Table 1 Summary of polymer-supported reactions
Yield (%)a
LC-Purity (%)
>95
ES-MSb
Yield (%)a
LC-Purity (%)
ES-MSb
2a
2b
2c
2d
2e
2f
5a
5b
5c
5d
5e
5f
6a
6b
7a
7b
7c
7d
7e
7f
8a
8b
9a
9b
9c
9d
9e
9f
95
95
95
95
95
95
27
23
45
60
65
40
25
77
Quant.
Quant.
Quant.
Quant.
96
—
—
—
—
—
—
—
—
—
—
—
—
—
—
10b
10c
10d
10e
11a
11b
11c
11d
11e
12
70
60
Quant.
Quant.
Quant.
77
>98
>95
>98
>98
>92
>98
>95
85
>98
>95
>95
>95
>98
>95
>98
>98
>98
90
>98
>95
>95
>98
>95
>95
>95
>95
>98
>98
272.07 (ϩ)
286.99 (ϩ)
260.07 (ϩ)
260.07 (ϩ)
292.22 (ϩ)
322.28 (ϩ)
337.19 (ϩ)
310.22 (ϩ)
310.05 (ϩ)
351.20 (ϩ)
437.17 (ϩ)
450.13 (Ϫ)
169.86 (ϩ)
187.08 (ϩ)
200.07 (ϩ)
175.46 (ϩ)
174.98 (ϩ)
173.11 (ϩ)
240.94 (Ϫ)
198.11 (ϩ)
228.20 (ϩ)
216.14 (ϩ)
216.15 (ϩ)
247.95 (ϩ)
278.12 (ϩ)
293.16 (ϩ)
266.09 (ϩ)
266.19 (ϩ)
>95
>95
>95
>95
>95
>95
>95
>98
>98
>95
>98
90
89
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
13
14
15a
15b
15c
15d
15e
15f
16a
16b
16c
16d
16e
17a
17b
17c
17d
17e
92
>95
>98
>98
>98
>98
>98
>95
>98
>98
>95
>98
>98
>98
92
203.07 (ϩ)
233.20 (ϩ)
301.19 (Ϫ)
202.05 (ϩ)
201.99 (ϩ)
259.29 (ϩ)
247.20 (ϩ)
261.10 (ϩ)
198.10 (ϩ)
246.11 (ϩ)
261.08 (ϩ)
233.90 (ϩ)
234.09 (ϩ)
217.09 (ϩ)
242.09 (ϩ)
97
83
Quant.
Quant.
Quant.
Quant.
76
Quant.
82
10a
75
>98
a Yields for reaction from precursor compound. b Masses given are obtained in the mode denoted in brackets. Mass ions are generally M ϩ H,
M Ϫ H or in some cases M ϩ H Ϫ Butyl. For some of the products, no mass ion could be observed under ES-MS conditions. For those compounds,
characterisation by 1H NMR was regarded as sufficient.
be performed using a large excess of the nitro compound
(normally used neat),9 in order to give the nitroaldol condens-
ation products 3a–f and 4a,b in a very clean fashion. To facilitate
the elimination of these 1-hydroxy-2-nitro compounds they were
treated with 50% trifluoroacetic acid anhydride in dichloro-
methane resulting in the formation of the corresponding tri-
fluoroacetates, which were subsequently reacted with triethyl-
amine and gave the nitrostyrene derivatives 5a–f and 6a,b. The
work-up of this reaction involved treatment with aminomethyl
polystyrene and acidic Amberlyst A-15. The heterocyclic
pyrrole ring system was then constructed by a clean 1,3-dipolar
cycloaddition of tert-butyl isocyanoacetate and the nitro-
styrenes (5a–f, 6a,b) in the presence of the polymer supported
guanidine base 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in a
1:1 mixture of tetrahydrofuran and propan-2-ol to yield the
compounds 7a–f and 8a–b (Scheme 2).10,11 Further substitution
at the hetero atom in these compounds could be achieved by
reacting the pyrroles with an excess of an alkyl halide in the
presence of a polymer-supported phosphazene base to yield the
derivatives 9a–f, 10a–e and 11a–e.12,13 After completion of the
reaction, the excess of the halide was sequestered with amino-
methyl polystyrene in the normal way. A set of alkyl bromides
used in the work could be prepared easily by reacting alcohols
and carbon tetrabromide with polymer-bound triphenylphos-
phine14 (Scheme 3) and is illustrated for the preparation of
treatment with trifluoroacetic acid, upon which instantaneous
decarboxylation afforded the pyrroles 15a–f, 16a–e and 17a–e.
In conclusion we have generated an array of 19 1,2,3,4-
tetrasubstituted (9a–f, 10a–e, 11a–e, 12, 13, 14) and 16 1,3,4-
trisubstituted (15a–f, 16a–e, 17a–e) pyrrole derivatives without
any chromatographic purification step to demonstrate the
versatility of the orchestrated application of polymer-supported
reagents and sequestering agents in synthetic sequences. Many
further analogues could, in principle, be generated by this route.
All reactions produced essentially clean products, as was shown
by LC-MS and NMR-spectroscopy. All intermediates could
also be isolated by intercepting part of the reaction streams and
used in other synthesis programmes. Yields and purities of the
various compounds are given in Table 1.
Acknowledgements
We gratefully acknowledge financial support from the Stiftung
Stipendien-Fonds des Verbandes der Chemischen Industrie
(Germany, Post Doctoral Fellowship to J. H.), Pharmacia &
Upjohn S.p.A. Preclinical Research Center Nerviano Italy (to
M. C.), the BP endowment and the Novartis Research Fellow-
ship (to S. V. L.).
Notes and references
PPh2
1 (a) L. A. Thompson and J. A. Ellman, Chem. Rev., 1996, 96, 555;
(b) A. Akelah and D. C. Sherrington, Chem. Rev., 1981, 81, 557;
(c) S. J. Shuttleworth, S. M. Allin and P. K. Sharma, Synthesis, 1997,
1217; (d) S. W. Kaldor and M. G. Siegel, Curr. Opin. Chem. Biol.,
1997, 1, 101.
2 (a) M. J. Suto, L. M. Gayo-Fung, M. S. S. Palanki and R. Sullivan,
Tetrahedron, 1998, 54, 4141; (b) L. M. Gayo and M. J. Suto, Tetra-
hedron Lett., 1997, 38, 513; (c) J. J. Parlow, Tetrahedron Lett., 1996,
37, 5257; (d) S. W. Kaldor, M. G. Siegel, J. E. Fritz, B. A. Dressman
and P. J. Hahn, Tetrahedron Lett., 1996, 37, 7193; M. G. Siegel, P. J.
Hahn, B. A. Dressman, J. E. Fritz, J. R. Grunwell and S. W. Kaldor,
Tetrahedron Lett., 1997, 38, 3357; (e) D. L. Flynn, R. V. Devraj and
J. J. Parlow, Curr. Opin. Drug Discovery Dev., 1998, 1, 41.
OH
Br
DCM / CBr4
R
R
R: H, MeO, NO2
Scheme 3
benzyl bromide, p-methoxybenzyl bromide and p-nitrobenzyl
bromide, which were then applied in the synthesis of the pyrrole
derivatives 12, 13 and 14. For further elaboration of this
array of compounds, the tert-butyl ester could be cleaved by
J. Chem. Soc., Perkin Trans. 1, 1999, 107–110
109