Multicatalytic one-pot reaction of 1-(2-alkynylphenyl)ketoximes for generation of indole derivatives

Article abstract of DOI:10.1021/ol101487q

Multicatalytic one-pot Beckmann rearrangement/intramolecular cyclization/halogenation reaction of 1-(2-alkynylphenyl)ketoxime is reported, leading to the expected indole derivatives in good yield.

Full text of DOI:10.1021/ol101487q

ORGANIC
LETTERS
2010
Vol. 12, No. 18
3975-3977
Multicatalytic One-Pot Reaction of
1-(2-Alkynylphenyl)ketoximes for
Generation of Indole Derivatives
Guanyinsheng Qiu,† Qiuping Ding,† Hui Ren,‡ Yiyuan Peng,*,† and Jie Wu*,‡
Department of Chemistry, Fudan UniVersity, 220 Handan Road,
Shanghai 200433, China, and Key Laboratory of Green Chemistry of Jiangxi
ProVince, College of Chemistry and Chemical Engineering, Jiangxi Normal UniVersity,
Nanchang 330027, China
jie_wu@fudan.edu.cn; yypeng@jxnu.edu.cn
Received June 29, 2010
ABSTRACT
Multicatalytic one-pot Beckmann rearrangement/intramolecular cyclization/halogenation reaction of 1-(2-alkynylphenyl)ketoxime is reported,
leading to the expected indole derivatives in good yield.
The tandem reaction has been recognized as an attractive
strategy for molecular complexity generation.1 As part of a
program in our laboratory for natural product-like compound
construction,2,3 we identified that 2-alkynylbenzaldoxime was
a useful building block for N-heterocycle generation via
tandem reactions.3 On the other hand, it is well-known that
the Beckmann rearrangement of ketoximes is a fundamental
and commonly used tool for amide formation.4 Many
catalytic methods have appeared for the transformation
recently.5 For instance, Yamamoto and co-workers reported
that 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) was an
effective organocatalyst (cocatalyzed by HCl or ZnCl2) for
the Beckmann rearrangement under reflux in acetonitrile or
nitromethane.5h Encouraged by these results, we envisioned
that 1-(2-alkynylphenyl)ketoxime might be utilized as a
† Jiangxi Normal University.
‡ Fudan University.
(1) For selected examples, see: (a) Montgomery, J. Angew. Chem., Int.
Ed. 2004, 43, 3890. (b) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.; Liu,
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Angew. Chem., Int. Ed. 2006, 45, 7134. (i) Enders, D.; Grondal, C.; Hu¨ttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (j) Tietze, L. F.; Brasche,
G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
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10.1021/ol101487q  2010 American Chemical Society
Published on Web 08/20/2010

substrate in tandem reactions as well. We anticipated that
after a Beckmann rearrangement of 1-(2-alkynylphenyl)-
ketoxime 2-alkynylanilide would be afforded. Thus, the
intramolecular cyclization would occur in the presence of
suitable catalyst to generate an indole scaffold,6,7 which is a
core structure in both natural products and therapeutic
agents.8
Table 1. Initial Studies for the Multicatalytic One-Pot Reaction
of 1-(2-Alkynylphenyl)ketoxime 1a
As described, two separate catalytic systems are necessary
in the above two steps. Recently, a strategy involving two
or more catalysts in one pot to cooperatively catalyze a
chemical reaction has been demonstrated, which broadens
the reaction scope within organic synthesis.9,10 The proposed
tandem Beckmann rearrangement-intramolecular cyclization
reaction of 1-(2-alkynylphenyl)ketoxime led us to envision
the possibility to incorporate two catalytic systems to achieve
the indole synthesis. 1-(2-Alkynylphenyl)ketoxime could be
synthesized easily according to the literature method.11 To
validate our hypothesis, we carried out the initial studies
using (E)-1-(2-(2-phenylethynyl)phenyl)ethanone oxime 1a
as the substrate (Table 1).
entry
Lewis acid
CNC, CuCl2
CNC, Cu(OTf)2
CNC, CuI
CNC, PdCl2
CNC, PdCl2(MeCN)2
CNC, InCl3
CNC, PdCl2(MeCN)2, ZnCl2
CNC, PdCl2(MeCN)2InCl3
CNC, PdCl2(MeCN)2, InCl3
CNC, PdCl2(MeCN)2, InCl3
CNC, PdCl2(MeCN)2, InCl3
CNC, PdCl2(MeCN)2, InCl3
CNC, PdCl2(MeCN)2, InCl3
solvent
yield (%)a
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
toluene
DCE
MeCN
MeCN
complicated
complicated
complicated
25
35
b
-
41
80
35
trace
51
9
10
11
12c
13d
trace
60
As mentioned above, 2,4,6-trichloro-1,3,5-triazine (cya-
nuric chloride) has been demonstrated as an effective
organocatalyst in the presence of acid cocatalyst for the
Beckmann rearrangement.5h Thus, at the outset, the reaction
was catalyzed by cyanuric chloride (10 mol %) and CuCl2
(10 mol %) (Table 1, entry 1). However, the reaction was
complicated. Similar results were observed when Cu(OTf)2
or CuI was utilizied as a replacement of CuCl2 (Table 1,
entries 2 and 3). We were gratified to find that the desired
product 2a was obtained in 25% isolated yield when the
a Isolated yield based on 1-(2-alkynylphenyl)ketoxime 1. b Beckmann
rearrangement product was obtained in 90% yield. c The reaction was
performed at room temperature. d In the presence of 5 mol % of catalysts.
reaction was catalyzed by cyanuric chloride (10 mol %) and
PdCl2 (10 mol %) (Table 1, entry 4). Higher yield of indole
2a was generated when PdCl2(MeCN)2 was used in the
reaction (Table 1, entry 5). However, when the reaction was
cocatalyzed by cyanuric chloride and InCl3 (Table 1, entry
6), only the Beckmann rearrangement product was furnished
with 90% yield. We reasoned that the palladium catalyst was
mainly beneficial for the intramolecular cyclization process.
In addition, we noticed that in Yamamoto’s report an
additional acid catalyst would facilitate the Beckmann
rearrangement. Therefore, ZnCl2 or InCl3 was added in the
cyanuric chloride, and a PdCl2(MeCN)2 cocatalzyed tandem
reaction of (E)-1-(2-(2-phenylethynyl)phenyl)ethanone oxime
1a (Table 1, entries 7 and 8) occurred. With an expectation
to achieve increased efficacy, we improved the experimental
procedure: cyanuric chloride with ZnCl2 or InCl3 was added
in the reaction first. After consumption of (E)-1-(2-(2-
phenylethynyl)phenyl)ethanone oxime 1a, PdCl2(MeCN)2
was then added. To our delight, the desired product 2a was
generated in 41% and 80% yield, respectively. A blank
experiment indicated that only a trace amount of product
was afforded without the addition of cyanuric chloride (data
not shown in Table 1). Further screening of solvents showed
that the reaction worked the most effectively in MeCN.
Inferior results were observed when the reaction was
performed in other solvents (Table 1, entries 9-11). A trace
amount of product 2a was detected when the reaction
occurred at room temperature (Table 1, entry 12). Lower
yield was isolated when the amount of catalysts was reduced
to 5 mol % (Table 1, entry 13).
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G. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
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With the optimal conditions in hand, we thus examined
the scope of the multicatalytic one-pot Beckmann rearrange-
ment/intramolecular cyclization reactions of 1-(2-alkynylphe-
2009, 7, 4526
.
(11) Takao, S.; Kondo, Y.; Miura, N.; Hayashi, K.; Yamanaka, H.
Heterocycles 1986, 24, 2311.
3976
Org. Lett., Vol. 12, No. 18, 2010

realized that the reaction worked efficiently in the presence
of 2.0 equiv of CuCl2, which led to the desired 3-chloroindole
3a in 66% yield (Table 3, entry 1). A similar result was
Table 2. Multicatalytic One-Pot Beckmann Rearrangement/
Intramolecular Cyclization Reactions of 1-(2-Alkynylphenyl)-
ketoximes
Table 3. Synthesis of 3-Chloroindoles via Multicatalytic
One-Pot Reactions of 1-(2-Alkynylphenyl)ketoximes
entry
R1
R2
R3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
CH3CH2
CH3CH2
CH3CH2
C6H5
CH3
CH3
CH3
yield (%)a
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
C6H5
80 (2a)
74 (2b)
62 (2c)b
62 (2d)
53 (2e)
-c (2f)
74 (2g)
70 (2h)
60 (2i)
53 (2j)
4-CH3C6H4
4-CH3OC6H4
n-C4H9
cyclopropyl
SiMe3
entry
R1
R2
C6H5
C6H5
4-CH3C6H5
C6H5
R3
CH3
CH3CH2
CH3CH2
CH3
yield (%)a
1
2
3
4
5
6
H
H
H
66 (3a)
70 (3b)
61 (3c)
50 (3d)
70 (3e)
63 (3f)
C6H5
5-Cl
5-CH3
5-CH3
4-CH3C6H4
4-CH3OC6H4
n-C4H9
C6H5
4-CH3C6H4
CH3
CH3
9
10
11
12
13
14
a Isolated yield based on 1-(2-alkynylphenyl)ketoxime 1.
C6H5
C6H5
C6H5
-
d (2k)
52 (2l)
66 (2m)
70 (2n)
5-Cl
5-CH3
5-CH3
generated when R3 was replaced by an ethyl group (Table
3, entry 2). Other 1-(2-alkynylphenyl)ketoximes with a
chloro, methyl group attached on the aromatic ring were
examined as well, and all reactions worked well to give the
desired product 3 in reasonable yield.
4-CH3C6H4
a Isolated yield based on 1-(2-alkynylphenyl)ketoxime 1. b A byproduct
was formed concomitantly. c The reaction was complex. d Only the
Beckmann rearrangement product was isolated.
In conclusion, we have developed a novel approach to
indole derivatives via a multicatalytic one-pot Beckmann
rearrangement/intramolecular cyclization/halogenation reac-
tion of 1-(2-alkynylphenyl)ketoxime. The starting materials
are easily accessible, and the final product could be further
elaborated via known palladium-catalyzed cross-coupling
reactions. Using 1-(2-alkynylphenyl)ketoxime as a substrate
in other tandem reactions is under investigation currently.
nyl)ketoximes. The results are shown in Table 2. This
multicatalytic one-pot reaction was found to be workable
for 1-(2-alkynylphenyl)ketoximes with electron-withdrawing
and -donating substituents on the aromatic backbone. Reac-
tions employing the substrates with an alkyl group (n-butyl
or cyclopropyl substituent) attached to the Ct C triple bond
proceeded smoothly as well to generate the desired products
in good yields (Table 2, entries 4, 5, and 10). However, the
reaction was complex when R2 was replaced by the trim-
ethylsilyl group (Table 2, entry 6). It should be noted that a
byproduct was formed concomitantly when R2 was changed
as the 4-methoxyphenyl group (Table 2, entry 3). For the
substrate with the phenyl group (R3) attached to the oxime,
no desired product was detected, and only the Beckmann
rearrangement product was isolated (Table 2, entry 11).
To broaden the utility of this tandem reaction, we
conceived that an additional step for halogenation was
possible. Thus, further investigation by adding copper(II)
chloride was explored for the tandem reaction of (E)-1-
(2-(2-phenylethynyl)phenyl)ethanone oxime 1a.12 Finally, we
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20972030) and the
Science & Technology Commission of Shanghai Municipal-
ity (09JC1404902) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
of compounds 2 and 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101487Q
(12) Tang, S.; Xie, Y. X.; Li, J. H.; Wang, N. X. Synthesis 2007, 1841.
Org. Lett., Vol. 12, No. 18, 2010
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