Ag2O-mediated intramolecular oxidative coupling of acetoacetanilides for the synthesis of 3-acetyloxindoles

Article abstract of DOI:10.1055/s-0030-1258584

The intramolecular oxidative Csp-Csp coupling of N-substituted acetoacetanilides was achieved by using Ag₂O as the oxidant. The reaction constitutes a convenient approach toward 3-acetyloxindoles from unfunctionalized acetoacetanilides. Georg T

Full text of DOI:10.1055/s-0030-1258584

LETTER
2607
Ag O-Mediated Intramolecular Oxidative Coupling of Acetoacetanilides for
2
the Synthesis of 3-Acetyloxindoles
I
Z
ntramolecular
O
h
xidative Co
e
upling of
A
n
cetoacetanil
gi des sen Yu, Lijuan Ma, Wei Yu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. of China
Fax +86(931)8915557; E-mail: yuwei@lzu.edu.cn
Received 7 July 2010
8
ic synthesis. Generally, the alkyl radicals have to be gen-
erated by homolytic cleavage of C–X bonds. But when the
alkyl radical center is at the a-position of the carbonyl
compounds, they can be generated directly from carbonyl
compounds by the action of one-electron oxidants. Re-
cently, Kündig et al. reported a novel synthesis of 3-alkyl-
2
3
Abstract: The intramolecular oxidative Csp –Csp coupling of N-
substituted acetoacetanilides was achieved by using Ag O as the ox-
idant. The reaction constitutes a convenient approach toward 3-
acetyloxindoles from unfunctionalized acetoacetanilides.
2
Key words: 3-acetyloxindoles, acetoacetanilides, Ag O, oxidative
2
coupling
3
-aryl-oxindoles from N-methyl-N-phenyl-2-phenylpro-
panamide and its derivatives via the intramolecular oxida-
2
3
9
tive Csp –Csp coupling. The reaction proved to be a
free-radical process, which involved the addition of a-car-
bonylalkyl radicals to the phenyl ring. The a-carbonyl-
3
-Acyloxindoles are of synthetic interest due to their ex-
istence in many pharmaceutically interesting compounds
as well as their usefulness in the synthesis of other hetero-
cyclic compounds. Several methods are available for the
synthesis of 3-acyloxindoles, two of which employ the
transitional-metal-catalyzed intramolecular C–C coupling
1
alkyl radicals were generated by the CuCl -mediated
2
oxidation of the corresponding enolate precursors. Inde-
pendently Taylor et al. reported a very similar process for
the synthesis of 3,3-disubstituted-oxindoles and 3-alkyl
1
,2
of the b-keto anilide derivatives. One is the rhodium-
10
2
substituted-oxindoles. This synthetic design was similar
to that of Nair et al. who tried to prepare 3-acetyloxindole
catalyzed aromatic C–H insertion of a-diazo anilides. A
relevant but different strategy is to transform b-keto 2-io-
11
directly from acetoacetanilide. In the work of Nair et al.,
the one-electron oxidant cerium(IV) ammonium nitrate
doanilides to 3-acyloxindoles via the CuI/L-proline-cata-
1
lyzed a-arylation.
(
CAN) was employed to generate the a-keto radical.
Recently, the synthetic strategy of forming C–C bond via
the coupling of unfunctionalized carbon atoms (oxidative
coupling) has gained prominence due to its high atom
economy. Efforts have been made to achieve the cou-
pling of Csp –H carbon with aryl Csp –H carbon. The a-
arylation of carbonyl compounds is of great synthetic im-
However, the desired reaction failed to take place, and in-
stead, the oxamate product was obtained when the reac-
tion was performed in the presence of O (Scheme 2).
2
3
With these aforementioned works in mind, we were inter-
ested to see whether 3-acyloxindoles could be synthesized
from b-keto anilides via the free-radical-mediated in-
3
2
4
5
portance, and it is highly desirable to develop means to
realize the process via the direct Csp –Csp coupling
3
2
tramolecular Csp –Csp coupling. Herein we wish to re-
port our preliminary results.
3
2
6
,7
(
Scheme 1). One strategy to address this issue is to em-
The study was initiated by employing copper salts to pro-
mote the oxidation of N-methyl acetoacetanilide. Howev-
er, the expected reaction did not took place when CuCl2,
Cu(OAc) , and Cu(OTf) were used as the oxidant. As
ploy the alkyl-free radical addition to arenes or heteroar-
enes. The free-radical addition to aromatic rings has been
known for a long time and has found application in organ-
2
2
copper salts failed to effect the reaction, we turned to oth-
O
O
12
13
er oxidants. CAN and Mn(OAc)3 are the most com-
monly used one-electron oxidants to generate free radicals
from 1,3-dicarbonyl compounds. As mentioned above,
the reaction of CAN and acetoacetanilide in MeOH was
H
[O]
Ar
+
Ar
H
R3
R3
R2 R1
R2 R1
Scheme 1
OH
O
CAN
CAN, O2
O
O
MeOH, r.t.
N
N
O
N
CO2Me
H
H
H
Scheme 2
SYNLETT 2010, No. 17, pp 2607–2610
x
x
.x
x
.2
0
1
0
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258584; Art ID: W10610ST
Georg Thieme Verlag Stuttgart · New York
©

2
608
Z. Yu et al.
LETTER
investigated before, but no oxindole product was Table 1 Screening of the Reaction Conditionsa
1
1
obtained (Scheme 2). We chose N-methyl acetoacetanil-
ide as the substrate and reinvestigated the effect of CAN.
However, no reaction was found to take place in MeOH.
When MeCN was used as solvent, only a small amount of
high polar products was formed, with the majority of start-
ing material remained. Using Mn(OAc) ·2H O as oxidant
O
O
OH
O
oxidant, base
DMF, 50 °C
N
N
Me
Me
3
2
also failed to deliver the desired results. After some more Entry
exploration of the reaction conditions, we found that when
Oxidant
Ag
Solvent
DMF
Base
CO
Yield (%)b
1
4
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
2
O
K
2
3
57
Ag O was used as oxidant in combination with base, the
2
desired 3-acetyloxindole could be generated. The reaction
conditions were optimized by varying the base, solvent,
and reaction temperature (Table 1). The best result was
obtained when the reaction was performed in DMF at 50
–c
Ag O
DMF
Na CO
2
2
3
Ag O
DMF
Cs CO
3
63
2
2
Ag O
DMF
K PO ·7H O 35
3 4 2
2
°
C in the presence of 2.0 equivalents of Cs CO , with 1.1
2 3
Ag O
DMF
CsOAc
NaOt-Bu
KOt-Bu
DBU
–c
equivalents of Ag O as oxidant, and N-methyl 3-acetylox-
2
2
indole was obtained in 63% isolated yield (Table 1, entry
Ag O
DMF
38
25
–c
2
3
). The reaction could take place at room temperature too,
but it took several days for the reaction to complete. The
effects of several silver salts were also examined. 3-
Acetyloxindole was generated when Ag CO was used,
Ag
2
O
DMF
Ag O
DMF
2
2
3
but the yield was low. AgBF and AgNO did not effect
Ag
2
O
DMF
none
–c
4
3
the reaction at all. These results are also summarized in
Table 1.
1
1
1
1
1
1
1
Ag O
MeCN
DCE
Cs CO
39
2
2
3
3
3
3
3
3
3
3
3
Ag O
Cs CO
n.r.d
2
2
The optimized reaction conditions were then applied to a
variety of substituted acetoacetanilides 1, and the results
are outlined in Table 2. After reaction, the starting materi-
als were consumed completely, and 3-acetyloxindoles 2
were generated in moderate to good yields for the chosen
substrates except 1r, which was decomposed under the re-
actions conditions (entry 18, Table 2). Apart from com-
pounds 2, no other products could be obtained. The lost
mass balance was apparently due to the decomposition of
–c
Ag O
toluene
1,4-dioxane
DMSO
DMA
DMF
Cs CO
2
2
Ag O
Cs CO
–c
2
2
Ag O
Cs CO
54
57
27
n.r.d
2
2
Ag O
Cs CO
2
2
Ag CO
Cs CO
2
3
2
1
and/or the reaction intermediates. The yields for the
17
AgBF
4
DMF
Cs
2
CO
ortho-substituted substrates were generally lower than
those for their para- and meta-substituted counterparts,
probably due to the steric reasons. Compound 1j was con-
verted to two regional isomers, with the less sterically hin-
dered 2j-1 being the major product (entry 10). For
substrates containing Cl and Br at the phenyl ring, dehalo-
genation product 2a was formed, and reactions were not
complete in 7 hours. Longer reaction time would lead to
the deceasing of the yields. Similar dehalogenation was
1
8
AgNO3
DMF
Cs CO
complex
mixture
2
a
Reaction conditions: 50 °C, argon atmosphere, Ag O (1.1 equiv),
base (2.0 equiv), 7 h.
Isolated yield.
Starting material decomposed.
2
b
c
d
No reaction took place.
substrate sensitiveness of the reaction reflected the diffi-
culty in realizing the direct intramolecular Csp –Csp
9
also observed by Kündig et al. Considering the free-rad-
2
3
ical nature of the process, the loss of Cl and Br was not
surprising. Raising the reaction temperature to 80 °C
could make the reaction complete in 4 hours for these sub-
strates, and the dehalogenation was mitigated. For exam-
ple, only trace amount of 2a was detected for 1d and 1o if
the reaction was carried out at 80 °C (entries 4 and 15). In
the case of 1s, however, the reaction afforded 2a as the
single isolated product irrespective of the reaction temper-
ature (entry 19).
coupling of anilides. Beside the sensitiveness to substrate
variations, the properties of the oxidant played a critical
role. As aforementioned, while several oxidants are capa-
ble of generating a-keto radicals, only Ag O was effective
2
for the transformations of acetoacetanilides to 3-acetylox-
indoles. In light of the synthetic usefulness of 3-acyloxin-
doles, it is much desirable to find more effective oxidation
conditions which would have a broader substrate scope.
In summary, the synthesis of 3-acetyloxindoles from ace-
toacetanilides via the direct intramolecular coupling of the
This protocol could be extended to compounds 3, which
were transformed to the corresponding 3,3-disusbtituted
oxindoles 4 in reasonable yields (Table 3). On the other
hand, when substrate 5 was subjected to the reaction con-
ditions, the reaction failed to take place (Scheme 3). The
2
3
Csp –H and Csp –H centers was realized by using Ag O
2
as the oxidant. This method is advantageous in that there
is no need for the prefunctionalization such as prehaloge-
nation at the substrates. Further work is being done in our
Synlett 2010, No. 17, 2607–2610 © Thieme Stuttgart · New York

LETTER
Intramolecular Oxidative Coupling of Acetoacetanilides
2609
Table 2 Ag O-Mediated Oxidative Coupling of Acetoacetanilides
1
Table 3 Synthesis of Oxindoles 416
2
a
O
O
O
O
OH
O
Ag2O, Cs2CO3
R
R
O
R1
Ag2O, Cs2CO3
DMF
DMF, 50 °C
R1
N
N
O
N
N
Me
Me
R2
R2
4
3
1
2
Entry
3
R
4
Yield (%)
Entry Substrate R1
R2
Reaction time Product, yield
c
1
2
3
3a
3b
3c
3d
H
4a
4b
4c
4d
51
70
74
46
(
h)
(%)
4-Me
4-EtO
2-Me
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
Me
Me
Me
Me
Me
Me
7
7
2a 63
4-Me
4-EtO
4-Cl
4-Br
2-Me
2b 65
4
7
2c 57
a
4b
The reaction temperature was 80 °C for 3a.
2d 53
4b
7
2e 39, 2a 27
2f 50
O
Ag2O, Cs2CO3
DMF, 80 °C
no reaction
1g
1h
1i
2-MeO Me
7
2g 35
N
O
4b
4b
7
2h 12, 2a 15
2i 14, 2a 11
2j-1 48, 2j-2 26d
2k 71
Me
2-Cl
2-Br
3-Me
H
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
5
Scheme 3
1
1
1
1
1
1
1
1
1
1
1j
1k
1l
7
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
4-Me
4-EtO
4-F
7
2l 63
1m
1n
1o
1p
1q
1r
1s
7
2m 66
2n 48
7
Acknowledgment
4-Cl
2-Me
4b
7
2o 33
The authors thank the National Natural Science Foundation of Chi-
na (No. 20772053) for financial support.
2p 43
2-MeO Bn
4b
4b
4b
2q 33
References and Notes
2-Br
3-Cl
Bn
Bn
dec.
(1) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115; and references cited
therein.
2a 63
(
2) Etkin, N.; Babu, S. D.; Fooks, C. J.; Durst, T. J. Org. Chem.
990, 55, 1093.
1
a
The reaction was carried out on 0.5 mmol scale. The reaction tem-
(3) For reviews, see: (a) Beccalli, E. M.; Broggini, G.;
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1
5
perature was 50 °C unless otherwise specified.
b
The reaction temperature was 80 °C.
Isolated yield.
c
(
4) (a) For reviews, see: Li, C.-J. Acc. Chem. Res. 2009, 42,
OH
O
335. (b) For a recent example, see: Li, Y.-Z.; Li, B.-J.; Lu,
X.-Y.; Lin, S.; Shi, Z.-J. Angew. Chem. Int. Ed. 2009, 48,
3817.
O
O
N
Me
N
Me
(5) For a recent review, see: Johansson, C. C. C.; Colacot, T. J.
Angew. Chem. Int. Ed. 2010, 49, 676.
6) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126,
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2j–1
2j–2
(
7
Chem. Int. Ed. 2005, 44, 609. (c) Richter, J. M.; Whitefield,
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applied to diversely functionalized substrates in high effi-
ciency.
(
7) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131,
17387.
Synlett 2010, No. 17, 2607–2610 © Thieme Stuttgart · New York

2
610
Z. Yu et al.
LETTER
(
8) For reviews, see: (a) Bowman, W. R.; Storey, J. M. D.
Chem. Soc. Rev. 2007, 36, 1803. (b) Rowlands, G. J.
Tetrahedron 2009, 65, 8603. (c) Rowlands, G. J.
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Celite and washed with EtOAc. The filtrate was added into
sat. NH Cl solution and extracted with EtOAc for three
4
times. The combined organic phase was washed with brine
and dried with anhyd MgSO . The solvent was then removed
4
(
9) Jia, Y. X.; Kündig, E. P. Angew. Chem. Int. Ed. 2009, 48,
under reduced pressure, and the residual was subjected to
silica gel chromatography to give the product 2.
(16) General Procedure for the Reactions of 3
1
636.
10) (a) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249.
b) Pugh, D. S.; Klein, J. E. M. N.; Perry, A.; Taylor, R. J. K.
(
(
To a solution of 3 (0.5 mmol) in DMF (10 mL) was added
Cs CO (1.0 mmol) and Ag O (0.55 mmol). The mixture was
Synlett 2010, 934.
2
3
2
(
(
(
(
(
11) Nair, V.; Sheeba, V. J. Org. Chem. 1999, 64, 6898.
12) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
13) Snider, B. B. Chem. Rev. 1996, 96, 339.
stirred under argon at 50 °C for 7 h (for 3a, the reaction
temperature was 80 °C). After the reaction was complete, the
mixture was filtered though Celite and washed with EtOAc.
14) Lee, Y. R.; Kim, B. S. Tetrahedron Lett. 1997, 38, 2095.
15) General Procedure for the Reactions of 1
To a solution of 1 (0.5 mmol) in DMF (5 mL) was added
Cs CO (1.0 mmol) and Ag O (0.55 mmol). The mixture was
The filtrate was added into sat. NH Cl solution and extracted
4
with EtOAc for three times. The combined organic phase
was washed with brine and dried with anhyd MgSO . The
4
solvent was then removed under reduced pressure, and the
residual was subjected to silica gel chromatography to give
the product 4.
2
3
2
stirred under argon at 50 °C for 7 h (or at 80 °C for 4 h). After
the reaction was complete, the mixture was filtered though
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