A tandem radical cyclization approach to 3-(2-oxopyrrolidin-3-yl)indolin-2-ones, potential intermediates toward complex indole-heterocycles

Article abstract of DOI:10.1016/j.tetlet.2007.11.194

A series of substituted 3-(2-oxopyrrolidin-3-yl)indolin-2-one derivatives have been synthesized by tris(trimethylsilyl)silane (TTMSS) induced tandem radical cyclization as key step.

Full text of DOI:10.1016/j.tetlet.2007.11.194

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1066–1070
A tandem radical cyclization approach to 3-(2-oxopyrrolidin-
3-yl)indolin-2-ones, potential intermediates toward
complex indole-heterocycles
*
´
´
Marc Pudlo, Stephane Gerard, Catherine Mirand, Janos Sapi
`
´
FRE CNRS 2715 ‘Isolement, Structure, Transformations et Synthese de Substances Naturelles’, Faculte de Pharmacie,
IFR 53 Biomole´cules, Universite´ de Reims-Champagne-Ardenne, 51 Rue de Cognacq-Jay, F-51096 Reims, France
Received 23 September 2007; revised 26 November 2007; accepted 30 November 2007
Available online 4 December 2007
Abstract
A series of substituted 3-(2-oxopyrrolidin-3-yl)indolin-2-one derivatives have been synthesized by tris(trimethylsilyl)silane (TTMSS)
induced tandem radical cyclization as key step.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Tandem radical cyclization; TTMSS; Oxindole; 3-(2-Oxopyrrolidin-3-yl)indolin-2-one
Indole alkaloids and dihydroindole containing natural
products have been attractive molecular targets due to their
varying biological activities.1 The 1,3-dihydroindol-2-one
(oxindole) ring, especially the 3,3-spiro-oxindole core is a
key structural unit of numerous natural products (horsfi-
line, spirotryprostatins, alstonisine, gelsemine, welwistatin,
rhynchophylline, etc.),2 while many non-natural 3-aryl-
methylidene oxindoles have been designed as potential
kinase inhibitors.3 Stereocontrolled construction of such
hetero-polycyclic ring systems bearing contiguous quater-
nary carbon atoms remains a real challenge in organic
chemistry. Among the numerous powerful methods
tandem radical reaction involving transannular cyclization
excelled by its efficiency.4
As part of our ongoing program aiming at the synthesis
of pyrrolidone fused tryptamines (b-carbolines)5 we were
recently interested in the synthesis of their 2-indolone coun-
terpart. Although some related 2-oxindol-3-yl-pyrrolidines
or piperidines have been reported,6 neither the simplest
derivative of this series, the 3-(2-oxopyrrolidin-3-yl)indo-
lin-2-one 1, nor other 3,30-disubstituted analogs have been
described so far (Fig. 1).
Fig. 1. 3-(2-Oxopyrrolidin-3-yl)indolin-2-one core and its potential synthetic applications.
*
Corresponding author. Tel.: +33 (0)326918022; fax: +33 (0)326918029.
E-mail address: janos.sapi@univ-reims.fr (J. Sapi).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.194

M. Pudlo et al. / Tetrahedron Letters 49 (2008) 1066–1070
1067
1
tified in H NMR as a mixture (55:45) of rotamers. N-
Acylation introducing more readily cleavable mesyl (2g)
or t-butoxycarbonyl (2i) functions was carried out by the
1
classical pathway. In both cases only one set of H and
13C NMR signals were observed probably due to the elec-
tron withdrawing character of substituents. Ester function
bearing N-benzylamides (2j,l) was obtained by simple func-
tional group transformations.13 1H NMR spectrum of 2j
displayed an almost equivalent ratio (52:48) of s-cis and
s-trans conformers. On the contrary, vinylogous amide 2l
appeared to exist as one conformer, presumably the vinyl
group diminishes the rotational barrier through competi-
tive delocalization.14
Treatment of 2a (R = H) with n-Bu3SnH afforded the
known 3-methyloxindole derivative 3a with much lower
yield than reported15 probably due to purification difficul-
ties. It is known that higher yield of cyclized product can be
obtained with tris(trimethylsilyl)silane (TTMSS) due to the
longer lifetime of the radical intermediate.16 This latter is
crucial for the aimed tandem radical cyclization pur-
poses.17 For this reason and for more convenient purifica-
tion procedure radical cyclization was tried with TTMSS
(1.2 equiv) in the presence of AIBN (0.2 equiv) (Table 1).
Indeed, cyclization of 2a (R = H) or 2b (R = CH3) with
TTMSS in gently boiling toluene afforded oxindole deriva-
tives (3a,b18) in 43% and 55% yield, respectively. Higher
yields were observed in the case of amide 2e (R = CON
(Me)Bn) and ester 2c19 substituted oxindoles probably
due to the more stable radical intermediate.
Scheme 1. Tandem radical cyclization pathway to 3-(2-oxopyrrolidin-3-
yl)indolin-2-one derivatives.
Functionalized 3-pyrrolidone substituted oxindoles may
be important intermediates for further synthetic transfor-
mations. Thus, conveniently substituted analogs (C3 substi-
tution: CH2CH2NProt; C30 substitution: o-aminophenyl)
could be considered as valuable intermediates for the syn-
thesis of the polycyclic ring system of structurally closed
cytotoxic alkaloids perophoramidine7 and communesins.8
Herein, we disclose our preliminary results for the prep-
aration of 3-pyrrolidone substituted oxindoles prospecting
a rapid assemblage of other polycyclic indole-derivatives by
tandem radical cyclization followed by simple functional
group transformations (Scheme 1).
Our initial investigations were focused on finding reac-
tion conditions for aryl radical initiated 5-exo-trig ring
closure using simple model compounds. Except for scarce
examples,9 such radical cyclizations affording simple
3-substituted oxindoles10 or more complex 3-spiro-oxin-
doles11 were initiated by tri-n-butyltin hydride.
For our preliminary studies some simple precursors (2a–c)
were prepared by acylation of o-iodoaniline with acryloyl-
chloride or with a,b-unsaturated acids in the presence of
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride (DMTMM) as coupling agent (Scheme 2).12 N-
Benzyl-N-methyl-carboxamide 2e and its allyl analog 2f
were also obtained from 2d by DMTMM-mediated cou-
pling. The required s-cis conformation of the o-iodoacrylo-
ylanilide10c,e moiety was achieved by N-methylation with
methyliodide and sodium hydride as base. Similarly, to
insure an s-cis conformation N-alkylation or N-acylation
of the second amide function was envisaged. Thus, methyl-
ation of 2f led to the corresponding tertiary amide 2h iden-
With these optimized conditions in hand, we began our
investigations by examining the favored 5-exo-trig/5-exo-
trig type tandem radical cyclization (Table 2). Firstly, N-
allyl-acrylamide 2f was treated with TTMSS (1.2 equiv)
and AIBN (0.2 equiv) in toluene at 100–110 °C for 10–
12 h.20 After purification, monocyclized product 3f was
only obtained in 38% yield. As presumable, the lack of
the second cyclization is due to the unfavored s-trans con-
formation of the secondary amide (2f: R1 @ H). On the
contrary, when N-mesyl-substituted counterpart 2g was
Scheme 2. Preparation of the precursors of radical cyclizations (2a–l). Reagents and conditions: (i) Et3N, CH2Cl2, 0 °C to rt; (ii) DMTMM, NMM, THF,
rt; (iii) NaH, THF, 0 °C then CH3I, THF, 0 °C to rt (2a: 71%; 2b: 30%; 2c: 62%); (iv) KOHaq, EtOH (100%); (v) Bn–NH–CH3 or allylamine, DMTMM,
NMM, THF, rt (2e: 93%; 2f: 93%); (vi) (a) (COCl)2, DMFcat, CH2Cl2, 0 °C to rt, (b) Ms–NH–allyl, or Bn–NH–CH2–CH@CH–CO2CH3, Et3N, CH2Cl2
(2g: 93%; 2j: 92%); (vii) NaH, THF, 0 °C to rt then CH3I, THF (2h: 63%); (viii) (Boc)2O, DMAP, Et3N, CH3CN (2i: 74%); (ix) Bn–NH–CH(CO2CH3)–
CH2–SPh, DMTMM, NMM, THF, rt (2k: 63%); (x) (a) m-CPBA, CH2Cl2, 0 °C then toluene, reflux (2l: 73%).

1068
M. Pudlo et al. / Tetrahedron Letters 49 (2008) 1066–1070
Table 1
Preliminary studies affording 3-substituted oxindoles 3
R
R
O
I
O
N
N
3
2
Entry
No.
R
Conditions
No.
Yield (%)
1
2
3
4
5
a
2a
2a
2b
2e
2c
H
H
Bu3SnH, AIBN, toluene, 100–110 °C, 8 h
TTMSS, AIBN,c toluene, 80 °C, 10 h
TTMSS, AIBN, toluene, 100–110 °C, 12 h
TTMSS, AIBN, toluene, 100–110 °C, 10 h
TTMSS, AIBN, toluene, 100–110 °C, 10 h
3a
3a
3b
3e
3c
27a,b
43b
55b
72
CH3
CON(CH3)Bn
CO2C2H5
99
Reaction stopped at 80% conversion.
Isolated yield from tarry side products with double (column and preparative thin layer) chromatography.
Added in ten portions over 6 h.
b
c
submitted to the same conditions monocyclized product 3g
and pyrrolidinone–oxindole 1g were obtained in 24% and
31% yield, respectively. When cyclization was attempted
in a twofold concentrated solution (0.025 mol/L) tandem
cyclization derivative 1g was only isolated (45%).21
Similarly, cyclization of N-methyl substituted substrate
2h afforded 3-(4-methyl-2-oxopyrrolidine-3-yl)indoline-2-
one (1h) in 34% yield.22 In the case of N-Boc-substituted
amide 2i tandem radical cyclization was accompanied by
N-deprotection giving rise to 1i in 40% isolated yield. By
Table 2
Tandem radical cyclization pathway to 3-(2-oxopyrrolidin-3-yl)indolin-2-ones (1)a
1
1
1
R
R
N
R
2
N
R
O
N
2
O
5
O
R
3
I
TTMSS-AIBN
4
R
3
+
toluene, 100-110 °C
O
N
O
O
N
N
10-12 h
2
3
1
Entry
1
Substrate (2)
R1 R2
Product (3)
Product (1)
R1
R2
Yieldb (%)
38
R1
R3
Yieldb (%)
2f
2g
2g
2h
2i
H
3f
H
2
3
4
5
6
Ms
Ms
CH3
Boc
Bn
3g
Ms
24
1g
1g
1h
1i
Ms
Ms
CH3
CH3
CH3
CH3
31c
45
34
40
78
CH3
H
2j
1j
Bn
CO CH
2
CO CH
3
2
3
7
2l
Bn
1l
Bn
C(5)CO2CH3
36
56d
CO CH
2
3
a
Cyclizations were carried out at 0.025 mol/L concentration.
Isolated yield from tarry side products with (double, column, and preparative thin layer for entries 1–4) chromatography.
Cyclization was conducted at 0.0125 mol/L concentration.
b
c
d
n-Bu3SnH mediated cyclization.

M. Pudlo et al. / Tetrahedron Letters 49 (2008) 1066–1070
1069
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analogy with protected indole or pyrrole derivatives such
N-Boc cleavage can be explained by thermal deprotec-
tion.23 The stabilizing effect of electron withdrawing groups
bearing by the double bond was also examined. As
expected, when an ester group was attached to the allyl-
amine moiety (2j) the corresponding substituted pyrrol-
idino-oxindole 1j was obtained in good yield (78%). This
high yield confirmed that at higher temperature radical
cyclization is no more correlated to conformer popula-
tion.24 However, tandem cyclization of vinylogous amide
2l afforded the corresponding ester lactam 1l in lower yield
(36%) accompanied with numerous side products. This
lower yield can be explained by bulkiness of hydride
reagent (TTMSS) involved in the final reduction of the
highly congested amidyl radical. Indeed, when cyclization
was carried out in the presence of n-Bu3SnH lactam ester
1l was isolated in 56% yield.25 Ester functions in 1j and
1l can be considered as anchoring points for further func-
tional group transformations.
´
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In conclusion, we have developed a simple aryl radical
induced 5-exo-trig/5-exo-trig type tandem cyclization reac-
tion for the synthesis of the 3-pyrrolidone substituted oxin-
dole (1) moiety, appearing in some biologically important
polycyclic alkaloids. Further studies on the optimization
of reaction conditions and the application of this method
to the synthesis of more complex molecules are in progress.
Acknowledgments
Financial support of CNRS and University of Reims is
gratefully acknowledged. M.P. thanks the French Ministry
of Education and Research for a fellowship. Spectroscopic
measurements by C. Petermann (NMR), D. Patigny and
P. Sigaut (MS) are gratefully acknowledged.
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1
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25. Selected spectroscopic data for 1l (mixture (65:35) of two diastereo-
1
mers) major: H NMR (CDCl3, 300 MHz): d 1.13–1.26 (m, 1H, H4),
2.15–2.28 (m, 1H, H4), 3.21 (s, 3H, NCH3), 3.42 (dd, J = 9.7, 3.1 Hz,
1H, H3), 3.49 (s, 3H, CO2CH3), 3.87 (t, J = 8.3 Hz, 1H, H5), 4.21 (d,
J = 3.1 Hz, 1H, H30), 5.20 (JA,B = 14.8, 1 Hz, 2H, CH2Ph), 6.82 (d,
J = 7.7 Hz, 1H, H70), 6.93–7.46 (m, 8H, Bn, H40, H50, H60) ppm. 13C
NMR (CDCl3, 75.5 MHz): d 23.8 (C4), 26.3 (NCH3), 42.2 (C3), 45.3
(C30), 45.9 (CH2Ph), 52.2 (CO2CH3), 56.4 (C5), 107.9 (C70), 122.8
(C60), 124.6 (C30a), 125.4 (C40), 127–129 (C50, Bn), 135.3, 144.8
(C70a), 171.1 (CO2CH3), 174.4 (CONBn), 176.2 (CONMe) (ppm).
20. General procedure for tandem radical cyclizations: In a flame-dried
three-necked ballon, equipped with magnetic stirring, reflux con-
denser, Teflon valve with septum and curved glass-finger for the
addition of solid AIBN (0.2–0.8 equiv) a degassed dry toluene
solution of substrate (2) (0.025 mol/L) was added by syringe. To this
solution at 100–110 °C under nitrogen atmosphere was added solid
AIBN and a degassed solution of TTMSS (1.2–2 equiv) in toluene.
After completion of the reaction the solvent was evaporated, the
residue was dissolved in acetonitrile, extracted with hexane
(2 ꢀ 10 mL). The acetonitrile phase was dried (MgSO4), filtered,
and evaporated to dryness under reduced pressure. The residue was
purified by column chromatography and in some cases the collected
fractions were repurified by preparative thin-layer chromatography.
21. 3-Pyrrolidone substituted oxindoles (1g–j,l) were isolated by chroma-
tography as an unseparable mixture of two diastereomers (major:
minor 65–75%:35–25%) which was subjected to spectroscopic mea-
surements (IR, 1H NMR, 13C NMR, and MS).
Minor: 1H NMR (CDCl3, 300 MHz): d 2.01–2.16 (m, 1H, H-4), 2.31–
0
2.51 (m, 1H, H4), 3.21 (s, 3H, N1 CH3), 3.49 (s, 3H, CO2CH3), 3.55
(dd, J = 9.5, 3.2 Hz, 1H, H3), 3.90 (t, J = 10.5 Hz, 1H, H5), 4.07
(JA,B = 14.8 Hz, 2H, CH2Ph), 4.16 (d, J = 3.2 Hz, 1H, H30), 6.84 (d,
J = 6.1 Hz, 1H, H70), 6.93–7.46 (m, 8H, Bn, H40, H50, H60) ppm. 13C
NMR (CDCl3, 75.5 MHz): d 26.2 (C-4), 26.3 (NCH3), 41.6 (C3), 45.1
(C30), 46.0 (CH2Ph), 52.5 (CO2CH3), 56.8 (C5), 108.1 (C70), 122.7
(C60), 124.6 (C30a), 125.1 (C40), 127.0–129.0 (C50, Bn), 135.3, 144.8
(C70a), 171.1 (CO2CH3), 174.4 (CONBn), 176.2 (CONMe) ppm. MS
EI, m/z, % = 378 (M+Å, 32), 361 (23), 319 (7), 287 (10), 246 (14), 156
(90), 139 (100). HREIMS: calcd for C22H22N2O4, 378.1580; found,
378.1597.
22. These relatively low yields can be explained by decomposition,
polymerization of monocyclized products.