Cu(II)-mediated ortho C-H alkynylation of (hetero)arenes with terminal alkynes

Article abstract of DOI:10.1021/ja507704b

Cu(II)-promoted ortho alkynylation of arenes and heteroarenes with terminal alkynes has been developed to prepare aryl alkynes. A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction, thus providing an alternative disconnection to Sonogashira coupling.

Full text of DOI:10.1021/ja507704b

Communication
pubs.acs.org/JACS
Cu(II)-Mediated Ortho C−H Alkynylation of (Hetero)Arenes with
Terminal Alkynes
Ming Shang,† Hong-Li Wang,† Shang-Zheng Sun,§ Hui-Xiong Dai,*,† and Jin-Quan Yu*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§Department of Chemistry, Innovative Drug Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, China
S
* Supporting Information
alkynylation of highly reactive acidic C−H bonds or electron-rich
heteroarenes has also been demonstrated (eq 2).7 Notably,
ABSTRACT: Cu(II)-promoted ortho alkynylation of
arenes and heteroarenes with terminal alkynes has been
developed to prepare aryl alkynes. A variety of arenes and
terminal alkynes bearing different substituents are
compatible with this reaction, thus providing an alternative
disconnection to Sonogashira coupling.
Chang10 reported an example of Pd-catalyzed C−H alkynylation
of arenes with terminal alkynes bearing a bulky silyl group (eq 3).
A Cu-mediated C−H coupling with terminal alkynes was also
recently made possible by the use of Daugulis’ aminoquinoline
directing group.11 However, this method does not allow for the
synthesis of aryl alkynes because of the subsequent cyclization
reaction of the amide directing group with the o-alkynyl group,
thus preventing the broad range of synthetic applications of o-
alkynylbenzoic acids.12−19 Moreover, electron-deficient arenes
and heteroarenes have not been demonstrated therein. In
contrast to the development of other C−H activation trans-
formations, alkynylation of inert aryl C−H bonds with
unactivated terminal alkynes remains at an early stage. Herein
we detail a Cu(II)-promoted ortho C−H alkynylation of
benzamides, including heteroarylamides, with a wide range of
terminal alkynes to afford synthetically useful aryl alkynes (eq 4).
Considering the potential interference of terminal alkynes in
the C−H activation step, we anticipated that a highly efficient C−
H activation process may be required for the development of
alkynylation of aryl C−H bonds. Prompted by our Cu-mediated
ortho C−H amination reactions using an amide−oxazoline
directing group,20 we subjected amide 1a to various conditions in
the presence of the alkyne coupling partner p-tolylacetylene (2a).
Encouragingly, we found that C−H alkynylation of N-
arylbenzamide substrate 1a with 3 equiv of 2a proceeded in
the presence of 1 equiv of Cu(OAc)2 and 2 equiv of Na2CO3 in
dimethyl sulfoxide (DMSO) at room temperature to give the
desired product 3a in 5% yield (Table 1, entry 1). Through
further evaluation of the reaction conditions, we discovered that
the yield was improved to 68% when the reaction temperature
was increased to 60 °C (entry 3). Notably, higher reaction
temperatures led to substantially lower yields (entries 4 and 5),
and thus, 60 °C was found to be the optimal temperature.
Monitoring of the reaction at 100 °C by 1H NMR and LC−MS
identified a major side product (∼60%) formed via cyclization of
the amide onto the alkyne, similar to a previous report [see the
Supporting Information (SI)].11 This observation suggests that
the high reactivity of this directing group to allow the reaction to
proceed at mild temperature is crucial for the formation the aryl
ryl alkynes are important structural motifs because of their
A
ubiquity in natural products, pharmaceuticals, and materi-
als.1 Not only are alkynyl groups present in a variety of products
with functional significance, but they can also participate in many
cross-coupling, metathesis, and cycloaddition reactions.2 There-
fore, the development of efficient synthetic methodologies to
construct alkyne motifs is of broad interest. In the past several
decades, the Sonogashira coupling reaction has been extensively
studied and practiced in both academic and industrial settings.3
Recently, with the rapid development of transition-metal-
catalyzed C−H functionalization,4 direct C−H alkynylation of
arenes and heteroarenes has received much attention.5−8 To
avoid the homocoupling of terminal alkynes under oxidative
conditions,9 preactivated alkynating reagents such as alkynyl
halides5 and benziodoxolone-based hypervalent iodine reagents6
have been successfully explored as coupling partners in C−H
activation reactions (eq 1). The use of terminal alkynes for
Received: June 2, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja507704b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a b
,
a b
,
Table 1. Optimization of the Reaction Conditions
Table 2. Scope of Aromatic Amides
a
Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), Cu(OAc)2 (0.1
b
mmol), base (0.2 mmol), DMSO (3.0 mL), air, 12 h. Determined by
1H NMR analysis of the crude reaction mixtures using CH2Br2 as an
c
internal standard. About 60% cyclized byproduct was formed.
d
e
f
DMSO (5.0 mL). Cu(OAc)2 (0.06 mmol). Cu(OAc)2 (0.04
g
h
i
mmol). Cu(OAc)2 (0 mmol). NaOAc (0.1 mmol). NaOAc (0.05
mmol).
alkynes without subsequent cyclization. Among the various bases
screened, NaOAc gave the highest yield of 75% (entries 6−12).
The yield increased to 80% when the reaction was run at lower
concentration (entry 13). A variety of copper salts are reactive,
with Cu(OAc)2 being the optimal choice (see the SI). Reducing
the quantity of Cu(OAc)2 to 40% lowered the yield to 53%
(entry 15). The use of 3 equiv of the alkyne is necessary because a
substantial amount of alkyne homocoupling occurs under these
conditions. Air is a more suitable oxidant than oxygen for this
reaction because a high concentration of molecular O2 promotes
ortho hydroxylation as well as alkyne homocoupling (see the SI).
It should also be noted that no reactivity was observed in the
absence of copper (entry 16). Finally, decreasing the amount of
NaOAc to 1 equiv afforded the alkynylation product in 85% yield
(entry 17).
With these optimized conditions in hand, we proceeded to
examine the substrate scope. As shown in Table 2, a wide variety
of substituted benzamides are reactive. Alkynylation of electron-
rich methyl-, tert-butyl-, and phenyl-substituted arenes gave the
corresponding products in 41−68% yield (3b−e). Naphthalene
substrate 1f was also alkynylated to give 3f in 70% yield. Electron-
deficient arenes bearing halide, trifluoromethyl, and acetyl
groups reacted under these conditions to afford the desired
alkynylated products in moderate to good yields (3g−n, 43−67%
yield). The halogen (3i−k) and vinyl (3o) substituents in the
products are useful handles for further synthetic elaborations.
The scope of terminal alkynes was also extensively examined
(Table 3). Alkynylation of 1a with a variety of substituted
phenylacetylenes proceeded to give the desired products in
moderate to good yields (4b−f, 48−63% yield). Alkyne 2h
bearing a thiophene moiety was also compatible, albeit providing
a lower yield (4g, 40%). Importantly, aliphatic alkynes, including
n-pentyl-, tert-butyl-, cyclopropyl-, and cyclohexyl-substituted
acetylenes, were all compatible (4h−k, 46−67% yield).
Interestingly, a conjugated enyne also underwent the alkynyla-
a
Reaction conditions: 1a−o (0.1 mmol), 2a (0.3 mmol), Cu(OAc)2
(0.1 mmol), NaOAc (0.1 mmol), DMSO (5.0 mL), 60 °C, air, 12 h.
Isolated yields are shown.
b
tion to give the corresponding product in moderate yield, leaving
the olefin moiety intact (4l, 46% yield), thus introducing a highly
functionalizable unit onto the arene.
To investigate the applicability of this alkynylation reaction in
medicinal chemistry, we tested a number of heterocyclic
substrates (Table 4).4f,21−23 Gratifyingly, alkynylation of pyrrole,
indole, benzofuran, pyrazole, and imidazole proceeded to give
the desired heteroaryl alkynes 3p−t in synthetically useful yields.
The strongly coordinating pyridine-based substrates could also
be alkynylated under the developed reaction conditions (3u−x,
30−54% yield). Because of the versatility of the alkyne moiety,
these alkynylated heteroarenes should be highly useful for
medicinal chemistry.24
We also conducted the reaction on a gram scale and obtained
3a in 62% yield (eq 5), thus demonstrating the scalability of this
reaction. The directing group was readily removed by exposing
product 3a to a standard amide hydrolysis sequence to produce
the corresponding benzoic acid (Scheme 1).
Alkynylated benzoic acids can be converted to various useful
heterocycles and valuable synthons, such as isoindolin-1-ones,12
isoquinolin-1-ones,12 pyran-2(2H)-ones,13 furan-2(5H)-ones,13
alkyls,13 alkenes,14,15 triazoles,16 quinoxalines,17 1,2-diketones,17
B
dx.doi.org/10.1021/ja507704b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a b
,
Table 3. Scope of Terminal Alkynes
Scheme 1. Removal of the Directing Group
6H-indolo[2,3-b][1,6]naphthyridines,18 and indenones19
(Scheme 2).
Scheme 2. Transformations of o-Alkynylbenzoic Acids
a
Reaction conditions: 1a (0.1 mmol), 2b−m (0.3 mmol), Cu(OAc)2
(0.1 mmol), NaOAc (0.1 mmol), DMSO (5.0 mL), 60 °C, air, 12 h.
Isolated yields are shown. Na2CO3 (0.2 mmol), 80 °C.
b
c
Finally, significant inter- and intramolecular isotope effects
were observed (Scheme 3), suggesting that a simple electrophilic
ab
,
Table 4. Scope of Heteroaromatic Amides
Scheme 3. Isotope Effects
aromatic substitution (SEAr) pathway is unlikely to be involved
in this reaction. The lack of H incorporation in 3a-d1 also
indicates that the C−H insertion process is not reversible.
In conclusion, we have developed a Cu-promoted C−H
alkynylation of arenes and heteroarenes with terminal alkynes.
This protocol provides a generally useful method to prepare aryl
alkynes as an alternative synthetic disconnection to Sonogashira
coupling.
a
Reaction conditions: 1p−x (0.1 mmol), 2a (0.3 mmol), Cu(OAc)2
(0.1 mmol), NaOAc (0.1 mmol), DMSO (5.0 mL), 60 °C, air, 12 h.
Isolated yields are shown. 80 °C.
b
c
C
dx.doi.org/10.1021/ja507704b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
hxdai@sioc.ac.cn
yu200@scripps.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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We gratefully acknowledge Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, the CAS/SAFEA
International Partnership Program for Creative Research Teams,
the Recruitment Program of Global Experts, and The Scripps
Research Institute for financial support. This work was supported
by NSF under the CCI Center for Selective C−H Functionaliza-
tion (CHE-1205646).
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dx.doi.org/10.1021/ja507704b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX