Regioselective introduction of heteroatoms at the C-8 position of quinoline N-oxides: Remote C-H activation using N-oxide as a stepping stone

Article abstract of DOI:10.1021/ja5053768

Reported herein is the metal-catalyzed regioselective C-H functionalization of quinoline N-oxides at the 8-position: direct iodination and amidation were developed using rhodium and iridium catalytic systems, respectively. Mechanistic study of the amidation revealed that the unique regioselectivity is achieved through the smooth formation of N-oxide-chelated iridacycle and that an acid additive plays a key role in the rate-determining protodemetalation step. While this approach of remote C-H activation using N-oxide as a directing group could readily be applied to a wide range of heterocyclic substrates under mild conditions with high functional group tolerance, an efficient synthesis of zinquin ester (a fluorescent zinc indicator) was demonstrated.

Full text of DOI:10.1021/ja5053768

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Article
Regioselective Introduction of Heteroatoms at the C-8 Position of Quinoline
N-Oxides: Remote C-H Activation Using N-Oxide as a Stepping Stone
Heejun Hwang, Jinwoo Kim, Jisu Jeong, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja5053768 • Publication Date (Web): 11 Jul 2014
Downloaded from http://pubs.acs.org on July 14, 2014
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Journal of the American Chemical Society
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Regioselective Introduction of Heteroatoms at the C-8 Posi-
tion of Quinoline N-Oxides: Remote C−H Activation Using N-
Oxide as a Stepping Stone
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Heejun Hwang,‡,†,§ Jinwoo Kim,‡,†,§ Jisu Jeong,‡,† and Sukbok Chang*,†,‡
‡Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305ꢀ701, Korea
†Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305ꢀ701, Korea
KEYWORDS: Quinoline N-oxides, C−H activation, iodination, amidation, remote functionalization
ABSTRACT: Reported herein is the metalꢀcatalyzed regioselective C−H functionalization of quinoline Nꢀoxides at the 8ꢀposition:
direct iodination and amidation were developed using rhodium and iridium catalytic systems, respectively. Mechanistic study of the
amidation revealed that the unique regioselectivity is achieved through the smooth formation of Nꢀoxideꢀchelated iridacycle and
that an acid additive plays a key role in the rateꢀdetermining protodemetalation step. While this approach of remote C−H activation
using Nꢀoxide as a directing group could readily be applied to a wide range of heterocyclic substrates under mild conditions with
high functional group tolerance, an efficient synthesis of Zinquin ester (a fluorescent zinc indicator) was demonstrated.
Scheme 1. C−H Functionalization of Quinoline N-Oxides
ꢀ INTRODUCTION
Quinolines are an important structural motif found in nuꢀ
merous natural and synthetic compounds with broad applicaꢀ
tions in medicinal1 and materials chemistry.2 As a result, deꢀ
velopment of synthetic procedures for the facile derivatization
of quinolines has been actively investigated.3 Although certain
functional groups can be introduced into the quinoline skeleꢀ
ton, it often requires multi steps or harsh conditions in most
conventional approaches.4 On the other hand, significant adꢀ
vance has been recently made in the direct C−H functionalizaꢀ
tion of readily available compounds.5 This strategy has also
been successfully applied for the direct C−C and C−X bond
formation of quinolines6 or their Nꢀoxide derivatives,7 wherein
the latter can be readily interconverted to the former one.
While a number of catalytic procedures have been reported for
the C−H activation of quinolines, most of them allow funcꢀ
tionalization at the Cꢀ2 position.6dꢀf Indeed, only a few cases
are known to reveal the catalytic activation of quinolines at
sites other than Cꢀ2 including our own8a and Sawamura’s.8b
Similarly, direct introduction of certain functional groups into
quinoline Nꢀoxides turned out to be facile, but, again only at
the orthoꢀposition relative to the Nꢀoxide moiety. In fact,
This aspect is especially noteworthy in view of the fact that
Cꢀ8 functionalized quinolines are widespread having imꢀ
quinoline Nꢀoxides were employed for the alkylation,7f,7g
alkenylation,7a,7c alkynylation,7e arylation,7b,7d acetoxylation,7h
portant utilities in diverse areas. In particular, as shown in
and amidation7i all at the Cꢀ2 position under the corresponding
Figure 1, notable biological activities are displayed by 8ꢀ
catalytic conditions (Scheme 1a). In contrast, direct introducꢀ
aminoquinolines such as Primaquine (commercialized antimaꢀ
larial reagent),1b Zinquin (fluorescent sensor for Zn(II)),10 or
tion of synthetically valuable functional groups at the 8ꢀ
position has not been achieved except a very recent example
IWRꢀ1ꢀendo (inhibitor of Wnt signaling and an axin stabiꢀ
lizer).11 They are also effective ligands used in coordination
of the Cꢀ8 alkenylation of quinoline Nꢀoxides using Rh(I)
catalyst.9 However, this reaction takes place at high temperaꢀ
chemistry.12 In addition, 8ꢀaminoquinolines are widely emꢀ
ployed as an effective bidentate chelate for the C−H functionꢀ
alization of pendant sp2 or sp3 hydrocarbons.13 While quinoline
tures leading to a mixture of E/Z isomeric products.
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Nꢀoxides are known to readily coordinate to various metal
oxides was smooth under mild catalytic conditions when Nꢀ
species such as Cu, Ni, Zn, Fe, Co, or Ti,14 we hypothesized
that the desired Cꢀ8 functionalization has been largely unꢀ
solved presumably due to the difficulty in the selective forꢀ
mation of the corresponding metallacycles at that position.
iodosuccinimide (NIS, 1.5 equiv) was used as a halogenating
reagent, and the scope of this iodination reaction is presented
in Table 1. Quinoline Nꢀoxide (1a) was iodinated selectively at
1
2
3
4
o
the Cꢀ8 position to afford 2a product in 82% yield at 50 C
using an in situ generated cationic Cp*Rh(III) catalyst, and the
structure of 2a was confirmed by an Xꢀray crystallographic
analysis. The reaction proceeded even at room temperature
albeit with slightly lower efficiency (56% yield). 6ꢀ
Methylquinoline Nꢀoxide (1b) displayed a similar reactivity
pattern leading to 2b, without reacting at the potentially labile
benzylic C−H bonds. While 3ꢀformylquinoline Nꢀoxide (1c)
worked in excellent efficiency to furnish 2c, functional group
tolerance was found to be high as demonstrated in the facile
iodination leading to products 2d−2f. Interestingly, iodination
of 2ꢀphenylquinoline Nꢀoxide (1g) was again regioselective at
the Cꢀ8 position (2g) leaving the potentially reactive phenyl
side chain intact. The same approach could be applied to other
hetereocyclic substrates. For instance, benzo[f]quinoline Nꢀ
oxide was smoothly iodinated exclusively at the Cꢀ5 position
(2h). In addition, iodination of quinoxaline Nꢀoxide (1i) was
highly regioselective at the Cꢀ8 position without reacting at
the Cꢀ5 position to afford 2i albeit in moderate yield.
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Figure 1. Utilities of 8ꢀaminoquinoline derivatives.
These considerations led us to search for catalytic systems
enabling efficient formation of metallacycles of quinoline Nꢀ
oxides and smooth subsequent insertion of suitable functional
groups. In this aspect, we have developed two catalytic proceꢀ
dures for the direct Cꢀ8 functionalizations of quinoline Nꢀ
oxides: Rhꢀcatalyzed iodination and Irꢀcatalyzed amidation
under mild conditions (Scheme 1b).
Table 1. Selective C-8 Iodination of Quinoline N-Oxidesa
ꢀ
RESULTS AND DISCUSSION
Regioselective Direct C−H Iodination of Quinoline
N-Oxide. We originally envisioned two synthetic approaches
to access to 8ꢀaminoquinolines; i) regioselective C−H haloꢀ
genation of quinoline Nꢀoxides and subsequent Buchwaldꢀ
Hartwig Nꢀarylation15 (Scheme 2, Route A), and ii) direct C−H
amination at the same position (Route B). Since the formation
of 5ꢀmembered metallacycle intermediates by using Nꢀoxide
as a directing group was postulated to be essential for this
remote C−H functionalization, we decided to use quinoline Nꢀ
oxides as substrates for this purpose. The fact that quinolines
and their Nꢀoxides are readily interconverted under mild conꢀ
ditions7d,16 led us to extensively investigate this strategy.
Scheme 2. Synthetic Routes to 8-Aminoquinoline N-Oxides
a
Reaction conditions:
1 (0.1 mmol), NIS (1.5 equiv),
[Cp*RhCl2]2 (4 mol %), AgNTf2 (16 mol %) in 1,2ꢀdichloroethane
(1,2ꢀDCE, 0.5 mL): isolated product yields.
As described above, since 8ꢀhalogenated quinolines (Nꢀ
oxides) can easily be aminated according to the Buchwald–
Hartwig protocol,21 our developed iodination procedure is a
highly valuable synthetic tool to access to 8ꢀaminoquinolines.
Moreover, the fact that this catalytic reaction bears notable
features such as high regioselectivity, compatibility with diꢀ
verse functional groups, and mild conditions allows us more
opportunities for using 8ꢀiodoquinolines or their Nꢀoxides in
additional synthetic transformations, representatively in metalꢀ
mediated crossꢀcoupling reactions. Despite this attractive asꢀ
pect of the iodination approach, we decided to investigate
more extensively C−N bond formation of quinoline Nꢀoxides
since it can directly introduce the amino group at the Cꢀ8 posiꢀ
Although 8ꢀhaloquinolines can be used as starting materials
for the Nꢀarylation to afford 8ꢀaminoquinolines, they are also
highly versatile reactants for a variety of additional crossꢀ
coupling reactions.17 Again, it needs to emphasize that whereꢀ
as elegant examples of ortho C−H halogenation of aromatics
were revealed by Sanford,18 Glorius,19 and Ackermann,20 regiꢀ
oselective direct Cꢀ8 halogenation of quinolines or their Nꢀ
oxides has not been reported.
After exploring various reaction conditions (see the Supꢀ
porting Information for details), we were pleased to find that a
Rh(III) catalytic system facilitated the desired halogenation of
quinoline Nꢀoxides. While chlorination and bromination were
not satisfactory (< 20% yield), Cꢀ8 iodination of quinoline Nꢀ
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tion, thereby we commenced our studies of the Cꢀ8 amidation
of quinoline Nꢀoxides.
Reaction Scope of Direct C-8 Amidation of Quino-
1
2
3
4
5
6
7
8
line N-Oxide. With the optimized conditions in hand, we
next explored the substrate scope of quinoline Nꢀoxides in
reaction with 1.1 equiv of TsN3 (Table 3). Position of alkyl
substituents did not alter the reaction efficiency as shown with
methylated substrates (4b−4d). The observation that substrates
bearing a Cꢀ2 substituent underwent the amidation in high
yield (4c) is noteworthy in that coordination of the iridium
center to Nꢀoxide is not sterically interrupted by the presence
of a neighboring group (Cꢀ2). Halogenated quinoline Nꢀoxides
were amidated without difficulty although the position of halꢀ
ides influenced the reaction efficiency to some extent (4e−4i).
Various functional groups commonly used in synthetic chemꢀ
istry such as nitro (4j), esters (4k, 4l), acetal (4m), alkoxy
(4n), silyloxy (4o), carbamate (4p), and aldehyde (4q) were all
compatible with the present reaction conditions, thus signifiꢀ
cantly expanding synthetic utility of the current amidation
protocol.24
Optimization of Direct C-8 Amidation of Quinoline
N-Oxide. At the outset of our studies for the direct amidation
of quinoline Nꢀoxides, we examined optimal conditions in a
model reaction of quinoline Nꢀoxide (1a) with pꢀ
toluenesulfonyl azide (3a, Table 2). When our previously deꢀ
veloped Irꢀcatalytic conditions were applied,22,23 only low
o
product yield was obtained at 80 C (entry 1). The reaction
9
efficiency was found to be improved by certain additives.
While sodium acetate exhibited noticeable, but still unsatisfacꢀ
tory effects (entry 2), acetic acid (0.3 equiv) gave a significant
improvement (entry 3). We were pleased to see that the effiꢀ
ciency was further increased at lower temperature, giving rise
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o
to 92% yield of 4a at 50 C using 2 mol % of iridium catalyst
(entry 4). It needs to emphasize that the reaction is highly re-
gioselective in that no isomeric product (5) was formed under
the present conditions. Interestingly, the amidation took place
in high yield even at room temperature albeit requiring higher
loading of acetic acid (1 equiv) and prolonged reaction time
(entry 5). Solvents other than 1,2ꢀdichloroethane (1,2ꢀDCE)
were less effective (entries 6−7).
Strong acids such as trifluoroacetic acid or camphorsulfonic
acid (CSA) did not exhibit significant additive effect when
compared to acetic acid (entries 8−9). Although the addition of
pivalic acid or benzoic acid resulted in slightly higher additive
effects (entries 10−11), acetic acid was chosen for the subseꢀ
quent studies because it is more convenient to use (e.g. stock
solution) and easy to remove after the reaction. Silver salts,
employed in this procedure for the in situ generation of cationꢀ
ic metal species, were also found to affect the reaction effiꢀ
ciency to some extents (entry 12). Other commonly used cataꢀ
lytic systems such as rhodium, ruthenium, or palladium were
ineffective for this amidation (entries 13−15).
Table 3. Substrate Scope of Quinoline N-Oxidesa
[Cp*IrCl2]2 (2 mol %)
AgNTf2 (8 mol %)
O
O
R2
S
R1
R2
R1
N3
+
N
NH O-
4
AcOH (30 mol %)
1,2-DCE, 50 oC, 12 h
N
O-
CH3
H
Ts
1
3a
H3C
H3C
CH3
N
N
N
CH3
N
NH O-
NH O-
NH O-
NH O-
Ts
89% (
Cl
Ts
Ts
Ts
4a
4b
4c
4d
86% ( )
)
90% (
)
88% (
)
Cl
Br
Cl
N
R
N
NH O-
N
N
NH O-
Ts
NH O-
NH O-
Ts
Ts
Ts
4h b
R = H 61% (
CH3 78% (
)
b
72% (
)
4f
4g b
)
4e
73% (
)
60% (
4i
)
O
NO2
O
O
Table 2. Optimization of the Regioselective Amidationa
O
O
O
N
N
N
N
NH O-
NH O-
NH O-
NH O-
56% (
Ts
Ts
Ts
Ts
4j b
63% (
)
4k
4l
)
4m
67% ( )
64% (
)
O
OSi(i-Pr)3
MeO
(Boc)2N
temp yield
H
Entry
catalyst system
additive
‒
solvent
(oC) (%)b
N
N
N
N
NH O-
NH O-
1
2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/AgNTf2
[IrCp*Cl2]2/ AgSbF6
[RhCp*Cl2]2/ AgNTf2
1,2ꢀDCE
80
80
80
50
25
24
43
76
92
87
20
19
23
18
94
97
82
<1
<1
<1
NH O-
Ts
NH O-
Ts
Ts
Ts
AcONa 1,2ꢀDCE
AcOH 1,2ꢀDCE
AcOH 1,2-DCE
AcOH 1,2ꢀDCE
4n b
86% (
55% (
4o
)
4p
)
4q
87% ( )
69% (
)
3
4
5c
a Reaction conditions: 1 (0.2 mmol), 3a (1.1 equiv), [Cp*IrCl2]2 (2
mol %), AgNTf2 (8 mol %), AcOH (30 mol %) in 1,2ꢀDCE (0.5
mL): isolated product yields. b AcOH (1.0 equiv) at 80 °C.
6
AcOH 1,4ꢀDioxane 50
7
AcOH tꢀAmylOH 50
The scope of organic azides as the amide source was subseꢀ
quently investigated in reaction with 1a (Table 4). Alkanesulꢀ
fonyl azides were highly facile for this selective Cꢀ8 amidation
under the optimized conditions leading to the desired products
in high yields (6a−6c). Benzenesulfonyl azides bearing subꢀ
stituents were also reacted without difficulty (6d−6e). Amiꢀ
dation of quinoline Nꢀoxide proceeded also selectively with
naphthaleneꢀ1ꢀsulfonyl azide (6f). It was notable that acyl
azides participated in the direct amidation under the current Irꢀ
catalytic system giving rise to acylamido product (6g), thus
widening the scope of amide groups. However, arylꢀ and alkyl
azides did not react under the developed conditions.
8
CF3CO2H 1,2ꢀDCE
50
50
50
50
50
50
50
50
9
CSA
1,2ꢀDCE
1,2ꢀDCE
10
11
12
13
PivOH
PhCO2H 1,2ꢀDCE
AcOH
AcOH
1,2ꢀDCE
1,2ꢀDCE
1,2ꢀDCE
1,2ꢀDCE
14 [Ru(pꢀcymene)Cl2]2/ AgNTf2 AcOH
15 Pd(OAc)2 AcOH
a 1a (0.2 mmol), 3a (1.1 equiv), metal catalyst (2 mol %), Ag salt
(8 mol %), and additive (30 mol %) in solvent (0.5 mL). b NMR
yield (1,1,2,2ꢀtetrachloroethane as an internal standard). c 1 equiv
of AcOH for 24 h.
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Table 4. Substrate Scope of Organic Azidesa
(8g−8h). It needs to be emphasized that the products obtained
1
2
3
4
herein can serve as precursors of βꢀamino heterocycles which
have enormous utilities in medicinal, coordination, and synꢀ
thetic chemistry.25
[Cp*IrCl2]2 (2 mol %)
AgNTf2 (8 mol %)
+
R N3
N
O-
N
AcOH (30 mol %)
1,2-DCE, 50 oC, 12 h
NH O-
3
H
R
1a
6
5
6
7
8
Mechanistic Studies on the Present Reaction. To
shed light on the mechanistic aspects of the present selective
C−H amidation of quinoline Nꢀoxides, we first performed an
experiment to see kinetic isotope effects (KIE). Only small
values of kinetic isotope effects (kH/kD = 1.1~1.2) were measꢀ
ured from parallel competition reactions between 1a and 1aꢀd7
irrespective of the presence of acetic acid additive (Figure 2).
This result implies that the C−H bond cleavage may not be
involved in the rateꢀlimiting step26 and acid additives seem to
play a crucial role in later catalytic stages (vide infra).
N
N
N
NH O-
N
O
O
NH O-
NH O-
O
O
NH O-
S
S
S
O
S
O
Me
O
O
9
O
Br
78% (6b)
82% (6a)
87% (6c)
53% (6d)
10
11
12
13
14
15
16
17
18
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20
21
22
23
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60
N
N
O2N
O
NH O-
N
NH O-
O
NH O-
S
S
O
O
O
MeO
55% (6f)b
87% (6e)
62% (6g)
standar d
conditions
d7
d6
a Reaction conditions: 1a (0.2 mmol), 3 (1.1 equiv), [Cp*IrCl2]2 (2
mol %), AgNTf2 (8 mol %), AcOH (30 mol %) in 1,2ꢀDCE (0.5
mL): isolated product yields. b AcOH (1.0 equiv) at 80 °C.
N+
O-
N+
O-
N+
O-
N+
O-
TsHN
TsHN
1a-d7
4a-d6
1a
4a
(w/ AcOH, 25 oC)
(w/o AcOH, 50 oC)
kH/kD = 1.23
The present strategy of utilizing Nꢀoxide as a directing
group for the remote C−H amidation was examined with polyꢀ
aromatic heterocycles (Table 5). As anticipated, amidation of
acridine Nꢀoxide was facile to afford 8a in good yield. Likeꢀ
wise, Nꢀoxides of benzo[f]quinoline and phenanthridine were
amidated exclusively at the desired position (8b−8c), and
structure of the latter product was confirmed by Xꢀray crystalꢀ
lographic analysis. Interestingly, reaction of phenazine monoꢀ
oxide was highly regioꢀ and chemoselective to furnish 8d in
excellent yield, and no amidation occurred at the βꢀposition
relative to the unoxidized nitrogen atom. Similarly, benꢀ
zo[c]cinnoline monoꢀoxide was selectively amidated (8e). The
current protocol could be successfully applied to a bisꢀNꢀoxide
compound to lead to double amidation in good yield (8f) by
using 2.2 equiv of azide.
1.14
Figure 2. Comparison of C−H amidation profile (a) in the presꢀ
ence of 30 mol % of AcOH and (b) in the absence of AcOH.
An iridacycle complex 9 was isolated upon treatment of 1a
with a catalyst precursor (Scheme 3a),27 and its structure was
unambiguously determined by Xꢀray crystallographic analysis
(Figure 3). To the best of our knowledge, this represents the
first example of a discrete iridacycle bound to Nꢀoxide.28 The
isolated iridacycle (9) was found to catalyze an amidation
reaction (Scheme 3b), suggesting that it could be involved as
an intermediate in the catalytic cycle although this is not uneꢀ
quivocal evidence as this could be an offꢀcycle intermediate.
Table 5. Substrate Scope of Polyaromatic Heterocyclesa
O
O
[Cp*IrCl2]2 (2 mol %)
AgNTf2 (8 mol %)
S
N3
+
N
N
O-
AcOH (30 mol %)
1,2-DCE, 50 oC, 12 h
NH O-
CH3
H
Ts
7
3a
8
Ts
N
O-
Ts
N
N
H
Scheme 3. Preliminary Mechanistic Studies
N
NH O-
O-
N
H
Ts
8a
73% (
8b
78% (
8c
77% ( )
)
)
NaOAc (6 equiv)
(a)
N+
O-
Ts
N
[Cp*IrCl2]2
+
O- HN
N
N+
Cl
CH2Cl2, RT, 24 h
51%
Ts
Ir
-
N
H
N
9
N
O
1a
1a
NH O-
N
NH O-
N
O-
Ts
Ts
9 (4 mol %)
b
c
8d
8e
66% (
8f
83% ( )
93% (
)
)
AgNTf2 (4 mol %)
(b)
TsN3
+
N+
AcOH (30 mol %)
(1.1 equiv)
4a
(62%)
-
1,2-DCE, 50 oC, 12 h
TsHN
O
N
N
NH O-
NH O-
Ts
Ts
8g
71% (
8h
)
)
82% (
a Reaction conditions: 7 (0.2 mmol), 3a (1.1 equiv), [Cp*IrCl2]2 (2
mol %), AgNTf2 (8 mol %), AcOH (30 mol %) in 1,2ꢀDCE (0.5
mL): isolated product yields. At 80 °C. 2.2 equiv of 3a,
[Cp*IrCl2]2 (4 mol %), AgNTf2 (16 mol %), 80 °C, 24 h.
b
c
Again, the amidation was selective at the Cꢀ8 position of
quinoline Nꢀoxides even in the presence of substituted phenylꢀ
or naphthyl pendants that bear potentially reactive C−H bonds
Figure 3. Crystal structure of 9 with 50% displacement ellipsoids.
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On the basis of the above experimental data and precedent
ciency in two step from commercially available 6ꢀhydroxyꢀ2ꢀ
methylquinoline (Scheme 5). As anticipated, the main reaction
of an esterꢀsubstituted quinoline Nꢀoxide (11) proceeded with
high selectivity under the standard conditions to furnish the
desired product 12 in good yield. Deoxygenation of 12 was
facile with the use of zinc reagent leading to the desired prodꢀ
uct 13 in 54% overall yield (4 steps).
literature,29 a mechanistic pathway is proposed in Scheme 4. A
dimeric precursor [IrCp*Cl2]2 is converted by a silver salt to a
cationic species that undergoes the C−H bond cleavage of
substrates leading to a fiveꢀmembered iridacycle I, a neutral
analogue of which was isolated and characterized (Scheme
3a). Coordination of an azide to I will initiate a subsequent
amido insertion to afford an Ir(III) amido species III which
was detected by ESIꢀMS when R = Ts. At the final stage, it is
proposed that protodemetalation of III will take place as a
turnoverꢀlimiting step to afford an Irꢀcoordinated product V.
1
2
3
4
5
6
7
8
Scheme 5. Synthesis of Zinquin Ethyl Ester
9
O
O
O
RO
Br
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
EtO
HO
EtO
K2CO3
mCPBA
50 °C, 4 h
N
N
O-
Scheme 4. Proposed Reaction Pathway
N
DMF, RT, 12 h
[R = EtOC(O)CH2]
10
(94%)
11
(99%)
[Cp*IrCl2]2
O
RO
O
EtO
AcOH
standard
conditions
+
Zn (9.0 equiv)
N+
NH O-
2 AgNTf2
THF/NH4Cl (aq)
RT, 1 h
N
O-
N
R
TsHN
TsHN
13 (76%)
[Cp*Ir(III)]
N+
O-
12 (76%)
H+
H+
N+
NH O-
OAc
ꢀ CONCLUSION
R
Ir
I
V
(X-ray analysis)
Cp*
In conclusion, we have for the first time succeeded in the diꢀ
rect introduction of heteroatomic groups at the Cꢀ8 position of
quinoline Nꢀoxides. Two catalytic systems were developed:
Rhꢀcatalyzed iodination and Irꢀcatalyzed amidation of quinoꢀ
line Nꢀoxides. Both reactions were highly regioselective ocꢀ
curring at the Cꢀ8 position under mild conditions over a broad
range of substrates with excellent functional group tolerance.
In this approach, Nꢀoxide was utilized as a stepping stone for
the remote C−H functionalization. Mechanistic studies of the
amidation reaction revealed an important role of acid additives
promoting the rateꢀdetermining product releasing step. As the
utilities of the iodinated and amidated products accessible
through the present study are enormous, the present protocol is
anticipated to be an important synthetic tool.
N+
Ir O-
*Cp
N3
R
N+
IV
R
N
O-
Ir
H
Cp*
O
N+
O-
Ac
N2
N
II
Ir
Cp*
AcOH
N+
O-
R
N
R
Ir
Cp*
(R = Ts: ESI-MS detected)
III
N2
An observation that the reaction was sensitive to acid addiꢀ
tives (Figure 4a) implies that the protodemetalation process
can be facilitated by acid additives which may influence the
bond strength between metal and inserted amido moieties.30 In
addition, the fact that initial amidation rates31 were measured
to have first order dependence on the concentration of acetic
acid (Figure 4b) also led us to postulate that the additive can
facilitate this turnoverꢀdetermining step presumably passing
through IV (Scheme 4).
ASSOCIATED CONTENT
Detailed experimental procedures; data for new compounds, inꢀ
1
cluding H, 13C NMR and Xꢀray analysis. This material is availaꢀ
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sbchang@kaist.ac.kr
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Figure 4. (a) Reaction profile in the Irꢀcatalyzed amidation of
quinoline Nꢀoxide (1a) with TsN3 at 25 oC in the presence of variꢀ
ous acid additives (10ꢀCSA: 10ꢀcamphorsulfonic acid) (b) Plot of
initial amidation rates versus [AcOH] showing the first order.
This research was supported by the Institute for Basic Science
(IBS). We thank Jin Kim for the Xꢀray crystallographic analysis.
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