Cu(II)-Mediated C?C/C?O Bond Formation via C?H/C?C Bond Cleavage: Access to Benzofurans Using Amide as a Traceless Directing Group

Article abstract of DOI:10.1002/adsc.201901316

A copper-mediated synthesis of 2,3-disubstituted benzofurans with the assistance of an 8-aminoquinolyl auxiliary is described from readily available benzamides and benzoylacetonitriles. In this reaction, the C?C bond is successfully constructed via C?H ac

Full text of DOI:10.1002/adsc.201901316

Title: Cu(II)-Mediated C−C/C-O Bond Formation via C-H/C-C Bond
Cleavage: Access to Benzofurans Using Amide as a Traceless
Directing Group
Authors: Shuling Yu, Ningning Lv, Zhanxiang Liu, and Yuhong Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901316
Link to VoR: http://dx.doi.org/10.1002/adsc.201901316

10.1002/adsc.201901316
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cu(II)-Mediated C−C/C-O Bond Formation via C-H/C-C Bond
Cleavage: Access to Benzofurans Using Amide as a Traceless
Directing Group
Shuling Yu,a Ningning Lv,b Zhanxiang Liu,a Yuhong Zhang,*,a,b
a
Department of Chemistry, ZJU-NHU United R&D Center, Zhejiang University, Hangzhou 310027, People’s Republic
of China
Fax: (+ 86)-571-8795-3244; e-mail: yhzhang@zju.edu.cn
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Well-designed N,N-bidentate directing groups have
Abstract: A copper-mediated synthesis of 2,3-disubstituted
benzofurans with the assistance of an 8-aminoquinolyl shown a remarkable efficacy in transition-metal-
auxiliary is described from readily available benzamides
catalyzed
C(sp2)-H
and
C(sp3)-H
bond
functionalization reactions over the last decade.[10]
Among these transition metals, copper catalysts have
received considerable attention due to their
abundance, inexpensiveness and low toxicity. More
recently, the combination of copper salts with N,N-
bidentate directing groups has provided a promising
tool for the formation of carbon-carbon and carbon-
hetero bonds.[11] A series of novel direct couplings
with the assistance of bidentate auxiliaries in the
presence of copper catalysts have been developed.[12]
However, copper-catalyzed or -mediated cascade
coupling reactions involving multiple bond breakings
and reformations in a one-pot operation to furnish
various heterocycles remains quite limited.[13] In
2014, Liu group developed an elegant copper-
mediated cascade coupling of benzamides with ethyl
cyanoacetate involving C-C bond formation by ortho-
C−H activation and C–N bond formation to provide
isoquinolinone derivatives.[13a] Later, Dai and Yu
applied the benzamides to achieve various
isoindolinones using malonates as the coupling
and benzoylacetonitriles. In this reaction, the C−C bond is
successfully constructed via C−H activation, and C−O
bond is subsequently formed at the original position of the
amide group in a one-pot manner. The amide directing
group is detached simultaneously under the reaction
conditions through C-C bond cleavage. Surprisngly, the
distinct isoquinolinone products can be achieved by
changing the reaction conditions using ammonia as amine
source.
Keywords: traceless directing group; C-H activation;
cascade reaction; benzofurans synthesis; chemoselectivity
Transition-metal-catalyzed directing-group-assisted
C-H bond functionalization has proven to be a
powerful strategy for the construction of carbon-
carbon and carbon-hetero bonds because of its great
potential for step-economy and environmental
sustainability.[1] In all of transformations, the
directing group plays the key role for reaction
efficiency and regioselectivity control. However, the
installation and detachment of a directing group
require the extra and cumbersome steps, which
imposes severe limitations on application. To
overcome the above shortcomings, carboxyl has been
successfully used as a traceless directing group,
which can introduce a target functional group into a
specific position of the substrate and then be
completely removed by decarboxylation.[2] A range
partner assisted by
a
2-aminophenyloxazoline
directing group under Cu salt.[13e] Among these
transformations, the further removal of directing
groups from the target molecules is difficult after
completion of the reaction,[14] which imposes
limitations on further modification of the products.
Herein we report a copper-mediated cascade coupling
of benzamides with benzoylacetonitriles to enable
generation of benzofurans. In this transformation, the
amide directing group is simultaneously removed in
situ via sequential removal of 8-aminoquinoline
group[15] and decarboxylation in one pot.
Benzoylacetonitriles have been applied in the C(sp2)-
H bond functionalizations as directing groups,[16]
while the use of benzoylacetonitrile as the coupling
partner in C-H bond functionalization is still not
achieved yet. During our study we found that the
of
carboxyl
directed
ortho-C-H
functionalization/decarboxylation
including
arylation,[3] alkenylation,[4] alkylation,[5] amidation,[6]
and halogenation[7] has been exploited. In contrast to
carboxyl,[8] the applicability of other traceless
functionality as the directing group remains a big
challenge.[9]
1
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10.1002/adsc.201901316
Advanced Synthesis & Catalysis
reaction involves an 8-amino-quinoline-assisted
ortho-C−H activation for the formation of a new C-C
bond. The following removal of amide group by C-C
bond cleavage to form an unexpected C−O bond to
give the product of 2-aryl-3-cyanobenzofuran, which
is a key structural motif of hepatitis C virus (HCV)
inhibitor (Scheme 1).[17]
were used (Table 1, entries 11−17). The product was
not detected in the absence of copper salt (Table 1,
entry 18). The attempt to increase or decrease the
amount of Cu(OAc)2 just resulted in lower yields (see
the SI). To our delight, the isolated yield was further
improved to 65% by lowering the temperature from
130 C to 120 C and prolonging the reaction time to
10 h (Table 1, entry 19), and the formation of
byproduct isoquinolinone 3a’ was suppressed
drastically (see the SI, Table S4).
o
o
Scheme
1
Cascade coupling of benzamides with
benzoylacetonitriles assisted by 8-aminoquinoline group.
Table 1. Optimization of Reaction Conditions.[a,b]
Entry Cu salt
Base
Solvent Yield(%)[b]
1
2
3
4
5
6
7
8
Cu(OAc)2
DMSO
DMSO
DMSO
51
44
42
36
58
13
42
38
46
trace
27
51
38
35
nr
Na2CO3
K2CO3
Li2CO3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
tBuOK DMSO
tBuOLi DMSO
DBU
DMSO
tBuOLi DMF
tBuOLi NMP
tBuOLi DMPU
tBuOLi MeCN
tBuOLi DMSO
9
10
11
12
13
14
15[c]
16[c]
17[c]
18
19[d]
Scheme 2. Scope of Benzamides. [a]Reaction conditions: 1
(0.2 mmol), 2a (0.3 mmol), Cu(OAc)2 (0.4 mmol), tBuOLi
Cu(OAc)2·H2O tBuOLi DMSO
CuCl2
o
(0.4 mmol), DMSO (2.0 mL), 120 C, 10 h, air. [b]Isolated
tBuOLi DMSO
tBuOLi DMSO
tBuOLi DMSO
tBuOLi DMSO
tBuOLi DMSO
tBuOLi DMSO
tBuOLi DMSO
yield. [c]1 mmol scale.
Cu2(OH)2CO3
Pd(OAc)2
[Cp*RhCl2]2
Ni(OAc)2
-
With the optimal conditions available, we then
examined the substrate diversity as shown in Scheme
2. The introduction of electron-donating groups on
the para-position of the arene afforded the
benzofurans with slightly reduced yields (3b-3e, 3p),
while strong electron-withdrawing groups including
NO2, CF3, CN and COOMe substituted aromatic
amides afforded higher yields (3i-3l). Satisfyingly,
halogen groups were well tolerated (3f–3h), which
provides feasibility for further synthetic elaborations.
It is worthy to note that the regioselectivity of the
reaction favored the formation of less sterically
hindered benzofurans (3m and 3n). Furthermore,
ortho-substituted benzamide led to a sharp decrease
in yield (3o), indicating that the reaction is
particularly sensitive to steric hindrance. With respect
to the 1-naphthamide substrate, the reaction
proceeded well to produce the product 3q in 52%
yield. Significantly, this reaction could be carried out
on a 1 mmol scale to give access to 3a in reasonable
yield, and the structure of the benzofuran 3a was
explicitly characterized by single X-ray diffraction
analysis.[18]
nr
nr
nr
65
Cu(OAc)2
[a]Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Cu
salt (0.4 mmol), base (0.4 mmol), in solvent (2.0 ml),
under air atmosphere at 130 oC for 3 h.
[b]Isolated yield.
[c]Catalyst (10 mol%).
[d]120 oC for 10 h.
Initially, we commenced our investigations by
using 1a and 3-oxo-3-phenylpropanenitrile 2a as
benchmark
substrates.
Gratifyingly,
2-
phenylbenzofuran-3-carbonitrile 3a was obtained in
51% yield in the presence of Cu(OAc)2 and Na2CO3
o
at 130 C for 3 h (Table 1, entry 1), along with a
small amount of byproduct isoquinolinone 3a’ (see
the Supporting Information, SI). Encouraged by this
result, further screening of bases such as K2CO3,
Li2CO3, tBuOK, tBuOLi and DBU suggested that
tBuOLi exhibited the optimal efficiency (Table 1,
entries 2–6). Disappointingly, replacement of DMSO
with other solvents, including DMF, NMP, DMPU
and MeCN, was not beneficial to this transformation
(Table 1, entries 7–10). No improvement was
acquired when other Cu salts or other metal catalysts
2
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10.1002/adsc.201901316
Advanced Synthesis & Catalysis
Scheme 4. One-pot Construction of Isoquinolinones.
[a]Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol),
Cu(OAc)2 (0.6 mmol), Na2CO3 (0.6 mmol) and NH3•H2O
(0.3 ml), DMSO (2.0 mL), 80 oC, 24 h, air. [b]Isolated yield.
S
No benzofurans were detected when ammonia was
added in the reaction. Unexpectedly, isoquinolinones
(5a-5e) were obtained as the major products in good
yields (Scheme 4). This transformation possibly
initiated with the formation of 1-oxo-3-aryl-1H-
cheme 3. Scope of Benzoylacetonitriles. [a]Reaction
conditions: 1 (0.2 mmol), 2 (0.3 mmol), Cu(OAc)2 (0.4
o
mmol), tBuOLi (0.4 mmol), DMSO (2.0 mL), 120 C, 10 h,
air. [b]Isolated yield.
We further tested the substrate scope with a range
of substituted benzoylacetonitriles (Scheme 3). In
general, the electronic effect on the benzene ring of
benzoylacetonitriles exerted no obvious influence
upon the reaction. A series of para-substituted 3-oxo-
3-phenylpropanenitriles bearing electron-donating or
-withdrawing groups were reactive to furnish the
benzofurans in moderate yields (4a−4g). With Me, Br
or NO2 substituted on the para position of benzamide,
4h−4k were obtained. When the 3-position of 3-oxo-
3-phenylpropanenitriles was occupied by Cl or OMe,
4l and 4m were obtained in yields of 37% and 31%,
respectively. The ortho-substituted substrate gave the
corresponding 2-aryl-3-cyanobenzofuran in a lower
yield (4n), implying that the steric hindrance has a
negative effect on this reaction. 3,4-Dichloro-
isochromene-4-carbonitrile,[13e]
followed
by
replacement of the oxygen atom with nitrogen by
treatment with ammonia.[19]
substituted
and
3,4-difluoro-substituted
benzoylacetonitriles were smoothly transformed to
the corresponding products under the standard
conditions (4o and 4p). Notably, this transformation
could be successfully extended to 3-(Furan-2-yl)-3-
oxopropanenitrile
and
3-(thiophen-2-yl)-3-
oxopropanenitrile, providing the target molecules in
moderate yields (4q and 4r). The reaction failed to
deliver the desired product when 3-oxobutanenitrile
or pivaloylacetonitrile was used as the substrate (4s
and 4t).
Scheme 5. Experimental Mechanistic Studies.
To clarify the reaction mechanism, a series of
experiments were performed as shown in Scheme 5.
We carried out radical trapping experiment, and the
reaction was drastically inhibited by the radical
scavenger such as TEMPO and BHT (Scheme 5a). A
value of kinetic isotope effect (KIE) 1.86 was
observed from the competitive reac-tion of 1a and
1a-d5 with 2a, and a value of 1.56 was obtained from
two parallel reactions (Scheme 5b-5c). When the
o
reaction was carried out in 80 C for 3 h, the
intermediate 3-amino-4-benzoyl-1H-isochromen-1-
one (6) was isolated (Scheme 5d). The structure of 6
was further determined by X-ray crystallographic
3
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10.1002/adsc.201901316
Advanced Synthesis & Catalysis
analysis. When compound 6 was subjected to the
optimal reaction conditions, the desired product 3a
was obtained in 88% yield, suggesting that compound
6 was the key intermediate (Scheme 5e). A possible
pathway for the formation of intermediate 6 is
depicted in Scheme 6. The initial copper-mediated
ortho-C−H activation of 1a gives intermediate A,
which is disproportioned to form Cu(III) complex B.
The ligand exchange of B with benzoylacetonitrile
leads to the formation of intermediate C. The
subsequent reductive elimination gives intermediate
Scheme 7. Preparation of Aryl Amides.
In summary, we have developed a novel copper-
mediated cascade coupling reaction for the facile
synthesis of 2-aryl-3-cyanobenzofurans using
benzamide and benzoylacetonitrile as substrates. This
transformation first proceeds an ortho-C−H activation
to form a new C-C bond. Subsequently, a new C−O
bond is successfully constructed at the original
position of the amide group, which is simultaneously
removed by the cleavage of C-C bond in one pot and
extra step is avoided for the removal of amide
directing group. Isoquinolinone derivatives could be
obtained in the presence of ammonia by changing the
reaction conditions.
D,
which
undergoes
tautomerization
and
intramolecular O-nucleophilic reaction to deliver
cyclization product E. The hydrolysis of E generates
compound 6.
Experimental Section
General procedure for Cu(II)-mediated cascade
coupling to obtain benzofurans
To a test tube with a stir bar was added benzamides 1 (0.2
mmol), benzoylacetonitriles 2 (0.3 mmol), anhydrous
Cu(OAc)2 (73 mg, 0.4 mmol), tBuOLi (32 mg, 0.4 mmol),
in DMSO (2.0 mL) under air atmosphere, and stirred at
120 °C for 10 h. After the reaction was quenched by
addition of water, the mixture was extracted with ethyl
acetate, and the combined organic layer was dried over
sodium sulfate. Organic solvents were removed under
reduced pressure and the crude reaction mixture was
purified by column chromatography on silica gel column
with EtOAc/petroleum ether (1:20, v/v) as an eluent to
afford the desired product 3 or 4.
Scheme 6. Proposed Reaction Mechanism.
When TEMPO and BHT were used as radical
depressors to react with compound 6 under the
standard conditions, almost no product 3a was
observed (Scheme 5f). This result indicated that a
single electron transfer (SET) process might be
involved in the transformation of 6 to deliver product
3a. A plausible mechanism is proposed for this
transformation. The tautomerization of 6 gives the
isomer F, which carried out a ring-opening reaction
to form intermediate G. The following
decarboxylation of G affords phenyl radical H,[20]
which undergoes an intramolecular cyclization to
give intermediate I. The product 3a is obtained
through a further SET/deprotonation process (path
a).[21] Another possible pathway (path b) is the
tautomerization of H to form the intermediate J. The
subsequent intramolecular HAT process generates
radical intermediate K, which undergoes radical
cyclization to give radical intermediate L. The further
oxidation of L delivers the product 3a.
Acknowledgements
Funding from Natural Science Foundation of China (No.
21672186) and Important Project of Zhejiang province
(2017C03049) are highly acknowleged.
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10.1002/adsc.201901316
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
COMMUNICATION
Cu(II)-Mediated C−C/C-O Bond Formation via
C-H/C-C Bond Cleavage: Access to Benzofurans
Using Amide as a Traceless Directing Group
Adv. Synth. Catal. 2019, Volume, Page – Page
Shuling Yu, Ningning Lv, Zhanxiang Liu, Yuhong
Zhang*
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