Synthesis of oxindoles by palladium-catalyzed C-H bond amidation

Article abstract of DOI:10.1246/cl.2009.328

Treatment of N-tosylphenylacetamide derivatives with cop-per(II) acetate in the presence of a catalytic amount of palladi-um(II) acetate affords 3,3-disubstituted oxindoles. The reaction proceeds through the intramolecular metallation of an aromatic C-H b

Full text of DOI:10.1246/cl.2009.328

328
Chemistry Letters Vol.38, No.4 (2009)
Synthesis of Oxindoles by Palladium-catalyzed C–H Bond Amidation
Tomoya Miura, Yoshiteru Ito, and Masahiro Murakamiꢀ
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510
(Received January 15, 2009; CL-090055; E-mail: murakami@sbchem.kyoto-u.ac.jp)
Me
Treatment of N-tosylphenylacetamide derivatives with cop-
O
HOAc
Me
per(II) acetate in the presence of a catalytic amount of palladi-
um(II) acetate affords 3,3-disubstituted oxindoles. The reaction
proceeds through the intramolecular metallation of an aromatic
C–H bond and the following C–N bond formation by reductive
elimination.
Ts
N
Pd(OAc)
1a
H
Pd(OAc)2
HOAc
A
Cu(OAc)2
O2
Me Me
The development of efficient methods for the synthesis of
nitrogen-containing heterocycles using transition-metal catalysts
is of immense interest owing to the ubiquity of heterocyclic
cores in natural products and pharmaceuticals.1 Cyclization
through the direct conversion of C–H bonds into C–N bonds
would be attractive for the construction of these ring systems
in view of atom economy and synthetic simplicity.2 In 2005,
Buchwald and co-workers reported a palladium-catalyzed syn-
thesis of carbazoles from acetylated 2-phenylaniline via C–H
functionalization forming a C–N bond.3 Since then, the method
has been applied to the synthesis of other classes of heterocycles
using palladium- and/or copper-catalysts.4 Herein, we describe a
synthesis of oxindoles from N-tosylphenylacetamide derivatives
facilitated by a combination of Pd(OAc)2 and Cu(OAc)2.5
When N-tosyl-2-methyl-2-phenylpropanamide (1a) was
treated with Pd(OAc)2 (10 mol %) in p-xylene at 140 ꢁC for
14 h under an O2 atmosphere, the oxindole 2a was obtained in
15% yield (Table 1, Entry 1).6 The effect of reoxidants as addi-
tives was examined (Entries 2–5) to reveal that the reaction in
the presence of Cu(OAc)2 (1 equiv) gave 2a in 82% yield. Re-
ducing the amount of Cu(OAc)2 to 0.3 equiv and lowering the
reaction temperature to 100 ꢁC decreased the yield of 2a (Entries
6 and 7). The reaction under an O2 atmosphere proceeded faster
than that under an Ar atmosphere (Entry 8). Although 4-nitro-
benzenesulfonyl was also suitable as the protecting group of
O
Pd(0)Ln
N
Pd
Ts
B
2a
Scheme 1. A plausible reaction pathway.
the amide (Entry 9), no reaction took place with 4-methoxyben-
zyl-protected amide 1c (Entry 10).
A proposed reaction pathway for the production of 2a from
1a is depicted in Scheme 1. Initially, the amide moiety of 1a
binds to Pd(OAc)2 forming the palladium amide A with concom-
itant loss of a molecule of acetic acid. Then, cyclopalladation of
A occurs to produce the six-membered-ring palladacycle B to-
gether with another molecule of acetic acid.7 Finally, reductive
elimination affords 2a and a palladium(0) species, which is re-
oxidized to Pd(OAc)2 in the presence of Cu(OAc)2 under an
O2 atmosphere.
Under optimized reaction conditions, a variety of N-tosyl-
phenylacetamide derivatives reacted to afford the corresponding
oxindoles in yields ranging from 30% to 97% (Table 2).8 How-
ever, nonsubstituted substrates on the methylene carbon such as
N-tosylphenylacetamide failed to participate in the cyclization,
presumably due to the gem-dialkyl effect.9 The reaction of 1g
and 1h bearing a substituent at the para position gave the desired
oxindoles in good yields (Entries 4 and 5). Whereas an electron-
withdrawing chloro group was suitable as the meta substituent
(Entry 6), an electron-donating methoxy group retarded the
process (Entry 7). Notably, the C–H bond activation occurred
exclusively at the less hindered 6-position of 1i and 1j. A similar
electronic and steric effect was observed in the carbazole synthe-
sis reported by Buchwald et al.3
Table 1. Optimization of reaction conditionsa
Me
Me
Me Me
10 mol% Pd(OAc)2
reoxidant
H
N
R1
O
5Å molecular sieves
p-xylene, 14 h
N
O
R1
1
2
Entry
1
R1
Reoxidant (equiv) Gas T/ꢁC Yield/%b
1
2
3
4
5
6
7
8
9
10
1a Ts
1a Ts
1a Ts
1a Ts
1a Ts
1a Ts
1a Ts
1a Ts
1b Ns
none
O2
O2
O2
O2
O2
O2
O2
Ar
O2
O2
140
140
140
140
140
140
100
140
140
140
15
<5
<5
81
82
63
35
47
84
0
The removal of the N-tosyl group in the products was readily
achieved on treatment with magnesium in methanol under ultra-
sonic radiation (eq 1).10
PhI(OAc)2 (1)
Benzoquinone (1)
Ag2CO3 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (0.3)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Me
Me
Me
Me
5 equiv Mg
O
O
ð1Þ
MeOH, 2 h
ultrasound wave
N
N
Ts
2a
H
98%
1c PMB Cu(OAc)2 (1)
3a
aReactions conducted on a 0.2 mmol scale. bIsolated yield. Ns = 4-ni-
trobenzenesulfonyl.
In summary, we have demonstrated that the palladium-cata-
lyzed C–H bond amidation of N-tosylphenylacetamide deriva-
Copyright ꢀ 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.4 (2009)
329
Table 2. Synthesis of 3,3-disubstituted oxindoles 2a
Sakamoto, K. Hiroya, Org. Lett. 2007, 9, 2931. b) B.-J. Li,
S.-L. Tian, Z. Fang, Z.-J. Shi, Angew. Chem., Int. Ed.
2008, 47, 1115. c) G. Brasche, S. L. Buchwald, Angew.
Chem., Int. Ed. 2008, 47, 1932. d) J.-J. Li, T.-S. Mei, J.-Q.
Yu, Angew. Chem., Int. Ed. 2008, 47, 6452. e) J. A.
Jordan-Hore, C. C. C. Johansson, M. Gulias, E. M. Beck,
M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 16184. C–O bond
formation: f) S. Ueda, H. Nagasawa, Angew. Chem., Int. Ed.
2008, 47, 6411. C–S bond formation: g) K. Inamoto, Y. Arai,
K. Hiroya, T. Doi, Chem. Commun. 2008, 5529. h) K.
Inamoto, C. Hasegawa, K. Hiroya, T. Doi, Org. Lett. 2008,
10, 5147.
During the preparation of this manuscript, a C–H bond ami-
dation reaction of N-methoxyphenylacetamide derivatives in
the presence of Pd(OAc)2/CuCl2/AgOAc was disclosed by
Yu: M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130,
14058. Unlike the Yu case, no silver salt was required as a
reoxidant in the present reaction.
Entry
Substrate
Product
Yield/%b
H
N
Ts
O
O
N
Ts
1
2
1d
2d
84
39
H
N
Ts
O
O
N
Ts
5
1e
2e
Ph
Ph Me
Me
H
N
Ts
O
O
N
Ts
3
1f
2f
97
6
7
No reaction took place with substrate 1a under the Yu con-
ditions reported in reference 5.
Me
Me Me
Me
H
N
Both the proton-abstraction mechanism and the SEAr mech-
anism are conceivable for the C–H activation step. In refer-
ence 3b, other cyclization mechanisms via a Heck-type proc-
ess and a Wacker-type process onto the arene ring were pro-
posed by Buchwald and co-workers.
General procedure: To an oven-dried flask was added an-
hydrous Cu(OAc)2 (36.3 mg, 0.2 mmol, 1 equiv), powdered
˚
molecular sieves (80 mg, activated 5 A), Pd(OAc)2 (4.5 mg,
20 mmol, 10 mol %), and N-tosylphenylacetamide derivative
1 (0.2 mmol, 1 equiv). The flask was evacuated and filled
with O2. Freshly-distilled p-xylene (2 mL) was added via
syringe. The reaction mixture was stirred at 140 ꢁC for
14 h, and then quenched with addition of saturated aqueous
NH4Cl solution (30 mL). The resulting solution was extract-
ed with ethyl acetate (3 ꢂ 15 mL). The combined extracts
were washed with brine, dried over MgSO4, and filtered
through Florisil. The solvent was removed under reduced
pressure. The residue was purified by preparative thin-layer
chromatography (hexane/ethyl acetate = 3/1 or CHCl3
only) to give the corresponding oxindole 2.
Ts
O
O
R2
N
R2
Ts
4
5
R2 = Cl
1g
2g
2h
65
61
R2 = OMe 1h
8
Me
Me Me
H
Me
R2
R2
N
Ts
O
O
N
Ts
6
7
R2 = Cl
R2 = OMe 1j
1i
2i
2j
63
30
aConditions: 1 (0.2 mmol), Pd(OAc)2 (20 mmol, 10 mol %), Cu(OAc)2
˚
(0.2 mmol, 1 equiv), 5 A MS (80 mg), p-xylene (2 mL), 14 h under O2.
bIsolated yield.
tives provides a new synthetic route to 3,3-disubstituted oxin-
doles,11 which are important structural elements of indole alka-
loids and pharmacologically active compounds.12
9
a) M. E. Jung, J. Gervay, J. Am. Chem. Soc. 1991, 113, 224.
b) J. B. Sperry, D. L. Wright, J. Am. Chem. Soc. 2005, 127,
8034. c) S. M. Bachrach, J. Org. Chem. 2008, 73, 2466.
This work was partly supported by Grant-in-Aid for Scien-
tific Research (A) No. 19205013 from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
10 D. A. Alonso, P. G. Andersson, J. Org. Chem. 1998, 63,
9455.
11 For recent reports on the synthesis of 3,3-disubstituted oxin-
doles, see: a) C. V. Galliford, J. S. Martenson, C. Stern, K. A.
Scheidt, Chem. Commun. 2007, 631. b) D. B. England, G.
Merey, A. Padwa, Org. Lett. 2007, 9, 3805. c) J. Huang, E.
Bunel, M. M. Faul, Org. Lett. 2007, 9, 4343. d) K. G. Liu,
A. J. Robichaud, Tetrahedron Lett. 2007, 48, 461. e) Y.-X.
Jia, J. M. Hillgren, E. L. Watson, S. P. Marsden, E. P.
References and Notes
Reviews: a) D. M. D’Souza, T. J. J. Muller, Chem. Soc. Rev.
1
¨
2007, 36, 1095. b) M. Alvarez-Corral, M. Mun˜oz-Dorado, I.
´
´
´
Rodrıguez-Garcıa, Chem. Rev. 2008, 108, 3174. c) N. T.
Patil, Y. Yamamoto, Chem. Rev. 2008, 108, 3395.
Reviews: a) A. R. Dick, M. S. Sanford, Tetrahedron 2006,
62, 2439. b) H. M. L. Davies, J. R. Manning, Nature 2008,
451, 417.
a) W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem.
Soc. 2005, 127, 14560. b) W. C. P. Tsang, R. H. Munday, G.
Brasche, N. Zheng, S. L. Buchwald, J. Org. Chem. 2008, 73,
7603.
2
3
Kundig, Chem. Commun. 2008, 4040. f) Y. Yasui, H.
¨
Kamisaki, Y. Takemoto, Org. Lett. 2008, 10, 3303. g) R. A.
Altman, A. M. Hyde, X. Huang, S. L. Buchwald, J. Am.
Chem. Soc. 2008, 130, 9613.
12 Reviews: a) C. Marti, E. M. Carreira, Eur. J. Org. Chem.
2003, 2209. b) C. V. Galliford, K. A. Scheidt, Angew. Chem.,
Int. Ed. 2007, 46, 8748.
4
C–N bond formation: a) K. Inamoto, T. Saito, M. Katsuno, T.
Published on the web (Advance View) March 7, 2009; doi:10.1246/cl.2009.328