Palladium-catalyzed synthesis of 2-fluoroalkyl-3-methylene-3H-indoles through a domino carbopalladation/C-H activation process

Article abstract of DOI:10.1002/adsc.201000689

A novel palladium-catalyzed synthesis of substituted 3-methylene-3H-indoles from readily accessible alkynylimines has been developed. A wide variety of 2-fluoroalkyl-3-methylene-3H-indoles were synthesized in moderate to good yields through this cascade c

Full text of DOI:10.1002/adsc.201000689

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DOI: 10.1002/adsc.201000689
Palladium-Catalyzed Synthesis of 2-Fluoroalkyl-3-methylene-3H-
À
indoles Through a Domino Carbopalladation/C H Activation
Process
Zixian Chen,a,b Jiangtao Zhu,b Haibo Xie,b Shan Li,b Yongming Wu,b,*
and Yuefa Gonga,*
a
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074,
Peopleꢀs Republic of China
Fax : (+86)-27-8754-3632; e-mail: gongyf@mail.hust.edu.cn
Key laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-5492-5192; e-mail: ymwu@mail.sioc.ac.cn
Received: September 6, 2010; Published online: February 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000689.
Abstract: A novel palladium-catalyzed synthesis of
substituted 3-methylene-3H-indoles from readily ac-
cessible alkynylimines has been developed. A wide
variety of 2-fluoroalkyl-3-methylene-3H-indoles
were synthesized in moderate to good yields
through this cascade carbopalladation/C H activa-
tion process. This reaction can also be expanded to
non-fluorinated substrates.
struction of various aromatic and heteroaromatic
compounds, such as oxindoles, indenes.[5] The key step
in these reactions is the carbopalladation of an aryl-
palladium halide to the triple bond which affords an
intermediate that can participate in a wide variety of
useful synthetic processes. However, to the best of
our knowledge, there have been no reports concern-
ing alkynylimines as candidates for the palladium-cat-
alyzed domino annulation reactions. As part of our
À
À
À
Keywords: cascade reactions; C H activation; fluo-
rine; indoles; palladium
continuing efforts in C H bond activation and the
construction of fluorine-substituted heterocycles,[4d,6]
we report herein that 3-methylene-3H-indoles, which
are good precursors for substituted indoles, could be
À
prepared successfully through a carbopalladation/C
H functionalization process from alkynylimines.
The indole scaffold is a prominent and privileged
As listed in Table 1, N-(1,1,1-trifluoro-4-phenylbut-
structural motif found in numerous natural products 3-yn-2-ylidene)aniline 1a and iodobenzene were
and various bioactive compounds.[1] Biologically chosen as a model to explore the suitable reaction
active 2-fluoroalkylindole compounds have previously conditions. Initial experiments were performed using
been reported for developing pharmaceutically impor- 2 equivalents of iodobenzene, and 2.5 equivalents of
tant molecules,[2] as introducing fluorine atoms into NaOAc, in the presence of 10 mol% of PdCl2/
bioactive molecules may lead to changes in solubility, 20 mol% PPh3 as the catalyst, in DMF at 808C over-
lipophilicity, metabolic stability, conformation, and night. The desired 2-trifluoromethyl 3-methylene-3H-
hydrogen-bonding ability.[3] Therefore, different strat- indole product 2a was obtained in 71% yield (Table 1,
egies were developed to generate fluorine-containing entry 1), which was confirmed by X-ray crystal dif-
substituted indole derivatives, especially there are se- fraction studies (Figure 1).[7] Next, other palladium
verial methods reported lately using transition metals catalysts were examined. Both Pd
for constructing this heterocyclic unit.[4] Our group Pd
2A(dba)3 could give similar yields compared with
also described a palladium-catalyzed process to access PdCl2 (Table 1, entries 2 and 4). Remarkably, using
this skeleton.[4d]
Pd(OAc)2 alone produced the target product 2a in a
ACHTUNGRTEN(NUNG OAc)2 and
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
Recently, the transition metal-catalyzed direct func- slightly higher yield (Table 1, entry 6). Further solvent
À
tionalization of arene C H bonds assisted by neigh- screening experiments revealed that DMF was the
boring alkynyl groups has received considerable at- most suitable choice, other solvents gave decreased
tention, which serves as a powerful tool for the con- yields (Table 1, entries 7–9). Then, different bases
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Zixian Chen et al.
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Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
Solvent Base
Yield
[%][b]
1
2
3
4
5
6
7
8
PdCl2/PPh3
DMF
DMF
DMF
NaOAc 71
NaOAc 72
NaOAc 56
NaOAc 72
NaOAc 65
NaOAc 77
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG(dba)3·CHCl3/PPh3 DMF
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
N
R
ACHTUNGTRENNUNG
E
E
ACHTUNGTRENNUNG
DMSO NaOAc
7
DMA
NMP
DMF
DMF
DMF
DMF
DMF
DMF
NaOAc 66
NaOAc 61
9
10
11
12
13
14
15
KOAc
74
Na2CO3 85
NaHCO3 85
Figure 1. X-ray structure of 2a.
G
T
A
K2CO3
–
Na2CO3 59[c]
Na2CO3 86 (82)[d]
Next, the scope and limitations of this cascade reac-
tion were examined. Table 2 summarizes the results of
the reaction with a variety of N-arylalkynylimines
under optimized reaction conditions. Other fluoroalk-
yl groups, such as CF2CF3, CF2H, were attempted,
both gave good yields (Table 2, entries 1 and 2). En-
couraged by these results, we synthesized a non-fluo-
rine-containing alkynylimine. Surprisingly, the product
was also formed in moderate yield (Table 2, entry 3),
making this method more versatile. Changing the N-
aryl group revealed that the electronic effects signifi-
[a]
Reactions were carried out on a 0.3 mmol scale in DMF
(2 mL) at 808C with iodobenzene (2 equiv.) and base
(2.5 equiv.) unless otherwise stated.
[b]
Reported yields were based on 1a. Determined by
19F NMR. Values in parentheses are of isolated yields.
[c]
[d]
Pd
ACHTUNGTRENNUNG(OAc)2 (5 mol%) was used.
Na2CO3 (2.0 equiv.) was used.
were evaluated. The yield was improved considerably cantly affect the reactivity (Table 2, entries 4–11).
when Na2CO3 or NaHCO3 was used as the base Electron-donating groups gave good yields, while
(Table 1, entries 11 and 12). Stronger bases led to de- electron-withdrawing groups afforded the product
compose of the starting material (Table 1, entry 13). with reduced yields. A regioselectivity was observed
After optimization, the best reaction conditions were when the meta-position of the N-aryl ring was substi-
ascertained as 10 mol% Pd
ACHTUNGTRENNUNG
Na2CO3, and 2 equivalents of iodobenzene in DMF at aryl iodides, an isomeric mixture (E: Z=1:1) was iso-
808C (Table 1, entry 15).
Scheme 1. Reduction of the E,Z isomers.
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Palladium-Catalyzed Synthesis of 2-Fluoroalkyl-3-methylene-3H-indoles
Table 2. Synthesis of 3-methylene-3H-indoles.[a]
Entry
1
R1/R2/R3/Ar
1
Product
Yield [%][b]
84
CF3CF2/H/Ph/Ph
1b
2b
2c
2d
2e
2f
2
3
4
5
CF2H/H/Ph/Ph
1c
1d
1e
1f
80
40
82
87
COOEt/4-MeO/Ph/Ph
CF3/4-MeO/Ph/Ph
CF3/4-Me/Ph/Ph
6
CF3/2-Me/Ph/Ph
1g
2g
81
7
8
9
CF3/4-Br/Ph/Ph
CF3/4-CF3/Ph/Ph
CF3/4-acetyl/Ph/Ph
1h
1i
2h
2i
72
50
45
1j
2j
10
11
CF3/2-Cl/Ph/Ph
CF3/3-Me/Ph/Ph
1k
1l
2k
44
2la
2lb
59
28
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Zixian Chen et al.
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Table 2. (Continued)
Entry
R1/R2/R3/Ar
1
Product
Yield [%][b]
12
CF3/H/4-MeC6H4/4-MeC6H4
1m
2m
88
13
14
CF3/H/4-MeOC6H4/4-MeOC6H4
CF3/H/3-MeC6H4/3-MeC6H4
1n
1o
2n
2o
94
88
15
CF3/H/4-ClC6H4/4-ClC6H4
1p
2p
77
16
17
CF3/H/4-FC6H4/4-FC6H4
1q
1r
2q
2r
78
72
CF3/4-MeO/n-butyl/Ph
18
CF3/4-MeO/n-butyl/4-MeC6H4
1s
2s
70
[a]
Reactions were carried out on a 0.5-mmol scale in DMF (2 mL) at 808C with iodobenzene (2.0 equiv.) and base
(2.0 equiv.) unless otherwise stated.
Isolated yields.
[b]
further reduction was carried out providing racemic termined to be E by NOE studies (Table 2, entries 17
indole compounds. So a series of symmetrical prod- and 18).[10]
ucts were designed (Table 2, entries 12–16). Electron-
A possible mechanism for this transformation is
rich alkyne groups and aryl iodides delivered the proposed in Scheme 2. The first step is the oxidative
products in good yields, while electron-poor ones led addition of Pd(0) with aryl iodide, the formed arylpal-
to slightly declined yields, and aryl bromides were not ladium(II) species then coordinates to the triple bond
suitable substrates. If a hexyne group was involved, and subsequent syn carbopalladation affords a vinyl-
À
an aromatized indole with an exocyclic double bond palladium intermediate, The C H activation of the N-
was isolated in favorable yield, which may serve as a aryl group occurred providing a six-membered palla-
good building block for biologically active com- dacycle. Reductive elimination would then lead to the
pounds.[9] The olefin geometry of the products was de- formation of 2 and regenerate the Pd(0) species. The
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Palladium-Catalyzed Synthesis of 2-Fluoroalkyl-3-methylene-3H-indoles
Scheme 2. Proposed mechanism.
E,Z isomers of 2 could easily interconvert at room
temperature.
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In conclusion, we have designed a domino carbo-
À
palladation/C H activation process for the synthesis
of novel 2-fluoroalkyl-3-methylene-3H-indoles, which
are good precursors for the synthesis of biologically
important 2-fluoroalkyl-substituted indole derivatives.
A wide variety of functionalized 3-methylene-3H-in-
doles can be synthesized in good yields under mild
conditions.
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Experimental Section
A Schlenk tube was charged with PdCAHTUNGTERN(NUNG OAc)2 (10 mol%) and
Na2CO3 (2 equiv.), then DMF (2 mL), alkynylimine
1
(0.5 mmol), and aryl iodide (2.0 equiv.) were successively
added. The mixture was stirred at 808C until completion of
the reaction, then partitioned between ethyl acetate and
water, the organic layer was washed with brine, dried over
MgSO4, and concentrated under vacuum. The residue was
purified by column chromatography on silica gel to yield
product 2.
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This work was supported by the National Science Foundation
of China (No. 20772145).
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