Synthesis of Oxindoles by Bronsted Acid Catalyzed Radical Cascade Addition of Ketones

Article abstract of DOI:10.1055/s-0034-1381052

Oxindoles bearing ketone side chains in the 3-position can be synthesized by Bronsted acid catalysis from N-aryl methacrylamides, ketones, and hydroperoxides. The cyclized products are presumably formed in a radical cascade reaction, initiated by decay of intermediate alkenyl peroxides. In the case of acrylic substrates that do not undergo cyclization, γ-peroxyketones were isolated instead, indicating that the final cyclization step of the cascade does not take place in these cases.

Full text of DOI:10.1055/s-0034-1381052

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1973–1976
letter
1973
E. Boess et al.
Letter
Synlett
Synthesis of Oxindoles by Brønsted Acid Catalyzed Radical Cas-
cade Addition of Ketones
Esther Boess
O
Sofia Karanestora1
Alexandra-Eleni Bosnidou1
Bertrand Schweitzer-Chaput
Max Hasenbeck2
10 examples
28–90%
O
O
X = NR
N
R
Martin Klussmann*
O
t-BuOOH
[p-TsOH]
X
O
t-BuOO
X = NH, O
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mülheim an der Ruhr, Germany
klusi@mpi-muelheim.mpg.de
3 examples
7–45%
Ph
X
O
Received: 15.05.2015
Accepted after revision: 29.06.2015
Published online: 29.07.2015
a)
b)
R
O
+ R
DOI: 10.1055/s-0034-1381052; Art ID: st-2015-d0370-l
N
N
O
Abstract Oxindoles bearing ketone side chains in the 3-position can
be synthesized by Brønsted acid catalysis from N-aryl methacrylamides,
ketones, and hydroperoxides. The cyclized products are presumably
formed in a radical cascade reaction, initiated by decay of intermediate
alkenyl peroxides. In the case of acrylic substrates that do not undergo
cyclization, γ-peroxyketones were isolated instead, indicating that the
final cyclization step of the cascade does not take place in these cases.
2
1
+ R-OOH
[H+]
OR
O
O
O
O
3
+
OR
Scheme 1 Synthesis of oxindoles 1 by radical cascade addition using
N-aryl methacrylamides 2
Key words Brønsted acid catalysis, radicals, cyclization, heterocycles,
peroxides
Oxindoles 1 are synthetically interesting compounds as
they appear in natural products and pharmaceutically ac-
tive compounds or are used as building blocks for their syn-
thesis.3 Recently, the formation of oxindoles by radical cas-
cade reactions with N-aryl methacrylamides 2 has received
some attention.4–6 A variety of radicals formed in different
ways have been found to react with acrylamides 2 to give
substituted oxindole products 1 (Scheme 1, a). The reac-
tions are believed to proceed via a radical cascade reaction,
first by addition of the radicals to the acrylamide C–C dou-
ble bond, followed by intramolecular addition to the arene
ring and subsequent rearomatization.
Our group has recently discovered that ketone radicals
can be generated from the combination of ketones and tert-
butylhydroperoxide or hydrogen peroxide under acid catal-
ysis.7 The reaction is believed to proceed via alkenyl perox-
ides 3 that are formed in situ, which decompose rapidly by
homolytic O–O bond cleavage, forming α-carbonyl and oxyl
radicals (Scheme 1, b).7b This mixture of radicals could be
applied to the addition of ketones to styrenes, forming γ-
peroxyketones,7b or to facilitate oxidative C–H cross-cou-
pling reactions.7a Herein, we show that the acid-catalyzed
formation of ketone radicals can also be applied to cascade
radical reactions forming oxindoles.
We investigated the feasibility of this reaction by react-
ing N-phenyl, N-methyl methacrylamide 2a, and acetone
with tert-butylhydroperoxide (as a solution in decane) and
catalytic amounts of p-toluenesulfonic acid (p-TsOH) in ace-
tonitrile under argon, conditions similar to those that we
had developed for the addition of ketones to styrenes. The
oxindole 1aa was indeed formed in 55% yield (Table 1, entry
1).
Further variation of the solvent (Table 1, entries 2–4)
showed that chloroform gave an improved yield of 66%,
while performing the reaction neat resulted in very poor
yields (see the Supporting Information for additional de-
tails of this optimization study). Alternative acid catalysts
can be used (Table 1, entries 5–7), but p-TsOH remained the
best catalyst amongst those that we studied. In agreement
with our previous results,7 trifluoroacetic acid appears to
be the least active as a catalyst, while sulfonic acids are
most suitable. Without acid, at best traces of the product
could be detected (Table 1, entry 8). Increasing the acid
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1973–1976

1974
E. Boess et al.
Letter
Synlett
Table 1 Investigation of Reaction Conditionsa
R1
R1
R
p-TsOH (20 mol%)
t-BuOOH (3 equiv)
O
O
+
R
catalyst
50 °C, 18–24 h
N
R2
t-BuOOH (in decane)
O
N
R2
O
+
O
solvent
2
4a
1
N
N
O
50 °C, 18–24 h
(1 equiv)
R = CH2C(O)Me
O
2a
(1 equiv)
4a
1aa
(5 equiv)
O
Entry
Catalyst (mol%)
t-BuOOH (equiv) Solvent
Yield (%)b
R1
1ea, 55%
O
O
1
2
p-TsOH (10)
p-TsOH (10)
p-TsOH (10)
p-TsOH (10)
TFA (10)
2
2
2
2
2
2
2
2
2
3
2
2
3
MeCN
EtOAc
CHCl3
–
55
N
N
59
O
O
1aa, R1 = H, 90%
3
66
1ba, R1 = NO2, 70%
1ca, R1 = Cl, 87%
1da, R1 = OMe, 61%
4
18
5
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
acetone
acetone
16
O
O
6
H2SO4 (10)
MsOH (10)
–
50
N
N
Bn
7
53
1fa, 60%
1ga, 58%
8
traces
76
Scheme 2 Synthesis of oxindoles 1 by radical cascade addition of ace-
tone to N-aryl methacrylamides 2
9
p-TsOH (20)
p-TsOH (10)
p-TsOH (10)
p-TsOH (10)
p-TsOH (20)
10
11
12
13
74
48c
80d
90e
Oxindoles with different side chains could be synthe-
sized from other ketones in generally slightly lower yields
compared with the use of acetone (Scheme 3),9 as shown in
examplars using cyclopentanone and tetrahydropyran-4-
one (products 1ab and 1ac), and acetylacetone (1ad). Com-
pounds 1ab and 1ac were obtained as diastereomeric mix-
tures in ratios of approximately 60:40. Cyclohexanone and
methyl acetoacetate also reacted well, but we did not man-
age to purify the products sufficiently. In the case of cyclo-
hexanone, the product could not be separated from residual
2a.
a General conditions: 2a (0.2 mmol), acetone (1.0 mmol), t-BuOOH (0.4
mmol, 5.5 M in decane), catalyst (0.02 mmol), solvent (1.0 mL), degassed
by freeze-pump-thaw, 50 °C, under an atmosphere of argon, 18–24 h.
b Yields determined by 1H NMR analysis using an internal standard.
c 0.2 mmol acetone.
d Not degassed.
e Isolated yield.
loading to 20 mol% (Table 1, entry 9) and the peroxide load-
ing to three equivalents (Table 1, entry 10) further im-
proved the yield. Interestingly, employing equimolar
amounts of acetone still resulted in a relatively good yield of
48% (Table 1, entry 11). Using acetone in solvent amounts
instead of chloroform improved the yields further (Table 1,
entry 12), even if the reaction was performed without de-
gasing the acetone (the presence of oxygen most likely low-
ers the yield by trapping intermediate radicals). Applying
the findings of the reaction in chloroform, that is, perform-
ing the reaction in the absence of oxygen with 20 mol% cat-
alyst loading and three equivalents of t-BuOOH, resulted in
90% isolated yield of 1a (Table 1, entry 13). Thus, for reac-
tions with acetone as the ketone component, the conditions
of Table 1, entry 13 were taken; while the conditions of Ta-
ble 1, entry 9 were chosen for reactions with other ke-
tones.8–10
As has been observed before in nearly all related radical
cascade reactions, certain acrylic substrates do not give the
desired cyclized products.5 Likewise, we also failed to ob-
O
R2
2a
p-TsOH (20 mol%)
t-BuOOH (3 equiv)
N
O
R1
O
O
CHCl3
+
N
50 °C, 18–24 h
R2
4
1
R1
(5 equiv)
O
N
O
O
O
The reaction of other N-aryl acrylamide derivatives 2
with acetone led to the formation of the corresponding ox-
indoles 1 in good yields (Scheme 2).8 Electron-withdrawing
as well as electron-donating substituents on the arene ring
led to similarly good yields (1aa–ea),11,12 as did other alkyl
groups on the nitrogen (1fa,ga).
O
O
O
O
N
N
1ab
49%
1ac
28%
1ad
48%
Scheme 3 Synthesis of oxindoles 1 by radical cascade addition of ke-
tones using N-aryl methacrylamides 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1973–1976

1975
E. Boess et al.
Letter
Synlett
O
+ t-BuOOH
[p-TsOH]
Ot-Bu
t-BuOO
R1
O
O
O
O
O
p-TsOH (20 mol%)
t-BuOOH (3 equiv)
R1
O
5
50 °C
18–24 h
X
O
X
O
t-BuOOH
– t-BuOH
+
Ot-Bu
t-BuOO
O
O
O
O
t-BuOO
t-BuOO
R1
R1
X
t-BuOO
Ph
Ph
Ph
X
O
O
N
H
O
O
O
N
O
5a
37%
5b
45%
5c
X = NR (R = H)
+ R1 = Me, Alk
X = NH, O, R1 = H
7%a
t-BuOO
Scheme 4 Isolation of γ-peroxyketones 5 from reactions with acrylic
O
O
substrates that failed to cyclize. a In CHCl3 as solvent, 10 mol% catalyst.
R1
R1
H
O
t-BuOO
R1
– H
(– e–/H+)
O
O
tain oxindoles from secondary amides, from acrylamides
lacking the 2-methyl group or from phenyl methacrylate.
However, we could isolate γ-peroxyketones 5 in all these
cases (Scheme 4).13
Ph
N
N
X
O
R
R
Scheme 5 Suggested reaction mechanism
These products indicate that radical formation on the
ketone and addition to the acrylic olefin had indeed taken
place, but this was followed by an intermolecular reaction
(forming the peroxides 5), instead of the desired intramo-
lecular attack onto the arene ring. Potentially, this is a gen-
eral explanation for the failure of these substrates in all re-
lated radical cascade reactions. While we could not find
conditions to form the desired cyclized compounds, even
under microwave irradiation at 100 °C, these results at least
indicate a focus for future mechanistic studies. Finding the
reasons behind the failure of intramolecular radical attack
could reveal strategies to overcome this substrate limita-
tion. Moreover, compounds 5 could also be of synthetic val-
ue, as it has been shown before that γ-peroxyketones can be
converted into furans, carbazoles, 1,4-diketones, homoaldol
products, and alkyl ketones in a single step.7b,14
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1381052.
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References and Notes
(1) University of Ioannina, Department of Chemistry, 45110 Ioan-
nina, Greece.
(2) Universität zu Köln, Department of Chemistry, Greinstraße 6,
50939 Köln, Germany.
(3) (a) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F. ACS Catal. 2014,
4, 743. (b) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104.
(c) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821.
(d) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381.
(4) For an overview, see: Chen, J.-R.; Yu, X.-Y.; Xiao, W.-J. Synthesis
2015, 47, 604.
(5) (a) Wei, H.-L.; Piou, T.; Dufour, J.; Neuville, L.; Zhu, J. Org. Lett.
2011, 13, 2244. (b) Wu, T.; Zhang, H.; Liu, G. Tetrahedron 2012,
68, 5229. (c) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-
J.; Liu, Y.; Hu, M.; Xie, P.; Li, J.-H. Angew. Chem. Int. Ed. 2013, 52,
3638. (d) Zhou, M.-B.; Song, R.-J.; Ouyang, X.-H.; Liu, Y.; Wei,
W.-T.; Deng, G.-B.; Li, J.-H. Chem. Sci. 2013, 4, 2690. (e) Kong, W.;
Casimiro, M.; Merino, E. B.; Nevado, C. J. Am. Chem. Soc. 2013,
135, 14480. (f) Matcha, K.; Narayan, R.; Antonchick, A. P. Angew.
Chem. Int. Ed. 2013, 52, 7985. (g) Meng, Y.; Guo, L.-N.; Wang, H.;
Duan, X.-H. Chem. Commun. 2013, 49, 7540. (h) Zhou, S.-L.; Guo,
L.-N.; Wang, H.; Duan, X.-H. Chem. Eur. J. 2013, 19, 12970.
(i) Yuan, Y.; Shen, T.; Wang, K.; Jiao, N. Chem. Asian J. 2013, 8,
2932. (j) Jia, F.; Liu, K.; Xi, H.; Lu, S.; Li, Z. Tetrahedron Lett. 2013,
54, 6337. (k) Wang, H.; Guo, L.-N.; Duan, X.-H. Chem. Commun.
2013, 49, 10370. (l) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett.
2013, 15, 5254. (m) Shen, T.; Yuan, Y.; Jiao, N. Chem. Commun.
2014, 50, 554. (n) Zhang, J.-L.; Liu, Y.; Song, R.-J.; Jiang, G.-F.; Li,
J.-H. Synlett 2014, 25, 1031. (o) Wei, W.; Wen, J.; Yang, D.; Du, J.;
You, J.; Wang, H. Green Chem. 2014, 16, 2988. (p) Tian, Q.; He, P.;
Kuang, C. Synlett 2015, 26, 681. (q) Fuentes, N.; Kong, W.;
Based on previous suggestions for related reactions, the
above observations thus add a further detail to the reaction
mechanism (Scheme 5).
In summary, we have shown that acid-catalyzed radical
formation from ketones and tert-butyl hydroperoxide can
be applied to a radical cascade addition to N-aryl, N-alkyl-
methacrylamides, forming oxindoles bearing ketone side
chains. In the case of acrylic substrates not leading to the
desired cyclized products, γ-peroxyketones were isolated
instead, indicating that the initial radical attack on the ole-
fin is occurring but not the subsequent intramolecular re-
action.
Acknowledgment
Financial support from the DFG (Heisenberg scholarship to M.K., KL
2221/4-1) and the MPI für Kohlenforschung is gratefully acknowl-
edged.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1973–1976

1976
E. Boess et al.
Letter
Synlett
Fernández-Sánchez, L.; Merino, E.; Nevado, C. J. Am. Chem. Soc.
2015, 137, 964. (r) Niu, B.; Xie, P.; Bian, Z.; Zhao, W.; Zhang, M.;
Zhou, Y.; Feng, L.; Pittman, C. U.; Zhou, A. Synlett 2015, 26, 635.
(6) For related radical reactions, see: (a) Teichert, A.; Jantos, K.;
Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477. (b) Murphy, J. A.;
Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7, 3287.
(7) (a) Schweitzer-Chaput, B.; Sud, A.; Pinter, Á.; Dehn, S.; Schulze,
P.; Klussmann, M. Angew. Chem. Int. Ed. 2013, 52, 13228.
(b) Schweitzer-Chaput, B.; Demaerel, J.; Engler, H.; Klussmann,
M. Angew. Chem. Int. Ed. 2014, 53, 8737.
working with peroxides. In particular, neat peroxides should
not be heated or brought into contact with metals or metal
salts. Explosive triacetone triperoxide should not be formed
under the reaction conditions described here, as tert-butyl
hydroperoxide and not hydrogen peroxide is used. In addition,
the reaction conditions described here lead to the consumption
of hydroperoxides (as confirmed for hydrogen peroxide, see ref.
7a).
(11) Characterization Data of Compound 1da
1
Yellow oil. H NMR (500 MHz, DMSO): δ = 6.98 (d, J = 2.5 Hz, 1
(8) General Procedure for Reactions with Acetone
H), 6.93 (d, J = 8.5 Hz, 1 H), 6.83 (dd, J = 2.5, 8.5 Hz, 1 H), 3.73 (s,
3 H), 3.10 (s, 3 H), 2.10–1.85 (m, 4 H), 1.93 (s, 3 H), 1.24 (s, 3 H).
13C NMR (125 MHz, DMSO): δ = 207.4, 178.8, 155.6, 136.4,
134.3, 112.0, 110.3, 108.7, 55.5, 47.1, 37.9, 31.3, 29.7, 26.0, 23.3.
HRMS (ESI+): m/z [M+] calcd for C15H19N1O3Na: 284.125712;
found: 284.125640.
In an oven-dried Schlenk flask, 2a (1.5 mmol, 1 equiv) and t-
BuOOH (5.5 M solution in decane, 4.5 mmol, 3 equiv) were dis-
solved in acetone (7.5 mL). The resulting mixture was freeze-
pump-thaw degassed and allowed to warm to r.t. Then, p-TsOH
(0.30 mmol, 0.2 equiv) was added under a stream of argon, and
the reaction mixture was allowed to react overnight at 50 °C. It
was then diluted with acetone, a small amount of silica was
added and solvent removed. The residue was purified by
column chromatography on silica gel using mixtures of hexanes
and EtOAc to afford the pure products.
(12) Characterization Data of Compound 1ea
Yellow oil. 1H NMR (500 MHz, DMSO): δ = 6.69 (s, 1 H), 6.64 (s, 1
H), 3.10 (s, 3 H), 2.28 (s, 3 H), 2.24 (s, 3 H), 2.15–2.08 (m, 1 H),
1.99–1.87 (m, 2 H), 1.88 (s, 3 H), 1.82–1.74 (m, 1 H), 1.29 (s, 3
H). 13C NMR (125 MHz, DMSO): δ = 207.3, 179.3, 143.4, 137.2,
133.5, 126.3, 125.2, 107.1, 47.4, 38.2, 29.7, 29.6, 26.0, 22.0, 21.1,
17.6. HRMS (ESI+): m/z [M+] calcd for C16H21N1O2Na:
282.146448; found: 282.146440.
(9) General Procedure for Reactions with Other Ketones
In an oven-dried Schlenk flask, 2a (1.5 mmol, 1 equiv), ketone
(7.5 mmol, 5 equiv), and t-BuOOH (5.5 M solution in decane, 4.5
mmol, 3 equiv) were dissolved in dry CHCl3 (7.5 mL). The result-
ing mixture was freeze–pump–thaw degassed and allowed to
warm to r.t. Then, p-TsOH (0.30 mmol, 0.2 equiv) was added
under a stream of argon and after closing the flask, the reaction
mixture was allowed to react overnight at 50 °C. The reaction
mixture was then diluted with CHCl3, a small amount of silica
was added and solvent removed. The resulting powder was
purified by column chromatography on silica gel using mixtures
of hexanes and EtOAc to afford the pure products.
(13) Characterization Data of Compound 5b
Clear oil. 1H NMR (500 MHz, DMSO): δ = 7.48–7.43 (m, 2 H),
7.31–7.27 (m, 1 H), 7.14–7.10 (m, 2 H), 2.60 (app t, J = 7.8 Hz, 2
H), 2.17–2.10 (m, 1 H), 2.14 (s, 3 H), 2.05–1.99 (m, 1 H), 1.47 (s,
3 H), 1.23 (s, 9 H). 13C NMR (125 MHz, DMSO): δ = 207.3, 171.1,
150.5, 129.6, 125.9, 121.5, 82.7, 79.6, 36.7, 29.7, 28.8, 26.2, 19.9.
HRMS (ESI+): m/z [M+] calcd for C17H24O5Na: 331.151594;
found: 331.151520.
(14) (a) Zheng, X.; Lu, S.; Li, Z. Org. Lett. 2013, 15, 5432. (b) Zheng, X.;
Lv, L.; Lu, S.; Wang, W.; Li, Z. Org. Lett. 2014, 16, 5156.
(10) Warning: Although we never experienced any problem in
working with or handling the compounds described in this
work, precautions against explosions should be taken when
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1973–1976