N -substituted hydroxylamines as synthetically versatile amino sources in the iridium-catalyzed mild C-H amidation reaction

Article abstract of DOI:10.1021/ol501338h

N-Substituted hydroxylamines such as aroyloxy- or acyloxycarbamates were successfully employed as synthetically versatile amino precursors in the iridium-catalyzed direct C-H amidation of arenes. The reaction proceeds smoothly at room temperature over a broad range of substrates with high functional group tolerance to afford N-substituted arylamine products.

Full text of DOI:10.1021/ol501338h

Letter
pubs.acs.org/OrgLett
N‑Substituted Hydroxylamines as Synthetically Versatile Amino
Sources in the Iridium-Catalyzed Mild C−H Amidation Reaction
Pitambar Patel†,‡ and Sukbok Chang*,†,‡
†Center for Catalytic Hydrocarbon Functionalizations, 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
ABSTRACT: N-Substituted hydroxylamines such as aroyloxy- or
acyloxycarbamates were successfully employed as synthetically
versatile amino precursors in the iridium-catalyzed direct C−H
amidation of arenes. The reaction proceeds smoothly at room
temperature over a broad range of substrates with high functional
group tolerance to afford N-substituted arylamine products.
rylamines are a versatile building unit in synthetic
chemistry, and they are also an important pharmacophore
significant expansion of direct C−H amination approaches to
afford synthetically versatile N-substituted aniline products.
At the outset of our studies, we screened optimal amidation
conditions in a model reaction of 2-phenylpyridine 1a with 1.1
equiv of N-Boc-substituted benzoylhydroxyamine16 2a. The
desired amidation took place smoothly with an iridium
precursor, [IrCp*Cl2]2 (2.5 mol %), in the presence of a
AgNTf2 additive (10 mol %, Table 1, entry 1). In addition to a
A
in numerous natural products and synthetic compounds
displaying interesting biological activities.1 As a result, extensive
research efforts have been focused toward the development of
efficient synthetic procedures to introduce an amino group into
(hetero)arenes.2 In this regard, the Buchwald−Hartwig reaction
has been established as a standard protocol for the amination of
aryl halides.3 More recently, a new strategy based on metal-
catalyzed C−H activation has been scrutinized as a more
straightforward method employing arenes as a substrate in lieu
of aryl halides.4 Although this direct C−H amination approach
takes advantage of using arenes without prefunctionalization, it
frequently suffers from harsh reaction conditions, a narrow
substrate scope, and the need for external oxidants.5 In fact, this
reaction often works best with arene substrates that bear certain
activating or directing groups under oxidative conditions.6 In
addition, a range of amine precursors have been examined such
as chloroamines,7 hydroxylamines,8 N-fluorobenzene-
sulfonimide (NFSI),9 or sulfonamides.10 In this regard, we
also have investigated organic azides as a readily available and
convenient amino source in the direct C−H amination
reactions using Rh,11a−d Ru,11e and Ir11f−i catalytic systems.12
Glorius et al. recently reported an elegant example of Rh(III)-
catalyzed direct C−H amidation of arenes using aroyloxy-
carbamates as an amino source to obtain N-Boc protected
arylamine.13 Zhou et al. also developed the Rh-catalyzed direct
amination using nitrosobenzenes or N-hydroxycarbamates to
give synthetically valuable products.14
a
Table 1. Optimization of the Ir-Catalyzed Amidation
b
entry
catalyst
[IrCp*Cl2]2
additive
t (°C) yield (3a/4a, %)
1
2
3
4
5
AgNTf2
AgNTf2
none
50
25
25
25
25
25
25
25
80
80
76:9
74:7
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[RhCp*Cl2]2
[Ru(p-cymene)Cl2]2
Pd(OAc)2
11:0
AgOAc
AgOTs
KOAc
68:5
81:5
c
6
d
18:0
7
AgOTs
AgSbF6
AgNTf2
PhI(OAc)2
96:0 (92)
44:0
8
9
<10:0
0:0
c
10
a
Reaction conditions: 1a (0.1 mmol) and 2a (1.1 equiv) in 1,2-
b
1
dichloroethane (DCE, 0.5 mL). Yield and ratio were based on H
NMR of crude reaction mixture (Cl2CHCHCl2 as an internal
standard). 100 mol % of additive was used. 1a (1.2 equiv) and 2a
c
d
(0.1 mmol) for 10 h; isolated yield is in parentheses.
monoamidated product (3a), a bis-amidated minor compound
(4a) was also formed (3a/4a, 76:9). While the amidation
proceeded efficiently even at rt (entry 2), it became quite
sluggish without a silver salt (entry 3). Among various silver
additives screened, air stable AgOTs (entry 5) turned out to be
the most effective in view of the selectivity (see the Supporting
Information (SI) for details). When KOAc was used in lieu of
Continuing our efforts to develop efficient and selective
direct C−H amination procedures,11,15 we envisioned employ-
ing aroyloxycarbamates and their derivatives as aminating
sources under our previously developed iridium catalytic
systems.11f−i We were also curious about testing a postulate
that amidation efficiency might be related to the N−O bond
strength of the amino precursors. In this aspect, we have
successfully applied a range of aroyloxy- and acyloxycarbamates
to an Ir-catalyzed direct amidation of arenes, thus allowing a
Received: May 9, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501338h | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
silver species, only a poor yield was obtained (entry 6). The
reaction efficiency and selectivity were also sensitive to the
choice of solvents, and 1,2-dichloroethane (DCE) was selected
for the subsequent study. The formation of a bis-amidated
compound (4a) could be suppressed by changing the
stoichiometry of two reactants. Indeed, a monoamidated
product 3a was obtained exclusively without 4a when substrate
1a was employed in slight excess relative to an amidating
reagent 2a (1a/2a, 1.2:1; entry 7). Interestingly, the amidation
was much poorer when other catalyst systems were used. For
instance, whereas a Rh species [Cp*Rh(III)] catalyzed the
reaction in moderate efficiency (entry 8), the amidation was
not effective with Ru or Pd catalysts (entries 9−10).
Scheme 2. Scope of Amidating Reagents
a
Reaction conditions: 1a (0.2 mmol) and 2 (1.2 equiv) in 1,2-
dichloroethane (0.5 mL), R1 = 4-CO2Me-C6H4-. b At 50 °C. c 3 mol %
With the optimized conditions in hand, we next investigated
the scope of various amidating reagents in reaction with 2-
phenylpyridine at rt (Scheme 1). It was observed that a wide
d
of catalyst and 12 mol % of AgNTf2 at 60 °C. R1 = −CH3.
With the successful application of N-substituted O-benzoyl
or O-acyloxyamines as efficient amino sources, we were also
curious about whether N-substituted “free” hydroxylamines
could be employed for the direct C−H amidation. When N-
Boc-hydroxylamine was reacted with 2-phenylpyridine, the
desired product (3a) was obtained in low yield even at 80 °C
(eq 1). The efficiency was slightly improved when N-
benzoylhydroxylamine was used leading to 7 in 45% yield.
a
Scheme 1. Scope of Various Electrophilic Amidating Agents
a
With the optimal conditions and preliminary results of the
reactivity dependence on amidating reagents in hand, we
subsequently examined the scope of substrates in reactions with
N-Boc-substituted aroyloxyamine 2a (Scheme 3). Overall, the
amidation proceeded efficiently at rt irrespective of electronic
and/or steric variation in substrates. Indeed, 2-phenylpyridine
derivatives bearing electron-donating groups such as alkyl and
alkoxy (3b−3f, 3h) underwent the amidation in good yields.
Likewise, electron-withdrawing substituents including fluoro
(3g), ester (3i), phenyl (3j), trifluoromethyl (3k), and acetyl
(3l) groups did not deteriorate the reaction efficiency. The
structure of product 3i was unambiguously confirmed by an X-
ray diffraction.
Sensitive groups such as aldehyde (3m) and olefin (3n) were
compatible with the present conditions. Functional group
tolerance was excellent as demonstrated by the successful
reaction of substrates bearing free hydroxyl (3o), acetyl (3p),
and silyl (3q) groups. It needs to be mentioned that the
amidation is highly selective occurring at the ortho-position
relative to the 2-pyridinyl moiety even in the presence of ester
or ketone (3i, 3l), which were shown by us to work as effective
chelating groups under the Ir-catalyzed C−H functionalzia-
tion.11h Variation of the type of substituents and/or their
position in the pyridyl moiety of 2-phenylpyridine substrates
was viable as seen in the facile formation of 3r−3u. Direct
amidation at fused arenes such as 1,2-dihydroacenaphthylene
(3v) and naphthyl (3w) was also smooth under the present
conditions. The structure of 3w was confirmed by an X-ray
crystallographic analysis. The current amidation was convenient
for a scale-up process without difficulty. For example, amidation
of 1k with 2a could be performed in gram quantity using 1 mol
Reaction conditions: 2 (0.2 mmol) and 1a (1.2 equiv) in 1,2-
dichloroethane (0.5 mL); yields are based on NMR of crude reaction
mixture (Cl2CHCHCl2 as an internal standard); percentages given in
parentheses are isolated yields.
range of amidating reagents could be employed with high
efficiency irrespective of their electronic properties at the
benzoyl side: electron-withdrawing (2a−2f), neutral (2g), or
donating groups (2h−2j) gave comparable product yields. Not
only benzoyloxy derivatives but also acyloxy analogues such as
phenylacetyl (2k), pivaloyl (2l), and acetyl (2m) readily
participated in the reaction as efficient amidating reagents, thus
significantly expanding the scope of the present protocol.
Next, we investigated the feasibility of introducing various
types of N-carbamates at arene C−H bonds using N-substituted
aroyloxyamines (Scheme 2). We were pleased to see that a
range of synthetically useful N-substituents could readily be
employed for this purpose to furnish the desired products in
high yields. Trichloroethyl carbamate (Troc, 5) and carbox-
ybenzyl (Cbz, 6) were introduced satisfactorily. Other
derivatives such as those that include the benzoyl (Bz, 7) and
tosyl (Ts, 8) group were also synthesized efficiently. When N-
acetoxyacetamide was reacted with 2-phenylpyridine, the
desired acetamidation proceeded highly efficiently to afford 9
at 25 °C, releasing acetic acid as a byproduct. The fact that
various N-substituted aniline products could be accessed
through the present procedure offers synthetic flexibility in
the utilization of the obtained products. In fact, N-substituents
can be removed under acidic (N-Boc), basic (N-Ac and N-Bz),
or hydrogenation conditions (N-Cbz).17
B
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Letter
a
Scheme 3. Substrate Scope for the Ir-Catalyzed Amidation
Scheme 4. Preliminary Mechanistic Investigation
a
2a (0.2 mmol), 1 (1.2 equiv), [IrCp*Cl2]2 (2.5 mol %), and AgOTs
b
(10 mol %) in 1,2-dichloroethane (0.5 mL). AgNTf2 was used
instead of AgOTs at 50 °C.
% of the [Ir] catalyst to afford 3k in 78% yield (see the SI for
details).
Figure 1. Initial reaction rates with amidating reagents bearing
electronically different p-substituents.
Heterocyclic compounds other than pyridine were next
examined as plausible chelating groups in the present direct C−
H amidation approach (Scheme 3). 2-Phenylpyrazole, 2-
phenyl-2-oxazoline, 2-phenylpyrimidine, and 2-benzolypyridine
were readily amidated to afford the corresponding products
(10−13) in high yields. 1-Phenylisoquinoline (14) was also a
facile substrate for the present direct C−H amidation.
To obtain mechanistic insights into the present direct C−H
amidation reaction, a series of preliminary experiments were
carried out. A small value for primary kinetic isotope effects
(KIE = 1.19) was measured in a parallel experiment (Scheme
4a), implying that the C−H bond cleavage may not be involved
in the rate-limiting stage.14b,18 Two iridacyclic species (15 and
16), prepared separately (Scheme 4b), catalyzed the amidation
with similar efficiency (Scheme 4c), suggesting that those
complexes could be involved in the catalytic cycle under the
corresponding conditions. Interestingly, an iridacycle 16 was
found to contain an additional molecule of acetic acid, being
connected to an acetato ligand through the H-bond, and its
structure was unambiguously confirmed by X-ray crystallo-
graphic analysis.
benzoyl leaving group from the amidating reagents does not
affect the rate-controlling stage of the catalytic cycle.
Based on the above-mentioned mechanistic studies and
precedent literature,19 a catalytic cycle of the present Ir(III)-
catalyzed direct C−H amidation is proposed in Scheme 5, using
2-phenylpyridine as a model substrate. It is assumed that a
dimeric iridium species is converted to its monomeric sulfonato
complex upon the addition of the AgOTs additive. An
iridacycle I will be generated by the reaction of a substrate
with the in situ generated monomeric iridium species. As a next
step, a ligand exchange is believed to occur leading to II that
undergoes a migratory insertion to give an iridium amido
complex (IV) with the concomitant release of a carboxylic acid
presumably via III. Alternatively, a pathway involving Ir(V),
formed by the oxidative addition of the N−O bond to Ir(III),
cannot completely be ruled out at the present stage. Finally,
product 3a is formed by protodemetalation of IV with the
regeneration of a metal catalyst.
In summary, we developed an efficient iridium-catalyzed
direct C−H amidation of arenes using aroyloxy- or acyloxy-
carbamates as amino sources. A range of arene substrates was
selectively amidated at rt in high efficiency with excellent
functional group tolerance. The amidation procedure does not
require external oxidants or bases, and it can be scaled up
without difficulty. Various types of synthetically versatile N-
substituted aniline products were accessed including N-Boc, N-
Because it was intriguing to see the effects of the electronic
property of the leaving group on the reaction progress, initial
amidation rates were compared among amidating reagents
bearing electronically different substituents. Although electron-
donating groups induced the reaction to be slightly faster
compared to electron-withdrawing substituents (Figure 1), the
difference was not significant, implying that the cleavage of a
C
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Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedure and characterization of new com-
pounds (1H and 13C NMR spectra, and X-ray crystallographic
data). This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sbchang@kaist.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Institute of Basic Science
(IBS) in Korea.
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