Mechanism-Driven Approach To Develop a Mild and Versatile C?H Amidation through IrIII Catalysis

Article abstract of DOI:10.1002/chem.201702397

Described herein is a mechanism-based approach to develop a versatile C?H amidation protocol under Ir^III catalysis. Reaction kinetics of a key C?N coupling step with acyl azide and 1,4,2-dioxazol-5-one led us to conclude that dioxazolones are much more efficient in mediating the formation of a carbon?nitrogen bond from an iridacyclic intermediate. Computational analysis revealed that the origin of higher reactivity is asynchronous decarboxylation motion, which may facilitate the formation of Ir-imido species. Importantly, stoichiometric reactivity was successfully translated into catalytic activity with a broad range of substrates (18 different types), many of which are regarded as challenging to functionalize. Application of the new method enables late-stage functionalization of drug molecules.

Full text of DOI:10.1002/chem.201702397

A Journal of
Accepted Article
Title: Mechanism-Driven Approach to Develop a Mild and Versatile C-H
Amidation via Ir(III) Catalysis
Authors: Sukbok Chang, Yeongyu Hwang, and Yoonsu Park
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Mechanism-Driven Approach to Develop a Mild and Versatile C–H
Amidation via Ir(III) Catalysis
Yeongyu Hwang,+ Yoonsu Park,+ and Sukbok Chang*
Abstract: Described herein is a mechanism-based approach to
develop a versatile C–H amidation protocol under Ir(III) catalysis.
Reaction kinetics of a key C–N coupling step with acyl azide and
1,4,2-dioxazol-5-one led us to conclude that dioxazolones are much
more efficient in mediating the formation of carbon–nitrogen bond
from an iridacyclic intermediate. Computational analysis unraveled
that the origin of higher reactivity is placed on asynchronous
decarboxylation motion, which may facilitate the formation of Ir-imido
species. Importantly, stoichiometric reactivity was successfully
translated into the catalytic activity with a broad range of substrates
(18 different types of substrates), many of which were regarded as
challenging to functionalize. Applying the new method enables the
late-stage functionalization of drug molecules.
Introduction
Catalytic C–H activation mediated by transition metals
enables diverse functionalization of unactivated hydrocarbons in
a straightforward manner.[1] Growing demands of utilizing the
technique in multiple disciplines[2] promote the development of
Scheme 1. Mechanism-based development of C–H amidation. DG= directing
group.
efficient catalysts capable of selectively targeting specific C–H
bonds. From a fundamental perspective, understanding the
catalytic systems? By addressing those fundamental issues,
mechanistic details of the catalysis may provide a solution to
mild and versatile amination could be rationally achieved.
properly modulate the performance of the catalysts. Indeed,
Herein, we described such a study to develop a new
seminal mechanistic studies have provided valuable insights to
amidation protocol with Ir(III) catalyst, which was guided by
drive further directions, thus triggering the improvement in
insights gained from the study of stoichiometric C–N coupling.
catalytic performance.[3]
Integrated kinetic and computational analysis unraveled the
Among various C–H functionalization reactions, C–H
secret underlying the formation of high-valent Ir species, and
amination constitutes a valuable route to introduce an amino
such implications enabled us to disclose versatile catalyst
functionality into hydrocarbon substrates.[4] Challenges in
system applicable to a broad range of challenging substrates,
achieving efficient C–H amination catalysis mainly lie on
including those not reactive with previously reported procedures.
facilitating two key steps depicted in Scheme 1a. A number of
Our group has recently elucidated mechanistic details on
strategies, such as oxidative addition or concerted-metalation
the C–N coupling process with group
9 Cp*M(III)-based
deporotonation (CMD) mechanism, have been devised to
facilitate C–H bond cleavage to afford metallacyclic
catalysts with various aminating agents.[8a] We demonstrated
that a rhodacyclic complex was successfully coupled with
sulfonyl azides, affording C–N coupled Rh-amido complex at
elevated temperature.[8b] Our continued efforts to develop mild
C–H amination enabled us to scrutinize a new type of amidating
agents 1,4,2-dioxazol-5-ones,[9] which display superior ability in
mediating C–N coupling reactions. Detailed mechanistic studies
strongly corroborated the involvement of organometallic Rh(V)
and Ir(V)-imido species as the key intermediates.[8d] This notable
outcome ignited extensive subsequent studies with dioxazolones
as the amide source, especially focusing on the development of
Rh(III),[10] Ru(II),[11] or Co(III)[12] catalysts, leading to broad
applications in the facile preparation of synthetic valuables.[13]
Although dioxazolones have been taken much spotlights
recently, the origin of high catalytic activity is underexplored. For
instance, it is intriguing to see whether the effectiveness of
dioxazolone can also be applicable to other systems. In this
regards, we wondered if the superior reactivity of dioxazolones
in the C–N coupling would still be conserved in the isolobal
Ir(III)-based system. As the Ir(III) catalysts were continuously
proven to be effective for activating ortho C–H bonds of
a
intermediate.[5] Another challenge is to retain facile C–N coupling
in reactions with an aminating agent. In constrat to the C–H
cleavage, only few of understandings on the C–N couplings
were revealed to date with Cu,[6] Pd,[7] and Rh[8] catalysis.
Consequently, lack of principles on the C–N formation prevents
a rational design of effective reagents and catalysts. In essence,
which factors can affect the stoichiometric formation of carbon–
nitrogen bond? How can we rationally improve efficiency of the
[*]
Y. Hwang, Y. Park, Prof. Dr. S. Chang
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea)
and
Center for Catalytic Hydrocarbon Functionalizations, Institute for
Basic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: sbchang@kaist.ac.kr
[+]
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
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substrates bearing various directing groups including
synthetically useful functional moieties,[14] a valuable amidating
protocol would be anticipated if appropriate amidating agents
were employed. It should be noted that recent studies on the
Rh(III) and Co(III)-catalyzed C–H amidation with dioxazolones
are mostly limited to nitrogen-based directing groups, which are
laborious for the post-functionalization.[8c,10a,12-13,15]
kcal/mol of kinetic barrier, whereas the transition state for N2
dissociation from azide adduct iii’ lies at 18.1 kcal/mol higher in
energy. In consequence, the net reaction barriers to form Ir-
imido species from complex i are 20.3 and 34.9 kcal/mol with
dioxazolone and acyl azide, respectively. These computed
values are in qualitative agreement with experimentally
observed reactivity in Scheme 2.
Results and Discussion
To test the hypothesis, we commenced our study by
designing a stoichiometric model reaction to evaluate the
kinetics of the C–N coupling. A well-defined iridacycle 1, known
as an intermediate in catalytic C–H amination,[16] was subjected
to the key C–N bond formation (Scheme 2). When iridacycle 1
was exposed to acyl azide A at ambient temperature, no
detectable conversion was observed by 1H NMR spectroscopy in
o
12 h. Upon heating the reaction mixture to 40 C for 6 h, 38% of
1 was converted to a new iridium species. Surprisingly, the
o
same transformation was completed within one minute at 20 C
by replacing the azide by 1,4,2-dioxazol-5-one B. Indeed,
composition of the emerging iridium complex was characterized
as a C–N coupled Ir-amido complex 2: the solid-state structure
of 2 was confirmed by a single crystal XRD analysis.[17]
To understand the significant kinetic difference induced by
the type of amidating agents, a series of theoretical studies were
conducted. First, reaction energy profile was evaluated with two
amidating agents based on the widely-accepted mechanism
(Figure 1a).[8c,d] The mechanism constitutes three key steps:
ligand exchange with an amidating agent, oxidative formation of
Scheme 2. Stoichiometric C–N coupling with acyl azide and dioxazolone.
Analyzing the differences in the Ir-imido formation, we
noted that cleaving motions of N2 and CO2 are fundamentally
different. A two-bond cleaving event for CO2 liberation has the
higher structural degree of freedom than
a single-bond
dissociation step for the N2 clevage. Whereas the monotonic N–
N2 elongation is the only possible movement in the
dediazotization of acyl azides, a few distinctive modes can be
considered in the decarboxylation process of dioxazolones:
concerted and stepwise cleavages of N–O and C–O bonds.
Because we were unable to locate any physically meaningful
intermediates for stepwise mechanism, that cleaving motion was
excluded for further considerations. On the other hand, another
classification can be made within the concerted mechanism. The
N–O and C–O cleavages may take place either simultaneously
(synchronously) or independently (asynchronously, Figure 1b).
a
metal–imido species, and subsequent C–N reductive
elimination. Dissociation of OTFA anion in complex i yields a
coordinatively-unsaturated cationic species ii. Subsequent
coordination of azide to form iii’ requires 2.1 kcal/mol, whereas
dioxazolone coordination to form iii is favored by 3.9 kcal/mol.
Importantly, adduct species iii and iii’ are able to form the same
Ir-imido species iv by extruding CO2 and N2, respectively, and
despite the similar oxidative processes, computed reaction
barriers displayed notable differences in energy: the CO2
liberation easily takes place by traversing iii-TS with only 9.5
Figure 1. Computational mechanistic investigation on the stoichiometric C–N coupling.
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To carefully distinguish the translational motion,
conformational searches by systematically varying the lengths of
the N–O (rN-O) and C–O (rC-O) bonds were performed, as
described in Figure 1c.[17] The resulting PES and its contour plot
clearly indicated that the concerted cleaving motion is
asynchronous: the saddle point on the PES is placed on around
2.2 Ǻ of N–O and 1.7 Ǻ of C–O bonds, similar to that of
optimized iii-TS in Figure 1d. Any other critical points were not
found on other locations, corroborating the singularity of
concerted asynchronous TS in decarboxylation process.
We sought to understand how the asynchronicity affects
the reaction barrier. For this purpose, energy decomposition
analysis was performed to elucidate underlying electronic
influence (Figure 1e). The electronic energy difference between
iii and iii-TS was 4.6 kcal/mol lower than the transformation
from iii’ to iii’-TS, implying that electronic reorganizations in
transition states gave rise to the differences in the activation
barriers. While total distortion energy (ΔEdist) is more required for
liberating CO2 (59.1 kcal/mol) than that for dediazotization (37.3
kcal/mol), total interaction energy (ΔEint) between the Cp*Ir
fragment and dioxazolone moiety is much stronger (-42.5
kcal/mol) than that between analogous fragments for iii’-TS (-
16.1 kcal/mol), thus making the net electronic barrier lower in
energy. These energetic components, for the first time,
suggested that the electronic communication between Ir–
N(dioxazolone) is much developed on the iii-TS than that of Ir–
N(azide) on the iii’-TS. We rationalized that such strong
interaction is only possible with dioxazolone because
asynchronous CO2 cleavage maximizes the formation of empty
p-orbital in nitrogen, thus making stronger overlap between
Ir(d)–N(p*).[8d] As shown in Figure 1d, shorter Ir–N(dioxazolone)
(1.87 Ǻ) than Ir–N(azide) (2.03 Ǻ) further supports the stronger
Ir–N bonding.
Having the importance of synchronicity in the amidating
agent, we speculated that utilizing dioxazolones in catalytic
reaction possibly reduce the energetic span, thus leading to a
more efficient and robust C–H amidation procedure. To overview
general trends, four representative substrates, quinoline N-oxide,
enamide, enone, and acetophenone, were selected and
subjected to catalytic conditions (Figure 2). Significantly, the
catalytic amidations of the first three substrates were much
faster in reaction with dioxazolone.[18] When quinoline N-oxide
was monitered, it was readily amidated with dioxazolone B while
the azide analogue A was not reacted at all. (Figure 2a). In a
reaction of enamide substrate (Figure 2b), more pronounced
rate acceleration was observed: the initial rate with dioxazolone
B was at least ~367 times faster. As another notable example,
enone substrate was reacted almost exclusively with
dioxazolone while amidation with A did not proceed (Figure 2c).
In sharp contrast, reaction rates of acetophenone substrate were
rather similar with both amidating sources. It suggested that
lowering the C–N coupling barrier did not affect kinetic
performance of the catalytic reaction. The similar kinetics
observed from A and B suggested that C–N coupling may not
be involved in the turnover-limiting stage. A primary kinetic
isotope effect (KIE; kH/kD = 2.1) corroborated that C–H bond
cleavage is likely involved in a rate-limiting step. (Figure S5)
Figure 2. Comparative catalytic 1H NMR reaction profiles with acyl azide and
dioxazolone. R= C(O)ArF.
To test whether the efficiency of dioxazolone is maintained
in general, various types of substrates were further subjected to
the catalytic reactions with both dioxazolone and acyl azide
(Scheme 3). To our delight, a truly diverse range of substrates,
which displayed moderate to poor reactivity with acyl azides,
were readily amidated with dioxazolone. Enamides were
selectively amidated in satisfactory yields (3a) and N-
pivaloylindole was amidated exclusively at the C-7 position in
moderate yield (4). N-Pivaloylanilide was also efficiently
amidated (5) and quinoline N-oxide was amidated at the C-8
position with dioxazolone only (6) while the corresponding
benzoyl azide was not reacted at all. Triphenylphosphine oxide
was amidated in moderate yield (7). Vinyl moiety in enone and
methacrylate was amidated stereoselectively to furnish
synthetically valuable Z-enamide products in good yields (8–9).
Carboxylic acid was found to serve as an effective directing
group in the current C–H amidation with dioxazolone. Indeed,
benzoic acids, 2-thiophenecarboxylic acid, and methacrylic acid
were all amidated in satisfactory yields (10–12). Again, the
amidation efficiency in reactions of those carboxylic acids with
azide was seen to be much poorer. In addition, an amidation of
N,N-dimethylphenyl carbamate occurred smoothly (13).
Not only sp2 but also sp3 C–H bond was readily amidated
in case of 8-methylquinoline (14). Interestingly, the reaction of 2-
benzylpyridine was efficient (15a), where
a 6-membered
iridacycle intermediate will be formed in situ. In contrast, the
same reaction with acyl azides was totally ineffective. 2-
Benzoylpyridine was amidated in satisfactory yield (16).
Interestingly, a few substrates displayed similar amidation
efficiency between two amidating reagents. For instance, arene
sp2 C–H bonds of benzoate and acetophenone derivatives were
amidated equally well (17–18). Likewise, benzamide and N-
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Scheme 3. Substrate scope with B as the amide source. Yields with A are in parenthesis. Reaction conditions: substrate (0.1 mmol), amino source (1.1 equiv),
[Cp*IrCl2]2 (4.0 mol %), and AgNTf2 (16.0 mol %) at 50 oC for 12 h. R’= C(O)ArF. Additives: [a] AgOAc (30.0 mol %). [b] LiOAc (30.0 mol %). [c] AcOH (30.0
mol %). [d] AcOH (15.0 mol %) and Li2CO3 (15.0 mol %). Temperature: [e] Room temperature. [f] 30 oC. [g] 40 oC. Reaction time: [h] 5 h. [i] 6 h. [j] 24 h.
pivaloylindoline underwent the C–H amidation in excellent yields
in each case (19–20). It is noteworthy that the amidation product
yields were always greater or equal in reactions with
dioxazolone when compared to those with acyl azide even after
longer period (12 h), thereby implying that kinetic efficiency is
maintained over the course of the C–H amidation progresses.
The scope of dioxazolone amidating reagents was
reasonably broad to efficiently install benzoyl amido groups
bearing electron-withdrawing and neutral substituents (Scheme
4). However, phenyldioxazolone having an electron-donating
group was less effective (3f).
The current C–H amidation showed great reactivity also in
large scale synthesis (Scheme 5a). Introduction of amino
functionality into enamide could be conducted in a gram scale in
excellent yield with low catalyst loading. Synthetic utility of the
present C–H amidation protocol was next briefly examined. We
were pleased to see that our current procedure was successfully
adapted in the selective direct C–H amidation of highly
functionalized drugs or their derivatives (Scheme 5b-d). For
example, Zaltoprofen, known as anti-inflammatory drug,[19] was
readily amidated in high yield (21). Significantly, the existing
carboxylic acid and thio groups did not inhibit the reaction
efficiency under the present conditions. In addition, methyl ester
of Nalidixic acid[20] was selectively amidated at the C-5 position
(22), and its structure was unambiguously characterized by an
X-ray crystallographic analysis.[17] Carbamate derivative of
Estron was also successfully amidated at the sterically more
accessible site in excellent yield (23).
Scheme 4. Substrate scope with various dioxazolones. Reaction conditions:
substrate (0.1 mmol), 1,4,2-dioxazol-5-one (1.1 equiv), [Cp*IrCl2]2 (4.0 mol %),
and AgNTf2 (16.0 mol %) at 50 oC for 12 h. [a] At 80 oC. [b] For 24 h.
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In summary, we showcased that the understanding of
kinetics on the stoichiometric C–N coupling path enabled the
development of efficient catalytic C–H amidation. Theoretical
investigations unrevealed that asynchronous nature of the
decarboxylation process is the key feature of dioxazolones to
serve as an efficient amidating agent. Synthetic utility and
applicability of the new catalysts system in combination with
dioxazolones were successfully validated with a broad range of
challenging substrates, drugs and bioactive molecules. We
anticipate that the strategy disclosed herein may serve as an
inspiring example for the the rational appraoch towards the
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See Supporting Information for details.
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See Supporting Information for details.
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Acknowledgements
This research was supported by the Institute for Basic Science
(IBS-R010- D1).
Keywords: C–H amination, C–N coupling, dioxazolones, iridium
catalysis, late-stage C–H functionalization
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Entry for the Table of Contents
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Yeongyu Hwang, Yoonsu Park, Sukbok
Chang*
Page No. – Page No.
Title
A Mechanism-Driven Approach to
Develop a Mild and Versatile C–H
Having asynchronous transition state was identified as a secret for an efficient
amidating agent in catalytic C–H amidation. Combined reaction kinetics and
theoretical study guided the development of versatile Ir(III) catalysis with various
challenging substrates, including late-stage functionalization of drug molecules.
Amidation via Ir(III) Catalysis
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