Rh(III)- and Ir(III)-Catalyzed C-H alkynylation of arenes under chelation assistance

Article abstract of DOI:10.1021/ja501910e

An efficient Rh(III)- and Ir(III)-catalyzed, chelation-assisted C-H alkynylation of a broad scope of (hetero)arenes has been developed using hypervalent iodine-alkyne reagents. Heterocycles, N-methoxy imines, azomethine imines, secondary carboxamides, azo compounds, N-nitrosoamines, and nitrones are viable directing groups to entail ortho C-H alkynylation. The reaction proceeded under mild conditions and with controllable mono- and dialkynylation selectivity when both mono- and dialkynylation was observed. Rh(III) and Ir(III) catalysts exhibited complementary substrate scope in this reaction. The synthetic applications of the coupled products have been demonstrated in subsequent derivatization reactions. Some mechanistic studies have been conducted, and two Rh(III) complexes have been established as key reaction intermediates. The current C-H alkynylation system complements those previously reported under gold or palladium catalysis using hypervalent iodine reagents.

Full text of DOI:10.1021/ja501910e

Article
pubs.acs.org/JACS
Rh(III)- and Ir(III)-Catalyzed C−H Alkynylation of Arenes under
Chelation Assistance
Fang Xie,§ Zisong Qi,§ Songjie Yu, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
S
* Supporting Information
ABSTRACT: An efficient Rh(III)- and Ir(III)-catalyzed, chelation-
assisted C−H alkynylation of a broad scope of (hetero)arenes has
been developed using hypervalent iodine-alkyne reagents. Hetero-
cycles, N-methoxy imines, azomethine imines, secondary carbox-
amides, azo compounds, N-nitrosoamines, and nitrones are viable
directing groups to entail ortho C−H alkynylation. The reaction
proceeded under mild conditions and with controllable mono- and
dialkynylation selectivity when both mono- and dialkynylation was
observed. Rh(III) and Ir(III) catalysts exhibited complementary
substrate scope in this reaction. The synthetic applications of the
coupled products have been demonstrated in subsequent derivatiza-
tion reactions. Some mechanistic studies have been conducted, and
two Rh(III) complexes have been established as key reaction intermediates. The current C−H alkynylation system complements
those previously reported under gold or palladium catalysis using hypervalent iodine reagents.
stoichiometric amount of base.6c Despite the progress, the
substrate scope remains limited.
INTRODUCTION
■
Alkynes are fundamental building blocks in synthetic chemistry
To expand the substrate scope and to achieve C−H
activation of intrinsically different arenes, alkynylated hyper-
valent iodines have been employed as a versatile and powerful
alkynylating reagent.10 In particular, as an oxidized and
activated form of alkynes, 1-silylethynyl-1,2-benziodoxol-
3(1H)-ones (silyl-EBXs) are readily synthesized in large scales
in crystal forms and are stable toward air and moisture.11 Since
2009 Waser and co-workers have elegantly and systematically
applied EBXs to the electrophilic alkynylation of a range of
heterocycles such as indoles, pyrroles, and furans using gold
and palladium catalysts.12 Copper catalysts may also effect
alkynylation, as in Fujii and Ohno’s reported coupling of
bezamidines with EBXs,13 but the relevancy of C−H activation
remains mechanistically ambiguous. Thus when alkynylated
hypervalent iodines are employed, the arene substrates are
mostly limited to electron-rich (hetero)aromatics.14 Given
these limitations, it is necessary to develop a highly efficient and
general alkynylation method for broadly defined arenes via a
C−H activation pathway, particularly for generically and
intrinsically less reactive ones.
and in material science.1 Although aryl alkynes are readily
prepared from aryl halides by the Sonogashira reaction,2 it is
desirable and attractive to take advantage of the abundance of
C−H bonds in arenes by a transition-metal-catalyzed C−H
activation pathway. Indeed, this strategy has been increasingly
explored in the past several decades, and a plethora of new
synthetic methods have been developed toward the synthesis of
complex structures.3 Thus direct alkynylation of an aryl C−H
bond would be highly desirable because the C−H bond is
directly functionalized without preactivation, which is partic-
ularly important in the late stage functionalization of complex
structures.
In contrast to the vast majority of C−H arylation reactions,4
general methods of C−H alkynyation are limited that can be
applied to a range of arenes with different electronic and steric
characteristics. While it is desirable to apply terminal alkynes as
alkynylating reagents via C−H/C−H oxidative coupling, only a
narrow scope of heteroarenes such as thiophenes and highly
electron-poor arenes such as pentafluorobenzene has been
achieved.5
It is well-known that installation of a directing group
constitutes a common and effective strategy to entail C−H
activation of intrinsically less reactive arenes.3,4,15 In this
context, C−H activation of arenes catalyzed by RhCp* and
occasionally IrCp* complexes has garnered increasing
attention.15 However, Rh(III)-catalyzed C−H activation/C−C
To achieve efficient C−H alkynylation, haloalkynes have
been widely used.6−8 In 2002, Yamaguchi reported the first
example of C−H alkynylation of electron-rich arenes using
chloroalkynes.7 The C−H alkynylation of heterocycles was first
reported by Gevorgyan using palladium catalysis.8 In 2009
Chatani reported palladium catalyzed ortho alkynylation of
acetanilide with bromoalkynes via a C−H activation pathway.9
Recently, Chatani achieved the ortho C−H alkynylation of 2-
phenylpyridines with haloalkynes in the presence of a
Received: February 24, 2014
Published: March 4, 2014
© 2014 American Chemical Society
4780
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
coupling is mostly limited to olefination, arylation, and redox-
neutral insertion of the aryl C−H into a polar π bond,16 and no
Rh(III)-catalyzed C−H alkynylation of arenes has been
reported. On the other hand, we17a and Su17b have recently
reported the compatibility of Rh(III)-catalyzed C−H activation
with hypervalent iodine oxidants as in efficient azidation,
nitration, and amidation of arenes. We reasoned that
hypervalent iodine-alkynes such as EBXs are desirable
alkynylating reagents in rhodium(III)-catalyzed C−H activa-
tion. This is because, in addition to the precedents in C−H
alkynylation using these activated and polarized alkynes, the 2-
iodobenzoic acid coproduct may further facilitate the activation
of a C−H bond via a well studied carboxylate-assisted
concerted metalation-deprotonation (CMD) mechanism.18 As
a continuation of our interest in C−H activation, we aimed to
extend Rh(III)- and Ir(III)-catalyzed C−H functionalization to
alkynylation using hypervalent iodine oxidants. We now report
in full the efficient C−H alkynylation of a broad scope of
arenes, including the substrate scope, selectivity, and mecha-
nistic studies.
effect as an additive (entry 10), Cu(OTf)2 improved the
catalytic efficiency and afforded the expected alkynylation
product (3a) in moderate yield (entry 5). Gratifyingly, addition
of AgSbF6, Zn(OTf)2, or Zn(NTf2)2 gave comparably favorable
results, and the yield of the product was dramatically improved
even at room temperature (entries 2, 3, 6, 7). It is interesting to
note that AgSbF6 and zinc salts performed with comparable
efficiency. Although the exact nature of active catalytic species is
unclear, a cationic Rh(III) species is probably the real catalyst.
AgSbF6 is a well-known additive to activate the catalyst by
chloride abstraction to give a cationic Rh(III) species. On the
other hand, Zn(OTf)2 may play a dual role in both activating
the catalyst by reversible chloride abstraction and activating the
alkyne substrate because Zn(OTf)2 is known to electrophilically
activate TIPS-EBX in gold catalyzed C−H alkynylation.12c
Indeed, addition of Zn(OTf)2 to [RhCp*(MeCN)3](SbF6)2
catalyst improved the catalytic efficiency (entries 11, 12).
Therefore, for cost-effectiveness Zn(OTf)2 was selected as the
optimal additive. Control experiments revealed that no such
coupling occurred in the absence of the rhodium catalyst, and
switching the rhodium catalyst to the iridium congener resulted
in essentially no conversion (entry 13). Gratifyingly, the
catalyst loading can be reduced to 2 mol % without any loss of
the activity, under which conditions product 3a was isolated in
90% yield (entry 8).
RESULTS AND DISCUSSION
■
Optimization of the Reaction Conditions. We initiated
our studies with the screening of the conditions for the
coupling of 2-(m-tolyl)pyridine with 1-[(triisopropylsilyl)-
ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX, Table 1).
The 2-(m-tolyl)pyridine substrate was selected to ensure
monoalkynylation selectivity. It was found that [RhCp*Cl2]2
alone (4 mol %) exhibited no reactivity at room temperature.
Increasing the reaction temperature to 80 °C only resulted in a
low conversion (entry 2). While Cu(OAc)2 proved to have no
Substrate Scope. Following the optimized conditions, we
next explored the scope and limitation of this system (Schemes
1 and 2). 2-Phenylpyridines bearing different electron-donating,
-withdrawing, and halogen groups at the ortho and meta
positions of the phenyl ring all coupled smoothly with TIPS-
EBX with monoalkynylation selectivity. In contrast, a mixture
of mono- and dialkynation products was obtained for substrates
with the simple phenyl or para-substituted phenyl rings (3p−
3s′). Fortunately, adjusting the stoichiometry of the substrates
can further optimize the yield of both products. Thus the
dialkynylation product can be obtained in high yield (3t−3x)
when an excess of TIPS-EBX was used, and the mono-
alkynylation products were isolated in moderate to good yield
when an excess of the arene was used. The pre-installed formyl
(3p, 3p′), hydroxyl (3r, 3r′), and halogen (3b, 3g) groups in
the product should readily allow further functionalization.
a
Table 1. Optimization Studies
b
entry
additive
temp (°C)
solvent
yield
t
Other alkynes such as TES-EBX, TBDPS-EBX, and Bu-EBX
1
2
3
4
5
6
7
−
80
25
25
25
25
25
25
25
25
25
25
25
25
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
DCE
DCE
DCE
DCE
30%
89%
86%
nd
AgSbF6
also gave comparably high yield. In contrast, the reaction of
TMS-EBX and 2-phenylpyridine gave moderate yield (3l),
albeit with high monoselectivity. Here the decreased yield is
likely due to the lower stability of the TMS-EBX or the product
which lacks steric protection.12c The arene substrate is not
limited to phenyl rings. C−H alkynylation of indoles bearing
different electron-donating and -withdrawing groups reacted
exclusively at the 2-position with different alkynes in
consistently high efficiency (3aa−3af). The observed 2-
alkynylation is dominated by the directing effect, which stands
in contrast to the observed 3-alkynylation of protic indoles
under gold catalysis,12a,c where the electrophilic C−H
activation mechanism is operational. Although 2-alkynylation
has been achieved by using palladium catalysis,12b the N-
substituent is limited to an alkyl group. In addition to indoles,
thiophenes also coupled in high efficiency (3y,3z). Besides the
pyridine directing group, other heterocycles such as pyrimidine,
pyrazole, and oxazoline are also competent, although a higher
temperature is necessary for 2-phenylpyrimidines.
c
AgSbF6
CF3COOH
Cu(OTf)2
Zn(OTf)2
Zn(NTf2)2
Zn(OTf)2
Zn(NTf2)2
Cu(OAc)2
-
68%
92%
91%
90%
85%
nd
d
8
9
10
e
11
20%
62%
nd
f
12
Zn(OTf)2
AgSbF6
g
13
a
Reactions were carried out by using 2-(m-tolyl)pyridine (0.2 mmol),
TIPS-EBX (0.22 mmol), [RhCp*Cl2]2 (4 mol %), additive (20 mol %
for salts and 1 equiv for CF3COOH), solvent (2 mL), 25 °C, 16 h.
b
c
Isolated yield after column chromatography. AgSbF6 was used in 16
d
mol %. [RhCp*Cl2]2 (2 mol %) and Zn(OTf)2 (10 mol %) were
e
used. [RhCp*(MeCN)3](SbF6)2 (4 mol %) was used as a catalyst.
f
[RhCp*(MeCN)3](SbF6)2 (4 mol %) was used as a catalyst in
g
Substrate Scope. The scope of the directing group was
addition to Zn(OTf)2 (20 mol %) [IrCp*Cl2]2 (4 mol %) was used in
instead of [RhCp*Cl2]2.
further defined using a variety of readily functionalizable
4781
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
Scheme 1. C−H Alkynylation Assisted by Heterocyclic
Scheme 2. C−H Alkynylation Assisted by Other
ab
,
a b
,
Directing Groups
Functionalizable Directing Groups
a
Reactions conditions: arene (0.2 mmol), alkyne (0.22 mmol),
[RhCp*Cl2]2 (3 mol %), Zn(OTf)2 (0.024 mmol, 12 mol %), DCE
b
(2 mL), 80 °C, 16 h. Isolated yield after column chromatography.
c
d
AgNTf2 (0.024 mmol) was used in lieu of Zn(OTf)2. Arene (0.26
mmol) and the alkyne (0.2 mmol) were used.
alkynylation products in good yields (3ak, 3al) using Zn(OTf)2
as an additive. These nitrone-alkyne analogues have been
demonstrated by us and others to undergo Au(I)-, Ru(II)-, and
Ir(III)-catalyzed cyclization via an internal redox pathway to
afford useful heterocycles.20 The C−H alkynylation reaction is
readily applicable to a structurally related azomethine imine
(3am) in high yield,21 where the introduction of a meta methyl
group ensured high monoselectivity. Otherwise, both mono
and dialkynylation would occur. The arene substrate is not
limited to derivatives of carbonyl groups. Thus N-nitrosoani-
lines22 coupled with TBDPS-EBX to afford 3an in 64% yield.
Azobenzene (3ao) and azoxybenzene (3ap) also exhibited
comparable reactivity and selectivity. Protic directing groups
that form covalent bonds with rhodium are also applicable.
Acetanilides coupled with monoselectivity, albeit in moderate
isolated yield (3aq, 3ar).
Alkynylation of N-Pivaloyloxybenzamides. This cou-
pling reaction can be further extended to N-pivaloyloxybenza-
mide under modified, basic conditions. Thus product 4a was
isolated in high yield when CsOAc (20 mol %) was used as an
additive in methanol (Scheme 3), and no dialkynylation
product was detected. Under these operationally simple
conditions, a series of N-pivaloyloxybenzamides bearing
electron-donating and -withdrawing groups at different
positions are tolerated, and the products were isolated in
good to high yields (67−89%), although electron-poor N-
pivaloyloxybenzamides tend to react with somewhat lower
efficiency. The arene ring can also be extended to a thiophene
(4h). However, attempts to achieve the C−H alkynylation of
an olefinic substrate failed, and essentially no conversion was
achieved (4i). The synthetically important C(O)NHOPiv
group in these products should allow further diversified
functionalization by Rh(III) catalysis.23 In all cases, the
rhodium catalyst is necessary as evidenced by control
experiments.
a
Reactions conditions: arene (0.2 mmol), R-EBX (0.22 mmol),
[RhCp*Cl2]2 (2 mol %), Zn(OTf)2 (0.02 mmol, 10 mol %), DCE (2
b
mL), 25 °C, 16 h. Isolated yield after column chromatography.
c
d
Reaction was performed at 80 °C. Arene (0.26 mmol) and the
e
alkyne (0.2 mmol) were used. Arene (0.2 mmol) and the alkyne (0.46
mmol) were used.
directing groups under modified conditions with 3 mol % of the
rhodium catalyst (Scheme 2). A series of acetophenone O-
methyl oximes reacted with TBDPS-EBX in the presence of
AgNTf2 additive (80 °C) to afford the monoalkynylation
product in 59−75% yield (3ag−3aj), while lower yields were
obtained when Zn(OTf)2 were applied as an additive. Using
nitrone oxygen as a directing group,19 different N-tert-butyl-α-
phenylnitrones coupled with TIPS-EBX to afford the
Alkynylation of N-Methoxybenzamides by Iridium
Catalysis. Since N-methoxybenzamides are analogues of N-
pivaloyloxybenzamides and are known as important susbstrates
4782
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
Scheme 3. Rh(III)-Catalyzed C−H Alkynylation of N-
Scheme 4. Ir(III)-Catalyzed C−H Alkynylation of N-
a b
,
a b
,
pivaloyloxybenzamides
Methoxycarboxamides
a
Reactions conditions: N-pivaloyloxybenzamide (0.2 mmol), alkyne
(0.22 mmol), [RhCp*Cl2]2 (2 mol %), CsOAc (0.04 mmol, 20 mol
b
%), MeOH (2 mL), 25 °C, 16 h. Isolated yield after column
chromatography.
in C−H activation,24 were attempted the coupling of with
TIPS-EBX under Rh(III)-catalyzed conditions. However, no
desired coupling reaction occurred when the rhodium-catalyzed
conditions in the Scheme 4 were followed. To our delight,
although the [IrCp*Cl2]2 complex failed to catalyze the
alkynylation of 2-phenylpyridines, switching the rhodium
catalyst to this iridium25 congener (4 mol %) in the presence
of AgNTf2 (16 mol %) dramatically improved the reaction
efficiency. Thus the coupling of N-methoxybenzamide with
TIPS-EBX afforded 5a as the major product (68%), and only a
small amount (ca. 5%) of the dialkynylation product was
isolated. Under the iridium-catalyzed conditions, a broad scope
of such benzamides bearing a range of electron-donating and
-withdrawing groups at different positions in the benzene ring
are well-tolerated, and the yield of the isolated product ranges
from 51% to 76%, with no obvious correlation between the
yield and the electronic effect of the substituent. The isolated
yield is even higher for a thiophene-2-carboxamide (5s).
Furthermore, extension to olefinic substrates bearing this type
of directing group proved successful (5t, 5u, 5v), where the
products were isolated in essentially the same range of yield.
This indicates that iridium and rhodium catalysts can offer
complementary results in C−H activation of different
substrates.
Synthetic Applications. Synthetic applications of some
alkynylation products have been demonstrated (Scheme 5).
While desilylation of 3a using TBAF leads to decomposition
due to product instability, protection by N-oxide formation
followed by desilylation affords the terminal alkyne 7 (Scheme
5a). In contrast, alkyne 3ap underwent smooth desilylation to
afford 8, and further metal-free cyclization to indole 9 has been
documented (Scheme 5b).26 Reductive denitrosylation of 3an
yielded aniline 10 in high yield. Desilylation to 10a and
subsequent cyclization with TsN3 followed by acid hydrolysis is
a known procedure to give indolinone 11 (Scheme 5c).27
Treatment of 3ae with NaOEt in DMSO led to removal of the
pyrimidine directing group to afford a protic indole 12 (Scheme
5d). The alkynylated azobenzene 3ao is known to cyclize to an
a
Reactions conditions: arene (0.2 mmol), alkyne (0.22 mmol),
[IrCp*Cl2]2 (4 mol %), AgNTf2 (0.032 mmol, 16 mol %), DCE (2
mL), 30 °C, 16 h. Isolated yield after column chromatography.
b
isoindazole (13) by following a reported sequence (Scheme
5e).28 In addition to these transformations, desilylation of 5a by
TBAF treatment triggered a cyclization to give two isomeric
exocyclized olefins 14 (major) and 14′ (minor) (Scheme 5f).
Kinetic Isotope Effects. Some experiments have been
performed to probe the reaction mechanism (Scheme 6).
When rhodacyclic complex 1529 was applied as a catalyst (4
mol %) to the reaction of 2-(m-tolyl)pyridine and TIPS-EBX
under otherwise the same conditions, product 3a was isolated
in nearly the same yield (Scheme 6a). This suggests that 15 is
likely an active species or a direct precursor and C−H
activation is involved. Thus KIE studies have been performed
to gain further mechanistic details. The intermolecular
competition between 2-PhPy and 2-PhPy-d5 with TMS-EBX
1
at ∼20% conversion gave KIE = 4.8 on the basis of H NMR
analysis. In this experiment TMS-EBX was used to remove
complication of dialkynylation because essentially only the
monoalkynylation product (3l) was generated, although the
eventual isolated yield of this product was only moderate (55%,
Scheme 1). Since TIPS-EBX coupled with higher efficiency
than TMS-EBS, two different KIE measurements using TIPS-
EBX were then performed. In one experiment, under the
intermolecular competitive reaction conditions the coupling of
2-PhPy and 2-PhPy-d5, essentially only the monoalkynylation
product was detected at a low conversion (∼18% after 20 min),
and kH/kD = 5.7 was obtained. In the other experiment, two
independent and parallel coupling reactions of TIPS-EBX with
4783
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
2-PhPy and 2-PhPy-d5 at a low conversion for both experiments
gave kH/kD = 3.0 (Scheme 6b). All these values indicate that the
cleavage of the ortho C−H bond is likely involved in the rate-
limiting step. In line with the KIE values obtained by Rh(III)
catalysis, a KIE = 2.3 was also obtained from the competitive
coupling of PhC(O)NHOMe and PhC(O)NHOMe-d5 by
Ir(III) catalysis.
Scheme 5. Transformations of the Coupled Products
Rhodium Alkynyl Intermediate. We speculated that
rhodium alkynyl species could be an intermediate in the
catalytic cycle. Thus rhodium alkynyl complex 16 was prepared
and was designated as a catalyst (4 mol %) for the coupling of
2-phenylpyridine with TIPS-EBX (Scheme 6c). Indeed, 16
exhibited comparable activity, and traces of the unsymmetrically
dialkynylated product were also detected by GC-MS, indicating
that 16 is probably an intermediate. To probe the relevancy of
any organic radical species, TEMPO and BHT have been
applied as radical inhibitors to the coupling of 2-(m-
tolyl)pyridine and TIPS-EBX. The fact that the yield of the
expected product 3a was only marginally affected by either
reagent (87% and 84%, respectively) suggests that a radical
species seems less likely.
Isolation of Rhodium Vinyl Complex. To delve into the
interaction of a cyclometalated Rh(III) aryl species with the
hypervalent iodine-alkyne substrate, a stoichiometric reaction
has been performed using an equimolar amount of complex 15,
tBu-EBX, and AgNTf2 (Scheme 6d). To our delight, although
no Rh(V) species was obtained, an ester-functionalized Rh(III)
alkenyl complex 17 (Scheme 6d) was isolated in high yield.
Complex 17 was fully characterized by NMR spectroscopy and
1
by X-ray crystallography. In particular, H NMR spectroscopy
revealed the incorporation of a unit of the tBu-EBX, and in the
13C NMR spectrum (CD2Cl2), the Rh−C(vinyl) signal
resonates characteristically at δ = 139.2 (d, JRh−C = 27.8 Hz).
The structure of 17 was unambiguously established by X-ray
crystallography (Figure 1 and the SI), and it adopts a piano-
stool structure bearing an N−C−O tripodal ligand. The Bu
group and the phenylene group stay cis to each other in the
olefin unit.
Scheme 6. Mechanistic Studies
t
Figure 1. Molecular structure of complex 17 (cation only). Thermal
ellipsoids are shown at a level of 30% probability.
Relevancy of the Rhdoium Vinyl Complex in Catalysis.
Although no vinyl ester was observed as a product in the
coupling of arenes with the R-EBX (R = silyl or tBu) substrate,
the relevancy of complex 17 in the catalytic system was
evidenced using complex 17 as a catalyst (4 mol %) for the
coupling of 2-PhPy and TIPS-EBX, from which the
4784
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
dialkynylation product 3t was isolated in 85% yield together
with the monoalkynylation product (7%). Further evidence on
the role of complex 17 follows from the coupling of 2-PhPy and
Ph-EBX, which is known to be a much less efficient alkynylating
reagent likely due to lack of steric stabilization. Switching from
the silyl-EBX to the Ph-EBX substrate gave rise to a less clean
reaction. Nevertheless, a vinyl ester 18 was isolated as a major
product in 25% yield, and the identity of this vinyl ester has
been confirmed by NMR spectroscopy and by a simple
derivatization reaction (eq 1 and SI). These results suggest that
benzoate to afford an isolable rhodium(III) vinyl intermediate
(17). In the case of the coupling for the Ph-EBX substrate,
dechelation of complex 17 followed by coordination of 2-PhPy
and subsequent cyclometalation releases the vinyl ester product
(18).31 Alternatively, for silyl-EBX substrates, alkyne dissocia-
tion from C released the final product together with a Rh(III)
benzoate intermediate D. The catalyst is regenerated when
carboxylate-assisted C−H activation occurs when a coordinated
2-phenylpyridine undergoes subsequent concerted metalation-
deprotonation.18 In pathway (b), transmetalation between A
and the hypervalent iodine affords the alkynyl intermediate 16
and another hypervalent reagent E. Reductive elimination of 16
furnishes the final product and a Rh(I) species, which is
oxidized by the hypervalent iodine reagent E to provide the
same intermediate D. To probe this reductive elimination step,
complex 16 was allowed to decay in CD2Cl2, but essentially no
conversion occurred at 25 °C for 24 h in the presence or
absence of 2-PhPy, which indicates that path (b) is less likely.
A third possible mechanism (Scheme 7, path c) with no
metal alkynyl species is also proposed using acetanilide as a
substrate. Rhodacyclic intermediate A′ may undergo regiose-
lective migratory insertion into the alkyne unit to give an
alkenyl (F), and it should be noted that this regioselectivity is
expected because the alternative insertion selectivity that
generates F′ is both sterically and electronically unfavorable.
The α elimination of 2-iodobenzoate from F is then proposed
to afford a Rh(III) vinylidene intermediate G. 1,2-Migration of
the aryl (generally aryl tends to migrate preferentially to tBu) in
G followed by alkyne decoordination furnishes the coupled
product. This pathway is less likely because in the case of an
acetanilide, the Rh(III) vinylidene G is functionalized with a
proximate nucleophilic group, which should intramolecularly
trap the vinylidene32 to eventually yield an indole product I.
However, no such indole was detected by GC-MS, and the
same scenario applies to PhC(O)NHOPiv (Scheme 3).
Furthermore, the failure to observe any vinyl ether product in
the synthesis of 4a in methanol also argues against this
mechanism because the MeOH solvent may intermolecularly
trap the vinylidene. Therefore, on the basis of our rationale, we
tend to favor the path (a) with a Rh(III)−Rh(V)−Rh(III)
process.
Rh(III) alkenyl complex 17 is likely an intermediate in the
catalytic cycle and different types of products were obtained as
a result of the stereo and electronic effects of the alkynyl group
in the hypervalent iodine-alkyne reagent. To further probe the
relevancy of complex 17 in the catalytic cycle, a stoichiometric
reaction was performed using 17 and 2-PhPy (2.1 equiv) in
DCM (50 °C, 16 h). Only a small amount of the
monoalkynylation product was released from 17 and it was
isolated in 10% yield. This indicates that the tripodal N−C−O
ligand exhibits an inhibitive effect and that the elimination of
the 2-iodobenzoate group is likely involved in the catalytic cycle
(See Scheme 7).
Scheme 7. Mechanistic Proposals
CONCLUSION
■
We have developed the first Rh(III)- and Ir(III)-catalyzed
efficient ortho C−H alkynylation of diversified arenes using
hypervalent iodine-alkyne reagents.33 The reaction conditions
are mild, and both electron-poor and -rich arenes bearing a
broad scope of DGs are viable substrates. Rhodium and iridium
catalysts exhibited complementary substrate scope. In the case
of N-heterocyclic directing groups, both mono- and dialkyny-
lation may occur, and the selectivity is controllable. The
synthetic utility of these alkynylation products has been
demonstrated in synthetically useful derivatization reactions.
A rhodium(III) alkynyl complex and a Rh(III) vinyl complex
have been established as key intermediates. This system is
complementary to previously known systems of C−H
alkynylation of electron-rich (hetero)arenes under Au(I) and
Pd(II) catalysis. The relatively mild conditions, broadly defined
directing groups, tolerance of functional groups, and in some
cases controllability of mono- and diselectivity may allow
opportunity of synthetic applications.
Mechanistic Proposals. Given the observed experimental
results, three possible mechanisms have been proposed
(Scheme 7). In path (a), cyclometalation affords a rhodacyclic
intermediate (A, where X = a weakly coordinating ligand),
which oxidatively adds to the hypervalent iodine to give a
Rh(V)30 alkynyl (B). This oxidative addition could be
facilitated by electrophilic activation of the alkyne reagent by
the zinc or silver salt. Reductive coupling of B generates a
Rh(III) alkyne benzoate intermediate C. This benzoate ligand
is proposed to undergo reversible migratory insertion of the
4785
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
Y.; Tobisu, M.; Chatani, N. Synlett 2012, 23, 2763. (d) He, J.; Wasa,
M.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 3387.
(7) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc.
2002, 124, 8528.
(8) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742.
(9) (a) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250.
(b) Ano, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354.
(10) For reviews, see (a) Zhdankin, V. V.; Stang, P. J. Tetrahedron
1998, 54, 10927. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008,
108, 5299.
(11) For the original synthesis of TIPS-EBX, see: Zhdankin, V. V.;
Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.; Simonsen, A. J. J. Org. Chem.
1996, 61, 6547 The synthesis of EBXs was improved by Waser and
coworkers; see ref 12c.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, spectroscopic data for all new compounds,
and crystallographic data of complex 17 (PDF and CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
xwli@dicp.ac.cn
■
Author Contributions
§These authors contributed equally.
Notes
(12) (a) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed.
2009, 48, 9346. (b) Tolnai, G. L.; Ganss, S.; Brand, J. P.; Waser, J. Org.
Lett. 2012, 15, 112. (c) Brand, J. P.; Chevalley, C.; Scopelliti, R.;
Waser, J. Chem.Eur. J. 2012, 18, 5655. (d) Li, Y.; Waser, J. Beilstein J.
Org. Chem. 2013, 9, 1763. (e) Li, Y.; Brand, J. P.; Waser, J. Angew.
Chem., Int. Ed. 2013, 52, 6743.
(13) Ohta, Y.; Tokimizu, Y.; Ioshi, S.; Fujii, N.; Ohno, H. Org. Lett.
2010, 12, 3963.
(14) (a) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Dalian Institute of Chemical
Physics, Chinese Academy of Sciences and the National Natural
Science Foundation of China (Grant No. 21272231). We thank
Prof. Bo-Lin Lin for help discussions.
̀
2009, 11, 4156. (b) Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed.
REFERENCES
■
2009, 48, 9553. (c) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.;
Miura, M. Chem.Eur. J. 2010, 16, 1772. (d) Berciano, B. P.;
Lebrequier, S.; Besselievre, F.; Piguel, S. Org. Lett. 2010, 12, 4038.
(e) Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868. (f) de Haro, T.;
Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512. (g) Yang, L.; Zhao, L.
A.; Li, C. J. Chem. Commun. 2010, 46, 4184. (h) Brand, J. P.; Waser, J.
Org. Lett. 2012, 14, 744.
(1) (a) Diez-Gonzalez, S. Catal. Sci. Technol. 2011, 1, 166. (b) Palisse,
A.; Kirsch, S. F. Org. Biomol. Chem. 2012, 10, 8041. (c) Alabugin, I. V.;
Gold, B. J. Org. Chem. 2013, 78, 7777. (d) Hu, R.; Lam, J. W. Y.; Tang,
B. Z. Macromol. Chem. Phys. 2013, 214, 175. (e) Chinchilla, R.; Naj
C. Chem. Rev. 2014, 114, 1783.
(2) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084.
́
era,
́
(3) Selected reviews: (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev.
2002, 102, 1731. (b) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu,
J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (c) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2009, 110, 624. (d) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.Eur. J. 2010,
16, 2654. (e) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010, 111, 1293.
(g) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885. (h) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976. (i) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(j) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (k) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc.
Chem. Res. 2011, 45, 788. (l) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S.
Chem. Soc. Rev. 2011, 40, 5068. (m) Cho, S. H.; Kim, J. Y.; Kwak, J.;
Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (n) Chen, D. Y. K.; Youn,
W. S. Chem.Eur. J. 2012, 18, 9452. (o) Yamaguchi, J.; Yamaguchi, A.
D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (p) Wu, X. F.;
Neumann, H.; Beller, M. Chem Rev 2012, 113, 1. (q) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int.
Ed. 2012, 51, 10236. (r) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H.
Chem. Rev. 2012, 112, 5879. (s) Shang, X.; Liu, Z.-Q. Chem. Soc. Rev.
2013, 42, 3253. (t) Yan, G.; Wu, X.; Yang, M. Org. Biomol. Chem.
2013, 11, 5558.
(4) For selected examples, see: (a) Wang, X.; Leow, D.; Yu, J.-Q. J.
Am. Chem. Soc. 2011, 133, 13864. (b) Kuhl, N.; Hopkinson, M. N.;
Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 8230. (c) Wencel-Delord,
J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed.
2012, 51, 2247. (d) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.;
Lan, J.; You, J. Angew. Chem., Int. Ed. 2013, 52, 580. (e) Chatani, N.;
Aihara, Y. Chem. Sci. 2013, 4, 664. (f) Wan, L.; Dastbaravardeh, N.; Li,
G.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 18056.
(5) (a) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc.
2010, 132, 2522. (b) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2010, 12, 2358. (c) Jie, X.; Shang, Y.; Hu, P.;
Su, W. Angew. Chem., Int. Ed. 2013, 52, 3630.
(15) For reviews on Rh(III)-catalyzed C−H activation, see (a) Satoh,
T.; Miura, M. Chem.Eur. J. 2010, 16, 11212. (b) Colby, D. A.; Tsai,
A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2011, 45, 814.
(c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(16) For selected reports on rhodium-catalyzed C−H activation/C−
C coupling with p-bonds, see: (a) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X.
Angew. Chem., Int. Ed. 2013, 52, 6033. (b) Huang, X.; Huang, J.; Du,
C.; Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed. 2013, 52, 12970.
(c) Zeng, R.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2013, 135,
18284. (d) Zhang, X.-S.; Zhu, Q.-L.; Zhang, Y.-F.; Li, Y.-B.; Shi, Z.-J.
Chem.Eur. J. 2013, 19, 11898. (e) Wang, H.; Schroder, N.; Glorius,
̈
F. Angew. Chem., Int. Ed. 2013, 52, 5386.
(17) (a) Xie, F.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 52, 11862.
(b) Zhao, H.; Shang, Y.; Su, W. Org. Lett. 2013, 15, 5106.
(18) For reviews on carboxylate-assisted C−H activation, see:
(a) Ackermann, L. Chem. Rev. 2011, 111, 1315. (b) Ackermann, L. Acc.
Chem. Res. 2014, 47, 281.
(19) For stoichiometric C−H activation of nitrones, see: (a) Yao, Q.;
Zabawa, M.; Woo, J.; Zheng, C. J. Am. Chem. Soc. 2007, 129, 3088.
(b) Zhang, Y.; Song, G.; Ma, G.; Zhao, J.; Pan, C.-L.; Li, X.
Organometallics 2009, 28, 3233. For catalytic C-H activation of using
nitrones as a directing group, see: (c) Qi, Z.; Wang, M.; Li, X. Org.
Lett. 2013, 15, 5440.
(20) (a) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008,
47, 7040. (b) Pati, K.; Liu, R.-S. Chem. Commun. 2009, 5233. (c) Song,
G.; Chen, D.; Su, Y.; Han, K.; Pan, C. L.; Jia, A.; Li, X. Angew. Chem.,
Int. Ed. 2011, 50, 7791. For a review, see: (d) Xiao, J.; Li, X. Angew.
Chem., Int. Ed. 2011, 50, 7226.
(21) (a) Zhen, W.; Wang, F.; Zhao, M.; Du, Z.; Li, X. Angew. Chem.,
Int. Ed. 2012, 51, 11819. (b) Chen, Y.; Wang, F.; Zhen, W.; Li, X. Adv.
Synth. Catal. 2013, 355, 353.
(22) (a) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J. Am.
Chem. Soc. 2012, 135, 468. (b) Liu, B.; Song, C.; Sun, C.; Zhou, S.;
Zhu, J. J. Am. Chem. Soc. 2013, 135, 16625.
(23) Selected examples: (a) Guimond, N.; Gorelsky, S. I.; Fagnou, K.
J. Am. Chem. Soc. 2011, 133, 6449. (b) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (c) Wang,
(6) For a highlight, see: (a) Dudnik, A. S.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2010, 49, 2096. For recent reports, see: (b) Ano, Y.;
Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. (c) Ano,
4786
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787

Journal of the American Chemical Society
Article
H.; Grohmann, C.; Nimphius, C.; Glorius, F. J. Am. Chem. Soc. 2012,
134, 19592. (d) Hyster, T. K.; Knorr, L.; Ward, T. R.; Rovis, T. Science
2012, 338, 500. (e) Ye, B.; Cramer, N. Science 2012, 338, 504.
(f) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135,
5364. (g) Cui, S.; Zhang, Y.; Wu, Q. Chem. Sci. 2013, 4, 3421.
(24) For examples of metal-catalyzed C−H activation of N-
methoxybenzamides, see: (a) Guimond, N.; Gouliaras, C.; Fagnou,
K. J. Am. Chem. Soc. 2010, 132, 6908. (b) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350.
(c) Karthikeyan, J.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50,
9880. (d) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-
Milburn, K. I. Org. Lett. 2011, 13, 5326. (e) Li, B.; Feng, H.; Xu, S.;
Wang, B. Chem.Eur. J. 2011, 17, 12573. (f) Ackermann, L.; Fenner,
S. Org. Lett. 2011, 13, 6548. (g) Karthikeyan, J.; Haridharan, R.;
Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51, 12343. (h) Shi, Z.;
Grohmann, C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5393.
(25) For iridium(III)-catalyzed C−H activation that can give results
complementary to rhodium(III) catalysis, see: (a) Ueura, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2007, 72, 5362. (b) Itoh, M.; Hirano, K.;
Satoh, T.; Shibata, Y.; Tanaka, K.; Miura, M. J. Org. Chem. 2013, 78,
1365. (c) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem.
Soc. 2013, 135, 12861.
(26) Herrero, M. T.; de Sarralde, J. D.; SanMartin, R.; Bravo, L.;
Domínguez, E. Adv. Synth. Catal. 2012, 354, 3054.
(27) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163.
(28) Shirtcliff, L. D.; Weakley, T. J. R.; Haley, M. M.; Kohler, F.;
̈
Herges, R. J. Org. Chem. 2004, 69, 6979.
(29) For the synthesis of complex 15, see: Li, L.; Brennessel, W. W.;
Jones, W. D. Organometallics 2010, 29, 4593.
(30) For examples of Rh(V) species, see: (a) Duckett, S. B.; Perutz,
R. N. Organometallics 1992, 11, 90. (b) Wan, X.; Wang, X.; Luo, Y.;
Takami, S.; Kubo, M.; Miyamoto, A. Organometallics 2002, 21, 3703.
(c) Vyboishchikov, S. F.; Nikonov, G. I. Organometallics 2007, 26,
4160.
(31) The formation of product 18 via a postcoupling hydro-
esterification reaction between 2-iodobenzoioc acid and a putative
alkyne intermediate has been ruled out. Ester 18 was still isolated as
the major product from the reaction of 2-PhPy, Ph-EBX, and 2-iodo-5-
methylbenzioc acid (1 equiv); essentially no ester product
incorporating the 2-iodo-5-methylbenzioc acid unit was obtained.
(32) For intramolecular trapping of vinylidenes by OH or NH
groups, see: (a) O’Connor, J. M.; Hiibner, K.; Closson, A.; Gantzel, P.
Organometallics 2001, 20, 1482. (b) Chin, C. S.; Kim, M.; Lee, H.;
Noh, S.; Ok, K. M. Organometallics 2002, 21, 4785. (c) Li, X.; Vogel,
T.; Incarvito, C. D.; Crabtree, R. H. Organometallics 2005, 24, 62.
(d) Kumaran, E.; Fan, W. Y.; Leong, W. K. Org. Lett. 2014, 16, 1342 .
Note that in ref 32c, a hydroxyl group can even effectively trap an Ir-
bound vinylidine in the presence of an iridium hydride; no hydride
migration was detected..
(33) During the revision of the manuscript, the Loh group reported
(February 7, 2014) a similar system of Rh(III)-catalyzed C−H
alkynylation of N-pivaloyloxybenzamides using the same alkyne
reagents. See: Feng, C.; Loh, T. P. Angew. Chem., Int. Ed. 2014;
DOI: 10.1002/anie.201309198, where only N-pivaloyloxybenzamide
substrates were studied. Right after the publication of this article,
Glorius reported a related alkynylation of almides: see Collins, K. D.;
Lied, F.; Glorius, F. Chem. Commun. 2014; DOI: 10.1039/
C4CC01141D.
4787
dx.doi.org/10.1021/ja501910e | J. Am. Chem. Soc. 2014, 136, 4780−4787