A Direct Access to 7-Aminoindoles via Iridium-Catalyzed Mild C-H Amidation of N-Pivaloylindoles with Organic Azides

Article abstract of DOI:10.1021/acs.orglett.6b00662

Ir(III)-catalyzed regioselective direct C-7 amidation of indoles in reaction with organic azides has been developed. While its efficiency was varied by the choice of N-directing groups, N-pivaloylindoles were most effective in undergoing the desired amidation at room temperature over a broad range of substrates. The reaction was scalable, and deprotection of the chelation group was also facile.

Full text of DOI:10.1021/acs.orglett.6b00662

Letter
pubs.acs.org/OrgLett
A Direct Access to 7‑Aminoindoles via Iridium-Catalyzed Mild C−H
Amidation of N‑Pivaloylindoles with Organic Azides
Youyoung Kim,†,‡ Juhyeon Park, and Sukbok Chang*
†,‡
,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
*
S Supporting Information
ABSTRACT: Ir(III)-catalyzed regioselective direct C-7 amidation of indoles in reaction with organic azides has been developed.
While its efficiency was varied by the choice of N-directing groups, N-pivaloylindoles were most effective in undergoing the
desired amidation at room temperature over a broad range of substrates. The reaction was scalable, and deprotection of the
chelation group was also facile.
he privileged indole structure is widely present in natural
and synthetic products. In particular, 7-aminoindoles are
conceived: (i) a ring-generating route to indoles from amino-
1
3
T
installed acyclic starting materials and (ii) direct regioselective
4
,5
a key scaffold found in numerous biologically relevant
compounds to display a broad spectrum of bioactivities, serving
as antitumor agents, anion receptors, glucokinase activators, or
C−H functionalization (amination in this case) of indoles
6,7
using transition metal catalysts. Although the latter route has
distinct merits, owing to the inherent electronic property of the
indoles, electrophilic metalation takes place mainly at the C-3
position of an indole skeleton. In addition, direct activation of
C2−H bonds has also been known under certain catalytic
conditions.
2
nuclear hormone receptors (Scheme 1a). As a result, the
development of efficient synthetic routes to 7-aminoindoles is
highly desirable. In this context, two synthetic strategies can be
Regioselective C−H functionalization at the C-7 position of
indoles has been proven to operate only when proper N-
directing groups are employed in combination with suitable
catalytic systems. For instance, Hartwig et al. reported Ir-
Scheme 1. Bioactive 7-Aminoindoles
8
9
catalyzed C-7 borylation of N-silylindoles. In addition, Ma
10
and Shi independently showed that C-7 alkenylation and
arylation of indoles could be feasible with properly installed N-
directing groups by the action of Rh and Pd catalysis,
respectively. Our group reported a direct C-7 amination of
11
indolines with organic azides. Initially obtained 7-aminoindo-
lines can be readily oxidized to afford 7-aminoindoles as end
products. Although structural diversity to allow both amino-
indolines and aminoindoles can be achieved through this
indirect approach, we were curious if a direct C-7 amination of
indoles would be plausible. Herein, we report the development
of an Ir-catalyzed C7−H amination of N-pivaloylindoles with
organic azides (Scheme 1b). The reaction proceeds with
excellent regioselectivity over a broad range of indoles and
azides, thus offering a straightforward and efficient way of
accessing 7-aminoindoles.
We commenced our study to examine the amidation
conditions in a model reaction of N-pivaloylindole (1a) with
12
p-toluenesulfonyl azide (2a, Table 1). Inspired by Ma’s
Received: March 8, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
not formed in the absence of either IrCp*(OAc) or AgNTf
2
2
(
entries 11−12). Pleasingly, excellent product yield was
obtained at room temperature and even with reduced catalyst
loading (entry 13). The use of solvents other than 1,2-
dichloroethane (1,2-DCE) resulted in decreased product yields
(
entries 14−18).
With the optimized conditions in hand, we next investigated
temp
yield
b
entry
1
catalyst (mol %)
additive
(°C)
solvent
(%)
the scope of indoles in reaction with p-toluenesulfonyl azide
(Scheme 2). The structure of product 3a obtained from N-
[IrCp*Cl ] (5)/AgNTf
−
50
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
<1
60
n.r.
n.r.
20
77
27
2
2
2
2
(
20)
2
3
4
5
6
7
[IrCp*Cl ] (5)/AgNTf
NaOAc
NaOAc
NaOAc
KOAc
50
50
50
50
50
50
a
2
2
Scheme 2. Substrate Scope of Indoles
(
20)
[RhCp*Cl ] (5)/AgSbF
6
2
2
(
20)
[Ru(p-cymene)Cl ] (5)
2
2
/
AgSbF (20)
6
[IrCp*Cl ] (5)/AgNTf
2
2
2
2
2
(
20)
[IrCp*Cl ] (5)/AgNTf
AgOAc
AcOH
2
2
(
20)
[IrCp*Cl ] (5)/AgNTf
2
2
(
20)
8
9
[IrCp*Cl ] (5)
AgOAc
50
50
1,2-DCE
1,2-DCE
n.r.
44
2
2
IrCp*(OAc) (10)/
−
2
NaNTf (20)
2
10
IrCp*(OAc) (10)/
−
50
1,2-DCE
90
2
AgNTf (20)
2
11
12
13
IrCp*(OAc) (10)
−
−
−
50
50
25
1,2-DCE
1,2-DCE
1,2-DCE
n.r.
n.r.
94
2
AgNTf (20)
2
IrCp*(OAc) (5)/
2
AgNTf (10)
2
14
15
16
17
18
IrCp*(OAc) (5)/
−
−
−
−
−
25
25
25
25
25
THF
29
2
AgNTf (10)
2
IrCp*(OAc) (5)/
toluene
MeCN
EtOAc
MeOH
90
2
AgNTf (10)
2
IrCp*(OAc) (5)/
n.r.
74
2
AgNTf (10)
2
IrCp*(OAc) (5)/
2
AgNTf (10)
2
IrCp*(OAc) (5)/
n.r.
2
AgNTf (10)
2
a
1
a (0.20 mmol), 2a (0.22 mmol), catalyst, and additive (30 mol %) in
b
1
solvent (0.5 mL) for 12 h. Yields were based on H NMR analysis of
the crude mixture (CH Br : internal standard). n.r. = no reaction.
2
2
9
elegant approach, we initially introduced a N-pivaloyl group to
see whether it indeed can guide the desired C-7 selectivity in
our case. When a cationic Ir species generated in situ from
a
1
(0.20 mmol) and 2a (0.22 mmol) in 1,2-DCE (0.5 mL); isolated
b
[
IrCp*Cl ] and AgNTf was employed, the desired product 3a
2 2 2
yields. At 80 °C.
was formed only in trace amount at 50 °C (entry 1). On the
basis of our previous observation that acetate additives can
13
pivaloylindole was unambiguously confirmed by an X-ray
crystallographic analysis. We were pleased to observe that the
amidation took place smoothly irrespective of the position and
electronic nature of substituents, thus giving rise to the
corresponding C-7 amidated products in high efficiency and
regioselectivity. Indeed, substrates bearing methyl (3b and 3h),
alkoxy (3c, 3i, 3j, and 3m), fluoro (3d and 3n), bromo (3e and
3k), and chloro (3f and 3l) groups at the C4-, 5-, and 6-
position of indoles were all facile for the present amidation.
However, an indole substrate bearing a nitro group at the 5-
position was amidated in moderate efficiency (3g).
When a pregenerated iridium acetate complex, IrCp*(OAc)2,
Next, the scope of indoles substituted at the nitrogen-
containing cyclic moiety (e.g., at the 2- or 3-position) was
examined. Various functional groups positioned at C-3 did not
much diminish the amidation efficiency, as demonstrated by the
facile product formation of 3o−3r. In particular, amidated
was used as a catalyst in the presence of NaNTf , the desired
2
product was obtained in moderate yield (entry 9). The use of
AgNTf in place of NaNTf significantly improved the product
2
2
yield (entry 10). Not surprisingly, the aminated product 3a was
B
DOI: 10.1021/acs.orglett.6b00662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
indoles bearing chloro, silyl-protected alcohol, or ketone groups
would be potentially valuable for further synthetic trans-
formations. In contrast, the amidation did not take place when
Scheme 4. Synthesis of Biorelevant Compounds
2
-substituted indoles were subjected to the current conditions
(3s and 3t) although the exact reason is not clear at the present
stage. Amidation of 9-acetyl-2,3,4,9-tetrahydro-1H-carbazole
proceeded smoothly, leading to 3u in 76% yield.
Finally, the influence of N-directing groups on the amidation
efficiency was briefly examined. When sterically less hindered
N-acetyl, isobutyryl, or cyclohexanecarbonyl groups were
installed, lower product yields were obtained (3v−3x)
14
compared to N-pivaloylindole (3a). Even lower amidation
efficiency was observed with N-benzoylindole (3y). However, a
reaction of N-(1-adamantanecarbonyl)indole took place almost
quantitatively under the same mild conditions (3z), thus
strongly suggesting that a steric factor critically affects the
reaction efficiency.
successfully on a gram scale to give the corresponding 7-
amidoindoles in high yields (4b and 4m, respectively).
Pleasingly, the N-pivaloyl group of amidated indoles was easily
The scope of organic azides was subsequently investigated in
the amidation of N-pivaloylindole (Scheme 3). All arenesul-
removed also under mild conditions (Et N/MeOH at room
3
temperature), thus affording 7-aminoindoles 5a (ER-67836)
and 5b (ER-68394), both of which were revealed to display
a
Scheme 3. Scope of Organic Azides
2a−c
antitumor activity.
A plausible mechanism of the present C-7 amidation is
depicted in Scheme 5 based on our previous mechanistic
Scheme 5. Proposed Mechanistic Pathway
a
1
a (0.20 mmol) and 2 (0.22 mmol) in 1,2-DCE (0.5 mL); isolated
b
yields. At 50 °C.
fonyl azides examined were smoothly reacted with 1a to result
in excellent product yields irrespective of the substituents’
electronic property (4a−4e). Moreover, alkanesulfonyl azides
were also highly facile under the standard mild amidation
conditions (4f−4h). Thiophenesulfonyl azide was observed to
work as an effective amidating reagent (4i). In addition,
amidation reactions of 1a with 1-naphthalenesulfonyl azide and
1
2d,13b
investigations in the related C−H amination reactions.
A
cationic Ir(III) species, in situ generated by treating IrCp*-
(OAc) with AgNTf , will undergo a directed C7−H bond
2
2
activation of N-pivaloylindole via the chelation assistance of a
carbonyl oxygen atom to give rise to a six-membered iridacycle
(I). A subsequent coordination of organic azide to the iridium
metal center and then insertion of an imido group into the Ir−
2-phenylethene-1-sulfonyl azides occurred efficiently to furnish
the corresponding aminoindoles in high yields (4j−4k). On the
other hand, aryl azides, which were proven by us to be an
efficient aminating source in the Rh-catalyzed amination of
C bond are believed to occur with concomitant release of a N
2
molecule leading to an iridium amido intermediate (III).
Finally, a protodemetalation of III will deliver the 7-
aminoindole product with the regeneration of the active
iridium catalyst.
In conclusion, we have developed the Ir-catalyzed direct C−
H amidation of N-pivalolylindoles at the C-7 position by using
organic azides under mild conditions. A broad range of indoles
were efficiently amidated with excellent regioselectivity. The
1
5
benzamides, displayed only moderate efficiency under the
present iridium catalyst system (4l).
A notable aspect of the present procedure is that 7-
aminoindoles of high bioactivity can be directly accessed
under mild conditions (Scheme 4). As a preliminary
demonstration, the amidation of N-pivaloylindole (1a) and its
congener substituted with a chloro group (1f) was carried out
C
DOI: 10.1021/acs.orglett.6b00662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
procedure is convenient to perform on a gram scale and the N-
pivaloyl directing group can readily be removed, thus offering a
straightforward route to biologically relevant 7-aminoindole
compounds.
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Corresponding Author
E-mail: sbchang@kaist.ac.kr.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This research was supported by the Institute for Basic Science
IBS-R010-D1).
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