Quantitative Analysis on Two-Point Ligand Modulation of Iridium Catalysts for Chemodivergent C-H Amidation

Article abstract of DOI:10.1021/jacs.0c02079

The transition-metal-catalyzed nitrenoid transfer reaction is one of the most attractive methods for installing a new C-N bond into diverse reactive units. While numerous selective aminations are known, understanding complex structural effects of the key intermediates on the observed chemoselectivity is still elusive in most cases. Herein, we report a designing approach to enable selective nitrenoid transfer leading to sp2 spirocyclization and sp3 C-H insertion by cooperative two-point modulation of ligands in the CpXIr(III)(κ2-chelate) catalyst system. Computational analysis led us to interrogate structural motifs that can be attributed to the desired mechanistic dichotomy. Multivariate linear regression analysis on the perturbation on the η5-cyclopentadienyl ancillary (CpX) and LX coligand, wherein we prepared over than 40 new catalysts for screening, allowed for construction of an intuitive yet robust statistical model that predicts a large set of chemoselective outcomes, implying that the catalysts' structural effects play a critical role on the chemoselective nitrenoid transfer. On the basis of this quantitative analysis, a new catalytic platform is now established for the unique lactam formation, leading to the unprecedented chemoselective reactivity (up to >20:1) toward a diverse array of competing sites, such as tertiary, secondary, benzylic, allylic C-H bonds, and aromatic πsystem.

Full text of DOI:10.1021/jacs.0c02079

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Article
Quantitative Analysis on Two-Point Ligand Modulation
of Iridium Catalysts for Chemodivergent C–H Amidation
Yeongyu Hwang, Hoimin Jung, Euijae Lee, Dongwook Kim, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02079 • Publication Date (Web): 19 Apr 2020
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Journal of the American Chemical Society
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Quantitative Analysis on Two-Point Ligand Modulation of Iridium
Catalysts for Chemodivergent C–H Amidation
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Yeongyu Hwang,†,‡ Hoimin Jung,†,‡ Euijae Lee,†,‡ Dongwook Kim,‡,† and Sukbok Chang*,‡,†
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†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, South Korea
ABSTRACT: Transition metal-catalyzed nitrenoid transfer reaction is one of the most attractive methods for installing a new C–N
bond into diverse reactive units. While numerous selective aminations have been known, understanding complex structural effects of
the key intermediates on the observed chemoselectivity is still elusive in most cases. Herein, we report a designing approach to enable
selective nitrenoid transfer leading to sp2 spirocyclization and sp3 C–H insertion by cooperative two-point modulation of ligands in
the CpXIr(III)(κ2-chelate) catalyst system. Computational analysis led us to interrogate structural motifs that can attribute to the desired
mechanistic dichotomy. Multivariate linear regression analysis on the perturbation on the η5-cyclopentadienyl ancillary (CpX) and
LX coligand, wherein we prepared over than 40 new catalysts for screening, allowed for the construction of an intuitive yet robust
statistical model that predicts a large set of chemoselective outcomes, implying that catalysts’ structural effects play a critical role on
the chemoselective nitrenoid transfer. On the basis of this quantitative analysis, a new catalytic platform is now established for the
unique lactam formation, leading to the unprecedented chemoselective reactivity (up to >20:1) towards a diverse array of competing
sites, such as tertiary, secondary, benzylic, allylic C–H bonds and aromatic π-system.
selectivity. While these state-of-the-art examples of highly
chemoselective amination showcase competitions between
allylic C–H bonds and olefinic π-bonds with nitrenoids derived
from sulfamates or carbamates, the catalyst design for
chemoselective reactivity towards more diverse reacting sites
would be another interesting research direction.9 The key to
success in this realm would be to gain better understandings of
the nitrenoid intermediacy that will be critically influenced by
multiple physical organic descriptors.10 Specifically,
identifying the selectivity trends depending on the structural
effects of catalytic species was not obvious especially for the
chemoselective amination, thereby limiting the immediate
extension of the presently available catalytic protocols.
To this end, we envisioned to quantify structural effects that
merge the electronic and steric features of catalysts to elucidate
the underlying principles in the designed chemoselective
nitrene transfer (Scheme 1b). In performing the rigorous
analysis of the ligand effects, we initially approached this issue
within the context of catalyst modulation. For this purpose,
CpXIr(III)(κ2-chelate) species were regarded as an ideal
platform owing to the cooperative two-point tunability with η5-
cyclopentadienyl ancillary (CpX) in combination with LX
coligand.11 This approach was envisaged to provide an
opportunity for achieving unique chemoselectivity in the
nitrenoid transfer that cannot be enabled by a single-point
variation of catalyst systems.12 In this regard, we envisioned to
develop intuitive structural models that can accurately describe
the electronic/steric features of the key iridium nitrenoids. Most
importantly, statistical treatment on this analysis can readily
predict the reaction outcomes from a large set of catalyst
candidates that can be prepared by combination of newly tuned
CpX and LX ligands. Consequently, this multifaceted approach
could be adapted to establish a new catalytic protocol to
distinguish the subtle differences in competing reactive units.
Introduction
Selective C–H bond functionalization has been actively pursued
to obtain desired synthetic building units from readily available
starting materials.1 In particular, transition metal-catalyzed
nitrenoid transfer into either aliphatic C–H bonds2 or π-systems3
draws special attention since the individual process offers
structurally distinctive amine products, each of which can serve
as an versatile motif in natural products, bioactive molecules,
and materials.4 However, despite this feature, fine tuning of
chemo- or site-selectivity in the delivery of nitrenoids remains
rather challenging because the free energy difference in
competing transition states is only small in most cases.5
Conventionally, substrate-controlled approaches have been
predominantly utilized in order to avoid such a challenge,
whereby the substrate is specifically designed to allow only a
specific unit to react while suppressing the other paths.6 This in
turn limits the flexibility of accessible compounds.
On the other hand, an alternative strategy based on catalyst
design has been scarcely engaged even in intramolecular
reactions, mainly due to the lack of understanding of the
reaction mode and limited ability to fine-tune the catalysts.
Despite these problems, remarkable examples of the catalyst-
controlled chemoselective nitrene transfer were recently
reported (Scheme 1a). For instance, metal nitrenoids generated
from Ru, Mn or Fe-based catalyst systems were found to
undergo an allylic C–H insertion to afford allylic amine
products.7 In contrast, azirdination was favored from the same
substrate type by the action of a dirhodium catalyst.5a
Schomaker and coworkers elegantly showed that
chemoselective reactivity of silver nitrenoids can be achieved
to lead to either allylic C–H insertion or aziridination of homo-
allylic(allenic) carbamates.8 Interestingly, the coordination
geometry controlled by tuning stoichiometry of the employed
ligand was proposed to be responsible for the observed
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Scheme 1. Chemoselective Nitrenoid Transfer
(a) Previous works for chemoselective nitrene transfer
Table 1. Evaluation of Chemoselectivity with the
Previously Reported Catalytic Systemsa
1
2
3
4
5
6
7
8
Control by changing the identity of metal (Du bois, White)
skeletal
rearrangement
O
Me
N
X
X
O
n
H
O
cat. Rh
cat. Ru,Mn,Fe
HN
Me
O
N
O
O
R
O
NH2
O
catalyst (5 mol %)
H
n
R
n
X
oxidant
oxidant
R
HN
Me
Me
H
HN
Me
X = CO, SO2
Aziridination
Insertion
DCM or HFIP,
40 °C, 12 h
CO2
Me
Control by coordination geometry (Schomaker)
2a
3a
N
N
via spirocyclization
& CC migration
via CH insertion
Ag
1a
H
O
N
H
OTf
N
N
OTf
Ag
N
H
H
O
NH2
H
N
O
C5H11
entry
1
catalyst
Rh2(OAc)4
Rh2(esp)2
Co(TPP)
Ru(TPP)CO
Ru1
2a (%)
3a (%)
<1
2a:3a
O
HN
O
C5H11
C5H11
oxidant
oxidant
<1
<1
<1
<1
<2
5
-
-
H
9
Aziridination
Working hypothesis: quantifying the structural effect
Insertion
O
2
<1
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(b)
of catalytic species
Prediction
Cooperative tunability
Multivariate analysis
3
<1
-
CpX variation
4
12
-
R
Ir
5b
6b
7b
8b
48
1:>20
1:2.6
1:19
1.4:1
L
Cl
CpX effect
Can we predict
X
Electronic
nature of
Ir center
reaction outcomes?
(steric/eletronic)
Ru2
13
CpXIr(2-chelate)Cl
Ir1
2
38
LX ligand
(steric/electronic)
two-point modulation
intuitive model
Ir2
58
42
Multifaceted approach for engineering
This work
Development of new catalytic protocol
-
(PF6
)
tailored iridium catalysts
: tunable and chemoselective access to lactams by
(c)
Ru
N
N
Ru
Ir
R2
Ir
Rsmall
Rsmall
H2N
N
N
Cl
Cl
N
Me
Cl
Meoc
O
O
+
Ir
+
H
N
O
O
N
Ir
L
N
L
Ph
N
Ts
HN
X
X
R2
Ph
Ru2
MeO
O
EWG
R2
EWG
N
O2N
O
R1
H
R1
O
H
Ru1
Ir1
Ir2
R1
cat. Ir
spirocyclization
CC migration
aromatic CH
aReaction conditions: 1a (0.05 mmol) and catalyst (5 mol %)
R2
O
Rbig
O
R1
in dichloromethane (DCM, 0.6 mL). Yields were determined
+
N-precursor
Ir
N
L
1
HN
by H NMR analysis of the crude reaction mixture using
X
H
dibromomethane as an internal standard. bNaBArF (5 mol %)
R2
bulky
R1
4
R2
3° and 2° aliphatic,
allylic, benzylic CH
was added and run in hexafluoro-2-propanol (HFIP) solvent.
In entries 1-2, quantitative amounts of starting material were
remained. Otherwise, starting material was decomposed via
a Curtius-type rearrangement.
R1
CH insertion
First example of chemoselective lactam synthesis by cooperative tuning of Ir species
Robust linear-free energy relationship to interrogate the ligand effects
Up to >20:1 tunable chemoselectivity with various types of CH bonds
our previously optimized conditions,11 we predicted that 1a also
may undergo cyclizations to afford either δ-lactam (2a) or γ-
lactam (3a), the former of which we have recently proven to be
formed via a spirocyclization followed by the C–C migration
(vide infra).11a
Herein, we highlight a robust linear-free energy relationship
to achieve highly chemoselective reactivity of nitrenoids
towards sp2 spirocyclization or sp3 C–H insertion (Scheme 1c).
The cooperative two-point tunability of newly developed
CpXIr(III)(κ2-chelate) species permits not only the unique entry
of iridium species but rigorous analysis on catalysts’ structural
effect. Using computationally-derived descriptors to quantitate
steric and electronic impact of the ligand modulation, we
constructed a multivariate linear regression model to interrogate
the underlying selectivity trends. The resulting robust statistical
model enabled us to predict a large set of catalytic reactions
resulting from synergetic combination of CpX and LX ligand.
Such simplification for the reaction optimization facilitated the
development of a new catalytic platform that allows the high
level of tunable chemoselectivity (up to >20:1) for the lactam
formation. In particular, the tailored iridium catalysts ultimately
control over the diverse array of reacting sites, such as tertiary,
secondary, benzylic, allylic C–H bonds and aromatic π-system.
As shown in Table 1, previously established catalyst
systems known to mediate C−H amination reactions were
completely ineffective for the current lactam production
including Rh(II)-carboxylates and Co(II)-porphyrin (entry 1-
3).1c,3g In addition, Ru(II)-porphyrin species that was reported
as an efficient catalyst for the acylnitrene transfer to sulfides
and sulfoxides turned to be only poor in the formation of γ-
lactam 3a (entry 4).13a On the other hand, cationic (η5-
C5H5)Ru(II) species (Ru1) which was recently revealed as an
effective catalyst for the benzylic C−H amidation displayed
excellent selectivity towards the tertiary C(sp3)−H bond albeit
with moderate product yield.14 A chiral ruthenium species
(Ru2) was non-selective and sluggish (entry 6).15 Moreover,
Cp*-based iridium catalyst bearing N,N’-bidentate ligand (Ir1)
showed only moderate reactivity while it favors tertiary sp3
C−H amidation over spirocyclization (entry 7).
Remarkably, when the LX ligand was replaced from N,N’-
type (8-aminoquinoline derivative) to κ2-N,O-system as seen in
Ir2, the lactam formation took place quantitatively although the
chemoselectivity became low (entry 8). It is noteworthy that the
undesired Curtius decomposition pathway is suppressed
effectively with Ir2 catalyst. Based on this newly observed
excellent reactivity of Cp*Ir(III)(κ2-N,O-chelate) species
towards the carbonylnitrenoid transfer process, we decided to
Results and Discussion
Evaluation of Chemoselectivity with the Previously
Reported Catalysts. We commenced our study by evaluating
the chemoselectivity with the previously reported catalysts that
have been widely utilized in metal-nitrenoid catalysis (Table 1).
Initially, as a robust acylnitrene precursor,13 1,4,2-dioxazol-5-
one (1a) bearing potentially reactive tertiary C−H bond and
aromatic π-system was prepared to interrogate the supposed
selectivity. Given that carbonylnitrene transfer is facile under
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initiate a detailed study to optimize more chemoselective dioxazolone substrates (E(dxy) and E(dxz), respectively). Steric
parameters of both CpX and LX ligand were also interrogated.
Equivalent cone angles18 of CpX as well as hydroxyquinoline
ligands were evaluated as ΘCp and ΘLX, respectively. For CpX
ligands, Sterimol parameters (L, B1, and B5)19 were also
investigated since Rovis used them as key parameters in
describing the Rh-catalyzed cyclopropanation17c (see the
Supporting Information for details).
1
2
3
4
5
6
7
8
catalyst systems by cooperatively tuning both hydroxyquinoline
and cyclopentadienyl ligands. Moreover, we envisaged to
achieve an orthogonal selectivity to produce both δ-lactam and
γ-lactam through the design of the proper ligands.
Initial Findings and Parameter Selection. Extensive
studies on the mechanistic pathways of the iridium(III)-
catalyzed C−H amidation of dioxazolone substrates have
suggested the formation of Ir-nitrenoids as a key intermediate
(Scheme 2a).11, 13d Initiated by the chloride atom abstraction
from neutral Cp*Ir(κ2-chelate)Cl precursors, coordinatively
unsaturated cationic species, [Cp*Ir(LX)]+, is generated that is
catalytically active. Coordination of a dioxazolone will furnish
Scheme 2. Structural Model Analysis
(a) Reported reaction mechanism for iridium(III)-catalyzed CH amidation
9
benzo-fused
-lactams
10
11
12
13
14
15
16
17
18
19
20
21
22
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59
60
Ir
O
G
Product
determining
Dioxazolone
-CO2
an iridium-acylnitrenoid species via
a decarboxylative
L
N
Ir
L
X
oxidative coupling. Previous experimental and computational
analysis indicated that closed-shell singlet Ir-nitrenoid species
would be engaged in both aliphatic C(sp3)−H11b and aromatic
C(sp2)−H amidation,11a implying that the properties of the
common Ir-nitrenoid intermediate largely affects the reaction
pathway. Given that variation of 8-aminoquinoline ligands of
the Cp*Ir(κ2-chelate) catalyst system was observed to display
notable reactivity change in our previous C(sp3)−H lactam
synthesis,11b we wondered whether an elaborate two-point
modulation of both cyclopentadienyl (CpX) and N,O-bidentate
ligands may offer an opportunity towards the challenging
chemoselective nitrenoid transfer, which cannot be achieved by
a single-point tuning of ligands.
X
R
Oxidative process
H
-lactams
High-valent Ir-nitrenoid species
Key species in Ir(III)-catalyzed CH amidation
Oxidative formation of high-valent Ir-nitrenoid species
Cpx and LX ligand support the nitrenoid intermediacy
(b) Development of structural model system
Coordinatively
unsaturated
Iridium(III) system
X
Electronic & steric variation
by Cpx ligand
R
Ir
N
Cl
O
Planar structure
Cooperative tuning of LX ligand
To predict the structural effects of the envisaged two-point
ligand modulation on the resultant chemoselectivity, we first
employed a statistical approach based on a multivariate analysis.
In fact, recent studies done by Sigman and coworkers
demonstrated that statistical analysis with multivariate
regression models effectively interrogates the complicated
reaction outcomes in a quantitative manner.16 In contrast to the
transition states analysis, this statistical treatment requires
lower computational cost by using the ground state structure of
molecules. Moreover, construction of the reliable multivariate
linear regression model enables the virtual screening of ligand
candidates without an exhaustive synthetic effort. On the basis
of this consideration, we expected that the chemoselectivity
trend in our designed metal-acylnitrenoid transfer could be
delineated by using simple physical organic parameters derived
from the catalysts’ electronic and steric properties. To extract
such physical organic descriptors that may effectuate the
chemoselectivity, we first focused on the coordinatively
unsaturated cationic species, [CpXIr(LX)]+, which is proposed
as catalytically active species (Scheme 2b).
Next, we attempted to identify molecular descriptors from
the aforementioned coordinatively unsaturated iridium species
(Scheme 2c). The optimized structures by density functional
theory (DFT) calculations share a common geometry that an
iridium center and a hydroxyquinoline ligand lie on the same
plane that is perpendicular to the η5-cyclopentadienyl ligand
(CpX). Recently, Rovis and coworkers systematically evaluated
the steric and electronic properties of CpXRh(III) catalysts,17
and, therefore, we selected key parameters that can represent
electronic/steric effects in our case. To check the impact of
electronic effects on the chemoselectivity, widely utilized
descriptors including natural bond orbital (NBO) charge of the
Ir atom (NBOIr), and Hammett constants of substituents at the
C5-hydroxyquinoline (σLX) were considered. Moreover,
frontier orbital energies of filled dxy and unfilled dxz orbitals
were also checked as they are key orbitals interacting with
Computationally optimized
[CpxIr(LX)]+ species
How can we build a robust structural model?
(c) Parameter selection
Electronic parameters
Steric parameters
B1
B5
L
Cp
Ir
Ir
R
LX
O
Ir
R
N
X
O
R
N
O
N
X
X
X
z
filled
dxy
unfilled
dxz
X
X
y
Sterimol values
(L, B1, B5)
Equivalent cone angles of
CpX (Cp) and LX ligand (LX
x
NBO charge of Ir
Hammett constant of X
orbital energy
)
Construction of Multivariate Models. To construct a
multivariate model predicting the chemoselectivity, our
designed catalyst system was disassembled into three classes: Ir
complexes
bearing
parent
Cp*
with
substituted
hydroxyquinolines (Group I, Ir2–Ir19), those with varied CpX
ligand along parent 8-hydroxyquinoline (Group II, Ir2, Ir20–
Ir26), and catalysts with variable CpX and electronic/sterically
tuned hydroxyquinoline ligands (Group III, Ir27–Ir41). Group
I and Group II species were utilized as training set to construct
the desired multivariate model, where catalysts in Group III
were employed to externally validate the constructed statistical
model.
To find the parameters that can give precise correlation with
the measured chemoselectivity on the sp2 spirocyclization and
sp3 C–H insertion, we first checked the univariate relationship
between measured ΔΔG‡ with each parameter. The
chemoselectivity obtained from our newly developed Ir
catalysts is summarized in Table 2. Although substitution of
electron-withdrawing groups at the C5-position of the
hydroxyquinoline ligand favored the spirocyclization (Ir3–Ir9),
the observed chemoselectivity remained moderate to reach the
highest level when 5-nitrohydroxyquinoline ligand is present
(4.5:1). In stark contrast, bulky substituents at the C2-
hydroxyquinoline reversed the selectivity to highly favor the
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Table 2. Normalized Structure-Free Energy Relationship of Acylnitrene Transfer Reactiona
1
2
3
4
O
Me
N
O
Ir catalyst (10 mol %)
NaBArF4 (10 mol %)
Me
O
O
O
H
HN
Me
Me
H
HN
skeletal
rearrangement
Me
HFIP, 60 °C, 12 h
Me
 CO2
2a
3a
5
via spirocyclization
& CC migration
via CH insertion
1a
6
7
8
9
(a) LX ligand variation (Group I)
(b) CpX variation (Group II)
Orbital energy E(dxz) analysis
Cone angle ( LX) analysis

X
5-NO2
5,7-di-Cl
5,7-di-I
Ir9
4.5:1
2.8:1
R
2
Ir
G‡  0.13 LX + 17.56
G‡  3.57 E(dxz)  22.04
3
Ir
N
N
Cl
Ir10
Cl
R2 = 0.93
R2 = 0.66
4
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
Ir11
Ir12
1.6:1
1:1.9
7
6
Ir cat.
Ir2
X
2a 3a
:
2-Me-5,7-di-Cl
2-Me-5,7-di-Br
2-Me-5,7-di-I
Ir cat.
R
-
2a 3a
:
1.4:1
1:1.4
Me
Ir2
1.4:1
1.1:1
Ir13
Ir14
Ir15
1:2.5
1:3.2
1:6.1
iPr
tBu
Ph
Ir20
LX (°)
E(dxz) eV
 

5-tBu
5-Ph
5-F
Ir21
Ir22
1:1.6
1.0:1
Ir3
Multidimensional analysis
G‡  0.24 E(dxy) 0.66 LX  0.24
Multidimensional analysis
G‡  0.38 E(dxz) 0.25 Cp 0.14
Ir4
Ir5
Ir6
Ir7
Ir8
1.3:1
1.9:1
1.9:1
2.0:1
2.2:1
2-iPr-5,7-di-I
2-R'-5,7-di-I
R2 = 0.86
Q2LOO = 0.55
R2 = 0.97
Q2LOO = 0.96
Ir23
1.0:1
OMe
CF3
Ir16
Ir17
Ir18
1:5.7
1:5.6
1:8.3
5-Br
2-nPr-5,7-di-I
3.0:1
Ir24
CF3
Cy
5-Cl
2-isobutyl-5,7-di-I
Ir25
Ir26
1:2.0
5.5:1
5-CF3
Ir19 2-neopentyl-5,7-di-I 1:16.7
G‡ measured (kcal/mol)
G‡ measured (kcal/mol)
H


R' = CH2CH2(4-Me)C6H4
aReaction conditions: 1a (0.05 mmol), Ir catalyst (10 mol %), and NaBArF (10 mol %) in HFIP (0.6 mL). Yields were determined
4
by 1H NMR analysis of the crude reaction mixture using dibromomethane as an internal standard.
formation of C(sp3)–H insertion product as demonstrated by
Ir19 (1:16.7). Notably, Group I catalysts with the variation on
LX type ligands showed a clear correlation of the measured
selectivity with cone angles ΘLX (R2 = 0.93, Table 2a, top graph).
This linearity can be rationalized by assuming that LX ligands
bearing large substituents close to the metal center will lead to
γ-lactams mainly by the steric influence (Ir12–Ir19).
more complicated outcomes. For instance, when compared to
Cp*, although sterically bulky substituent on CpX ligand
favored C(sp3)–H amidation, this selectivity was not
significantly high (Ir21). However, a remote electronic
variation on the phenyl moiety at the CpX ligand displayed a
notable improvement as evidenced by Ir24. Most strikingly,
when Ir26 bearing no substituent at the X position of CpX was
employed, the highest chemoselectivity was observed to favor
sp2 spirocyclization over -lactam formation (5.5:1).
Although the above univariate correlation was found to be
reliable to some extents, a more robust model was envisioned
to construct based on a multivariate model. Indeed, we were
pleased to see that the addition of an electronic parameter E(dxy)
provided a more precise model with high coefficient of
determination (R2 = 0.97, Table 2a, bottom graph). This new
model was statistically evaluated by the leave-one-out cross
Based on the above experimental data, a statistical model
using a single variable descriptor was constructed (Table 2b, top
graph). It was intriguing to recognize that this model can present
a quantitative correlation of chemoselectivity with the iridium
frontier orbital energies of dxz [E(dxz)], implying that the CpX
ligand largely affects the electronic nature of the resultant Ir
complexes. Moreover, involvement of equivalent cone angles
of CpX (ΘCp) improved the overall quality of the fit (R2 = 0.86,
Table 2b, bottom graph). Of note, statistical modeling using
Sterimol parameters such as B1 instead of equivalent cone
angles of CpX ligand (ΘCp) also resulted in a similar
determination coefficient. Further studies on the appearance of
steric parameters suggested that the accessible CpX orientation
toward the incoming reactive units is important for selectivity.
In particular, the sterically less congested edge of the CpX
ligand facilitated the nitrenoid transfer more favorably towards
sp2 spirocyclization, which is consistent with the experimental
observation using Ir26 catalyst.
To interrogate the linear free energy relationship more
comprehensively, we sought to construct a global model that
can predict simultaneous variations on both types of ligands (25
reaction outcomes). Pleasingly, a quantitative linear regression
model was obtained by considering three parameters which
were previously recognized to account for the individual effect
of LX and CpX ligands (Scheme 3). The resulting mathematical
equation consisted of frontier orbital energies of dxz [E(dxz)],
equivalent cone angles of CpX (ΘCp) and LX ligand (ΘLX). This
validation (Q2
= 0.96). A correlation of orbital energies of
LOO
dxy underlines that electrophilic metal center facilitates the
spirocyclization pathway. As these are normalized models, the
magnitude of the coefficients indicates the numerical
contribution for the designed selective nitrene transfer. The
larger coefficient (–0.66) of the equivalent cone angles ΘLX
indicates that LX ligand significantly affects the molecular
geometry of the catalytically active species, which is well
consistent with the qualitative selectivity trend observed from
experiments. These results, however, suggest that more
precisely engineered electronic and steric features of the ligand
system is still desirable to develop highly selective catalysts,
eventually performing sp2 spirocyclization or sp3 C–H insertion
almost exclusively.
With the same approach, the influence of CpX ligand on the
chemoselectivity was also examined with the parent 8-
hydroxyquinoline as a fixed LX ligand (Group II). As depicted
in Table 2b, we further synthesized and tested a series of
CpXIr(III)(LX) species (LX = 8-hydroxyquinoline) with
elaborated electronic/steric variation on the cyclopentadienyl
cap. While an analogous perturbation was observed as in the
case of LX ligand tuning, engineering CpX moiety resulted in
4
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Journal of the American Chemical Society
multidimensional model displayed an excellent correlation (R2
= 0.93) and the leave-one-out cross validation (Q2
= 0.90),
and Ir37 that showed the comparable level of selectivity yet
better catalytic activities (see the Supporting Information for
details).
1
2
3
4
5
6
7
8
LOO
thus showing robustness of the developed model (see the
Supporting Information for details). On the basis of the
coefficients of the normalized parameters, equivalent cone
angles of LX (ΘLX) can be regarded as the most influential
factor to determine product ratio. Interestingly, single electronic
determinant, E(dxz), illustrated that the orbital energy is
dominant in modulating the electrophilicity of the resultant
iridium center. To check a possibility that E(dxz) mainly reflects
the ligand environments around the metal center, we compared
LUMO energy with another electronic parameter. However, for
catalysts sharing the same CpX ligand, the LUMO energies were
found to directly correlate with Hammett parameters of the
substituents at the C5-position of LX ligand. The steric
environment tuned by CpX ligands (ΘCp) displayed relatively
lower coefficient (–0.20), presumably due to the distance from
the metal center.
Evidences for Ligand Effects on the Selectivity-
Determining Stage. Having understood the details on the
origin of the unprecedented chemoselectivity towards either sp2
spirocyclization or sp3 C–H insertion, subsequent studies were
conducted to identify how the structural features engage in the
nitrenoid transfer. Again, our regression model indicated that
introduction of sterically bulky ligands will lead to higher
C(sp3)–H selectivity, while catalysts bearing less bulky ligands
and electron-withdrawing groups effectuate spirocyclization.
The optimal selective catalyst for the each designed acylnitrene
transfer are shown in Figure 1a. Solid state structure of Ir41 and
Ir19 was unambiguously confirmed by X-ray crystallographic
analysis to reveal the molecular geometry of two distinctive
CpXIr(III)(κ2-N,O-chelate) complexes (Figure 1b and 1c).
While the iridium center of Ir19 is more shielded by two
sterically bulky substituents on the hydroxyquinoline ligand,
neopentyl and iodo group at the C2 and C7-position,
respectively, this anisotropic effect is significantly reduced in
Ir41. The Ir–N and Ir–O bond lengths of Ir19 are slightly
longer (2.142(8) Å and 2.104(3) Å, respectively) than those of
Ir41 (2.073(6) Å and 2.091(3) Å), presumably due to the steric
congestion on the metal center of Ir19. Interestingly, sterically
less bulky edge of the Cp*H in Ir41 is oriented towards the
hydroxyquinoline rather than chloride atom, suggesting that the
geometry of Cp*H is influenced by the steric environment of
chelating units around the iridium center. Dihedral angles of
C1–O–Ir–Cl are very distinctive between these two different
types of iridium catalysts: 81.4° for Ir41 and 117.2° for Ir19.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Normalized Regression Model for the Global Set
(a) Both LX ligand/CpX variation (Group III)
Ir cat.
X
R
2a 3a
:
Ir cat.
X
R
2a:3a
iPr
Ir27
5,7-di-Cl
1.4:1
Ir35
Cy
5,7-di-Cl
1.0:1
iPr
Ir36
Ir37
Ir38
Ir39
Cy
Cy
2-R'-5,7-di-I
1:8.6
Ir28
Ir29
Ir30
Ir31
Ir32
2-Me-5,7-di-Cl 1:2.1
5,7-di-Cl 1.7:1
2-isobutyl-5,7-di-I 1:13.6
Ph
Cy 2-neopentyl-5,7-di-I 1:19.0
Ph
Ph
2-Me-5,7-di-Cl 1:1.8
5-tBu
H
H
H
3.6:1
8.4:1
5-NO2
2.6:1
5-CF3
(4-OMe)C6H4
Ir40
Ir41
5,7-di-Cl
1.6:1
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
5-NO2
Ir33
Ir34
5,7-di-Cl
5-CF3
4.3:1
3.4:1
14.0:1
R' = CH2CH2(4-Me)C6H4
(b) Multivariate regression model for the global set
C(sp3)H insertion
(a)
Spirocyclization
G‡  0.30 E(dxz) 0.20 Cp  0.74 LX  0.15
Cy
H
R
Ir
Ir
Ir
N
N
N
Cl
Cl
Cl
R2 = 0.93
Q2LOO = 0.90
O
O
O
Ir41
I
I
O2N
I
I
Ir18
R = isobutyl,
Ir41
Ir37
Ir19
neopentyl,
Ir18
Ir19
(b)
(c)
Ir37
Ir38
Ir
O
Ir
O
Cl
Cl
C1
C1
N
G‡ measured (kcal/mol)

N
The constructed model delineating the chemoselectivity level
was further validated by predicting ΔΔG‡ of catalysts in Group
III. Theoretically, 119 new Ir catalysts could be virtually
investigated on the basis of possible combination of 18 LX and
8 CpX ligands used as a training set. Thus, the predictive power
of our model to indicate the most optimal catalyst would be
practiced even without synthesizing all possible combinations.
Indeed, the predicted free energy difference among examined
catalysts in Group III was well matched with the measured
ΔΔG‡, as plotted in blue dots (Scheme 3b). Consequently, we
successfully extrapolated chemoselectivity trend by the
quantitative model of catalysts’ structural features (15 reaction
outcomes). The best performing catalyst for selective sp2
spirocyclization was Ir41 which has 5-nitrohydroxyquinoline
ligand in combination with Cp*H. Although the reaction using
Ir38 displayed the highest selectivity towards the C(sp3)–H
amidation, the moderate product yield led us to select Ir18, Ir19,
Ir41
Ir19
X-ray of
X-ray of
2.073(6) Å
2.091(3) Å
81.4(5)°
2.142(8) Å
2.104(3) Å
117.2(9)°
IrN
IrO
IrN
IrO
C1OIrCl
C1OIrCl
Figure 1. (a) Selected catalysts for tunable and chemoselective
acylnitrene transfer reaction. Solid state structure of (b) Ir41
and (c) Ir19. All hydrogen atoms are omitted for clarity
While the X-ray crystallographic analysis on two optimal
catalysts revealed distinct structural features, the influence of
spin states of the putative metal-nitrenoid intermediates on the
reaction outcome will be another issue to consider. For instance,
Du Bois and coworkers suggested that the diruthenium-
5
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catalyzed selective allylic C−H amination is enabled by a The above preliminary experimental results led us to believe
stepwise pathway involving radical intermediates.7a In our
newly developed iridium system, this possibility of an open-
shell nitrenoid transfer was first scrutinized by performing a
series of experiments (Scheme 4). Cyclization reactions of
deuterated dioxazolone 4 were found to display slightly
different kinetic isotope effect (KIE) depending on the catalysts
employed (Scheme 4a). However, both values are rather in a
similar range when compared to those obtained from
Cp*Ir(III)(κ2-N,N’-chelate) catalysts which we previously
that two types of catalyst systems selecting either
spirocyclization (Ir41) or C(sp3)−H insertion (Ir18 and Ir19)
share a common mechanistic feature involving closed-shell
singlet iridium nitrenoid intermediates II (Scheme 5a). Because
both the C−H insertion and spirocyclization are irreversible
processes to afford the corresponding lactam products,11 the
chemoselectivity trend can be interrogated by transition state
models on CN bond forming step. As depicted in Scheme 5b−c,
transition state models of sp2 spirocyclization and sp3 C−H
insertion are proposed on the basis of X-ray structures of Ir41
and Ir19, respectively. The relatively open environment and
more electrophilic iridium center in Cp*HIr(III)(LX) Ir41 (LX
= 5-nitrohydroxyquinoline) may enforce an orbital interaction
of the nucleophilic aromatic ipso-carbon with electrophilic Ir-
nitrenoid fragment. Moreover, less bulky edge of Cp*H ligand
will allow facile approaching of sterically encumbered aromatic
moiety of the model substrate to the nitrene site (Scheme 5b).
The resultant spiro-amido intermediate III subsequently
undergoes C−C bond migration, eventually leading to skeletal
rearranged benzolactams through an intermediate IV (Scheme
5a, left cycle).
By contrast, in case of Ir19, as seen by the X-ray
crystallographic analysis, larger substituents on the C2 and C7-
positions in hydroxyquinoline ligand along with Cp* cap endow
the complex with sterically more congested environment.
Whereas sterically less demanding aliphatic C−H bonds of
substrates can readily enter into a well-organized catalytic
pocket of Ir19 to enforce a concerted C−H insertion (Scheme
5c), an alternative spirocyclization would be disfavored within
such highly regulated steric environment. Consequently,
catalysts bearing larger substituents on both CpX and LX ligand
will favor the concerted C−H insertion through a transition state
V, thus leading to structurally distinctive -lactam products
(Scheme 5a, right cycle).
1
2
3
4
5
6
7
8
9
proposed to work via a closed-shell nitrenoid transfer.11b
A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
complete stereoretention was observed in the cyclization of
optically enriched dioxazolone 6 irrespective of catalyst types
employed (Scheme 4b). On the other hand, the reaction of a
dioxazolone substrate bearing para-hydroxy group (8) afforded
aza-spirodienone product (9). Although the reaction efficiency
was found to be differed between two types of catalyst, a
spirocyclization pathway is commonly operative (Scheme 4c).
Scheme 4. Experimental Mechanistic Studies
(a)
O
O
O
Ir catalyst (10 mol %)
NaBArF4 (10 mol %)
O
O
NH
ND
Ph
N
D
HFIP, 60 °C, 24 h
D
D
D
CO2
D
Ph
5H
H
5D
Ph
Ir41
Ir18
KIE value,
: 1.28 (45%)
: 1.12 (98%)
4
(b)
O
O
O
O
Above conditions
retention of
stereochemistry
NH
N
Ir41
Ir18
: >99% e.e. (91%)
: >99% e.e. (94%)
6
(>99% e.e.)
7
(c)
O
O
Ir catalyst (5 mol %)
NaBArF4 (5 mol %)
H
O
O
N
Ir41
Ir19
: >95%
: 37%
O
N
HFIP, 60 °C, 12 h
NPhth
NPhth
HO
CO2
9
8
Scheme 5. Proposed Transition State Model for Chemodivergent C−H Insertion and Spirocyclization
(a)
(b) Proposed TS model for selective sp2 spirocyclization (Ir41)
Orientation of
H substituent
H
H
R
+
O
Ir
O
+
+
Ir
N
L
N
Ir
O
L
N
N
X
Me
Me
R
H
X
O
Me
Me
bulky Me
NO2
Me
EWG
CC
migration
V
R
R
X = H
lower E(dxz) by EWG
N




III
X = Me(Cy)
less shielded iridium center
O
Me
X
sterically encumbered aromatic ipso-carbon
H
Spirocyclization
& CC migration
Concerted
CH insertion
O
H substituent of CpX towards incoming unit
Ir
O
O
+
+
Me
L
Ir
Ir
L
N
L
N
HN
spirocyclization favored
Me
Me
X
X
X
Ar
Me
Me
H
Me
VI
(c) Proposed TS model for selective sp3 CH insertion (
)
Me
Ir19
bulky
EWG
IV
CO2
R
R
Dioxazolone
O
H
II
+
CO2
Ir
H
Me
N
Me
Me
O
Me
N
O
H
Catalytic
pocket
Dioxazolone
I
HN
Me
O
HN
I
Me
R
R
H
N
R
X
higher E(dxz
)
Me




Model substrate
O
cat. CpXIr(LX)Cl + NaBArF
+
4
Me
Ir
O
N
congested iridium center
L
O
NaCl
sterically less demanding aliphatic CH bond
O
X
I
Me
H
Me
catalytic pocket generated by bulky
substituents around the iridium center
R
R
CH insertion favored
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Table 3. Catalyst-Controlled Chemoselective and Tunable C–H Amidationsa
1
2
3
4
5
6
7
8
9
migrated from the position para
to R1 to the meta-position
spirocyclization
& CC migration
O
O
R2
N
O
O
CH insertion
O
H
HN
Ir
Ir
HN
R2
0 ~ 25 °C
25 ~ 60 °C
R2
H
R1
R1
R1
2a-k
1a-k
3a-k
steric perturbation
aromatic -system vs tertiary CH
Me
O
N
O
O
O
sterically
congested
Me
N
O
O
O
O
O
H
Ir41
Ir19 Ir37
or
HN
Me
Ir41
Ir18
O
HN
HN
Me
H
H
Me Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HN
H
R
R
R
b,c,f,g
1a
)
R = H
Me
Cl
Br
(
(
(
(
2a
(:
2b
, 98%
, 98%
>20
3b
Ir19
3a
(: 1:
Ir19
, 46% (
)
, 71% (
)
)
1b
)
:1)
(
:
  >20
:1)
>20
)
1e
b,c
11
(: 1:
)
3e
2e
(:
, 20%
>10
, 84%
>20
1c
)
:1)
(: 1:
)
2c
(:
2d
1d
)
, 95%
>20
, 90%
3c
(: 1:
Ir19
3d
Ir37
, 68% (
, 61% (
)
:1)
( :
  >20
:1)
>20
  >20
1: )
)
(
:
aromatic -system vs secondary CH
aromatic -system vs allylic CH (vs olefinic -bond)
O
O
plausible
reaction site
O
O
N
O
N
O
O
O
NH
Ir41
Ir19
HN
Ir41
O
Ir18
O
HN
H
H
H
HN
H
b,c,h
2f
(:
, 87%
>20
3f
, 18%
1f
1g
e,f,g
b,c,f,g
:1)
2g
3g
, 98%
, 70%
2.6
(: 1:
)
11.7
(:
:1)
(
:
1:
  >20
, 6.8:1 d.r.)
aromatic -system vs benzylic CH
R
O
O
N
O
HN
R
Ir41
Ir18
O
O
H
HN
H
R
1h
)
R = H
Me
OMe
CF3
(
trans
(X-ray of
e,f,g
f,g
b,c,f,g
b,d,f,g
1i
1j
(
(
)
)
)
2h
2i
3h
3i
, 66%
, 92%
, 71%
, 67%
3h
)
12.5
  4
  >20
(:
:1)
(
:
:1)
(
(
:
1:
  >20
, >20:1 d.r.)
(
(
:
1:
, >20:1 d.r.)
2f
(X-ray of
)
1k
(
f,g
g
b,d,f,g
b,c,f,g
2j
2k
3j
3k
, 42%
, 47%
, 84%
, 55%
:
  >20
>20
(:
:1)
(
:1)
:
1:
  >20
, >20:1 d.r.)
: 1:
  >20
, >20:1 d.r.)
aReaction conditions: substrate (0.1 mmol), Ir catalyst (5 mol %), and NaBArF4 (5 mol %) in HFIP (1.2 mL) at 25 °C for 12 h.
1
Chemoselectivity and diastereomeric ratio (d.r.) were determined by H NMR of the crude mixture. Total yields of isomeric
amidated products are indicated. bCHCl3 was used as a solvent. cRun at 40 °C. dRun at 60 °C. eRun at 0 °C. fRun for 72 h. g10 Mol
% of catalyst was used. h2,2,2-Trifluoroethanol (100 μL) was added.
Evaluation of Tunable Chemoselectivity. Generality of the
On the other hand, a dioxazolone substrate 1g having a
potentially reactive allylic C−H bond was selectively converted
to the corresponding cyclic amide products by the action of
individual catalyst (2g and 3g). Importantly, a side pathway
leading to aziridine was not operative in both cases. For -
lactam formation with catalyst Ir18, not only tertiary and allylic
C−H bonds but also those at the benzylic position were
tunable and chemoselective construction of lactam scaffolds
was explored to employ various classes of dioxazolone
substrates. The high catalytic performance of optimal catalysts
led us to screen reaction at lower temperature, improving the
resultant chemoselectivity (Table 3). As predicted, catalyst Ir41
mediated a tandem process to furnish benzo-fused δ-lactams
(2a−2d) under extremely mild conditions, wherein
spirocyclization and subsequent C−C bond migration occurs
highly efficiently and selectively. In contrast, the optimal
catalysts Ir19 or Ir37 completely reversed the chemoselectivity
to favor C(sp3)−H amidation to afford the corresponding -
lactam products (3a−3d) albeit in slightly lower yields. When
sterically congested substrates (1e) were examined, while δ-
lactam was formed still efficiently (2e), the C(sp3)−H insertion
was sluggish in this case (3e). With a dioxazolone substrate
containing both aromatic π-system and secondary C−H bond
(1f), the similar reactivity trend was observed, where δ:γ-
isomeric ratio was >20:1 (2f) with catalyst Ir41 and 1:2.6 (3f)
with Ir19. Of note is that the tricyclic product 2f was formed
either via spirocyclization followed by C–N migration, or by a
direct SEAr-type process, and its solid structure was
unambiguously confirmed by an X-ray crystallographic
analysis.
successfully
applied
with
excellent
chemo-
and
diastereoselectivity (3h−3k). Various phenyl substituents such
as alkoxy, alkyl, and CF3 groups were compatible. The same
substrates were cyclized to the corresponding benzo-fused δ-
lactams (2h−2k). However, selectivity was observed to
decrease when a para-methyl substituent is present in the
benzyl moiety (2i). Overall, it needs to be emphasized that our
tunable and chemoselective amidation protocol will be broadly
applicable in accessing synthetically versatile lactam products
with diverse array of competing reactive units.20
Conclusions
In summary, we have successfully demonstrated that our
multifaceted designing approach enables the highly
chemoselective acylnitrene transfer towards either sp2
spirocyclization or sp3 C−H insertion. The newly designed
CpXIr(κ2-N,O chelate) catalytic system provided the unique
entry of iridium complexes by cooperative two-point
modulation of CpX and LX ligand. On the basis of this fast and
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C–H Amination: Scope, Mechanism, and Applications. Chem. Rev.
2017, 117, 9247-9301.
convenient tunability, structural effects of catalytic species
1
2
3
4
5
6
7
8
were rigorously identified by multivariate regression model
analysis, where we prepared over than 40 new catalysts for
screening. The resultant quantitative model led us to effectively
extrapolate the chemoselectivity level of catalysts from
simultaneous variations on both types of CpX and LX ligands.
Of particular interest is that selectivity trends could be
collaboratively modeled using 3 molecular descriptors, frontier
orbital energies of dxz [E(dxz)], equivalent cone angles of CpX
ligand (ΘCp) and LX ligand (ΘLX), from catalytically active
species. Consequently, a new catalytic platform further allowed
the establishment of unprecedented chemoselective nitrenoid
transfer, to date, towards a diverse array of competing sites,
such as tertiary, secondary, benzylic, allylic C–H bonds and
aromatic π-system.
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Paudyal, M. P.; Gao, H.; Xu, Q.-L.; Yousufuddin, M.; Devarajan,
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Synthesis of Unprotected N-H and N-Me Aziridines from Olefins.
Science 2014, 343, 61-65; (f) Paudyal, M. P.; Adebesin, A. M.;
Burt, S. R.; Ess, D. H.; Ma, Z.; Kürti, L.; Falck, J. R., Dirhodium-
catalyzed C-H arene amination using hydroxylamines. Science
2016, 353, 1144-1147; (g) Jiang, H.; Lang, K.; Lu, H.; Wojtas, L.;
Zhang, X. P., Asymmetric Radical Bicyclization of Allyl
Azidoformates via Cobalt(II)-Based Metalloradical Catalysis. J.
Am. Chem. Soc. 2017, 139, 9164-9167.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available
free of charge on the ACS Publications website.
Experimental procedures; characterization data; spectra
for all new compounds; crystallographic data; Cartesian
coordinates of all computed structures (PDF)
Crystallographic data for Ir19
Crystallographic data for Ir41
Crystallographic data for 2f
Crystallographic data for 3h
AUTHOR INFORMATION
Corresponding Authors
*sbchang@kaist.ac.kr
ORCID:
Yeongyu Hwang: 0000-0002-9637-997X
Hoimin Jung: 0000-0002-3026-6577
Euijae Lee: 0000-0002-2069-8042
Dongwook Kim: 0000-0003-4432-371X
Sukbok Chang: 0000-0001-9069-0946
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Institute of Basic Science (IBS-
R010-D1). Single crystal X-ray diffraction experiments with
synchrotron radiation were performed at the BL2D-SMC in Pohang
Accelerator Laboratory. H.J. is grateful to the National Research
Foundation of Korea (NRF) for the global Ph.D. fellowship (NRF-
2019H1A2A1076213).
(4) Hili, R.; Yudin, A. K., Making carbon-nitrogen bonds in
biological and chemical synthesis. Nat. Chem. Biol. 2006, 2, 284-
287.
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Table of Content (TOC) Graphic
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H
N
O
Multivariate analysis
CpXIr(2-chelate)
R
R1
Ir
X
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rearranged
H
R2
L
two-point
modulation
benzo-fused
-lactams
R
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Ir
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Chemodivergent
transformation
N
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R2
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H
NH
R2
Ligand engineering
by quantitative approach
R1
G‡ measured (kcal/mol)

-lactams
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