Copper-Catalyzed Cascade Synthesis of 2-Aryl-3-cyanobenzofuran and Dibenzo[ b, f]oxepine-10-carbonitrile Derivatives

Article abstract of DOI:10.1021/acs.joc.8b01443

The copper-catalyzed reaction of aryl aldehydes with 2-iodobenzylcyanides afforded 2-aryl-3-cyanobenzofurans in isolated yields of up to 74% in a cascade manner, which involves Knoevenagel condensation, aryl hydroxylation, oxa-Michael addition, and aromatization reactions. Conversely, 2-halo benzaldehydes as reacting partners with 2-iodobenzylcyanide regioselectively furnished dibenzo[b,f]oxepine-10-carbonitrile derivatives up to 85% isolated yields via tandem Knoevenagel condensation, aryl hydroxylation, and Ullmann coupling reactions.

Full text of DOI:10.1021/acs.joc.8b01443

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Article
Copper Catalyzed Cascade Synthesis of 2-Aryl-3-cyanobenzofuran
and Dibenzo[b,f]oxepine-10-carbonitrile Derivatives
Bharath KUMAR VILLURI, Sachin S. Ichake, Sabbasani Rajasekhara Reddy,
Veerababurao Kavala, Vijayalakshmi Bandi, Chun-Wei Kuo, and Ching-Fa Yao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01443 • Publication Date (Web): 12 Jul 2018
Downloaded from http://pubs.acs.org on July 12, 2018
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The Journal of Organic Chemistry
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Copper Catalyzed Cascade Synthesis of 2-Aryl-3-cyanobenzofuran and
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Dibenzo[b,f]oxepine-10-carbonitrile Derivatives
Bharath Kumar Villuri,a Sachin S. Ichake,a Sabbasani Rajasekhara Reddy,a,b Veerababurao Kavala,a Viꢀ
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jayalakshmi Bandi,a ChunꢀWei Kuoa and ChingꢀFa Yaoa*
aDepartment of Chemistry, National Taiwan Normal University, 88, Section 4, TingꢀChow Road, Taipei 116, Taiwan,
R.O.C.
bDepartment of Chemistry, School of Advanced Sciences, VIT University, Velloreꢀ632014, India.
Supporting Information Placeholder
ABSTRACT: The copper catalyzed reaction of aryl aldehydes with 2ꢀiodobenzylcyanides afforded 2ꢀarylꢀ3ꢀcyanobenzofurans in
isolated yields of up to 74% in a cascade manner, which involves Knoevenagel condensation, aryl hydroxylation, oxaꢀMichael adꢀ
dition and aromatization reactions. Conversely, 2ꢀhalo benzaldehydes as reacting partners with 2ꢀiodobenzylcyanide furnished regiꢀ
oselectively dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile derivatives up to 85% isolated yields via tandem Knoevenagel condensation, aryl
hydroxylation and Ullmann coupling reactions.
Introduction
cyanobenzofurans using preꢀinstalled oxygen (ꢀOꢀ) containing
arenes through the formation of the intermediate III (Scheme
1, eq 3).11
Benzofuran scaffolds are components of a wide variety of
therapeutic drugs.1 Notably, 2ꢀarylꢀ3ꢀcyanobenzofuran moieꢀ
ties are key intermediates in the synthesis of bioactive inhibiꢀ
tors of the hepatitis C virus (HCV).2 These moieties also have
desirable mechanochromic properties, giving them the potenꢀ
tial for serving as applications in organic light emitting diodes
(OLEDs).3 Although, many strategies have been developed for
the construction of 2ꢀarylꢀ3ꢀcyanobenzofurans, some alternate
and convenient protocols are needed to broaden the scope for
the synthesis of different types of substituted 2ꢀarylꢀ3ꢀ
cyanobenzofuran derivatives. These include, the direct cyaꢀ
nation of benzofurans,4 functional group interꢀconversion
(FGI) from 2ꢀarylꢀ3ꢀamidobenzofurans,5 an aromatic ring umꢀ
polong reaction of catechols with PhCOCH2CN,6 the cycloadꢀ
dition of benzyne with iodonium yillide,7 and by the intramoꢀ
lecular joining of a preꢀexisting oxygen (ꢀOꢀ) containing moieꢀ
ty on the side chain to its benzene ring at the ortho position
through CꢀO bond formation.8 Ruihu Wang et al. recently reꢀ
ported on the synthesis of 2ꢀphenylbenzofuran through the
hydroxyintermediate I, for use in the hydroxylation of ioꢀ
doarenes (Scheme 1, eq 1).9 Fan and coworkers also syntheꢀ
sized 3ꢀcyanoꢀ1Hꢀindoles using oꢀbromobenzylcynide and
arylaldehydes as starting materials through the amine intermeꢀ
diate II, in which, ammonium hydroxide was used as a nitroꢀ
gen source (Scheme 1, eq 2).10 Yanguang Wang et al.11a and
other groups reported on the synthesis of 2ꢀarylꢀ3ꢀ
In a continuation of our research efforts in exploring additionꢀ
al synthetic aspects of 2ꢀIodobezylcyanide surrogates for the
construction of various valuable heterocyles12 and based on
clues provided in literature cited above (Scheme 1, eq1ꢀeq3),
we hypothesized that if might be possible to prepare, 2ꢀarylꢀ3ꢀ
cyanobenzofuran derivatives through the in situ generation of
the hydroxyl intermediate III from iodoarene, using 2ꢀ
iodobenzylcyanides 2a and benzaldehyde 1a as starting mateꢀ
rials (Scheme 2, eq4). This might be achieved through
Knoevenagel condensation, aryl hydroxylation, oxaꢀMichael
addition and aromatization reactions in a cascade manner by
utilizing some previously reported copper mediating protoꢀ
cols.13 We further, hypothesized that the reaction of 2ꢀ
halobenzaldehydes with 2a, could result in the formation of
either seven membered oxepines 4 or benzofurans 3 (Scheme
2, eq5).
Results and Discussion
In order to verify our hypothesis for producing the proposed 2ꢀ
arylꢀ3ꢀcyanobenzofurans (Scheme 2, eq 4), a set of experiꢀ
ments was initially carried out by using 20 mol% of CuI as a
standard catalyst along with 3 equiv of Cs2CO3 in 2 ml of
DMSO solvent at 100 °C, and varying the amount of benzalꢀ
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investigating various additives other than TBAB and included
dehyde 1a, with 2ꢀiodobenzylcyanide 2a, ligands and addiꢀ
tives. The results are presented in Table 1.
TBAC (Tetra butyl ammonium chloride, TBAI (Tetra butyl
ammonium iodide), and CTAB (Cetyl trimethyl Ammonium
bromide), none of which were satisfactory (Entries 18 ꢀ 20).
1
2
3
4
Scheme 1. Recent relevant strategies for the synthesis of Inꢀ
dole and benzofurans
Table 1.Optimization of the synthesis of 2ꢀaryl
3ꢀcyanobenzofurans 3
5
6
7
8
9
O
CN
CN
Cu
Ligand
additive
36 h
O
3a
I
2a
1a
10
11
12
13
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Entrya
Catalyst
(20 mol %)
Base
(3 equiv )
Ligand
(50 mol %)
Yield (%)b,e
Additive
(0.5 equiv)
Solvent
(2 ml)
3a
1d
2
CuI
DMSO
ꢀꢀ
ꢀꢀ
ND
Cs2CO3
Cs2CO3
Cs2CO3
CuI
CuI
DMSO
DMSO
ꢀꢀ
ꢀꢀ
ꢀꢀ
Trace
ꢀꢀ
7
35c
40
L1
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuI
CuI
DMSO
DMSO
L2
L3
ꢀꢀ
ꢀꢀ
CuI
CuI
CuI
DMSO
DMSO
DMSO
L4
L5
L4
ꢀꢀ
55
59
ꢀꢀ
TBAB
Scheme 2. Current hypothesis
Cs2CO3
Cs2CO3
9
10
CuI
CuCl
DMSO
DMSO
L5
L5
67
71
TBAB
TBAB
Cs2CO3
Cs2CO3
Cs2CO3
11
CuBr
Cu(OAc)2
Pd(OAc)2
DMSO
DMSO
DMSO
L5
L5
L5
44
TBAB
TBAB
TBAB
12
Trace
ND
13
14
15
16
17
ND
tꢀBuOK
CuCl
CuCl
CuCl
CuCl
DMSO
DMSO
DMF
L5
L5
L5
L5
TBAB
TBAB
TBAB
K2CO3
18
Cs2CO3
Cs2CO3
20
ꢀꢀ
DMAc
TBAB
TBAC
Cs2CO3
Cs2CO3
Cs2CO3
18
19
20
CuCl
CuCl
CuCl
DMSO
DMSO
DMSO
L5
L5
L5
66
52
41
TBAI
An initial experiment, which was carried using standard reagents
(20 mol% of CuI, 3 equiv of Cs2CO3 in 2 ml of DMSO), with 1.1
equiv of 1a and 0.5 mmol of 2a, resulted in the decomposition of
the compound 2a, while compound 1a remained unreacted (entry
1). When 1.4 equiv of 2a and 0.5 mmol of 1a were used a trace
amount of the blue colored illuminiscent 3a was observed under
UV light (entry 2). Thus, all further reactions were carried out
using an excess amount of compound 2a (1.4 equiv). In order to
increase product yield, 50 mol% of a series of different ligands
such as tetraethylethaneꢀ1,2ꢀdiamine (L1), proline (L2), 2,2'ꢀ
bipyridine (L3), 1,10ꢀphenanthroline (L4) and 4,7ꢀdimethylꢀ1,10ꢀ
phenanthroline (L5) were examined under standard reagent
conditions with 0.5 mmol of 1a and 1.4 equiv of 2a. Among all of
the ligands tested, L5 was found to be the best, giving a maximum
yield of the product 3a of 55% (entries 3 and 7). To our delight,
the characteristic data (1H & 13C NMR) of this isolated compound
was found to be same as that of the previously reported 2ꢀarylꢀ3ꢀ
cyanobenzofuran. To further improve the yield in the reaction, we
used 0.5 equiv of TBAB (Tetra butyl ammonium bromide) as an
additive. The yields were increased to 59% with L4 and to 67%
with L5 (entries 8 and 9). A second set of experiments in which
20 mol% of var ious other copper salts were used, i.e., CuCl,
CuBr, Cu(OAc)2 and Pd(OAc)2 along with 50 mol% of the
additive. The results revealed that, CuCl gave the maximum yield
of the product at 71% (entry, 10) and CuBr gave a moderate yield
of the product, while the others resulted in trace amounts of the
product or decomposition (entries, 12&13). A third set of
experiments was directed at the effect of strong and weak bases
such as tBuOK and K2CO3, which resulted in the decomposition
of the reactants or a low product yield (Entries 14 & 15). In a
fourth set of experiments, designed to examine the effect of other
polar solvents such as DMF and DMAc, the use of DMF resulted
a 20 % product yield and no reaction was observed in DMAc
(Entries 16 &17). The final set of experiments involved
CTAB
OH
O
N
N
N
H
N
N
N
N
N
N
L1
L2
L3
L4
L5
(a) All reactions were performed on a 0.5 mmol scale of 1a and
1.4 equiv of 2a at 90 °C under an open air atmosphere; (b) NMR
yields; (c) Isolated yield; (d) 2a (0.5 mmol) and 1a (1.1 equiv).
(d) N.D: not determined (due to decomposion of 2a); (e) In all the
entries, 5ꢀ50 % of unreacted benzaldehyde 1a was recovered due
to the decomposition of 2a at 90 °C, except in the case of entries
9,10 & 18.
Entry 10, in Table 1 provides information on the optimized
reaction conditions, based on the above observations.
Having the afore mentioned reaction conditions in hand, the
scope of the methodology with diverse aldehydes and 2ꢀ
iodobenzylcyanide substrates was examined (Table 2). Reacꢀ
tions of benzaldehyde 1 derivatives containing electron withꢀ
drawing groups Cl and CN at para positions and 2ꢀ
iodobenzylcyanide furnished 3b and 3c in 48% and 31% yield,
respectively. The decreased yield of 3c can be attributed to the
strong deactivating effect of the 4ꢀCN group. F and Cl substitꢀ
uents at the meta positions afforded 3d in 65% and 3e in 32%
yields. In the case of a strong electron donating group (OMe)
at the para position, the corresponding 3ꢀcyanoꢀ2ꢀ
phenylbenzofuran derivatives were produced in 50 % yield. A
meta methoxy substituted aldehyde gave the desired product
3g in 47% yield. Next, the effects of moderate electron donatꢀ
ing groups (Me) in aldehyde substrates such as 4ꢀMe, 3ꢀMe
and 2ꢀMe benzaldehydes with 2ꢀiodobenzylcyanide were inꢀ
vestigated. The reaction of the 4ꢀmethylbenzaldehyde subꢀ
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The Journal of Organic Chemistry
benzaldehyde; (e) Reaction time is 10 h; (f) Reaction time is 12 h;
strate gave the desired product 3h in 68 % and 3ꢀ
methylbenzaldehyde afforded the corresponding product 3i in
65%, while, 2ꢀmethylbenzaldehyde provided a slightly lower
yield (48%) of the desired product 3j compared with the reacꢀ
tions of 4ꢀmethyl and 3ꢀmethylbenzaldehyde derivatives,
which likely due to the effect of the ortho methyl group. We
next examined the reactions of 1ꢀnaphthyladehyde and 2ꢀ
naphthylaldehyde with 2ꢀiodobenzylcyanide under the optiꢀ
mized conditions. In both the cases, the desired 3ꢀcyanoꢀ2ꢀ
phenylbenzofuran derivatives (3k, 3l) were obtained in good
yields. The reactions of disubstituted benzaldehydes containꢀ
ing the electron donating groups (OMe) and methylenedioxy
with 2ꢀiodobenzylcyanide were studied. The reactions affordꢀ
ed the corresponding 3ꢀcyanoꢀ2ꢀphenylbenzofuran derivatives
3m and 3n in 59% and 50%, respectively. However, the reacꢀ
tion of 3,4ꢀdichlorobenzaldehyde gave only a 41% of the 3ꢀ
cyanoꢀ2ꢀphenylbenzofuran derivative (3o). It is noteworthy
that chloro substituted compounds other than at the meta posiꢀ
tion resulted in moderate yields of the products (3b & 3o). In
particular, a chloro substitution at the meta position delivered
a lower yield (3e). We subsequently examined the reaction of
a benzaldehyde containing a tri electron releasing group and 2ꢀ
iodobenzylcyanide under the optimized conditions. The reacꢀ
tion furnished the desired product (3p) in good yield (70%).
Consequently, we investigated the reactions of various heteroꢀ
cyclic rings containing aldehyde groups and 2ꢀ
iodobenzylcyanide. With furaldehyde, the reaction resulted in
the desired product (3q) in 21% yield, whereas with pyridine
and quinoline substituents, the reactions provided the correꢀ
sponding products (3r) and (3s) in 66% and 74% yields, reꢀ
spectively.
(g) mixture of compounds; (h) 1.8 equivof 2a was used; (i) 10 ꢀ
15 % of unidentified mixture of compounds were absorved; (j)
Traces amounts to 5% of corresponding aldehyde 1 along with 3
were absorved in some of the reactions.
1
2
3
4
5
6
7
8
We also tested the scope of the methodology with respect to
substituted 2ꢀiodobenzylcyanide substrates and benzaldehyde.
The reaction between 2ꢀiodobenzylcyanide equipped with
methoxy group and benzaldehyde, produced the corresponding
product (3t) in a 52% yield. In addition, 3,4ꢀdimethoxy substiꢀ
tuted 2ꢀiodobenzylcyanide reacted with benzaldehyde in the
present reaction to give the desired 3ꢀcyanoꢀ2ꢀ
phenylbenzofuran derivative (3u) in 62% yield, whereas the
desired product (3v) was produced in 51% yield in the case of
4ꢀmethoxybenzaldehyde. Unfortunately, the developed protoꢀ
col failed to produce (3w) and (3x) and resulted in a mixture
of compounds when bromo substituted 2ꢀiodobenzylcyanide
was used.
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The developed catalytic system was tested for the synthesis of
either seven membered oxepines 4 or benzofurans 3 as per our
proposed hypothesis (Scheme 2, eq5). Apart from benzofuran
scaffolds, dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile derivatives are
also known to be valuable derivatives in medicinal chemisꢀ
try.14b In spite of this, only a few synthetic methods using 2ꢀ
hydroxybenzylcyanide as reacting partner with 2ꢀhalo benzalꢀ
dehydes have been reported.15 Unlike these reports, the synꢀ
thesis of dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile derivatives 4
using 2ꢀiodo benzylcyanides 2a as the reaction partner with 2ꢀ
halo benzaldehydes which includes 2ꢀbromo, 2ꢀchloro and 2ꢀ
iodo benzaldehyde derivatives proceeded well.
In all three cases, dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile (4A)
was produced exclusively in yields of 70%, 72% and 61%,
respectively, within a short period of time (1 h). Hence, the
synthesis of dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile derivatives 4
gave the expected products in 31ꢀ85% isolated yields using 2ꢀ
iodobenzylcyanide 2a as a reacting partner with the 2ꢀ
bromobenzaldehydes (1B–1E), as shown in Table 3.
Table 2. Scope for the synthesis of 2ꢀarylꢀ3ꢀ
cyanobenzofurans 3
CN
R1
CN
CuCl (20 mol %)
L5 (50 mol %)
R1
ArCHO
Ar
R2
I
Cs2CO3 (3.0 equiv)
TBAB (0.5 equiv)
R2
O
2
1
3 3a - 3x a,b & j
R1 = H, OMe, Br
2 = H, OMe
(
)
Table 3. Synthesis of dibenzo[b,f]oxepineꢀ10ꢀ
carbonitrile derivatives 4a
R
CN
CN
CN
O
x
O
O
3a = 66 %, X = H
3bi = 48 %, X = 4-Cl
3cf,i= 31%, X = 4-CN
3d = 65%, X = 3-F
3ef,i= 32%, X = 3-Cl
3fh= 50%, X = 4-OMe
3gh= 47%, X = 3-OMe
3h = 68%, X = 4-Me
3i = 65%, X = 3-Me
3j = 48%, X = 2-Me
3l = 67%
CN
3k = 60%
CN
OMe
O
O
O
OMe
3mh = 59%
O
3nh = 50%
CN
CN
OMe
Cl
O
O
Cl
3oc = 41%
MeO
3pc = 70%
CN
CN
CN
R1
R2
O
O
R3
O
N
3qe = 21%
O
3re = 66%
3t = 52%, R1 = OMe, R2 = H, R3 = H
CN
3u = 62%, R1 = OMe, R2 = OMe, R3 = H
3vd = 51%, R1 = OMe, R2 = OMe, R3 = OMe
3w = --g, R1 = Br, R2 = H, R3 = H
O
N
(a) Reaction conditions: 1 (1.0 mmol), 2a (1.1 equiv) and DMSO
(3.0 ml) under open air atmosphere; (b) 1 is 2ꢀiodo benzaldehyde;
(c) 1 is 2ꢀchloro benzaldehyde.
3sc,e = 74%
3x = --g, R1 = Br, R2 = H, R3 = OMe
(a) Reaction conditions: 1 (1.0 mmol), 2 (1.4 equiv) and DMSO
(4.0 ml) for 36 h at 90 °C under open air atmosphere; (b) Isolated
yields based on 1; (c) The additive TBAB was not added; (d)
Consistent with earlier reports in the literature, based on the
proposed mechanism by Deping Wang et al.14a, a possible
mechanism in which the reaction proceeds through Metal/L
Reaction performed on
a 0.4 mmol scale for 4ꢀOMe
3
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catalyzed hydroxylation of aryl halides14,9 is shown in Scheme
column chromatography was performed on 63ꢀ200 mesh silica
1
2
3
4
5
6
7
8
3. In addition, based on mechanistic studies of Xue and
coworkers14c, it was evident that upon aryl hydroxylation, the
OH group of the resulting intermediate D originated from waꢀ
ter. In addition, based on our observations, the formation of
gel using freshly distilled nꢀhexane and ethyl acetate as eluꢀ
1
ents. H and 13C NMR spectra were recorded on a Bruker Asꢀ
cend spectrometer 600, 400 and 150, 100 MHz, respectively.
Chemical shifts are reported in parts per million (ppm) on the
δ scale by using CDCl3 or d6ꢀDMSO as an internal standard.
Multiplicities were indicated by using abbreviations such as s
= singlet; d = doublet; t = triplet; q = quartet; m = multiplet.
Coupling constants are expressed in Hertz (Hz). High Resoluꢀ
tion Mass Spectra (HRMS) were recorded on ESI, EI+ve and
EI–ve modes. The melting points (mp) were recorded on an
Electro Thermal FARGO MPꢀ2D capillary melting point apꢀ
paratus.
dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile derivatives
4 provides
clear evidence that the formation of 2ꢀarylꢀ3ꢀ
cyanobenzofurans 3 proceeds through an aryl hydroxylation
reaction. Considering the above aspects as mechanistic supꢀ
port, a possible mechanism was formulated in such a way that,
in the initial step, the intermediate A is formed in the presence
of a base via a Knoevenagel condensation reaction from 1 and
2 by releasing a water molecule. Intermediate A then underꢀ
goes oxidative addition to produce intermediate B by the
Cu(I)/Ligand. Further, intermediate B undergoes nucleophilic
addition by CsOH which is generated from Cs2CO3 and water
to form intermediate C. Intermediate C then further undergoes
reductive elimination to produce D, and reꢀinitiates the [Cu(I)]
catalytic cycle. Finally, Intermediate D, undergoes oxaꢀ
Michael addition and aromatization to produce the desired
compound 3.13a On the contrary, 2ꢀhalo benzaldehyde as reactꢀ
ing partner results in the Ullmann coupling product 4 from
intermediate D as the major product.
9
10
11
12
13
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i. General procedure for the synthesis of compounds 3a-3v.
A 10 ml vial was charged with 1.0 mmol of aryl aldehyde, 1.4
mmol of 2ꢀiodobenzylcyanide, 20 mol% of CuI, 50 mol % of
ligand, 3.5 equiv of Cs2CO3 and 0.5 equivalents of TBAB and
4 ml of DMSO. The resulting reaction mixture was placed on
an oil bath that was preheated to 90 oC and stirred for about 36
h under an open atmosphere. The progress of reaction was
monitored by TLC at 2h time points. After the reaction
reached completion, 10 ml of ethyl acetate was added and
filtered from the salts. Brine was added to the filtrate and the
solution and extracted with ethyl acetate (2 x 10 ml). The resiꢀ
due was purified by column chromatography on silica gel usꢀ
ing nꢀHexane/ethyl acetate as eluents to obtain the pure prodꢀ
ucts 3a-3v.
CN
Cu(I)/L
L
X
Cu
I
B
ii. General procedure for the synthesis of compounds 4A-4E.
CN
I
L
A 10 ml vial was charged with 1.0 mmol of aryl aldehyde, 1.4
mmol of 2ꢀiodobenzylcyanide, 20 mol% of CuI, 40 mol % of
ligand and 3.0 equiv of Cs2CO3 and 4 ml of DMSO. The reꢀ
sulted reaction mixture was placed on an oil bath that was
CN
2CsOH
X
A
L
I
Cs CO
2
+ H O
3
X
2
Base - H O
2
Cu
o
preheated to 100 C and stirred under an open atmosphere.
1
2
C
L
OH
The progress of the reaction was monitored by TLC. After the
reaction reached completion, the reaction mixture was added
to 10 ml of ethyl acetate and the salts removed by filtration.
Brine was then added to the filtrate and the solution extracted
with ethyl acetate (2 x 10 ml). The residue was purified by
column chromatography on silica gel using nꢀHexane/ethyl
acetate as eluents to obtain pure products 4A-4E.
CN
Ullmann
coupling
i.oxa-Michael
addition
4
3
X
ii.aromatization
X = H
X = I, Br & Cl
OH
D
Scheme 3. Possible reaction path way
iii. Analysis data of 3a-3v and 4A- 4E.
CONCLUSION
2ꢀphenylbenzofuranꢀ3ꢀcarbonitrile (3a)
In summary, we report on the synthesis of 2ꢀaryl 3ꢀ
cyanobenzofurans and dibenzo[b,f]oxepineꢀ10ꢀ
Eluent: nꢀhexane (100%); Off White Solid; Yield: 144 mg
1
3
(66%); Mp: 80–81 °C. H NMR (CDCl3, 400 MHz): δ 8.20
carbonitrilederivatives 4 through Copper catalysis, using 2ꢀ
iodobenzylcyanides 2 and 2ꢀaryl aldehydes 1. The new apꢀ
proach developed is regioselective and proceeds through a
cascade one pot reaction to produce several substituted five
membered benzofurans and seven membered oxepines
through the formation of multiple new bonds under atmosꢀ
pheric oxygen.
(dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.71 (dd, J = 8.2 Hz, 1.6 Hz,
1H), 7.60ꢀ7.53(m, 4H), 7.43ꢀ7.39 (m, 2H. 13C NMR (CDCl3,
100 MHz): δ 161.9, 153.6, 131.5, 129.4, 128.1, 127.5, 126.8,
126.7, 128.6, 124.9, 120.2, 114.5, 111.9, 88.4. HRMS (EI):
Calcd for C15H9NO [M]+ 219.0684, found: 219.0686.
2ꢀ(4ꢀchlorophenyl)benzofuranꢀ3ꢀcarbonitrile (3b)
Eluent: nꢀhexane (100%); White Solid; Yield: 122 mg (48%);
Mp: 132–133 °C. 1H NMR (CDCl3, 400 MHz): δ 8.13 (dd, J =
8.8 Hz, 2.0 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.6
Hz, 1H), 7.51 (dd, J = 8.8 Hz, 2.0 Hz, 2H), 7.45ꢀ7.37 (m, 2H).
13C NMR (CDCl3, 100 MHz): δ 160.7, 153.6, 137.6, 129.8,
127.9, 127.3, 126.9, 126.5, 125.1, 120.3, 114.3, 111.9, 88.8.
HRMS (EI): Calcd for C15H8ClNO [M]+ 253.0294, found:
253.0295.
EXPERIMENTAL SECTION
General Information
Unless otherwise stated, all reagents and solvents were purꢀ
chased from commercial suppliers and were used directly
without further purification. The 10 ml sealed vials were
cleaned by drying in an oven overnight and cooled to room
temperature prior to use. All reactions that required anhydrous
conditions were conducted under an argon atmosphere. Flash
2ꢀ(4ꢀcyanophenyl)benzofuranꢀ3ꢀcarbonitrile (3c)
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Eluent: nꢀhexane / ethyl acetate (99 ml / 1 ml); White Solid;
114.6, 111.9, 88.2, 21.7. HRMS (EI): Calcd for C16H11NO
[M]+ 233.0841, found: 233.0841.
Yield: 76 mg (31%); Mp: 228ꢀ229 °C. 1H NMR (CDCl3, 400
MHz): δ 8.31 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 7.6 Hz, 2H),
7.77 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),7.52ꢀ7.43
(m, 2H). 13C NMR (CDCl3, 100 MHz): δ 159.0, 153.9, 133.1,
131.8, 127.8, 127.1, 126.9, 125.4, 120.6, 118.2, 114.5, 113.7,
112.2, 91.0. HRMS (EI): Calcd for C16H8N2O [M]+ 244.0637,
found: 244.0638.
1
2
3
4
5
6
7
8
2ꢀ(oꢀtolyl)benzofuranꢀ3ꢀcarbonitrile (3j)
Eluent: nꢀhexane (100%); White Solid; Yield: 57 mg (50%);
Mp: 67 ꢀ 68 °C. 1H NMR (CDCl3, 400 MHz): δ 7.76 (d, J =
6.8 Hz, 2H), 7.59 (dd, J = 6.6, 2.2 Hz, 1H), 7.46 ꢀ7.42 (m,
3H), 7.39 ꢀ 7.26 (m, 2H), 2.54 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 164.5, 154.0, 138.0, 131.7, 131.3, 130.3, 127.4,
126.8, 126.5, 126.4, 124.8, 122.2, 114.0, 112.0, 91.7, 21.0.
HRMS (EI): Calcd for C16H11NO [M]+ 233.0841, found:
233.0842.
2ꢀ(3ꢀfluorophenyl)benzofuranꢀ3ꢀcarbonitrile (3d)
Eluent: nꢀhexane (100%); White Solid; Yield: 154 mg (65%);
Mp: 137ꢀ138 °C. 1H NMR (CDCl3, 400 MHz): δ 8.01 (d, J =
7.6 Hz, 1H), 7.84 (dd, J = 9.2Hz, 1H), 7.71 (d, J = 7.6 Hz,
1H), 7.57 (d, J = 8.0 Hz, 1H), 7.54 ꢀ7.48 (m, 1H), 7.45 ꢀ 7.37
(m, 2H), 7.22 (t, J = 2.0 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ 164.4 (d, JCꢀF = 246.0 Hz), 160.2, 153.6, 131.2 (d, JCꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(naphthalenꢀ1ꢀyl)benzofuranꢀ3ꢀcarbonitrile (3k)
Eluent: nꢀhexane (100%); White Solid; Yield: 161 mg (60%);
Mp: 126ꢀ127 °C. 1H NMR (CDCl3, 400 MHz): δ 8.23 (d, J =
8.4 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 8.10ꢀ7.95 (m, 2H), 7.81
(d, J = 6.2 Hz, 1H), 7.68ꢀ7.59 (m, 4H), 7.49ꢀ7.46 (m, 2H).13C
NMR (CDCl3, 100 MHz): δ 164.0, 154.3, 134.1, 131.6, 132.3,
130.8, 129.6, 129.0, 127.8, 126.9, 126.6, 125.5, 125.4, 125.2,
125.0, 120.4, 113.9, 112.2, 92.7. HRMS (EI): Calcd for
C19H11NO [M]+ 269.0841, found: 269.0841.
= 8.0 Hz), 130.0, 129.9 (d, JCꢀF = 8.0 Hz), 127.2, 127.1,
F
125.1, 122.5 (JCꢀF = 3.0 Hz), 120.3, 118.5 (JCꢀF = 21.0 Hz),
114.1, 113.7 (JCꢀF = 24.0 Hz), 112.0, 89.3. HRMS (EI): Calcd
for C15H8FNO [M]+ 237.0590, found: 237.0589.
2ꢀ(3ꢀchlorophenyl)benzofuranꢀ3ꢀcarbonitrile (3e)
Eluent: nꢀhexane (100%); White Solid; Yield: 81 mg (32%);
Mp: 139ꢀ140 °C. 1H NMR (CDCl3, 400 MHz): δ 8.14 (s, 2H),
7.34 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.49 (d, J =
4.4 Hz, 2H), 7.46ꢀ7.40 (m, 2H). 13C NMR (CDCl3, 100 MHz):
δ 160.1, 153.7, 135.6, 131.7, 129.7, 127.3, 127.1, 126.6,
125.2, 124.8, 120.4, 114.0, 112.0, 89.3. HRMS (EI): Calcd for
C15H8ClNO [M]+ 253.0294, found: 253.0293.
2ꢀ(naphthalenꢀ2ꢀyl)benzofuranꢀ3ꢀcarbonitrile (3l)
Eluent: nꢀhexane (100%); White Solid; Yield: 180 mg (67%);
Mp: 128ꢀ129 °C. 1H NMR (CDCl3, 400 MHz): δ 8.67 (s, 1H),
8.25 (d, J = 7.6 Hz, 1H), 7.97 (s, 2H), 7.87 (s, 1H), 7.73 (d, J
= 6.0 Hz, 1H), 7.57 (s, 3H), 7.41 (s, 2H).13C NMR (CDCl3,
100 MHz): δ 161.9, 153.7, 134.6, 133.2, 129.3, 129.2, 128.2,
128.1, 127.6, 127.3, 127.2, 126.7, 125.3, 124.9, 122.9, 120.2,
114.6, 111.9, 88.6. HRMS (EI): Calcd for C19H11NO [M]+
269.0841, found: 269.0841.
2ꢀ(4ꢀmethoxyphenyl)benzofuranꢀ3ꢀcarbonitrile (3f)
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); White Solid;
Yield: 124 mg (50%); Mp: 151ꢀ152 °C. 1H NMR (CDCl3, 400
MHz): δ 8.15 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H),
7.54 (d, J = 8.8 Hz, 1H), 7.39 ꢀ 7.34 (m, 2H), 7.04 (d, J = 8.8
Hz, 2H), 3.89 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 162.3,
162.1, 153.3, 128.6, 127.7, 126.1, 124.8, 128.7, 119.6, 114.9,
114.8, 111.7, 86.5, 55.7. HRMS (EI): Calcd for C16H11NO2
[M]+ 249.0790, found: 249.0789.
2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)benzofuranꢀ3ꢀcarbonitrile (3m)
Eluent: nꢀhexane / ethyl acetate (98 ml / 2 ml); White Solid;
Yield: 155 mg (59%); Mp: 143ꢀ144 °C. 1H NMR (CDCl3, 400
MHz): δ 7.77 (dd, J = 8.2, 1.7 Hz, 1H), 7.67 (dd, J = 6.2, 2.6
Hz, 1H), 7.62 (d, J = 1.2 Hz, 2H), 7.54 ꢀ 7.52 (m, 1H), 7.39 ꢀ
7.35 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.07 (s, 2H).13C NMR
(CDCl3, 100 MHz): δ 161.8, 153.3, 150.4, 148.6, 127.6, 126.3,
124.8, 122.1, 122.1, 119.9, 114.8, 111.7, 109.2, 106.7, 102.1,
87.0. HRMS (EI): Calcd for C16H9NO3 [M]+ 263.0582, found:
263.0582.
2ꢀ(3ꢀmethoxyphenyl)benzofuranꢀ3ꢀcarbonitrile (3g)
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); White Solid;
Yield: 118 mg (47%); Mp: 85ꢀ86 °C. 1H NMR (CDCl3, 400
MHz): δ 7.78 (d, J = 6.8 Hz, 1H), 7.68 (s, 2H), 7.56 (d, J = 7.6
Hz, 1H), 7.45 ꢀ 7.37 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 3.90 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 161.7, 160.2, 153.5,
130.5, 129.1, 127.4, 126.6, 124.9, 120.2, 119.2, 117.8, 114.5,
111.9, 111.3, 88.5, 55.7. HRMS (EI): Calcd for C16H11NO2
[M]+ 249.0790, found: 249.0792.
2ꢀ(3,4ꢀdimethoxyphenyl)benzofuranꢀ3ꢀcarbonitrile (3n)
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); White Solid;
Yield: 139 mg (50%); Mp: 162ꢀ163 °C. 1H NMR (CDCl3, 400
MHz): δ 7.82 (dd, J = 8.4, 2.0 Hz, 2H), 7.70 ꢀ 7.67 (m, 2H),
7.56 ꢀ7.54 (m, 1H), 7.39 ꢀ7.36 (m, 2H), 6.99 (d, J = 8.4 Hz,
1H), 4.01 (s, 3H) 3.97 (s, 3H).13C NMR (CDCl3, 100 MHz): δ
162.2, 153.3, 151.8, 149.5, 127.6, 126.1, 124.8, 120.8, 120.5,
119.9, 115.0, 111.7, 111.5, 109.2, 102.1, 86.7, 56.3, 56.2.
HRMS (EI): Calcd for C17H13NO3 [M]+ 279.0895, found:
279.0894.
2ꢀ(pꢀtolyl)benzofuranꢀ3ꢀcarbonitrile (3h)
Eluent: nꢀhexane (100%); White Solid; Yield: 158 mg (68%);
Mp: 136ꢀ137 °C. 1H NMR (CDCl3, 400 MHz): δ 8.09 (d, J =
8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H),
7.42 ꢀ 7.33 (m, 4H), 2.44 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 162.3, 153.4, 142.0, 130.1, 127.6, 126.7, 126.4,
125.3, 124.8, 120.0, 114.7, 111.8, 87.5, 21.8. HRMS (EI):
Calcd for C16H11NO [M]+ 233.0841, found: 233.0842.
2ꢀ(3,4ꢀdichlorophenyl)benzofuranꢀ3ꢀcarbonitrile (3o)
Eluent: nꢀhexane (100%); White Solid; Yield: 118 mg (41%);
Mp: 136 ꢀ 137 °C. 1H NMR (CDCl3, 400 MHz): δ 8.24 (d, J =
1.6 Hz, 1H), 8.07 (dd, J = 8.4, 2.0 Hz, 1H), 7.23 (t, J = 7.2 Hz,
1H), 7.63 ꢀ 7.58 (m, 2H), 7.48 ꢀ 7.40 (m, 2H). 13C NMR
(CDCl3, 100 MHz): δ 159.1, 153.7, 135.7, 134.1, 131.5, 128.3,
127.8, 127.3, 127.1, 125.6, 125.3, 120.4, 113.9, 112.1, 89.6.
HRMS (EI): Calcd for C15H7Cl2NO [M]+ 286.9905, found:
286.9904.
2ꢀ(mꢀtolyl)benzofuranꢀ3ꢀcarbonitrile (3i)
Eluent: nꢀhexane (100%); White Solid; Yield: 135 mg (58%);
Mp: 70 ꢀ71 °C. 1H NMR (CDCl3, 400 MHz): δ 8.00 (d, J = 8.4
Hz, 2H), 7.70 (dd, J = 6.6, 2.2 Hz, 1H), 7.56 (dd, J = 6.6, 1.4
Hz, 1H), 7.44 ꢀ7.37 (m, 3H), 7.35 (d, J = 6.4 Hz, 1H), 2.46 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 162.1, 153.5, 139.2,
132.3, 129.3, 128.0, 127.5, 127.2, 126.5, 124.8, 124.0, 120.1,
2ꢀ(2,5ꢀdimethoxyꢀ4ꢀmethylphenyl)benzofuranꢀ3ꢀcarbonitrile
(3p)
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Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); White Solid;
13C NMR (CDCl3, 100 MHz): δ 161.6, 161.2, 149.4, 148.2,
148.1, 127.9, 121.2, 119.7, 115.3, 114.8, 100.7, 95.7, 86.6,
56.7, 56.6, 55.7. HRMS (EI): Calcd for C18H15NO4 [M]+
309.1001, found: 309.1004.
Yield: 205 mg (70%); Mp: 127 ꢀ 128 °C. 1H NMR (CDCl3,
400 MHz): δ 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.2 Hz,
1H), 7.40 ꢀ 7.36 (m, 2H), 7.28 (s, 1H), 6.87 (s, 1H), 3.97 (s,
3H) 3.88 (s, 3H) 2.31 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
159.0, 153.2, 152.0, 151.8, 132.5, 128.4, 126.1, 124.5, 120.1,
114.7, 114.6, 114.2, 111.6, 110.7, 91.6, 56.3, 55.4, 17.1.
HRMS (ESI): Calcd for C18H16NO3 [M+H]+ 294.1125, found:
294.1130.
1
2
3
4
5
6
7
8
dibenzo[b,f]oxepineꢀ10ꢀcarbonitrile (4A)
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); Pale Yellow
1
Solid; Yield: 153 mg (70%); Mp: 162 ꢀ 163 °C. H NMR
(CDCl3, 400 MHz): δ 7.57 (d, J = 8.0, 1H), 7.45ꢀ7.41 (m, 3H),
7.26 ꢀ 7.19 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 158.5,
157.6, 142.5, 133.0, 132.1, 130.6, 128.5, 128.2, 126.4, 125.8,
125.6, 122.1, 121.9, 118.7, 114.2. HRMS (EI): Calcd for
C15H9NO [M]+ 219.0684, found: 219.0684.
2ꢀ(furanꢀ2ꢀyl)benzofuranꢀ3ꢀcarbonitrile (3q)
9
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); Brown Solid;
Yield: 44 mg (21%); Mp: 86 ꢀ 87 °C. 1H NMR (CDCl3, 400
MHz): δ 7.69 (s, 2H), 7.55 (d, J = 6.8 Hz, 1H), 7.39 (s, 2H),
7.22 (s, 1H), 6.64 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ
153.7, 153.6, 145.7, 143.7, 126.7, 126.6, 125.1, 120.2, 113.5,
113.4, 112.7, 111.9, 87.2. HRMS (EI): Calcd for C13H7NO2
[M]+ 209.0477, found: 209.0477.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3ꢀdimethoxydibenzo[b,f]oxepineꢀ10ꢀcarbonitrile (4B)
Eluent: nꢀhexane / ethyl acetate (90 ml / 10 ml); Yellow Solid;
1
Yield: 237 mg (85 %); Mp: 139 ꢀ 140 °C. H NMR (CDCl3,
400 MHz): δ 7.55 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H),
7.37 (s, 1H), 7.26 ꢀ 7.18 (m, 2H), 7.76 (s, 1H), 6.66 (s, 1H),
3.92 (s, 3H), 3.85 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
157.4, 152.3, 148.7, 131.6, 131.1, 130.3, 129.3, 128.8, 128.6,
128.6, 126.2, 123.5, 114.1, 111.9, 105.5, 99.2, 96.9, 81.2.
HRMS (EI): Calcd for C17H13NO3 [M]+ 279.0895, found:
279.0894.
2ꢀ(pyridinꢀ2ꢀyl)benzofuranꢀ3ꢀcarbonitrile (3r)
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); Pale green
1
Solid; Yield: 145 mg (66%); Mp: 136 ꢀ 137 °C. H NMR
(CDCl3, 400 MHz): δ 8.82 (d, J = 4.4 Hz, 1H), 8.08 (d, J =
8.0, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H),
7.61 (d, J = 8.4 Hz, 1H) 7.48 ꢀ7.39 (m, 3H). 13C NMR (CDCl3,
100 MHz): δ 160.1, 154.0, 150.6, 127.3, 125.1, 125.1, 121.5,
120.6, 113.8, 112.2, 91.3. HRMS (ESI): Calcd for C14H9N2O
[M+H]+ 221.0709, found: 221.0715.
[1,3]dioxolo[4',5':4,5]benzo[1,2ꢀb]benzo[f]oxepineꢀ10ꢀ
carbonitrile (4C)
Eluent: nꢀhexane / ethyl acetate (90 ml / 10 ml); Yellow Solid;
1
Yield: 179 mg (68 %); Mp: 176 ꢀ 177 °C. H NMR (CDCl3,
2ꢀ(quinolinꢀ2ꢀyl)benzofuranꢀ3ꢀcarbonitrile (3s)
400 MHz): δ 7.55 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H),
7.31 (s, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H),
6.75 (s, 1H), 6.64 (s, 1H), 6.00 (s, 2H). 13C NMR (CDCl3, 100
MHz): δ 157.4, 152.3, 148.7, 131.6, 131.1, 130.3, 129.3,
128.8, 128.6, 128.6, 126.2, 123.5, 114.1, 111.9, 105.5, 99.2,
96.9, 81.2. HRMS (EI): Calcd for C16H9NO3 [M]+ 263.0582,
found: 263.0582.
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml); Pale green
1
Solid; Yield: 200 mg (74%); Mp: 181ꢀ182 °C. H NMR
(CDCl3, 400 MHz): δ 8.35 ꢀ 8.29 (m, 2H), 8.2 (d, J = 8.8 Hz,
1H), 7.88 ꢀ 7.78 (m, 3H), 7.68 (d, J = 8.4 Hz, 5H), 7.62 (t, J =
7.2 Hz, 1H), 7.52 ꢀ 7.43 (m, 2H). 13C NMR (CDCl3, 100
MHz): δ 160.2, 154.3, 148.4, 146.6, 137.5, 130.7, 130.4,
128.4, 128.3, 127.8, 127.5, 125.5, 120.8, 118.4, 113.9, 112.4,
92.2. HRMS (ESI): Calcd for C18H11N2O [M+H]+ 271.0866,
found: 271.0873.
2ꢀchlorodibenzo[b,f]oxepineꢀ10ꢀcarbonitrile (4D)
Eluent: nꢀhexane (100%); Yellow Solid; Yield: 79 mg (31 %);
Mp: 144 ꢀ 145 °C. 1H NMR (CDCl3, 400 MHz): δ 7.60 (d, J =
1.9 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H),
7.39 (s, 1H), 7.31 ꢀ 7.17 (m, 4H). 13C NMR (CDCl3, 100
MHz): δ 157.4, 152.3, 148.7, 131.6, 131.1, 130.3, 129.3,
128.8, 128.6, 128.6, 126.2, 123.5, 114.1, 111.9, 105.5, 99.2,
96.9, 81.2. HRMS (EI): Calcd for C15H8ClNO [M]+ 253.0294,
found: 253.0293.
5ꢀmethoxyꢀ2ꢀphenylbenzofuranꢀ3ꢀcarbonitrile (3t)
Eluent: nꢀhexane / ethyl acetate (90 ml / 10 ml); Yellow Solid;
Yield: 129 mg (52%); Mp: 119 ꢀ 120 °C. 1H NMR (CDCl3,
400 MHz): δ 8.17 (dd, J = 8.0, 1.6 Hz, 2H), 7.56 ꢀ 7.51 (m,
3H), 7.46 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.13
(d, J = 2.4 Hz, 1H), 7.00 (dd, J = 9.0, 2.6 Hz, 1H), 3.89 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 162.4, 157.6, 148.5,
131.3, 129.4, 128.3, 128.2, 126.6, 116.0, 114.7, 112.6, 101.8,
88.5, 56.2. HRMS (EI): Calcd for C16H11NO2 [M]+ 249.0790,
found: 249.0789.
benzo[b]naphtho[2,1ꢀf]oxepineꢀ8ꢀcarbonitrile (4E)
Eluent: nꢀhexane / ethyl acetate (95 ml / 5 ml);Yellow Solid;
Yield: 140 mg (52 %); Mp: 199ꢀ200 °C. 1H NMR (CDCl3, 400
MHz): δ 8.59 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.2, 1H), 7.62
(t, J = 8.4 Hz, 4H), 7.58 (s, 1H), 7.46 ꢀ7.41 (m, 2H),7.27 (d, J
= 9.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 157.4, 152.3,
148.7, 131.6, 131.1, 130.3, 129.3, 128.8, 128.6, 128.6, 126.2,
123.5, 114.1, 111.9, 105.5, 99.2, 96.9, 81.2. HRMS (EI):
Calcd for C19H11NO [M]+ 269.0841, found: 269.0841.
5,6ꢀdimethoxyꢀ2ꢀphenylbenzofuranꢀ3ꢀcarbonitrile (3u)
Eluent: nꢀhexane / ethyl acetate (90 ml / 10 ml); Yellow Solid;
Yield: 173 mg (62%); Mp: 147 ꢀ 148 °C. 1H NMR (CDCl3,
400 MHz): δ 8.12 (d, J = 7.2 Hz, 2H), 7.52 ꢀ 7.47 (m, 3H),
7.10 (d, J = 6.0 Hz, 2H), 3.97 (d, J = 4.4 Hz, 6H). 13C NMR
(CDCl3, 100 MHz): δ 160.8, 149.9, 148.5, 148.4, 130.7, 129.3,
128.5, 126.1, 119.6, 114.8, 100.8, 95.7, 88.4, 56.7, 56.6.
HRMS (EI): Calcd for C17H13NO3 [M]+ 279.0895, found:
279.0893.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
5,6ꢀdimethoxyꢀ2ꢀ(4ꢀmethoxyphenyl)benzofuranꢀ3ꢀcarbonitrile
(3v)
1
Xꢀray crystallographic data for 3d, 3k and 4B; H and 13C
Eluent: nꢀhexane / ethyl acetate (90 ml / 10 ml); White Solid;
Yield: 63 mg (51%); Mp: 198ꢀ199 °C. 1H NMR (CDCl3, 400
MHz): δ 8.07 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 6.0 Hz, 2H),
7.03 (d, J = 8.0 Hz, 2H), 3.96 (d, J = 5.2 Hz, 6H), 3.89 (s, 3H).
NMR spectral data for representative compounds (PDF)
Accession Codes
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The Journal of Organic Chemistry
Functionalized Benzofurans via Intramolecular Heck Coupling: Apꢀ
CCDC 1825548 for 3d, CCDC 1825549 for 3k and CCDC
1835897 for 4B are the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
plication to Enantioselective Total Synthesis of Daphnodorin B. Org.
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Ring Closure of αꢀAryl Ketones. Org. Lett. 2009, 11, 4978ꢀ4981. (c)
Chen, C.; Dormer, P. G. Synthesis of Benzo[b]furans via CuI Cataꢀ
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Y.; Zhou, C.; Wang, R. Copperꢀcatalyzed hydroxylation of aryl halꢀ
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derivatives in neat water. Green Chem. 2015, 17, 3910ꢀ3915.
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through OneꢀPot Cascade Reactions. J. Org. Chem., 2016, 81, 9530ꢀ
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AUTHOR INFORMATION
Corresponding Author
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*Eꢀmail: cheyaocf@ntnu.edu.tw.
(11) (a) Zhang, L.; Peng, Z.; Wen, Q.; Li, X.; Lu, P.; Wang, Y.
CopperꢀCatalyzed Preparation of 2ꢀArylꢀ3ꢀcyanobenzofurans with
Bright Blue Photoluminescence. Org. Lett. 2016, 18, 728ꢀ731. (b)
Zhou, W.; Zhang, Y.; Li, P.; Wang, L. Synthesis of (Z)ꢀ3ꢀ
ORCID
ChingꢀFa Yao: 0000ꢀ0002ꢀ8692ꢀ5156
aryloxyacrylonitriles,
(E)ꢀ3ꢀaryloxyꢀacrylonitriles
and
3ꢀ
Notes
cyanobenzofurans through the sequential reactions of phenols with
propiolonitriles. Org. Biomol. Chem. 2012, 10, 7184. (c) Yuan, H.; Bi,
K.ꢀJ.; Li, B.; Yue, R.ꢀC.; Ye, J.; Shen, Y.ꢀH.; Shan, L.; Sun, Y.;
Zhang, W.ꢀD. Synthesis of (Z)ꢀ3ꢀaryloxyacrylonitriles, (E)ꢀ3ꢀaryloxyꢀ
acrylonitriles and 3ꢀcyanobenzofurans through the sequential reacꢀ
tions of phenols with propiolonitriles. Org. Lett. 2013, 15, 7184ꢀ7196.
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W.; Ruan, J. –Y.; Yao, C. ꢀF. Synthesis of 1,2,3ꢀFused Indole Polyꢀ
heterocycles by Copper Catalyzed Cascade Reaction. Eur. J. Org.
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C. –Y.; Kuo, C. ꢀW.; Yao, C. ꢀF. Synthesis of Benzopyridoindolone
Derivatives via a OneꢀPot Copper Catalyzed Tandem Reaction of 2ꢀ
Iodobenzamide Derivatives and 2ꢀIodobenzylcyanides. J. Org. Chem.
2017, 82, 7280ꢀ7286. (c) Villuri, B. K.; Konala, A.; Kavala, V.; Koꢀ
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Approach for the Synthesis of Dibenzo[b,f]1,8ꢀnaphthyridine Derivaꢀ
tives. Adv. Synth. Catal. 2017, 359, 3142ꢀ3153.
(13) (a) Allen, S. E.; Walvoord, R. R.; PadillaꢀSalinas, R.; Koꢀ
zlowski, M. C. Aerobic CopperꢀCatalyzed Organic Reactions. Chem.
Rev. 2013, 113, 6234ꢀ6458. (b) Lewis, E. A.; Tolman W. B. Reacꢀ
tivity of Dioxygen−Copper Systems. Chem. Rev. 2004, 104, 1047ꢀ
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M. P. Enantioselective CopperꢀCatalyzed 1,3ꢀDipolar Cycloadditions
Chem. Rev. 2008, 108, 2887ꢀ2902. (e) Chemler, S. R.; Fullera, P.
H. Heterocycle synthesis by copper facilitated addition of heteroaꢀ
toms to alkenes, alkynes and arenes. Chem. Soc. Rev. 2010, 39, 1302ꢀ
1315. (f) Zhang, Z.; Yan, X.; Zhang, G.; Liu, Q.; Ma, N.; Liu, T.;
Shi, L. Copper(I)ꢀcatalyzed domino allylic C(sp3)–H aminative cyꢀ
clization/oxidative reaction and its application toward pyrrolo[3,4ꢀ
d]pyrimidinones Tetrahedron 2016, 72, 3077ꢀ3083. (g) Zhang, Z.;
Qian, J.; Zhang, G.; Ma, N.; Liu, Q.; Liu, T.; Sun, K.; Shi,
L. Copper(I) catalyzed C(sp2)–N bond formation: synthesis of pyrꢀ
rolo[3,2ꢀc]quinolinone derivatives. Org. Chem. Front. 2016, 3, 344ꢀ
348. (h) Yan, X.; Zhang Z.; Zhang, G.; Ma, N.; Liu, Q.; Liu, T.;
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(14) (a) Wang, D.; Kuang, D.; Zhang, F.; Tang, S.; Jiang, W. Triꢀ
ethanolamine as an Inexpensive and Efficient Ligand for CopperCataꢀ
lyzed Hydroxylation of Aryl Halides in Water. Eur. J. Org. Chem.
2014, 315ꢀ318. (b) Xia, S.; Gan, L.; Wang, K.; Li, Z.; Ma, D. Copper
Catalyzed Hydroxylation of (Hetero)aryl Halides under Mild Condiꢀ
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We wish to acknowledge the Ministry of Science and Techꢀ
nology of the Republic of China (MOST 103ꢀ2113Mꢀ003ꢀ
008ꢀMY3) and National Taiwan Normal University (NTNU)
(103ꢀ07ꢀC) for providing financial assistance. We also wish to
thank the Instrumentation Centre at National Taiwan Normal
University. We are grateful to Mr. TingꢀShen Kuo (Xꢀray), Ms.
HsiuꢀNi Huan (HRMS), and Ms. ChiuꢀHui He (NMR) for
providing the analytical data presented in this paper.
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