Ruthenium-catalyzed synthesis of indole derivatives from: N -aryl-2-aminopyridines and alpha-carbonyl sulfoxonium ylides

Article abstract of DOI:10.1039/c8ob02818d

Indole is a ubiquitous structural motif with important applications in many areas of chemistry. Given this, a simple and efficient Ru(ii)-catalyzed synthesis of indole via intermolecular annulation of N-aryl-2-aminopyridines and sulfoxonium ylides was proposed and accomplished. Excellent selectivity and good functional group tolerance of this transformation were observed. This protocol provides easy access to a wide variety of useful indoles in the presence of a commercially available [Ru(p-cymene)Cl₂]₂ catalyst. A possible mechanism for the reaction pathway was also proposed. More importantly, this reaction will offer a useful method for the construction of enantioenriched indole frameworks.

Full text of DOI:10.1039/c8ob02818d

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Ruthenium-catalyzed synthesis of indole
derivatives from N-aryl-2-aminopyridines
and alpha-carbonyl sulfoxonium ylides†
Cite this: DOI: 10.1039/c8ob02818d
Received 12th November 2018,
Accepted 3rd December 2018
Xin-Feng Cui,a Zi-Hui Ban,a Wa-Fa Tian,b Fang-Peng Hu,a Xiao-Qiang Zhou,a,c
a
Hao-Jie Ma,a Zhen-Zhen Zhana and Guo-Sheng Huang
*
DOI: 10.1039/c8ob02818d
rsc.li/obc
Indole is a ubiquitous structural motif with important applications ment of an efficient, atom-economical and environmentally
in many areas of chemistry. Given this, a simple and efficient Ru(II)- benign synthetic strategy appears to be attractive and highly
catalyzed synthesis of indole via intermolecular annulation of desirable.
N-aryl-2-aminopyridines and sulfoxonium ylides was proposed
In recent years, researchers have focused on the develop-
and accomplished. Excellent selectivity and good functional group ment of transition-metal-catalyzed C–H bond functionalization
tolerance of this transformation were observed. This protocol pro- for the construction of C–C and C–heteroatom bonds.4 This
vides easy access to a wide variety of useful indoles in the presence strategy takes advantage of the ubiquitous C–H bond in unacti-
of a commercially available [Ru(p-cymene)Cl2]2 catalyst. A possible vated arenes as the direct source. Various transition metal
mechanism for the reaction pathway was also proposed. More complexes involving Ru,5 Rh,6 Pd,7 Ir8 and Co9 have been effec-
importantly, this reaction will offer a useful method for the tively applied for the ortho C–H functionalization of the pyri-
construction of enantioenriched indole frameworks.
midyl moiety and other directing groups. Moreover, efficient
synthesis of indole derivatives using transition metals has also
been greatly employed. Among them, transition metal-cata-
lyzed C–H activation/metal–carbenoid insertion provides an
effective and atom-economical approach for C–X (X = C, N, O
and S, etc.) bond construction. Significant work by Li10 and co-
workers has realized efficient synthesis of indoles using the
imidamides and diazo compounds as substrates by employing
this strategy [Scheme 1, eqn (1)]. Very recently, Li11 and
Mishra12 reported Ir(III)- and Rh(III)-catalyzed intermolecular
indole synthesis which also employed diazo compounds as car-
benes [Scheme 1, eqn (2)]. However, diazo substrates face the
drawbacks of being potentially unstable explosives (Table 1).
The skeleton of indole is widely prevalent in biologically active
compounds, natural products and materials.1 Owing to the
great structural diversity of biologically active indoles, highly
convenient methods for their synthesis have been constantly
pursued for a long time and varieties of approaches have been
achieved. Among them, the well-established Fischer indole
synthesis2 and Larock indole synthesis3 have attracted signifi-
cant attention because of their extensive application prospects.
However, these reactions also face some nonignorable draw-
backs. For example, the Fischer reaction can be limited in
scope due to the stability of the hydrazine component and
strong acidic reaction conditions. Moreover, poor selectivity
was also observed when it was applied to synthesize 4- or
6-monosubstituted indoles; on the other hand, expensive
multi-substituted 2-iodinated anilines are required as starting
materials in the Larock indole synthesis. As a result, develop-
aState Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou 730000, China. E-mail: hgs@lzu.edu.cn
bInstitute of Organic Chemistry, Jiangxi Science &Technology Normal University,
Key Laboratory of Organic Chemistry, Jiangxi Province, Nanchang 330013, China.
E-mail: tianwf12@lzu.edu.cn
cCollege of Chemistry and Material, Weinan Normal University, Shanxi Province,
Weinan 714099, China. E-mail: zhouxq2017@163.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02818d
Scheme 1 Transition-metal-catalyzed synthesis of indole derivatives.
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Table 1 Optimization studies on the synthesis of indolesa
additives and found that the yield could not be further
improved compared to the Zn(OAc)2 additive (entries 4–9).
Further optimization studies indicated that the addition of a
cationic generator i.e. silver hexafluoroantimonate (AgSbF6),
could further improve the yield, indicating that AgSbF6 was the
most effective cationic generator. Subsequently, screening of
solvents revealed that 1,2-dichloroethene was the optimal
choice (entries 13–17). Temperature also significantly influ-
enced this reaction, as 1a showed low reactivity at 90 °C or
110 °C (entry 18). Surprisingly, when the reaction was carried
out under a N2 atmosphere, a dramatic increase in the reaction
yield (78%) was observed (entry 19). Control experiments
revealed that no reaction occurred when the catalyst [Ru(p-
cymene)Cl2]2 was absent, which indicated that the metal cata-
lyst was essential for this transformation (entry 20).
With an optimized catalytic system in hand, we examined
the scope of N-phenylpyrimidin-2-amines (Scheme 2).
N-(Substituted phenyl)-2-pyridin-amines bearing halide substi-
tuents (4-F, 4-Cl, and 4-Br) and other electron-donating groups
(4-Me, 4-iPr, 4-OMe) were well tolerated and gave the corres-
ponding products (3ba–3ga, 69–83%) in moderate to good
yields. N-Phenyl-pyridin-2-amine bearing an electron-with-
drawing group (1j), halide groups (1h, 1i) or an alkyl group
(1k) at the meta position all coupled smoothly with 2a to
furnish the corresponding indoles in good yields (3ha–3ka).
The substituent on the pyridine ring of N-(substituted phenyl)-
2-pyridin-amines showed obvious electronic effects on the
reaction activity, affording the products 3la–3pa in moderate to
good yields (49–93%). When disubstituted substrates (1t, 1u)
Entry Catalyst
Ag salts Additive
Solvent Yieldb
1
2
3
4
5
6
7
8
[IrCp*Cl2]2
[RhCp*Cl2]2
Cp*Co(CO)I2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
—
—
—
—
—
—
—
—
—
Zn(OAc)2 DCE 18
Zn(OAc)2 DCE
Zn(OAc)2 DCE
Zn(OAc)2 DCE
11
0
48
29
0
15
37
15
63
53
53
HOAc
DCE
Cu(OAc)2 DCE
CsOAc
PivOH
NaOAc
DCE
DCE
DCE
9
10
11
12
13
14
15
16
17
18
19
20
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgBF4
[Ru(p-cymene)Cl2]2 AgNTf2
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
Zn(OAc)2 DCE
Zn(OAc)2 DCE
Zn(OAc)2 DCE
Zn(OAc)2 CH3CN 40
Zn(OAc)2 TFE
Zn(OAc)2 PhCF3
Zn(OAc)2 THF
Zn(OAc)2 DMSO
Zn(OAc)2 DCE
Zn(OAc)2 DCE
Zn(OAc)2 DCE
14
13
53
0
55c,59d
78e
—
AgSbF6
0
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol%),
Ag salts (10 mol%), additive (1 equiv.) and a solvent (2.5 mL) at 100 °C
for 12 h. b Isolated yields after column chromatography. c At 90 °C. d At
110 °C. e Under a N2 atmosphere.
Sulfur ylides have been known as potentially safe precursors were used, the substituted indole derivatives 3qa and 3ra were
of metal carbenes.13 They are safe to synthesize and provide obtained with 75% and 92% yields, respectively. The large
crystalline, bench-stable compounds. They are widely used as N-(naphthalene-2-yl)pyridine-2-amine also readily participated
important building blocks in annulation reactions with in the coupling reaction to provide product 3sa in 43% yield.
nucleophilic directing groups. For example, in 2018, Fan14 pre-
sented a highly regioselective synthesis of diversely substituted
benzo[a]carbazoles and indolo[2,1-a]-isoquinolines using
2-arylindoles with sulfoxonium ylides. In the same year,
Zeng15 developed an alternative synthetic approach toward
1,2-benzothiazines through Ru(II)-catalyzed coupling-cycliza-
tion of sulfoximines with alpha-carbonyl sulfoxonium ylides.
Sulfoxonium ylides used as methylene synthons are also
widely applied in other organic syntheses, including metal-free
catalytic systems.13b Encouraged by these eminent studies,
herein a simple Ru-catalyzed synthesis of indole was developed
by introducing N-aryl-2-aminopyridines with alpha-carbonyl
sulfoxonium ylides as substrates [Scheme 1, eqn (3)].
At the outset of this study, we first performed a reaction
between N-aryl-2-pyridinamine (1a, 0.20 mmol) and sulfoxo-
nium ylide (2a, 0.30 mmol) using [IrCp*Cl2]2 (5 mol%) as a
catalyst in dichloroethane (2.5 mL) at 100 °C under an
enclosed atmosphere for 12 h. The desired product 3aa was
obtained in 18% yield (entry 1). Other catalysts such as
[RhCp*Cl2]2 and Cp*Co(CO)I2 gave inferior results (entries 2
and 3). To our delight, the isolated yield of 3aa dramatically
Scheme 2 Scope of anilines in the synthesis of indoles. Reaction con-
ditions: 1a (0.2 mmol), 2a (0.3 mmol), [Ru(p-cymene)Cl2]2 (5 mol%),
increased to 48% when [Ru(p-cymene)Cl2]2 was used as a cata-
AgSbF6 (10 mol%), Zn(OAc)2 (1 equiv.) and DCE (2.5 mL) at 100 °C for
lyst (entry 4). Encouraged by this result, we investigated other 12 h. Isolated yields after column chromatography.
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In addition to anilines, the scope of the reaction with sul-
foxonium ylides was also explored (Scheme 3). In general, the
coupling reaction of substrate 1a and various benzoyl-substi-
tuted sulfoxonium ylides afforded the annulated products in
good yields. The corresponding products were obtained in
good yields with electron-withdrawing groups (F, Cl, Br and
CF3) or electron-donating groups (Me and MeO−) attached to
the para-position and meta-position of the benzoyl ring of sul-
foxonium ylides (3ab–3aj). When the disubstituted sulfoxo-
nium ylide (2k) was explored, the reaction afforded the desired
product (3ak) in good yield. Moreover, introduction of a
methyl group to the ortho-position of benzoyl was also toler-
ated (3al), despite the fact that it provided a lower yield. To our
delight, this catalytic system could be further extended to α-2-
thienoyl sulfoxonium ylide, which could also react with 1a to
give 3am in 74% yield. The versatility of this robust catalytic
system was further mirrored by successfully using alkyl substi-
tuted sulfoxonium ylides, which provided the corresponding
product (3an) in good yield.
Scheme 4 Gram-scale synthesis.
To demonstrate the synthetic utility of this catalytic reac-
tion, a 6 mmol scale synthesis of 3aa was carried out, and a
good yield of 72% was still obtained (Scheme 4). We attempted
to remove the pyridyl group in the product, but unfortunately
failed by following various typical conditions.
Based on literature reports,8b,16,17 a plausible mechanism
for the annulation of 1a with 2a was proposed as depicted in
Scheme 5. Initially, the dimeric precursor [Ru(p-cymene)Cl2]2 is
converted into [Ru(II)X2] as an active catalyst through the anion
exchange. Next, nitrogen coordination of 1a is followed by cyclo-
Scheme 5 Proposed mechanism for the formation of indoles.
metalation to deliver a six-membered ruthenacycle intermediate
A. Coordination of sulfur ylide 2a and subsequent elimination of
DMSO generate Ru(II) carbene B, which then undergoes migratory
insertion of the Ru–aryl bond into the activated carbene to afford
a seven-membered ruthenacycle intermediate C. Protonolysis of
the Ru–C bond by HX gives the corresponding intermediate D,
together with the regeneration of the Cp*Ru(II) catalyst.
Intramolecular nucleophilic attack of the imine on the carbonyl
group produces D, which undergoes dehydration, furnishing 3aa.
Conclusions
We reported a ruthenium-catalyzed direct C–H functionalization
and cross-annulation between N-phenylpyrimidin-2-amines and
α-aroyl sulfur ylides toward a series of functionalized indoles in
good to moderate yields. This catalytic system features mild con-
ditions and a wide range of substrates with excellent functional
group tolerance, with DMSO and H2O being the only byproducts.
Conflicts of interest
There are no conflicts to declare.
Notes and references
Scheme 3 Scope of sulfoxonium ylides in the synthesis of indoles.
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Ru(p-cymene)Cl2]2
(5 mol%), AgSbF6 (10 mol%), Zn(OAc)2 (1 equiv.) and DCE (2.5 mL) at
100 °C for 12 h. Isolated yields after column chromatography.
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