Synthesis of 2-vinylbenzofurans via the copper-catalyzed multicomponent reactions involving an oxa-michael/arylation/vinylation cascade

Article abstract of DOI:10.1021/ol502506g

2-Vinylbenzofurans have been synthesized via the copper-catalyzed one-pot, three-component reactions of o-iodophenols, in situ generated allenes, and dichloromethane. Cascade transformation of oxa-Michael addition, C-arylation, and sp³C-H/sp

Full text of DOI:10.1021/ol502506g

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Vinylbenzofurans via the Copper-Catalyzed
Multicomponent Reactions Involving an Oxa-Michael/Arylation/
Vinylation Cascade
Jie-Ping Wan,*,† Hang Wang,†,‡ Yunyun Liu,† and Hanfeng Ding*,‡
†College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, P. R. China
‡Department of Chemistry, Zhejiang University, 148 Tianmushan Road, Hangzhou 310028, P. R. China
S
* Supporting Information
ABSTRACT: 2-Vinylbenzofurans have been synthesized via the
copper-catalyzed one-pot, three-component reactions of o-
iodophenols, in situ generated allenes, and dichloromethane.
Cascade transformation of oxa-Michael addition, C-arylation, and
sp3C−H/sp3C−Cl conversion-based vinylation has been involved
in realizing the construction of this 2-vinylbenzofuran framework.
eveloping novel organic transformations, especially those
that functionalize inert chemical bonds such as the C−H
Scheme 1. (a) Vinylation of Pyridine Derivatives. (b)
Benzofuran Synthesis
D
bond, constitutes a research topic of extensive significance.
Because of the tremendous endeavors of chemists, the chemistry
of C−H activation and functionalization has made substantial
progress during the past decade.1 While the powerful C−H
activation strategy has contributed enormously to the progress of
organic synthesis, the frequent reliance of such chemistry on the
presence of directing groups (DG), noble metal catalysis, and/or
the assistance of oxidants has drastically hindered its broad
application.
As one of the fundamental and most broadly utilized
functional groups, the CC double bond occupies a central
and irreplaceable position in organic synthesis. While classical
olefination methods such as elimination, Wittig olefination,
Henry condensation, and Knoevenagel reaction are currently the
dominant strategies for producing CC bonds, searching for
new approaches that do not rely on the prior prepared functional
groups is presently a central aim in this area. Very recently,
interesting methods of Cu- and Fe-catalyzed and metal-free
oxidative C−H functionalization have been found useful for
generating the CC bond of vinylated aromatics (Scheme 1).2
Despite these important advances, C−H bond conversion-based
methods for CC bond construction remain rather rare. The
exploration of additional routes is thus an issue of urgency.
As a component of numerous natural products and biologically
relevant organic compounds,3 the benzofuran ring has received
tremendous interest as a synthetic target. Among the large
number of known synthetic methods, transition-metal-catalyzed
tandem reactions provide powerful tools for accessing this and
other related heterocycle compounds.4,5 While a variety of
different chemical transformations have been involved in the
tandem reactions, transition-metal-catalyzed C−C bond for-
mation is among the most prevalently employed. For example,
Maiti and co-workers have developed a practical synthesis of
benzofurans through the Pd/Cu-catalyzed C−H oxygenation/
C−H olefination of phenols and alkenes, wherein three sp2C−H
bonds were functionalized to enable the annulation (eq 2,
Scheme 1).6 In addition, the Pd-catalyzed intramolecular tandem
C−H arylation/isomerization of o-bromophenyl allyl esters,7 Ru-
catalyzed tandem dehydration/C−H oxygenation,8 and Cu-
catalyzed tandem C−C/C−O coupling9 represent other
practical protocols.10 Interestingly, despite the extensive research
efforts being directed at benzofuran synthesis, the synthetic
Received: August 25, 2014
© XXXX American Chemical Society
A
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Letter
methods for obtaining benzofurans with a vinyl fragment at C2-
position are not known. Herein, we report the first copper-
catalyzed one-pot synthesis of 2-vinylbenzofurans from o-
iodophenols 1, Wittig reagents 2, acyl chlorides 3, and
dichloromethane 4,11 wherein the vinyl fragment is generated
via the direct conversion of sp3C−H and sp3C−Cl bonds,
following a C-arylation-based cascade for benzofuran ring
formation (eq 3, Scheme 1).
hydroxyquinoline (L2), L-proline (L3), cyclic β-ketoester L4,
and enaminone L5, showed that the ligand also impacted the
result, and L1 was among the best candidates (entries 1 and 7−
10, Table 1). Finally, the optimal amount of Cs2CO3 was 4 equiv
based on the results (entries 11 and 12, Table 1). Additionally, a
control experiment using o-bromophenol provided 6a with 29%
yield.
In light of these optimization experiments, the scope of this
protocol was subsequently investigated. As shown in Scheme 2, a
Initially, o-iodophenol 1a, Wittig reagent 2a,12 propionyl
chloride 3a, and dichloromethane (DCM) 4 were employed in a
model reaction. To obtain the product 6a, the prior treatment of
2a and 3a with Et3N in DCM was first conducted for the in situ
preparation of allene 5a.13 Subsequent employment of 1a and 4
with copper catalysis was able to provide the vinylbenzofuran 6a.
Extensive optimization experiments were then conducted. The
temperature, solvent, catalyst species/loading, ligand, base
additive, as well as reaction medium were all screened in order
to obtain a satisfactory yield. Our typical results at optimizing the
catalyst species and ligands were outlined in Table 1 (see the
a
Scheme 2. Tandem Synthesis of Various 2-Vinylbenzofurans
Table 1. Typical Experiments in Optimizing the Metal
a
Catalyst and Ligand
b
entry
Cu cat.
ligand
yield (%)
1
2
CuI
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
39
53
CuBr
3
CuBr2
Cu2O
29
4
19
5
Cu(OAC)2·H2O
FeCl3
24
6
trace
11
7
CuBr
8
CuBr
16
9
CuBr
32
10
CuBr
28
c
11
CuBr
32
d
12
CuBr
39
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), 3a (0.75
mmol), copper cat. (0.1 mmol), ligand (0.3 mmol), and Cs2CO3 (2.0
mmol) in DMSO/n-hexane (2 mL/3 mL) in the presence of 5 Å MS
b
(150 mg) at 90 °C for 12 h in a sealed tube. Yields of isolated
a
Isolated yields.
c
d
products based on 1a. 1.5 mmol Cs2CO3 is used. 3.0 mmol Cs2CO3
is used.
range of Wittig reagents, acyl chlorides, and o-iodophenols all
engaged in the protocol, as expected, and many different vinyl
benzofurans were acquired in generally moderate-to-good yields.
According to the results, the entries employing electron-deficient
aryl ketone-based Wittig reagents usually provided the
corresponding products with slightly higher yields than other
entries (6g, 6h, 6j, and 6k). On the other hand, most entries
using cyano-based Wittig reagents gave relatively lower yields of
the corresponding 3-cyanobenzofurans probably because of the
lower efficiency of these Wittig reagents (6m, 6n, 6o, and 6q).
The functional groups on o-iodophenol and acyl chloride,
however, did not noticeably influence the reaction results.
Although alkyl chlorides with both linear and branched groups
were found to be applicable, attempts at employing aryl
containing acyl chlorides such as 2-phenylacetyl chloride were
not successful. As an issue of higher importance, we also made
Supporting Information for additional data on optimization). At
first, by employing 1,10-phenanthroline (1,10-phen. L1) as
ligand, the entries in the presence of different copper catalysts
demonstrated that CuBr possessed the best catalytic activity
(entries 1−5, Table 1), and no expected transformation was
observed in the entry employing FeCl3 (entry 6, Table 1).
Examination on the effect of different ligands, including 8-
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extensive efforts to investigate the reactivity of other alkyl
dichlorides. Related substrates, including 1,1-dichloroethane,
1,1-dichloropropane, 2,2-dichloropropane, and 2,2-dichloroace-
tonitrile were employed, respectively. Unfortunately, none of the
experiments gave the desired benzofuran products either with
standard operation or modified operation probably because of
their lower reactivity caused by the steric hindrance from the
alkyl/aryl substitution. In addition, an entry using CH2Br2 as the
alternative of CH2Cl2 in the model reaction provided 6a with
similar yield, implying that dichloro- and dibromoalkanes possess
similar reactivity in the reaction. Furthermore, employing o-
iodoaniline did not yield a potential synthesis of indoles by a
similar transformation.
Scheme 4. Plausible Mechanism
Subsequently, in order to confirm participation of dichloro-
methane in the formation of the CC bond, the control isotope-
labeling experiment was conducted. When CD2Cl2 was utilized
as the alternative substrate in the model reaction, as
hypothesized, the deuterium-labeled product 6a-d2 was isolated
in 47% yield (eq 1, Scheme 3), which unambiguously confirmed
Scheme 3. Control Experiments
In conclusion, we have developed a new copper-catalyzed
cascade reaction for the synthesis of vinylbenzofuran scaffolds.
With the cascade benzofuran construction and the subsequent
CH2Cl2-based CC bond formation, together with the multiple
transformations including the conversions of the sp3C−H bond
and sp3C−Cl bonds involved, the significance of the present
work lies not only in providing a facile synthetic method toward
unprecedented 2-vinylbenzofurans, but more importantly in
disclosing the new reactivity of the inert dichloromethane as a
reaction partner in the construction of terminal CC bonds.
that dichloromethane served as the source of the terminal
methylene of the CC bond. In addition, another control
experiment employing directly the benzofuran 7a and dichloro-
methane under standard conditions gave vinylbenzofuran 6a in
46% yield (eq 2, Scheme 3), which supported the fact that the
CC double bond was generated via direct sp3C−H bond
conversion.
With these results in hand, we tentatively summarized the
general reaction mechanism. As outlined in Scheme 4, product 6
is formed through two main catalytic cycles, the cycle I for
copper-catalyzed tandem benzofuran annulation and the cycle II
for sp3C−H and sp3C−Cl conversion-based vinylation. Initially,
the in situ prepared allenes 5 underwent oxa-Michael addition in
the presence of o-iodophenol to afford intermediates 8,14 under
the catalysis of Cu(I). The active methylene-based intra-
molecular C-arylation reaction proceeds via the intermediates
9 and 10 to give benzofurans 7. According to the structure of 7
and related literature on the Cu-catalyzed sp3C−Cl bond
conversion,11a the second catalytic cycle is assumed to be
initiated by the γ-deprotonation of 7 in the presence of a base.
This deprotonation process activated the methylene adjacent to
C2 of the benzofuran via another intermediate 11 which could
incorporate Cu(I) catalyst and proceed to 12. Subsequently, the
active sites containing Cu(I) in 12 insert into the C−Cl bond in
CH2Cl2 via the oxidative addition transformation and proceed to
intermediate 13. The following reductive elimination on 13 then
leads to the formation of intermediates 14 while releasing the
Cu(I) catalyst for recycling. Finally, in the presence of a base, the
products 6 were generated via a conventional β-elimination on
the alkyl chloride fragment in 14.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional data on condition optimization, general experimental
information, synthetic procedure, and characterization data as
1
well as H/13C NMR spectra of all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wanjieping@jxnu.edu.cn.
*E-mail: hfding@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work is financially supported by NSFC of China (Grant Nos.
21102059, 21202064, and 21202144) and the Department of
Education of Jiangxi Province (Grant No. GJJ13245).
C
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