Synthesis of 2-substituted indoles by iridium (III)-catalyzed C–]H functionalization of N-phenylpyridin-2-amines

Article abstract of DOI:10.1016/j.tetlet.2019.03.027

A highly regioselective synthesis of 2-substituted indoles was realized through Ir(III)-catalyzed C–]H functionalization of N-phenylpyridin-2-amines followed by the reaction with sulfoxonium ylides and intramolecular cyclization under mild conditions. The reaction completed with broad range of substrate scopes and gave various 2-substituted indoles in up to 98% yields.

Full text of DOI:10.1016/j.tetlet.2019.03.027

Accepted Manuscript
Synthesis of 2-Substituted Indoles by Iridium (III)-Catalyzed C-H Functional-
ization of N-phenylpyridin-2-amines
Lei Zhang, Junyu Chen, Jinkang Chen, Licheng Jin, Xiangyun Zheng, Xinpeng
Jiang, Chuanming Yu
PII:
S0040-4039(19)30235-7
https://doi.org/10.1016/j.tetlet.2019.03.027
TETL 50668
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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1 January 2019
8 March 2019
11 March 2019
Please cite this article as: Zhang, L., Chen, J., Chen, J., Jin, L., Zheng, X., Jiang, X., Yu, C., Synthesis of 2-Substituted
Indoles by Iridium (III)-Catalyzed C-H Functionalization of N-phenylpyridin-2-amines, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.03.027
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Tetrahedron Letters
Synthesis of 2-Substituted Indoles by Iridium (III)-Catalyzed C-H Functionalization
of N-phenylpyridin-2-amines
Lei Zhang, Junyu Chen, Jinkang Chen, Licheng Jin, Xiangyun Zheng, Xinpeng Jiang*, and Chuanming
Yu*
College of pharmaceutical sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly regioselective synthesis of 2-substituted indoles was realized through Ir(III)-catalyzed
C–H functionalization of N-phenylpyridin-2-amines followed by the reaction with sulfoxonium
ylides and intramolecular cyclization under mild conditions. The reaction completed with broad
range of substrate scopes and gave various 2-substituted indoles in up to 98% yields.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Iridium
Sulfoxonium ylides
C-H functionalization
Indole
Introduction
Indole is a privileged scaffold with numerous applications
in both life sciences and material sciences [1]. In particular,
2-arylindoles [2] and 2-aliphatic substituted indoles [3] are
intriguing structural motifs owing to their presence in a series
of marketed drugs (Figure 1). Consequently, tremendous
efforts have been devoted to constructing 2-substituted indole
scaffolds. Recently, Rh- [4], Pd- [5], Ru- [6], Ni- [7] and other
transition metals [8] catalyzed C−H functionalization provided
a fundamental step for the preparation of various 2-substituted
indoles.
Scheme 1 Synthesis of 2-substituted indoles via annulative
C–H activation.
Fig.1 Selected drugs containing 2-substituted indoles
(Scheme 1b). More recently, Kim and Cui applied diazo
compounds and vinyl azides to synthesize 2-substituted indoles
(Scheme 1c and 1d) [11]. Despite the significant advance made
in this field, the previous methods still suffer from limited
n a roup [9] reported a Rh(III)-catalyzed
synthesis of 2-methylindoles with stoichiometric copper(II) as
oxidant (Scheme 1a). hortly after Jana roup [10]
developed a palladium-catalyzed synthesis of 2-arylindole

substrate scopes or the need for potential dangerous diazo
compounds. Therefore, the development of a versatile and safe
method is highly desirable. Li [12] and others [13] found that
sulfoxonium ylides could worked as a safer carbene precursors
in variou C−H activation catalyzed by Rh(III) [14], Ru(II)
[15], and Co(III) [16]. Based on our previous work [17],
herein, we wish to report an Ir(III)-catalyzed synthesis of
2-substituted indoles from N-phenylpyridin-2-amines and
ulfoxonium ylide via C−H functionalization and cyclization.
Sulfoxonium ylides bearing electron-donating or withdrawing
groups at para-position of the aromatic ring displayed high
reactivity, providing the desired products 3a–3h in 65–95%
yields. Similarly, meta- and ortho- substituted sulfoxonium
ylides with methyl, methoxy, chloro, bromo, and flouro groups
could also afforded desired products 3i-3o in 77-88% yields.
Moreover, disubstituted benzoyl sulfoxonium ylides were well
tolerated in this transformation, providing the corresponding
products 3p and 3q in 87% and 80% yields. Furthermore, this
reaction was not limited to phenyl substrates, sulfoxonium
ylides containing a thiophene ring or naphthalene gave 3r and
3s in 73% and 87% yields respectively. Comparably,
sulfoxonium ylides with alkyl substituents showed better
reactivity to deliver the corresponding products 3t-3w in
56%-98% yields.
Results and Discussion
We initiated our studies with N-phenylpyridin-2-amine 1a and
sulfoxonium ylide 2a as model substrates in the presence of
[IrCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %) and PivOH (1 eq)
o
in DCE under Ar at 100 C for 12 h. We were delighted to
obtain the desired product 4a in 44% yield and byproduct 4aa
in 33% yield, which was formed by the reaction of 4a and the
second sulfoxonium ylide (Table 1, entry 1). It was found that
silver salts had a significant influence on the reaction. To our
delight, AgOAc gave the best result and increased the yield of
4a to 75% (entrie −5). creening of solvents revealed that
DCE is the preferred solvent in this transformation (entries
5-8). Moreover, acetic acid was a better additive than PivOH,
afforded the product 4a in 81% yield (entry 9). Increasing the
amount of 2a could not improve the yield due to the increased
amount of byproduct 4aa (entry 10). Control experiments
confirmed that poor yields of 4a were obtained when additive
was omitted (entry 11). Furthermore, when the directing group
replaced by –COMe or –CONMe2 the reaction was
complicated (entry 12 and 13). Therefore, the optimal reaction
conditions were established as 1a (0.4 mmol), 2a (0.48 mmol,
1.2 equiv), [IrCp*Cl2]2 (5 mol %), AgOAc (20 mol %), and
HOAc (0.4 mmol, 1 eq) in DCE (3 mL) stirred at 100 oC for 12
h under Ar protection.
Table 2
Scope of substituted sulfoxonium ylidesa.
Table 1
Optimization of reaction conditionsa
Entry
1
2
3
4
5
6
7
[Ag]
solvent yield of 4a(%)b
yield of 4aa (%)b
AgSbF6
AgOTf
AgBF4
AgNTf2
AgOAc
DCE
DCE
DCE
DCE
DCE
44
44
44
19
75
66
33
31
81
34
45
-
33
9
37
38
10
-
38
9
-
a Reaction Conditions: 1a (0.4 mmol), 2 (0.48 mmol, 1.2 eq), [Cp*IrCl2]2 (5
mol %), AgOAc (20 mol %), HOAc (1 eq), 12 h, 100 oC, Ar.
AgOAc toluene
After exploration of sulfoxonium ylides, we investigated
the scope and limitation of N-phenylpyridin-2-amines (Table
3). N-Phenyl-2-aminopyridines bearing electron-donating and
withdrawing groups at para position of benzene ring all
reacted smoothly with sulfoxonium ylides with high efficiency
and gave corresponding 2-arylindoles 4b-4e in 66–85% yields.
Accordingly, good to high isolated yields obtained for
meta-substituted substrates 4f–4h indicated full tolerance of
various substituents. In sharp contrast, ortho-methylaniline
were ineffective substrates in this reaction, giving 4i and 4j in
32% and 22% yields. Luckily, the yield of 4j could improved
to 66% by prolonging the reaction time to 24 h. Moreover,
disubstituted aniline also well tolerated and gave coupling
product 4k in 67% yield. To demonstrate the synthetic utility
AgOAc
AgOAc
AgOAc
AgSbF6
AgOAc
AgOAc
AgOAc
TFE
THF
DCE
DCE
DCE
DCE
DCE
8
9c
10d
11e
12f
13g
65
-
-
-
-
a Reaction Conditions: 1a (0.4 mmol), 2a (0.48 mmol, 1.2 eq), [Cp*IrCl2]2:
o
(5 mol %), [Ag]: (20 mol %), PivOH: (1 eq), 12 h, 100 C, Ar. DCE =
1,2-dichloroethane, PivOH = pivalic acid, TFE = 2,2,2-trifluoroethanol,
DG = 2-pyridinyl.
b Isolated yield.
c HOAc as an additive.
d 2a (0.88 mmol, 2.2 eq).
e No additive
f DG = -COMe
g DG = -CONMe2
of
this
protocol,
a
scale-up
reaction
of
With the optimized reaction conditions in hands, we
investigated the reaction of various sulfoxonium ylides (Table
2). The reaction proceeded smoothly to afford indoles in good
yields with excellent functional group compatibility.
N-phenylpyridin-2-amine 1a and 2a was carried out under the
optimized conditions, giving corresponding product 4a in 82%
yield (Scheme 2).

Table 3
subsequent C–H cleavage generated a six-membered iridacycle
intermediate I. Then the coordination of the sulfoxonium ylide
2a reacted with I and followed by the elimination of DMSO to
produce a metal-carbenoid intermediate II. The iridium (III)
intermediate III was generated by migratory insertion of the
Ir-aryl bond into the activated carbine, which then underwent
protonation to generate intermediate IV and Cp*Ir(III) species
for the next catalytic cycle. Finally, intermediate IV underwent
intramolecular nucleophilic cyclization and dehydration to
furnish the final product indole 4a.
Scopes of substituted N-phenylpyridin-2-aminesa
a Reaction Conditions: 1 (0.4 mmol), 2a (0.48 mmol, 1.2 eq), [Cp*IrCl2]2
(5 mol %), AgOAc (20 mol %), HOAc (1 eq), 12 h, 100 oC, Ar. b 24 h.
Scheme 2 Gram-scale reaction.
Scheme 4. Proposed Reaction Mechanism
In conclusion, we disclosed a Cp*Ir(III)-catalyzed highly
efficient coupling reaction of anilines with sulfoxonium ylides
by using pyridinyl as a directing group. The reaction provides
a concise synthetic strategy to 2-substituted indoles with good
to excellent yields under mild conditions. The further
investigations on its synthetic applications are currently
underway in our laboratory.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NSFC) (Grant No. 21676252 and
21506191).
Supplementary data
Scheme 3 Mechanistic studies.
Supplementary data associated with this article can be
found, in the online version, at https://
For gaining insight into the reaction mechanism, the kinetic
isotope effect (KIE) has been measured [18]. The KIE value of
intermolecular competition (kH/kD = 1.2) and parallel reactions
(kH/kD = 1.1) indicated that C–H activation is possibly not the
rate-determine step in this transformation (scheme 3a and 3b).
Moreover, a competition experiment has been performed using
substrates bearing different electronic properties [15d]. The
reaction of 1b/1d afforded the corresponding products 4b/4d in
1.88:1 ratio based on HPLC analysis, indicating that an
electron-donating group tended to favor the reaction (Scheme
3c).
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3
1. Ir(III)-catalyzed C–H activation synthesize 2-substituted indoles efficiently.
2. Various functional groups tolerated and gave 2-substituted indoles in good yields.
3. KIE experiments were conducted to probe the possible mechanism.

4
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Synthesis of 2-Substituted Indoles by Iridium(III)-Catalyzed Leave this area blank for abstract info.
C-H Functionalization of N-phenylpyridin-2-amines
Lei Zhang, Junyu Chen, Jinkang Chen, Licheng Jin, Xiangyun Zheng, Xinpeng Jiang*, and Chuanming Yu*
An efficient Ir(III)-catalyzed C–H functionalization for the synthesis of 2-substituted indoles from N-phenylpyridin-2-amines and sulfoxonium
ylides have been developed. The reaction accomplished with broad range of substrate scopes and gave various 2-substituted indoles in up to 98%
yields.