Scope and Mechanistic Studies of the Cationic Ir/Me-BIPAM-Catalyzed Asymmetric Intramolecular Direct Hydroarylation Reaction

Article abstract of DOI:10.1021/om501260w

(Chemical Equation Presented). Results of mechanistic studies on asymmetric hydroarylation of α-keto amides via direct C-H bond addition to a carbonyl group catalyzed by a cationic Ir/Me-BIPAM complex are presented in this paper. A catalytic cycle involvi

Full text of DOI:10.1021/om501260w

Article
pubs.acs.org/Organometallics
Scope and Mechanistic Studies of the Cationic Ir/Me-BIPAM-
Catalyzed Asymmetric Intramolecular Direct Hydroarylation Reaction
Tomohiko Shirai† and Yasunori Yamamoto*,‡
‡
†Graduate School of Chemical Sciences and Engineering and Division of Chemical Process Engineering, Faculty of Engineering,
Hokkaido University, Sapporo, 060-8628, Japan
S
* Supporting Information
ABSTRACT: Results of mechanistic studies on asymmetric hydro-
arylation of α-keto amides via direct C−H bond addition to a
carbonyl group catalyzed by a cationic Ir/Me-BIPAM complex are
presented in this paper. A catalytic cycle involving C−H bond
cleavage to give an Ar-[Ir]+ intermediate, insertion of a carbonyl
group into the aryl-iridium bond, giving iridium alkoxide, and finally
reductive elimination to reproduce active [Ir]+ species is proposed.
The mechanistic insight for the iridium hydride species indicated
that the C−H bond cleavage is caused in a reversible manner.
Furthermore, the kinetic isotope effect was measured by product
analysis of the reaction to compare H/D, and it was determined that
kH/kD was 1.85. These experimental results suggest that the C−H
bond cleavage step is not included in the turnover-limiting step. In
addition, Hammett studies of substrates (ρ = −0.99) demonstrated that electron-donating groups at the para position to the
reactive C−H bond accelerate the reaction rate. This linear relationship obtained in the Hammett plot indicates that the
nucleophilicity of the aryl-iridium intermediate is an important factor in this reaction. All of the data indicate that carbonyl
insertion into aryl-iridium is included in the turnover-limiting step of the catalytic cycle.
Scheme 1. Cationic Ir/Me-BIPAM-Catalyzed
Enantioselective Intramolecular Direct Hydroarylation
INTRODUCTION
■
Asymmetric control in the construction of quaternary carbon
centers is an important methodology to synthesize various
pharmaceuticals and natural products. The asymmetric
addition1 of aryl boron reagents to C−O or C−N double
bonds such as ketones2−5 and ketimines6 is a general synthetic
route for tertiary alcohols or amines having chiral quaternary
carbon skeletons. However, these methods generate stoichio-
metric metal salt wastes as byproducts. Thus, an enantiose-
lective direct C−H bond addition reaction that does not
require an organometallic reagent is highly desirable in terms of
the atom and synthetic step economy. However, there have
been few reports on asymmetric nucleophilic addition of a C−
H bond to the carbonyl group by a transition metal catalyst.7
Our group recently reported cationic Ir/Me-BIPAM-catalyzed
enantioselective intramolecular direct hydroarylation of α-keto
amides (Scheme 1).8 This transformation provides a con-
venient synthetic route for chiral 3-substituted 3-hydroxy-2-
oxindole derivatives with asymmetric induction. While some
pioneering works have been reported,9 only limited mechanistic
information is available for aryl sp2 C−H bond addition to
carbonyl groups. Herein, we report the results of mechanistic
studies of our newly developed intramolecular enantioselective
hydroarylation reaction.
RESULTS AND DISCUSSION
■
Substrate Scope. The cationic Ir/Me-BIPAM catalyst
system achieves highly reactive and enantioselective hydro-
arylation of a wide range of α-keto amides. In optimized
reaction conditions, the reaction occurred solely at the
sandwiched C−H bond between the N,N-dimethyl carbamoyl
group and keto amide group10 to provide the corresponding
oxindole products. Our developed method is the first example
of highly enantioselective direct C−H bond addition to
carbonyl compounds and displays broad functional group
Received: December 9, 2014
Published: July 8, 2015
© 2015 American Chemical Society
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tolerance (Table 1). Although the N,N-dimethyl carbamoyl
group serves as the best directing group, other directing groups
Scheme 2. Formation of Iridium Hydride Species
a
Table 1. Substrate Scope
b
Entry
R =
R′ =
R″ =
C6H5 (1a)
yield [%] ee [%]
1
2
3
4
5
6
H
H
>99 (2a)
98 (2b)
99 (2c)
80 (2d)
94 (2e)
93 (2f)
97 (2g)
97 (2h)
90 (2i)
87 (2j)
88 (2k)
97 (2l)
85 (2m)
90 (2n)
96 (2o)
85 (2p)
96 (2q)
95 (2r)
93 (2s)
85 (2t)
92 (2u)
95 (2v)
86 (2w)
66 (2x)
98 (S)
98
90
98
91
91
84
97
92
97
94
98
80
93
91
95
94
92
90
92
87
86
90
70
H
H
4-CF3C6H4 (1b)
4-FC6H4 (1c)
H
H
H
H
4-BrC6H4 (1d)
4-PhC6H4 (1e)
4-CH3C6H4 (1f)
4-PhOC6H4 (1g)
3-CF3C6H4 (1h)
3-CH3C6H4 (1i)
2-FC6H4 (1j)
H
H
H
H
c
7
H
H
as those for iridium hydride species, were observed between
−20 to −30 ppm at temperatures over 100 °C. While iridium
hydride was detected at 100 °C, the product was obtained in
only 21% yield for catalytic reaction conditions (Scheme 3).
These results clearly demonstrate that a high temperature (135
°C) is essential for the steps except for C−H bond cleavage in
the catalytic cycle.
8
H
H
c
9
H
H
10
H
H
c
11
H
H
2-naphthyl (1k)
3,5-(CF3)2C6H3 (1l)
3,4-(CH2O2)C6H3 (1m)
C6H5 (1n)
12
H
H
c
13
H
H
14
15
16
17
18
19
20
21
22
23
24
CH3
CF3
Cl
H
H
H
C6H5 (1o)
Scheme 3. Effect of Temperature
H
C6H5 (1p)
H
CH3 (1q)
H
H
CH2CH3 (1r)
CH(CH3)2 (1s)
C6H5 (1t)
H
H
H
CH3
CH3
CH3
CH3
CH3
H
4-CF3C6H4 (1u)
4-FC6H4 (1v)
4-CH3C6H4 (1w)
4-CH3OC6H4 (1x)
H
H
H
To obtain additional data for the reaction mechanism, we
carried out an asymmetric hydroarylation reaction of substrate
1s in the presence of D2O (6 equiv) under our optimized
conditions (Scheme 4). The reaction was quenched in 1 h, and
a
Reaction conditions: α-keto amides (0.25 mmol), [Ir(cod)2](BArF )
4
(5 mol %), and (R,R)-Me-BIPAM (1.1 equiv to Ir) in DME (1 mL)
was stirred for 16 h at 135 °C. The letter within the parentheses
b
indicates the absolute configuration of the chiral center within the
c
product. 5 mol % of [Ir(cod)((R,R)-Me-bipam)](BArF ) was used as
4
Scheme 4. Deuterium Labeling Experiment
the catalyst.
such as acetyl and benzoyl groups are also effective. In most
cases, complete regioselectivity, high yield, and excellent
enantioselectivity were obtained. This transformation demon-
strates a broad functional group tolerance on the aromatic
ketone (entries 1−13). Additionally, high enantioselectivity was
maintained even when the aromatic ring of the aniline side has
a substituent such as a CH3, Cl, or CF3 group (entries 14−16).
Similarly, the method can be extended easily to a variety of
aliphatic α-keto amides to produce 3-alkyl-3-hydroxy-2-
oxindoles in high enantioselectivities (90−94% ee; entries
17−19). Finally, the reaction of α-keto amides bearing a methyl
group on the nitrogen atom was also attempted. In most cases,
desired products were obtained with good yields and
enantioselectivities (entries 20−23), but a moderate result
was observed only in the case of electron-donating methoxy-
bearing substrate (entry 24).
the mixture was purified to produce the unreacted substrate 1s-
D (30%) and product 2s-D (68%). Deuterium incorporation
was observed at the ortho position of the keto amide group
(11%-D at Hb and 44%-D at Hd), the ortho position of the N,N-
dimethyl carbamoyl group (10%-D at Ha) in the substrate, and
the 5- and 7-positions of the product (11%-D at Ha and Hd) on
the integration ratio of the 1H NMR spectra of 1s-D and 2s-D.
These results may arise from the fact that the C−H bond
cleavage occurs in a fast and reversible manner prior to the
carbonyl insertion.7,9g,h In addition, deuterium incorporation
was also observed at the N,N-dimethyl carbamoyl group in both
the substrate (1s-D) and product (2s-D).
Mechanistic Studies. For mechanistic investigations, we
first observed iridium hydride species that form via C−H bond
cleavage (Scheme 2). In order to ascertain the C−H bond
1
cleavage step, monitoring of H NMR spectra of a mixture of
Ir/Me-BIPAM complex and 1a in DME-d10 at various
temperatures was conducted. As a result, some signals, such
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Next, isotope labeling studies were undertaken, with separate
rate constants being measured for reactions. The intermolecular
kinetic isotope effect (KIE) of the reaction employing
substrates 1a and 1a-D was found to be 1.85 at the early
stage of the reaction (Scheme 5).9h,j These experimental
Scheme 5. Kinetic Isotope Effect
observations for the C−H bond cleavage step suggest that C−
H bond cleavage occurs before the turnover-limiting step in the
catalytic cycle (secondary isotope effect can be observed)
(Figure 1).11 In Figure 1, the turnover-limiting step is the
Figure 2. Hammett plot using substrates 1a and 1n−p.
aryl-iridium intermediate (an electron-donating substituent
increases the nucleophilicity of the aryl-iridium species).
Next, the Hammett plot for substituents (Y) at the para
position to the ketone group was also attempted to confirm the
hypothesis as mentioned above (Figure 3). If the Hammett plot
Figure 1. Proposed energy diagram.
second step, and the reaction rate is shown as k2[B]. The
concentration of B depends on the equilibrium of reversible C−
H bond cleavage/formation having rate constants k1 and k−1,
respectively. Due to the deuterium substitution, the equilibrium
is greatly affected, and thus the concentration of B is reduced.
As explained above, although iridium hydride species formed
easily at a low temperature (100 °C), the reaction only
proceeded smoothly at a high temperature (135 °C) to give the
desired product, and H/D scrambling was observed in the
deuterium labeling experiment. These results indicated that the
k−1 step is much faster than the k2 step, and the obtained value
of the kinetic isotope effect (1.85) results from an equilibrium
isotope effect on the C−H bond cleavage step.
Figure 3. Hammett plot using substrates 1a−c and 1f (NH) or 1t−1w
(NMe).
To finally determine the turnover-limiting step of this
reaction, a Hammett study was performed. The investigation
focused on insertion of a carbonyl group into the aryl-iridium
bond. First, substrates having an electron-donating or electron-
withdrawing substituent (X) at the para position to the reactive
C−H bond were subjected to competing reactions. Hammett
plot analysis using substrates (1a, 1n−1p) provided a linear
relationship in a plot of log(kX/kH) versus σ, where ρ was
determined to be −0.99 (Figure 2). This result shows that the
reaction rate of a substrate having an electron-donating
substituent at the para position to the reactive C−H bond is
faster than that of a substrate having an electron-withdrawing
substituent, and it can be considered that this relationship
displays the reactivity for insertion of a carbonyl group into the
shown in Figure 2 displays reactivity for carbonyl insertion into
aryl-iridium, a linear relationship having a positive gradient
should be obtained in Figure 3. Unfortunately, a clear
substituent effect was not observed. The Hammett plot
displayed a linear relationship between log(kX/kH) and σ,
resulting in a small ρ value of −0.099. This result is probably
due to a keto amide skeleton being activating by the electron-
withdrawing amide group, and the substituent effect was thus
neutralized. In other words, the reactivity for the insertion step
is determined by nucleophilicity of the aryl-iridium inter-
mediate. In order to ascertain the effect by the electron-
withdrawing amide group, we further tested by changing the
electronic nature of the amide moiety. The Hammett plot using
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N-Me substrates displayed an insufficient ρ value of −0.34.
These experiments demonstrate the strong activation of amide
group. In our developed reaction, the electronic effect of the
substituent X in Figure 2 plays a key role in control of
reactivity.
These experimental and kinetic data suggest that the
turnover-limiting step in this reaction is more closely related
to the insertion of a carbonyl group into the aryl-iridium
intermediate than to the C−H bond cleavage step.9h
We propose a catalytic cycle for the cationic Ir/Me-BIPAM-
catalyzed enantioselective intramolecular direct hydroarylation
(Scheme 6). First, the precatalyst mixture of [Ir(cod)2](BArF )
4
Scheme 6. Proposed Catalytic Cycle
Figure 4. DFT calculations of aryl-iridium intermediate optimized at
the B3LYP/LANL2DZ level.
and (R,R)-Me-BIPAM forms active complex a. Subsequently, a
cationic active species reacts with substrate 1 to afford aryl-
iridium intermediate b, which is coordinated with the two
carbonyl groups of the amides. In this state, an equilibrium
exists between complex b and c. Asymmetric hydroarylation of
the ketone carbonyl group would proceed from c, thus
producing enantiomerically enriched iridium alkoxide species
d. Finally, reductive elimination occurs to give product 2 and
regenerate the active species.
The absolute configuration of oxindole product 2a was
established to be S by X-ray analysis.8 However, no X-ray
structure of an active chiral catalyst is yet available because of
the difficulty in synthesizing a single crystal of the cationic Ir/
Me-BIPAM complex. To further investigate the carbonyl
insertion process (intermediate c in Scheme 6), DFT
calculations were performed with B3LYP/LANL2DZ level of
theory. At first, the two minimum energy modes of Ar-
[Ir((R,R)-Me-BIPAM)]-H (intermediate b in Scheme 6) were
calculated (Figure 4). Next, the turnover-limiting and stereo-
determining step, which is coordinated with the two carbonyl
groups (the aryl-iridium intermediate c in Scheme 6) were
calculated (Figure 5). The conformation c2 giving the
experimentally observed S product has a low energy for
reaction from the intermediate in which the carbonyl oxygen is
coordinated to the iridium center at the Si-face after the C−H
bond cleavage process. Conversely, coordination at the Re-face
of the carbonyl group (c1) has a higher energy than Si-face
coordination (c2) (ΔEc1‑c2 = 3.10 kcal/mol). Thus, the
Figure 5. DFT calculations of enantioselection models at the B3LYP/
LANL2DZ level.
enantioselective insertion to Si-face of the carbonyl group can
be rationalized by less steric congestion intermediate c2.
CONCLUSION
■
In conclusion, the detailed mechanism for enantioselective
intramolecular direct hydroarylation of α-keto amides catalyzed
by a cationic iridium/Me-BIPAM complex is described. The
turnover-limiting step in the catalytic cycle was determined to
1
be the carbonyl insertion step to the aryl-iridium bond by H
NMR experiments, kinetic isotope effect studies, and Hammett
studies.
EXPERIMENTAL SECTION
■
General Procedure. To a flame-dried flask, [Ir(cod)2]-
(BArF ) (0.0125 mmol, 5 mol %) and (R,R)-Me-BIPAM
4
(0.0138 mmol, 5.5 mmol %) and dry dimethoxyethane (1.0
mL) were added under an N2 atmosphere. The solution was
stirred at room temperature for 30 min, followed by the
addition of α-keto amides (0.25 mmol). The reaction mixture
was then heated at 135 °C. After being stirred for 16 h, the
mixture was purified with silica gel column chromatography
(eluent: n-hexane/ethyl acetate) to afford pure 3-substituted 3-
hydroxy-2-oxindole.
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ASSOCIATED CONTENT
* Supporting Information
Text, tables, and figures providing experimental details, spectral
and/or analytical data for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/om501260w.
■
S
(7) Tsuchikama, K.; Hashimoto, Y.-K.; Endo, K.; Shibata, T. Adv.
Synth. Catal. 2009, 351, 2850−2854.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yasuyama@eng.hokudai.ac.jp. Tel/Fax: +81-11-706-
8117.
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science.
■
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