Iridium(III)-Catalyzed Direct Arylation of C-H Bonds with Diaryliodonium Salts

Article abstract of DOI:10.1021/jacs.5b06758

By developing a new Ir(III)-catalyzed C-C cross-coupling, a versatile method for direct arylation of sp² and sp³ C-H bonds in ketoximes, nitrogen-containing heterocycles, various arenes, and olefins has been established. The key to this arylation depends on the appropriate choice of catalyst and the use of diaryliodonium triflate salts as the coupling partners. This transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage C-H arylation of complex compounds. Mechanistic studies by density functional theory calculations suggested that the sp³ C-H activation was realized by a triflate-involved concerted metalation-deprotonation process, and the following oxidation of Ir(III) to Ir(V) is the most favorable when a bistriflimide is contained in the diaryliodonium salt. Calculations indicated that both steps are enabled by initial anion exchange between the reactant complexes.

Full text of DOI:10.1021/jacs.5b06758

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Article
Iridium(III)-Catalyzed Direct Arylation of C-H Bonds with Diaryliodonium Salts
Pan Gao, Wei Guo, Jingjing Xue, Yue Zhao, Yu Yuan, Yuanzhi Xia, and Zhuangzhi Shi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b06758 • Publication Date (Web): 08 Sep 2015
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Iridium(III)-Catalyzed Direct Arylation of C-H Bonds with Diarylio-
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Pan Gao,†,§ Wei Guo,‡ Jingjing Xue,† Yue Zhao,† Yu Yuan,§ Yuanzhi Xia,*, ‡ and Zhuangzhi Shi*,†
†State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, School
of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
§College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China
ABSTRACT: By developing a new Ir(III)ꢀcatalyzed CꢀC crossꢀcoupling, a versatile method for direct arylation of sp2 and sp3 CꢀH
bonds in ketoximes, nitrogenꢀcontaining heterocycles, various arenes and olefins has been established. The key to this arylation
depends on the appropriate choice of catalyst and the use of diaryliodonium triflate salts as the coupling partners. This transforꢀ
mation has good functional group compatibility and can serve as a powerful synthetic tool for lateꢀstage CꢀH arylation of complex
compounds. Mechanistic studies by DFT calculations suggested that the sp3 CꢀH activation were realized by a triflateꢀinvolved
CMD process, and the following oxidation of Ir(III) to Ir(V) is the most favorable when a bistriflimide is contained in the diarylioꢀ
donium salt. Calculations indicated both steps are enabled by initial anionꢀexchange between the reactant complexes.
Scheme 1. The Development of Transition-metal-catalyzed
sp3 C-H Arylation Reactions.
INTRODUCTION
Transitionꢀmetalꢀcatalyzed CꢀH activation reactions have emerged
as one of the most useful and powerful tools in organic synthesis.1
The aliphatic CꢀH bonds, which are ubiquitous in organic moleꢀ
cules are most challenging targets for effective and selective funcꢀ
tionalization to construct a variety of CꢀC and Cꢀheteroatom
bonds. Direct CꢀH arylation has advantages over traditional couꢀ
pling protocols especially when the regioselective introduction of
halides in a particular synthetic intermediate is problematic or
requires multistep operation.2 Notable advances have been made
in sp3 CꢀH arylation reactions in different compounds chelating
with directing groups (Scheme 1).3 Early studies were initiated by
Pd(II)ꢀcatalyzed direct arylation of 8ꢀmethylquinoline which was
a good substrate because of its chelating ability.4 In order to funcꢀ
tionalize alkyl CꢀH bonds in more synthetically useful substrates,
many strategies have been developed. Yu et al. demonstrated
Pd(II)ꢀcatalyzed direct arylation of aliphatic acids, amides, amino
acid derivatives and peptides by using external ligands such as
amino acids, pyridines, quinolines and so on to control the reacꢀ
tivity and selectivity of the catalyst.5 Another powerful strategy
exploited chelation assistance is the utilization of a bidentate diꢀ
prominent structural motif which can convert to many bioactive
natural products and pharmaceutically important compounds such
as 15ꢀketo Latanoprost acid,11a 6ꢀGinerol,11b Symphyoketone11c
and Loxoprofen11d (Scheme 2). To the best of our knowledge,
there is no general method available for the introduction of a pheꢀ
nyl group in the βꢀposition of ketoximes via aliphatic CꢀH activaꢀ
tion. Herein, we demonstrate [(Cp*IrCl2)2]ꢀcatalyzed intermolecuꢀ
lar direct arylation of sp3 CꢀH bonds in ketoximes with diarylioꢀ
donium triflate salts. Moreover, heterocycleꢀdirected
recting group such as picolinamide or 8ꢀaminoquinolinyl moiety
in palladiumꢀcatalyzed CꢀH arylation reactions.6 Remarkably,
Nakamura7, Chatani8 and Ackermann9 et al. recently discovered
that the Fe and Ni catalysts were also applicable in aliphatic CꢀH
arylation in conjunction with the bidentate directing groups.
Despite the great progress made in this field, these wellꢀ
established CꢀH activation reactions still have several limitations.
First, the cyclometalation intermediates are formed in presence of
different ligands, oxidants, bases and solvents, thereby making
discovery of a versatile catalytic system applicable to various
substrates difficult. Second, the substrates are typically limited to
8ꢀmethylquinoline, carboxylic acids, aliphatic amines and their
related derivatives and expanding the scope to include other types
of substrates remains a critical challenge. Third, arylation of meꢀ
thyl groups adjacent to quaternary centers is described in most
cases especially in Fe and Ni catalytic systems.7ꢀ9 Ketoxime is an
ideal directing group, which can be easily introduced and reꢀ
moved from the substrates.10 The βꢀarylated ketoxime is a
Scheme 2. β-Arylketone Motifs in Natural Products and
Pharmaceutical Compounds.
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Table 1. Optimization the Reaction Conditions.a
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entry
catalyst (mol%)
additives (equiv)
solvent
T(oC)
Yield of 3aa(%)b
1
2
[(Cp*IrCl2)2] (5) + AgNTf2 (20)
[(Cp*IrCl2)2] (5) + AgNTf2 (20)
[(Cp*IrCl2)2] (5) + AgNTf2 (20)
[(Cp*IrCl2)2] (5) + AgNTf2 (20)
[(Cp*IrCl2)2] (5) + AgNTf2 (20)
[(Cp*IrCl2)2] (2.5) + AgNTf2 (10)
[(Cp*IrCl2)2] (2.5) + AgNTf2 (15)
[(Cp*IrCl2)2] (1) + AgNTf2 (6)
ꢀ
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
DCE
100
100
100
100
100
100
100
100
70
28 (95 : 5)
6 (99 : 1)
30 (97 : 3)
43 (95 : 5)
86 (96 : 4)
65 (98 : 2)
89 (98 : 2), (86%)c
71 (97 : 3)
81 (97 : 3)
67 (98 : 2)
17 (98 : 2)
19 (99 : 1)
67 (75 : 25)
0
CsOPiv (3.0)
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3
AgOAc (3.0)
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PivOH (3.0)
5
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
AcOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
PivOH (3.0) + 4Å MS
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8
9
[(Cp*IrCl2)2] (2.5) + AgNTf2 (15)
[(Cp*IrCl2)2] (2.5) + AgNTf2 (15)
[(Cp*IrCl2)2] (2.5) + AgNTf2 (15)
[(Cp*IrCl2)2] (2.5) + AgNTf2 (15)
[(Cp*IrCl2)2] (2.5) + AgNTf2 (15)
[(Cp*RhCl2)2] (5) + AgSbF6 (20)
[{RuCl2(pꢀcymene)}2] (5) + AgPF6 (20)
[(Cp*Co(CO)2I2)2] (5) + AgSbF6 (20)
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13d
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16
100
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100
100
100
100
acetone
cyclohexane
cyclohexane
cyclohexane
cyclohexane
0
0
b
a Reaction Conditions: 1a (0.60 mmol), 2a (0.20 mmol), catalyst, additives, and in solvent (1.0 mL) at 100 oC, 12 h, under Ar. Yield was
determined by GC analysis of mixture and values in parentheses indicated the mono/di ratio of products. cIsolate yield. dusing 0.4 mmol 1a.
sp3 CꢀH bonds, various aryl and vinylic CꢀH bonds are also comꢀ
patible in this versatile catalytic system. The synthetic application
and plausible mechanism of the current reaction were also studied.
ings to 2.5 mol% [(Cp*IrCl2)2] and 10 mol% AgNTf2 resulted in a
reduced yield (entry 6). However, the addition of a slight excess
of AgNTf2 (15 mol%) maintained the high reactivity, affording
the product 3aa in 89% yield (entry 7). Notably, when 1 mol%
catalyst loading (entry 8) or lower reaction temperature (70 °C)
was used (entry 9), the conversions are still high. Further examiꢀ
nation of other cheaper acids such as AcOH provides worse reꢀ
sults (entry 10). The solvent strongly affected the reactivity of this
reaction. When the reaction was performed in polar solvents such
as DCE and acetone, the yield was remarkably decreased (entries
11ꢀ12). The using of three equivalent of oxime 1a resulted in the
predominant formation of monoꢀarylated product 3aa and changꢀ
ing the substrate ratio led to an increase in amount of byproduct
4aa (entry 13). Note that other common catalytic systems, includꢀ
ing [(Cp*RhCl2)2], [Ru(pꢀcyeme)Cl2] and [Cp*Co(CO)2I2] could
not form any arylation products (entries 14ꢀ16).
RESULTS AND DISCUSSION
Direct arylation of aliphatic C-H bonds with Diaryliodonium
Salts. Halfꢀsandwich Ir(III) complexes have received recent reꢀ
search interest in CꢀH activation because of their catalytic activity
toward various chemical transformations.12, 13 However, most of
these reactions proceed through cleavage of aryl CꢀH bonds, and
aliphatic CꢀH activation reactions are still rare.10dꢀe, 14 In 2014, Li
et al. developed Ir(III)ꢀcatalyzed CꢀH alkynylation of (hetꢀ
ero)arenes using hypervalent iodineꢀalkyne reagents.15 Inspired by
this chemistry, we reasoned that diaryliodonium triflate salts16
could be desirable arylating reagents making the challenging aliꢀ
phatic CꢀH activation feasible via concerted metalationꢀ
deprotonation (CMD) mechanism.17 To evaluate the potential of
the high valent iridium catalyst for aliphatic CꢀH activation, we
first investigated the reactions of pinacolone oxime (1a) with pꢀ
tolyl (mesityl)iodonium triflate (2a). By employing 20 mol%
AgNTf2 as the halide abstractor and 5 mol% [(Cp*IrCl2)2] as the
precatalyst to generate cationic Cp*Ir(III) in situ in cyclohexane at
With the optimized conditions in hand, we first investigated the
substrate scope of ketoximes with pꢀtolyl(mesityl)iodonium triꢀ
flate (2a). In the case of substrates 1aꢀ1c, with the increasing of
steric bulk from methyl to nꢀpropyl adjacent to the quaternary
centers, the yield of the corresponding products 3aaꢀ3ca gradually
decreased. Ketoxime 1d occurred exclusively at the methyl group
adjacent to the quaternary center. Interestingly, a functionalized
ketoxime 1e derived from ethyl acetoacetate was also employed
successfully in this reaction. Most importantly, ketoximes 1fꢀ1j
with αꢀhydrogens were compatible for this process and afforded
monoꢀarylation products 3faꢀ3ja in moderate yields. Reactions of
1g, which contains multiple possible sites for the direct arylation,
showed extremely high selectivity for activation of primary βꢀCꢀH
bonds in lieu of those at secondary carbon centers. The six and
sevenꢀmembered ring ketoximes 1kꢀ1m were efficiently arylated
to afford the desired products 3kaꢀ3ma in good yield, probably
because of the less flexible nature of these cyclic conformers.
o
100 C, we indeed observed the desired product 3aa by GCꢀMS
analysis, with a very small amount of disubstituted byproduct 4aa
(entry 1). However, the addition of base such as CsOPiv was
proved to be disadvantageous to the reaction, as the yield was
markedly decreased (entry 2). Switching the additive to AgOAc
increased the yield to 30% (entry 3), and the use of PivOH as an
alternative to AgOAc resulted in a significantly improved yield
(entry 4). During our research, we found the fresh distilled cycloꢀ
hexane was much better than old one. Consequently, addition of
4Å MS indeed improves the efficiency of the reaction, affording
3aa in 86% yield (entry 5). The application of lower catalyst loadꢀ
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Table 2. Scope of the sp3 C-H Arylation of Ketoximes and Nitrogen-containing Heterocycles.a
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a Reaction Conditions: 1 (0.60 mmol), 2a (0.20 mmol), 2.5 mol% [(Cp*IrCl2)2], 15 mol% AgNTf2, 3.0 equiv PivOH and 200 mg 4Å MS in
cyclohexane (1.0 mL) at 100 oC, 12 h, under Ar; isolated yield. bIsolate as a mixture of oxime E/Z isomers. cUsing 0.30 mmol 1.
Ketoxime 1n with olefinic double bond was compatible though in
reduced yield and the alkene arylation product was not obꢀ
served.16e Since the heterocycles including pyridine, pyrazine,
quinoline, pyrazole, isoxazole and so on are commonly occurring
structural motifs found in numerous pharmaceuticals and biologiꢀ
cally active compounds,18 we envisioned that a reliable method
for direct arylation of these heterocycleꢀdirected sp3 CꢀH bonds
would be very meaningful. To our delight, we found a variety of
heterocycles were effective directing groups, and functionalizaꢀ
tion of methyl groups containing αꢀhydrogens were well tolerated
under this optimized procedure. Both pyridine and quinoline subꢀ
strates with unactivated sp3 CꢀH bonds underwent arylation to
afford monoꢀsubstituted products 3oaꢀ3sa in good yields. Addiꢀ
tionally, reactions of pyrazine derivatives 1tꢀ1v bearing two N
atoms chelating with catalyst still proceeded very well. It was
interesting to find that the reaction of fiveꢀmemberedꢀring heteroꢀ
cycles such as pyrazole 1w and isoxazole 1x were also proved
facile and occurred exclusively at the methyl group.
chemical transformations. Electronꢀwithdrawing substituted group
such as ethyl ester could be tolerated in this protocol although
reduced yield was observed (3am). We were pleased that the couꢀ
pling of the polycyclic and heterocyclic aromatic motif were posꢀ
sible and proceeded in moderate to excellent yields (3anꢀ3ap),
thus further enhancing the scope of our reaction.
Late-stage sp3 C-H arylation of complex molecules. The
Lanostaneꢀtype triterpenoids have been demonstrated to exert
diverse bioactivities, particularly cytotoxic, antitumor and antiꢀ
inflammatory activities. Encouraged by this successful Ir(III)ꢀ
catalyzed sp3 CꢀH arylation reactions, we turned our attention to
utilize this method as a key step for regioselective CꢀH arylation
of Lanostane. As shown in Scheme 3, our synthesis commenced
with the preparation of oxime 4b using commercial available
substrate Lanosterol 4a. Under the catalytic system, substrate 4c
Scheme 3. Potential Route from Lanosterol to C(β)-
Arylated Lanostane 4d.
Next, we sought to expand this transformation to the transfer
of diverse aryl groups and we were pleased to find that a range of
substituted diaryliodonium triflates worked well with pinacolone
oxime (1a). (Table 3). Aromatic groups displaying electronꢀ
neutral and electronꢀrich substituents at the metaꢀ and paraꢀ
position (3abꢀ3ac & 3aeꢀ3ah) were transferred in particularly
good yields from the corresponding diaryliodonium triflates.
Orthꢀmethyl substituted aryl derivative led to a reduced yield
(3ad), presumably as a result of increased steric congestion
around the iridicycle intermediate, preventing oxidation or reducꢀ
tive elimination steps. Useful halogenated arenes were accommoꢀ
dated (3aiꢀ3al), thereby providing possibilities for subsequent
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Table 3. Aryl Transfer in Aliphatic C-H arylation of Pinacolone Oxime 1a.a
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a Reaction Conditions: 1 (0.60 mmol), 2 (0.20 mmol), 2.5 mol% [(Cp*IrCl2)2], 15 mol% AgNTf2, 3.0 equiv PivOH and 200 mg 4Å MS in
cyclohexane (1.0 mL) at 100 oC, 12 h, under Ar; isolated yield. bUsing Ph2IOTf instead of PhMesIOTf.
could be employed in selective direct arylation of the C(β) methyl
group affording product 6 in 68% yield with completely regioseꢀ
lective as confirmed by Xꢀray diffraction. The further deprotecꢀ
tion19 and reduction of 4c could form the C(β)ꢀarylated Lanostane
4d.20
Broad C-H Arylation of Arenes and Alkenes with Diarylio-
donium Salts. Although the direct sp2 CꢀH arylation reactions
have been well developed in the presence of different transition
metals including Pd, Ni, Cu, Ru, Rh and so on,22 Ir(III)ꢀcatalyzed
CꢀH arylation of arenes still remains relatively rare.23 With the
developed catalytic system in hand, we next aimed to extend it to
sp2 CꢀH bonds. Heterocycleꢀdirected arylation was evaluated
firstly. Phenylpyridine 6a, benzo[h]quinoline (6b) and 1ꢀ
(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (6c) underwent smooth couplings
affording the corresponding products with yields between 48ꢀ87%.
The arylation reactions also worked well for other arenes includꢀ
ing Oꢀmethyloxime 6d, Nꢀphenyl amides 6eꢀ6g, benzamides 6hꢀ6i,
heterocycle 6j and benzoic acid (6k) Among these substrates,
while Nꢀphenyl amide 6g contains several aliphatic and aryl CꢀH
bonds that are available for CꢀH arylation, only sp2 CꢀH activation
product 7ga was detected in 74% yield. This suggests that the sp3
CꢀH activation is more difficult as compared with the sp2 CꢀH
activation. Interestingly, Glorius et al. recently found that Rh(III)ꢀ
catalyzed halogenation of electronꢀrich heterocyclic compounds
such as 6j at the 3ꢀposition of furan and the inherent 5ꢀposition
was suppressed by the Rh(III) catalyst.24 In our catalytic system,
we also observed 7ja as the sole arylation product in excellent
yield with complete regiochemistry.25 The palladiumꢀcatalyzed
coupling of olefins with aryl or vinyl halides, known as the Heck
reaction, is one of the most powerful methods to form a new carꢀ
bonꢀcarbon bond in modern synthetic chemistry.26 However, this
reaction occurred with E selectivity and multiꢀsubstituted vinylic
substrates have low reactivites. To further explore our catalytic
system, the compatibility of this crossꢀcoupling reaction with
vinylic substrates was examined. In case of the enamide 6l with
both vinylic and allylic CꢀH bonds, the sp2 CꢀH arylation product
7la can be selectively obtained, indicating the functionalization of
a vinylic CꢀH bond is also much more favorable. Reaction of
differently substituted enamides 6mꢀ6n, Oꢀmethyloxime 6o and
even vinyl carboxylic acids 7pꢀ7q can yield the desired products
7maꢀ7qa in 42ꢀ99% yields. Remarkably, these coupling reactions
Scheme 4. Late-stage sp3 C-H Arylation of Oleanolic Acid
and Removal of the Auxiliary Group.
Oleanolic acid is a nonꢀtoxic, hepatoprotective triterpenoid
found in Phytolacca Americana which exerts antitumor and antiꢀ
viral properties. It was also found to exhibit weak antiꢀHIV and
weak antiꢀHCV activities, and more potent synthetic analogs are
being investigated as potential drugs.21 To further illustrate the
functionalꢀgroup tolerance and synthetic versatility of this develꢀ
oped method, we next surveyed it in selective arylation of this
complex natural compound (Scheme 4). We began our synthesis
with Oleanolic acid 5a, which was converted to the corresponding
ketoxime 5b in three steps. Similarly, the arylation of the 5b with
Ph2IOTf (2b) provided arylated product 5c in 38% yield with
complete selective arylation of the βꢀC position confirmed by 2D
NMR. The auxiliary group of 5c was then removed in HCl
(aq)/MeOH solution to give a free ketone intermediate 5d in nearꢀ
ly quantitative yield, which can recover to C(β)ꢀarylated Oleanolic
acid via further reduction and hydrolysis.
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an Ir(V) species B’ ahead of CꢀH activation is also possible
(Pathway B).
Table 4. Ortho C-H Arylation of Various Arenes and Ole-
fins.a
1
2
3
4
Scheme 5. Plausible Catalytic Cycle for Ir(III)-catalyzed
sp3 C-H Arylation of Ketoximes.
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To uncover which pathway is more favorable for the current
sp3 CꢀH arylation, DFT calculations29 at the M06 level were first
performed to simulate the reaction between butanꢀ2ꢀone Oꢀmethyl
oxime (1) and Ph2IOTf (2b). First of all, the generation of possiꢀ
ble reactant complexes was studied (Scheme 6). According to the
reaction condition, cationic complex [Cp*IrNTf2]+ could possibly
act as a catalytically active species in the system, and reactant
complex RCꢀNTf2 may be generated first. To evaluate the possiꢀ
bility for the formation of complexes containing other counterions,
the equilibrium of RCꢀNTf2 to RCꢀOTf and RCꢀOPiv, respectiveꢀ
ly, by anion exchange with 2b and HOPiv additive were calculatꢀ
ed. The relative free energies in Scheme 6 show that such anion
exchange reactions should be facile as the formation of RCꢀOTf
and Ph2INTf2 is almost an energetically neutral process while RCꢀ
OPiv is unfavorable thermodynamically by 3.6 kcal/mol. Alternaꢀ
tively, the exchange of the neutral ligand between RCꢀNTf2 and
RCꢀI was also calculated, showing the reactant complex of 2b
(RCꢀI) is more stable by 2.7 kcal/mol.
As the energy gaps among the possible reactant complexes are
relatively small (Scheme 6), the energies for subsequent transforꢀ
mations from these complexes are compared in Scheme 7. For
complexes containing the oxime substrate, the βꢀCꢀH activation
could be realized via a concerted metallationꢀdeprotonation (CMD)
a Reaction Conditions: 1a (0.22 mmol), 2 (0.20 mmol), 2.5 mol%
[(Cp*IrCl2)2], 15 mol% AgNTf2, 3.0 equiv PivOH and 200 mg 4Å
o
MS in cyclohexane (1.0 mL) at 100 C, 12 h, under Ar; isolated
Scheme 6. Energetics for the Generation of Possible Cati-
onic Reactant Complexes.29
yield.
occurred with complete Z selectivity. This stereoselectivity is
highly valuable because of its potential synthetic applications.
Mechanistic Investigations. As the Ir(III)ꢀcatalyzed aliphatic Cꢀ
H arylation by diaryliodonium salt has not been studied previousꢀ
ly, we next sought to gain a more detailed mechanistic underꢀ
standing of the transformation. The mechanistic studies of Pd(II)ꢀ
catalyzed aryl CꢀH arylation reactions with diaryliodonium salts
via a PdII/PdIV redox cycle were elaborated in Sanford's group.27
In light of their work, we depict a plausible catalytic cycle in
Scheme 5. First, an iridium species A induces CꢀH cleavage of
oxime 1 to generate an iridicycle complex B. Oxidation of the
intermediate B with diaryliodonium salt 2 forms an Ir(V) species
C,28 which then undergoes reductive elimination leading to the
desired product 3 (Pathway A). Since more traditional nucleoꢀ
philes like PhB(OH)2 and PhSiMe3 were ineffective phenylating
reagents in our catalytic and stoichiometric reaction conditions, an
alternative process involving oxidation of the iridium species A to
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Scheme 7. Computational Results (Energies in kcal/mol).29
using Ph2INTf2 as an oxidant, which could be formed exergoniꢀ
1
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3
4
5
6
7
8
cally from reaction of RC-NTf2 with Ph2IOTf (Scheme 6), an
activation barrier of 9.4 kcal/mol was calculated (X = NTf2),
which is 7.8 kcal/mol lower than the oxidation by the originally
added oxidant Ph2IOTf (X = OTf), showing the dramatic differꢀ
ence in calculated energies with different counterions (In TS2-X
the counterion is associated with the iodide moiety and no interacꢀ
tion with the Ir atom is found, geometries are given in the Supꢀ
porting Information). The larger exergonicity associated with the
formation of IN2-OTf than IN2-NTf2 could be attributed to steric
reason because the latter intermediate is more crowded with a
bulkier NTf2 ligand. The involvement of a pivalate anion in the
oxidation step was also studied and found to have a lowest barrier
of 8.4 kcal/mol, however, such a possibility was considered to be
less likely because the high energy associated with the formation
of Ph2IOPiv.32 Thus, the IN2-NTf2 is suggested as a possible
Ir(V) species formed in the reaction. Finally, the C(sp3)ꢀ C(sp2)
coupling could be realized by reductive elimination from IN2-
NTf2, which occurs facilely via TS3-NTf2 with a barrier of 9.1
kcal/mol and generates product complex PC-NTf2 highly exerꢀ
gonically (Scheme 7c).
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Based on the above results, the whole potential energy surface
depicted in Scheme 7c suggests the triflateꢀinvolved CꢀH activaꢀ
tion requires a highest activation barrier of 24.1 kcal/mol from
RC-I, and the C(β)ꢀarylation product will be formed irreversibly
with facile oxidation and reductive elimination steps. Further
support of the calculated energy profile could be obtained by the
result of isotopically labeled substrate D3-1k, which led to a conꢀ
siderable kinetic isotope effect for both parallel experiments
(kH/kD ≈ 4.0) and competition experiments (kH/kD ≈ 4.6) in
Scheme 8.33 It should be noted that the KIE results are also conꢀ
sistent with the involvement of Ph2INTf2 as an oxidant (Scheme
7c), because if the Ph2IOTf is a reaction partner in this step, the
relative energy of TS2-OTf will be 6.1 kcal/mol higher than TS1-
OTf on the potential energy surface, making the CꢀH activation
step reversible.
To make clear if the arylation could be achieved by the alternaꢀ
tive mechanism of sequential oxidation/CꢀH activation (Pathway
B, Scheme 5), the reaction from the most stable reactant complex
RC-I was studied theoretically (Scheme 7d). The oxidation of
Ir(III) to Ir(V) via TS1’ requires a barrier of 26.4 kcal/mol. This is
less favorable by 2.3 kcal/mol compared with the CꢀH activation
via TS1-OTf (the energy difference of 2.6 kcal/mol between RC-
OTf and RC-I was taken into consideration). The generated Ir(V)
species IN1’ is calculated to be even slightly higher in energy
than TS1’. Incorporation of oxime 1 forms a more stable complex
IN2’, however, the following CꢀH activation are impossible with
activation barriers over 60 kcal/mol. This should be attributed to
the fact that the Ir center is coordination saturated in IN2’, and
dissociation of one of the ligands was observed during optimizaꢀ
tions of the CMD transition states. Thus, Pathway B could be
discarded according to the calculated energies.
process via TS1-X (Scheme 7a), in which the anionic ligand (X)
is a base for deprotonation of the C(β)ꢀH bond (Calculations
found that from RC-X the direct insertion of Ir(III) into the C(β)ꢀ
H bond to form an Ir(V)ꢀH species is higher in energy, details are
given in the Supporting Information). Accordingly, the CꢀH actiꢀ
vation is the least favorable when the NTf2 anion is contained,
which requires an activation barrier of 29.1 kcal/mol to generate
iridicycle IN1. A remarkably reduced activation barrier of 21.5
kcal/mol was calculated from RC-OTf,30 suggesting the triflateꢀ
involved CMD process is much more favorable (The geometry of
TS1-OTf indicates the CꢀH bond is cleaved via a 6ꢀmembered
ring TS, see the Supporting Information for details). Although a
comparable activation barrier of 21.3 kcal/mol was predicted from
RC-OPiv, an overall barrier of 25.0 kcal/mol should be required
if considering the fact that RC-OPiv is 3.7 kcal/mol higher in
energy than RC-OTf. Upon the generation of iridicycle IN1, the
oxidation of Ir(III) to Ir(V) with diaryliodonium salt was next
studied (Scheme 7b),31 which occurs via TS2-X and releases one
molecule of PhI into the reaction media. Theoretically, different
counterions could be possibly contained in the diaryliodonium salt
due to the low energy anion exchange reactions. Indeed, when
Scheme 8. Kinetic Isotope Effect Studies.
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In previous reports, the diaryliodonium tetrafluoroborate (2b’)
bonds in ketoximes, heterocycles such as pyrazine, pyrazole and
isoxazole but also applied this CꢀC coupling in various aryl and
vinylic CꢀH bonds. This protocol can also serve as an efficient
tool for lateꢀstage CꢀH arylation of complex molecules in synthetꢀ
ic and medicinal chemistry. Therefore, this transformation has
significant potential application, particularly as a result of the high
selectivities. Further investigation of the mechanism of this transꢀ
formation was carried out by DFT calculations, which suggested
the reaction is initiated by anionꢀexchange between cationic reacꢀ
tant complex and diaryliodonium triflate. Such a process enables
the triflateꢀinvolved CMD for CꢀH activation and the following
oxidation of Ir(III) to Ir(V) by Ph2INTf2, which are the most faꢀ
vorable among other possibilities. These findings should be useful
for future development of new sp3 CꢀH activations.
was utilized as the arylating reagent for Pdꢀcatalyzed sp2 CꢀH
arylation reactions.27d, 34 However, in our conditions, the diarylioꢀ
donium triflate (2b) was a superior coupling partner as diarylioꢀ
donium salts with other counterions (2b’ and 2b’’) were totally
unreactive (Scheme 7a). To understand this divergence, the reacꢀ
tion between 1 and 2b’ was studied theoretically by similar proꢀ
cedure described above. It was found that the pivalate anion may
be involved in the C(β)ꢀH deprotonation process for generation of
iridicycle IN1. However, higher energy is required for the followꢀ
ing oxidation by Ph2INTf2. The predicted activation energy for the
whole reaction between 1 and 2b’ is 26.5 kcal/mol (Scheme 9b,
detailed potential energy surfaces and discussion are given in the
Supporting Information), being in qualitative agreement with the
experiments that only trace of product was obtained.
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ASSOCIATED CONTENT
Scheme 9. Different Counterions in Diaryliodonium salts
Investigation.
Supporting Information. A brief statement in nonsentence forꢀ
mat listing the contents of material supplied as Supporting Inforꢀ
mation should be included, ending with “This material is available
free of charge via the Internet at http://pubs.acs.org.” For instrucꢀ
tions on what should be included in the Supporting Information as
well as how to prepare this material for publication, refer to the
journal’s Instructions for Authors.
AUTHOR INFORMATION
Corresponding Author
shiz@nju.edu.cn
xyz@wzu.edu.cn
Notes
The authors declare no competing financial interest.
In addition, it's also noticed that a primary βꢀcarbon is necesꢀ
sary for this CꢀH arylation and γꢀcarbon has much lower reactivity
compared with βꢀcarbon, since ketoximes 8aꢀ8c failed to this
reaction. The unique βꢀselectivity of this current methodology
could also be understood by the calculated mechanism. The reacꢀ
tion between pentanꢀ2ꢀone Oꢀmethyl oxime (8a) and 2b was simꢀ
ulated to see whether βꢀ or γꢀarylation product could be formed.
Calculated results found increased activation energies are required
for both the CꢀH activation and oxidation steps, and the latter step
becomes the rateꢀdetermining step. Higher activation energies are
required for both the βꢀ and γꢀarylations of 8a (32.8 and 37.1
kcal/mol, respectively, Scheme 10) as results of the increased
energies for the oxidation processes (activation energies in
Scheme 10 are determined by the energy gap between the most
stable reactant complex and the oxidation TS, details are given in
the Supporting Information).
ACKNOWLEDGMENT
We thank the “1000ꢀYouth Talents Plan”, the “Jiangsu Speciallyꢀ
Appointed Professor Plan”, NSF of China (Grant 21402086,
21401099), NSF of Jiangsu Province (Grant BK20140594). This
work was also supported by a Project Funded by the Priority Acaꢀ
demic Program Development of Jiangsu Higher Education Instituꢀ
tions. Y.X. acknowledges financial support from NSFC (Grant
21372178) and NSF of Zhejiang Provincial (LY13B020007) and
stateꢀofꢀtheꢀart facility support from the High Performance Comꢀ
putation Platform of Wenzhou University.
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(29) All calculations were done at the (PCM)M06/6ꢀ31G(d)ꢀLANL2DZ
level by running Gaussian 09. Relative solvation free energies were used
for discussion. Computational details and citation of the software are
given in the Supporting Information.
(30) If the arylation of sp2 CꢀH bond follows a similar mechanism, the
calculated energy for triflateꢀinvovled C(sp2)ꢀH activation step of
acetophenone Oꢀmethyl oxime is only 15.6 kcal/mol, being consistent
with the more facile cleavage of the sp2 CꢀH bonds.
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