Rhodium(III)-catalyzed intermolecular cyclization of anilines with sulfoxonium ylides toward indoles

Article abstract of DOI:10.1016/j.cclet.2019.01.033

Rhodium(III)-catalyzed synthesis of indole derivatives has been realized via cascade reaction of C–H alkylation/nucleophilic cyclization starting from readily available N-phenylpyridin-2-amines and sulfoxonium ylides. Notably, this transformation could smoothly proceed with high yields, good regioselectivity, and feature broad group tolerance and under redox-neutral condition to avoid external oxidant. The titled products are potentially important building blocks in the organic synthesis through various chemical transformations.

Full text of DOI:10.1016/j.cclet.2019.01.033

Accepted Manuscript
Title: Rhodium(III)-catalyzed intermolecular cyclization of
anilines with sulfoxonium ylides toward indoles
Authors: Zhihao Shen, Chao Pi, Xiuling Cui, Yangjie Wu
PII:
DOI:
Reference:
S1001-8417(19)30060-9
https://doi.org/10.1016/j.cclet.2019.01.033
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Chinese Chemical Letters
Please cite this article as: Shen Z, Pi C, Cui X, Wu Y, Rhodium(III)-catalyzed
intermolecular cyclization of anilines with sulfoxonium ylides toward indoles, Chinese
Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.01.033
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Communication
Rhodium(III)-catalyzed intermolecular cyclization of anilines with
sulfoxonium ylides toward indoles
Zhihao Shen, Chao Pi, Xiuling Cui*, Yangjie Wu*
Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of
Henan Universities, Zhengzhou University, Zhengzhou 450052, China
Graphical Abstract
C2-substituted indoles were efficiently prepared with excellent regio-selectivity from N-phenylpyridin-2-amines and sulfoxonium ylides via
cascade reaction of C−H alkylation/nucleophilic cyclization
ARTICLE INFO
ABSTRACT
Article history:
Rhodium(III)-catalyzed synthesis of indole derivatives has been realized via cascade
reaction of C−H alkylation/nucleophilic cyclization starting from readily available
N-phenylpyridin-2-amines and sulfoxonium ylides. Notably, this transformation could
smoothly proceed with high yields, good regioselectivity, and feature broad group
tolerance and under redox-neutral condition to avoid external oxidant. The titled products
are potentially important building blocks in the organic synthesis through various
chemical transformations.
Received 3 January 2019
Received in revised form 21 January 2019
Accepted 23 January 2019
Available online
Keywords:
Rhodium
Cyclization
Aniline
Sulfoxonium ylide
Indole
Indoles, as important building blocks in organic synthesis, are commonly encountered in natural products, pharmaceutical
molecules and functional materials [1], such as anti-Alzheimer's disease, imaging agent for protein misfolding, inhibitor of the
plasmodium falciparum and cell necrosis (Fig. 1) [2]. Consequently, developing mild and efficient access to indole motif is of great
significance. Organic chemists have been making great efforts to effectively synthesize indoles [3].
Conventional pathway involves the classical Fischer indole syntheses (Scheme 1a) [4], which suffer from tedious procedures,
low atomic economy and relatively harsh reaction conditions. Recently, transition-metal-catalyzed direct C-H bond activation has
emerged as a powerful tool for the synthesis of indole and its derivatives. In this context, indoles have been prepared from anilines
by oxidative alkyne annulation via C-H/N-H bond functionalization catalyzed by transition-metals, such as palladium, rhodium,
ruthenium and nickel (Scheme 1b) [5]. Unfortunately, these procedures were usually limited in regioselectivity when using

asymmetric alkynes as substrates and relied on the external oxidants. Kim, Wang, Li and Yao groups independently reported
internal molecular cyclization of diazo compounds with anilines to access indoles catalyzed by Rh and Ir under redox-neutral
conditions (Scheme 1c) [6]. Despite these approaches are highly efficient and step economic, the application of diazo compounds
still remains limited, especially mono-substituted diazo compounds. Subsequently, Jana group demonstrated
a
ruthenium(II)-catalyzed steric controlled synthesis of 2-methylindole from anilines and allyl acetate [7]. Very recently, our group
developed a palladium-catalyzed efficient cyclization reaction of anilines with vinyl azides [8], which delivered a straightforward
approach to 2-arylindole derivatives with excellent regioselectivity and overcame the problem of chemo- and region-selectivity. In
the meantime, sulfoxonium ylide has been developed as a versatile carbene source owing to its considerable higher security and
being easily handled in comparison with diazo compounds and azides [9]. To further explore and enrich annulative synthesis of
indoles, we herein proposed a protocol to various 2-substituted indoles starting from anilines using sulfoxonium ylides as carbene
precursors through Rh(III) catalyzed a C−H alkylation−nucleophilic cyclization cascade reactions (Scheme 1d). During preparation
of this manuscript, Huang reported a similar work [10]. Compared to Huang’s work, this method is advantageous with higher yield,
less amount of additive and avoiding an inert gas protection.
Fig. 1. Selected examples illustrating the importance of the compounds with indole.
Scheme 1. Synthetic strategies toward indole derivatives.

Initially, N-phenylpyridin-2-amine 1a and sulfoxonium ylide 2a were chosen as model substrates to optimize the reaction
conditions (Table 1). By treating 1a (0.1 mmol) and 2a (0.12 mmol) in the presence of [Cp*RhCl2]2 (4 mol%) and AgSbF6 (16 mol%)
o
in DCE at 100 C under air, the target product 3aa was isolated in 34% yield (entry 1). The structure of 3aa was confirmed by
single-crystal X-ray diffraction analyses (CCDC 1874504). No desired product was detected using CoIII, IrIII, RuII and PdII as catalysts
(entries 2-5). To our delight, the yield of 3aa was dramatically improved to 63% when AgNTf2 was used (entries 6-8). Subsequently,
a variety of additives including NaOAc, NaOTf, HOPiv and Zn(OTf)2 were evaluated in the presence of [Cp*RhCl2]2/AgNTf2
catalyst system, and Zn(OTf)2 was shown to be the most efficient additive (entries 9-12) [11]. Encouraged by these promising data,
other solvents were screened under the identical reaction conditions, and the DCE solvent proved to be superior to others, such as
CH3CN, THF, toluene and HFIP (entries 13-16). Surprisingly, decreasing the loading of Zn(OTf)2 to 10 mol% led to increase of the
yield of 3aa (90%, entry 17). Further studies of different catalyst loadings revealed that only 3 mol% of catalyst system provided the
best yield (entry 18). When the solvent was reduced to 1.5 mL, the desired product was obtained in 93% yield (entry 19). In addition,
the similar result was given under N2. Finally, the optimal reaction conditions were identified as follows: N-phenylpyridin-2-amine
(0.1 mmol), sulfoxonium ylide (0.12 mmol) in the presence of [Cp*RhCl2]2 (3 mol%)/AgNTf2 (12 mol%) with Zn(OTf)2 (10 mol%)
in DCE (1.5 mL) at 100 oC under air for 18 h.
Table 1
Optimization of the reaction conditions.a
Entry
Catalyst system
Additive
(equiv.)
－
－
－
－
Solvent
Yield
(%)b
34
Trace
NR
1
2
3
4
[Cp*RhCl2]2/AgSbF6
[Cp*IrCl2]2/AgNTf2
[Cp*Co(CO)I2]/AgSbF6
[Ru(p-cymene)Cl2]2/
AgSbF6
DCE
DCE
DCE
DCE
Trace
5
6
7
Pd(OAc)2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgOTf
DCE
DCE
DCE
NR
63
55
－
－
－
8
9
[Cp*RhCl2]2/AgBF4
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
[Cp*RhCl2]2/AgNTf2
DCE
DCE
DCE
DCE
DCE
CH3CN
THF
toluene
HFIP
DCE
DCE
DCE
DCE
42
49
66
Trace
75
27
49
53
NR
90
－
NaOAc (0.5)
NaOTf (0.5)
HOPiv (1.0)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.1)
Zn(OTf)2 (0.1)
Zn(OTf)2 (0.1)
Zn(OTf)2 (0.1)
10
11
12
13
14
15
16
17
18c
19d
20d,e
92
93
93
o
a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), catalyst (4 mol%), additive and solvent (2 mL) at 100 C for 18 h under air unless
otherwise noted.
b Isolated yields.
c [Cp*RhCl2]2 (3 mol%)/AgNTf2 (12 mol%).
d In DCE (1.5 mL).
e Under N2. THF= tetrahydrofuran, HFIP=1,1,1,3,3,3-hexafluoro-2-propanol.
With the optimized reaction conditions in hand, we first explored the reactivity of various sulfoxonium ylides with
N-2-pyridyl-substituted aniline (1a). As shown in Scheme 2, substituted benzoyl sulfoxonium ylides bearing donating group
(4-methyl), withdrawing groups (4-CF3 and 4-NO2) and halogens (4-F, 4-Cl and 4-Br) all coupled smoothly with
N-phenylpyridin-2-amine to deliver the corresponding products in good to excellent yields (3ab-3ag). In addition, ortho- and

meta-substituted benzoyl sulfoxonium ylides were also suitable for this reaction, affording the corresponding products in high yields
(3ah-3ak). Disubstituted benzoyl sulfoxonium ylide (3al) was coupled with 2a to provide indole in 58% yield. Meanwhile, this
transformation also displayed an excellent tolerance toward sulfoxonium ylides including naphthyl and heterocycles (3am-3ao).
More importantly, methyl and tert-butyl-substituted sulfoxonium ylides afforded the corresponding products 3ap and 3aq in 94% and
37% yields, respectively. tert-Butyl group showed poor reactivity perhaps due to its steric hindrance [12].
Next, the scope of N-arylpyridin-2-amines was investigated as shown in Scheme 3. It was found that N-2-pyridyl-substituted
anilines with electron-withdrawing or electron-donating groups at diverse positions of the aromatic ring all underwent smoothly to
afford the corresponding products in good to excellent yields (3ba-3fa, 3ha-3fa). These substituents have no significant effect on this
reaction. Moreover, disubstituted N-phenylpyridin-2-amines also gave high yield (3ma-3oa). Moderate regioselectivity of 3ga:3ga'
(2:1) was detected for the substrate 2g, and the major coupling product 3ga corresponds to C-C coupling at a less hindered position
[5g,8,13]. In addition, directing groups on the N-atom of anilines, such as acetyl and pivaloyl showed less reactivity under the
optimized reaction conditions (3qa and 3ra). N-Pyrimidinyl aniline was also found to be a good substrate for this annulation reaction
to afford corresponding product 3pa in 72% [14].
Scheme 2. Scope of sulfoxoinum ylides. Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), [Cp*RhCl2]2 (3 mol%)/AgNTf2 (12 mol%),
Zn(OTf)2 (10 mol%), DCE(1.5 mL), 100 oC, 18 h. Isolated yields.

Scheme 3. Substrate scope of N-substituted amines. Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), [Cp*RhCl2]2 (3 mol%)/AgNTf2 (12
mol%), Zn(OTf)2 (10 mol%), DCE (1.5 mL) at 100 oC for 18 h. Isolated yields.
To show the utility of this catalytic system, a gram-scale synthesis of 3aa was performed under standard reaction condition with
71% yield (Scheme 4).
Scheme 4. Large-scale synthesis.
Next, the deprotection of the pyridyl group of 3aa was carried out under certain conditions, affording free N-H indole derivatives
in 88% yield (Scheme 5a) [15]. Subsequently, considering the privileged structural features and biological activities of
N-pyridyl-2-arylindoles, we attempted to develop the direct C-H functionalization at the C7-position. As shown in Scheme 5, the
acetoxylation and alkenylation of the obtained product delivered the corresponding products catalyzed by Ru(II)/Rh(III) in good
yields respectively (Schemes 5b and c) [16,17]. These transformations further confirmed the practicability of the protocol.

Scheme 5. Chemical transformation of the product.
To better understand the reaction mechanism, several control experiments were carried out (Scheme 6). Initially, when performing
the H/D exchange of N-phenylpyridin-2-amine (1a) with CD3OD under standard condition in the absence of sulfoxonium ylide (2a),
incorporation (17% D) at the ortho-position of 1a was observed, suggesting the reversibility of ortho-metalation step (Scheme 6a).
Next, the kinetic isotope effect via intermolecular competition reaction of 1a and 1a-d5 with 2a was investigated under standard
reaction condition and kH/kD = 1.2 was obtained, which indicates that the C-H bond cleavage may not be involved in the
rate-determining step (Scheme 6b). Finally, intermolecular competition experiments with differently substituted anilines displayed
electron-withdrawing aniline (1k) to be converted preferentially (Scheme 6c).
Based on the control experiments and literature reports [9c,11a,18], a plausible reaction mechanism is proposed (Scheme 7). An
active Rh(III) complex A is generated from the reaction of aniline and [Cp*RhCl2]2 in the presence of AgNTf2 or Zn(OTf)2 via the
direct ortho-metalation process. Subsequent nucleophilic attack of sulfoxonium ylide on Rh(III) complex A gives the intermediate B,
which successively undergoes the α-elimination of DMSO to produce a Rh(V) carbene C. Then migratory insertion affords the
six-membered rhodacyclic intermediate D. The protondemetalation of species D delivers ortho-alkylate E and regenerates the active
Rh(III) complex for the next catalytic cycle. Finally, the desired product is obtained by an intramolecular nucleophilic attack and the
release of H2O.
Scheme 6. Control experiments.

Scheme 7. Plausible catalytic cycle.
In conclusion, we have realized a rhodium(III)-catalyzed redox-neutral coupling of N-functionalized anilines with sulfoxonium
ylides, which provides an efficient method for the synthesis of indole derivatives. Mechanistically, the indoles are obtained through a
C−H alkylation−nucleophilic cyclization cascade. Moreover, this transformation could smoothly proceed with high yields, good
regioselectivity, no external oxidants, broad substrate scope and excellent functional group tolerance.
Acknowledgments
We greatly acknowledge partial financial support from the Ministry of Science and Technology of China (No. 2016YFE0132600),
and Zhengzhou University.
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