Pd-Catalyzed C-H activation/oxidative cyclization of acetanilide with norbornene: Concise access to functionalized indolines

Article abstract of DOI:10.1039/c4cc03062a

An efficient Pd-catalyzed oxidative cyclization reaction for the synthesis of functionalized indolines by direct C-H activation of acetanilide has been developed. The norbornylpalladium species formed via direct ortho C-H activation of acetanilides is supposed to be a key intermediate in this transformation. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03062a

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Pd-Catalyzed C–H activation/oxidative cyclization
of acetanilide with norbornene: concise access to
functionalized indolines†
Cite this: Chem. Commun., 2014,
0, 8370
5
Received 24th April 2014,
Accepted 2nd June 2014
Yang Gao, Yubing Huang, Wanqing Wu,* Kefan Huang and Huanfeng Jiang*
DOI: 10.1039/c4cc03062a
www.rsc.org/chemcomm
An efficient Pd-catalyzed oxidative cyclization reaction for the
synthesis of functionalized indolines by direct C–H activation of
acetanilide has been developed. The norbornylpalladium species
formed via direct ortho C–H activation of acetanilides is supposed
to be a key intermediate in this transformation.
In the past decades, metal-catalyzed C–H activation/coupling reac-
tions have been widely explored and extensively employed in natural
1
product synthesis, materials science and pharmaceutical chemistry.
2
Among them, the oxidative Heck reaction, as pioneered by Fujiwara
and Moritani, has become one of the most important and
Scheme 1 Strategies for norbornene based indoline products.
3
distinct metal-catalyzed C–C bond-forming processes. In addition,
metal-catalyzed C–H activation/alkyne cyclization for various use- could undergo reductive elimination to afford the oxidative
4
a–c
4d,e
4f
ful heterocyclics, such as indoles,
isoquinolines,
pyrroles,
cyclization products.
4g
4h
isocoumarins, and pyridines, has attracted considerable atten-
On the other hand, norbornylpalladium species has been
tion. However, as for alkenes, the C–H activation/oxidative cycliza- previously synthesized and its chemistry has been a widespread
7
8a,b
8c
8d
8e–g
tion has been rarely realized since the comparative oxidative Heck concern. Catellani,
Larock, Saito and Lautens
et al. have
reaction is usually the dominant process. In 2008, Booker-Milburn reported several examples of the formation of nitrogen-containing
reported the first example employing 1,3-dienes in ortho-C–H heterocycles by the annulation of iodoanilines with norbornene
5
activation of aryl urea to afford indolines. Recently, in the work compounds (Scheme 1a). However, most of these transformations
6a
6b
of Glorius and our related work, the coordinative saturation of are limited to the organohalide substrates, which always require
the metal center has been shown to facilitate this chemical multi-step procedures and generate a large amount of salt waste.
process. Considering that C–H activation/oxidative cyclization of Considering the atom economy and the importance of indoline
9
alkene is still a great challenge, we devoted to develop a new products. the development of a more direct C–H activation/
strategy to fulfil this transformation. Notably, suppressing the oxidative cyclization process is urgently needed. Herein, we report
b-hydride elimination and preventing the formation of Heck-type an efficient Pd-catalyzed oxidative cyclization reaction for the
products is the key to the success of this reaction. We anticipated synthesis of functionalized indolines by direct C–H bond activation
that the strained alkenes, such as norbornenes, could offer a of acetanilides (Scheme 1b).
solution to control the corresponding b-hydride elimination due to
Our initial investigations of this Pd-catalyzed C–H activation/
its strained structure and the intermediate A without syn-b-hydrogen oxidative cyclization reaction were commenced with acetanilide (1a)
and norbornene (2a) as model substrates. Firstly, when 1a and 2a
were treated with 10 mol% of Pd(OAc)
120 1C, only a trace amount of expected product was detected
Table 1, entry 1). Considering that the oxidants might play an
important role in this oxidative cyclization reaction, various
frequently employed oxidants, such as 1,4-benzoquinone (BQ),
silver and copper salts, were examined (see ESI† for details). To
our delight, the yields were increased significantly when 2.0 equiv.
2 2
under 1 atm O in DMSO at
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn, cewuwq@scut.edu.cn;
Fax: +86 20-87112906; Tel: +86 20-87112906
(
†
Electronic supplementary information (ESI) available: Experimental section,
1
13
characterization of all compounds, copies of H and C NMR spectra for selected
compounds. CCDC 988826. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc03062a
8370 | Chem. Commun., 2014, 50, 8370--8373
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a
Table 1 Optimization of the reaction conditions
b
c
Scheme 2 X-ray crystallographic analysis of 3o.
Entry
Oxidant (equiv.)
Additive
Yield (%)
1
2
3
4
5
6
7
8
9
1 atm O
BQ (2)
2
—
—
—
—
—
—
—
—
o5
10
30
15
25
38
38
45
70 (66)
21
the formation of two indoline regioisomers with high selectivity, 3n
and 3o were almost the exclusive products. In addition, the structure
of 3o was further confirmed by X-ray crystallographic analysis
Ag
AgOAc (2)
Ag CO (2)
Cu(OTf) (2)
2
O (2)
2
3
10
(Scheme 2). Intriguingly, the reaction of N-(3,4-dichlorophenyl)-
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
(2)
acetamide led to the formation of two regioisomers with decreased
(1) + 1 atm O
(1) + 1 atm O
(1) + 1 atm O
(1) + 1 atm O
(1) + 1 atm O
2
2
2
2
2
0
selectivity (a/a = 5/1), while a 7/4 value was observed when using
NaOAc
10
11
12
T
S
OHꢀH
CF COOH
PivOH
2
O
N-(3-fluorophenyl)acetamide as the substrate. Evidently, both
the electronic character and steric demand of the substituents
influenced the selectivity of this transformation. To further demon-
3
8
51
a
Reaction conditions: unless otherwise noted, all reactions were per- strate the synthetic potential of this method, various norbornene
2
formed with 1a (0.3 mmol), 2a (0.6 mmol), Pd(OAc) (10 mol%) in
derivatives were also introduced to this oxidative cyclization reaction
and the corresponding indoline products 3r–3u were obtained in
moderate yields (46–66%). Moreover, this reaction showed a good
selectivity to the C–C double bond of norbornene when tetrahydro-
b
DMSO (2.0 mL) at 120 1C for 10 h. 1.0 equiv. of additive was added.
c
Determined by GC based on 1a. The value in parentheses is the yield
of the isolated product.
of oxidants were employed in the reaction system (entries 2–8). 1H-4,7-methanoindene was employed as the substrate (Table 2).
Among them, Cu(OAc) gave the best result and the yield of 3a was
To further highlight the versatility of this reaction, other
increased from 5% to 38% (entry 7). Further attempts revealed that directing groups were also tested (eqn (1)). We found that the 2-
.0 equiv. of Cu(OAc) and 1 atm O
was the optimal oxidation pyrimidyl and propionyl groups could be utilized as the direct-
2
1
2
2
system. Then, different additives were also tested (entries 9–12). ing group in addition to the acetyl group, and the desired
Strong acids (TsOHꢀH O, TFA) did not show positive effects on the oxidative cyclization products 4c and 4e were formed in 56%
2
yields since side reactions of norbornene might occur under these and 76% yields, respectively. However, tosyl, methyl and tri-
conditions. However, when 1.0 equiv. of NaOAc was added as an fluoroacetyl did not serve as proper directing groups. It is
additive, the yield of 3a increased significantly to 70% and this result important to note that the 2-pyrimidyl group was easily
1
1
indicated that NaOAc might be beneficial for the C–H activation step. removed from indoline and the corresponding N-free indo-
Thus, the optimal catalytic system for this reaction was: 1a line product 4f could be obtained in good yield (90%, eqn (2)).
(
0.3 mmol), 2a (0.6 mmol), Pd(OAc)
NaOAc (1 equiv.) in DMSO (2.0 mL) under 1 atm O
0 h. It should be noted that the reaction proved to be totally
2
(10 mol%), Cu(OAc)
2
(1 equiv.),
2
at 120 1C for
1
(
(
1)
2)
diastereoselective affording polysubstituted indoline branched in the
configuration exo to the bicyclic unit (confirmed by X-ray crystallo-
10
graphic analysis).
With the optimal reaction conditions in hand, we then examined
the scope of this C–H activation/oxidative cyclization transformation.
Generally, various acetanilides with different substituents were found
to be suitable reaction partners for this process. A series of para-
substituted acetanilides including some with electron-donating
groups (Me, OMe, OCF , and OPh) and some with electron-
To gain more insight into the mechanism of these reactions,
3
withdrawing groups (F, Cl, and Br) were well tolerated and converted we performed a deuterium competition experiment between
to the corresponding indoline products 3a–3h in moderate to good substrate 1a and [D ]-1a, and a kinetic isotope effect (KIE) of k
yields. It should be noted that substituents on the aromatic ring of
E 2.3 (eqn (3)) was observed, which indicated that the C–H
/
H
5
k
D
the acetanilide were found to influence the efficiency of the oxidative activation of arenes was the rate-determining step.
cyclization significantly. Electron-rich substrates tended to give
relatively high yields, whereas electron-deficient substrates displayed
a much lower reactivity. Moreover, ortho-Me, -OMe and -F substituted
acetanilides proceeded smoothly to afford the desired products 3i–3k
with a slight increase in the yields. Notably, N-(naphthalen-1-yl)acet-
amide also displayed a similar reactivity. Next, meta-substituted
(3)
acetanilides were tested. To our delight, good selectivity was observed
A tentative mechanism for the Pd-catalyzed intermolecular
with 3,4-dimethyl and 3-methoxy substituted acetanilides, leading to oxidative cyclization of acetanilides and norbornenes is proposed
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a,b
Table 2 Substrate scope of various acetanilides and norbornenes
Scheme 3 Possible reaction mechanism.
The authors thank the National Natural Science Foundation of
China (21172076 and 21202046), the National Basic Research Pro-
gram of China (973 Program) (2011CB808600), Guangdong Natural
Science Foundation (10351064101000000 and S2012040007088), and
the Fundamental Research Funds for the Central Universities
(2014ZP0004 and 2014ZZ0046) for financial support.
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2
2
2
b
c
1
2
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12
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6
3
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7
8
In conclusion, we have developed an efficient Pd-catalyzed
oxidative cyclization reaction for the synthesis of functionalized
indolines by direct C–H bond activation of acetanilide. Compared
to the oxidative Heck reaction, this oxidative cyclization suppresses
the b-hydride elimination and prevents the formation of Heck-type
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1
1
0 The CCDC number of 3o is 988826. See the ESI† for details.
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