Synthesis of indoles through highly efficient cascade reactions of sulfur ylides and N-(ortho-chloromethyl)aryl amides

Article abstract of DOI:10.1002/anie.201203657

Batting the ylides: A simple procedure carried out under mild conditions allows the direct and efficient synthesis of structurally diverse indoles. This approach involves a cascade reaction of sulfur ylides and N-(ortho-chloromethyl) aryl amides (see scheme). Copyright

Full text of DOI:10.1002/anie.201203657

Angewandte
Chemie
DOI: 10.1002/anie.201203657
Indole Synthesis
Synthesis of Indoles through Highly Efficient Cascade Reactions of
Sulfur Ylides and N-(ortho-Chloromethyl)aryl Amides**
Qing-Qing Yang, Cong Xiao, Liang-Qiu Lu, Jing An, Fen Tan, Bin-Jie Li, and Wen-Jing Xiao*
As a consequence of its prevalence as a “privileged” structure
in many natural isolates and therapeutic agents, the indole
framework has continued to capture the interest of chemists
worldwide.[1] Consequently, numerous efforts have been
devoted to the development of efficient methods to construct
the indole architecture.[2] Work on this problem dates back to
the seminal studies by Fischer and Jourdan,[3] which led to the
synthesis of indoles by heating phenylhydrazines with ketones
or aldehydes in the presence of a protic acid or a Lewis acid
catalyst (Scheme 1A). Despite its extensive applications[4]
development of new methods for the synthesis of indoles.
Over the past several decades, protocols have emerged that
rely on transition-metal-catalyzed processes. For example,
heteroannulation and cyclization reactions of 2-alkynylani-
[8]
lines,[6] reductive cyclizations,[7] C H activations, and other
À
processes[9] have become extremely attractive methods for the
formation of indoles (Scheme 1B). Despite these achieve-
ments, the further development of efficient and practical
procedures to construct the indole skeleton that minimize the
use of special reagents, cost, time, and steps remains highly
desirable. Herein, we disclose an unprecedented cascade
process of sulfur ylides and N-(ortho-chloromethyl)aryl
amides under very mild conditions, which allows a highly
efficient synthesis of structurally diverse indoles
(Scheme 1C).
As pioneered by Corey and Chaykovsky,[10] sulfur ylides
are versatile synthetic reagents in synthetic organic chemis-
try.[11] For example, the research groups of Aggarwal,[12]
Tang,[13] Xiao,[14] and others[15] have developed many elegant
reactions of sulfur ylides to generate functionalized cyclic
compounds. As part of our ongoing research program on
methods to synthesize carbo- and heterocycles,[16] we have
devised and tested a general strategy for the synthesis of
indoles that relies on cascade reactions of sulfur ylides.
In the initial phase of this study we investigated the
reaction of dimethyl (2-oxo-2-phenylethyl)sulfonium ylide
(1a) with N-(2-(chloromethyl)phenyl)-4-methylbenzenesul-
fonamide (2a) in CH2Cl2 and in the presence of Cs2CO3
(2.5 equiv) at room temperature. Interestingly, a cascade
Scheme 1. Strategies for the synthesis of indoles. TM=transition
metal.
and various improvements,[5] the Fischer indole synthesis
has several limitations, including poor regioselectivity with
nonsymmetric ketones, a restricted range of starting materi-
als, and harsh reaction conditions such as the use of strong
acids and/or elevated temperatures.[2] As a consequence, the
demand for alternative efficient methods has encouraged the
reaction
took
place
to
afford
(1H-indol-2-yl)-
(phenyl)methanone (3aa) in 48% yield (Table 1, entry 1).
An increase in the amount of the base to 5.0 equivalents
caused a sharp increase in the yield of this reaction to 73%
(Table 1, entry 2). The solvent was found to have a dramatic
impact on the efficiency of the reaction (Table 1, entries 2–8).
Notably, xylenes were identified as optimal for the formation
of 3aa (Table 1, entry 8). Other bases (Table 1, entries 8–11)
and changing the substrate concentrations (Table 1, entries 8,
12, and 13) did not lead to an improvement in the reaction
efficiency.
With the optimal reaction conditions established (Table 1,
entry 8; 5.0 equiv Cs2CO3 in xylenes at RT), we next inves-
tigated the substrate scope of the reaction by employing
a variety of sulfur ylides (1). As summarized in Table 2,
various sulfur ylides were found to participate in this cascade
process. For example, sulfur ylides bearing electron-neutral
(Table 2, entry 1), electron-rich (Table 2, entries 2 and 3), and
electron-deficient (Table 2, entries 4–9) substituents on the
aryl ring underwent this reaction to furnish the corresponding
products in generally high yields (75–92%). In addition, the
[*] Q.-Q. Yang, Dr. L.-Q. Lu, F. Tan, B.-J. Li, Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: wxiao@mail.ccnu.edu.cn
Prof. Dr. W.-J. Xiao
State Key Laboratory of Applied Organic Chemistry
Lanzhou Universitry, Lanzhou 730000 (China)
C. Xiao
College of Chemistry, Peking University
Beijing 100871 (China)
[**] We are grateful to the National Science Foundation of China
(nos. 21072069 and 21002036) and the National Basic Research
Program of China (2011CB808603) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203657.
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Table 1: Optimization of the reaction conditions.[a]
Finally, to demonstrate preparative utility, the reaction was
carried out on a gram scale. To our delight, the reaction
proceeded efficiently to afford the desired product without an
apparent loss in the reaction yield (Table 2, entry 17).
Of equal importance is the observation that significant
structural variation of the N-(ortho-chloromethyl)aryl amide
substrate is possible. As shown in Table 3, electron-rich and
Entry
Solvent
Conc. [m]
Base
Equiv.
Yield [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
Et2O
MeCN
THF
MeOH
toluene
xylenes
xylenes
xylenes
xylenes
xylenes
xylenes
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
tBuOK
TMG
Cs2CO3
Cs2CO3
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
48
73
trace
58
64
trace
75
82
67
trace
33
Table 3: Synthesis of indoles from various N-(ortho-chloromethyl)aryl
amides.[a]
9
10
11
12
13
Entry
R
R2
Product
Yield [%][b]
70
77
0.025
1
H
H (2a)
H (2b)
H (2c)
H (2d)
H (2e)
H (2 f)
H (2g)
H (2h)
H (2i)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
82
78
90
95
84
76
87
71
57
95
95
45
87
2[c]
3[c]
4[c]
5[c]
6
5-Me
3-Me
3,4-Me2
4,5-(MeO)2
6-Cl
5-Cl
4-Cl
5-Br
H
[a] Reaction conditions: 1a (0.33 mmol), 2a (0.3 mmol), base, solvent
(3, 6 or 12 mL), RT. [b] Yield of isolated product. TMG=tetramethyl-
guanidine.
Table 2: Synthesis of indoles from various sulfur ylides.[a]
7
8
9
10[c]
11[c]
12
13
Me (2j)
Ph (2k)
H (2l)
3aj
3ak
3al
5-Cl
5-OH
5-OMe
Entry
R1
Product
Yield [%][b]
H (2m)
3am
1
2
3
4
5
6
7
8
Ph (1a)
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
82
75
81
78
81
87
86
92
91
65
87
25 (30)
40 (60)
63
68
34 (61)
74
[a] Reaction conditions: 1a (0.33 mmol), 2 (0.3 mmol), Cs2CO3
(5.0 equiv), xylenes (6 mL), RT. [b] Yield of isolated product. [c] RT for
2 h, and then 608C.
p-MeOC6H4 (1b)
p-MeC6H4 (1c)
m-BrC6H4 (1d)
p-ClC6H4 (1e)
p-NO2C6H4 (1 f)
p-FC6H4 (1g)
o-FC6H4 (1h)
m-NO2C6H4 (1i)
2-thioenyl (1j)
2-furanyl (1k)
OEt (1l)
electron-poor N-(ortho-chloromethyl)aryl amides, with dif-
ferent substitution patterns on the benzene ring, all partici-
pated in the process, thereby providing the corresponding
indoles in moderate to high yields (Table 3, entries 2–9).
Incorporation of methyl and chloro substituents at the ortho,
meta, or para positions relative to the sulfonanilide nitrogen
atom did not retard the cascade reaction, thus demonstrating
that steric effects in the N-aryl amide component did not alter
the efficiency of the process (Table 3, entries 2, 3, and 6–8).
9
10
11
12[c]
13[c,d]
14[e]
15[c]
16[c]
17[f]
3ja
3ka
3la
OEt (1l)
tBu (1m)
PhCH2CH2 (1n)
3li
3ma
3na
3oa
3aa
=
Ph-CH CH (1o)
Ph (1a)
Furthermore,
disubstituted
N-(ortho-chloromethyl)aryl
[a] Reaction conditions: 1 (0.33 mmol), 2a (0.3 mmol), Cs2CO3
(5.0 equiv), xylenes (6 mL), RT. [b] Yield of isolated product. Values in
parentheses are the yields of one-pot procedures. See the Supporting
Information for more details. [c] RT for 2 h, and then 608C. [d] 2i was
used in place of 2a. [e] KOH (5.0 equiv) was used in place of Cs2CO3.
[f] Gram scale: 1a (8.8 mmol, 1.59 g), 2a (8 mmol, 2.37 g), Cs2CO3
(40 mmol, 13 g), xylenes (40 mL).
amide substrates were found to react to form cyclization
products in high yields (Table 3, entries 4 and 5). In addition,
substrates with substituents at the benzylic position also
underwent the transformation to produce the corresponding
products in excellent yields (Table 3, entries 10 and 11). To
our knowledge, such cyclic adducts can not be obtained by
Friedel–Crafts reactions of 2-acylindoles. A similar result was
observed when a free hydroxy group was introduced into the
indole framework (Table 3, entry 12), and the product 3al was
reported to be a novel CaMKII inhibitor.[17a] Moreover, (5-
methoxy-1H-2-indolyl)phenylmethanone (3am), which has
been identified to be as active as paclitaxel and exhibit
antiangiogenic activity,[17b] can be synthesized in only one step
in 87% yield (Table 3, entry 13).
scope of this reaction was extended to include a variety of
stable sulfur ylides, such as those containing heteroaryl
(Table 2, entries 10 and 11) and ethoxy substituents
(Table 2, entries 12 and 13). Furthermore, alkylacyl-substi-
tuted sulfur ylides, such as 1m and 1n, gave the corresponding
products in moderate yields (Table 2, entries 14 and 15), and
alkenylacyl-substituted substrate could also be tolerated
under the model reaction conditions (Table 2, entry 16).
Importantly, the reaction of sulfonium salt 4a with 2a was
also found to be applicable to the synthesis of 2-benzoylin-
2
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was added. The mixture was stirred at room temperature. Upon
dole, thus simplifying the procedure further [Eq. (1)]. This
one-pot procedure was also applied successfully to the
completion of the reaction, as monitored by TLC, the crude mixture
was subjected to flash chromatography on silica gel (silica: 200–300;
eluent: petroleum ether/ethyl acetate = 10:1) to provide pure indole
3aa in 82% yield.
Received: May 11, 2012
Published online: && &&, &&&&
synthesis of other indoles such as 3la, 3li, and 3oa (Table 2,
entries 12, 13, and 16). Furthermore, the process is not limited
to stable carbonyl ylides. Dimethyloxosulfonium methylide,
generated in situ from trimethylsulfoxonium iodide 5, reacted
well with 2a to form indoline in 81% yield, which was
followed by an E1cb elimination to afford unsubstituted
indole 6a in 91% yield [Eq. (2); DMSO = dimethyl sulfoxide,
HMDS = hexamethyldisilazane].
Keywords: cascade reaction · indoles · nitrogen heterocycles ·
sulfur ylides
.
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Scheme 2. Possible mechanism for the cascade reaction.
process is initiated by addition of sulfur ylide 1a to the aza-o-
quinodimethane intermediate A, generated in situ from N-
(ortho-chloromethyl)aryl amide 2a under the basic condi-
tions.[18a–d] This step is followed by cyclization with loss of
dimethylsulfide to generate indoline B, which then undergoes
an E1cb elimination to afford C. This is then aromatized to
give the indole 3aa.[18e] Observations made in two additional
experiments provided evidence to support the proposed
mechanism.[19]
In summary, an unprecedented and robust method for the
synthesis of indoles from stable sulfur ylides and N-(ortho-
chloromethyl)aryl amides, which takes place by a cascade
reaction sequence, has been developed. This process occurs
under mild conditions, utilizes simple operations, and affords
indole products in generally high yields. Further studies to
expand the scope of the sulfur ylides are currently ongoing.
Experimental Section
Representative procedure: After stirring a solution of sulfur ylide 1a
(0.33 mmol) and Cs2CO3 (1.5 mmol) in xylenes (6 mL) for 0.5 h, N-(2-
(chloromethyl)phenyl)-4-methylbenzenesulfonamide (2a; 0.3 mmol)
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[19] For some mechanism studies, see the Supporting Information.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Indole Synthesis
Q.-Q. Yang, C. Xiao, L.-Q. Lu, J. An, F. Tan,
B.-J. Li, W.-J. Xiao*
&&&& — &&&&
Synthesis of Indoles through Highly
Efficient Cascade Reactions of Sulfur
Ylides and N-(ortho-Chloromethyl)aryl
Amides
Batting the ylides: A simple procedure
carried out under mild conditions allows
the direct and efficient synthesis of
structurally diverse indoles. This
approach involves a cascade reaction of
sulfur ylides and N-(ortho-chloromethyl)-
aryl amides (see scheme).
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!