Copper/silver-mediated direct ortho-ethynylation of unactivated (hetero)aryl C-H bonds with terminal alkyne

Article abstract of DOI:10.1002/chem.201405594

A copper/silver-mediated oxidative ortho-ethynylation of unactivated aryl C-H bonds with terminal alkyne has been developed.The reaction uses the removable PIP directing group and features broad substrate scope, high functional-group tolerance, and compatibility with a wide range of heterocycles, providing an efficient synthesis of aryl alkynes. This procedure highlights the potential of copper catalysts to promote unique, synthetically enabling C-H functionalization reactions that lie outside of the current scope of precious metal catalysis.

Full text of DOI:10.1002/chem.201405594

DOI: 10.1002/chem.201405594
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CÀH Activation |Hot Paper|
Copper/Silver-Mediated Direct ortho-Ethynylation of Unactivated
(Hetero)aryl CÀH Bonds with Terminal Alkyne
Yue-Jin Liu, Yan-Hua Liu, Xue-Song Yin, Wen-Jia Gu, and Bing-Feng Shi*[a]
Abstract: A copper/silver-mediated oxidative ortho-ethynyla-
tion of unactivated aryl CÀH bonds with terminal alkyne has
been developed. The reaction uses the removable PIP direct-
ing group and features broad substrate scope, high func-
tional-group tolerance, and compatibility with a wide range
of heterocycles, providing an efficient synthesis of aryl al-
kynes. This procedure highlights the potential of copper cat-
alysts to promote unique, synthetically enabling CÀH func-
tionalization reactions that lie outside of the current scope
of precious metal catalysis.
Introduction
arenes bearing different directing groups with electrophilic
alkyne species. Chatani and co-workers reported palladium-
and ruthenium-catalyzed alkynylation of benzamides, anilides,
and 2-arylpyridines with alkynyl bromides (Scheme 1a).[4a–f]
More recently, the groups of Loh and Li independently demon-
strated rhodium- or iridium-catalyzed alkynylation of a broad
range of arenes with hypervalent alkynyl iodine reagents
(Scheme 1a).[5a,b] However, these methods also have draw-
backs, including the use of precious metal catalysts, such as
palladium, rhodium, and iridium. Moreover, these methods rely
on the use of alkynyl halides or hypervalent alkynyl iodine cou-
pling partners, which are less readily available than the corre-
sponding terminal alkynes. Recently, You and co-workers re-
ported a copper-mediated oxidative alkynylation and intramo-
lecular annulations of arenes with terminal alkynes. This proto-
col provided an efficient access to the 3-methyleneisoindolin-
1-one scaffold, however, aryl alkynes could not be obtained
due to the facile intramolecular annulation.[9]
Alkynes are among the most important structural motifs in
a large number of natural products, pharmaceuticals, and ma-
terials.[1] Consequently, the development of efficient strategies
for the synthesis of functionalized alkynes has received tre-
mendous interest during the past several decades, and several
transition metal-catalyzed transformations have been devel-
oped for this purpose, including: 1) The palladium/copper-cat-
alyzed Sonogashira coupling reaction between aryl halides and
terminal alkynes;[2] 2) the oxidative coupling of aryl and alkyl
CÀH bonds with alkynylhalides[4] or hypervalent iodine re-
agents;[5] and 3) the oxidative coupling of aryl CÀH bonds with
terminal alkynes.[6–8] From the viewpoint of atom and step
economy, the final category of reactions is appealing in that it
inherently obviates prefunctionalization of both coupling part-
ners. Several seminal examples of this transformation have
been developed recently. In 2010, Su and co-workers demon-
strated a Cu-catalyzed alkynylation of electron-deficient poly-
fluoroarenes with terminal alkynes.[6a] Shortly thereafter, the
groups of Miura,[6b,c] Chang,[6d] and others[6e,f] reported the oxi-
dative alkynylation of azoles containing acidic CÀH bonds with
terminal alkynes. Recently, Su and co-workers disclosed a palla-
dium-catalyzed direct alkynylation of thiophenes and furans.[7c]
One major limitation across this series of reactions is that they
all generally rely on the use of activated substrates, such as
those containing acidic CÀH bonds (e.g., polyfluoroarenes and
azoles) or electron-rich heteroarenes (e.g., indole, thiophene,
furan).
To expand the substrate scope beyond electronically activat-
ed arenes, an alternative approach is the catalytic coupling of
[a] Y.-J. Liu, Y.-H. Liu, X.-S. Yin, W.-J. Gu, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (P. R. China)
E-mail: bfshi@zju.edu.cn
Homepage: http://mypage.zju.edu.cn/bfshi
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405594.
Scheme 1. Synthesis of aryl alkynes by transition metal-catalyzed CÀH alky-
nylation of unactivated arenes.
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These limitations encouraged us to develop a protocol for
the direct alkynylation of unactivated (hetero)aryl CÀH bonds
with terminal alkynes using copper as the catalyst, which we
discuss herein. The advantages of this method are: 1) The use
of inexpensive copper as the catalyst; 2) compatibility with
a broad range of heterocyclic substrates; and 3) the ability of
simple terminal alkynes to serve as the coupling partners
(Scheme 1b).[10]
Table 1. Optimization of the reaction conditions.[a]
Entry
x [mol%]
[Ag] (equiv)
additive (equiv)
Yield [%][b]
1
2
3
4
5
6
7
8
50
50
50
50
50
50
50
50
50
30
30
30
Ag2CO3 (1)
AgOAc (1)
Ag2O (1)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Na2CO3 (2)
Li2CO3 (2)
K2CO3 (2)
Et3N (2)
Na2CO3 (2), Et3N (0.8)
Na2CO3 (1), Et3N (0.8)
Na2CO3 (1), Et3N (0.8)
Na2CO3 (1), Et3N (0.8)
Na2CO3 (1), Et3N (0.8)
55
38
36
12
9
37
32
64 (3)
65 (3)
80 (10)
78 (12)[c]
trace
Since the seminal work of Yu and co-workers on copper-cat-
alyzed direct CÀH functionalization of 2-arylpyridines in
2006,[11] copper-catalyzed CÀH functionalization of aromatic
compounds has attracted significant attention.[12] A number of
C(sp2)ÀH bond functionalization reactions have been reported,
including CÀX (X=N, O, S, halogen) and C(aryl)ÀC(aryl) bond
formation, mediated by catalytic or stoichiometric amounts of
copper.[13,16] However, to our knowledge, there are no previous
examples of copper-catalyzed alkynylation of unactivated
C(sp2)ÀH bonds.[10] Recently, we developed a bidentate direct-
ing group[14–16] derived from 2-(pyridin-2-yl)isopropylamine
(PIP-amine), which has shown remarkable reactivity in CÀH
functionalization.[17] We speculated that a copper-catalyzed
CÀH alkynylation could be achieved using the N,N-bidentate
PIP directing group based on the following rationale: 1) It is
well known that some N,N-bidentate ligands, such as 1,10-phe-
nanthroline and 1,2-diamines facilitate the closely related
Castro–Stephens reaction;[18] 2) Wang and co-workers demon-
strated stoichiometric cross-coupling of a structurally well-de-
fined arylÀCuIII complex with terminal alkynes to form aryl al-
kynes;[19] and 3) the PIP auxiliary is known to facilitate CÀH ac-
tivation, presumably generating a CNN pincer-type copper in-
termediate, which is hypothesized to stabilize high-valent
copper intermediates.[14b,16e,17d]
AgF (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1.5)
Ag2CO3 (2)
none
9
10
11
12
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Cu(OAc)2 (x mol%),
[Ag], and additives in 1,4-dioxane (1 mL) at 1408C for 3.5 h; [b] 1H NMR
yield. The yield of dialkynylated product is given in parentheses; [c] yields
of isolated product.
substituents at different positions of the aromatic ring per-
formed well in the reaction, providing the desired aryl alkynes
in good yields. An array of different functional groups, such as
fluoro (3e–g), trifluoromethyl (3h–j), chloro (3k and l), bromo
(3o), alkoxy (3m and p), cyano (3r), and nitro (3s) groups
were compatible with this protocol. When meta-methyl or -tri-
fluoromethyl arenes were employed as substrates, alkynylated
products 3c and 3i were obtained exclusively, likely due to
steric interactions. In contrast, meta-alkoxy substrate 1m pre-
dominantly led to alkynylation adjacent to oxygen, possibly in-
dicating that coordination of the alkoxy substituent stabilizes
the aryl–copper intermediates. meta-Fluoro substrate 1 f also
reacted predominantly adjacent to fluorine, perhaps due to en-
hanced kinetic acidity of the corresponding CÀH bond. This
observation can be rationalized by invoking a concerted metal-
ation/deprotonation (CMD) pathway.
Results and Discussion
To test this possibility, we initiated our investigations by at-
tempting to couple benzamide 1a with TIPS–alkyne 2 in the
presence of Cu(OAc)2 and stoichiometric Ag2CO3 and Na2CO3
under aerobic conditions. To our delight, the desired aryl
alkyne 3a was obtained in 55% yield (Table 1, entry 1). Among
various silver salts that were tested, Ag2CO3 gave the best yield
(Table 1, entries 1–4). We then examined a number of inorganic
and organic bases and found that the combination of 1 equiv-
alent of Na2CO3 and 0.8 equivalents of Et3N gave the highest
yield (Table 1, entries 5–9). The presence of Et3N as an organic
base might facilitate the deprotonation of the terminal alkyne.
Through further optimization, the desired product 3a could be
produced in 90% yield (monoalkynylated/dialkynylated ratio=
6.5:1) under the following conditions: 30 mol% Cu(OAc)2,
2 equiv Ag2CO3, 1 equiv Na2CO3, 0.8 equiv Et3N and 1.5 equiv
TIPS-alkyne 2 in 1,4-dioxane under air at 1408C for 3.5 h
(Table 1, entry 11). Notably, silver was observed to be essential
for the reaction, since only trace alkynylated product was de-
tected in the absence of silver salts (Table 1, entry 12).
Notably, a wide range of heterocycles including pyridines,
a pyridazine, a pyrimidine, thiophenes and a furan, were also
compatible with this protocol (Scheme 3). Notably, 2-fluoroiso-
nicotinamide 4b, nicotinamides 4e–g, and pyridazine-4-car-
boxamide 4h tended to react at the kinetically more acidic
CÀH bonds, consistent with a CMD pathway. The connectivity
of 5 f was unambiguously confirmed by single-crystal X-ray dif-
fraction (see the Supporting Information, Figure S1).[20]
To highlight the synthetic versatility of this reaction protocol,
we successfully removed the PIP directing group under mild
conditions. A sequence consisting of N-nitrosylation, followed
by the hydrolysis with lithium hydroperoxide, gave the corre-
sponding ortho-alkynylated benzoic acid 6 in a good yield
(Scheme 4).[17a] Although the bulky TIPS group is essential for
this protocol, it could be easily removed by treatment with
tetra-n-butylammonium fluoride (TBAF) to produce the termi-
Following identification of the optimized conditions, we
next explored the substrate scope of this protocol (Scheme 2).
Both electron-rich and -deficient benzamides bearing various
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Scheme 3. Substrate scope for alknylation of heteroarene CÀH bonds.
Unless otherwise specified, the reaction conditions used were as follows: 4
(0.1 mmol), 2 (0.15 mmol), Cu(OAc)2 (30 mol%), Ag2CO3 (0.2 mmol), Na2CO3
(0.1 mmol) and Et3N (0.08 mmol) in 1,4-dioxane (1 mL) at 1408C for 3.5 h.
Yields of isolated product are given. [a] 3 equiv Ag2CO3; [b] 7 h.
Scheme 4. Removal of the PIP and TIPS Groups.
ve.[12b] Moreover, when the reaction was performed in the pres-
ence of 1 equivalent of 1,4-dinitrobenzene, TEMPO, 1,1-diphe-
nylethylene, or hydroquinone, (known radical traps), it still pro-
ceeded smoothly to afford aryl alkyne 3a (see the Supporting
Information). These experiments ruled out the involvement of
radicals in the catalytic cycle.
Scheme 2. Substrate scope for alknylation of arene CÀH bonds. Unless oth-
erwise specified, the reaction conditions used were as follows: 1 (0.1 mmol),
2 (0.15 mmol), Cu(OAc)2 (30 mol%), Ag2CO3 (0.2 mmol), Na2CO3 (0.1 mmol)
and Et3N (0.08 mmol) in 1,4-dioxane (1 mL) at 1408C for 3.5 h. Yields of iso-
lated product are given. [a] 3 equiv Ag2CO3; [b] 7 h.
An intermolecular kinetic isotope experiment between 1a
and [D5]1a gave a kinetic isotope effect (KIE) value of 3.6,
whereas the intramolecular competition experiment of the
substrate [D1]1a afforded a large KIE value of 7.5 (Scheme 5).
Wang and co-workers reported that azacalix[1]arene[3]pyri-
dine could undergo a disproportionative CÀH activation with
a CuII complex to form a structurally well-defined aryl–CuIII spe-
cies, which reacted rapidly with alkynyllithium reagents to pro-
duce the desired aryl alkynes.[19a] These precedents and our
own preliminary studies suggest that a CuII-mediated, basic-
ligand-enabled CMD, rather than a CuIII-mediated SEAr path-
way, is likely operative in the present reaction. Although the
exact role of AgI is unclear at this point, we rationalize that be-
nal alkyne, which could serve as a versatile handle for further
synthetic elaboration.
Subsequently, we conducted further experiments to probe
the mechanism of the reaction. Intermolecular competition ex-
periments between binary mixtures of electron-rich and elec-
tron-poor amides, 1s/1p and 1s/1d, revealed that electron-de-
ficient arenes reacted preferentially. This observation is incon-
sistent with a simple electrophilic aromatic substitution (SEAr)
pathway (see the Supporting Information). These experiments
also rule out a single-electron transfer (SET) mechanism, in
which electron-rich substrates are comparatively more reacti-
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Acknowledgements
Financial support from the National Basic Research Program of
China (2015CB856600), the NSFC (21422206, 21272206), the
Fundamental Research Funds for the Central Universities
(2014QNA3008), Zhejiang Provincial NSFC (Z12B02000) and
Qianjiang Project (2013R10033) is gratefully acknowledged. We
thank Mr. Ji-Yong Liu for help with X-ray analysis.
Keywords: alkynylation · CÀH activation · copper · cross-
coupling · directing groups
Scheme 5. Kinetic isotope experiments.
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Conclusion
In conclusion, we have developed a copper/silver-mediated ox-
idative ethynylation of unactivated (hetero)aryl CÀH bonds
with terminal alkyne using our recently developed PIP auxiliary.
The reaction proceeds with a catalytic amount of copper and
is characterized by broad substrate scope, tolerance to an
array of functional groups, and compatibility with a wide
range of biologically important heterocycles. Moreover, this
protocol demonstrated new modes of reactivity enabled by
the PIP directing group in copper-catalyzed CÀH activation.
Additional mechanistic studies and applications to other cata-
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Experimental Section
General procedure for ethynylation of unactivated (hetero)aryl CÀH
bonds: To a 50 mL sealed tube was added substrate (0.1 mmol),
Cu(OAc)2 (5.4 mg, 0.03 mmol), Ag2CO3 (55.2 mg, 0.2 mmol), Na2CO3
(10.6 mg, 0.1 mmol), Et3N (12 mL, 0.08 mmol), and 1,4-dioxane
(1 mL). The mixture was stirred at room temperature for 10 mins,
then heated at 1408C in a preheated oil bath for 3.5 h. The reac-
tion mixture was cooled to room temperature, diluted with ethyl
acetate (15 mL) and quenched with saturated ammonia solution
(10 mL). The aqueous phase was extracted with ethyl acetate (3ꢁ
10 mL). The combined organic phase was dried with anhydrous
magnesium sulfate. After concentration, the resulting residue was
purified by preparative TLC using hexane/EtOAc as the eluent to
afford the product.
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[20] CCDC 1011982 (5 f) contains the supplementary crystallographic data
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[21] According to the elegant work by the Stahl group, Ag2CO3 could react
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Received: October 10, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
CÀH Activation
Y.-J. Liu, Y.-H. Liu, X.-S. Yin, W.-J. Gu,
B.-F. Shi*
&& – &&
A copper/silver-mediated oxidative
ortho-ethynylation of unactivated aryl
CÀH bonds with terminal alkyne has
been developed using a removable bi-
dentate directing group (PIP; see
sopropylamine. The reaction provides
an efficient synthesis of aryl alkynes
with broad substrate scope, high func-
tional-group tolerance, and compatibili-
ty with a wide range of heterocycles.
Copper/Silver-Mediated Direct ortho-
Ethynylation of Unactivated
(Hetero)aryl CÀH Bonds with Terminal
Alkyne
scheme) derived from 2-(pyridine-2-yl)i-
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!