Palladium-catalyzed tandem diperoxidation/C - H activation resulting in diperoxy-oxindole in air

Article abstract of DOI:10.1021/ol101664y

A highly efficient and facile palladium-catalyzed tandem diperoxidation and C - H activation process was reported, which provides a new pathway for the synthesis of biologically active diperoxides as well as oxindole derivatives from readily available starting materials in excellent chemical yields.

Full text of DOI:10.1021/ol101664y

ORGANIC
LETTERS
2
010
Vol. 12, No. 20
482-4485
Palladium-Catalyzed Tandem
Diperoxidation/C-H Activation Resulting
in Diperoxy-oxindole in Air
4
Guanghui An, Wei Zhou, Guangqian Zhang, Hao Sun, Jianlin Han,* and Yi Pan*
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination
Nanjing UniVersity, Nanjing, 210093, China
hanjl@nju.edu.cn; yipan@nju.edu.cn
Received July 19, 2010
ABSTRACT
A highly efficient and facile palladium-catalyzed tandem diperoxidation and C-H activation process was reported, which provides a new
pathway for the synthesis of biologically active diperoxides as well as oxindole derivatives from readily available starting materials in excellent
chemical yields.
4
Peroxides are a privileged structural motif found in many
important natural products and pharmaceutical agents, which
show antitumor, anticancer, and antiparasite activities.
tions. In this communication, we report a new palladium-
catalyzed tandem process, including diperoxidation of olefins
and C-H activation under acidic conditions, which generates
diperoxy-oxindoles (Scheme 1).
1
Artemisinin is an efficient antimalarial medicine with the
2
essential peroxide unit for its high antimalarial potency.
However, the development for the synthesis of the peroxides
3
still remains challenging, especially for diperoxides. To date,
there has been only one report that mentioned the transition-
metal-catalyzed diperoxidation of olefin under basic condi-
Scheme 1
(
1) For reviews, see: (a) Rahm, F.; Hayes, P. Y.; Kitching, W.
Heterocycles 2004, 64, 523–575. (b) Casteel, D. A. Nat. Prod. Rep. 1999,
6, 55–73.
2) For artemisinin, see: (a) Posner, G. H.; O’Neill, P. M. Acc. Chem.
Res. 2004, 37, 397–404. (b) Posner, G. H.; Oh, C. H. J. Am. Chem. Soc.
992, 114, 8328–8329. (c) Meshnick, S. R.; Thomas, A.; Ranz, A.; Xu,
C. M.; Pan, H. Z. Mol. Biochem. Parasitol. 1991, 49, 181–190.
3) For examples of synthesis of peroxides and diperoxides, see: (a)
1
(
1
C-H activation has attracted considerable attention owing
to its higher atom economy, shorter synthetic routes, and
(
5
readily available precursors. Numerous efforts have been
Harris, J. R.; Waetzig, S. R.; Woerpel, K. A. Org. Lett. 2009, 11, 3290–
6
3
2
293. (b) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc.
008, 130, 8134–8135. (c) Xiao, Z.; Yao, J.; Yang, D.; Wang, F.; Huang,
devoted to develop the synthesis of oxindoles from amides
via C-H activation methods or related C-C bond formation
S.; Gan, L.; Jia, Z.; Jiang, Z.; Yang, X.; Zheng, B.; Yuan, G.; Zhang, S.;
Wang, Z. J. Am. Chem. Soc. 2007, 129, 16149–16162. (e) Gu, X.; Zhang,
W.; Salomon, R. G. J. Am. Chem. Soc. 2007, 129, 6088–6089. (f) Schneider,
C.; Boeglin, W. E.; Yin, H.; Stec, D. F.; Voehler, M. J. Am. Chem. Soc.
7
methods. These powerful methods require a specifically
functionalized starting material and result in a special
2
2
006, 128, 720–721. (g) Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc.
005, 127, 2796–2797.
(4) Yu, J. Q.; Corey, E. J. Org. Lett. 2002, 4, 2727–2730.
10.1021/ol101664y  2010 American Chemical Society
Published on Web 09/14/2010

subclass of oxindoles. To our knowledge, the synthesis of
diperoxy oxindole has not been reported yet, and dihydroxy
a
Table 1. Optimization of Reaction Conditions
oxindole as a structure motif in nature products such as TMC-
8
9
5A has never been synthesized effectively from a simple
precusor. To complement previous powerful approaches, we
now report a new protocol for synthesis of oxindole and
dihydroxyindoles based upon C-H activation.
In the initial study, N-phenylacrylamide (1a) was attempted
b
entry
catalyst
oxidant
solvent
HOAc
yield (%)
to react with tert-butyl hydroperoxide catalyzed by Pd(OAc)
2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
none
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
(t-BuO)
2
t-BuOOAc
t-BuOOBz
n.r.
70
52
in acetic acid without the protection of inert atmosphere. The
reaction resulted in diperoxy-oxindole 2a, and its structure
has been identified by single-crystal X-ray diffraction analysis
Pd(OAc)
Pd(PPh
Pd(MeCN)
PdCl
2
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
3
)
4
2
Cl
2
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
19
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
(
Figure 1). Pd(OAc)
2
was found to be most effective for this
2
CuCl ,
1
1
1
1
1
1
1
1
Cu(OAc)
Ag CO
AgOAc
2
2
3
PhI(OAc)
2
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
3
CF COOH
DMSO
DMF
2 2
ClCH CH Cl
a
Reaction conditions: 1 mmol of substrate with 10.0 equiv of oxidant
and 5 mol % catalyst in 10.0 mL of solvent at 80 °C for 6 h under air.
b
Isolated yields.
With the optimized reaction conditions in hand, the scope
and limitation of the reaction were examined with varieties of
N-arylacrylamide substrates (Figure 2). The diperoxy oxindole
products were obtained in moderate to excellent yields. The
Figure 1. X-ray crystallography for 2a.
catalytic reaction with the best yield (Table 1, entries 1-5).
The variation of catalyst from Pd(OAc) to Pd(PPh lowered
the yield, while Pd(CH CN) Cl and PdCl did not promote
2
3 4
)
3
2
2
2
this reaction at all and starting material was almost recovered
in both cases. Additionally, other metal catalysts were tested,
and none of them promoted the reaction (see Supporting
Information). Meanwhile, the oxidant was found to be crucial
for the reactions, and the reaction proceeded smoothly only
in the presence of t-BuOOH (entries 6-13). Various solvents
were tested, and acetic acid was found to be the most efficient
media for the reaction (entries 14-17).
(
5) For recent reviews of C-H activation, see: (a) Xu, L. M.; Li, B. J.;
Yang, Z.; Shi, Z. J. Chem. Soc. ReV. 2010, 39, 712–733. (b) Lyons, T. W.;
Sanford, M. S. Chem. ReV. 2010, 110, 1147–1169. (c) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. ReV. 2010, 110, 624–655. (d) Giri,
R.; Shi, B. F.; Engle, K. M.; Maugel, N.; Yu, J. Q. Chem. Soc. ReV. 2009,
3
8, 3242–3272. (e) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew.
Chem., Int. Ed. 2009, 48, 5094–5115.
6) (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem. 2007, 119, 8902–
(
8
8
2
912. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
748–8758. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–
219.
(
7) For synthesis of oxindole via C-H activation methods or related C-C
bond formation from C-H bonds, see: (a) Ueda, S.; Okada, T.; Nagasawa, H.
Chem. Commun. 2010, 46, 2462–2464. (b) Perry, A.; Taylor, R. J. K. Chem.
Commun. 2009, 3249–3251. (c) Miura, T.; Ito, Y.; Murakami, M. Chem.
Lett. 2009, 38, 328–329. (d) Jiang, T. S.; Tang, R. Y.; Zhang, X. G.; Li,
X. H.; Li, J. H. J. Org. Chem. 2009, 74, 8834–8837. (e) Jia, Y. X.; Kundig,
E. P. Angew. Chem., Int. Ed. 2009, 48, 1636–1639. (f) Wasa, M.; Yu, J. Q.
J. Am. Chem. Soc. 2008, 130, 14058–14059. (g) Pinto, A.; Neuville, L.; Zhu,
J. P. Angew. Chem., Int. Ed. 2007, 46, 3291–3295. (h) Hennessy, E. J.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084–12085.
Figure 2. Palladium-catalyzed tandem reaction. (Conditions: 1 (1
mmol) and t-BuOOH (10 mmol) in 10.0 mL of acetic acid at 80
°
C for 6 h. Isolated yields were reported.)
(
8) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu,
R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990–995.
Org. Lett., Vol. 12, No. 20, 2010
4483

reaction can tolerate the ortho-halo substituents at the aromatic
ring and afforded the diperoxidated products with the halogen
group remaining (2e, 2g, 2l, 2m, and 2n, Figure 2). The
tolerance of ortho-halo in the substrates illustrates that this is a
new palladium-catalyzed process, which is different from the
remarkably powerful Pd-catalyzed intramolecular arylation
direct couplings of Csp2-H and Csp3-H centers. In the
alternative routine (Scheme 4, pathway b), the substrate
undergoes aromatic C-H alkenylation (Heck type reaction)
followed by diperoxidation. The third possible routine
(Scheme 4, pathway c) may proceed through a three-step
pathway: a Wacker-type oxidation, reductive elimination, and
peroxidation. To investigate the reaction mechanism, attempts
to isolate the intermediate A1 and A3 were made. However,
the cyclization was too rapid, and A1 and A3 could not be
detected directly in almost all cases. Then, compound 5 was
used to examine the possibility of pathway b, but no diperoxy
oxindole 2a was detected under the typical reaction condi-
tions. Attempts to perform the reaction in the presence of
radical scavengers (BHT, benzoquinone, or iodine) led only
to recovery of 1a. These inhibitors would not be expected
to suppress the Wacker-type oxidation that forms the first
step of pathway c.
9
oxindole synthesis reported by Hartwig and Kundig’s radical
7b,e
oxidation formation of oxidoles.
The catalytic system failed for the substrate 1o, and almost
all the starting material was recovered (Scheme 2). Interest-
Scheme 2
ingly, for the case of 1p, no diperoxidated product was found
with amide 4 detected in 34% chemical yield (Scheme 2).
Furthermore, these obtained diperoxy oxindoles can be
easily transformed to dihydroxy oxindoles (3) by a hydro-
genation reaction (Scheme 3). Dihydroxy oxindoles are an
Scheme 5. Proposed Mechanism of the Tandem Process
Scheme 3. Reduction of 2a to 3-Hydroxy Oxindole Derivative 3
1
0
important type of biologically active 3-hydroxy oxindoles
and can also be transformed into other oxindole analogues.
3
a,f,4,7a,b,e
On the basis of the previous studies,
we envi-
sioned that N-phenylacrylamide may proceed through three
proposed tandem pathways to construct a diperoxidated
The proposed mechanism is shown in Scheme 5. First,
peroxidation reaction of 1a occurs, affording diperoxide A1
4
through a radical process. Next, A1 undergoes an electro-
philic attacking by cationic Pd(II) on an aromatic C-H bond
with the aid of the ortho directing group, to generate
palladium intermediate B1. The ability of the unsubstituted
anilide to coordinate Pd(II) while donating electron density
into the arene may explain the greater reactivity relative to
N-alkyl amides. The conversion of the aryl-Pd intermediate
to the dihydroindole requires activation of a C-H bond
without cleavage of an adjacent peroxide. This is, to our
knowledge, an unprecedented transformation. Abstraction of
a hydrogen to create a carbon radical appears unlikely given
the results with radical inhibitors described above; in
addition, an R-peroxyl radical would be expected to rapidly
fragment to form a ketone. The presence of Pd(II) and
t-BuOOH could in theory oxidize the C-H bond to form a
reactive cation. However, it is more likely that the aryl-Pd(II)
intermediate inserts into the neighboring C-H bond to form
Scheme 4. Initial Hypothetical Pathway for the Tandem Process
oxindole core structure. The first possible pathway (Scheme
, pathway a) involves a sequence of diperoxidation and
4
4484
Org. Lett., Vol. 12, No. 20, 2010

an Ar-Pd-R intermediate which can undergo reductive
elimination to establish the C-C bond.
series of diperoxy-oxindoles, and the new methodology
will be used to access a series of 3-hydrooxindoles of
interest for biological investigation.
In summary, we have developed a novel and facile
palladium-catalyzed tandem process via diperoxidation and
C-H activation. This is really the first highly efficient
catalytic diperoxidation reaction by using readily available
starting materials. The current system provides a new
pathway for the synthesis of biologically active diperox-
ides, as well as oxindole functionalities. The following
research will focus on bioactivity investigation of the new
Acknowledgment. We gratefully acknowledge the finan-
cial support from the National Natural Science Foundation
of China (No. 20772056 and 20932004). The Jiangsu 333
program (for Pan) and the setup fund of Nanjing University
(for Han) are also acknowledged.
(
9) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–3415. (b)
Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
3, 6546–6553.
10) For recent reviews and application of bioactive 3-hydroxy oxindole,
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for new compounds, and
single-crystal X-ray diffraction analysis of 2a. This material
is available free of charge via the Internet at http://pubs.acs.org.
6
(
see: (a) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20–38. (b) Erkizan,
H. V.; Kong, Y.; Merchant, M.; Schlottmann, S.; Barber-Rotenberg, J. S.;
Yuan, L.; Abaan, O. D.; Chou, T.-H.; Dakshanamurthy, S.; Brown, M. L.;
Uren, A.; Toretsky, J. A. Nat. Med. 2009, 15, 750–756.
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