Harnessing Secondary Coordination Sphere Interactions That Enable the Selective Amidation of Benzylic C-H Bonds

Article abstract of DOI:10.1021/jacs.9b07795

Engineering site-selectivity is highly desirable especially in C-H functionalization reactions. We report a new catalyst platform that is highly selective for the amidation of benzylic C-H bonds controlled by π-πinteractions in the secondary coordination sphere. Mechanistic understanding of the previously developed iridium catalysts that showed poor regioselectivity gave rise to the recognition that the π-cloud of an aromatic fragment on the substrate can act as a formal directing group through an attractive noncovalent interaction with the bidentate ligand of the catalyst. On the basis of this mechanism-driven strategy, we developed a cationic (ν⁵-C₅H₅)Ru(II) catalyst with a neutral polypyridyl ligand to obtain record-setting benzylic selectivity in an intramolecular C-H lactamization in the presence of tertiary C-H bonds at the same distance. Experimental and computational techniques were integrated to identify the origin of this unprecedented benzylic selectivity, and robust linear free energy relationship between solvent polarity index and the measured site-selectivity was found to clearly corroborate that the solvophobic effect drives the selectivity. Generality of the reaction scope and applicability toward versatile γ-lactam synthesis were demonstrated.

Full text of DOI:10.1021/jacs.9b07795

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Article
Harnessing Secondary Coordination Sphere Interactions
Enables the Selective Amidation of Benzylic C-H Bonds
Hoimin Jung, Malte Schrader, Dongwook Kim, Mu-Hyun Baik, Yoonsu Park, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07795 • Publication Date (Web): 26 Aug 2019
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Journal of the American Chemical Society
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Harnessing Secondary Coordination Sphere Interactions Enables
the Selective Amidation of Benzylic C−H Bonds
Hoimin Jung,†,‡ Malte Schrader,§ Dongwook Kim,‡,† Mu-Hyun Baik,‡,†,* Yoonsu Park,‡,†,* 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
§Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, Münster 48149, Germany
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ABSTRACT: Engineering site-selectivity is highly desirable especially in C−H functionalization reactions. We report a new catalyst
platform that is highly selective for the amidation of benzylic C−H bonds controlled by - interactions in the secondary
coordination sphere. Mechanistic understanding of the previously developed iridium catalysts that showed poor regioselectivity
gave rise to the recognition that the -cloud of an aromatic fragment on the substrate can act as a formal directing group through
an attractive non-covalent interaction with the bidentate ligand of the catalyst. Based on this mechanism-driven strategy, we
developed a cationic (η5-C5H5)Ru(II) catalyst with a neutral polypyridyl ligand to obtain a record-setting benzylic selectivity in an
intramolecular C−H lactamization in the presence of tertiary C−H bonds at the same distance. Experimental and computational
techniques were integrated to identify the origin of this unprecedented benzylic selectivity, and robust linear free energy
relationship between solvent polarity index and the measured site-selectivity was found to clearly corroborate that the solvophobic
effect drives the selectivity. Generality of the reaction scope and applicability towards versatile γ-lactam synthesis were
demonstrated.
Scheme 1. Site-selective C–H amination via nitrene
Introduction
transfer.
The selective functionalization of C–H bonds is a central
theme in transition metal-based catalysis. In principle,
site-selectivity towards a specific C–H bond is dictated by
a.
Previous works: selective sulfamate ester formation
HN
FG
FG
H
site-selective
CH amidation
NH2
FG
Ph
R2
NH
H
H
a
complex interplay of multiple kinetic and
H
cat. [M]
thermodynamic factors.1 For instance, secondary C–H
bonds are sterically less demanding than tertiary
counterparts and can therefore be accessed more easily by
metal catalysts, generally leading to faster reactions.2 In
some cases, the electronic richness on the tertiary position
can effectively stabilize intermediates that derive from C–
H bond cleavage to favor activation of the tertiary C–H
bond.3 Unusual electronic structures, such as multiple
accessible spin states found in high-valent metal-
carbenoids4 and -nitrenoid5 species, further complicate the
activation mechanisms. As a result, predicting and
rationally designing selective C–H bond cleavage reactions
has been notoriously difficult.
Ph
R2
Ph
R2
OTf
N
Ru
O
N
N
N
+
N
N
Ag
Mn
N
X–
N
N
Ru
Cl
N
N
N
N
Du Bois, 2011
Schomaker, 2014
White, 2015
b.
metal-acylnitrenoid

Harnessing
for -lactam formation
B
T
H
H
H
H
Ph
Me
Me
NH
catalysts
Me
Me
Me
Me
Ph
Ph
N
HN
+
[M]
?
2B
Mechanistic Challenge
How to guide the site-selective CH functionalization?
2T
O
O
O
acylnitrenoid
c. This work
selective amidation
this work
: Discovery of a modular catalyst platform for
Catalytic C–H amination is one of the most direct
approaches to installing nitrogen functionalities onto
organic compounds via C–H functionalization.6 Recent
efforts to harness the power of C–H amination for
preparing pharmaceutically active products7 dramatically
increased the complexity of substrates that can be
processed giving high levels of control even when other
reactive functionalities are present. Selective benzylic C–H
amination attracted special attention in this context
(Scheme 1a), because the benzylamine scaffold is of
particular pharmaceutical importance.8 Du Bois firstly
addressed this issue by designing a sulfamate ester
substrate9 containing benzylic and tertiary C–H bonds
positioned at the same distance. In this system, benzylic-
to-tertiary (B:T) ratio was shown to be moderate at ~1.5:1,10
while sterically bulky catalysts enabled selective amidation
at the tertiary position.9,11
Trost et al.
L
L
Ru+
C
H amidation
catalysis
Hydrosilylation
catalysis

S
S
[in-situ]
S
commercials
new catalysts
 First use of Trost's Ru(II) complex
as a new platform for C–H amidation
 Record-setting benzylic selectivity
N
P
N
P
N
P
O
+
N
O
N
C
Ru N
N
N
H
H
B
T
> 20 : 1
for lactamization up to
:
premix
 Robust predictive model indicated
solvophobic effects during catalysis
key  interaction
Schomaker reported a remarkable series of silver-based
catalysts that facilitate C–H functionalization at the
benzylic over tertiary position at a ratio of 5.8:1.12,13 In
addition, White recently showed that iron and manganese-
based catalysts can display exceptional selectivity towards
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the benzylic position in the introduction of sulfamate ester
catalysts bearing either N,N’ or N,O-bidentate ligands (Ir1
moieties.14 While these systems are state-of-art examples of
selective catalysis, most of them are confined to sulfamate
ester formation. Moreover, strategic concepts for enforcing
the benzylic selectivity is scarce at the present.
to Ir4) offered excellent amidation reactivity, but produced
almost equimolecular amount of γ-lactams 2B and 2T.
Chiral iridium catalysts (Ir520 and Ir621) that previously
enabled asymmetric induction afforded diminished
reactivity and selectivity. Inspired by the elegant recent
work of Yu,22 the (p-cymene)Ru(II)-based catalyst (Ru1)
was also tested, but it only gave moderate selectivity (2B:2T
= 2.1:1). Displacement of the chiral diamine ligand to
aminoquinoline functionalities (Ru2) yielded poor
regioselectivity, suggesting that none of the currently
known catalysts for the γ-lactam formation gives
satisfactory results and highlighting the fundamental
difficulty in differentiating the benzylic from tertiary C–H
bonds mentioned above. Because identifying catalysts
capable of effectively carrying out γ-lactam forming
reactions is challenging on its own right, a conventional
screening of a large diversified set of catalysts is neither
possible nor desirable. Thus, we sought to more
comprehensively understand the reaction mechanism and
1
2
3
4
5
6
7
8
We recently found that 5-membered cyclic amides can
be formed by driving C–H insertion upon accessing the
reactive metal-acylnitrenoid intermediates.15 Experimental
and computational analyses validated the closed-shell
reactivity of the employed iridium-based catalysts, where
singlet metal-nitrenoid species are engaged in electrophilic,
two-electron C–H insertion processes. Considering
aforementioned issue on the B:T selectivity, we wondered
whether selective benzylic C–H amidation could be
achieved in the presence of electron-rich tertiary C–H
bonds (Scheme 1b). The importance of benzyl-
functionalized lactams further motivated us to target such
selective catalysis.16 This pursuit is challenging, however,
because there is no rational strategy for distinguishing the
benzylic positions in a putative 6-membered cyclic
transition state.
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identify
a conceptual feature that may allow for
Thus, we attempted to construct
a
conceptual
engineering high levels of B/T selectivity using the
acylnitrene intermediate.
foundation based on the reaction mechanism that may
allow for engineering such B:T selectivity. In an iterative
search that incorporated insights from both computational
and experimental studies, we identified a novel ruthenium
catalyst system that displays an exceptional selectivity
towards benzylic C–H amidation (Scheme 1c). Specifically,
DFT calculations suggested that non-covalent interactions
between the catalyst and the substrate may be exploited to
direct the reactivity towards the benzylic position. The
cationic (η5-C5R5)Ru(II) complexes (R= H or Me), which is
a renowned catalyst for Trost’s hydrosilylation17 and allylic
substitution18 reactions, were found to be ideal for this new
strategy. This new platform allows for rapidly prepararing
a variety of so-far inaccessible catalysts by simply
premixing the commercially available metal precursor and
neutral ligands on demands. Such operational simplicity
was further leveraged for parallel screening of ligand
effects, and a novel catalyst was identified that led to
unprecedented site-selectivity towards benzylic position
with B:T ratios as high as 25:1. Integrated experimental and
computational mechanistic studies on the origin of the
site-selectivity confirmed the active role of π-π interactions
under the Curtin-Hammett situation. The highly reactive
yet selective nature of the new system further enabled
catalytic production of various γ-lactams from versatile
amide agents, 1,4,2-dioxazol-5-ones.
Scheme 2. Evaluation of B:T selectivity with previously
reported catalysts.a
H
H
H
H
Ph
HN
Me
catalyst (5 mol %)
NaBArF4 (5 mol %)
Me
Me
NH
Ph
N
Me
Me
Me
Ph
+
O
CD2Cl2 or TCE-d2
CO2
O
2B
2T
1
O
O
O
Ir
Ir
Ir
Ir
N
N
N
N
Cl
Cl
Cl
Cl
O
N
N
MeO
O
Meoc
Meoc
Cl
Ir3
MeO
b
Ir4
, 47% yield
= 1.7:1
Ir1
B T
:
Ir2
, >95% yield
, 96% yield
, >95% yield
B T
b
B T
:
:
B T
= 1 1.3
:
= 1:1.1
: = 1:1.5
Ru
Ru
N
Ir
Ir
Ts
Ts
Cl NPhth
Cl
N
Cl
N
Cl
N
N
N
H2N
H2N
Meoc
Ph
Mes
MeO
Ru2
O
Ph
Mes
Ir5
Ir6
Ru1
, 44% yield
, 46% yield
, 47% yield
, 78% yield
B T
:
B T
:
B T
:
B T
: = 1.0:1
= 1.3:1
= 1.6:1
= 2.1:1
aReactions were performed for 12 hours at room
temperature; yields and B:T-selectivities were determined
by crude 1H NMR analysis using 1,1,2-trichloroethane as an
internal standard. Otherwise stated, single diastereomer
was observed for compound 2B. bRetrieved from reference
Results and Discussion
Evaluation of B:T selectivity against known
catalysts. Initially, we sought to utilize a model substrate
that allows for systematically evaluating the performance
of various catalysts towards the B:T selectivity. For this
purpose, 1,4,2-dioxazol-5-one 1 containing both benzylic
and tertiary C–H bonds at the γ- and γ’-positions was
selected owing to its robust nature as an acylnitrene
precursor.19 Various catalysts that previously displayed
notable reactivity for γ-lactam formation were tested and
the results are summarized in Scheme 2. Iridium(III)
15.
TCE,
1,1,2,2-tetrachloroethane.
Meoc,
methyloxycarbonyl.
Computer-Aided Design Strategy. Mechanistically,
the regioselectivity is determined at the step of C–H
insertion, as highlighted in Scheme 3. Previous studies
established
a
mechanism involving the oxidative
decarboxylation of the catalyst-substrate adduct I to give a
highly reactive iridium-acylnitrenoid intermediate II.23
Whereas complex II may have several distinct conformers,
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Journal of the American Chemical Society
II-B and II-T illustrated in Scheme 3 are most relevant to energy of 4.6 kcal/mol (II-B to II-T, then to II-T-TS). The
1
2
3
4
5
6
7
8
the key C–H insertion step leading to the benzylic and
tertiary amidation, respectively. Since traversing the 6-
membered C–H insertion transition states might
irreversibly lead to the corresponding lactam products,15
the process determining the selectivity can be analyzed by
employing the Curtin-Hammett principle that gives
control over the two possible reaction pathways.
computed free energy difference between II-B-TS and II-
T-TS (ΔΔG‡= 0.6 kcal/mol) taken at face value suggests
that the tertiary C–H bond activation is slightly preferred
over the benzylic C–H activation, and this finding is
consistent with an experimental trend observed in Scheme
2. But, given that these reaction steps have very low
barriers of ~5 kcal/mol and follow immediately the likely
rate-determining decarboxylation step, these seemingly
reasonable agreement between theory and experiment
must be evaluated with some caution. Nonetheless, the
calculations are fully consistent with the experimental
findings and a closer inspection of the factors that
determine the C–H bond insertion is justified.
Interestingly, the optimized transition state geometries
reveal a critical insight that is useful for a possible catalyst
design strategy. As highlighted in Figure 1, there is a
potential π-π interactions in the intermediate conformer
II-B that precedes the benzylic insertion, which is absent
in the conformer II-T. In II-B the phenyl moiety of the
substrate is arranged in parallel orientation to the
quinoline ligand of the catalyst at a π-π distance of 3.65 Å,
well within the expected distance of a π-π stack.26 This
attractive interaction, however, weakens as the bulky
phenyl moiety approaches the metal center for the
benzylic activation and at the transition state II-B-TS the
π-π stack is lost, as a detailed analysis of the intrinsic
reaction coordinate (IRC) trajectory unambiguously
confirmed (Figure S7).
Intrigued by this computational analysis, we envisioned
that if the attractive π-π interaction can be maintained
throughout the C–H insertion event, it may offer a new way
of enhancing the B:T selectivity towards benzylic
functionalization in the absence of any coordinating
group. As depicted in Scheme 4, we anticipated that the
barrier associated with the benzylic activation could be
lowered, while the barrier for the tertiary C–H bond
remains unaffected. To test this idea, we imagined that an
aromatic ligand with an extended π-system may be a
reasonable candidate. At the same time, we were also
mindful of the electronic structure of the metal-nitrenoid
Scheme 3. Distinctive reaction pathways to 2B and 2T.
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O
O
+
Ir
N
O
L
L
benzylic
CH insertion
R
X
I
O
2B
2T
+ N
H
Ir
X
CO2
L
H
H
Ph
II-B
+
O
Ir
N
tertiary
CH insertion
R
X
II
O
N
+
Ir
Me
L
H
H
X
Me
Ph
II-T
The reaction mechanism was investigated in detail using
the representative iridium catalyst Ir2 at the B3LYP-D3/cc-
pVTZ(-f) level of density functional theory24,25 and the key
findings are summarized in Figure 1. As shown in a full
reaction energy diagram in Figure S6, the putative iridium-
nitrenoid species II can be generated from an adduct I by
traversing the decarboxylation transition state with an
activation barrier of 13.2 kcal/mol. Extensive
conformational search of the resulting intermediate
located two active intermediate conformers II-B and II-T,
which are thermodynamically more stable than their
parent linear conformer II by 2.8 and 2.3 kcal/mol,
respectively, thus identifying II-B as the lowest energy
intermediate. Complex II-B can undergo benzylic C–H
insertion with a barrier of 5.2 kcal/mol (II-B to II-B-TS),
whereas tertiary functionalization requires slightly less
G
(kcal/mol)
benzylic tertiary
II-B-TS
(2.37)
II-T-TS
(1.77)
O
Ir
N
N
N
R
iPr
MeO

II
(0.0)
II-B
3.655
Å
II-T
(–2.28)
O
Ir
N
II-B
N
(–2.81)
N
H
H
R
O
N
H
H
O
O
[Ir]
MeO
[Ir]
N
[Ir]
N
H
H
H
Ph
II-B-TS
Ph
Ph
H
II-B
II
II-T
Figure 1. Potential energy profile of the Ir2 system for B:T selectivity-demanding stages.
3
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species and the influence from the ancillary ligand Cp* synthesized by reacting metal-chloride dimers and free
phen ligand.33 Catalytic amounts of these complexes were
subsequently subjected to a solution of dioxazolone 1 with
concomitant addition of sodium organoborate to generate
cationic species having one vacant coordination site. To
our surprise, the dicationic complexes did not display any
reactivity (entries 2-4). Analysis of the crude mixtures
indicated that quantitative amount of the starting
1
2
3
4
5
6
7
8
because they were previously identified as critical factors
in other C–H functionalization reactions.27 To incorporate
these concerns, we sought to systematically examine d6-
based catalysts, such as Ir(III), Rh(III), and Ru(II)
complexes that are known to mediate metal-acylnitrenoid
formation from carbonylnitrene precursors, e.g.
dioxazolones and acyl azides.28
materials remained unreacted after 12
h at room
Scheme 4. Catalyst design strategy for benzylic selectivity.
temperature. We reasoned that this lack of reactivity might
be due in part to thermodynamic inaccessibility of
dicationic metal-nitrenoid species. Kinetic barrier for the
key oxidative decarboxylation is expected to be much
higher in energy because of the highly electrophilic nature
of putative dicationic metal-nitrenoid intermediate.
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Challenge
loss of  stacking
during C–H insertion
O
Ir
N
O
Ir
N
N
N
N
R
N
H
H
iPr
MeO
R
MeO

How to conserve  stacking?
Scheme 5. Reaction Development.a
H
H
Steric & electronic
control by Cp tuning
H
H

Me
Ph
HN
Me
Ph
N
catalyst (5 mol %)
additive (10 mol %)
Me
NH
Me
-
Charge and oxidation state
Me
Me
O
N
Ph
+
M
+
M
control by metals
N
N
L
L
+
O
H
H
N
O
TCE
- stacking to guide
other -rich ligands
N
1
2B
2T
-
O
O
O
2B 2T
:
entry
catalyst
addtivie
yield (%)
NaBArF
NaBArF
NaBArF
NaBArF
1:1.1
<5
Ir2
96
<5
<5
<5
61
80
44
70
88
1
2
3
4
5
6
7
8
9
4
4
4
4
Searching for a new catalyst platform that satisfies the
aforementioned criteria, we became interested in
polypyridine ligands that have neutral molecular charge
and rich aromatic π-clouds in a rigid planar backbone, such
as 1,10-phenanthroline (phen). Indeed, free polypyridine
compounds are known for participating in π-π interactions
with various organic fragments, and the extent of such
interaction further increases substantially upon bidentate
σ-coordination to a Lewis acidic metal center due to
coordinatively induced π-polarization (Scheme 4).29 Most
prominently, Barton demonstrated that the phen
functionality in the [Ru(phen)3]2+ complex can readily
intercalate into DNA through strong π-π interactions with
nucleobase pairs.30 Interestingly, recent examples in
transition metal catalysis accentuated the importance of π-
π stacking in catalytic activity and selectivity.31 Zhu
discovered an iron/phen-based catalyst that enables
benzylic selective hydrosilylation of styrene derivatives.32
Mechanistic studies have identified that π-π interaction
between a substrate and the catalyst guided the excellent
regio-selectivity. In a similar vein, Schomaker and co-
workers have found that π-π stacking is operative in
silver/polypyridyl amine catalysis for selective C–H
amidation of sulfamidate esters.12b Computational study
suggested that the pyridyl moiety coordinated to a silver
catalyst displays active non-covalent interaction through
space. In this system, benzylic C–H functionalization is
favored over tertiary activation up to 5.8:1 in B:T selectivity.
Reaction development. Motivated by these examples
and our own computational analysis, we sought to prepare
metal complexes bearing neutral phen ligands to harness
potential π-π interactions for lowering the activation
barrier for the benzylic C–H cleavage (Scheme 5). Targeted
[Cp*Ir(phen)Cl]Cl (Ir7) and analogous rhodium (Rh1) and
ruthenium (Ru3) congeners were independently
Ir7
<5
Rh1
Ru3
Ru4
Ru5
<5
7.4
8.3
:1
:1
-
-
-
-
-
1.3:1
2.0:1
[Cp*Ru(MeCN)3](PF6)
[CpRu(MeCN)3](PF6)
Ru5b
14
:1
R
+
Cl-
+
-
+
R
R
R
(PF6
Cl-
R
N
)
Ru
N
M
N
Ru
N
N
Cl
Cl
N
N
Me
Ir7
M= Ir,
Ru3
Ru4
Ru5
R= Me,
R= H,
Rh1
M=Rh,
aReactions were performed for 12 h at room temperature;
yields and B:T-selectivities were determined by crude H
1
NMR analysis using 1,1,2-trichloroethane as an internal
standard. bRun in hexafluoro-2-propanol (HFIP) solvent.
The inactivity of the dicationic complexes on the lactam
formation highlights the importance of catalyst charge on
the amidation reactivity. It led us to pursue a new catalyst
platform having a d6 configuration where a molecular
charge of +1 could be maintained upon complexation with
neutral phen ligand. One possible class of the catalysts that
meet this criteria includes a group 8 Cp*Ru(II) complex,
which has been mainly utilized as effective pre-catalyst for
alkyne hydrosilylation17 and allylic substitution18 reactions.
In fact, while arene-coordinated ruthenium(II) complexes,
such as (p-cymene)Ru(II) chloride dimers, have been
extensively studied in the C–H amidation chemistry
recently,34 a related Cp*Ru(II) complex has received much
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Journal of the American Chemical Society
less attention, and there is no literature example for
NMR analysis using 1,1,2-trichloroethane as an internal
standard. bDetermined by HPLC analysis. cRun at 40 oC
1
2
3
4
5
6
7
8
utilizing this type of catalysts for C–H amidation reactions.
The targeted Cp*Ru(II)/phen complex Ru4 was simply
prepared by mixing commercially available solvento-
complex [Cp*Ru(MeCN)3](PF6) and phen ligand. To our
delight, mono-cationic Ru4 catalyst indeed displayed
amidation reactivity, and afforded the desired γ-lactam
products in overall yield of 61% (entry 5, Scheme 5). More
significantly, the B:T selectivity was found to be in favor of
the benzylic position by as much as 7.4 times. This B:T ratio
is remarkable when compared to the reactions with the
previously known catalysts shown in Scheme 2. An obvious
optimization of this encouraging result is to test the
simpler Cp variants. Interestingly, substitution of the Cp*
ancillary ligand with Cp groups further enhanced the
reactivity and selectivity to afford 80% combined yield and
8.3:1 of the B:T ratio (entry 6). Control reactions in the
absence of phen ligand afforded significantly lowered
activities (entries 7-8), suggesting that the 1,10-
phenanthroline ligand plays an important role in the
selectivity determining process, as designed. Utilizing
HFIP as solvent gave rise to an even higher selectivity of
14:1 and product yield of 88% (entry 9). Of note, evaluation
of solvent effects with the previous catalysts in Scheme 2
gave only a marginal impact on the selectivity, showcasing
the unique selectivity of the newly scrutinized CpRu(II)
platform.
We firstly examined commercially available 1,10-
phenanthroline derivatives as potential ligands, and the
results are summarized in Scheme 6. Electronic variation
resulted in high selectivity with variable product yields,
possibly due to the electronic perturbation on the π-cloud
(L2 to L8). Among them, 5-nitro-1,10-phenanthroline (L5)
gave quantitative conversion to the benzyl-amidated γ-
lactam 2B with excellent site-selectivity, reaching up to
25.4:1 ratio (2B:2T), which is arguably a record-setting
selectivity in the intramolecular C–H amidation reactions
when benzylic and tertiary C–H bonds compete with each
other. The ligand pool was further extended to include a
related family of bidentate nitrogen donors. Whereas the
bipyridyl framework provided variable selectivities and
reactivities (L9 to L12), 4,5-diazafluoren-9-one (L13) and
1,10-phenanthroline-5,6-dione (L14) ligands that had been
studied for aerobic oxidation reactions35 displayed
excellent activities towards selective C–H amidation
reactions. In comparison, the 8-aminoquinoline scaffold
(L15, L16), which was effective in iridium(III) catalysis,15
resulted in decreased efficiency and selectivity.
Benzylic selectivity over other reactive positions.
We next wondered whether our new catalyst system is
tolerant to stereo-electronic perturbations of the
substrates. Utilizing the pre-mixing strategy to generate an
active catalyst, a score of substrates was subjected to the
optimal conditions with ligand L5 (Figure 2). Installing
electron-withdrawing groups on the aromatic moiety
eroded the B:T selectivity to some extent. For example,
whereas the p-chloro substituent displayed excellent
regioselectivity (17:1, 3B), the trifluoromethyl group only
gave moderate selectivity (4.9:1, 4B). Interestingly, notable
increase in the selectivity was observed when electron-rich
ligand L2 was used in lieu of L5. The use of ligands with
electron-donating groups may enhance the proposed 
interactions with electron-deficient aryl groups in
substrates, thus eventually increasing the benzylic
selectivity. On the other hand, electron-donating
substituents such as methoxy group offered almost
exclusive benzylic selectivity (>20:1, 5B and 6B). This
electronic trend is easy to understand considering the
substituent effects on the benzylic bond strengths. Similar
qualitative observation was made in a recent study by
Schomaker and co-workers in silver-catalyzed selective C–
H amidation reactions.12b Steric variation on the tertiary
moiety afforded excellent benzylic regio-selectivity, as
exemplified by a substitution of isopropyl with cyclohexyl
group (7B). Moreover, a new type of substrate 8 that
contains phenylethyl and isobutyl groups at the α-carbon
to the dioxazolone moiety also displayed a high level of
benzylic selectivity yet with moderate diastereoselectivity
(9B). Of particular note, otherwise identical reactions with
the iridium catalyst (Ir2) resulted in poor site-selectivity in
most of the cases examined, clearly highlighting
extraordinary selectivity by the current ruthenium catalyst
system.
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 6. Ligand effects on (η5-C5H5)Ru(II)-catalyzed
C−H amidation of dioxazolones.a
H
H
Me
Me
Ph
N
H
H
Ph
HN
Me
Me
NH
cat. [CpRu(MeCN)3]PF6
Me
Me
Ph
L
cat.
O
+
O
HFIP
1
2B
2T
O
O
O
MeO
Cl
Ph
N
N
N
N
N
N
N
N
MeO
Cl
Ph
L1
L2
L3
L4
14
20
20
20
88% yield, :1
78% yield, > :1 84% yield, > :1
95% yield, > :1
O2N
Cl
N
N
N
N
N
N
N
N
L5
>95% yield, > :1
L6
L7
L8
20
20
20
20
90% yield, > :1 91% yield, > :1
76% yield, :1
b,c
25.4
(
:1
)
MeO
N
N
N
N
N
N
N
N
MeO
L9
L10
L11
L12
12
20
77% yield, > :1
15
72% yield, :1
14
37% yield, :1
80% yield, :1
Meoc
NH
NH2
N
N
O
O
MeO
N
O
N
MeO
N
N
L13
L14
L15
45% yield, 3.5:1
L16
49% yield, 3.5:1
b,c
18.4
20
87% yield, > :1
>95% yield,
:1
aReactions were performed for 12 h at room temperature;
1
yields and B:T-selectivities were determined by crude H
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Page 6 of 13
electronic perturbation
1
2
Cl
F3C
MeO
MeO
MeO
3
4
5
6
H
H
H
H
H
Me
Me
HN
Me
Me
Me
Me
Me
Me
Me
Me
HN
HN
HN
HN
O
2B
3B
4B
5B
6B
O
O
O
O
7
8
9
17:1
4.9
73% yield,
>20
rr
c
77% yield,
8.1
:1 rr
c
a
a
a
>20
>20
>20
:1 rr
82% yield,
:1 rr
86% yield,
Ir2
:1 rr
82% yield,
76% yield,
Ir2
:1 rr
75% yield,
:1 rr
a
Ir2
: 79% yield, 1.5:1 rr
Ir2
: 71% yield, 2:1 rr
: 45% yield, 2.1:1 rr
Ir2
: 82% yield, 2.0:1 rr
: 80% yield, 1:1.4 rr
vs. 2o C(sp3)H bond
steric perturbation
-substitution
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
O
H
H
H
H
O
Ph
HN
Ph
O
HN
H
O
N
Me
Ph
N
O
Me
H
H
HN
Me
Me
Ph

Me
Me
Ph
O
O
O
7B
8
9B
10
11B
O
>20
99% yield,
:1 rr
b
9
88% yield, :1 rr, 2.1:1 dr
: 64% yield, 2:1 rr, 6.4:1 dr
>20
72% yield,
: 66% yield, >20:1 rr
:1 rr
Ir2
Ir2
Ir1
: 90% yield, 12.6:1 rr
vs. aromatic carbon
vs. allylic CH bond
nPr
H
H
H
H
H
H
Ph
Ph
Ph
N
nPr
nPr
Ph
Ph
N
O
Ph
HN
HN
NH
+
NH
O
+
O
12
O
O
O
O
O
13A
13B 13A >20
15A
13B
14
15B
O
O
72% yield,
: 20% yield,
:
=
:1 rr
= 3.6:1 rr
83% yield,
15B 15A 2.8
:
=
12.7
:1 rr, :1 dr
15B 15A
: 52% yield, : = 1:2.7 rr, 2.7:1 dr
Ir2
13B 13A
Ir2
:
o
Figure 2. Benzylic selectivity over other reactive sites. Reactions were performed in HFIP solvent for 12 hours at 40 C;
1
benzylic selectivities were determined by crude H NMR analysis; isolated yields. Otherwise noted, single diastereomer
was formed upon the reactions. rr, regiomeric ratio; dr. diastereomeric ratio. aTCE as solvent. bRetrieved from reference
15. cL2 instead of L5.
Further elaboration was made with substrates that
contain potentially reactive positions. For example,
subjecting substrate 10 with γ-secondary bonds gave rise to
excellent level of benzylic selectivity. A dioxazolone
substrate bearing β-phenyl moiety (12) is interesting
because benzo-fused δ-lactam 13A could be formed via an
saturated acetonitrile solution, and its
X
ray-
crystallographic analysis unambiguously assigned its solid-
state structure. Selectivity in the lactam formation with
this isolated ruthenium catalyst was observed to be
identical (Scheme 7b) when compared to what was found
using the catalyst obtained in situ by the pre-mixing
protocol described in Scheme 6. This result confirms the
active involvement of Ru6 in the catalytic process.
ipso
spiro-lactamization/skeletal
rearrangement
sequence.36 Whereas reaction with Ir2 indeed gave a
mixture of 13B and 13A, the current ruthenium system
exclusively afforded γ-lactam 13B in 72% yield. When γ-
The predominant cleavage of C–H bonds with lower BDE
is often taken as an indirect evidence for open-shell
reactivity. For example, Che observed a quantitative
correlation between reaction rate constants and bond
dissociation energies (BDEs) in related stoichiometric C–H
amidation reactions via H-atom abstraction.37 Thus, we
were mindful of the possibility that the observed high B:T
ratio might arise from the radical character of the putative
Ru-nitrenoid intermediate because BDE of benzylic C–H
bond (86 kcal/mol) is lower in energy than that of tertiary
position (96 kcal/mol).1 To examine this hypothesis, we
performed a series of diagnostic experiments aimed to
probe for radical reactions. A catalytic reaction with a
substrate 16-d2 having syn-dideuterio group gave a KIE
value of 2.2 (Scheme 7c), which is in a similar range with
our previously observed KIE of 1.5 for the closed-shell
iridium catalysts.15 Product analysis showed that the
diastereomeric lactam 18 that may be formed by generating
a carbon-centered radical followed by epimerization, was
not detected. Moreover, the catalytic conversion of the
enantio-enriched dioxazolone (S)-19 afforded a complete
allylic
C−H
bonds
competes
with
benzylic
functionalization, diastereoselective formation of 15B was
observed albeit only displaying moderate regioselectivity.
Evidences for π-π interactions during catalysis. To
further elucidate the mechanistic origin of the
unprecedentedly high selectivity towards the benzylic C–
H bond, integrated experimental and computational
mechanistic studies were conducted. Two independent
factors were envisaged to be relevant to inducing the
benzylic selectivity: (a) radical character of a putative
ruthenium-nitrenoid intermediate, and (b) non-covalent
interaction between catalyst and substrate in the
selectivity-determining step. At the outset, we sought to
characterize the active catalyst. Treatment of
tris(acetonitrile) Ru complex with ligand L5 in TCE solvent
immediately generated complex Ru6 upon concomitant
1
release of two acetonitrile molecules, as monitored by H
NMR spectroscopy (Scheme 7a). Single crystal of Ru6
could be obtained after slow diffusion of diethyl ether into
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1
2
3
4
L5
cat. CpRu(MeCN)3PF6/
1
2B
2T
+
10
solvent
9
2B 2Ta
entry
solvent
ET(30)
:
Measured G
5
6
7
8
CCl4
Toluene
Benzene
THF
32.4
33.9
34.3
37.5
39.7
40.7
41.3
54.1
59.8
65.3
1
2
1.32
1.38
1.38
1.40
1.60
1.66
1.65
1.80
1.94
2.01
8.27:1
9.17:1
9.16:1
9.48:1
13.0:1
14.3:1
14.2:1
18.0:1
22.5:1
25.4:1b
8
6 7
3
4
5
9
TCE
5
10
11
12
13
14
15
16
17
18
19
CH2Cl2
DCE
6
2
y = 0.021x + 0.72
R2 = 0.93
7
3 4
8
Q2L1O = 0.89
CCl3CH2OH
CF3CH2OH
HFIP
1
9
10
Figure 3. Linear free-energy relationship of the B:T selectivity on a solvent polarity scale. ET(30) values were retrieved
from reference 39b. Measured −ΔΔG‡ values were calculated from −ΔΔG‡ = RT ln([2B]/[2T]) at 313.15 K. aDetermined by
crude 1H NMR analysis. bDetermined by HPLC analysis. DCE, 1,2-dichloroethane.
retention of stereochemistry, confirmed by chiral HPLC
explained above, the 1,10-phenanthroline ligand contains a
delocalized π-cloud that can form a π-π sandwich dimer
with aromatic functionalities of the substrate to give
stabilization energy in the range of 2~3 kcal/mol.26c One
way for experimentally probing such interactions is to
interrogate the solvent influence on the catalyst activity. In
fact, Diederich and co-workers discovered that the
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
analysis (Scheme 7d). While the thermal generation of a
Ru-nitrenoid species having an open-shell state cannot be
completely ruled out at the current stage, these
experimental results strongly suggest that the Ru-
catalyzed reaction follows a closed-shell mechanism.
Scheme 7. Experimental mechanistic studies.
magnitude
of
molecular
association
between
+
macromolecular cyclophane host and pyrene substantially
increases when more polar solvents are employed (Scheme
8a).38 The observed trend was further quantified by a
linear-free energy relationship, where experimentally
measured association constants were directly correlated
with the empirical solvent polarity parameter, ET(30).39
Indeed, Iverson further showed that degree of aromatic π-
π interactions between aedamer monomers are positively
proportional to the ET(30) values (Scheme 8b).40
a
-
(PF6
)
L5
(1 equiv.)
-
Ru
N
PF6
N
N
Ru
MeCN
rt
, 5 min
NCMe
Me
MeCN
X-ray
O2N
Ru6
b
Ru6
(5 mol %)
81% yield
1
2B 2T
+
2B 2T
:
> 20:1
HFIP
c
O
Scheme 8. Quantifying solvophobic effects with empirical
solvent polarity parameter, ET(30).
O
O
D
O
Ru6
cat.
NH
Ph
ND
H
O
+
Ph
N
a.
b.
Diederich (1990)
Iverson (2001)
D
D
17 17
KIE (
[Ru]
/
D) = 2.2
D
D
H
Ph
O
16-d2
17H
17D
OR
O
N
N
R
O
O
O
N
rebound
1,5-HAT
D
R
O
O
N
O
H
NH
R
R
H
OR
not
R'
N
O
R'
Ph
R
R
D
D
O
D
observed
Ph
18
radical epimerization
O
O
O
O
d
standard
conditions
O
 Linear free-energy relationship between association
constants (Ka) and empirical solvent polarity scale (ET)
 Stronger binding observed with more polar solvents
99% ee
NH
O
N
retention
57%
H
(S)-19
20
One unanswered question in our proposed mechanism
is that under a two-electron mechanism manifold, the
tertiary C–H bond cleavage is frequently favored over
benzylic functionalization. Representative examples
include the Rh(II)-catalyzed C–H amidation by Du Bois9
and Ir(III)-catalyzed C–H amidation from our laboratory.15
To rationalize this aspect, we investigated the importance
of the interactions in the second coordination sphere. As
These studies quantitatively showcased solvophobic
effects, which states that cohesive force between polar
solvent molecules drive strong interactions between non-
polar solutes.
Thus, we envisioned that perturbation of the 2B:2T
selectivity might be observed if π-π stacking plays an
important role in rendering the benzylic selectivity.
Typical organic solvents with a wide range of ET(30) values
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Journal of the American Chemical Society
were tested and the results are enumerated in Figure 3.
Page 8 of 13
1
2
3
4
5
6
7
8
While moderate to excellent yields were obtained with the
subjected solvents, a clear trend was observed in selectivity
that more polar solvents promote reactivity at the benzylic
C–H bonds. Specifically, non-polar solvents, such as
tetrachloromethane and benzene, displayed selectivities in
the range of 9:1, whereas alcoholic solvents afforded much
higher selectivities. This observation was quantitatively
supported by a linear free energy relationship between
solvent polarity indices and experimentally obtained ΔΔG‡
value (Figure 3, right). Robust regression model with R2
and leave-one-out cross-validated R2 (Q2L1O) values of 0.93
and 0.89, respectively, implies that polarity of solvent
directly impacts on the selectivity. As the ET(30) values
positively correlate with both the extent of π-π stacking38,40
and the selectivity observed herein, we concluded that the
aforementioned hydrophobic effect is critical in the
selectivity-determining step for the benzylic C−H
amidation.
DFT calculations further corroborate the proposed
mechanism, as summarized in Figure S8. The calculated
intermediate and transition state structures indicate that
the π-π stacking interaction is maintained at the
intermediate (IV-B) and transition states (IV-B-TS) to give
a barrier that is 1.4 kcal/mol lower than what is required for
the C–H activation at the tertiary position (Figure 4a). This
free energy difference is in excellent agreement with the
experiment. The structures shown in Figure 4a highlights
that it is the π-π stacking interaction that arrests the
intermediate IV into the conformer IV-B and allows for
overriding the innate preference for the tertiary position.
The existence of these non-covalent interactions was
further confirmed by the reduced density gradient method
devised by Yang and coworkers (Figure 4b).41
General applicability to γ-lactam synthesis.
Motivated by the exceptional performance of the currently
developed Ru catalyst system, we sought to extend the
method for the synthesis of γ-lactams in a more general
sense. From a synthetic standpoint, our approach to cyclic
amide is of general interest because the dioxazolone
reactant is easy to prepare from the corresponding
carboxylic acid, which is one of the most abundant
feedstock chemicals available. As described previously, the
challenge associated with the lactamization lies in
suppressing Curtius-type rearrangements that affords
undesired side-product, while enforcing the desired C–H
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
a
b
.
.
+
O
N
Ru
N
N
H
3.715 Å
3.695 Å
H
O2N

IV-B-TS
Figure 4. Optimized structure and NCI plot41 of IV-B-TS.
O
O
[CpRu(MeCN)3]PF6 (5 mol %)
L5
O
O
O2N
2 steps
(6 mol %)
N
O
NH
OH
N
N
HFIP (2 mL)
40 °C, 12 hr
L5
O
O
O
O
O
O
NH
NH
NH
NH
NH
NH
Ph
, 92%
17
F
Cl
Br
CF3
Me
21
22
23
24
25
1.5 g scale: 86%
, 82%
, 73%
, 71%
, 70%
, 70%
NH
O
O
O
O
O
O
NH
NH
NH
NH
NH
S
OMe
OMe
tBu
OMe
OtBu
, 45%
a
a
a
a,b,c
26
29
30
, 88%
, 90%
27
28
, 95%
,68%
31
, 78%
O
O
O
O
H
N
O
O
NH
NH
Ph
NH
Ph
NH
Ph
, 84%
O
NH
Ph
O
Me
Ph
, 75%
a
34,
35,
37
, 84%
>20:1 d.r.
81%
>20:1 d.r.
94%
>20:1 d.r.
a,b,c
36
33
32
, 69%
O
O
O
H
N
NH
NH
NH
NH
O
Ph
Ph
b,c
a
b,c
b,c
38
, 75%
39
40
41
42
, 68%
, 75%
, 46%
, 58%
a
b
Figure 5. General application to the selective γ-lactam synthesis. 1,1,2,2-TCE as a solvent. 10 mol % of catalyst was
used. cRun at 60 oC.
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Journal of the American Chemical Society
insertion reaction.15 To test the performance of the new
Conclusions
1
catalyst system, we extensively screened ligands including
nitrogen, phosphine, and N-heterocyclic carbenes and
interrogated their effects on the chemo-selectivity with γ-
phenylpropyl dioxazolone as a model substrate, as listed in
Scheme S3. As the acetonitrile ligand in the pre-catalyst
can be readily displaced with neutral bidentate donors by
a priori mixing, we envisioned to perform a rapid screening
of ligand effects in the desired amidation. It is interesting
that this fast screening effort was not possible in previously
employed iridium systems with anionic ligands because
base-mediated ligand complexation has always been a
bottleneck for the catalyst discovery.15,20-22,36 Taking full
advantage of this pre-mixing technique, we designed a
parallel screening protocol that may accelerate the
discovery of better catalysts by employing stock solutions
of the reaction elements and multi-channel pipettes, which
is essentially the procedure utilized in high-throughput
experimentation.42 Specifically, to a series of targeted
ligands measured in reaction vials were added a stock
solution of [CpRu(MeCN)3](PF6) precatalyst via multi-
channel pipette and the reactions were placed under
vigorous stirring at room temperature for 5 min. Within all
tested ligands, in situ chelation was confirmed by 1H NMR
monitoring or intense color change. Subsequent addition
of a substrate allowed for an interrogation of the ligand
influence on the amidation efficiency in a short period of
time.
When a premixed Ru/L5 system was employed, aliphatic
dioxazolones containing γ-benzylic C–H bonds were
readily converted to cyclic amides in good to excellent
yields (Figure 5). Representative γ-phenylpropyl
dioxazolone was cyclized to furnish product 17 in 92% yield,
and the reaction could be scaled to gram-scale without
difficulty. Halide substituents at the para-position (21-23)
and electron-withdrawing CF3 group (24) were compatible
with the present conditions. Electron-donating
substituents such as p-alkyl (25, 26) and 3,4-dimethoxy
groups (28), also offered good to excellent product yields
except for tert-butoxy group (29). In comparison with the
previously reported iridium systems,15 the present
ruthenium catalysis shows broader scope on substrates
especially bearing electron-donating substituents. Other
aromatic groups including napthyl (30), thiophenyl (31),
and benzofuryl (32) groups were successfully applicable to
the optimal conditions. Notably, sterically encumbered
α,α-dimethyl substitutions were tolerated by the
ruthenium catalyst (33). Of note, we previously observed
sluggish conversion when this type of substrates were
subjected to iridium-based catalysts owing to undesired
decomposition to the corresponding isocyanates.15 High
level of diastereselective cyclization was achieved using
dioxazolones having β-substituents (34-37). Additional
types of substrates bearing various γ C–H bonds including
tertiary (38, 39), secondary (40), allylic (41), and
propargylic (42) groups were also readily cyclized to
furnish the corresponding lactams.
We showcased that π-π stacking is an excellent
molecular feature to exploit for differentiating the benzylic
from tertiary C–H bonds. A mechanistically driven
hypothesis enabled the development of a highly modular
catalyst system that has been rarely utilized for C–H
amidation reactions. By installing a chelating ligand with
an extended π-cloud it was possible to maintain a π-π
stacking interaction with the phenyl group of the substrate
throughout the selectivity determining transition state,
which directed the C–H bond functionalization towards
the benzylic position. This simple and convenient access to
various catalysts is of particular interest because base-
mediated ligand complexation with anionic ligands is a
prerequisite for most of the previously reported systems.
Fully integrated experimental and computational analysis,
especially linear free energy relationship between solvent
polarity index and the selectivity, indicated that the π-π
stacking in secondary coordination sphere plays a pivotal
role for inducing the selectivity under the closed-shell
reactivity regime. Other factors described in Scheme 4,
however, also played additional roles in affording the
desired regioselectivity. The change to the neutral ligand
required the exchange of the Ir(III)-center of the catalyst
with the isolobal Ru(II), and the steric tension at the metal
center was also variable between Cp* and Cp supporting
ligands. We anticipate that our strategy and discovery
could expand the horizon of catalyst development in C−H
functionalization reactions and related fields.
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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)
AUTHOR INFORMATION
Corresponding Authors
*S.C. Email: sbchang@kaist.ac.kr
*Y.P. Email: yoonsu.park@kaist.ac.kr
*M.-H.B. Email: mbaik2805@kaist.ac.kr
Notes
ORCID:
Hoimin Jung: 0000-0002-3026-6577
Mu-Hyun Baik: 0000-0002-8832-8187
Yoonsu Park: 0000-0003-1511-0635
Sukbok Chang: 0000-0001-9069-0946
ACKNOWLEDGMENT
We thank support from the Institute for Basic Science (IBS-
R10-D1 and IBS-R10-A1) in Korea. We thank Ms. Hyeyun Keum
for helpful discussions.
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H
H
B
T
Ph
HN
H
H
Me
Me
Ph
Me
Ru LL
NH
Ph
N
O
Me
+
B
T
Catalyst + Ligand
premixing
O
O
O
Selective benzylic C–H insertion
(up to 25.4 : 1)
O
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Experimental probe on
attractive  interaction
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Mechanism-driven design of catalytic system
N
N
+
O
N
Ru
N
N
H
H
O2
N
computer-aided
design
key  interaction
parallel ligand
screening

solvent polarity
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