Copper-mediated tandem oxidative C(sp2)-H/C(sp)-H alkynylation and annulation of arenes with terminal alkynes

Article abstract of DOI:10.1021/ol501023n

The copper-mediated tandem oxidative C(sp²)-H/C(sp)-H cross-coupling and intramolecular annulation of arenes with terminal alkynes has been developed, which offers a highly efficient approach to the 3-methyleneisoindolin-1-one scaffold. In this oxidative coupling process, Cu(OAc)₂ acts as both the promoter and the terminal oxidant. This protocol features a wide substrate scope; high functional group tolerance; exclusive chemo-, regio-, and stereoselectivity; and simple, easily available, and inexpensive reaction system. The transformation has demonstrated for the first time that Cu(OAc)₂ can be renewable after undergoing an oxidative reaction.

Full text of DOI:10.1021/ol501023n

Letter
pubs.acs.org/OrgLett
Copper-Mediated Tandem Oxidative C(sp2)−H/C(sp)−H Alkynylation
and Annulation of Arenes with Terminal Alkynes
Jiaxing Dong, Fei Wang, and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Hospital, West China Medical School, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R.
China
S
* Supporting Information
ABSTRACT: The copper-mediated tandem oxidative C(sp2)−H/
C(sp)−H cross-coupling and intramolecular annulation of arenes
with terminal alkynes has been developed, which offers a highly
efficient approach to the 3-methyleneisoindolin-1-one scaffold. In
this oxidative coupling process, Cu(OAc)2 acts as both the
promoter and the terminal oxidant. This protocol features a wide
substrate scope; high functional group tolerance; exclusive chemo-,
regio-, and stereoselectivity; and simple, easily available, and
inexpensive reaction system. The transformation has demonstrated for the first time that Cu(OAc)2 can be renewable after
undergoing an oxidative reaction.
ver the past years, the transition-metal-catalyzed oxidative
C−H/C−H cross-coupling reactions have emerged as a
direct alkynylation of aromatic C−H bonds with alkynyl halides
or pseudohalides.6 Doubtlessly, the direct oxidative coupling
between arenes and terminal alkynes via double C−H bond
cleavage is a more straightforward approach to these molecules.
Although a few heteroarenes could smoothly undergo oxidative
C(sp2)−H/C(sp)−H cross-coupling with terminal alkynes,7
the application of this strategy to simple arenes is still largely
underdeveloped.7b,8 In 2010, Nevado, Su, and Miura
independently revealed the gold- or copper-catalyzed oxidative
alkynylation of simple arenes via 2-fold C−H bond cleavage.
However, the scope of arenes was limited to extremely
electron-excessive polyalkoxybenzenes or electron-deficient
polyfluoroarenes. Inspired by aromatic ortho-C−H activation
via a double coordination strategy,2d,6c,9,10 we herein wish to
disclose the copper-mediated tandem transformation involving
sequential oxidative C(sp2)−H/C(sp)−H alkynylation and
intramolecular annulation of unactivated arenes with terminal
alkynes with the assistance of 8-aminoquinoline, which not only
tolerates a broad range of arenes and terminal alkynes but also
offers a highly effective strategy to synthesize biologically
important 3-methyleneisoindolin-1-ones (Scheme 1).11
We initially focused our investigation on the copper-
mediated cross-coupling of N-(quinolin-8-yl)benzamide 1a
with phenylacetylene 2a (Table 1). Gratifyingly, (Z)-3-
benzylidene-2-(quinolin-8-yl)isoindolin-1-one 3a was obtained
in 25% yield when a stoichiometric amount of Cu(OAc)2·H2O
was employed in toluene at 140 °C for 24 h (Table 1, entry 1).
Due to the existence of excess 2a and Cu(II) salt, the
homocoupling of 2a was inevitable to give 2aa. Further
optimization of solvents showed t-AmylOH was the best choice
O
powerful tool for the formation of C−C bonds and have
become one of the hottest research topics in synthetic organic
chemistry.1 In general, these types of transformations require
high-priced precious metal catalysts such as Rh, Pd, and Ru in
combination with a stoichiometric amount of metal oxidant
including copper and silver salt. From a practical and industrial
viewpoint, it would be highly appealing and desirable to explore
inexpensive and abundant alternatives that are endowed with
high catalytic performance, versatility, and excellent and
complementary chemo- and regioselectivity. Recently, Miura
and Yu independently disclosed the stoichiometric copper-
promoted oxidative cross-coupling reactions between two
(hetero)arenes through a 2-fold C(sp2)−H cleavage to forge
the (hetero)aryl−(hetero)aryl scaffolds without the assistance
of other precious metal catalysts.2 Lei described the
stoichiometric silver-promoted oxidative C(sp3)−H/C(sp)−H
functionalization of 1,3-dicarbonyl compounds with terminal
alkynes for the construction of polysubstituted furans and
pyrroles.3 These pioneering works have demonstrated that a
stoichiometric amount of copper or silver salt can serve as both
the promoter and the terminal oxidant. Undoubtedly, these less
expensive and easily available stoichiometric systems would
pave a new pathway for innovating oxidative C−H/C−H cross-
coupling reactions. Nevertheless, this realm is still in its infancy,
and the issues of diversity and efficiency remain to be
addressed.
The synthesis of arylacetylenes is among the most
fundamental and important synthetic transformations due to
the unique reactivity of acetylenes including addition, oxidation,
reduction, and in particular cyclization.4 To date, the
introduction of acetylenic groups into aromatic scaffolds mostly
relies on the Sonogashira reactions5 and the recently emerged
Received: April 8, 2014
© XXXX American Chemical Society
A
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Letter
a
,b
Scheme 1. Tandem Oxidative C(sp2)−H/C(sp)−H Cross-
Coupling and Intramolecular Annulation of Arenes with
Terminal Alkynes
Scheme 2. Scope of N-(Quinolin-8-yl)benzamides
a
Table 1. Optimization of Reaction Conditions
b
c
a
entry
Cu-salt (equiv)
solvent
yield (%) 3a /2aa
Reaction conditions: 1 (0.25 mmol), 2 (0.625 mmol, 2.5 equiv),
Cu(OAc)2 (3.0 equiv), and t-AmylOH (2.0 mL) at 120 °C for 24 h. b
Isolated yields.
1
2
3
4
Cu(OAc)2·H2O (4.0)
Cu(OAc)2·H2O (4.0)
CuCl2 (4.0)
toluene
25/35
57/60
trace/8
n.d./2
89/46
91/44
77/53
31/52
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
8-yl)benzamides bearing the chloro or bromo group on the
aromatic ring selectively underwent the oxidative alkynylation
reaction, and the competitive Sonagashira reaction did not take
place (Scheme 2, 3f−h). Moreover, the reaction performed well
when the quinoline ring had a methoxyl group at the 5-position
(Scheme 2, 3j). In addition, single-crystal X-ray diffraction of 3a
(Scheme 2) and 2D NMR spectrum of 3b demonstrated that
the product was formed in the Z-type.12
CuI (4.0)
d
5
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
de
,
6
7
8
df
,
dg
,
a
Reactions were carried out using 1a (0.25 mmol), 2a (0.75 mmol, 3.0
equiv), and copper salt in 2.0 mL of dry solvent for 24 h at 140 °C
under an N2 atmosphere. Isolated yields. Yields determined with
GC-MS by using naphthalene as an internal standard. 120 °C. 2.5
equiv of 2a. 2.0 equiv of 2a. 0.5 mmol of 1a and 0.25 mmol of 2a.
b
c
d
e
Subsequently, we turned our attention to test the generality
of terminal alkynes (Scheme 3). Aryl alkynes bearing both
f
g
a
,b
Scheme 3. Scope of Terminal Alkynes
(Table 1, entry 2). Cu(OAc)2 proved to be the most efficient
oxidant and promoter (Table 1, entry 5), whereas CuCl2 gave a
trace amount of product 3a, and CuI was totally ineffective.
Subsequently, other reaction parameters including the loading
of phenylacetylene, the ratio of two substrates, and the reaction
temperature were investigated (Table 1, entries 5−8). Finally,
the best result was observed when 2.5 equiv of phenylacetylene
2a was used in combination with Cu(OAc)2 (3.0 equiv) in t-
AmylOH at 120 °C for 24 h (for a detailed optimization study,
see the Supporting Information). Under the optimized
conditions, a series of structurally similar benzamides A−D
were examined, but no cross-coupled product was observed
except for the nearly quantitative formation of 2aa. These
control experiments showed the indispensable role of the 8-
aminoquinoline moiety for this reaction.
Next, we set out to explore the scope of N-(quinolin-8-
yl)benzamide partners as summarized in Scheme 2. To our
delight, the reaction system could accelerate the tandem
reaction of a wide array of N-(quinolin-8-yl)benzamides with
terminal alkynes, delivering a series of functionalized 3-
methyleneisoindolin-1-ones in moderate to excellent yields.
The positions of substituent on arenes had a negligible effect on
the transformation. No matter whether the substituent was
installed on the ortho-, meta-, or para-position of arenes, the
reaction proceeded smoothly (Scheme 2, 3b−d). N-(Quinolin-
a
For reaction conditions see Scheme 2. b Isolated yields. c 3.0 equiv of
terminal alkynes, 140 °C.
electron-withdrawing groups (Scheme 3, 4c−g and 4j) and
electron-donating groups (Scheme 3, 4a, 4b, 4h, 4i, and 4l)
were all successfully engaged in this transformation. Functional
groups such as ester, aldehyde, acyl, nitrile, fluorine, chlorine,
and bromine could be tolerated under the current conditions,
which may allow high diversity in the synthesis of function-
alized 3-methyleneisoindolin-1-ones. An alkyne containing a
naphthalene moiety could also be employed without any
difficulty (Scheme 3, 4m). In addition to aryl alkynes,
cyclopropyl acetylene, 1-hexyne, and (triisopropylsilyl)-
acetylene could also be compatible in the transformation,
delivering 4n, 4p, and 4o in acceptable yields, respectively.
B
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Letter
Although Cu(OAc)2 is one of the cheapest metal oxidants,
we tried to recycle the copper to further reduce the cost and
waste after the reaction. Indeed, Cu(OAc)2 could be
regenerated after simple treatment of copper residue with
bubbles of air in acetic acid solution and subsequent vacuum
drying (eq 1). The regenerated Cu(OAc)2 could smoothly
promote the tandem reaction (eq 2).
isoindolinone skeleton, although attempts to isolate the
coupled ortho-alkynyl benzamides failed. In addition, N-
phenyl-2-(phenylethynyl)benzamide 8 failed to undergo the
annulation reaction (eq 8), which suggested that the acidity of
the N−H bond in benzamide was vital to the trans-
formation.2d,13
We finally investigated whether the N−H bond cleavage
occurred during the formation of some metallic species.
Treatment of N-deuterated benzamide D-1c with or without
2a under the optimized conditions for 15 min both led to a
significant loss of deuterium content (eq 9). When the reaction
To get some insights into the mechanism of this tandem
reaction, a series of controlled experiments were performed.
First, a stoichiometric amount of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO), frequently used as radical scavenger
in transition-metal-mediated reactions, had a negligible effect
on the reaction between 1a and 2a, which indicated that a free-
radical pathway might be ruled out (Table S1, entry 18). Next,
we found that no reaction occurred when terminal alkyne 2a
was replaced by internal alkyne 5 (eq 3). Notably, copper
phenylacetylide 6 could give rise to the desired product 3a (eq
4). These observations suggested that the Cu(I)-alkynyl
intermediate might serve as a reactive species. However, the
addition of extra Cu(OAc)2 as a terminal oxidant was essential
to achieve this oxidative C(sp2)−H/C(sp)−H cross-coupling
reaction. Only a trace amount of 3a was observed in the
absence of Cu(OAc)2 (eq 5).
time was extended to 24 h, the product 3c was obtained in 61%
yield with <5% deuterium remaining at the alkenyl position (eq
10). When 1a reacted with 2a in MeOH-d4, 90% deuterium was
incorporated at the alkenyl position (eq 11). In addition, when
the N−H bond was blocked by a methyl group, no cross-
coupled product was found (eq 12). These outcomes hinted
that the N−H bond cleavage might be involved in the
formation of cyclometallic intermediates.
On the basis of the above observations, a tentative
mechanism is proposed in Scheme 4. First, the disproportio-
nation of Cu(II) gives Cu(III) and Cu(I). Next, the acetate-
ligand-assisted cupration of 2a with Cu(I) generates copper
phenylacetylide 6, which undergoes a bidentate chelation
process with 1a to deliver intermediate IM1 with the assistance
of a Cu(III) species and acetate ion (comproportionation
reaction).2b,d,14 Subsequently, the Cu(OAc)2-promoted oxida-
Subsequently, we found that ortho-alkynyl benzamide 7 could
smoothly be transformed to the target molecule 3a in the
presence of either Cu(OAc)2 or CuOAc (eq 6). To exclude the
Scheme 4. Proposed Mechanism
possibility of the reaction between N−H and C(sp)−H bonds,
ortho-blocked benzamide 1m was treated with phenylacetylene
2a. Neither the N-alkynylation product 9 nor the N-alkenlation
product 10 was detected, and 1m was recovered in 95% yield
(eq 7). These factors demonstrated that the domino reaction
first underwent the direct oxidative C(sp2)−H/C(sp)−H cross-
coupling followed by the intramolecular annulation to form the
C
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for the first time the copper-mediated tandem oxidative
C(sp2)−H/C(sp)−H cross-coupling and intramolecular annu-
lation of unactivated arenes with terminal alkynes, delivering a
wide array of functionalized 3-methyleneisoindolin-1-ones. In
the oxidative cross-coupling process, Cu(OAc)2 serves as both
the promoter and the terminal oxidant. The transformation has
demonstrated for the first time that Cu(OAc)2 can be
renewable after undergoing an oxidative reaction. The present
protocol exhibits the following features: (1) a simple, easily
available, and inexpensive reaction system; (2) no extra ligand,
base, and additive is required; (3) wide substrate scope; (4)
excellent functional group tolerance; and (5) exclusive chemo-,
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) For detailed 2D NMR spectra of 3b, 3c, and 3k, see Supporting
Information.
(13) The H NMR chemical shifts of NH in 7 and 8 are 11.22 and
AUTHOR INFORMATION
Corresponding Author
■
1
9.20 ppm, respectively (CDCl3, 25 °C).
*E-mail: jsyou@scu.edu.cn.
Notes
(14) At this stage, we cannot completely exclude the following
possible pathway to intermediate IM1: cupration of 2a with Cu(II) to
generate 12 and subsequent ligand exchange with 1a to form IM1,
although attempts to capture intermediate 12 failed. For a similar
mechanism proposed by Miura et al., see refs 2b and 2d.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Basic
Research Program of China (973 Program, 2011CB808601)
and the National NSF of China (Nos. 21025205, 21272160,
and 21321061).
(15) After the reductive elimination, the triple bond in situ
coordinates with Cu(I) to form IM4. The N− anion of benzamide
then attacks the alkyne moeity from the opposite side of copper(I),
followed by the protonation to deliver the specific Z-type product 3a.
However, at this moment, it is unclear why this reaction shows
predominant preference for the formation of the five-membered ring
over the six-membered ring.
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