Oxidatively Induced Reductive Elimination: Exploring the Scope and Catalyst Systems with Ir, Rh, and Ru Complexes

Article abstract of DOI:10.1021/jacs.9b00364

Direct conversion of C-H bonds into C-C bonds is a promising alternative to the conventional cross-coupling reactions, thus giving rise to a wide range of efficient catalytic C-H functionalization reactions. Among the elementary stages in the catalytic C-

Full text of DOI:10.1021/jacs.9b00364

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Article
Oxidatively Induced Reductive Elimination: Exploring the
Scope and Catalyst Systems with Ir, Rh, and Ru Complexes
Jinwoo Kim, Kwangmin Shin, Seongho Jin, Dongwook Kim, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Feb 2019
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Oxidatively Induced Reductive Elimination: Exploring the
Scope and Catalyst Systems with Ir, Rh, and Ru Complexes
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Jinwoo Kim,†,‡,§ Kwangmin Shin,‡,§ Seongho Jin,†,‡ Dongwook Kim,‡ and Sukbok Chang*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
‡Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon 34141, South Korea
Supporting Information
ABSTRACT: Direct conversion of C–H bonds into C–C bonds is a promising alternative to the conventional cross-coupling
reactions, thus giving rise to a wide range of efficient catalytic C–H functionalization reactions. Among the elementary stages
in the catalytic C–C bond formation, reductive elimination constitutes a key step of the catalytic cycle, and, therefore, extensive
studies have been made to facilitate this process. In this regard, oxidation on the metal center of a post-transmetalation
intermediate would be an appealing approach. Herein, we have explored the substrate scope, catalyst systems, and oxidation
tools to prove that the oxidatively induced reductive elimination (ORE) plays a critical role in the product-releasing C–C bond
formation. Notably, we have demonstrated that ORE broadly operates with a series of half-sandwich d6 Ir(III)-, Rh(III)-, and
Ru(II)-aryl complexes. We have described that the metal center oxidation of the isolable post-transmetalation intermediates
by means of chemical- or electro-oxidation can readily deliver the desired arylated products upon reductive elimination even
at ambient temperature. Computation studies delineated the thermodynamics of the reductive elimination, where the activation
barriers are shown to be significantly reduced upon increasing the oxidation states of the intermediates. We were also
successful to corroborate this ORE in the corresponding Rh-methyl complex. In addition, catalytic conditions were optimized
to incorporate this mechanistic understanding into the Ir, Rh, and Ru-catalyzed C–C bond formations under mild conditions.
Rh(III), and isoelectric Ru(II) systems in regard to the
oxidatively induced reductive elimination process.9-11 It
was revealed that ORE operates commonly in each metal
system, eventually leading to mild catalytic C–H arylation
reactions.12 Significantly, the key post-transmetalation
intermediates of Ir-, Rh-, and Ru-complexes were isolated
and fully characterized by X-ray diffraction analysis.
Cyclic voltammetry studies and DFT calculations strongly
support the experimental results that oxidation of those
transmetalation intermediates does facilitate the otherwise
demanding reductive elimination process. An analogous
mechanistic study on the C–H methylation was also
performed on a Rh system to prove that the high-valent
pathway also operates in this case. Finally, we have
demonstrated that the ORE pathway can be applied to the
Ir, Rh, and Ru catalytic systems under mild conditions.
INTRODUCTION
Transition metal-catalyzed C–H bond activation and
subsequent oxidative C–C bond formation using
organometallic carbon nucleophiles has emerged as a
promising alternative to the conventional cross-coupling
procedures,1 leading to a more straightforward synthetic
route to introduce carbon moieties.2 On the basis of the
well-established elementary steps in palladium catalysis in
particular, the C–C bond formation has been postulated to
proceed via transmetalation followed by direct reductive
elimination (Scheme 1a, top).3 On the other hand, an
alternative high-valent pathway, where the reductive
elimination is enabled by oxidation of the metal center of
key post-transmetalation intermediate, has been
appreciated in catalysis recently (Scheme 1a, bottom).4 It
is noteworthy in that oxidative promotion of otherwise
challenging reductive elimination process has long been
documented albeit mainly in a stoichiometric manner.5,6
In this context, we recently reported that the oxidatively
induced reductive elimination (ORE) pathway operates in
the Cp*Ir(III)-catalyzed C(sp2)–H arylation with
arylsilanes by the action of suitable oxidants (Scheme
1b).7 Along with our continuous interests in the
intermediacy of high-valent species in C–H
functionalizations,8 this finding called into further
question whether ORE can be extended and generalized
into other catalyst systems. Herein, we present detailed
studies on the exploration of substrate scope, catalyst
systems, and oxidation tools (Scheme 1c). In particular,
we have investigated the comparative behaviors of Ir(III),
RESULT AND DISCUSSION
At the outset of this study, we initially performed
computational analysis to validate the feasibility of the
envisioned oxidatively induced reductive elimination of
the presupposed transmetalated intermediates (Figure 1).
As the model post-transmetalation complexes, we
envisioned to investigate Cp*Ir(III), Cp*Rh(III), and (p-
cymene)Ru(II)-aryl complexes, presumably obtainable
from a cyclometalation of benzo[h]quinoline (1a) and
subsequent transmetalation of an aryl group (Ir-Ar, Rh-
Ar, and Ru-Ar, respectively). DFT calculations on these
presupposed species were first carried out to see whether
oxidation can take place on the metal center. Indeed, the
complex Ir-Ar revealed a metal-centered HOMO, and,
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moreover, expulsion of one electron from this neutral
the neutral and singly-oxidized cationic species,
respectively. These computational results suggest that the
one-electron oxidation of the presumed Rh- and Ru-aryl
complexes occurs indeed at the metal center. The orbital
analysis revealed that the HOMO of each transmetalation
intermediate constitutes nonbonding metal d orbitals.
species provided metal-centered β-LUMO, thereby
suggesting that the first oxidation of the iridacycle occurs
at the Ir-metal center. Moreover, the corresponding
analogues derived from Cp*Rh(III) and (p-cymene)Ru(II)
(Rh-Ar and Ru-Ar) also exhibited the similar behavior on
the metal-centered HOMO and β-LUMO configuration in
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Scheme 1. Oxidatively induced reductive elimination for d6 Ir-, Rh-, and Ru-catalyzed C–C bond formation.
(a) Plausible reaction pathways for TM-catalyzed C–C bond
(b) Previous work: Oxidatively induced Ir-catalyzed C–H arylation
formation with aryl/alkyl nucleophiles
using arylsilane
Me
Me
via 'Direct reductive elimination'
Me
Me
Ar Si(OEt)
-
O
NHR
H
3
O
NHR
Me
IrIII
cat. Cp*IrIII
(generally proposed)
heat
X
O
Ar
THF, 25 o
C
RHN
Ar
Isolated
Me
cat. [M]
DG
DG
DG
C
L
R
[M']
Mn
C
H
C R
R
Me
Facile R.E.
DG
C
L
[Ox.]
Me
Me
Mn+m
Through high-valent
Ir species
Me
IrIV
[Ox.]
R
DG
Ar
via 'Oxidatively induced reductive elimination'
C
(still elusive)
(c) This work: Mechanistic studies on Ir-, Rh-, and Ru-catalyzed C–H aryl-/alkylation via 'oxidatively induced reductive elimination' pathway
ligand
DG
Ru
Rh
Ir
DG
H
Ar B(OR)2
or
[M]
[O]
n
M
M =
+
DG
R
R
H3C B(OR)2
C
Ar Me
=
R
Characterized
High E barrier
Facile R.E. at r.t.
m+
ligand
ligand
[Ox.]
n+m
n
M
DG
M
DG
R
R
DG
DG
C
C
m = 1 or 2
R
R
ORE in d6 Ir, Rh, and Ru systems
Isolation & characterization of intermediates
Application to catalytic conditions




Theoretical rational with DFT calculation
Figure 1. Preliminary DFT calculation study on model substrates. (a) Kohn-Sham orbital plots of HOMO of the postulated
post-transmetalation intermediates (left) and β-LUMO of the singly-oxidized cationic species (right). Isovalue = 0.1. (b)
Orbital diagram of Ir-aryl species Ir-Ar. (c) NBO charge change upon oxidation of intermediate Ir-Ar. For orbital analysis
and NBO charge change for Rh and Ru analogues, see the Supporting Information.
(a)
m = 0, HOMO
m = 1, -LUMO
(b)
m+
d
x
2-y2
2
- e-
Ir(III+m)
N
d
z
CF3
HOMO
CF3
dxy dyz
Ir-Ar
LAr

N
LBQ

dxz
Ar
Ir
m+
C
z
- e-
N
Rh(III+m)
HOMO-9
y
x
N
HOMO-11
CF3
Rh-Ar
(c)
0.103
0.294
-0.053
-0.030
m+
IrIII
- e-
IrIV
- e-
N
N
Ru(II+m)
N
CF3
CF3
CF3
Ru-Ar
-0.064
0.014
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Furthermore, the NBO charge of each metal center was
their 13C NMR chemical shift at δ 147.5 and δ 166.4 ppm
(doublet, 1JRh-C = 36.7 Hz) in CD2Cl2, respectively.
Encouraged by the successful isolation of Ir- and Rh-
aryl species, we also attempted to capture an isoelectric
(p-cymene)Ru(II)-aryl analogue. We were delighted to
see that the proposed transmetalation also operates albeit
under slightly modified conditions, providing the desired
aryl ruthenacycle Ru-Ar in 77% yield (Scheme 3b). 13C
NMR signal of the transmetalated aryl ipso carbon
appeared at δ 170.0 ppm. It should be mentioned that the
transmetalation of in situ generated aryl borate did not take
place in the absence of copper species, leading us to
assume that Cu-aryl species forms first and subsequently
transfers its aryl moiety to the metallacycles (M-OTFA,
M: Ir, Rh, and Ru) to produce the desired post-
transmetalation intermediates (M-Ar, M: Ir, Rh, and
Ru).14
calculated to be significantly increased upon oxidation
(from 0.103, 0.058, and -0.211 to 0.294, 0.232, and 0.142
for Ir, Rh, and Ru species, respectively) while that of two
metal-bonded carbons was relatively less sensitive to the
oxidation, further substantiating the metal-centered
oxidation in those model complexes (See the Supporting
Information for details).
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Scheme 2. Preparation of pre-transmetalation
complexes.
(a)
AgOTFA (4.0 eq.)
M
N
Li2CO3 (2.0 eq.)
OTFA
[Cp*MCl2]2
N
+
CH2Cl2 (0.03 M)
25 °C, 24 h
1a
(2.0 eq.)
M = IrIII 86%
RhIII 60%
M = Ir Ir-OTFA
Rh Rh-OTFA
(b)
Scheme 3. Preparation of Ir-, Rh- and Ru-aryl species.
Ru
Above conditions
N
1a
(2.0 eq.)
[(p-cymene)RuCl2]2
+
OTFA
O
B
O
Me
(2.0 eq.)
Me
(a)
60%
F3C
2a
Cu(OAc)2 (50 mol %)
Ru-OTFA
M
M
(nBu)4NF·xH2O (2.0 eq.)
N
N
OTFA
THF, 25 oC, 12 h
M = IrIII 77%
RhIII 89%
After obtaining the theoretical insights, we next
attempted to capture experimentally the postulated key
transmetalation intermediates. As the first step,
metallacycles were prepared from stoichiometric
cyclometalation reactions of Ir, Rh, and Ru metal
precursors with benzo[h]quinoline (Scheme 2),13 and the
corresponding neutral metallacyclic compounds Ir-
OTFA, Rh-OTFA, and Ru-OTFA were isolated in
reasonable yields. As the next step, stoichiometric
transmetalation of aryl group was tried. Among various
arylating agents examined, we were pleased to find that
arylboronic esters were readily transmetalated to the
metallacycles. (4-Trifluoromethyl)phenyl neopentyl-
glycol borate (2a) as a representative coupling partner was
found to smoothly react with metallacycles Ir-OTFA and
Rh-OTFA in the presence of Cu(OAc)2 (0.5 equiv) and
ammonium fluoride promoter (TBAF, 2.0 equiv) to form
the corresponding post-transmetalation intermediates Ir-
Ar and Rh-Ar in 77% and 89% yields, respectively
(Scheme 3a). Significantly, both complexes were stable
upon exposure to air for a few weeks. The ipso carbon of
the transmetalated aryl group of Ir-Ar and Rh-Ar showed
CF3
M = Ir Ir-OTFA
Rh Rh-OTFA
M = Ir Ir-Ar
Rh Rh-Ar
O
O
Me
(2.0 eq.)
Me
(b)
F3C
B
2a
Cu(OAc)2 (50 mol %)
tBuOK (2.0 eq.)
Ru
Ru
N
N
OTFA
THF, 25 oC, 12 h
77%
CF3
Ru-OTFA
Ru-Ar
The structure of all three transmetalated metal-aryl
complexes were unambiguously determined by single
crystal X-ray diffraction analyses (Figure 2). In Ir-Ar, the
distance between the Ir center and ipso carbon of the
transmetalated aryl group is 2.050(2) Å, being similar to
that of the previously reported analogous benzamide
complex (2.050 Å).7 Bond length of the metal–C(aryl)
bond of the corresponding Rh and Ru species is 2.035(2)
Å and 2.071(2) Å, respectively, and that between metal
center and benzo[h]quinolinyl carbon is in a similar range
for all three metal complexes.
(a)
(b)
(c)
Estimates
Estimates
2.0349(19) Å
Estimates
Ir–C(Ar)
2.050(2) Å
2.055(2) Å
Rh–C(Ar)
Ru–C(Ar)
Ru–C(BQ)
2.071(2) Å
2.059(2) Å
Ir–C(BQ)
Rh–C(BQ) 2.0478(18) Å
C(Ar)-Rh-C(BQ) 85.85(7)°
C(Ar)-Ir-C(BQ) 85.67(9)°
C(Ar)-Ru-C(BQ) 86.21(8)°



Figure 2. ORTEP diagrams of (a) aryl iridacycle Ir-Ar, (b) aryl rhodacycle Rh-Ar, and (c) aryl ruthenacycle Ru-Ar. (50%
probability ellipsoids for each species). Hydrogen atoms were omitted for clarity.
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The C–M–C angles are 85.67(9)°, 85.85(7)°, and
86.21(8)° for M = Ir, Rh, and Ru, respectively, revealing
a pseudo-octahedral geometry. Unlike Ir-Ar and Rh-Ar,
the aryl group of Ru-Ar is slightly bent toward the p-
cymene ligand showing M–C(ipso)–C(-CF3) = 166.3o.15
It should be emphasized that, to our best knowledge, Rh-
Ar represents the first example of such isolated
transmetalated species obtained from Cp*Rh(III)
derivatives while Rh(III)-catalyzed direct C–H arylation
with aryl nucleophiles has been known.9d,f,g,16 Likewise, to
our best knowledge, transmetalation of an aryl group on
the cyclometalated Ru(II) center has not been documented
despite of the widely reported Ru-catalyzed biaryl
coupling reactions.9a,k
and Ru-aryl complexes, we attempted to validate our
initial working hypothesis that oxidation of the post-
transmetalation complexes can facilitate the desired
reductive elimination to release the C–C coupled product.
Referring to the known oxidation potential of AgI (E1/2
=
0.41 V vs. Fc/Fc+ in THF), it was predicted that a silver(I)
oxidant can generate the postulated high-valent
metallacycle species from the isolated Ir-, Rh-, and Ru-
aryl intermediates.19 Indeed, when complexes Ir-Ar, Rh-
Ar, and Ru-Ar were treated with AgOTFA (2.2 equiv) in
THF solvent at room temperature, reductive elimination
occurred smoothly in all cases, and the desired arylated
product 3a was provided in 70%, 97%, and 92% yield,
respectively. In stark contrast, reductive elimination did
not take place even at 80 °C under oxidant-free conditions,
while the post-transmetalation species remained intact.
Importantly, the use of 1.0 equiv of AgOTFA gave rise to
3a in 64%, 69%, and 74% yields from Ir-Ar, Rh-Ar, and
Ru-Ar, respectively, implying that the reductive
elimination is induced by single-electron oxidation.
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(a)
Ru
N
Rh
Ir
N
N
E1/2(Ag/Ag+)
CF3
CF3
CF3
(0.41)
Epa(Ru-Ar)
Epa(Rh-Ar)
Epa(Ir-Ar)
(0.164)
(0.331)
(0.406)
Table 1. Stoichiometric ORE of Ir, Rh, and Ru-aryl
species in the presence of Ag(I) oxidant.
+
Potential(V vs. Fc/Fc , THF)
0.1
0.2
0.4
0.3
0.5
m+
(b)
Cp* or p-cymene
Cp* or p-cymene
Ar
N
Mn
M(n+m)
AgOTFA
N
N
Ar
Ar
THF
T, 12 h
Mn = IrIII, RhIII, RuII
20 A
3a
m = 1 or 2
Ar = (4-CF3)C6H4
heat, 80 °C
Yield (%)a
Rh-Ar Ru-Ar
Ag
T
Entry
(equiv) (°C)
Ir-Ar
70
1
2
3
2.2
1.0
-
25
25
80
97
60
92
74
64
n.d.b
n.d.
n.d.
Figure 3. (a) Comparison of the first Epa values for Ir, Rh,
and Ru aryl species in THF. (b) Narrow potential window
CV of Ir, Rh, and Ru aryl species around the first oxidation
potential. (scan rate = 800 mV/s)
aYield was determined by H NMR spectroscopy using 1,1,2,2-
1
tetrachloroethane as an internal standard. bn.d., not detected.
For a quantitative evaluation on the current oxidative
acceleration of the reductive elimination from the post-
transmetalation intermediates, we performed DFT
To investigate redox behavior of the obtained post-
transmetalation complexes, a series of cyclic voltammetry
studies were conducted (Figure 3, and also see the
calculations (Figure 4). As anticipated, the activation
‡
barrier (ΔGRE
) was calculated to be decreased
Supporting
Information
for
details).
Cyclic
voltammogram of Ir-Ar showed the first quasi-reversible
redox event at E1/2 = 0.325 V (Epa = 0.406 V, scan rate =
800 mV/s), which was tentatively assigned to the IrIII/IrIV
redox couple.7 The second irreversible oxidation was
measured at Epa = 0.821 V (800 mV/s), which was
assigned to the oxidation of IrIV species to IrV. On the other
hand, CV of Rh-Ar displayed a single irreversible
oxidation peak at Epa = 0.331 V (800 mV/s).17 Finally, CV
of Ru-Ar revealed a single oxidation wave at Epa = 0.164
V (800 mV/s), indicating that this complex tends to be
more easily oxidized compared to the Ir and Rh
counterparts. At this stage, it is not clear whether these
irreversible redox events are related to single-electron
transfer or two-electron oxidation due to the potential
inversion.18
dramatically upon oxidation of the metal centers. For
instance, the postulated reductive elimination requires
41.2, 19.1, and 5.6 kcal/mol starting from IrIII, IrIV, and
IrV-aryl precursors, respectively. Likewise, ΔGRE‡ of Rh-
Ar and Ru-Ar was also significantly reduced upon
metallic oxidation of the transmetalation complexes. In
the case of Rh-Ar, it was shown to change from 28.9
kcal/mol (RhIII) to 9.4 kcal/mol (RhIV), thus suggesting a
facile reductive elimination from the supposed Rh(IV)
precursor even at ambient temperature.20 The energy
barrier for the reductive elimination from Ru-Ar was also
‡
mitigated upon oxidation: ΔGRE = 33.9, 14.8, and 8.9
kcal/mol from RuII, RuIII, and RuIV species, respectively.
These computational estimations are fully consistent with
the experimental results in Table 1.
Having identified the redox behaviors of the Ir-, Rh-
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‡
m+
TS-RE
TS-RE
Cp* or p-cymene
TS-RE
CF3
Mn+m
‡
GRE
M-Pdt
M-Pdt
N
GRE
8
M-Ar
M-Ar
9
C–C Bond length of the
transtion state
Activation energy for the
reductive elimination
Reductive elimination
exothermicity
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(a)
(b)
(c)
IrIII(41.2)
m+
RuII(33.9)
Cp* or p-cymene
RhIII(28.9)
Mn+m
IrIV(19.1)
N
RuIII(14.8)
RhIV(9.4)
RuIV(8.9)
CF3
IrV(5.6)
m = 0 to 2
RhV(0.6)
M-Ar
Figure 4. Representative data of calculated energy profiles for reductive elimination from Ir, Rh, and Ru-aryl intermediates
with different oxidation states. (a) The activation barriers for reductive elimination from neutral, cationic, and dicationic Ir,
Rh, and Ru-aryl species. Note its decreasing tendency along the increase in the metal oxidation state. (b) Energy difference
between each metal-aryl complex and the reductive elimination product. (c) The distance between ipso carbons of
benzo[h]quinoline and (4-trifluoromethyl)phenyl moiety in each transition state. See the Supporting Information for the detail.
Upon oxidation of the metal center, the reductive
elimination process was calculated to become exothermic
with more negative ΔGRE (Figure 4b). Along with this, the
distance between two ipso carbons (benzo[h]quinolinyl
and transmetalated aryl moieties) in the transition state
was more elongated at the higher oxidation, thus leading
to more reactant-like transition state structure according to
the Hammond postulate (Figure 4c). With the above
computational results altogether that reduction in ΔGRE
reversal in the exothermicity, and change in the transition
state geometry, it strongly supports that the reductive
elimination is indeed promoted both kinetically and
thermodynamically upon oxidation.
pathway where reductive elimination takes place right
after the transmetalation, we propose an alternative high-
valent pathway in the presupposed Ir-, Rh-, and Ru-
catalyzed C–H arylation. We surmised that if each
mechanistic step, cyclometalation, transmetalation, and
reductive elimination, takes place in concordance with
each other, the catalytic cycle will successfully operate to
provide C–H arylated product.
‡
,
Table 2. Catalytic C–H arylation via oxidatively induced
reductive elimination pathway.a
25~50 °C
O
IrIII
RhIII
RuII
N
B
+
O
N
Scheme 4. Catalytic cycle for the oxidatively induced
X
reductive elimination.
3a-c
1a
2a X =CF3
X
2b
CH3
Br
1a
2c
Mn
Cyclometalation
T
(°C)
Yield
(%)
[Ox.]
Entry
X
Catalyst
[Cp*IrCl2]2
[Cp*RhCl2]2
N
L
Mn
L
1
2
CF3
CF3
25
25
25
50
25
25
50
25
25
50
75
75
38b
60b
66
Mn-1
3
CF3 [(p-cymene)RuCl2]2
CF3 [(p-cymene)RuCl2]2
Mn-2
ArB(OR)2, CuII
Transmetalation
4
3a
5
Br
Br
[Cp*IrCl2]2
[Cp*RhCl2]2
RE
N
3a
Low-valent
pathway
L
6
81
65b
Mn
Ar
RE
7
Br
[(p-cymene)RuCl2]2
[Cp*IrCl2]2
Ar = (4-CF3)C6H4
8
CH3
CH3
95
N
L
[Ox]
Mn+1
9
[Cp*RhCl2]2
90
16b
Ar
High-valent
pathway
10
CH3 [(p-cymene)RuCl2]2
aReaction conditions: 1a (0.10 mmol), 2 (2.0 equiv), catalyst (5
mol %), AgNTf2 (20 mol %), Cu(OAc)2 (50 mol %), AgF (2.2
equiv) in THF/TFE (1:1, 0.5 mL), 12 h. Yields were determined
by H NMR spectroscopy using 1,1,2,2-tetrachloroethane as the
internal standard. Ag2O (2.2 equiv) and Cu(OTf)2 (50 mol %)
Based on the above mechanistic descriptions, we
envisaged that oxidatively induced reductive elimination
(ORE) would be operative even in the catalytic C–H
arylation of benzo[h]quinoline with arylboronic esters
(Scheme 4). Instead of the generally accepted low-valent
1
b
were used instead of AgF and Cu(OAc)2
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To see the feasibility of the postulated high-valent
eventually giving rise to a broadly applicable C–H
arylation procedure in catalytic cycle. We thus examined
direct C–H arylation on various substrates using
arylboronic ester coupling partner with Cp*Ir(III) as the
representative catalyst system (Scheme 5).9e,23 Pleasingly,
a wide range of substituted phenyl boronic esters were
smoothly reacted with benzo[h]quinoline (1a) at room
temperature irrespective their electronic variation (3a–3d).
Pyridyl and amide moieties were found to be effective
directing groups (3e–3f). Olefinic C–H arylation
proceeded stereoselectively under the present conditions
(3g). Quinoline N-oxide was arylated exclusively at the C-
pathway in catalytic systems, we preliminarily examined
C–H arylation of benzo[h]quinoline (1a) with
representative aryl borates (2) by employing each Ir, Rh,
and Ru catalyst in the presence of silver(I) oxidant (Table
2). Reaction of 1a with 2a (X = CF3) took place smoothly
at room temperature with Cp*Ir(III) or Cp*Rh(III)
catalysts in the presence of Cu(OAc)2 transmetalating
reagent, providing 75% yield of 3a in each case (entries
1–2). On the other hand, the same reaction with (p-
cymene)Ru(II) catalyst was a bit sluggish (entry 3), thus
requiring slightly elevated temperature (50 °C) to obtain
3a in 60% by using Ag2O and Cu(OTf)2 instead of AgF
and Cu(OAc)2 (entry 4).21 Variation on the substituents of
arylboronic esters was then briefly examined (entries 5–
10). p-Bromophenyl moiety was transferred without
difficulty under the catalytic conditions using Ir, Rh, and
Ru catalysts, yielding 66%, 81%, and 65% of 3c (entries
8–10). On the other hand, in case of p-tolyl boronic ester
2b, Ru catalyst was less effective than Ir or Rh systems 3c
(entries 8–10).22
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position at ambient conditions to afford the
corresponding product 3h in high yield. Substrates bearing
weak coordinating groups participated efficiently in the
C–H arylation but at slightly higher temperature (50 °C).
For instance, α-tetralone was arylated selectively at the
peri position in reasonable yield (3i). Biologically relevant
chromone was also effectively arylated to give 3j in 81%
yield. In the same line, propiophenone and 1-
acetylcyclohenene were reacted with aryl borate under the
present Ir catalytic conditions to afford 3k and 3l,
respectively. Notably, this reaction represents the first
example of Ir-catalyzed direct C–H arylation using
arylboronic esters. In addition, the Ir catalyst system
displayed high compatibility with diverse directing groups
for the C–H arylation when compared to the
corresponding Rh or Ru systems. It should be mentioned
that Sorensen et al. reported an Ir(III)-catalyzed C–H
alkylation of aromatic aldehydes using alkylboron
reagents.24
Our current working hypothesis that product-releasing
reductive elimination is enabled by the oxidation of metal
center of transmetalated intermediates led us next to
surmise that external electric potential may also induce the
same ORE process.4h,6b,25 As a preliminary study, we
briefly performed an electrolysis of Ir-Ar in 0.3 M
nBu4NPF6 electrolyte solution (Scheme 6). To minimize
side reactions presumably arising from excessive potential,
we arbitrarily chose the external potential as an average
value of the first anodic peak Epa (50 mV/s) and the onset
potential Eonset. We were delighted to find that the desired
reductive elimination of Ir-Ar did occur by the electro-
oxidation to afford the C–H arylated product 3a in
quantitative yield. Without the electric potential, no
conversion was observed even in the prolonged time.26
Scheme 5. Effect of directing groups in the Cp*Ir-
catalyzed C–H arylation with ArB(OR)2.a
[Cp*IrCl2]2 (5 mol %)
AgNTf2 (20 mol %)
AgF (2.2 eq.)
DG
H
DG
Ar
Cu(OAc)2 (50 mol %)
O
B
+
PhCF3/TFE, 25 o
C
Ar
O
1
2
3
Substrate
Product
N
Substrate
Product
X
N+
O-
N
H
N+
O-
H
1h
3h:
84%
CF3
1a
3a X = CF3 93%
3b
3c
3d
Me 98%
Br 96%
Cl 98%
H
H
O
O
b
1i
1j
3i
3j
: 72%
O
CF3
N
N
O
O
H
O
1e
3e
: 69%
CF3
b
: 81%
CF3
O
O
O
tBu
tBu
N
H
O
N
O
H
H
1f
3f
: 77%
CF3
H
b
1k
3k
: 59%
CF3
O
tBu
Scheme 6. Preliminary study for electrolytic reductive
elimination through oxidatively induced pathway.
tBu
O
N
H
O
N
H
nPr
3g
H
nPr
1g
CF3
: 53%
H
b
1l
3l
: 62%
CF3
N
Ir
N
aReaction conditions: 1 (0.10 mmol), 2 (2.0 equiv), catalyst (5
0.3 M TBAPF6,
THF:TFE=1:1
const. E
mol %), AgNTf2 (20 mol %), Cu(OAc)2 (50 mol %), and AgF (2.2
CF3
3a
o
equiv) in PhCF3/TFE (1:1, 0.5 mL) for 12 h at 25 C. Isolated
CF3
yields are reported. bRun at 50 °C.
25 °C
, 6 h
E > Eonset quant
No potential not detected
Ir-Ar
We subsequently wondered whether arylboronic esters
can also be transmetalated to metallacycles obtainable
from substrates bearing various directing groups, thus
Encouraged by the successful demonstration on the
oxidatively induced reductive elimination in the above
catalytic C–H arylation with Ir, Rh, and Ru catalyst
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systems, we next wondered whether the similar high-
Me was performed (Figure 6). As anticipated, the energy
barrier for this reductive elimination from Rh-Me was
found to be dramatically reduced upon increasing the
valent pathway would work also in a C–H methylation
reaction.27 We first attempted to synthesize a metallacycle
methyl complex for a model study.28 Pleasingly, when
Rh-OTFA was treated with 2,5,5-trimethyl-1,3,2-
dioxaborinane (4) in the presence of tBuOK at room
temperature, a cyclometalated rhodium-methyl complex
Rh-Me was formed and isolated in 48% yield (Scheme 7).
‡
oxidation state (ΔGRE = 28.5, 8.6, and 0.8 kcal/mol for
RhIII, RhIV, and RhV, respectively). As a result, it implies
that the C–C bond formation from RhIII-Me is challenging
but that it will be much more facile at the higher oxidation
states. The reductive elimination process becomes more
exothermic as the oxidation state of the rhodium center of
Rh-Me increases, suggesting that as in the case of Rh-Ar,
the product-forming reductive elimination is more feasible
thermodynamically and kinetically upon oxidation. In
accordance with the Hammond postulate, the transition
states for the reductive elimination also display longer
C(sp2)–C(methyl) distance as the oxidation state of the
metal center increases, being reminiscence to the reactant
metallacycle.
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The transmetalated methyl group displayed characteristic
1
doublets in H and 13C NMR spectra at  -0.40 (2JH-Rh
=
2.40 Hz) and  -1.94 (1JC-Rh = 27.94 Hz) ppm in CD2Cl2,
respectively. This Rh-Me complex was observed to be
stable under air exposure for several weeks. It is
interesting that, unlike the aryl group transfer to Rh-
OTFA (Scheme 3a), copper additive was not required in
the transmetalation of the methyl group. Although the
exact mechanism of this methyl transmetalation is not
fully understood at the present stage, we tentatively
assume that it may be attributed to the relatively electron-
rich property of the methyl group.16,29 It should be
mentioned that the transfer of a methyl group from boronic
esters to a Cp*-rhodacycle has not been reported, and to
our best knowledge, this represents the first example of
isolating a rhodacycle methyl complex.
Rh
N
Me
Scheme 7. Preparation of Rh-Me using methyl boronic
ester.
Rh-Me
Estimates
O
Me
Me
Me
B
Rh–CH3
2.175(6) Å
2.085(6) Å
4
(2.0 eq.)
Rh–C(sp2)
O
C(sp2)-Rh-C(Me) 85.1(4)°
tBuOK (2.0 eq.)

Rh
Rh
N
N
THF, 25 oC, 12 h
Me
OTFA
48%
Figure 5. ORTEP diagram of methyl rhodacycle Rh-Me.
(50% probability ellipsoids for each species). Hydrogen
atoms were omitted for clarity.
Rh-OTFA
Rh-Me
Structural analysis of the newly prepared Rh-Me
complex was next carried out with measurement of its
electrochemical behavior. The solid structure of Rh-Me
was determined by a single crystal XRD analysis (Figure
5). The Rh–C(methyl) bond length is 2.175(6) Å, slightly
longer than Rh–C(aryl) distance of the aryl counterpart
(Figure 2b), and the C(sp2)–M–C(methyl) angle of Rh-Me
‡
n+
n+
Rh(III+n)+
Rh(III+n)+
N
Rh(I+n)+
CH3
CH3
N
N
CH3
Rh(III+n)-Me
Rh(I+n)-Pdt
TS-RE
TS-RE(31)
(28.5)
is 85.1(4)°, thus displaying
a
pseudo-octahedral
RhI-Pdt
(24.5)
TS-RE(42)
(8.6)
pianostool structure. The cyclic voltammogram of Rh-Me
showed an irreversible oxidation at Epa = 0.159 V (800
mV/s), being significantly lower when compared to its
aryl counterpart (Rh-Ar, 0.331 V), implying that metallic
oxidation of Rh-Me would be more feasible than that of
Rh-Ar species (See the Supporting Information for
details). An orbital analysis on Rh-Me revealed that
oxidation indeed will occur at the metal center of this
transmetalated methyl complex as in case of its aryl
analogue (Rh-Ar). However, at the current stage, it is not
clear whether this irreversible peak represents an one-
electron transfer or two-electron oxidation.
We next wondered whether the metallic oxidation of
Rh-Me will also promote the desired carbon-methyl bond
forming reductive elimination. For the quantitative
estimation, computational analysis on the postulated
reductive elimination from various oxidation states of Rh-
TS-RE(53)
(0.8)
RhIII-Me
RhIV-Me
(0.0)
RhV-Me
RhII-Pdt
(-8.9)
(0.0)
(0.0)
RhIII-Pdt
(-32.3)
Figure 6. Calculated energy profiles for reductive
elimination from Rh-Me in various oxidation states. See
the Supporting Information for the detailed calculation
results.
Next, we briefly examined a stoichiometric ORE
experiment (Scheme 8). Consistent with the
computational prediction, reductive elimination of Rh-Me
proceeded smoothly at room temperature by the action of
chemical oxidant, AgOTFA (2.2 equiv) herein, giving rise
to 10-methylbenzo[h]quinoline 5 in quantitative yield.
When 1 equiv of silver oxidant was employed, 5 was
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obtained in 64% yield under otherwise identical
The Supporting Information is available free of charge on
the ACS Publication website
conditions. Again, we assume that this result suggests that
the reductive elimination of Rh-Me proceeds via the
formation of singly-oxidized RhIV-Me intermediate. No
background reductive elimination was detected from Rh-
Me under thermal conditions (80 oC) without silver
oxidant. We also observed that the mechanistic
understanding was readily applied to the Rh-catalyzed C–
H methylation process under mild conditions (Scheme 8b).
Experimental procedures, analysis data and NMR
spectra for products, and details of the computational
studies including coordinates of all the species
discussed (PDF)
Crystallographic data of Ir-Ar, Rh-Ar, Ru-Ar, Ir-Me,
Rh-Me, and Ru-Me (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*sbchang@kaist.ac.kr
Scheme 8. Oxidatively induced reductive elimination
from Rh-Me intermediate using Ag(I) oxidant under
stoichiometric and catalytic conditions.
ORCID
(a)
Sukbok Chang: 0000-0001-9069-0946
w/o Ag(I), 80 °C
Author Contributions
§J. K. and K. S. contributed equally.
n+
AgOTFA
(x eq.)
Rh(III+n)
CH3
Rh
N
N
N
Notes
CH3 THF
25 °C, 12 h
5
Me
[Ag] (eq.) Yield
The authors declare no competing financial interest.
n = 1 or 2
2.2
1.0
98%
64%
Rh-Me
ACKNOWLEDGEMENTS
This research was supported by the Institute for Basic
Science (IBS-R010-D1) in Korea.
(b)
[Cp*RhCl2]2 (5 mol %)
AgNTf2 (20 mol %)
AgF (2.2 eq.)
O
B
+
N
N
REFERENCES
THF:TFE = 1:1
O
H3C
CH3
25 °C, 12 h, 85%
(1) Applications II: Transition Metal Compounds in Organic
Synthesis 2, Hiyama, T., Ed. Comprehensive Organometallic
Chemistry III From Fundamentals to Applications; Crabtree, R.
H.; Mingos, D. M. P. Elsevier Science: 2007; Vol. 11.
(2) Handbook of C-H Transformations: Applications in Organic
Synthesis, Dyker, G., Ed. Wiley-VCH: 2005.
1a
4
5
(2.2 eq.)
CONCLUSION
In conclusion, we have proved that the oxidatively
induced reductive elimination (ORE) can be significantly
extended to Ir-, Rh-, and Ru-catalyst systems for the C–H
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arylation.
Arylboronic
esters
were
efficiently
transmetalated to afford the key post-transmetalation
intermediates which were fully characterized to include
X-ray structural analysis for the first time. In parallel with
computational studies and electrochemical analyses on the
isolated
transmetalated
species,
experimental
observations confirmed that metallic oxidation
dramatically changes the potential energy surface, thus
eventually allowing otherwise inaccessible product-
releasing reductive elimination to operate under mild
conditions. The current approach based on the high-valent
reductive elimination pathway was also successfully
applied to the catalytic conditions with various
cyclometalating substrates. In addition, a transmetalated
Rh-methyl intermediate was isolated for the first time, and
its analogous behavior toward ORE was also investigated.
The present study clearly demonstrates that ORE is a
convincing strategy to enable a catalytic system by
facilitating the key C–C bond-forming stage. We
anticipate that our current results would provide further
insights on the elementary stages in coupling reactions to
eventually offer an opportunity for exploring previously
inaccessible catalytic reactions.
ASSOCIATED CONTENT
Supporting Information
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Satoh, T.; Miura, M. An Efficient Waste-Free Oxidative
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under Air. Org. Lett. 2007, 9, 1407-1409. (c) Tsai, A. S.; Tauchert,
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Polycyclic Isoquinoline Salt Synthesis via C–H Activation with
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(see the Supporting Information for details).
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deboronation of the boronic ester. In fact, when a more electron-
rich boronate (e.g., 3,4-dimethoxyphenyl boronic ester) was
employed, only a trace amount of the desired C–H arylated
product was obtained. See the Supporting Information for details.
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