofuran core may generate a diverse library of fluorophores with large
Stokes shifts.
Synthesis of 1,3-dihydroisobenzofuran derivatives requires functionalizing benzylic
methylene, which typically relies on reactions catalyzed by transition metal salts or
complexes [34-39]. This functionalization has also been achieved using metal-free catalysts
such as diphenyl phosphate [40], MsOH [41], chiral phosphoric acids [42] and ammonium
salts [43, 44], in which oxidant was usually needed. Another alternative is direct benzylic C-H
3

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activation by photoredox catalysis [45]. We recently reported a novel method for synthesizing
a new type of 1,3-dihydroisobenzofuran derivatives C by reacting exo-cyclic enol ethers with
imines in the presence of stoichiometric potassium tert-butoxide (t-BuOK, 1.2 equivalent)
[
46].
Here we improve on that approach by reacting exo-cyclic enol ethers with aldehydes
directly, instead of with imines, in the presence of a catalytic amount of t-BuOK (20 mol%).
This method is much more efficient because it does not require the preparation of imines from
aldehydes and it does not release amine as a by-product. More importantly, this approach
allows the concise generation of structurally diverse 1,3-dihydroisobenzofuran derivatives as
novel fluorophores with fluorescence emission wavelengths varying from 438 to 597 nm and
remarkable Stokes shifts of up to 166 nm.
2
. Results and discussion
2
.1. Reaction optimization
As shown in Table 1, we used (Z)-1-benzylidene-1,3-dihydroisobenzofuran (A1) and
-methoxybenzaldehyde (B1) as the model substrates to investigate the reaction of exo-cyclic
4
enol ether with aldehyde. Firstly, we screened several kinds of bases for the reaction of A1
and B1 in DMF, and found that the reaction proceeded to afford the product C1 after 10 h in
o
4
6% yield at 80 C in the presence of 20 mol% t-BuOK (entry 1). Other bases such as
KHMDS and KOH also gave similar results, but NaH gave only 24% yield (entries 2-4).
When DBU and K CO were used, no reaction was observed due to the weak basicity (entries
2
3
5
and 6). Interestingly, adding 18-crown-6 (30 mol%) to the reaction substantially increased
4

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o
the yield of C to 80% after only 4.5 h at 80 C (entry 7). Increasing the reaction temperature
o
to 110 C led to a complete reaction with 82% yield within 2 h (entry 8). The effect of organic
solvents was also examined, and it is noteworthy that DMSO used in the reaction of
15
exo-cyclic enol ethers with imines was ineffective in the reation of exo-cyclic enol ethers
with aldehydes and product C1 was not detected (entry 9). The reactions in THF or toluene
gave substantially decreased yields and the reactions in acetonitrile or dichloroethane (DCE)
led to no desired product (entries 10-13). The amount of catalyst proved crucial to the reaction
of A1 with B1, and C1 was not generated when the amount of t-BuOK was decreased to 10
mol% (entry 14).
<Table 1>
2
.2. Substrate scope
Next, we studied the scope of the reaction using a series of aldehydes and various
o
exo-cyclic enol ethers (Table 2). The reaction was examined in DMF at 110 C, using 20
mol% of t-BuOK as the catalyst and 30 mol% of 18-crown-6 as the additive. A series of
benzaldehydes with para-substituted electron-donating groups, such as methoxy, methylthio,
t-butyl and methyl groups, readily reacted with 1,3-dihydroisobenzofuran A to give the
products C1-C4 in moderate to high yields, and the methoxy group gave the best yield of 81%.
The fact suggests that the stronger electron-donating ability of methoxy group contributes to
the higher yield. Notably, when more strongly electron-donating N,N-dimethylamino,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl were used as the para-substituents of
benzaldehyde, the reactions of A with them proceeded smoothly to afford the products C5-C8
5

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in excellent 88-99% yields. In contrast, 2-methoxy and 3,4-dimethoxy substituted
benzaldehydes were tested in the reactions with A, only 52% and 53% yields were observed
for the products C9 and C10, respectively. Nevertheless, 2,4-dimethoxy benzaldehyde reacted
with A to give product C11 in 90% yield. The different yields between C10 and C11 reveals
that the electron-donating ability in ortho-position is stronger than that in meta-position. It is
noteworthy that benzaldehyde, benzaldehydes containing electron-withdrawing substituents,
naphthaldehydes or alkylaldehydes were ineffective in this catalytic reaction.
Subsequently, we tested the reactions of a series of exo-cyclic enol ethers with
2
4
-(dimethylamino)benzaldehyde. Exo-cyclic enol ethers in which R was a phenyl ring
para-substituted with electron-donating methoxy and methyl groups or electron-withdrawing
chloro, trifluoromethyl, and cyano groups reacted well to afford the desired products
2
C12-C16 in 83-89% yields. If R of exo-cyclic enol ethers was changed to 2-methoxyphenyl,
2
4
7
-chlorophenyl, 3-chlorophenyl or 2-naphthyl, the reactions of exo-cyclic enol ethers with
-(dimethylamino)benzaldehyde also proceeded smoothly to afford the products C17-C20 in
1
5%-93% yields. Substituting the R position of exo-cyclic enol ethers with methyl or chloro
group gave products C21 and C22 in 89% and 98% yield, respectively. The exo-cyclic enol
1
2
ether carrying two methoxy groups at R and 4-methoxyphenyl at R gave product C23 in
1
only 53% yield, while the exo-cyclic enol ether carrying a fluoro atom at R and
2
4
4
4
-fluorophenyl at R afforded product C24 in decreased 34% yield. Finally, we used
-(piperidin-1-yl)benzaldehyde to react with the exo-cyclic enol ethers containing
2
1
-hydroxymethylphenyl, 4-cyanophenyl at R or a cyano group at R , the reactions produced
C25-C27 in 63-82% yields.
6

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<Table 2>
2
.3. Reaction Mechanism
Based on the experimental results, we proposed the reaction mechanism of exo-cyclic
enol ethers A and aldehydes B (Scheme 1). First, deprotonation of exo-cyclic enol ethers A in
the presence of t-BuOK affords intermediate D, which adds to aldehydes B to produce E. The
oxygen anion B traps a proton, leading to the key intermediate F. Then, deprotonation of F
gives G which undergoes an E2 elimination to afford the desired product C.
<Scheme 1>
2
.4. Photophysical properties
After the facile preparation of these 1,3-dihydroisobenzofuran derivatives, we then
examined their photophysical properties. The UV absorption spectra of compounds C1-C27
in dichloromethane are shown in Fig. 1. As shown in Fig. 1a-1e, we can see that the
maximum absorption wavelength of each product has little difference. In general, the products
C1-C4 and C9-C11 bearing MeO, SMe, t-Bu or Me groups have similar absorption spectra
and their absorption peaks are located around 380 nm in the range of 350 and 450 nm, which
suggests that the above substituents possess the similar electron-donating ability. In contrast,
when piperidyl, N,N-dimethyl, pyrrolidyl and morpholinyl were introduced to form products
C5-C8 and C12-C27, the absorption peaks are all red-shifted. The results are ascribed to the
stronger electron-donating ability of N atom than O, S and C atoms. In particular, compounds
C16 and C26-C27 containing N,N-dimethyl or piperidyl in combination with strong
electron-withdrawing cyano group obviously red-shift absorption peaks to 438 and 431 nm.
7

ACCEPTED MANUSCRIPT
Such D-π-A molecules may contribute to electron transfer from donor to acceptor and thus
making the absorption peaks red-shift. In the range from 350 to 500 nm, we calculated the
maximum molar absorption coefficient of each product and the results were recorded in Table
3
. Among all of the products, C5 shows the best light absorption ability.
Fig. 1>
<
In order to study the solvent effect on the absorption spectra of our target products, we
took compound C16 for example and found that the absorption spectra have nearly no
difference in solvents with different polarity (Fig. 2). The absorbance of C16 in toluene is
smaller than that in other solvents. The spectra in CH Cl , EtOAc, THF and dioxane are
2
2
nearly overlapped. When the test was studied in DMF and DMSO, the absorption peaks are
slightly red-shifted.
<Fig. 2>
Subsequently, we tested the fluorescence property of products C1-C27. The fluorescence
spectra were depicted in Fig. 3a-3e and the maximum emission wavelengths (λE-max) of each
product were listed in Table 3. The Stokes shift was accordingly obtained from λE-max and
λA-max and the fluorescence quantum yield (Φ ) of each product was calculated by using
F
Rhodamine 6G as the standard (0.88 in ethanol) [47]. The corresponding calculation
equations are presented in Supporting Information. As shown in Table 3, the compounds
C1-C4 and C9-C11 which carry methoxy, methylthio, t-butyl or methyl groups on one
benzene ring showed poor fluorescence quantum yields, with the maximum emission
8

ACCEPTED MANUSCRIPT
wavelengths (λE-max) ranging from 438 to 473 nm. In contrast, compounds C5-C8 carrying
dimethylamine, pyrrolidine, piperidine or morpholine substituent on one benzene ring showed
stronger fluorescence in CH Cl (enhanced Φ compared with those of C1-C4 and C9-C11 in
2
2
F
Table 3), which are consistent with those reported by You for 1,2-disubstituted benzimidazole
fluorescent scaffolds [48]. Moreover, compounds C5-C8 also exhibited large Stokes shifts
ranging from 108 to 126 nm and red-shifted λE-max values ranging from 505-523 nm. The
results obtained further demonstrate the stronger electron-donating ability of N atom than O,
S and C atoms, which helps to electron transition from ground state to excitation state upon
irradiation by light.
<Fig. 3>
Analysis of the compound series C12-C20 and C21-C24 reflected that substitution with
electron-donating nitrogen atom red-shifted λE-max and increased the Stokes shift. In the case
of compounds C12-C20, which carry N,N-dimethylamino group on one benzene ring,
attaching OMe, Me, Cl, CF or CN groups to the other benzene ring increased λ
and the
3
E-max
Stokes shift. For example, compound C15 with a para-trifluoromethyl group showed an
λE-max of 550 nm and a Stokes shift of 142 nm; compound C16 with a para-cyano group
showed an λE-max of 582 nm and a Stokes shift of 144 nm. A similar trend was found in the
compound series C21-C24, in which the 1,3-dihydroisobenzofuran core was substituted by
methyl, chloro, methoxy or fluoro group. To our surprise, compound C24 which carries two
fluoro groups, gave the highest fluorescence quantum yield in our experiment scope (ΦF:
0
.15). In comparison with compounds C12 and C17, we can see that the position of methoxy
9

ACCEPTED MANUSCRIPT
exerts influences on fluorescent properties in which C17 has a lower Φ but a red-shifted
F
emission wavelength than C12. Further introduction of two methoxy groups on the
1
,3-dihydroisobenzofuran core of C12 decreases Φ and induces slight blue-shift of λE-max.
F
Nevertheless, compounds C13 and C21 have no obvious change in fluorescent properties
Table 3). When N,N-dimethyl and methyl in C13 were replaced by piperidyl and
hydroxymethyl, the resulting compound C25 has the same Φ and 18 nm red-shift of λ
(
F
E-max
compared with those of C13. The influence of substituent position on fluorescent properties
was further investigated on compounds C14, C18 and C19 in which chlorine atom was para-,
ortho- and meta-substituted. As shown in Table 3, we can see that they have a similar λE-max
and C18 has a smaller Φ but a large Stokes shift than C14 and C19. When chlorine atom was
F
substituted on the 1,3-dihydroisobenzofuran core to form C22, the fluorescence quantum
yield and Stokes shift are both increased due to the short D-π-A structure. Optimizing the
donor-acceptor structure also allowed us to red-shift λE-max and increase the Stokes shift. For
instance, compounds C15 and C16 containing trifluoromethyl or cyano group have longer
λE-max and remarkable Stokes shifts due to the strong electron-withdrawing ability of the
substituents. Changing the substitution on the benzene ring from N,N-dimethylamino to
piperidinyl and attaching a cyano group to the other benzene ring afforded compound C27,
which exhibited the longest λE-max in our experiment (597 nm) and an impressive Stokes shift
of 166 nm. The λE-max and Stokes shift are sharply decreased upon change of the position of
cyano group, taking C26 for example, the two values are decreased by 44 and 51 nm,
respectively. The superior fluorescence properties of C27 are attributed to the substantial
contribution of an intramolecular charge transfer (ICT) from the electron donor (piperidinyl)
1
0

ACCEPTED MANUSCRIPT
to the electron acceptor (CN) upon excitation by light [17, 18].
<Table 3>
3
. Experimental
3
.1. Materials and instruments
All manipulations were carried out under a nitrogen atmosphere using standard Schlenk
techniques. DMF was distilled under reduced pressure from calcium hydride. THF and
toluene were distilled under nitrogen from sodium-benzophenone. Acetonitrile and
1
,2-dichloroethane were distilled under nitrogen from calcium hydride. DMSO was dried with
activatory 4Å molecular sieves before used. t-BuOK (1 M in THF) and KHMDS (0.91 M in
THF) used in the catalytic reactions were purchased from a commercial source. The
exo-cyclic enol ethers, 4-(piperidin-1-yl)benzaldehyde, 4-(pyrrolidin-1-yl)benzaldehyde and
4
-morpholinobenzaldehyde were prepared according to literature methods [49-54]. Other
chemicals were obtained from commercial sources, and were used without further
purification.
1
13
H NMR and C NMR were recorded on Bruker 400 MHz spectrometer. HRMS were
obtained on a Waters LCT Premier XE spectrometer with acetonitrile or methanol as solvent.
The UV absorption and fluorescence spectra were tested using UV-Vis spectrophotometer and
1
fluorescence spectrophotometer provided by Varian. Chemical shifs (δ, ppm) in the H NMR
1
3
1
spectra were recorded using TMS as internal standard. Chemical shifs in C{ H } NMR
spectra were internally referenced to CHCl (δ = 77.16 ppm).
3
3
.2. Synthesis route
11

ACCEPTED MANUSCRIPT
Typical Procedure for the Preparation of 1,3-Dihydroisobenzofuran Derivatives . A
flame-dried sealed tube equipped with exo-cyclic enol ether (0.3 mmol) and 18-crown-6 (23.8
mg, 0.09 mmol) was pumped to vacuum and exchanged with nitrogen for three times.
Aldehyde (0.45 mmol), solution of t-BuOK in THF (60 ꢀL) and DMF (1 mL) were then
o
added successively under nitrogen atmosphere. The mixture was stirred at 110 C and the
reaction was monitored by TLC. After completion of the reaction, the mixture was cooled and
concentrated aqueous solution of NH Cl was added to quench the reaction. The resulting
4
mixture was extracted with CH Cl and the organic phase was washed with concentrated brine
2
2
and dried over Na SO . The solvent was evaporated under reduced pressure, and the residue
2
4
was passed through column chromatography on silica gel to afford the desired product C.
1Z,3Z)-1-Benzylidene-3-(4-methoxybenzylidene)-1,3-dihydroisobenzofuran (C1) [46].
Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v) on silica gel gave a
(
o
1
o
light green solid (79.5 mg, 81% yield). Mp: 112-115.2 C; H NMR (400 MHz, CDCl , 25 C)
3
δ 7.90 (d, J = 7.40 Hz, 2H), 7.87 (d, J = 8.80 Hz, 2H), 7.62-7.68 (m, 2H), 7.40-7.46 (m, 5H),
1
3
6
.98 (d, J = 8.84 Hz, 2H), 6.18 (s, 1H), 6.16 (s, 1H), 3.88 (s, 3H); C NMR (100.6 MHz,
o
CDCl , 25 C) δ 158.5, 152.0, 150.5, 135.3, 134.1, 133.6, 129.9, 129.3, 128.9, 128.7, 128.4,
3
+
1
27.9, 126.5, 120.0, 119.7, 114.2, 99.6, 99.2, 55.5; HRMS (ESI, TOF) calcd for C H O
23 19 2
+
[
M+H] : 327.1380, found: 327.1389.
1Z,3Z)-1-Benzylidene-3-(4-(methylthio)benzylidene)-1,3-dihydroisobenzofuran (C2).
Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v) on silica gel gave a
(
o
1
light yellow-green solid (54.0 mg, 53% yield). Mp: 123.8-126.8 C; H NMR (400 MHz,
o
CDCl , 25 C) δ 7.89 (d, J = 7.88 Hz, 2H), 7.84 (d, J = 8.28 Hz, 2H), 7.63-7.68 (m, 2H),
3
1
2

ACCEPTED MANUSCRIPT
1
3
7
.41-7.46 (m, 4H), 7.28-7.33 (m, 3H), 6.20 (s, 1H), 6.15 (s, 1H), 2.54 (s, 3H); C NMR
o
(
100.6 MHz, CDCl , 25 C) δ 151.9, 151.6, 136.7, 135.1, 133.9, 133.9, 132.1, 129.3, 129.3,
3
1
28.9, 128.7, 128.5, 126.8, 126.7, 120.0, 119.9, 99.8, 99.4, 16.1; HRMS (ESI, TOF) calcd for
+
+
C H OS [M+H] : 343.1151, found: 343.1151.
23
19
(1Z,3Z)-1-Benzylidene-3-(4-(tert-butyl)benzylidene)-1,3-dihydroisobenzofuran
(C3).
Column chromatography (eluent = petroleum ether/ethyl acetate 100:1 v/v) on silica gel gave
o
1
a light green solid (59.7 mg, 56% yield). Mp: 134.0-137.0 C; H NMR (400 MHz, CDCl , 25
3
o
C) δ 7.92 (d, J = 7.88 Hz, 2H), 7.85 (d, J = 8.28 Hz, 2H), 7.65-7.67 (m, 2H), 7.40-7.47 (m,
1
3
o
7
1
9
H), 6.19 (s, 2H), 1.38 (s, 9H); C NMR (100.6 MHz, CDCl , 25 C) δ 152.0, 151.4, 149.8,
3
35.2, 134.1, 133.9, 132.3, 129.3, 129.1, 128.7, 128.6, 128.4, 126.6, 125.6, 120.0, 119.9, 99.8,
+
+
9.6, 34.8, 31.5; HRMS (ESI, TOF) calcd for C H O [M+H] : 353.1900, found: 353.1880.
2
6
25
(1Z,3Z)-1-Benzylidene-3-(4-methylbenzylidene)-1,3-dihydroisobenzofuran
(C4).
Column chromatography (eluent = petroleum ether/ethyl acetate 100:1 v/v) on silica gel gave
o
1
a grass-green solid (46.4 mg, 50% yield). Mp: 110.2-113.2 C; H NMR (400 MHz, CDCl ,
3
o
2
5 C) δ 7.91 (d, J = 7.56 Hz, 2H), 7.81 (d, J = 8.08 Hz, 2H), 7.63-7.67 (m, 2H), 7.40-7.46 (m,
1
3
5
H), 7.23-7.28 (m, 2H), 6.18 (s, 1H), 6.18 (s, 1H), 2.40 (s, 3H); C NMR (100.6 MHz,
o
CDCl , 25 C) δ 152.0, 151.3, 136.6, 135.2, 134.1, 133.8, 132.3, 129.4, 129.3, 129.1, 128.7,
3
+
1
28.5, 128.5, 126.6, 120.0, 119.9, 99.9, 99.5, 21.5; HRMS (ESI, TOF) calcd for C H O
23 19
+
[
M+H] : 311.1430, found: 311.1434.
-((Z)-((Z)-3-Benzylideneisobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethylaniline
C5) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v) on silica
4
(
o
1
gel gave a yellow solid (100.4 mg, 99% yield). Mp: 145.6-148.2 C; H NMR (400 MHz,
1
3

ACCEPTED MANUSCRIPT
o
CDCl , 25 C) δ 7.92 (d, J = 7.84 Hz, 2H), 7.82 (d, J = 8.72 Hz, 2H), 7.59-7.65 (m, 2H),
3
1
3
7
.34-7.49 (m, 5H), 6.79 (d, J = 8.68 Hz, 2H), 6.14 (s, 2H), 3.03 (s, 6H); C NMR (100.6
o
MHz, CDCl , 25 C): δ 152.3, 149.3, 135.6, 134.4, 133.3, 129.8, 129.2, 128.6, 128.4, 126.2,
3
+
1
23.5, 119.9, 119.4, 112.5, 100.5, 98.5, 40.6; HRMS (ESI, TOF) calcd for C H NO
24 22
+
[
M+H] : 340.1696, found: 340.1705.
-(4-((Z)-((Z)-3-Benzylideneisobenzofuran-1(3H)-ylidene)methyl)phenyl)pyrrolidine
C6) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v) on silica
1
(
o
1
gel gave a dark yellow solid (100.2 mg, 91% yield). Mp: 195.8-199.2 C; H NMR (400 MHz,
o
CDCl , 25 C) δ 7.92 (d, J = 7.44 Hz, 2H), 7.82 (d, J = 8.72 Hz, 2H), 7.59-7.65 (m, 2H),
3
7
3
1
.33-7.46 (m, 4H), 7.21-7.26 (m, 1H), 6.64 (d, J = 8.36 Hz, 2H), 6.15 (s, 1H), 6.14 (s, 1H),
1
3
o
.38 (br s, 4H), 2.04 (t, J = 6.52 Hz, 4H); C NMR (100.6 MHz, CDCl , 25 C) δ 152.4,
3
48.8, 146.8, 135.6, 134.6, 133.2, 129.9, 129.1, 128.6, 128.3, 128.2, 126.1, 122.4, 119.9,
+
+
1
19.3, 111.8, 100.9, 98.3, 47.7, 25.6; HRMS (ESI, TOF) calcd for C H NO [M+H] :
26 24
3
66.1852, found: 366.1860.
-(4-((Z)-((Z)-3-Benzylideneisobenzofuran-1(3H)-ylidene)methyl)phenyl)piperidine
C7) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v) on silica
1
(
o
1
gel gave a yellow-green solid (109.4 mg, 96% yield). Mp: 142.0-146.0 C; H NMR (400
o
MHz, CDCl , 25 C) δ 7.91 (d, J = 7.48 Hz, 2H), 7.82 (d, J = 8.80 Hz, 2H), 7.60-7.66 (m, 2H),
3
7
3
2
.37-7.46 (m, 4H), 7.22-7.26 (m, 1H), 7.00 (d, J = 8.04 Hz, 2H), 6.16 (s, 1H), 6.14 (s, 1H),
1
3
.26 (t, J = 5.32 Hz, 4H), 1.75 (br s, 4H), 1.60-1.65 (m, 2H); C NMR (100.6 MHz, CDCl ,
3
o
5 C): δ 152.2, 150.7, 149.9, 135.4, 134.3, 133.5, 129.6, 129.2, 128.6, 128.4, 126.3, 125.7,
+
1
19.9, 119.5, 116.1, 100.2, 98.8, 50.3, 25.9, 24.5; HRMS (ESI, TOF) calcd for C H NO
27 26
1
4

ACCEPTED MANUSCRIPT
+
[
M+H] : 380.2009, found: 380.2017.
-(4-((Z)-((Z)-3-Benzylideneisobenzofuran-1(3H)-ylidene)methyl)phenyl)morpholine
C8) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 60:1 v/v) on silica
4
(
o
1
gel gave a yellow-green solid (100.5 mg, 88% yield). Mp: 189.6-192.2 C; H NMR (400
o
MHz, CDCl , 25 C) δ 7.91 (d, J = 6.52 Hz, 2H), 7.85 (d, J = 8.68 Hz, 2H), 7.61-7.67 (m, 2H),
3
7
4
1
9
3
.39-7.45 (m, 5H), 6.97 (d, J = 8.68 Hz, 2H), 6.17 (s, 1H), 6.14 (s, 1H), 3.90 (t, J = 4.80 Hz,
1
3
o
H), 3.25 (t, J = 4.88 Hz, 4H); C NMR (100.6 MHz, CDCl , 25 C) δ 152.1, 150.3, 149.8,
3
35.4, 134.2, 133.6, 129.6, 129.2, 128.8, 128.6, 128.4, 126.8, 126.4, 120.0, 119.6, 115.5, 99.8,
+
+
9.1, 67.0, 49.1; HRMS (ESI, TOF) calcd for C H NO [M+H] : 382.1802, found:
2
6
24
2
82.1803.
1Z,3Z)-1-Benzylidene-3-(2-methoxybenzylidene)-1,3-dihydroisobenzofuran
Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v) on silica gel gave a
(
(C9).
o
1
light yellow-green solid (50.7 mg, 52% yield). Mp: 173.4-176.4 C; H NMR (400 MHz,
o
CDCl , 25 C) δ 8.47 (dd, J = 1.48 Hz, J = 7.80 Hz, 1H), 7.90 (d, J = 7.52 Hz, 2H),
3
1
2
7
.72-7.75 (m, 1H), 7.64-7.67 (m, 1H), 7.38-7.43 (m, 4H), 7.22-7.26 (m, 2H), 7.10 (t, J = 7.48
1
3
Hz, 1H), 6.94 (d, J = 8.16 Hz, 1H), 6.66 (s, 1H), 6.18 (s, 1H), 3.92 (s, 3H); C NMR (100.6
o
MHz, CDCl , 25 C) δ 156.3, 152.0, 151.9, 135.2, 134.3, 133.8, 129.3, 129.2, 129.1, 128.7,
3
1
28.5, 127.9, 126.5, 124.0, 120.9, 120.2, 119.9, 110.5, 99.5, 93.5, 55.7; HRMS (ESI, TOF)
+
+
calcd for C H O [M+H] : 327.1380, found: 327.1329.
2
3
19
2
(1Z,3Z)-1-Benzylidene-3-(3,4-dimethoxybenzylidene)-1,3-dihydroisobenzofuran (C10)
[
46]. Column chromatography (eluent = petroleum ether/ethyl acetate 60:1 v/v) on silica gel
o
1
gave a light green solid (57.0 mg, 53% yield). Mp: 164.8-166.6 C; H NMR (400 MHz,
1
5

ACCEPTED MANUSCRIPT
o
CDCl , 25 C) δ 7.89 (d, J = 7.32 Hz, 2H), 7.62-7.67 (m, 3H), 7.35-7.43 (m, 4H), 7.29-7.31
3
(m, 1H), 7.21-7.25 (m, 1H), 6.92 (d, J = 8.36 Hz, 1H), 6.18 (s, 1H), 6.16 (s, 1H), 4.00 (s, 3H),
1
3
o
3
1
5
.94 (s, 3H); C NMR (100.6 MHz, CDCl , 25 C) δ 152.1, 150.5, 149.1, 148.2, 135.3, 134.1,
3
33.7, 129.3, 129.0, 128.6, 128.4, 128.2, 126.6, 121.9, 119.9, 119.6, 111.3, 111.2, 100.0, 99.3,
+
3
+
6.3, 56.0; HRMS (ESI, TOF) calcd for C H O [M+H] : 357.1485, found: 357.1495.
2
4
21
(
1Z,3Z)-1-Benzylidene-3-(2,4-dimethoxybenzylidene)-1,3-dihydroisobenzofuran (C11).
Column chromatography (eluent = petroleum ether/ethyl acetate 60:1 v/v) on silica gel gave a
o
1
yellow-green solid (96.1 mg, 90% yield). Mp: 123.8-127.6 C; H NMR (400 MHz, CDCl ,
3
o
2
1
1
5 C) δ 8.40 (d, J = 8.64 Hz, 1H), 7.89 (d, J = 7.44 Hz, 2H), 7.68-7.71 (m, 1H), 7.63-7.66 (m,
H), 7.38-7.44 (m, 4H), 7.21-7.26 (m, 1H), 6.64 (dd, J = 2.40 Hz, J = 8.68 Hz, 1H), 6.58 (s,
1
2
1
3
H), 6.52 (d, J = 2.44 Hz, 1H), 6.15 (s, 1H), 3.90 (s, 3H), 3.89 (s, 3H); C NMR (100.6 MHz,
o
CDCl , 25 C) δ 159.9, 157.6, 152.2, 150.6, 135.5, 134.5, 133.6, 130.0, 129.2, 128.7, 128.6,
3
1
28.4, 126.3, 119.9, 119.8, 117.1, 104.9, 98.9, 98.4, 93.5, 55.7, 55.6; HRMS (ESI, TOF) calcd
+
+
for C H O [M+H] : 357.1485, found: 357.1488.
2
4
21
3
4-((Z)-((Z)-3-(4-Methoxybenzylidene)isobenzofuran-1(3H)-ylidene)methyl)-N,N-dimet
hylaniline (C12) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 60:1
o
1
v/v) on silica gel gave a yellow solid (92.1 mg, 83% yield). Mp: 156.4-159.4 C; H NMR
o
(
400 MHz, CDCl , 25 C) δ 7.86 (d, J = 8.80 Hz, 2H), 7.82 (d, J = 8.80 Hz, 2H), 7.58-7.62 (m,
3
2
3
1
H), 7.35-7.38 (m, 2H), 6.98 (d, J = 8.88 Hz, 2H), 6.82 (br s, 2H), 6.12 (s, 1H), 6.11 (s, 1H),
1
3
o
.88 (s, 3H), 3.03 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C): δ 158.1, 150.9, 149.5, 149.2,
3
34.2, 133.6, 129.6, 128.8, 128.4, 123.7, 119.6, 119.4, 114.1, 112.6, 99.9, 98.3, 55.5, 40.7;
+
2
+
HRMS (ESI, TOF) calcd for C H NO [M+H] : 370.1802, found: 370.1810.
2
5
24
1
6

ACCEPTED MANUSCRIPT
N,N-Dimethyl-4-((Z)-((Z)-3-(4-methylbenzylidene)isobenzofuran-1(3H)-ylidene)methy
l)aniline (C13) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v)
o
1
on silica gel gave a yellow solid (91.2 mg, 86% yield). Mp: 164.6-168.2 C; H NMR (400
o
MHz, CDCl , 25 C) δ 7.82 (d, J = 8.32 Hz, 4H), 7.58-7.63 (m, 2H), 7.35-7.38 (m, 2H),
3
1
3
7
.23-7.26 (m, 2H), 6.80 (d, J = 8.32 Hz, 2H), 6.12 (s, 2H), 3.03 (s, 6H), 2.40 (s, 3H); C
o
NMR (100.6 MHz, CDCl , 25 C): δ 151.7, 149.4, 149.3, 136.0, 134.4, 133.5, 132.7, 129.7,
3
1
29.4, 129.0, 128.4, 128.3, 123.6, 119.8, 119.4, 112.6, 100.2, 98.6, 40.7, 21.5; HRMS (ESI,
+
+
TOF) calcd for C H NO [M+H] : 354.1852, found: 354.1855.
2
5
24
4-((Z)-((Z)-3-(4-Chlorobenzylidene)isobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethy
laniline (C14) [55]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v)
o
1
on silica gel gave an orange-yellow solid (99.8 mg, 89% yield). Mp: 179.2-181.4 C; H NMR
o
(
400 MHz, CDCl , 25 C) δ 7.84 (d, J = 8.60 Hz, 2H), 7.78 (d, J = 8.84 Hz, 2H), 7.60-7.64 (m,
3
1
3
2
H), 7.37-7.41 (m, 4H), 6.80 (d, J = 8.28 Hz, 2H), 6.16 (s, 1H), 6.09 (s, 1H), 3.04 (s, 6H); C
o
NMR (100.6 MHz, CDCl , 25 C) δ 152.7, 149.4, 149.2, 134.5, 134.2, 133.1, 131.4, 129.8,
3
1
29.4, 129.4, 128.7, 128.4, 123.3, 119.9, 119.4, 112.6, 100.9, 97.3, 40.6; HRMS (EI, TOF)
+
calcd for C H ClNO [M] : 373.1233, found: 373.1230.
2
4
20
N,N-Dimethyl-4-((Z)-((Z)-3-(4-(trifluoromethyl)benzylidene)isobenzofuran-1(3H)-ylid
ene)methyl)aniline (C15). Column chromatography (eluent = petroleum ether/ethyl acetate
o
1
8
0:1 v/v) on silica gel gave a dark yellow solid (100.6 mg, 82% yield). Mp: 207-208.5 C; H
o
NMR (400 MHz, CDCl , 25 C) δ 7.99 (d, J = 8.20 Hz, 2H), 7.79 (d, J = 8.88 Hz, 2H),
3
7
.61-7.66 (m, 4H), 7.36-7.46 (m, 2H), 6.80 (d, J = 8.92 Hz, 2H), 6.19 (s, 1H), 6.14 (s, 1H),
1
3
o
3
.05 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C) δ 154.0, 149.6, 149.0, 139.2, 134.8, 132.8,
3
1
7

ACCEPTED MANUSCRIPT
1
29.9, 129.8, 128.5, 128.1, 127.6, 127.2, 126.0, 125.5 (q, J = 3.81 Hz), 123.3, 122.9, 120.2,
+
1
19.5, 112.5, 101.6, 97.0, 40.6; HRMS (EI, TOF) calcd for C H F NO [M] : 407.1497,
2
5
20 3
found: 407.1499.
4-((Z)-((Z)-3-(4-(Dimethylamino)benzylidene)isobenzofuran-1(3H)-ylidene)methyl)be
nzonitrile (C16). Column chromatography (eluent = petroleum ether/ethyl acetate 60:1 v/v)
o
1
on silica gel gave an orange solid (92.1 mg, 84% yield). Mp: 199.2-202.2 C; H NMR (400
o
MHz, CDCl , 25 C) δ 7.96 (d, J = 8.32 Hz, 2H), 7.77 (d, J = 8.72 Hz, 2H), 7.62-7.68 (m, 4H),
3
1
3
7
.37-7.47 (m, 2H), 6.79 (d, J = 8.76 Hz, 2H), 6.22 (s, 1H), 6.11 (s, 1H), 3.06 (s, 6H);
C
o
NMR (100.6 MHz, CDCl , 25 C) δ 154.9, 149.7, 148.8, 140.4, 134.9, 132.5, 132.3, 130.1,
3
1
30.0, 128.5, 128.3, 122.7, 120.3, 119.7, 119.5, 112.4, 108.4, 102.3, 96.8, 40.5; HRMS (EI,
+
TOF) calcd for C H N O [M] : 364.1576, found: 364.1577.
2
5
20
2
4-((Z)-((Z)-3-(2-Methoxybenzylidene)isobenzofuran-1(3H)-ylidene)methyl)-N,N-dimet
hylaniline (C17) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 60:1
o
1
v/v) on silica gel gave a yellow solid (91.2 mg, 80% yield). Mp: 187.4-190.2 C; H NMR
o
(
400 MHz, CDCl , 25 C) δ 8.50 (d, J = 7.72 Hz, 1H), 7.81 (d, J = 8.56 Hz, 2H), 7.71 (d, J =
3
6
6
3
1
1
3
.88 Hz, 1H), 7.58-7.61 (m, 1H), 7.35-7.38 (m, 2H), 7.21-7.24 (m, 1H), 7.09-7.14 (m, 1H),
.93 (d, J = 8.20 Hz, 1H), 6.78 (d, J = 8.60 Hz, 2H), 6.59 (s, 1H), 6.12 (s, 1H), 3.92 (s, 3H),
13
o
.01 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C): δ 156.3, 152.4, 149.4, 149.3, 134.4,
3
33.8, 129.7, 129.2, 129.0, 128.3, 127.3, 124.6, 123.7, 120.9, 120.2, 119.3, 112.6, 110.6,
+
+
00.2, 92.2, 55.8, 40.6; HRMS (ESI, TOF) calcd for C H NO [M+H] : 370.1802, found:
2
5
24
2
70.1775.
-((Z)-((Z)-3-(2-Chlorobenzylidene)isobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethy
4
1
8

ACCEPTED MANUSCRIPT
laniline (C18) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v)
o
1
on silica gel gave a yellow solid (84.2 mg, 75% yield). Mp: 154.2-157.2 C; H NMR (400
o
MHz, CDCl , 25 C) δ 8.55 (d, J = 7.92 Hz, 1H), 7.71-7.80 (m, 3H), 7.61 (d, J = 7.52 Hz, 1H),
3
7
3
1
.33-7.44 (m, 4H), 7.11-7.19 (m, 1H), 6.76 (d, J = 8.68 Hz, 2H), 6.55 (s, 1H), 6.16 (s, 1H),
1
3
o
.02 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C) δ 153.6, 149.4, 149.0, 134.6, 133.4, 133.2,
3
32.4, 129.8, 129.7, 129.6, 128.5, 127.1, 126.8, 123.2, 120.4, 119.4, 112.5, 101.2, 94.0, 40.6;
+
+
HRMS (ESI, TOF) calcd for C H ClNO [M+H] : 374.1306, found: 374.1306.
2
4
21
4-((Z)-((Z)-3-(3-Chlorobenzylidene)isobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethy
laniline (C19) [55]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v)
o
1
on silica gel gave an orange solid (101.3 mg, 90% yield). Mp: 118.6-120.6 C; H NMR (400
o
MHz, CDCl , 25 C) δ 8.22 (t, J = 1.68 Hz, 1H), 7.82 (d, J = 8.88 Hz, 2H), 7.61-7.64 (m, 2H),
3
7
.52 (d, J = 7.76 Hz, 1H), 7.29-7.42 (m, 3H), 7.20 (dd, J = 1.00 Hz, J = 7.96 Hz, 1H), 6.84
1 2
1
3
(
d, J = 8.80 Hz, 2H), 6.19 (s, 1H), 6.08 (s, 1H), 3.03 (s, 6H); C NMR (100.6 MHz, CDCl ,
3
o
2
1
5 C) δ 153.3, 149.5, 149.0, 137.4, 134.6, 134.5, 132.9, 129.8, 129.7, 129.5, 128.4, 127.8,
26.5, 126.0, 123.1, 120.1, 119.4, 112.7, 101.3, 97.1, 40.6; HRMS (EI, TOF) calcd for
+
C H ClNO [M] : 373.1233, found: 373.1229.
24
20
N,N-Dimethyl-4-((Z)-((Z)-3-(naphthalen-2-ylmethylene)isobenzofuran-1(3H)-ylidene)
methyl)aniline (C20) [46]. Column chromatography (eluent = petroleum ether/ethyl acetate
8
0:1 v/v) on silica gel gave an orange-yellow solid (108.5 mg, 93% yield). Mp: 178.5-180.5
o
1
o
C; H NMR (400 MHz, CDCl , 25 C) δ 8.55 (s, 1H), 7.90-7.94 (m, 4H), 7.82-7.87 (m, 2H),
3
7
.67-7.69 (m, 1H), 7.62-7.64 (m, 1H), 7.38-7.50 (m, 4H), 6.86 (d, J = 8.84 Hz, 2H), 6.29 (s,
13
o
1
H), 6.19 (s, 1H), 3.06 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C) δ 151.7, 148.4, 148.3,
3
1
9

ACCEPTED MANUSCRIPT
1
33.4, 133.0, 132.3, 132.1, 131.2, 128.8, 128.2, 127.4, 127.1, 126.9, 126.7, 126.2, 125.7,
25.1, 124.5, 122.5, 118.9, 118.4, 111.5, 99.7, 97.6, 39.6; HRMS (ESI, TOF) calcd for
1
+
+
C H NO [M+H] : 390.1852, found: 390.1861.
28
24
4-((Z)-((Z)-3-Benzylidene-5-methylisobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethy
laniline (C21) [55]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v)
o
1
on silica gel gave a yellow solid (94.6 mg, 89% yield). Mp: 163.0-166.0 C; H NMR (400
o
MHz, CDCl , 25 C) δ 7.91 (d, J = 7.84 Hz, 2H), 7.81 (d, J = 8.72 Hz, 2H), 7.40-7.51 (m, 4H),
3
7
3
1
.20-7.26 (m, 2H), 6.79 (d, J = 8.64 Hz, 2H), 6.11 (s, 1H), 6.08 (s, 1H), 3.02 (s, 6H), 2.45 (s,
1
3
o
H); C NMR (100.6 MHz, CDCl , 25 C) δ 152.3, 149.5, 149.2, 138.6, 135.7, 133.7, 132.2,
3
30.6, 129.6, 128.6, 128.4, 126.1, 123.8, 120.0, 119.2, 112.7, 99.7, 98.3, 40.7, 21.8; HRMS
+
(
EI, TOF) calcd for C H NO [M] : 353.1780, found: 353.1781.
2
5
23
4-((Z)-((Z)-3-Benzylidene-5-chloroisobenzofuran-1(3H)-ylidene)methyl)-N,N-dimethyl
aniline (C22) [55]. Column chromatography (eluent = petroleum ether/ethyl acetate 80:1 v/v)
o
1
on silica gel gave a yellow solid (109.5 mg, 98% yield). Mp: 175.5-178.5 C; H NMR (400
o
MHz, CDCl , 25 C) δ 7.89 (d, J = 7.60 Hz, 2H), 7.79 (d, J = 8.76 Hz, 2H), 7.60 (s, 1H), 7.51
3
(d, J = 8.28 Hz, 1H), 7.44 (t, J = 7.56 Hz, 2H), 7.32-7.35 (m, 1H), 7.23-7.28 (m, 1H), 6.78 (d,
1
3
o
J = 8.72 Hz, 2H), 6.11 (s, 2H), 3.03 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C) δ 151.1,
3
1
49.5, 148.5, 135.1, 134.9, 134.2, 133.0, 129.8, 129.5, 128.7, 128.5, 126.6, 123.2, 120.5,
+
1
19.9, 112.5, 101.1, 99.6, 40.6; HRMS (EI, TOF) calcd for C H ClNO [M] : 373.1233,
2
4
20
found: 373.1234.
4-((Z)-((Z)-5,6-Dimethoxy-3-(4-methoxybenzylidene)isobenzofuran-1(3H)-ylidene)met
hyl)-N,N-dimethylaniline (C23). Column chromatography (eluent = petroleum ether/ethyl
2
0

ACCEPTED MANUSCRIPT
acetate 40:1 v/v) on silica gel gave a brown-yellow solid (68.2 mg, 53% yield). Mp:
o
1
o
1
8
6
1
5
79.6-182.6 C; H NMR (400 MHz, CDCl , 25 C) δ 7.84 (d, J = 8.56 Hz, 2H), 7.79 (d, J =
3
.60 Hz, 2H), 6.96-7.01 (m, 4H), 6.81 (d, J = 8.28 Hz, 2H), 5.96 (s, 1H), 5.94 (s, 1H), 3.99 (s,
13
o
H), 3.87 (s, 3H), 3.02 (s, 6H); C NMR (100.6 MHz, CDCl , 25 C) δ 157.9, 151.1, 150.8,
3
49.7, 149.1, 129.3, 128.6, 127.4, 126.7, 124.0, 114.1, 112.7, 101.1, 100.9, 98.4, 96.8, 56.3,
+
5.5, 40.7; HRMS (EI, TOF) calcd for C H NO [M] : 429.1940, found: 429.1937.
2
7
27
4
4
-((Z)-((Z)-5-Fluoro-3-(4-fluorobenzylidene)isobenzofuran-1(3H)-ylidene)methyl)-N,
N-dimethylaniline (C24). Column chromatography (eluent = petroleum ether/ethyl acetate
0:1 v/v) on silica gel gave a yellow solid (37.9 mg, 34% yield, 0.12 mmol t-BuOK and 0.18
8
o
1
o
mmol 18-crown-6 were used). Mp: 190.8-193.0 C; H NMR (400 MHz, CDCl , 25 C) δ
3
7
.84-7.89 (m, 2H), 7.75 (d, J = 8.48 Hz, 2H), 7.53-7.57 (m, 1H), 7.24-7.26 (m, 1H), 7.10-7.14
1
3
(
m, 3H), 6.78 (d, J = 8.40 Hz, 2H), 6.07 (s, 1H), 6.05 (s, 1H), 3.03 (s, 6H); C NMR (100.6
o
MHz, CDCl , 25 C) δ 164.4, 162.7, 162.0, 160.3, 151.0, 149.4, 148.5, 135.0 (d, J = 9.55
3
C-F
Hz), 131.4, 131.3, 130.5, 130.0 (d, JC-F = 7.85 Hz), 129.6, 123.2, 121.1 (d, JC-F = 9.08 Hz),
17.4 (d, JC-F = 24.7 Hz), 115.6 (d, JC-F = 21.4 Hz), 112.5, 106.2 (d, JC-F = 24.4 Hz), 100.3,
1
+
9
8.4, 40.6; HRMS (EI, TOF) calcd for C H F NO [M] : 375.1435, found: 375.1443.
24 19 2
(4-((Z)-((Z)-3-(4-(Piperidin-1-yl)benzylidene)isobenzofuran-1(3H)-ylidene)methyl)phe
nyl)methanol (C25). Column chromatography (eluent = petroleum ether/ethyl acetate 10:1
v/v) on silica gel gave a yellow solid (99.0 mg, 81% yield, 0.12 mmol t-BuOK and 0.18 mmol
o
1
o
1
8-crown-6 were used). Mp: 196.6-198.6 C; H NMR (400 MHz, CDCl , 25 C) δ 7.91 (d, J
3
=
8.00 Hz, 2H), 7.81 (d, J = 8.64 Hz, 2H), 7.63 (t, J = 8.12 Hz, 2H), 7.44 (d, J = 8.12 Hz, 2H),
7
.37-7.41 (m, 2H), 7.00 (d, J = 8.48 Hz, 2H), 6.15 (s, 2H), 4.74 (s, 2H), 3.26 (t, J = 4.84 Hz,
2
1

ACCEPTED MANUSCRIPT
1
3
o
4
H), 1.73-1.75 (m, 4H), 1.61-1.65 (m, 2H); C NMR (100.6 MHz, CDCl , 25 C) δ 152.3,
3
1
50.8, 149.9, 138.8, 135.0, 134.4, 133.5, 129.6, 129.2, 128.6, 128.5, 127.4, 125.7, 119.9,
+
1
19.5, 116.2, 100.3, 98.5, 65.5, 50.3, 25.9, 24.5; HRMS (EI, TOF) calcd for C H NO [M] :
2
8
27
2
4
09.2042, found: 409.2039.
1Z,3Z)-3-Benzylidene-1-(4-(piperidin-1-yl)benzylidene)-1,3-dihydroisobenzofuran-5-c
arbonitrile (C26) Column chromatography (eluent = petroleum ether/ethyl acetate 60:1 v/v)
(
o
1
on silica gel gave an orange-yellow solid (77.0 mg, 63% yield). Mp: 236.6-239.6 C; H NMR
o
(
400 MHz, CDCl , 25 C) δ 7.88-7.91 (m, 3H), 7.81 (d, J = 8.80 Hz, 2H), 7.60-7.68 (m, 2H),
3
7
.43-7.48 (m, 2H), 7.28-7.31 (m, 1H), 6.98 (d, J = 8.84 Hz, 2H), 6.24 (s, 1H), 6.20 (s, 1H),
1
3
o
3
.27-3.31 (m, 4H), 1.74 (br s, 4H), 1.63-1.65 (m, 2H); C NMR (100.6 MHz, CDCl , 25 C)
3
δ 151.2, 150.4, 148.3, 137.7, 134.6, 133.9, 132.1, 130.2, 128.8, 128.6, 127.1, 124.4, 124.2,
1
20.2, 118.8, 115.7, 111.6, 103.7, 100.7, 49.8, 25.8, 24.5; HRMS (EI, TOF) calcd for
+
C H N O [M] : 404.1889, found: 404.1890.
28
24
2
4-((Z)-((Z)-3-(4-(Piperidin-1-yl)benzylidene)isobenzofuran-1(3H)-ylidene)methyl)benz
onitrile (C27). Column chromatography (eluent = petroleum ether/ethyl acetate 60:1 v/v) on
o
1
silica gel gave an orange-yellow solid (99.5 mg, 82% yield). Mp: 227.8-230.6 C; H NMR
o
(
400 MHz, CDCl , 25 C) δ 7.95 (d, J = 8.28 Hz, 2H), 7.76 (d, J = 8.68 Hz, 2H), 7.62-7.68 (m,
3
4
4
1
H), 7.38-7.48 (m, 2H), 6.99 (d, J = 8.56 Hz, 2H), 6.21 (s, 1H), 6.12 (s, 1H), 3.27-3.31 (m,
1
3
o
H), 1.74-1.76 (m, 4H), 1.63-1.67 (m, 2H); C NMR (100.6 MHz, CDCl , 25 C) δ 154.8,
3
51.0, 149.3, 140.3, 134.7, 132.7, 132.3, 130.1, 129.8, 128.8, 128.3, 124.8, 120.3, 119.7,
+
1
19.6, 115.8, 108.5, 101.9, 97.1, 50.0, 25.8, 24.5; HRMS (EI, TOF) calcd for C H N O [M] :
2
8
24
2
4
04.1889, found: 404.1891.
2
2

ACCEPTED MANUSCRIPT
4
. Conclusions
In summary, we have developed a facile method to synthesize 1,3-dihydroisobenzofuran
derivatives using t-BuOK as the catalyst. The resulting compounds proved to be served as
tunable fluorophores, for which the maximum emission wavelengths ranged from 438 to 597
nm and the Stokes shift reached up to 166 nm. The results might open a gate for the further
application of the readily available 1,3-dihydroisobenzofuran framework as the novel
chromophore in electronic devices and fluorescence probes.
Acknowledgements
This work was supported by NSFC/China, NCET (NCET-13-0798), the Innovation
Program of Shanghai Municipal Education Commission (Project No. 12ZZ050), the Basic
Research Program of the Shanghai Committee of Science and Technology (Project No.
1
3NM1400802) and the Fundamental Research Funds for the Central Universities.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/.
References
[
1] Wu WP, Liu YQ, Zhu DB. π-Conjugated molecules with fused rings for organic
field-effect transistors: design, synthesis and applications. Chem Soc Rev 2010; 39: 1489-502.
2] Beaujuge PM, Reynolds JR. Color control in π-conjugated organic polymers for use in
electrochromic devices. Chem Rev 2010; 110: 268-320.
3] Facchetti A. π-Conjugated polymers for organic electronics and photovoltaic cell
applications. Chem Mater 2011; 23: 733-58.
[
[
2
3

ACCEPTED MANUSCRIPT
[
4] Namba K, Osawa A, Ishizaka S, Kitamura N, Tanino K. Direct synthesis of fluorescent
1
,3a,6a-triazapentalene derivatives via click–cyclization–aromatization cascade reaction. J
Am Chem Soc 2011; 133: 11466-469.
5] Burchak ON, Mugherli L, Ostuni M, Lacapère JJ, Balakirev MY. Combinatorial discovery
[
of fluorescent pharmacophores by multicomponent reactions in droplet arrays. J Am Chem
Soc 2011; 133: 10058-61.
[
6] Siamaki AR, Sakalauskas M, Arndtsen BA. A palladium-catalyzed multicomponent
coupling approach to π-conjugated oligomers: assembling imidazole-based materials from
imines and acyl chlorides. Angew Chem Int Ed 2011; 50: 6552-56.
[
7] Zhao DB, Wang WH, Yang F, Lan JB, Yang L, Gao G, et al. Copper-catalyzed direct C
arylation of heterocycles with aryl bromides: discovery of fluorescent core frameworks.
Angew Chem Int Ed 2009; 48: 3296-300.
[
8] Kunzelman J, Kinami M, Crenshaw BR, Protasiewicz JD, Weder C. Oligo(p-phenylene
vinylene)s as a “new” class of piezochromic fluorophores. Adv Mater 2008; 20: 119-22.
9] Harriman A, Mallon LJ, Elliot KJ, Haefele A, Ulrich G, Ziessel R. Length dependence for
[
intramolecular energy transfer in three- and four-color donor−spacer−acceptor arrays. J Am
Chem Soc 2009; 131: 13375-86.
[
10] Zhao ZJ, Wang ZM, Lu P, Chan CYK, Liu DD, Lam JWY, et al. Structural modulation of
solid-state emission of 2,5-bis(trialkylsilylethynyl)-3,4-diphenylsiloles. Angew Chem Int Ed
009; 48: 7608-11.
11] Caruso Jr A, Siegler MA, Tovar JD. Synthesis of functionalizable boron-containing
2
[
2
4

ACCEPTED MANUSCRIPT
π-electron materials that incorporate formally aromatic fused borepin rings. Angew Chem Int
Ed 2010; 49: 4213-7.
[
12] Ren Y, Baumgartner T. Dually switchable heterotetracenes: addressing the photophysical
properties and self-organization of the P−S system. J Am Chem Soc 2011; 133: 1328-40.
13] Namba K, Osawa A, Ishizaka S, Kitamura N, Tanino K. Direct synthesis of fluorescent
,3a,6a-triazapentalene derivatives via click–cyclization–aromatization cascade reaction. J
Am Chem Soc 2011; 133: 11466-9.
14] Zhang ZY, Xu B, Su JH, Shen LP, Xie YS, Tian H. Color-tunable solid-state emission of
,2′-biindenyl-based fluorophores. Angew Chem Int Ed 2011; 50: 11654-7.
15] Bryant Pollock J, Schneider GL, Cook TR, Davies AS, Stang PJ. Tunable Visible Light
Emission of Self-Assembled Rhomboidal Metallacycles. J Am Chem Soc 2013; 135:
3676-9.
16] Frath D, Massue J, Ulrich G, Ziessel R. Luminescent materials: locking π-conjugated and
heterocyclic ligands with boron(III). Angew Chem Int Ed 2014; 53: 2290-310.
17] Zhao DB, Li GC, Wu D, Qin XR, Neuhaus P, Cheng YY, et al. Regiospecific
[
1
[
2
[
1
[
[
N-heteroarylation of amidines for full-color-tunable boron difluoride dyes with
mechanochromic luminescence. Angew Chem Int Ed 2013; 52: 13676-80.
[
18] Huang YM, Song FJ, Wang Z, Xi PH, Wu NJ, Wang ZG, et al. Dehydrogenative Heck
coupling of biologically relevant N-heteroarenes with alkenes: discovery of fluorescent core
frameworks. Chem Commun 2012; 48: 2864-6.
[
19] Liu B, Wang Z, Wu NJ, Li ML, You JS, Lan JB. Discovery of a full-color-tunable
2
5

ACCEPTED MANUSCRIPT
fluorescent core framework through direct C–H (hetero)arylation of N-heterocycles. Chem
Eur J 2012; 18: 1599-603.
[
20] Choi EJ, Kim E, Lee Y, Jo A, Park SB. Rational perturbation of the fluorescence
quantum Yield in emission-tunable and predictable fluorophores (seoul-fluors) by a facile
synthetic method involving C–H activation. Angew Chem Int Ed 2014; 53: 1346-50.
[
21] Sun HB, Liu SJ, Lin WP, Zhang KY, Lv W, Huang X, et al. Smart responsive
phosphorescent materials for data recording and security protection. Nat Commun 2014; 5:
601-9.
3
[
22] Liu SJ, Sun HB, Ma Y, Ye SH, Liu XM, Zhou XH, et al. Rational design of
metallophosphors with tunable aggregation-induced phosphorescent emission and their
promising applications in time-resolved luminescence assay and targeted luminescence
imaging of cancer cells. J Mater Chem 2012; 22: 22167-73.
[
23] Xu WJ, Liu SJ, Sun HB, Zhao XY, Zhao Q, Sun S, et al. FRET-based probe for fluoride
based on a phosphorescent iridium(III) complex containing triarylboron groups. J Mater
Chem 2011; 21: 7572-81.
[
24] Ma Y, Liu SJ, Yang HR, Wu YQ, Yang CJ, Liu XM, et al. Water-soluble phosphorescent
iridium(III) complexes as multicolor probes for imaging of homocysteine and cysteine in
living cells. J Mater Chem 2011; 21: 18974-82.
[
25] Sharon E, Lvesque SA, Munkonda MN, Sévigny J, Ecke D, Reiser G, et al. Fluorescent
2
N ,N3-ε-adenine nucleoside and nucleotide probes: synthesis, spectroscopic properties, and
2
6

ACCEPTED MANUSCRIPT
biochemical evaluation. ChemBioChem 2006; 7: 1361-74.
[
26] Greco NJ, Tor Y. Furan decorated nucleoside analogues as fluorescent probes: synthesis,
photophysical evaluation, and site-specific incorporation. Tetrahedron 2007; 63: 3515-27.
27] Butler RS, Cohn P, Tenzel P, Abboud KA, Castellano RK. Synthesis, photophysical
behavior, and electronic structure of push−pull purines. J Am Chem Soc 2009; 131: 623-33.
[
[
[
28] Kim YK, Ha HH, Lee JS, Bi X, Ahn YH, Hajar S, et al. J Am Chem Soc 2010; 132: 576-.
29] Kim D, Jun H, Lee H, Hong SS, Hong S. Development of new fluorescent xanthines as
kinase inhibitors. Org Lett 2010; 12: 1212-5.
30] Cao J, Zhao CC, Wang XZ, Zhang YF, Zhu WH. Target-triggered deprotonation of
-hydroxyindole-based BODIPY: specially switch on NIR fluorescence upon selectively
[
6
2
+
binding to Zn . Chem Commun 2012; 48: 9897-9.
31] Kim E, Koh M, Lim BJ, Park SB. Emission wavelength prediction of a full-color-tunable
fluorescent core skeleton, 9-aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one. J Am Chem Soc
011; 133: 6642-9.
32] Li M, Wu XM, Wang Y, Li YS, Zhu WH, James TD. A near-infrared colorimetric
fluorescent chemodosimeter for the detection of glutathione in living cells. Chem Commun
014; 50: 1751-3.
33] Zamilpa A, Herrera-Ruiz M, del Olmo E, López-Pérez JL, Tortoriello J, San Feliciano A.
Anxiolytic effects of benzalphthalides. Bioorg Med Chem Lett 2005; 15: 3483-6.
34] Wang H, Li G, Engle KM, Yu JQ, Davies HML. Sequential C–H functionalization
[
2
[
2
[
[
reactions for the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans. J
Am Chem Soc 2013; 135: 6774-7.
2
7

ACCEPTED MANUSCRIPT
[
35] Guan BT, Wang BL, Nishiura M, Hou ZM. Yttrium-catalyzed addition of benzylic C–H
bonds of alkyl pyridines to olefins. Angew Chem Int Ed 2013; 52: 4418-21.
36] Li GC, Qian SY, Wang CX, You JS. Palladium(II)-catalyzed dehydrogenative
[
cross-coupling between two C –H bonds: unexpected C=C bond formation. Angew Chem
sp3
Int Ed 2013; 52: 7837-40.
[
37] Nishioka Y. Uchida T. Katsuki T. Enantio- and regioselective intermolecular benzylic and
allylic C–H bond amination. Angew Chem Int Ed 2013; 52: 1739-42.
38] Liu W, Groves JT. Manganese-catalyzed oxidative benzylic C–H fluorination by fluoride
ions. Angew Chem Int Ed 2013; 52: 6024-7.
39] Cho SW, Hartwig JF. Iridium-catalyzed borylation of secondary benzylic C–H bonds
directed by a hydrosilane. J Am Chem Soc 2013; 135: 8157-60.
[
[
[
[
40] Haibach MC, Deb I, Kandta De C, Seidel D. J Am Chem Soc 2011; 133: 2100-3.
41] Chen DF, Han ZY, He YP, Yu J, Gong LZ. Metal-free oxidation/C(sp )–H
3
functionalization of unactivated alkynes using pyridine-N-oxide as the external oxidant.
Angew Chem Int Ed 2012; 51: 12307-10.
[
42] Mori K, Ehara K, Kurihara K, Akiyama T. Selective activation of enantiotopic
C(sp3)−hydrogen by means of chiral phosphoric acid: asymmetric synthesis of
tetrahydroquinoline derivatives. J Am Chem Soc 2011; 133: 6166-9.
[
43] Xue QC, Xie J, Li HM, Cheng YX, Zhu CJ. Metal-free, highly efficient
organocatalytic amination of benzylic C–H bonds. Chem Commun 2013; 49: 3700-2.
44] Benfatti F, Capdevila MG, Zoli L, Benedetto E, Cozzi PG. Catalytic stereoselective
benzylic C–H functionalizations by oxidative C–H activation and organocatalysis. Chem
[
2
8