Complete Switch of Selectivity in the C-H Alkenylation and Hydroarylation Catalyzed by Iridium: The Role of Directing Groups

Article abstract of DOI:10.1021/jacs.5b09824

A complete switch in the CpIr(III)-catalyzed paths between C-H olefination and hydroarylation was found to be crucially dependent on the type of directing groups. This dichotomy in product distribution was correlated to the efficiency in attaining syn-coplanarity of olefin-inserted 7-membered iridacycles. Theoretical studies support our hypothesis that the degree of flexibility of this key intermediate modulates the β-H elimination, which ultimately affords the observed chemoselectivity.

Full text of DOI:10.1021/jacs.5b09824

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Communication
Complete Switch of Selectivity in the C-H Alkenylation and
Hydroarylation Catalyzed by Iridium: The Role of Directing Groups
Jiyu Kim, Sung-Woo Park, Mu-Hyun Baik, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09824 • Publication Date (Web): 08 Oct 2015
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Complete Switch of Selectivity in the C−H Alkenylation and
Hydroarylation Catalyzed by Iridium: The Role of Directing Groups
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Jiyu Kim,†,‡ SungꢀWoo Park,*,‡,† MuꢀHyun Baik,‡,† and Sukbok Chang*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305ꢀ701, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305ꢀ701, Korea
Supporting Information Placeholder
Scheme 1. Arene C−H Alkenylation and Alkylation
ABSTRACT: A complete switch in the Cp*Ir(III)ꢀcatalyzed
paths between C−H olefination and hydroarylation was found to
be crucially dependent on the type of directing groups. This
dichotomy in product distribution was correlated to the efficiency
in attaining synꢀcoplanarity of olefinꢀinserted 7ꢀmembered
iridacycles. Theoretical studies support our hypothesis that the
degree of flexibility of this key intermediate modulates the βꢀH
elimination,
which
ultimately
affords
the
observed
chemoselectivity.
Metalꢀcatalyzed carbonꢀcarbon bond formation has played a
pivotal role in synthetic chemistry.1 For instance, olefination of
aryl halides (Mizoroki–Heck reaction) has become one of the
most efficient routes to vinylarenes.2 More recently, direct C−H
alkenylation of arenes was actively investigated as
a
straightforward approach to the same products (Scheme 1a).3 In
this process, a metal alkyl intermediate generated in situ upon the
migratory insertion of a metal aryl species into alkenes, undergoes
βꢀhydride elimination to give olefinated products.1c,4 However,
the change of catalyst and/or reaction conditions can alter the
reaction pathway significantly; for instance, giving rise to
alkylated compounds upon protonolysis.5 Several catalytic
systems are known for the hydroarylation of olefins (Muraiꢀtype
reaction) to give alkylarene products selectively.6
Chelating groups play a central role in the metalꢀcatalyzed
direct C−H functionalization. For example, they give access to
metallacyclic intermediates that are thought to be the reactive
intermediates.7 While directing groups often affect reaction
efficiency, in addition to determining regioselectivity, the
coordination ability of these pendants often affects the catalytic
performance.8 Sanford et al. described the perturbation of the
kinetics of catalysis by structurally and/or electronically
modifying the directing groups.9 Their ability to dramatically
change the chemoselective pathway by the same catalyst system
has not been described to the best of our knowledge.10 We herein
present a novel example where an identical catalyst system
switches the product distribution between C−H olefination and
hydroarylation depending on the type of directing groups (Scheme
1b). Computational studies were also conducted to support our
working hypothesis that the structural flexibility of the key
iridacycle intermediate is central to attaining a synꢀcoplanar
conformation, which in turn determines the efficiency of the βꢀ
hydride elimination.
A distinct dichotomy in product distribution was initially
observed in the Cp*Ir(III)ꢀcatalyzed reaction of ethyl acrylate
with arene substrates bearing two different types of directing
groups (eq 1): whereas a hydroarylated product was formed
almost exclusively in good yield with the pyridyl chelation, an
olefinated compound was obtained with high selectivity when an
amide directing group was present (see the Supporting
Information for details). This result clearly indicated that the
directing groups can act as switches that enable either C−H
olefination or hydroarylation by the same catalyst system.
Significantly, this outcome was distinctive for the Cp*Ir(III)
catalyst only in regard to the reaction efficiency and product
selectivity. Similar systems, such as [Ru(pꢀcymene)Cl2]2 or
[Cp*RhCl2]2 that are known catalysts for the highly facile C−H
functionalization do not show the same behavior, however.11
Instead, they provided either a mixture of two products with
moderate selectivity or showed poor activity. A Cp*ꢀmodified
catalyst, such as [IrCl2(η5ꢀC5Me4H)]2, displayed lower activity
than [Cp*IrCl2]2 (see the Supporting Information for details).
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Generality of this dramatic effect of directing groups on the
reaction path was examined next. First, range of 2ꢀ
We then wondered whether other directing groups and
different olefins could also reproduce this notable selectivity
switch. The Irꢀcatalyzed hydroarylation was highly favored over
1
2
3
4
5
6
7
8
a
phenylpyridine derivatives was found to undergo hydroarylation
with high selectivity (Table 1). In this reaction, double
hydroarylation took place to different extents, but the formation of
olefinated compounds was almost negligible, especially with
substrates bearing electronꢀneutral or donating substituents.
However, when a nitro group was placed at the 2ꢀpyridyl moiety,
the selectivity was slightly decreased (entries 7−8), but still
favoring the hydroarylation. No branched hydroarylated isomers
were observed under the conditions tested.
A totally different outcome of selectivity was observed in the
reaction of benzamides with ethyl acrylate (2 equiv) using the
same Cp*Ir catalyst system (Table 2). In this case, olefinated
products were formed almost exclusively (>98:2), and this
excellent selectivity was maintained irrespective of the electronic
variation in benzamide substrates.12 Analysis of the crude reaction
mixture revealed that 1 equiv of ethyl propionate was formed
simultaneously.
olefination in reaction of 2ꢀphenylpyridine with
a styrene
derivative and methyl vinyl ketone, albeit in low to moderate
yields (16a and 17a, respectively). Pyrazole and pyrimidine were
also found to be effective chelators leading to hydroarylated
products with high selectivity (18a and 19a, respectively). On the
other hand, a high level of selectivity to deliver olefinated
products was observed with substrates bearing oxygen chelators
such as anilide (20c). Notably, this selectivity pattern was
maintained with substrates bearing ketone chelators.1b,1c,13 For
instance, chromone (21c: Xꢀray structure shown in SI) and
isobutyrophenone (22c) were selectively olefinated. In addition,
an olefination path was predominant in reaction of a ketone
substrate with a styrene derivative (23c). The observed high
selectivity from both cyclic and acyclic ketone substrates (21c vs
22c) implies that the cyclic nature of directing group is not
required for the selectivity.
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Scheme 2. Selectivity on Various Directing Groupsa,b
Table 1. C−H Hydroarylation with 2-Pyridyl Groupa
Entry
R
Products (%)b
(a+b / c)c
1
2
3
4
5
6
7
8
R1=H, R2=H, R3=H
1a: 47
1b: 20
2b: <1
3b: 48
4b: 10
5b: 07
6b: 30
7b: <1
8b: <1
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
R1=Me, R2=H, R3=H
R1=H, R2=H, R3=OMe
R1=H, R2=H, R3=Cl
R1=H, R2=H, R3=CF3
R1=H, R2=H, R3=CHO
R1=NO2, R2=H, R3=H
R1=H, R2=NO2, R3=H
2a: 58
3a: 16
4a: 45
5a: 29
6a: 48
7a: 33
8a: 32
91:9
97:3
aSubstrate (0.2 mmol) and ethyl arylate (1.2 equiv) in 1,2ꢀdichloroethane.
bIsolated yield. c Ratio of alkyl(mono+bis):alkenyl products, determined
by 1HꢀNMR of the crude reaction mixture.
a See the Supporting Information for detailed reaction conditions: isolated
yields. bRatio of hydroarylated/olefinated products in the crude reaction
mixture determined by 1HꢀNMR analysis.
Table 2. C−H Alkenylation with Amide Groupa
The most plausible mechanism that gives access to the C−H
hydroarylation and olefination pathways depending on the
directing group is depicted in Scheme 3. Both reactions share
identical steps at the beginning: C−H bond cleavage gives I,
followed by olefin coordination (II) and migratory insertion to an
alkene leading to the 7ꢀmembered iridacycle III.4 The initial C−H
bond cleavage step appeared irreversible in H/D exchange studies,
both in hydroarylation of 2ꢀphenylpyridine and alkenylation of Nꢀ
tꢀbutylbenzamide (see SI). Iridacycles I obtained from each type
of substrates catalyzed the corresponding hydroarylation (X = N)
Entry
R
Products (%)b
(c+d / a)c
1
2
3
4
5
6
7
R1=H, R2=H, R3=t-Bu
R1=H, R2=Me, R3=t-Bu
R1=OMe, R2=H, R3=t-Bu
R1=CF3, R2=H, R3=t-Bu
R1=CH2OH, R2=H, R3=t-Bu
R1=H, R2=H, R3=Me
9c: 80
9d: 08
10d: 05
11d: <1
12d: <1
13d: <1
14d: <1
15d: <1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>>98:2
and olefination (X
= O) reaction. The olefinꢀcoordinated
10c: 80
11c: 57
12c: 25
13c: 77
14c: 94
iridacycle II (X = N, R = Ph) was isolated and its structure was
characterized by Xꢀray crystallography (see SI). Significant
deuterium incorporation (31%) was seen exclusively at the αꢀ
position relative to carbonyl of alkylated product when deuterated
2ꢀphenylpyridine was reacted with ethyl acrylate. In the
olefination of benzamides with 2 equiv of ethyl acrylate, 1 equiv
of alkene worked as a sacrificial hydrogen acceptor5e as seen by
the stoichiometric formation of ethyl propionate. In addition, an
olefinꢀinserted 7ꢀmembered iridacycle III (X = N, R = CONHt-
Bu) was characterized by NMR and HRMS analysis.
R1=H, R2=H, R3=Adamantyl 15c: 65
aSubstrate (0.2 mmol) and ethyl arylate (2 equiv) in 1,2ꢀdichloroethane.
bIsolated yield. c Ratio of alkenyl(mono+bis):alkyl products, determined
by the 1HꢀNMR of the crude reaction mixture.
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for the chemoselectivity. The present study is a novel example
Scheme 3. Mechanistic Proposal
1
2
3
that illuminates aspects of reaction control by directing groups to
determine not only regioselectivity but also chemoselectivity in
C−H functionalizations.
N
Y
-
H
[NTf2
]
Identified
X
Ir
H
Y
R
4
5
6
7
8
9
I
Y
Catalytic activity
N
Figure 1. a) Energy profile of βꢀH elimination from III of 2ꢀ
phenylpyridine and Nꢀmethylbenzamide. b) Relaxed PES
scanning along the rotating torsional angle IrꢀCαꢀCβꢀH from III to
the artificial synꢀcoplanarity.
O
R
H
Y
Y
R
H
-
[NTf2
]
H+
O
X
Ir
a)
R
Y
II
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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R
X-Ray analysis
R
N-chelator
Ir
Ts-IIIa
Ts-IVa
Ts-IIIb
Ts-IVb
O
R
-
[NTf2
Y
]
H
Me
Y
Me
Me
Me
H
Me
Ir
Ir
X
Ts-IIIa
N
R
R
X
H
2.19
Ir
CO2Et
N
23.0
O-chelator
syn-coplanar
H
Y
H
H
Ts-IVa
H
III
H
Me
Me
IIIa (2-phenylpyridine)
Me
Me
17.4
Me
15.6
difficult to access
Identified
H
Me
Ir
IVa
Me
Me
N
CO2Et
Me
Me
Ts-IIIb
7.9
CO2Et
H
Ir
2.12
H
N
IVb
Ts-IVb
5.9
5.8
5.5
2.4
Va
Vb
H
Me
Me
Me
Me
0.0
Me
Me
Me
Me
Me
Me
2.16
O
Me
G
CO2Et
Me
Me
Ir
Me
kcal/mol
Me
MeHN
H
H
Ir
Density functional calculations supported our mechanistic
proposal,14 with computed reaction energy profile shown in
Figure 1a: (i) The βꢀhydride elimination is slightly uphill by 5.5
and 2.4 kcal/mol from the iridacycles III for 2ꢀphenylpyridine and
Nꢀmethylbenzamide, respectively. (ii) The most difficult step is
associated with the formation of a high energy intermediates IVa
and IVb, each containing an agostic Ir−(βꢀCH) bond. (iii) βꢀ
Hydride elimination from the agostic intermediate is nearly
barrierless.
O
H
CO2Et
H
Ir
CO2Et
O
2.13
MeHN
MeHN
H
H
Agostic intermediates
IIIb (N-methylbenzamide)
b)
H
0.0 o
H
93.0 o
R
N
18.5 kcal/mol
[Ir]
N
Ar
H
Ar
H
H
H
On first sight, the transition state energy difference of 15.1
kcal/mol vs. the product energy difference of only 3.1 kcal/mol is
puzzling, but these differences highlight the foundation of how
the chemoselectivity is achieved: To allow βꢀhydride elimination,
the iridacycle III must undergo significant structural change. And
two features are key to discriminating the Nꢀ and Oꢀdonor ligands.
First, the Ir(III) center presents a hard Lewis acidic binding site,
which is a good match for the Nꢀdonor ligands that are hard Lewis
bases. The resulting Ir(III)ꢀN bonds are strong and robust leading
to a relatively rigid iridacycle.15 The Oꢀdonor ligands, however,
are relatively soft Lewis bases and, as a result, the Ir(III)ꢀO bonds
are much more flexible. Second, the computed structures of the
iridacycle reveal that there are significant structural differences, as
illustrated in Figure 1b. The dihedral angle of IrꢀCαꢀCβꢀH in the
iridiacycle IIIb is 57.0° whereas it is 93.0° in IIIa. A synꢀ
coplanar geometry, where this angle becomes 0°, is required to
promote βꢀhydride elimination. Our calculations estimate that this
flattening requires 9.3 and 18.5 kcal/mol, respectively. Thus, both
the MꢀL bond characteristics and the iridacycle geometry allow
IIIb to reach the key intermediate much more easily than IIIa.
In summary, the path of Cp*Ir(III)ꢀcatalyzed C−C bond
formation was found to be controlled by directing groups on the
chelating ligand. While synꢀcoplanarity of key 7ꢀmembered
iridacycle intermediates can be attained readily with carbonyl
directing groups eventually leading to olefinated products, strong
nitrogen chelators favor the hydroarylation process. Theoretical
studies strongly support our hypothesis on this mechanistic
dichotomy and provide an intuitively comprehensible explanation
R
IIIa (2-phenylpyridine)
0.0 o
[Ir]
57.0 o
H
H
R
O
[Ir]
O
9.3 kcal/mol
Ar
R
H
H
Ar
H
H
R = CO2Et
IIIb (N-methylbenzamide)
7-membered iridacycles (non-agostic)
syn-coplanar form
ASSOCIATED CONTENT
Supporting Information
Procedures and additional data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
swpark908@kaist.ac.kr; sbchang@kaist.ac.kr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Institute for Basic Science (IBSꢀ
R10ꢀD1) in Korea. We thank Dr. Jeung Gon Kim for insightful
3
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788. (c) Leow, D.; Li, G.; Mei, T.ꢀS.; Yu, J.ꢀQ. Nature 2012, 486, 518. (d)
discussions. Donghyeon Gwon, Yoonsu Park, and Heejun Hwang
are also appreciated for their help. We also thank one reviewer for
insightful comments.
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(15) DFT calculations carried out to validate the coordination ability for
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