Iridium-catalyzed C-H amination with anilines at room temperature: Compatibility of iridacycles with external oxidants

Article abstract of DOI:10.1021/ja502270y

Described herein is the development of an iridium-catalyzed direct C-H amination of benzamides with anilines at room temperature, representing a unique example of an Ir catalyst system that is compatible with external oxidants. Mechanistic details, such as the isolation and characterization of key iridacycle intermediates, are also discussed.

Full text of DOI:10.1021/ja502270y

Communication
pubs.acs.org/JACS
Iridium-Catalyzed C−H Amination with Anilines at Room
Temperature: Compatibility of Iridacycles with External Oxidants
Hyunwoo Kim,‡,† Kwangmin Shin,‡,† and Sukbok Chang*,†,‡
†Center for Catalytic Hydrocarbon Functionalization, Institute of Basic Science (IBS), Daejeon 305-701, Korea
‡Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, Korea
S
* Supporting Information
Scheme 1. [Cp*Ir(III)]-Catalyzed C−H Functionalization
ABSTRACT: Described herein is the development of an
iridium-catalyzed direct C−H amination of benzamides
with anilines at room temperature, representing a unique
example of an Ir catalyst system that is compatible with
external oxidants. Mechanistic details, such as the isolation
and characterization of key iridacycle intermediates, are
also discussed.
yclometalated iridium(III) half-sandwich complexes have
received intensive research interest because of their
C
catalytic activity toward various chemical transformations.1 In
particular, these isolable Ir complexes are known to mediate a
range of C−H functionalizations in a stoichiometric manner.2
However, Cp*Ir(III) metallacycles have been observed to be
catalytically inactive under oxidative conditions, mainly due to
structural robustness and incompatibility with external oxidants.
Notable advances, however, have been made in the ligand-
assisted Ir-catalyzed C−H borylation,3 in which the desired
oxidative C−H functionalization is facilitated by utilizing B−B or
B−H bonds as an internal oxidant.3,4 In addition, we developed
an Ir-catalyzed direct C−H amidation by employing organic
azides as a nitrogen source as well as an internal oxidant via N−
N2 bond cleavage.5 Despite this progress, it remains to be
determined whether cyclometalated Ir(III) complexes are
compatible with external oxidants, thus eventually enabling a
catalytic cycle in oxidative C−H functionalization (Scheme 1A).
As a straightforward and economical approach, catalytic
transformation of unreactive C−H bonds to C−heteroatom
bonds has been extensively investigated.1a,6 In particular, inspired
by great advances in the Cu- and Pd-catalyzed cross-coupling of
(hetero)aryl halides with amines leading to C−N bond
formation,7 metal-mediated direct C−H amination received
intensive research focus in recent years.8 While important issues
remain to be addressed in this area in terms of substrate scope,
reaction conditions, and functional group tolerance, most
previous intermolecular C−H aminations employ either
(sulfon)amide-based coupling partners9a,b or preactivated
amine precursors.5,9c−n
results in significantly decreased activity of employed catalyst
systems, mainly because of the highly nucleophilic nature of
anilines.12 As a result, the development of mild catalytic C−H
amination procedures allowing the use of anilines is an important
research goal. These considerations led us to investigate Ir-
catalyzed C−H amination of arenes with anilines, giving rise to
the development of a room-temperature amination of benzamides
with anilines (Scheme 1B).
After a number of trials (see the Supporting Information (SI)
for details), we were able to synthesize an iridacyclic species (2)
by treating benzamide 1a with [IrCp*Cl2]2 in the presence of
AgOTFA and Li2CO3 (Scheme 2A). The structure of the
iridacycle 2 was unambiguously characterized by X-ray crystallo-
graphic analysis. It shows a three-legged piano stool geometry,
Scheme 2. Preliminary Stoichiometric Reactions
In this regard, there remains a major challenge: direct
utilization of non-preactivated amines as a reactant.10 In
particular, the use of anilines as a nitrogen source without
preactivation is highly desirable considering the fact that a wide
range of anilines are accessible, and the resulting arylamine
products are useful in organic synthesis, medicinal chemistry, and
materials science.11 However, the direct use of anilines usually
Received: March 5, 2014
Published: April 6, 2014
© 2014 American Chemical Society
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Communication
a
with two slightly longer Ir−C bonds (2.24 and 2.23 Å) to the
Cp* ring than the remaining three (2.12, 2.14, and 2.14 Å). The
distance between the Ir and the carbonyl O atom is 2.12 Å, the
same as that between Ir and the trifluoroacetato O atom. It
revealed that the Ir metal is coordinated to the carbonyl O atom
rather than the amide nitrogen atom, in contrast to the previously
reported palladacycle complexes in which the metal bonds to an
amide nitrogen atom.13 It should be empathized that, to the best
of our knowledge, this species 2 represents the first example of a
crystal structure of an iridacycle generated from a benzamide. We
were pleased to see that the new iridacycle 2 underwent
amination upon treatment with (4-trifluoromethyl)aniline (3a)
at 25°C in the presence of a Ag(I) species and copper acetate to
afford 4a in 65% yield after protonolysis (Scheme 2B).
Table 2. Substrate Scope of Anilines
Encouraged by the above results of the stoichiometric
amination, we were strongly driven to search for optimal
conditions that would allow the reaction to be catalytic (Table 1).
N-Adamantylbenzamide (1a) was chosen as a model substrate
since we initially envisaged that the steric bulky of the N-alkyl
group could help the facile formation of an iridacyclic
intermediate.14
a
Table 1. Optimization of Reaction Parameters
a
1a (0.2 mmol) and 3 (0.21 mmol) in DCE (0.66 mL) at 25°C for
b
c
24h (isolated yields). Conducted at 80°C, 3h. For 48h.
examined,9a,k,15 the amination did not proceed at all (entries 9
and 10). When a separately prepared iridium acetate complex,
[IrCp*(OAc)2],16 was used as a catalyst, the desired product was
obtained in excellent yield (entry 11). It was noteworthy that
Pd(OTf)2 or Cu(OAc)2 (1.0 equiv) metal systems, which were
previously employed in the C−H amidation/amination reac-
tions,10f,15 were ineffective for the present amination with aniline
3a (entries 12, 13).
With the optimized conditions for the Ir-catalyzed direct C−H
amination in hand, we next investigated the scope of the current
procedure by testing various aniline derivatives in the reaction
with N-adamantylbenzamide 1a (Table 2). Anilines bearing
electron-withdrawing substituents, such as trifluoromethyl (3a),
trifluoromethylthio (3b), sulfonyl (3c−e), and triflic (3f) groups,
smoothly participated in the amination in moderate to high
yields. Anilines having a meta-substituent (3g,h) afforded the
desired products in moderate yields. In addition, we found that a
series of disubstituted anilines also reacted to furnish the
corresponding amination products (5i−n). Interestingly, ani-
lines possessing both electron-donating and -withdrawing groups
underwent the amination with high efficiency (5i−k). Anilines
bearing mono- or dihalogens showed reasonable reactivity (5l−
n). Functional group tolerance was excellent in the current
amination procedure as demonstrated by the successful reactions
with anilines bearing sensitive groups such as thioether, sulfonyl,
triflate, and halides. Meanwhile, reactivity of aniline or its
derivatives bearing electron-donating substituents was observed
to be low, and no desired products were obtained under present
conditions. In addition, N-substituted anilines were not reacted
even at higher temperature (100°C), providing a clue about the
reaction mechanism (vide infra).
a
1a (0.2 mmol), 3a (0.21 mmol), catalyst, oxidant, and additive in 1,2-
b
1
dichloroethane (DCE, 0.66 mL) for 24h. Yield based on H NMR
analysis of the crude reaction mixture using CH2Br2 as the internal
oxidant (isolated yield in parentheses). n.r. = no reaction. N-
c
d
Fluorobenzenesulfonimide. DMSO (2.0 mL) solvent.
We were delighted to observe that a catalytic reaction indeed
did proceed in the presence of Cu(OAc)2 and AgNTf2 co-
additives (entry 1). However, the amination did not occur in the
absence of Ag additives (entries 2, 3). Surprisingly, this catalytic
amination was found to be high-yielding even at room
temperature (entry 4). The efficiency was decreased significantly
in the absence of Cu(OAc)2 (entry 5). The Ir catalyst was
essential for the amination (entry 6). The type of acetate
additives turned out to be important, and among various acetates
screened (e.g., entries 7 and 8; see SI for full data), Cu(OAc)2
(0.5 equiv to 1a) was most effective. Likewise, the choice of
oxidants was another key to success. For instance, when
frequently employed oxidants such as NFSI or Na2S2O8 were
The present amination method was successfully applied to a
wide range of benzamides with 3a as the coupling partner (Table
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a
Table 3. Substrate Scope of Benzamides
Scheme 3. Mechanistic Studies
that only Ag(I) salt was effective.19 Although more compre-
hensive studies are required to elucidate details of an amino-
transfer pathway, this result suggests that the amination may
proceed via formation of a high-valent Ir(V) nitrenoid species
(8), potentially consistent with enhanced reactivity with
electron-poor anilines. It is proposed that 8 will subsequently
undergo a nitrenoid insertion and then proto-demetalation to
deliver an aminated product with concurrent regeneration of
Cp*Ir(III) species. An alternative pathway involving an Ir(III)/
Ir(I) cycle, in which Ir(III) amido species (9) undergoes
reductive elimination and the resulting Ir(I) is reoxidized, is
reasoned to be less likely (Scheme 3C).
a
1 (0.2 mmol) and 2a (0.21 mmol) in DCE (0.66 mL) at 25°C for
b
24h (isolated yields). At 80°C in α,α,α-trifluorotoluene (0.66 mL) for
3h.
3). It was revealed that the reaction efficiency was maintained
irrespective of the electronic properties of the substrate (6a−e).
As anticipated, the amination took place at the sterically more
accessible C−H bonds (6f,g). Again, functional group tolerance
was excellent, as seen in the successful amination of benzamides
having free or acetate-masked hydroxyl groups (6h,i). Moreover,
the reaction was not greatly affected by varying the N-alkyl group
on the benzamide substrate (6j−m).17 In fact, not only
benzamides bearing simple N-alkyl moieties (6j,k), but also
derivatives bearing a stereogenic center were readily aminated
with retention of stereochemical purity (6l,m). N-Alkyl-
substituted amide products obtained in this study can readily
be converted to the corresponding N-arylanthranilic acids or 2-
(arylamino)benzamides according to the reported procedures.9m
To investigate the mechanistic details of the present Ir-
catalyzed C−H amination reaction, a series of stoichiometric
reactions using isolated iridacycles was initially planned. When an
iridacycle species 2 was treated with aniline 3a, the desired
amination did not occur in the absence of Ag(I) oxidant. Instead,
an aniline-coordinated iridacycle complex (7) was obtained
quantitatively (Scheme 3A). The structure of 7 was unambig-
uously characterized by NMR and X-ray analyses. The bond
length between the Ir metal center and nitrogen atom of aniline
in 7 was 2.16 Å, in the range of several aniline complexes
previously known.12,18
Based on the above mechanistic studies and relevant
literature,1a−c,2e,20 we depict a plausible catalytic cycle in Scheme
4. First, an Ir species induces an irreversible C−H cleavage of
Scheme 4. Proposed Mechanistic Pathway
benzamides to generate a cyclometalated Ir(III) complex II,
believed to be a rate-limiting step on the basis of kinetic isotope
effect studies (see SI for details). A ligand exchange of acetate
with aniline delivers an isolable cationic aniline complex III.
Oxidation of a metallacycle III is proposed to occur forming an
Ir(V)-nitrenoid species IV that then undergoes an anilino-group
transfer leading to an Ir complex V. Finally, proto-demetalation
Stoichiometric reactions of 7 provided interesting results:
whereas treatment of 7 with Cu(OAc)2 alone failed to induce any
conversion; the desired aminated product (4a) was obtained by
adding Ag oxidant in the presence of Cu(OAc)2 (Scheme 3B).
Other oxidants were also examined for this reaction, revealing
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Journal of the American Chemical Society
Communication
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from V will occur to deliver desired N,N-diarylamine products
with regeneration of the catalyst.
In conclusion, we report an Ir-catalyzed direct C−H amination
of benzamides using simple aniline coupling partners without
preactivations. This advance is a significant example of an iridium
catalyst system being compatible with external oxidants to allow
an anilino-group transfer even at room temperature for the first
time. A catalytic cycle involving high-valent Ir species is
proposed, and further methodologies of C−H functionalization
are anticipated to be developed based on this mechanistic
understanding.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sbchang@kaist.ac.kr
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Institute of Basic Science
(IBS). We thank Mr. Jaeyune Ryu (KIST) for helpful discussions,
and Mr. Jin Kim and Jinseong Gwak for X-ray analysis.
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