Iridium-Catalyzed Direct Regioselective C4-Amidation of Indoles under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.7b00730

An efficient Ir-catalyzed amidation of indoles with sulfonyl azides is disclosed, affording diverse C4-amidated indoles exclusively under mild conditions. In this protocol, a variety of indoles with commonly occurring functional groups such as formyl, acetyl, carboxyl, amide, and ester at the C3 position are well tolerated.

Full text of DOI:10.1021/acs.orglett.7b00730

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Direct Regioselective C4-Amidation of Indoles
under Mild Conditions
Shuyou Chen, Boya Feng, Xuesong Zheng, Jiangliang Yin, Shiping Yang, and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29
Wangjiang Road, Chengdu 610064, P. R. China
S
* Supporting Information
ABSTRACT: An efficient Ir-catalyzed amidation of indoles
with sulfonyl azides is disclosed, affording diverse C4-amidated
indoles exclusively under mild conditions. In this protocol, a
variety of indoles with commonly occurring functional groups
such as formyl, acetyl, carboxyl, amide, and ester at the C3
position are well tolerated.
uring the past few years, C−H activation has proven to be
D
an economical and straightforward tool with promising
applications in the functionalization of organic molecules.1 An
important aim in the field of C−H activation is to control the
regioselectivity of reactions. Indole, a nitrogen-containing
framework with seven potentially reactive positions, widely
presents in bioactive molecules and pharmaceutical products.2
The direct modification of indole ring via transition-metal-
catalyzed C−H activation has become an effective approach for
the construction of diversiform indoles.3 In general, electrophilic
metalation usually occurs at the C3 position of indole owing to its
higher electron density.4 Regioselective functionalization of the
C2 position can also be realized by using a directing group or
selection of specific conditions.5 In contrast, only a few examples
on the selective C−H activation/functionalization of C4−C7
positions of indoles have been disclosed.3c,6
Figure 1. Potential pharmaceutical scaffolds that contain 4-amino-
substituted indoles.
The C−N bond is one of the most ubiquitous bonds in organic
molecules.7 Therefore, the construction of the C−N bond is
always an attractive topic in organic chemistry. Recently,
transition-metal-catalyzed direct C−H activation/amination of
(hetero)arenes has emerged as a concise and highly efficient
strategy for the synthesis of (hetero)aromatic amines.8 Despite
significant progress, selective C−H activation/amination of the
indole core is still underdeveloped.6f−h,9 4-Amino-indoles exhibit
potential applications in pharmaceuticals, including as an
antiproliferative agent, HIV protease inhibitor, kinase inhibitor,
and 5-HT6 receptor antagonist (Figure 1).10 Although direct C−
H amination of indoles represents one of the most ideal
approaches to 4-amino-indoles, the inherent poor electronic
nature of the C4 position of indole impedes the selective
functionalization of this site. The introduction of a directing
group at the C3 position might be helpful to address this issue.
However, a selectivity issue between the C2 and C4 positions still
exists. Typically, C−H activation prefers to take place at the more
reactive C2 position rather than the C4 position when a directing
group is installed at the C3 position of indoles (Figure 2).9c,11
Quite recently, with the assistance of the bulky N-pivaloyl
group, Chang et al. developed an Ir-catalyzed regioselective C7−
H amidation of indoles.6h In this work, we wish to disclose an Ir-
Figure 2. Competitive C−H activation at the C2 and C4 positions of
indole through the chelation assistance.
catalyzed C4−H amidation of indoles using the commonly
occurring functional groups, such as formyl, acetyl, carboxyl,
amide, and ester, as a weakly coordinating directing group.
Our investigation started with the amidation of 1H-indole-3-
carbaldehyde 1a, using 4-methylbenzenesulfonyl azide 2a as the
nitrogen source, [Cp*IrCl2]2/AgSbF6 as the catalyst system, and
silver acetate as the additive in DCE at 25 °C for 24 h under an air
atmosphere (Table 1). To our delight, the reaction condition is
compatible with the NH-free indoles, and the desired amidated
product could be obtained in 72% yield without the 2-substituted
compound detected (Table 1, entry 1). The yield was slightly
decreased by employing Cu(OAc)2·H2O as the additive (Table
Received: March 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00730
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat. (mol %/mol %)
additive
AgOAc
solvent
yield (%)
1
[Cp*IrCl2]2/AgSbF6 (5:20)
[Cp*IrCl2]2/AgSbF6 (5:20)
[Cp*IrCl2]2/AgSbF6 (5:20)
Cp*Ir(OAc)2/AgSbF6 (10:20)
Cp*Ir(OAc)2/AgSbF6 (10:20)
Cp*Ir(OAc)2/AgNTf2 (10:20)
Cp*Ir(OAc)2/AgNTf2 (7.5:15)
Cp*Ir(OAc)2/AgNTf2 (5:10)
Cp*Ir(OAc)2/AgNTf2 (7.5:15)
Cp*Ir(OAc)2/AgNTf2 (7.5:15)
Cp*Ir(OAc)2/AgNTf2 (7.5:15)
Cp*Ir(OAc)2 (7.5)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhCl
dioxane
DMF
DCE
DCE
DCE
DCE
DCE
72
2
Cu(OAc)2·H2O
KOAc
60
3
20
4
AgOAc
70
5
−
−
−
−
−
−
−
−
−
−
−
−
73
6
92
7
90
8
72
9
32
10
11
12
13
14
15
16
<5
n.d.
n.d.
n.d.
n.d.
n.d.
[Cp*IrCl2]2/AgNTf2 (5:20)
Cp*Co(CO)I2/AgNTf2 (10:20)
[Cp*RhCl2]2/AgNTf2 (5:20)
[Ru(p-cymene)Cl2]2/AgNTf2 (5:20)
n.d.
a
b
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst and additive (0.3 equiv) in solvent (1 mL) under air at 25 °C for 24 h. Isolated
yield. DCE = ClCH2CH2Cl. n.d. = no detected.
a
1, entry 2). Only a 20% yield was gained after KOAc was adopted
in the system (Table 1, entry 3). Pleasingly, altering the iridium
species to Cp*Ir(OAc)2 afforded 3aa in 70% yield while the
removal of AgOAc hardly affected the yield (Table 1, entries 4
and 5). Fortunately, 3aa was finally generated in 92% yield with a
Cp*Ir(OAc)2/AgNTf2 (10:20) catalyst system (Table 1, entry
6). Reducing the loading of catalyst to 7.5 mol % showed no
effect on the yield (Table 1, entry 7). However, further reducing
the amount of catalyst resulted in the reduction of yield to 72%
(Table 1, entry 8). In addition, other solvents, such as PhCl, 1,4-
dioxane, and DMF, led to low output or even no product (Table
1, entries 9−11). Neither Cp*Ir(OAc)2 nor a combination of
[Cp*IrCl2]2/AgNTf2 (5:20) could promote the amidation of 1a,
Scheme 1. Scope of Indoles
indicating the essential roles of both OAc− and NTf2 in this
−
reaction (Table 1, entries 12 and 13). Other transition metal
catalysts, including Cp*Co(CO)I2, [Cp*RhCl2]2, and [Ru(p-
cymene)Cl2]2, were not suitable for this reaction (Table 1,
entries 14−16). Finally, the optimal reaction conditions are
composed of Cp*Ir(OAc)2 (7.5 mol %) and AgNTf2 (15 mol %)
in DCE at 25 °C for 24 h.
With the optimal conditions in hand, we then investigated the
scope of this catalytic system. As shown in Scheme 1, a range of
substituted indoles were tested. Both the electron-withdrawing
and -donating groups such as ester, methyl, methoxyl, and
halogen substituted groups at different positions on the phenyl
ring were tolerated well, affording the amidated products in
moderate to excellent yields, but the electronic nature of
substituents could significantly influence the yields. The
electron-withdrawing groups delivered a higher yield than the
electron-donating groups (3ca and 3da vs 3ba). Notably, the
amidated product with the 6-bromo-substituent was obtained in
a synthetically useful yield, which would provide an active site for
further functionalization (3ea). Furthermore, the substituent on
the five-membered ring was also tolerated, exemplified by the
product 3fa. More importantly, the scope of this catalyst system
was also extended to the indoles with other C3 functional groups
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), Cp*Ir(OAc)2
(7.5 mol %) and AgNTf2 (15 mol %) in DCE (1 mL) at 25 °C under
b
air for 24 h. 1-Pivaloyl-1H-indole-3-carbaldehyde was used as the
substrate. At 60 °C. Pym = 2-pyrimidyl.
c
such as acetyl, ester, carboxyl, and amide. These indole
derivatives smoothly afforded the C4 amidated products in
moderate to good yields with exclusive C4 selectivity (3ha, 3ia,
3ja, and 3ka). Interestingly, when N-pivaloyl indole-3-
carbaldehyde was attempted under the standard conditions, an
N-deprotected product 3aa was obtained in 56% yield. However,
no desired product was obtained in the case of 1-(pyrimidin-2-
yl)-1H-indole-3-carbaldehyde (3la).
B
DOI: 10.1021/acs.orglett.7b00730
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Organic Letters
Letter
Subsequently, the scope of sulfonyl azides was investigated. As
shown in Scheme 2, both the electron-withdrawing and
Scheme 3. Gram-Scale Synthesis of 3aa and Deprotection of
the Amidated Products
a
Scheme 2. Scope of Organic Azides
Scheme 4. H/D Exchange Experiment
According to the previous reports6h,12 and the above
experimental results, a proposed mechanism is illustrated in
Scheme 5. Initially, the anion exchange of Cp*Ir(OAc)2 with
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), Cp*Ir(OAc)2
(7.5 mol %) and AgNTf2 (15 mol %) in DCE (1 mL) at 25 °C under
air for 24 h. At 60 °C. Cp*Ir(OAc)2 (10 mol %) and AgNTf2 (20
mol %).
b
c
Scheme 5. Proposed Mechanism
-donating group substituted aryl sulfonyl azides proceeded
smoothly, giving the desired products in good to excellent yields.
The phenyl sulfonyl azide with ortho-methyl substitution
required an elevated temperature of 60 °C, affording 3ac in
62% yield. N-(3-Formyl-1H-indol-4-yl)thiophene-2-sulfona-
mide (3ai) was obtained in 80% yield. Moreover, ethanesulfonyl
azide could also couple with 1a, delivering 3aj in 78% yield.
In addition, we also tried the reactions with a combination of
Ir/Ag (1:1) as the catalyst. In the case of 3aa, a comparative yield
was obtained. However, diminished yields were observed in
some cases such as 3ga, 3ac, 3ae, and 3af (38%, 46%, 84%, and
88% yields, respectively).
Considering the synthetic utility of the amidation reaction, the
scalability of the reaction was further examined, presenting a 68%
yield of 3aa (1.48 g) at 60 °C (Scheme 3, eq 1). By using
concentrated sulfuric acid, 3aa and 3ad could be deprotected to
give 4-amino-1H-indole-3-carbaldehyde (4aa) in 72% and 52%
yields, respectively (Scheme 3, eqs 2 and 3). This result indicates
that an electron-rich substituent at the phenyl sulfonamide ring
could facilitate the deprotection of the amidated indoles.
To determine the mechanism, a H/D exchange experiment
was conducted (Scheme 4). When CD3COOD was added into
the reaction system under the optimal conditions, the C4−H
bond of the indole ring was deuterated in 66% yield without
deuteration at the C2−H bond. This result indicates that the C−
H activation at the C4 position is reversible and the directing
group in this reaction prefers to assist the cleavage of the C4−H
rather than the C2−H.
AgNTf2 possibly forms an IrCp*(OAc)(NTf2) species.6g,h,13
The subsequent cyclometalation with 1a delivers the 6-
membered cycloiridium intermediate A through the C−H
bond cleavage of the C4 position. The azide 2a then coordinates
to the iridium center of A to form the intermediate B, followed by
the migratory insertion of the imido group to the Ir−aryl bond,
affording the intermediate C with the extrusion of N2. Finally, the
C
DOI: 10.1021/acs.orglett.7b00730
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Letter
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species by protonation.
In conclusion, an efficient Ir-catalyzed C4 amidation of
substituted indoles with sulfonyl azides under mild conditions
has been developed. A variety of indoles are employed to afford
the amidated products with exclusive C4 selectivity. The
procedure disclosed herein is not only applicable to N-
unprotected indoles but also compatible with diverse commonly
occurring functional groups such as formyl, acetyl, carboxyl,
amide, and ester at the C3 position of indoles. Further
application of this method is currently underway in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00730.
Detailed experimental procedures, characterization data,
and copies of 1H and 13C NMR spectra of key
intermediates and final products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsyou@scu.edu.cn.
ORCID
(9) For examples of C−N bond formation of indoles, see: (a) Shuai,
Q.; Deng, G.; Chua, Z.; Bohle, D. S.; Li, C.-J. Adv. Synth. Catal. 2010,
352, 632. (b) Shi, J.; Zhou, B.; Yang, Y.; Li, Y. Org. Biomol. Chem. 2012,
10, 8953. (c) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2014, 136, 3354. (d) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, M. Adv.
Synth. Catal. 2014, 356, 1491.
Jingsong You: 0000-0002-0493-2388
Notes
(10) (a) Magedov, I. V.; Frolova, L.; Manpadi, M.; Bhoga, U.; Tang, H.;
Evdokimov, N. M.; George, O.; Georgiou, K. H.; Renner, S.; Getlik, M.;
Kinnibrugh, T. L.; Fernandes, M. A.; Slambrouck, S. V.; Steelant, W. F.
A.; Shuster, C. B.; Rogelj, S.; van Otterlo, W. A. L.; Kornienko, A. J. Med.
Chem. 2011, 54, 4234. (b) Suter, L.; Haiker, M.; de Vera, M. C.;
Albertini, S. Pharmacogenomics J. 2003, 3, 320. (c) Bonini, C.;
Chiummiento, L.; Di Blasio, N.; Funicello, M.; Lupattelli, P.;
Tramutola, F.; Berti, F.; Ostric, A.; Miertus, S.; Frecer, V.; Kong, D.-
X. Bioorg. Med. Chem. 2014, 22, 4792. (d) Lu, L.; Wu, Z.; Lu, T. Strait
Pharm. J. 2012, 24, 11.
(11) (a) Song, W.; Lackner, S.; Ackermann, L. Angew. Chem., Int. Ed.
2014, 53, 2477. (b) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J.
Am. Chem. Soc. 2015, 137, 531. (c) Manikandan, R.; Madasamy, P.;
Jeganmohan, M. Chem. - Eur. J. 2015, 21, 13934. (d) Tan, G.; He, S.;
Huang, X.; Liao, X.; Cheng, Y.; You, J. Angew. Chem., Int. Ed. 2016, 55,
10414.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the financial support from the National NSF of China
(No 21432005).
■
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D
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