NHC triggered cascade metal-free synthesis of 2,3-diarylated indoles under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2011.09.041

A new cascade strategy to the synthesis of 2,3-diarylated indoles via the metal-free reaction of aryl aldehyde and aryl amine triggered by N-heterocyclic carbene (NHC) under solvent-free conditions, has been disclosed. The protocol has the advantages of easy work-up, high yields, wide application scope, and an environmentally benign procedure compared with the reported methods.

Full text of DOI:10.1016/j.tetlet.2011.09.041

Tetrahedron Letters 52 (2011) 6162–6165
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NHC triggered cascade metal-free synthesis of 2,3-diarylated indoles under
solvent-free conditions
Changsheng Yao a, , Donglin Wang b, Jun Lu b, Bingbin Qin b, Honghong Zhang b, Tuanjie Li b, Chenxia Yu b
⇑
a School of Chemistry and Engineering, Key Laboratory of Biotechnology for Medicial Plant, Xuzhou Normal University, Xuzhou, Jiangsu 221116, PR China
b School of Chemistry and Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Xuzhou Normal University, Xuzhou, Jiangsu 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Revised 1 September 2011
Accepted 9 September 2011
Available online 17 September 2011
A new cascade strategy to the synthesis of 2,3-diarylated indoles via the metal-free reaction of aryl alde-
hyde and aryl amine triggered by N-heterocyclic carbene (NHC) under solvent-free conditions, has been
disclosed. The protocol has the advantages of easy work-up, high yields, wide application scope, and an
environmentally benign procedure compared with the reported methods.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reaction
Indoles
NHC
Solvent-free synthesis
R
HO
Introduction
R
NH2
N
Ar
Ar
Ar
Ar
O
S
3
The indole skeleton is one of the most prominent frameworks
found in numerous natural products and synthetic compounds
with vital medicinal value.1 The synthesis of indoles has captivated
chemists for more than a century and numerous approaches have
been developed, such as the classical Fisher indole synthesis,2 the
Gassman indole synthesis,2,3 the Reissert indole synthesis,2 the
Leimgruber–Batcho indole synthesis2,4, and the Bischler indole
synthesis.2,5 Indole derivatives, particularly 2,3-disubstituted
indoles play an important role in the field of medicinal chemistry
due to their various potential biological and pharmacological activ-
ities.6 It has gained broad attention to the synthesis of 2,3-disubsti-
tuted indoles in recent years.7 The classical strategy to the
synthesis of 2,3-disubstituted indoles should be metal-catalyzed
transformations.8 Only a few compounds were synthesized con-
cisely via the reaction of benzoin9 or 2-bromo-1,2-diphenyletha-
none10 with aryl amines. Although these methods are effective,
some limitations are associated with these procedures, including
tedious workup, low yields, long reaction times, and the use of or-
ganic solvents. Thus, developing a general and economical process
for the synthesis of 2,3-disubstituted indoles remains a continuing
challenge for organic chemists. Recently, the progress in the field of
solvent-free reactions is gaining much attention for their high
efficiency and eco-friendliness.11 Many organic reactions and
complex transformations have been reported to proceed efficiently
under solvent-free conditions.11–13
ArCHO
N
H
Solvent-free
TsOH, Solvent-free
OH
1
2
4
Scheme 1. A NHC-triggered cascade solvent-free synthesis of 2,3-diarylated
indoles.
In past decades, N-heterocyclic carbene (NHC)-catalyzed umpo-
lung reactions have drawn considerable attention of a number of
organic chemists due to their wide applications in organic synthe-
sis.14 A large number of NHC-catalyzed inter- and intramolecular
benzoin condensation reactions15 have been reported to construct
various functionalized organic compounds. Cascade reactions have
been widely applied in preparing compound libraries to screen for
functional molecules due to their inherent simple experimental
procedures, high bond forming efficiency, and great diversity gen-
erating potential.16,17 Several successful cases of NHC-triggered
cascade reactions were reported recently.14,17 Inspired by this
and in continuing our work on the design and efficient synthesis
of biologically potential active heterocyclic compounds,18 we shall
disclose herein a rapid and facile method to prepare the 2,3-diary-
lated indoles via a NHC triggered cascade reaction (Scheme 1) un-
der solvent-free and metal-free conditions.
Results and discussion
Firstly, we examined the benzoin reaction of 3-chlorobenzalde-
hyde in different solvents in the presence of carbene precursor B
⇑
Corresponding author. Fax: +86 516 83500365.
E-mail address: csyao@xznu.edu.cn (C. Yao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.041

C. Yao et al. / Tetrahedron Letters 52 (2011) 6162–6165
6163
Table 1
Condition screening for the benzoin reaction of 3-chlorobenzaldehyde
O
O
Precatalyst
Cl
Cl
Base
solvent
OH
Cl
Entry
Precatalyst (mol %)
Base (mol %)
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
B (10)
B (10)
B (10)
B (10)
B (10)
A (10)
C (10)
D (10)
E (10)
F (10)
B (10)
B (10)
B (10)
B (10)
B (10)
B (10)
B (10)
B (5)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
DBU (50)
Et3N (50)
K2CO3 (50)
Cs2CO3 (50)
DBU (60)
DBU (70)
DBU (75)
DBU (80)
DBU (75)
DBU (75)
DBU (75)
DBU (75)
C2H5OH
THF
DMF
H2O
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
55
5
5
5
5
3
4
4
4
4
4
3
3
3
3
2
56
32
28
37
66
27
19
23
37
0
28
58
62
68
70
82
68
62
82
79
86
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
9
10
11
12
13
14
15
16
17
18
19
20
21
0.75
0.75
1.5
0.75
0.75
0.75
B (20)
B (30)
B (10)
a
Isolated yield.
HO
HO
N
N
N
S
Br
N
S
I
I
A
B
C
N
N
N
N
N
N
Cl
Cl
I
D
E
F
and an amine base (DBU, 1,8-diazabicyclo[5.4.0]-undec-7-ene) at
50 °C. As can be seen in Table 1, the solvent-free system exhibits
better yield and greater reaction rate than the other counterparts.
Next, the precatalyst and base effect on the reaction was investi-
gated under solvent-free conditions. Precatalyst F proved to be
unsuitable for this reaction. Precatalyst A and C as well as precat-
alyst D and E are less active for this reaction. Organic bases Et3N
resulted in poor conversion (28%). A similar result was obtained
in the case of inorganic base K2CO3 (58%) and Cs2CO3 (62%). It indi-
cated that DBU was the optimal base. Subsequently, the reaction
was performed with different catalyst loading, base loading under
solvent-free conditions, and repeated many times at 50 °C. It was
found that the reaction proceeded better in the presence of
10 mol % of B and 75 mol % of DBU under solvent-free conditions.
Later, we examined the temperature effect on the reactions. As
can be seen in Table 1, the highest yield of the product was ob-
tained at 55 °C. To promote the conversion of benzoin to substi-
tuted indoles, a range of nonvolatile Brønsted acids and aryl
amines were added directly to the reaction system after the benzo-
ins were formed. In order to optimize the reaction conditions of
cyclization, the loadings of several acids were investigated under
solvent-free conditions at different temperatures (Table 2). The re-
sults showed that the reaction catalyzed by p-toluenesulfonic acid
(TsOH) loading of 200 mol % under solvent-free conditions at
140 °C gave the expected product in the highest yield (78%). Unfor-
tunately, the product was obtained in low yields when the reaction
was catalyzed by SA and H2SO4.
On the basis of the optimized reaction conditions identified, the
application scope of this reaction sequence was examined. The
results are summarized in Table 3. Both amines bearing either
electron-donating groups (such as methoxyl group) or electron-
withdrawing groups (such as halide group) afforded high yields of
2,3-diarylated indoles derivatives. Besides, the reaction between
benzoins and 3-methoxyaniline gave 6-methoxy-2,3-aryl-1H-in-
doles regiospecifically. Meanwhile, the results also indicated that
thisprotocolcouldsuccessfullybe appliedto thearomaticaldehydes
bearing electron-withdrawing groups, such as halogens. However,
electron-rich aromatic aldehydes, heteroaromatic aldehyde, and
fatty aldehyde could not participate in this cascade reaction.
All of the synthesized compounds were characterized by IR, 1H
NMR, and HRMS. The structure of 4d was also confirmed by X-ray
crystallographic analysis (Fig. 1).19
Although the detailed mechanism of the above mentioned reac-
tion remains to be fully clarified, the formation of 2,3-diarylated in-
doles could be explained by a possible reaction sequence presented
in Scheme 2. In the initial step, aryl aldehyde was converted to ben-
zoin in the presence of NHC. The subsequent reaction between ben-
zoin and amine with theaidofanacidgavethecorrespondingindoles.

6164
C. Yao et al. / Tetrahedron Letters 52 (2011) 6162–6165
Table 2
Condition optimization for the reaction of 1,2-bis(3-chlorophenyl)-2-hydroxyethanone and 3-methoxyaniline
Cl
NH2
Cl
H3CO
OCH3
HO
O
acid
solvent-free
N
H
Cl
Cl
Entry
Acid (mol %)
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
SA (120)
130
130
130
130
130
130
130
130
130
130
120
140
150
6
6
5
5
4.5
4.5
4
3.5
3.5
4
24
11
35
26
47
52
66
72
72
70
26
78
69
H2SO4 (120)
TsOH (120)
TsOH (100)
TsOH (150)
TsOH (180)
TsOH (190)
TsOH (200)
TsOH (210)
TsOH (220)
TsOH (200)
TsOH (200)
TsOH (200)
9
10
11
12
13
6
3
3.5
a
Isolated yield.
Table 3
Synthesis of product 4 under solvent-free conditions
R
HO
R
NH2
N
I
Ar
Ar
Ar
Ar
O
S
(10 mol%)
3
ArCHO
N
H
TsOH (200 mol%)
Solvent-free
OH
DBU (75 mol%)
Solvent-free
2
4
1
Entry
Ar
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
4-FC6H4
3-FC6H4
2-FC6H4
3-CH3O
3-CH3O
3-CH3O
3-CH3O
3-CH3O
3-CH3O
3-CH3O
3-CH3O
3-CH3O
H
H
H
4-Cl
4-CH3
4-CH3O
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
88
85
84
65
63
78
71
74
Trace
78
80
67
85
83
80
78
4-BrC6H4
4-ClC6H4
3-ClC6H4
3,4-Cl2C6H3
3-CH3OC6H4
Thien-2-yl
4-FC6H4
3-FC6H4
3,4-Cl2C6H3
4-FC6H4
9
10
11
12
13
14
15
16
4-FC6H4
4-FC6H4
C6H5
Figure 1. Crystal structure of 4d.
a
Isolated yield.
added and the mixture was kept at 140 °C. Upon completion, mon-
itored by TLC, the reactant was cooled to room temperature and
was purified by column chromatography (silica gel, mixtures of
ethyl acetate/petroleum ether, 1:20, v/v) to afford the desired pure
product. 4f mp: 160.1–162.0 °C; IR (potassium bromide) (v, cmÀ1):
3326, 1595, 1197, 1016, 788, 697; 1H NMR (400 MHz, DMSO-d6):d
11.62 (s, 1H, NH), 7.51 (s, 1H, ArH), 7.43 (t, J = 7.6 Hz, 1H, ArH), 7.36
(d, J = 8.0 Hz, 5H, ArH), 7.31(t, J = 7.6 Hz, 2H, ArH), 6.95 (s, 1H, ArH),
6.75 (d, J = 8.8 Hz, 1H, ArH), 3.81 (s, 3H, CH3); HRMS (ESI) m/z:
Calcd for [MÀH]À C21H14Cl2NO: 366.0452 found: 366.0450; 13C
NMR (100 MHz, DMSO-d6):d 156.5, 137.2, 137.0, 134.2, 133.2,
131.5, 130.5, 130.3, 129.0, 128.3, 127.3, 127.1, 126.5, 126.2,
121.9, 119.3, 112.7, 110.5, 94.4, 55.2.
In summary, we have developed a novel cascade reaction trig-
gered by NHC, which is a more direct and efficient way to construct
skeletons of indoles. The ready availability of the starting materi-
als, atom economy of the reaction, and the useful skeleton of the
products would make this strategy quite attractive.
Experimental section
Aryl aldehyde (1.0 mmol), Precatalyst B (0.029 g) and DBU
(0.114 g) were triturated together in an agate morlar for 45 min
at 55 °C. Then, TsOH (0.344 g) and aryl amines (0.5 mmol) were

C. Yao et al. / Tetrahedron Letters 52 (2011) 6162–6165
6165
R
HO
H2N
N
HO
HO
Ar
Ar
S
Ar
Ar
O
H
ArCHO
OH
H
R
Ar
Ar
R
R
OH2
Ar
Ar
OH
N
Ar
Ar
Ar
Ar
OH
OH
H
- H2O
R
N
N
N
H
R
Ar
Ar
Ar
Ar
- H
R
N
H
N
Scheme 2. A proposed reaction mechanism.
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Acknowledgments
We are grateful for financial support by A Project Funded by the
Priority Academic Program Development of Jiangsu Higher Educa-
tion Institutions, the Major Basic Research Project of the Natural
Science Foundation of the Jiangsu Higher Education Institutions
(09KJA430003), Natural Science Foundation of Xuzhou City
(XM09B016), Graduate Foundation of Xuzhou Normal University
(2010YLB029) and Qing Lan Project (08QLT001).
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.041.
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b = 8.315(4), c = 13.649(8) Å, b = 112.819(9)o, V = 1800.6(17) Å3, Mr = 457.16,
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l(Moka
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