Solid-phase synthesis of indol-2-ones by microwave-assisted radical cyclization

Article abstract of DOI:10.1055/s-2004-820052

Solid-phase synthesis of indol-2-ones (2-oxindoles) by means of aryl radical cyclization of resin-bound N-(2-bromophenyl)acrylamides using Bu ₃SnH is described. Among various solvents tested, DMF was found to be the best choice for the radical cyclization inducing a reagent concentration effect of the polymer support. The reaction proceeded smoothly under microwave irradiation to give the desired indol-2-ones within a very short reaction time in comparison to conventional thermal heating. In this reaction, various indol-2-ones were synthesized by using commercially available 2-bromoanilines and acryloyl chloride derivatives.

Full text of DOI:10.1055/s-2004-820052

LETTER
1049
Solid-Phase Synthesis of Indol-2-ones by Microwave-Assisted Radical
Cyclization
Solid-Phase
Synthiesis of
I
ndol-2-on
a
es by Mic
r
s
owave-A
s
h
sisted Radic
i
al CyclizationAkamatsu, Koichi Fukase,* Shoichi Kusumoto
Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043, Japan
Fax +81(6)68505419; E-mail: koichi@chem.sci.osaka-u.ac.jp
Received 17 January 2004
We first investigated the conditions for aryl radical cy-
clization on solid support by using resin-bound N-(2-bro-
mophenyl)-3-phenylacrylamide 7Aa, where Rink amide
resin [copoly(styrene-1% DVB)] was used as a support.
Abstract: Solid-phase synthesis of indol-2-ones (2-oxindoles) by
means of aryl radical cyclization of resin-bound N-(2-bromo-
phenyl)acrylamides using Bu3SnH is described. Among various
solvents tested, DMF was found to be the best choice for the radical
cyclization inducing a reagent concentration effect of the polymer The aryl radical cyclization reaction of resin-bound 7Aa
support. The reaction proceeded smoothly under microwave irradi-
by using Bu3SnH and AIBN did not proceed at all under
ation to give the desired indol-2-ones within a very short reaction
conventional reaction conditions (reflux in toluene, THF,
time in comparison to conventional thermal heating. In this reac-
or dioxane for 2 d). We then searched for reaction condi-
tion, various indol-2-ones were synthesized by using commercially
tions suitable for solid-phase radical reaction using
available 2-bromoanilines and acryloyl chloride derivatives.
Bu3SnH and AIBN, and found that the aryl radical cy-
Key words: radical reactions, microwave, indol-2-one, combinato-
clization proceeded in DMF (130 °C, 23 h). The desired
rial chemistry, solid-phase synthesis
indol-2-one 8Aa was obtained by cleavage from the resin
by TFA in ca. 70% yield with 30% unreacted olefin as
judged by the 1H NMR spectrum of crude 8Aa. This was
Indol-2-one (2-oxindole) has been known as an important
a rather surprising result, since the corresponding aryl
pharmacophore of various drugs and their candidates such
radical cyclization in DMF solution did not proceed at all
as anti-rheumatism,1 growth hormone secretagogue,2
(data not shown). In fact, DMF has not been used as a sol-
growth factor receptor inhibitor for antitumor,3 and neuro-
vent for radical reactions using Bu3SnH and AIBN, since
protective.4 The same heterocycle is also known as a core
the solubility of Bu3SnH in DMF was low. Bu3SnH is
structure of many alkaloids.5 Various methods for the syn-
expected, however, to be concentrated on hydrophobic
thesis of indol-2-ones have been reported. In many cases,
polystyrene support in polar DMF. At the beginning of the
the heterocyclic structure was constructed by Heck
reaction, Bu3SnH was suspended in DMF. After comple-
reaction6 and aryl radical cyclization of the corresponding
tion of the reaction, most of the Bu3SnH and the resulting
Bu3SnBr were adsorbed on the resin. Such a reagent con-
o-haloanilides.7 However, synthesis of indol-2-one librar-
ies using a combinatorial approach has not been reported
centration effect probably promoted the radical cycliza-
so far.
tion on the solid-support. Tin reagents were then readily
In the present study, we report the synthesis of an indol-2-
one library by means of aryl radical cyclization reactions
on solid-support. To our knowledge, the solid-phase
synthesis of indol-2-ones via the aryl radical cyclization
has never been described, though the radical cyclization
reactions have been frequently used for the synthesis of
carbocyclic and heterocyclic rings.8 In fact, aryl radical
cyclizations have rarely been applied to solid-phase syn-
thesis of nitrogen heterocycles. In general, the aryl radical
cyclization requires long reaction times under refluxing in
toluene or benzene. Since the reaction rates on solid-sup-
port are generally lower than those in solutions, the aryl
radical cyclization on solid support may not proceed well
under conventional reaction conditions. As an exceptional
case, Lown et al. reported solid-phase aryl radical cycliza-
tion onto a vinyl chloride by using tri-n-butyltin hydride
(Bu3SnH) and 2,2¢-azobisisobutyronitrile (AIBN) to af-
ford a chloromethyl indole derivative.9
washed out of the resin by using CH2Cl2 and MeOH.
Recently, microwave-assisted synthesis has attracted
wide attention, since it accelerates the reaction rate, in-
creases the yield, and sometimes offers superior selectiv-
ity over thermally driven reactions. In particular,
microwave irradiation enhances the reaction rates of Pd-
catalyzed C–C coupling such as the Stille, Suzuki, Heck,
and Sonogashira reactions. We expected microwave irra-
diation would also promote radical reactions using
Bu3SnH, since metal reagents and catalysts might be good
absorbers of microwave.10
In fact, Curran et al. reported that the radical cyclization
reaction of aryl halide in solution was efficiently promot-
ed by microwave irradiation to give the indole derivative
with very short reaction time (5 min) in good yield
(93%).10a In the present study, the radical cyclization of
polymer-bound N-(2-bromophenyl)-3-phenylacrylamide
7Aa proceeded smoothly under microwave irradiation (50
W, 60 min) by using DMF as a solvent to afford the de-
sired indol-2-one 8Aa in good yield with high purity
(Scheme 1; Table 1, entry 1).11 By contrast, the aryl
SYNLETT 2004, No. 6, pp 1049–1053
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820052; Art ID: U01704ST
© Georg Thieme Verlag Stuttgart · New York

1050
H. Akamatsu et al.
LETTER
R2
COCl MeO
COOH
Me
COOH
R4
R4
NH2
Br
R3
Cl
R3
+
c
HO
A
D
B
E
H
C
R1
O
O
3
4
5
COOH
COOH
COOH
O
O
d,e
Me
MeO
F
O
R4
COOH
HN
Me
R2
COCl
COCl
Br R3
Me
G
I
6
R1
COCl
Me
Me
COCl
O
J
K
a,b
f
NHFmoc
Figure 1 Acrylic acid and cinnamic acid derivatives 3 and 4
Cl
NH
1
2
O
O
O
NH2
Br
NH2
Br
NH2
Br
R2
NH2
R4
g,h
N
N
NH
7Xx
X = A–K
x = a–e
R2
Me
F
O
R4
a
c
b
e
Br R3
R1
8Xx
Me
NH2
Br
X = A–K
x = a–e
R3
NH2
R1
F3CO
Me
Br
Scheme 1 Reagents and conditions: (a) 20% piperidine–DMF; (b)
4-(chloromethyl)benzoyl chloride, i-Pr2NEt, CH2Cl2; (c) (COCl)2,
DMF, CH2Cl2; (d) PS-i-Pr2NEt, CH2Cl2; (e) PS-Trisamine; (f) 6,
NaH, DMF; (g) Bu3SnH (10 equiv), AIBN (1 equiv), DMF, MW (50
W, 45 min); (h) 10% TFA–CH2Cl2
d
Figure 2 2-Bromoanilines 5
were prepared from 2-bromoanilines 5 and acryloyl chlo-
rides (or cinnamoyl chlorides) 4 by using PS-i-Pr2NEt
(ARGONAUT TECHNOLOGIES, 3.83 mmol/g) as a
base. Acid chlorides were prepared from acrylic acids (or
cinnamic acids) 3 and oxalyl chloride if acyl chlorides
were not commercially available. After the reaction with
5, the excess acyl chloride was quenched by addition of
PS-Trisamine (ARGONAUT TECHNOLOGIES, 3.58
mmol/g). The reaction mixture was filtered and the filtrate
was concentrated to give the crude 6. Although the crude
acrylamides 6 contained 5 and some unidentified by-prod-
ucts, the latter contaminants were readily removed at the
subsequent step after the introduction of 6 to the resin.
Only the desired 6 reacted with the resin-bound benzyl
chloride 2 to give the solid-supported acrylamides 7 in a
pure state. The radical cyclization of the acrylamides 7 on
solid support was carried out by using Bu3SnH and AIBN
under microwave irradiation.13,14 The resulting resin was
then treated with 10% TFA.14 The reaction mixture was
passed through an anion-exchange resin (VARIAN
BOND ELUT® Jr-PSA) and the eluate was concentrated
in vacuo to give the desired indol-2-ones.14 The yields and
purities of indol-2-ones 8 are summarized in Table 1. The
purities were determined by HPLC analysis using an
evaporative light-scattering detector. Reduced products,
6-endo products, and the starting material 7 were not or
hardly obtained. Various indol-2-ones were synthesized
from commercially available acrylic acid derivatives
(Figure 1) and 2-bromoanilines (Figure 2). When cin-
namoyl chlorides and 2-bromoanilines were used, indol-
2-ones were obtained in satisfactory yields with high to
radical cyclization in solution using N-(2-bromophenyl)-
N-methyl-3-phenylacrylamide (9) under microwave irra-
diation (toluene, 50 W, 40 min) scarcely proceeded
(Scheme 2). The present solid-phase synthesis of indol-2-
one is, hence, obviously superior to the conventional
solution synthesis.
Me
N
Me
N
O
Bu3SnH, AIBN,
DMF or toluene
O
Br
MW or heat
Ph
Ph
9
10
Scheme 2
We then applied the microwave-assisted aryl radical
cyclization on solid-phase to the synthesis of an indol-2-
one library, where two points of diversity were introduced
using readily available acryloyl chlorides or cinnamic
acids and 2-bromoanilines (Figures 1 and 2). The route
for the solid-phase synthesis of indol-2-one is shown in
Scheme 1. The reaction sequence began with deprotection
of Fmoc-protected Rink amide resin (NOVABIOCHEM,
1% divinylbenzene cross-linked polystyrene resin, 0.46
mmol/g, 100–200 mesh) 1 using a solution of 20% piperi-
dine in DMF. 4-(Chloromethyl)benzoyl chloride was then
coupled onto the resin to give the resin-bound benzyl
chloride 2. The chloride on resin 2 was substituted with N-
(2-bromophenyl)acrylamides 6 in the presence of NaH to
give the resin-bound acrylamides 7.12 The acrylamides 6
Synlett 2004, No. 6, 1049–1053 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of Indol-2-ones by Microwave-Assisted Radical Cyclization
1051
moderate purity (Table 1, entries 1–26). When aliphatic ported on amphiphilic polyethylene glycol-polystyrene
alkenes such as acryloyl chlorides were used (Table 1, graft polymer showed higher catalytic activity in allylic
entries 27–40), the desired indol-2-ones were also ob- substitution,15a–15d Suzuki–Miyaura reaction,15e,f Sono-
tained in satisfactory yields (45–88%) and purity (66– gasira reaction,15g and so on, in aqueous media than in or-
100%).
ganic solvents. On the other hand, Morphy et al. reported
that perfluorous solvents can accelerate a wide range of
reactions by virtue of the reagent concentration effects on
polymer-support in fluorous media.16 The acceleration of
reaction rates by reagent concentration effects hence
proved to be an additional strong advantage of solid-phase
synthesis.
As described, solid-phase synthesis of indol-2-ones was
achieved by virtue of the reagent concentration of Bu3SnH
on polystyrene support under microwave flash heating.
Acceleration of solid-phase reactions using reagent con-
centration effects was first reported by Uozumi et al.15
They found that the palladium-phosphine complexes sup-
Table 1 Yields and Purities of Indol-2-ones
Entry
1
Substrate
7Aa
7Ab
7Ac
7Ad
7Ae
7Ba
7Bb
7Bc
Product
8Aa
8Ab
8Ac
8Ad
8Ae
8Ba
8Bb
8Bc
8Bd
8Be
8Ca
8Cb
8Cc
8Cd
8Da
8Db
8Dc
8Dd
8Ea
8Eb
8Ec
8Ed
8Fa
8Fb
R1
H
R2
H
R3
R4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Yield (%)a Purity (%)b
C6H5
80
93
91
100
55
90
92
77
100
60
66
66
77
72
78
70
70
63
97
99
85
61
73
78
90
100
86
78
78
100
100
90
84
77
70
93
91
81
93
81
91
79
75
74
77
68
86
96
2
Me
F
H
C6H5
3
H
C6H5
4
Me
OCF3
H
Me
H
C6H5
5
C6H5
6
H
3-OMe-C6H4
3-OMe-C6H4
3-OMe-C6H4
3-OMe-C6H4
3-OMe-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
3,4-OCH2O-C6H3
3,4-OCH2O-C6H3
3,4-OCH2O-C6H3
3,4-OCH2O-C6H3
C6H5
7
Me
F
H
8
H
9
7Bd
7Be
Me
OCF3
H
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7Ca
7Cb
7Cc
7Cd
7Da
7Db
7Dc
7Dd
7Ea
7Eb
7Ec
H
Me
F
H
H
Me
H
Me
H
Me
F
H
H
Me
H
Me
H
Me
F
H
H
7Ed
7Fa
Me
H
Me
H
7Fb
Me
H
C6H5
25
26
27
7Fc
7Fd
7Ga
8Fc
8Fd
8Ga
F
H
C6H5
Me
Me
–
57
79
86
98
97
86
Me
H
Me
H
C6H5
(CH2)4
Synlett 2004, No. 6, 1049–1053 © Thieme Stuttgart · New York

1052
H. Akamatsu et al.
LETTER
Table 1 Yields and Purities of Indol-2-ones (continued)
Entry
28
29
30
31
32
33
34
35
36
37
38
39
40
Substrate
7Gb
7Gc
7Ha
7Hb
7Hc
7Ia
Product
8Gb
8Gc
8Ha
8Hb
8Hc
8Ia
R1
Me
F
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
R3
R4
–
Yield (%)a Purity (%)b
(CH2)4
(CH2)4
H
86
71
61
61
54
86
88
86
45
52
47
53
56
89
85
–
H
H
74
Me
F
H
H
93
H
H
70
H
diMe
diMe
diMe
Me
Me
Me
H
H
89
7Ib
8Ib
Me
F
H
75
7Ic
8Ic
H
66
7Ja
8Ja
H
H
69
7Jb
8Jb
Me
F
H
78
7Jc
8Jc
H
79
7Ka
7Kb
8Ka
8Kb
H
Me
Me
100
100
Me
H
a Yield of the crude products.
b Purity was based on the peak area of HPLC of crude products as detected by evaporative light scattering.
Banaigs, B.; Amade, P. J. Nat. Prod. 2000, 63, 981. (c)Liu,
H.-M.; Feng, X.-Z. Phytochemistry 1993, 33, 707.
The present method for a solid-phase synthesis of indol-2-
ones through radical cyclization allows facile introduction
of diversity by use of various acrylic acid derivatives and
2-bromoanilines. Radical reaction on solid-support pro-
ceeded smoothly by using DMF as a solvent under micro-
wave irradiation.
(d) Weniger, B.; Jiang, Y.; Anton, R.; Bastida, J.; Varea, T.;
Quirion, J.-C. Phytochemistry 1993, 32, 1587. (e) Lin, L.-
Z.; Cordell, G. A.; Ni, C.-Z.; Clardy, J. Phytochemistry
1991, 30, 1311. (f) Lin, L.-Z.; Cordell, G. A.; Ni, C.-Z.;
Clardy, J. Phytochemistry 1990, 29, 3013. (g) Cui, C.-B.;
Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651.
(h) Jossang, A.; Jossang, P.; Hadi, H. A.; Sévenet, T.; Bodo,
B. J. Org. Chem. 1991, 56, 6527.
Acknowledgment
(6) (a) Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich,
M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am.
Chem. Soc. 2003, 125, 6261. (b) Grigg, R.; Millington, E.
L.; Thornton-Pett, M. Tetrahedron Lett. 2002, 43, 2605.
(c) Grigg, R.; Major, J. P.; Martin, F. M.; Whittaker, M.
Tetrahedron Lett. 1999, 40, 7709. (d) Ashimori, A.;
Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc.
1998, 120, 6477. (e) Matsuura, T.; Overman, L. E.; Poon, D.
J. J. Am. Chem. Soc. 1998, 120, 6500. (f) Arumugam, V.;
Routledge, A.; Abell, C.; Balasubramanian, S. Tetrahedron
Lett. 1997, 38, 6473. (g) Ashimori, A.; Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58, 6949.
(7) (a) Ganguly, A. K.; Wang, C. H.; David, M.; Bartner, P.;
Chan, T. M. Tetrahedron Lett. 2002, 43, 6865.
The present study was financially supported in part by Special
Coordination Funds and Grant-in-Aid for Creative Scientific Re-
search ‘In vivo Molecular Science for Discovery of New Bio-
functions and Pharmaceutical Drugs’ No. 13NP0401 from the
Ministry of Education, Culture, Sports, Science and Technology.
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Synlett 2004, No. 6, 1049–1053 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of Indol-2-ones by Microwave-Assisted Radical Cyclization
1053
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(11) The reaction temperature rose to 100 ºC within 3 min, to
120 °C within 10 min and to 170 ºC within 20 min, and then
remained constant.
(12) The reaction of 2-bromoaniline 5 with resin-bound benzyl
chloride, benzyl bromide, and trityl chloride did not proceed
at all owing to low reactivity of the amino group of 5.
Introduction of 2-bromoaniline 5 to 4-(formyl-3-methoxy-
phenoxy)butyryl AM resin by reductive alkylation also
failed.
mmol) and AIBN (8 mg, 0.05 mmol), and then sealed with a
Teflon septum. The vial was positioned in the cavity of the
microwave reactor and irradiated with a maximum power of
50 W for 45 min. After cooling, the resin was collected by
filtration and washed with MeOH (5 × 1 mL) and CH2Cl2 (5
× 1 mL). The resin was treated with 10% TFA in CH2Cl2 (1
mL), and the mixture was agitated for 30 min at r.t. The
reaction mixture was passed through VARIAN BOND
ELUT® Jr-PSA and eluted with 5% MeOH in CH2Cl2 (3 mL)
to give desired indol-2-one 8Aa. Compound 8Aa: 1H NMR
(CDCl3) d = 7.64 (d, J = 8.4 Hz, 2 H, ArH), 7.17–7.28 (m, 4
H, ArH), 7.08–7.10 (m, 2 H, ArH), 7.03 (d, J = 7.2 Hz, 1 H,
ArH), 6.97 (dd, J = 7.6, 0.8 Hz, 1 H, ArH), 6.93 (d, J = 8.8
Hz, 2 H, ArH), 6.46 (d, J = 7.6 Hz, 1 H, ArH), 5.08 (d, J =
16.0 Hz, 1 H, NCH2Ar), 4.63 (d, J = 16.0 Hz, 1 H, NCH2Ar),
3.87 (dd, J = 8.0, 4.0 Hz, 1 H, COCHAr), 3.48 (dd, J = 13.6,
4.0 Hz, 1 H, CH2Ar), 3.18 (dd, J = 13.6, 8.0 Hz, 1 H, CH2Ar).
ESI-MS (+ve): m/z = 357.2 [M + H]+.
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(13) Focused microwave irradiations were carried out with a
DiscoverTM Focused Microwave Synthesis (CEM
Corporation).
(14) A vessel for microwave reaction was filled with the resin-
bound N-(2-bromophenyl)-3-phenylacrylamide 7Aa (108
mg, 0.05 mmol), DMF (1 ml), Bu3SnH (0.134 ml, 0.50
(16) Morphy, J. R.; Rankovic, Z.; York, M. Tetrahedron Lett.
2001, 42, 7509.
Synlett 2004, No. 6, 1049–1053 © Thieme Stuttgart · New York