Copper-Catalyzed Preparation of 2-Aryl-3-cyanobenzofurans with Bright Blue Photoluminescence

Article abstract of DOI:10.1021/acs.orglett.5b03704

Copper-catalyzed cascade synthesis of 2-aryl-3-cyanobenzofurans from o-hydroxybenzaldehydes and arylacetonitriles in the presence of copper acetate and sodium methoxide is reported. The synthesized 2-aryl-3-cyanobenzofurans emit bright blue under UV light with a quantum yield up to 88.9%. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03704

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Preparation of 2‑Aryl-3-cyanobenzofurans with
Bright Blue Photoluminescence
Lianpeng Zhang,† Zhixing Peng,† Qiaodong Wen, Xihui Li, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: Copper-catalyzed cascade synthesis of 2-aryl-3-
cyanobenzofurans from o-hydroxybenzaldehydes and arylacetoni-
triles in the presence of copper acetate and sodium methoxide is
reported. The synthesized 2-aryl-3-cyanobenzofurans emit bright
blue under UV light with a quantum yield up to 88.9%.
ompounds containing a benzofuran ring are abundant and
important in nature. They have been widely used in life1
Scheme 1. Literature Approaches to 2-Aryl-3-
cyanobenzofurans and Our Design
C
and material2 science. For instance, the benzofuran skeleton
constitutes a part of the bioactive molecules that could effectively
inhibit hepatitis C virus (HCV) (Figure 1). Published
Figure 1. Molecules effectively inhibiting hepatitis C virus.
2-aryl-3-cyanobenzofurans (Scheme 1, route f).14 Here, we
report a green reaction between 2-hydroxybenzaldehyde and
PhCH2CN in the presence of copper salt, which produces 2-aryl-
3-cyanobenzofuran with only a loss of water.
approaches to this class of bioactive molecules include the
synthesis of 2-aryl-3-cyanobenzofurans as intermediates.3 Two
strategies have been developed for the construction of 2-aryl-3-
cyanobenzofurans. One is the direct cyanation of 2-arylbenzofur-
an with the benzofuran ring formation preceding the C−CN
bond formation, and the other involves formation of the
benzofuran ring as the last step. Direct cyanation has been
approached by SEAr of 2-arylbenzofuran with BrCN in the
presence of Lewis acid (Scheme 1, route a).4 Transition metal
(TM) catalyzed cyanation of benzofurans or 3-halobenzofurans
with various cyanide sources such as DMF,5 K4Fe(CN)6,6 and
CuCN7 provides an alternative method. By using functional
group inversion (FGI), 3-cyanobenzofurans could be derived
from the corresponding amides (Scheme 1, route b).8
Considering the option with C−CN bond formation prior to
benzofuran ring formation, a series of works have hitherto
focused on TM-catalyzed C−C and C−O coupling (Scheme 1,
routes c and d).9−12 For more specific examples, electrochemical
oxidation of catechols in the presence of PhCOCH2CN could
provide 3-cyanobenzofurans by using the strategy of “aromatic
ring umpolung” (Scheme 1, route e).13 As an interesting
example, cycloaddition of benzyne with iodonium ylide produces
Initially, we tested the reaction of 2-hydroxy-5-methylbenzal-
dehyde (1a, 0.5 mmol) and PhCH2CN (2a, 0.75 mmol) in the
presence of hydrated copper acetate (0.1 mmol) and NaOMe (2
mmol) in 2 mL of DMSO in air at 100 °C for 15 h. After the
reaction, 3a was isolated in 54% yield. The structure of 3a was
established by its single-crystal analysis.15 Attracted by this result,
we optimized the reaction conditions. Among the solvents
tested, DMSO was the optimal choice (Table S1, entries 1−4).
When toluene was used, reaction did not occur with 31%
recovery of 1a. When NMP was used, 6-methyl-3-phenyl-2H-
chromen-2-one (4) was obtained in 52% yield except for the
formation of 3a in 28% yield. By altering the atmosphere from air
to O2, the yield of 3a slightly decreased. If anhydrous copper
acetate was used, the yield of 3a increased to 69% (Table S1,
entry 5). After the reaction mixture was further dried by addition
of 0.1 g of 4 Å MS, the yield of 3a decreased to 38%. The yield of
Received: December 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03704
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3a decreased to 45% if the reaction was conducted in N2. By
screening other Cu(II) and Cu(I) sources (Table S1, entries 6−
16), Cu(OAc)2 was found to be the optimal choice. Metal copper
could also catalyze the reaction and provide 3a in 54% yield
(Table S1, entry 17). Moreover, the reaction could be catalyzed
by Pd(OAc)2, and 3a was isolated in 52% yield either with
NaOMe or with Na2CO3 (Table S1, entries 18 and 19). To our
surprise, 3a could be obtained in 35% yield without any metal
catalysts (Table S1, entry 20). However, any further explorations
aiming to increase the yield without metal catalyst failed (Table
S1, entries 21−27). In comparison with other bases, NaOMe was
found to be optimal (Table S1, entries 28−37). Reaction did not
occur when no base was used (Table S1, entry 38). The optimal
amount of NaOMe was found to be 4 equiv of 1a (Table S1,
entries 39 and 40). Dried DMSO, distilled from CaH2, provided
3a in 74% yield (Table S1, entry 41). Decreasing the catalyst
loading to 0.1 equiv of 1a slightly decreased the yield of 3a (Table
S1, entry 42). Finally, the standard reaction conditions were
established. A mixture of 1a (0.5 mmol), 2a (0.75 mmol),
Cu(OAc)2 (0.1 mmol), NaOMe (2.0 mmol), and dry DMSO (2
mL) was reacted at 100 °C in air for 15 h.
substituted benzyl cyanides, such as Cl, F, and CH3O, 3o, 3p,
and 3q were obtained in 76%, 52%, and 47% yields, respectively.
With Cl or Br substituted on 5-position of salicyclic aldehyde,
3r−u were obtained in yields varying from 62% to 69%. 2-
Hydroxy-4-(diethylamino)benzaldehyde provided 3v in 35%
yield. By using Pd(OAc)2 as the catalyst, the yield of 3v increased
to 54%. 2-(Pyridin-2-yl)acetonitrile could also be applied and
provided 3w in 67% yield. The methyl on salicyclic aldehyde
could be altered from the 5-position to the 3-position. Thus, 3x
was isolated in 72% yield, similar to the yield of 3a. When the 3-
position of salicyclic aldehyde was occupied by tert-butyl, 3z and
3A were obtained in yields of 41% and 72%, respectively. It
implies that the steric hindrance from salicyclic aldehyde side is
not significant. A higher reaction temperature was necessary for
the preparation of 3B and 3C.
This green methodology provided a shortcut to the
preparation of the molecules shown in Scheme 1. Thus, as an
intermediate in the preparation of those bioactive molecules, 3D
could be prepared in a sequence of reduction, oxidation,16 and
annulations from commercially available 2-hydroxy-4-nitro-
benzoic acid (Scheme 2).
With the optimized reaction conditions in hand, we tested for
substrate diversity (Figure 2). A broad range of benzyl cyanides
Scheme 2. Preparation of 3D
In order to understand the mechanism, we carried out the
controlled experiments. First, cyanation of benzofuran or 2-
phenylbenzofuran with PhCH2CN/Cu(OAc)2 or CuCN was
orthogonally tested. No cyanation product was detected. It
implied that C−CN bond formation took place prior to the
benzofuran ring formation. Second, we assumed PhCH(OH)-
CN17 to be the intermediate. However, no reaction occurred
when PhCH(OH)CN was applied as starting material, rejecting
our assumption. Thereafter, we assumed that the Knoevenagel
condensation product (5) was the intermediate (Scheme 3). No
Scheme 3. Controlled Experiments
Figure 2. Scope of benzyl cyanides. Reaction conditions: (a) 1a (0.5
mmol), 2 (0.75 mmol), dry DMSO (2 mL), with a drying tube; iolated
yield based on 1a; (b) 110 °C; (c) 18 h; (d) conducted with 10 mol %
Pd(OAc)2 and K2CO3 (4.0 equiv).
were applied. Substituents on the para position of benzyl
cyanides could be altered to Me, MeO, Cl, F, Br, and CF3, which
provided the corresponding 2-aryl-3-cyanobenzofurans 3b−g in
yields varying from 42% to 74%. 2-(4-Nitrophenyl)acetonitrile
afforded 3h in 22% yield at a raised reaction temperature. A
relatively lower yield (3i, 24%) was also observed when 2-(2-
nitrophenyl)acetonitrile was used. Comparing the pair of 3k and
3l, the steric effect is obvious. Moreover, 2-(thiophene-2-
yl)acetonitrile could also be applied for this reaction and
provided 3m in 66% yield. We further tested the substrate scope
of 2-hydroxybenzaldehydes. Reaction of salicyclic aldehyde with
PhCH2CN provided 3n in 55% yield. With other para-
reaction occurred when 5 was used as a single starting material
(eq 1), rejecting our assumption again. A turning point occurred
when this test was carried out by supplementarily adding
TMSCN (1.5 equiv) and KF (2 equiv). In this case, 3a was
isolated in 56% yield (eq 2). We tried to isolate 5 by stopping the
reaction after 3 h. Instead of obtaining 5, we isolated
B
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iminocoumarin 6. By extending the reaction time to 6 h,
coumarin 4 was isolated (eq 3). Compound 6 could not be
converted into 3a unless PhCH2CN was supplementally added.
Thus, it is obvious that free cyanide anion plays a key factor in
achieving a successful transformation. A stripe test indicated that
free cyanide anion existed during the reaction process.18
301 nm. A similar situation is observed for the pair of 3k and 3l.
Compound 3l absorbs light at a lower energy band with a higher
molar absorption coefficient than 3k does.
The substituent effect of the 5-position of benzofuran on the
absorption spectra is not apparent. Compounds 3a, 3n, 3r, and
3u present similar absorption spectra. However, with Et2N
occupied on the 6-position of benzofuran, 3v absorbs light at 386
nm (ε = 1.93 × 104). In comparison with 3v, 3w absorbs light at a
lower energy band (402 nm) because of pyridinyl group. A good
electron push−pull system exists in the molecule of 3w. For
comparison, we synthesized 8 (Figure 3). With cyano substituted
Based on the above observations, we postulated a working
mechanism (Scheme 4). Knoevenagel condensation in situ
Scheme 4. Possible Reaction Mechanism
Figure 3. Absorption and emission spectra of 8, 3v, and 7d.
generated 5 that equilibrated with 6. Compound 6 could be
partially, but irreversibly, converted into 4. In the presence of
Cu(II) and O2, PhCH2CN was oxidized, and cyanide anion was
in situ formed. Subsequent anion transfer19 led to the formation
of A. Oxa-Michael addition and aromatization provided 3a.
Aryl nitriles could be smoothly extended to aryl amides. Thus,
amides (7a−e) were prepared by using KOH in t-BuOH at 60 °C
for 12 h (Scheme 5).
on the 3-position of benzofuran, absorption of 3v is red-shifted in
comparison with naked 8. However, when the cyano group is
replaced by amide, the conjugation is interupted. The dihedral
angle for benzofuran and benzene in 7d is calculated to be 21.7°.
As a result, absorption of 7d is blue-shifted in comparison with
the absorption of 3v.
Compounds 3a−g emit bright light at about 370 nm with a
Stokes shift about 50 nm. Their quantum yields are in a range
from 41.0% to 88.2% except for 3f (Φ = 23.9%). Compound 3c
shows a quantum yield of 88.2% because of the methoxy group. A
relatively lower quantum yield is found for 3f because of the
bromine effect. Compounds 3h and 3i emit light at 392 and 374
nm with quantum yields of 0.2% and 8.0%, respectively. The low
quantum yields could be ascribed to the nitro group. The largest
Stokes shift (97 nm) is observed for 3k in the family of 2-aryl-3-
cyanobenzofurans. Compounds 3a, 3n, 3r, and 3u emit light
about 365 nm with a Stokes shift about 50 nm. Quantum yields of
3a, 3n, 3r, and 3u are found to be 41.0%, 39.3%, 23.2%, and 2.3%,
respectively. By installing Et2N− on the 6-position of
benzofuran, 3v (Φ = 88.9%) shows the highest quantum yield
in the family of 2-aryl-3-cyanobenzofurans. Emission spectra of 8,
3v, and 7d are shown in Figure 3. Hydrolysis of cyano to amide
led to blue-shifted absorption and red-shifted emission. As a
result, 7d presents the largest Stokes shift (125 nm).
Emission spectra depend on the solvent polarity. As a typical
example, emission spectra of 3w in different solvents are shown
in Figure 4a. The maximum emission wavelength is gradually
red-shifted when the solvent changes from cyclohexane (CH) to
toluene (Tol), dioxane (DIO), THF, DCM, EtOH, MeCN,
MeOH, and finally to DMSO. The color change under UV light
(365 nm) is significant. As we can see from Figure 4c, the color
changes from bright blue to light blue to green when solvent
changes from CH to THF to DMSO. We also tested for the
fluorescent variation when 3w aggregates. In this case,
aggregation caused by quenching (ACQ) is observed (Figure
4b). As the water fraction in THF solution increased, a gradually
decreased fluorescent intensity was measured accompanied by a
gradually red-shifted emission. When the ratio of water to THF
Scheme 5. Preparation of Aryl Amides
During the preparation of 3, we found that these compounds
(3a−D) were strongly emissive under UV light and the structure
of 2-aryl-3-cyanobenzofuran was indeed a new fluorophore.
Because of the versatile uses of fluorescence in life and material
sciences, we measured their photophysical properties. Results are
summarized in Table S2.
The maximum absorption wavelength (λmax) for 3a−g in
CH2Cl2 is about 320 nm with a molar absorption coefficient (ε)
around 2.60 × 104. The substituent effect of the para-position of
2-phenyl is not apparent. It is observed that 3h absorbs light at
357 nm (ε = 2.64 × 104), while 3i absorbs light at 301 nm (ε =
0.56 × 104). The absorption behavior is largely dependent on the
dihedral angle arising from benzofuran and the arene on 2-
position of benzofuran. The smaller the dihedral angle is, the
larger the maximum absorption wavelength and the higher molar
absorption coefficient presents. Thus, the red-shifted absorption
of 3h could be ascribed to the planarization of the phenyl and
benzofuran. Compound 3i, possessing a larger dihedral angle
(41.3°) due to the existence of the o-nitro group, absorbs light at
C
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Figure 4. (a) Normalized emission spectra of 3w in different solvents;
(b) emission spectra of 3w in different ratios of water in THF; (c)
solution color of 3w under UV light, from left to right: CH, THF,
DMSO, H2O/THF(85/15).
increased to 85 to 15, bright yellow emission of 3w was seen
under UV light (Figure 4c). A similar phenomenon is observed
for compound 7e (see the SI).
In conclusion, we have developed a green methodology for the
preparation of 2-aryl-3-cyanobenzofurans by using o-hydrox-
ybenzaldehydes and arylacetonitriles in the presence of copper
acetate and sodium methoxide. Many substituents tolerate the
reaction conditions and produce 2-aryl-3-cyanobenzofurans in
moderate to good yields. The cascade process includes
Knoevenagel condensation, cyanide anion transfer, intramolec-
ular nucleophilic addition, and aromatization. Furthermore, 2-
aryl-3-cyanobenzofurans are bright blue under UV irradiation.
The highest quantum yield in dilute methylene chloride is
determined to be 88.9%. Moreover, emission depends on the
solvent polarity. When the solvent is changed from cyclohexane
to THF and finally to DMSO, an emission color of 3w is
accordingly altered from bright blue to light blue and finally to
green. It implies that compound 3w might be used as a
fluorescent probe for the detection of environmental variation,
such as solvent polarity.
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(15) X-ray crystal structure of 3a, which is numbered CCDC 1438893,
is available from the Cambridge Crystallographic Data Centre.
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Soc. 2009, 131, 1187.
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134, 2528. (b) Pawar, A. B.; Chang, S. Chem. Commun. 2014, 50, 448.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03704.
Detailed synthetic procedures and characterization data
for all products (PDF)
UV−vis absorption and fluorescence spectra (PDF)
Crystallographic information for compound 3a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pinglu@zju.edu.cn.
*E-mail: orgwyg@zju.edu.cn.
Author Contributions
†L.Z. and Z.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the National Natural Science Foundation of
China (Nos 21472173 and 21272203) for financial support.
■
REFERENCES
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D
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