Table 1 Oxindoles prepared by Pummerer cyclisation on solid phase
Entry
Amide
Oxindole(s)
1
2
Scheme 5 Reagents and conditions: i, oxone, DMF–H
CO , KI, allyl bromide, DMF, 60 °C; iii, SmI , DMPU, THF, rt, 30%
overall yield for six steps on resin.
2
O (4 : 1), rt; ii,
K
2
3
2
3
4
We thank The Carnegie Trust for the Universities of Scotland
Postgraduate Research Scholarship to L. A. M.), Celltech R&D
CASE award, L. A. M.) and the Socrates-Erasmus exchange
(
(
programme (R. D. G.) for financial support.
Notes and references
5
6
†
The loading of free SH sites was determined by the immobilisation of
cleavage and
N-methyl-N-phenyl a-bromoacetamide, followed by SmI
isolation/quantification of N-methyl-N-phenyl acetamide. The discrepancy
between the loading obtained by this method and that obtained by sulfur
microanalysis ( ~ 1 mmol g ) is presumably due to oxidative cross-linking
of the thiol functional groups.
2
21
Typical experimental procedure: Sulfoxide resin 8 (0.172 mmol) was
swollen in 1,2-dichloroethane and TFAA (0.243 ml, 1.72 mmol) was added
at room temperature. After 2 h, BF
and the reaction stirred at room temperature for 18 h. The suspension was
then filtered and the resin washed with H O, THF, THF–H O (3 : 1, 1 : 1,
: 3), THF, (MeOH, CH Cl ) 3 3 and THF. The resin was then dried under
3 2
·OEt (0.327 ml, 2.58 mmol) was added
2
2
1
2
2
7
21
high vacuum (nmax CNO stretch 1714 cm ). To a pre-swollen solution of
oxindole resin 9 (0.158 mmol) in THF (4 ml) was added DMPU (0.153 ml,
1
2
.26 mmol), and SmI (4.74 ml of a 0.1 M soln. in THF, 0.474 mmol). The
a
b
reaction was stirred at room temperature for 18 h. After filtration, the
solution phase was collected and concentrated in vacuo. Filtration through
a short pad of silica gel, washing with 30% EtOAc in hexane, and
concentration in vacuo, gave oxindole 10 (11 mg, 0.074 mmol, 47%).
Isolated, overall yields after four steps. Cyclised using TFAA and
c
3 2
BF ·OEt . Cyclised using TFAA.
1
,3-dihydro-indol-2-one (entry 7, X = I), cleavage of the
1
For recent reviews on linkers and cleavage strategies for solid phase
organic synthesis, see: (a) I. W. James, Tetrahedron, 1999, 55, 4855; (b)
F. Guillier, D. Orain and M. Bradley, Chem. Rev., 2000, 100, 2091.
sulfur-link to resin can be achieved chemoselectively in the
presence of the aryl iodide.10
Crucially, no aqueous work up is needed after cleavage of the
product from resin. In the majority of cases, the products could
be separated from DMPU and inorganic by-products by simple
filtration through a short pad of silica after which they were
2 F. McKerlie, D. J. Procter and G. Wynne, Chem. Commun., 2002,
84.
3
5
For reviews of the area, see: (a) A. Padwa, D. E. Gunn Jr. and M. H.
Osterhout, Synthesis, 1997, 1353; (b) A. Padwa, D. M. Danca, J. D. Ginn
and S. M. Lynch, J. Braz. Chem. Soc., 2001, 12, 571.
1
13
11
found to give satisfactory H and C NMR spectra.
4
5
See ref. 3a and references cited therein.
As the sulfur link to resin remains intact after the Pummerer
cyclisation to form oxindoles, further synthetic steps on resin
allow access to elaborated oxindole frameworks. By way of
illustration we have oxidised resin-bound oxindole 11 to sulfone
Sulfonium ions have recently begun to find application in solid-phase
chemistry: (a) in Pd-catalysed cross-coupling reactions, C. Vanier, F.
Lorgé, A. Wagner and C. Mioskowski, Angew. Chem., Int. Ed., 2000,
39, 1679; (b) in cyclopropanations and epoxidations, E. La Porta, U.
Piarulli, F. Cardullo, A. Paio, S. Provera, P. Seneci and C. Gennari,
Tetrahedron Lett., 2002, 43, 761; (c) in the Pummerer cleavage of a
sulfoxide linker, C. Rolland, G. Hanquet, J.-B. Ducep and G. Solladié,
Tetrahedron Lett., 2001, 42, 7563.
S. Kobayashi, I. Hachiya, S. Suzuki and M. Moriwaki, Tetrahedron
Lett., 1996, 37, 2809.
For the preparation of a different thiol resin via a thiourea see ref. 5a.
(a) K. S. Ravikumar, J.-P. Bégué and D. Bonnet-Delpon, Tetrahedron
Lett., 1998, 39, 3141; (b) H. E. Russell, R. W. A. Luke and M. Bradley,
Tetrahedron Lett., 2000, 41, 5287.
12. Efficient alkylation was then carried out to give the allylated
sulfone 13. Thus our approach proceeds with assistance from
the sulfur link in two different oxidation states. Cleavage of the
link with SmI
2
and DMPU gave the expected product 14 as a
: 1 mixture of regioisomers in 30% overall yield (six steps)
6
9
(Scheme 5).
7
8
In conclusion, we have described the first Pummerer
cyclisations on solid-phase. The cyclisation reactions are
enabled by a sulfur atom linking the substrate to the resin.
Crucially, the sulfur link remains intact during the cyclisation
allowing further solid-phase modification of the basic hetero-
cyclic scaffold. We have investigated the generality of the
approach by preparing a range of oxindoles. Finally, by utilising
the linking sulfur atom a second time but in a different oxidation
state, we have illustrated how Pummerer products can be readily
manipulated on resin. The application of our Pummerer
approach to the synthesis of other heterocyclic systems is
currently under investigation.
3 2
9 It has been noted that BF ·OEt is not required for electronically
activated systems. (a) T. Shinohara, A. Takeda, J. Toda, Y. Ueda, M.
Kohno and T. Sano, Chem. Pharm. Bull., 1998, 46(6), 918; (b) T. Saitoh,
T. Ichikawa, Y. Horiguchi, J. Toda and T. Sano, Chem. Pharm. Bull.,
2
001, 49(8), 979.
1
0 Aryl and alkyl halides can be readily reduced using SmI with additives
2
such as HMPA: J. Inanaga, M. Ishikawa and M. Yamaguchi, Chem.
Lett., 1987, 1485.
11 Routine chromatography was used for the few examples where minor
uncharacterised by-products were obtained.
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