Cross-Dehydrogenative C-H Amination of Indoles under Aerobic Photo-oxidative Conditions

Article abstract of DOI:10.1021/acs.orglett.7b00026

A novel cross-dehydrogenative C(sp²)-H amination catalyzed by an organic photocatalyst is reported. The reaction is mediated by 2-tert-butylanthraquinone as a photocatalyst, harmless visible light, and aerobic oxygen as the sole oxidant without a transition-metal catalyst and or external oxidant.

Full text of DOI:10.1021/acs.orglett.7b00026

Letter
pubs.acs.org/OrgLett
Cross-Dehydrogenative C−H Amination of Indoles under Aerobic
Photo-oxidative Conditions
Tomoaki Yamaguchi, Eiji Yamaguchi, and Akichika Itoh*
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
S
* Supporting Information
ABSTRACT: A novel cross-dehydrogenative C(sp2)−H amina-
tion catalyzed by an organic photocatalyst is reported. The
reaction is mediated by 2-tert-butylanthraquinone as a photo-
catalyst, harmless visible light, and aerobic oxygen as the sole
oxidant without a transition-metal catalyst and or external
oxidant.
irect C−H bond functionalization is one of the most
rare; therefore, the development of catalytic and oxidative
D
challenging reactions in organic chemistry, and many
formation of N-radicals is important in organic chemistry.
Furthermore, we are involved in the development of photo-
organo-catalytic oxidative reactions employing aerobic oxygen.8
We have already reported the cross-dehydrogenative coupling
reaction via the aerobic photo-oxidative generation of an
iminium intermediate from tertiary amines followed by addition
of a nucleophile.9 In this reaction, single-electron transfer was
mediated by a photocatalyst, and the amines were converted
into radical cation species. Accordingly, we envisioned that
oxidative C−H amination of heterocycles with amidyl radicals,
which are often used as radical intermediates in photo-
reactions,10 could be achieved if the single-electron transfer of
secondary amines proceeds by our oxidation system. Our
oxidative strategy does not require preactivation of amines and
keeps byproducts to a minimum because molecular oxygen is
used as a sole oxidant (Scheme 1). Hence, this method will be
researchers have developed various reactions to tackle the
problem.1 In particular, intra- and intermolecular C−H
aminations are explored energetically because aromatic and
heteroaromatic amines are frequently present in pharmaceut-
icals, agrochemicals, and organic materials.2 Generally, these
molecules are generated by nucleophilic aromatic substitution,
reduction of nitroarenes, or a cross-coupling reaction such as
Buchwald−Hartwig amination and Ullmann-type coupling
reaction.3 These typical methodologies are valuable and used
frequently; however, they require prefunctionalization of
starting materials. In contrast, direct C−H amination does
not require prefunctionalization of arenes, and various reactions
such as ligand-directed, intramolecular, and intermolecular
reactions have been reported.4 Furthermore, the direct
amination of simple arenes and heteroarenes with N-centered
radicals using visible light and photoredox catalysts has been
achieved.5 These photoreactions do not need directing groups
in substrates or high temperature; however, they require
preparation of amine derivatives and expensive iridium or
ruthenium photocatalysts. Therefore, the development of a
simpler and more economical method is desired.
Scheme 1. Oxidative Generation of N-Centered Radicals and
the C−H Amination of Heterocycles
Meanwhile, the cross-dehydrogenative coupling (CDC)
reaction is an ideal reaction system because preactivation of
both substrates is unnecessary, reducing the reaction waste and
steps. Thus, C−H aminations via the CDC reaction have been
developed by using a transition-metal catalyst such as
palladium, copper, and iron or an organic reagent such as
Bu4NI and PhI(OAc)2.6 These reactions are superior but
require transition-metal catalysts, a stoichiometric or large
excess amount of the oxidant, and harsh reaction conditions.
With such a background, we propose to use the CDC reaction
with a N-centered radical, e.g., amidyl radical, to develop a
novel reaction that overcomes the above problems. Specifically,
a superior C−H amination can be achieved if a radical species is
formed by single-electron oxidation of a secondary amine. Very
recently, visible-light-induced oxidative C−H amidation has
been reported by Yu, Zhang et al.7 However, the methodologies
of catalytic C(sp2)−H amination under mild conditions are still
superior to others in atom and step economy if it can be
applied to the intermolecular C−H amination of heterocycles.
In particular, we focused on the amination of indoles, which are
important for both biological and functional material
chemistries. 3-Aminoindoles have received a lot of attention
as a significant structure in drug design for various diseases.11
Herein, we describe the catalytic amination of indoles via the
CDC reaction under aerobic photo-oxidative conditions.
Initially, we examined the C−H amination of 1-methyl-2-
phenylindole (2a) with phthalimide (1a) using 2-tert-
butylanthraquinone (2-t-Bu-AQN) and potassium carbonate
Received: January 5, 2017
© XXXX American Chemical Society
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Table 1. Optimization of the Oxidative C−H Amination of
Table 2. Oxidative C−H Amination of 2 Bearing Various
a
a,b
2a
Substituents at C2
entry
R
yield (%)
b
entry
catalyst
additive (mol %)
3aa (%)
1
Ph (3aa)
Me (3ab)
82
55
29
80
70
87
86
72
60
69
77
93
83
77
42
n.d.
1
2
3
2-t-Bu-AQN
K2CO3 (50)
K2CO3 (50)
85 (80)
0
2
3
CO2Me (3ac)
2-t-Bu-AQN
2-t-Bu-AQN
2-t-Bu-AQN
AQN
42
4
4-Me-C6H4 (3ad)
4-t-Bu-C6H4 (3ae)
4-OMe-C6H4 (3af)
4-CHO-C6H4 (3ag)
4-CO2Me-C6H4 (3ah)
4-Br-C6H4 (3ai)
4-CF3-C6H4 (3aj)
4-CH2OTBS-C6H4 (3ak)
3-OMe-C6H4 (3al)
2-Me-C6H4 (3am)
2-thienyl (3an)
c
4
d
K2CO3 (50)
K2CO3 (50)
K2CO3 (50)
K2CO3 (50)
K2CO3 (50)
K2CO3 (50)
K2CO3 (60)
K2CO3 (100)
0
5
5
26
6
6
68
7
7
AQN-2-CO2H
9,10-DCA
54
8
8
56
9
e
9
Ru(bpy)3Cl2
0
10
11
12
13
14
15
10
11
2-t-Bu-AQN
2-t-Bu-AQN
(82)
(81)
a
Reaction conditions: mixture of 1a (0.3 mmol), 2a (0.6 mmol),
catalyst, additive, and MS 4 Å (50 mg) in DMF (3 mL) was stirred for
20 h under an aerobic atmosphere irradiated with a 21-W fluorescent
4-pyridinyl (3ao)
H (3ap)
b
lamp. Yields were determined by 1H NMR analysis. Numbers in
c
16
parentheses refer to isolated yields. Reaction performed in the dark.
Reaction performed under an argon atmosphere. Ru(bpy)3Cl2 (5
a
d
e
Reaction conditions: mixture of 1a (0.3 mmol), 2 (0.6 mmol), 2-t-
Bu-AQN (10 mol %), K2CO3 (60 mol %), and MS 4 Å (50 mg) in
DMF (3 mL) was stirred for 20 h under an aerobic atmosphere
mol %) was used as a catalyst.
b
irradiated with a 21-W fluorescent lamp. Isolated yields.
in N,N-dimethylformamide (DMF) under an aerobic atmos-
phere with visible light irradiation (Table 1, entry 1). The
amination of indole at the C3 position proceeded well, and
pure 3aa was obtained in 80% yield. In the absence of the
photocatalyst or base, the product yield decreased (entries 2
and 3). Control experiments verified the necessity of both
visible light irradiation and molecular oxygen in the reaction
(entries 4 and 5). Solvent and base screening revealed that
DMF and potassium carbonate were well suited to this reaction
(for detailed results, see the Supporting Information). Photo-
catalyst screening revealed that anthraquinones and 9,10-
dicyanoanthracene provided the product in moderate yield, but
a commonly used photocatalyst tris(bipyridine)ruthenium(II)
chloride was found to be ineffective (entries 6−9) Moreover,
the amination reaction did not proceed well with other
photocatalysts such as eosin Y, rose bengal, or acridine (for
detailed results, see the SI). The product yield decreased by
reducing the loading of 2-t-Bu-AQN (for detailed results, see
the SI). With an increased amount of potassium carbonate, the
desired aminated product was obtained in 82% isolated yield
(entry 10). However, the yield of product was not improved by
addition of 100 mol % of base (entry 11).
After determining the optimal conditions, we investigated the
reaction of 1a with indoles bearing various substituents (Table
2). The desired product 3ab was obtained in moderate yield
when 1,2-dimethylindole was used as the substrate (entry 2).
Furthermore, the product yield was low when the electron poor
indole (2c) was used as a substrate (entry 3). These results
suggested that the stability of the generated radical at C2 is
crucial in this reaction. Next, we examined the effect of
substituents on the phenyl group. Electron-donating groups
such as alkyl and methoxy were suitable for this method, and
C3-aminated products were obtained in good to excellent yields
(entries 4−6). Furthermore, the direct C−H amination
proceeded well to yield the desired products in the presence
of electron-withdrawing groups (entries 7−10). Silyl-protected
aldohol could be employed under the reaction conditions
without any deprotection (entry 11). When the position of the
substituent was changed from para to meta or ortho, the desired
products were produced in high yield (entries 12 and 13).
Thienyl- or pyridinyl-substituted indole was converted into the
corresponding aminated indole in moderate to good yields
(entries 14 and 15). Unfortunately, N-methylindole (2p) was
not suited to these reaction conditions (entry 16).
We next investigated the effect of the substituent at the C1
position (Table 3). Starting materials and byproducts, which
Table 3. Oxidative C−H Amination of Substituted
a,b
Indoles
entry
R
R′
yield (%)
0
1
2
3
4
5
6
7
8
9
H
H
(3aq)
(3ar)
(3as)
(3at)
(3au)
(3av)
(3aw)
(3ax)
(3ay)
c
Ac
Ph
Bn
H
0 (13)
H
82
89
88
72
69
75
77
H
MOM
CH2CO2Me
Me
H
H
OMe
Me
Cl
Me
Me
a
Reaction conditions: mixture of 1a (0.3 mmol), 2 (0.6 mmol), 2-t-
Bu-AQN (10 mol %), K2CO3 (60 mol %), and MS 4 Å (50 mg) in
DMF (3 mL) was stirred for 20 h under an aerobic atmosphere
b
c
irradiated with a 21-W fluorescent lamp. Isolated yields. The yield of
2-phenyl-3-phthalimidoindole (3aq).
B
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could not be detected, were observed when 2-phenylindole
(2q) was used as substrate (entry 1). Furthermore, 2r could not
be converted to the desired compound (3ar) but gave 2-
phenyl-3-phthalimidoindole (3aq) in low yield (entry 2). By
contrast, 1,2-diphenylindole (2s) underwent this transforma-
tion with good yield (entry 3). These results suggested that the
electron density of indole is an important factor for this
reaction. Furthermore, indoles with removable groups, such as
Bn and MOM, worked well to give the 3-aminated products in
excellent yields (entries 4 and 5). Next, we investigated the
effect of the substituents at C5 of indoles. As a result, the
desired products were obtained in moderate yields regardless of
the electron density (entries 7−9). When the position of the
phenyl group was changed from C2 to C3, the C−H amination
proceeded at C2 in moderate yield (Scheme 2).
Scheme 3. Oxidative C−H Amination of 2a with Various
a,b
Substituted 1
a
Reaction conditions: mixture of 1 (0.3 mmol), 2a (0.6 mmol), 2-t-
Bu-AQN (10 mol %), K2CO3 (60 mol %), and MS 4 Å (50 mg) in
DMF (3 mL) was stirred for 20 h under an aerobic atmosphere
b
irradiated with a 21-W fluorescent lamp. Isolated yields.
Scheme 2. Direct C−H Functionalization of 2z
1c). On the other hand, moderate yield was observed when 1,8-
naphthalimide (1d) was used as a nitrogen source.
Several control experiments were conducted to investigate
the reaction mechanism. The yield of 3aa was decreased to 32%
by addition of TEMPO, which is a radical scavenger (Scheme 4,
In addition, we applied this catalytic system for other
heterocycles (Table 4). The aminated products were formed in
Scheme 4. Control Experiments
Table 4. Oxidative C−H Amination of Pyrroles and
a,b
Benzo[b]thiophene
eq 1). Furthermore, TEMPO adduct (8) was obtained when 1-
methylindole (2p) was used instead of 2a (Scheme 4, eq 2).
These results suggested that the amination proceeded by the
generation of an N-centered radical, followed by an addition to
indoles. The aminated product was obtained in excellent yield
regardless of the presence of potassium carbonate when
potassium phthalimide was used as a nitrogen source. This
result indicated that deprotonation of phthalimide may be
assisted by K2CO3 (for detailed results, see the SI). Moreover,
the generation of peroxide was detected by iodometry,
suggesting that molecular oxygen was converted to hydrogen
peroxide in this reaction (for detailed results, see the SI).
Figure 1 shows a plausible mechanism for this reaction,
which is postulated by considering all of the above results.
Initially, an N-centered radical is formed by deprotonation of 1a
and single-electron transfer to AQN*. The radical species adds
to indoles, followed by one-electron oxidation and aromatiza-
tion. On the other hand, AQN•− is oxidized by molecular
oxygen in the air to AQN, which is then converted by visible
light to AQN* to complete the catalytic system. However,
another path, such as AQN* quenched with 2, could not be
ruled out.12
a
Reaction conditions: mixture of 1a (0.3 mmol), 4 or 6 (0.6 mmol), 2-
t-Bu-AQN (10 mol %), K2CO3 (60 mol %), and MS 4 Å (50 mg) in
DMF (3 mL) was stirred for 20 h under an aerobic atmosphere
b
irradiated with a 21-W fluorescent lamp. Isolated yields.
low to moderate yields when substituted pyrroles were used as
substrates (entries 1−3). Moreover, 2-phenylbenzo[b]-
thiophene (6) could be employed for this reaction even
though the yield was low (entry 4).
Furthermore, we examined the amination of 2a with various
substituted phthalimides (Scheme 3). As a result, the desired
product yields decreased in the presence of electron-donating
and -withdrawing substituents at C4 of phthalimide (1b and
In conclusion, we have achieved the catalytic C−H amination
of indoles at room temperature. This methodology uses
harmless visible light, cheap and commercially available
C
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Figure 1. Plausible reaction mechanism.
photocatalyst and nitrogen source, and molecular oxygen as the
sole oxidant. Further applications of the N-centered radical for
other heterocycles and the nitrogen sources are being studied at
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00026.
(7) Tong, K.; Liu, X.; Zhang, Y.; Yu, S. Chem. - Eur. J. 2016, 22,
15669.
Experimental details and NMR spectra (PDF)
(8) (a) Yamaguchi, T.; Kudo, Y.; Hirashima, S.; Yamaguchi, E.; Tada,
N.; Miura, T.; Itoh, A. Tetrahedron Lett. 2015, 56, 1973. (b) Okada, A.;
Yuasa, H.; Fujiya, A.; Tada, N.; Miura, T.; Itoh, A. Synlett 2015, 26,
1705. (c) Shimada, Y.; Hattori, K.; Tada, N.; Miura, T.; Itoh, A.
Synthesis 2013, 45, 2684.
(9) Yamaguchi, T.; Nobuta, T.; Tada, N.; Miura, T.; Nakayama, T.;
Uno, B.; Itoh, A. Synlett 2014, 25, 1453.
́ ́ ́
(10) Sanchez-Sanchez, C.; Perez-Inestrosa, E.; García-Segura, R.;
Suau, R. Tetrahedron 2002, 58, 7267.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: itoha@gifu-pu.ac.jp.
ORCID
Akichika Itoh: 0000-0003-3769-7406
Notes
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V. M.; Gupta, A. A.; Jadav, P. A.; Patel, P. R. Bioorg. Med. Chem. 2007,
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The authors declare no competing financial interest.
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