torial synthesis.10 Additionally, azolium ylides have been
applied to a traceless solid-phase synthesis of 2-substituted
azoles.11
via polymerization of 2,3-dimethyl-7-vinylquinolizinium
bromide.17 Here we wish to report our results in the
preparation of a library of cycloimmonium salts by Westphal
condensation on solid-phase.
Initially, some heterocyclic building blocks 1a-h, includ-
ing five- and six-membered heterocycles, benzofused or not,
were selected (Figure 1).
An interesting class of charged heterocycles is polycyclic
nitrogen bridgehead cycloimmonium salts. As an example,
quinolizinium salts have shown DNA intercalative properties
and antiproliferative activity.12 An easy way to access to
cycloimmonium and related salts is the Westphal condensa-
tion (Scheme 1). O. Westphal et al. reported in 1961 the
Scheme 1
Figure 1. Heterocyclic building blocks 1a-h.
condensation of a cycloimmonium salt, such as an N-alkyl-
substituted 2-picolinium salt, acting as an 1,4-dinucleophile
(C-C substrate) on 1,2-diketones in the presence of an
organic base, to give the corresponding substituted quino-
lizinium salts.13 Later on, A. N. Kost and co-workers
published the first examples of the use of N-N substrates,
in the condensation of 1,2-diaminopyridinium perchlorate
with 1,2-diketones to give pyrido[1,2-b]triazinium perchlo-
rates.14 Since 1990, our group has been working on the
Westphal condensation of N-C azinium and azolium
substrates to afford diverse aza-quinolizinium and related
cations.15
Anchoring of 1a-h was performed in two different ways
(Scheme 2). Wang resin (PS-DVB 1%, 0.80 mmol/g;
ArgoGel, 0.40 mmol/g) was chosen as a solid support. For
1a, the method reported by Hodge was performed, but it
was slightly modified by adding N-hydroxybenzotriazole
(HOBt) as an activator, in a mixture of DIC in DMF/CH2Cl2.
Then, the suspension was shaken overnight at room
temperature to give 2a. This method, however, was not
suitable for 1b-h, since low loadings of resins 2 were
obtained. These building blocks were first reacted with ethyl
Our recent interest in solid-phase and parallel synthesis
methods, as well as our long research in synthesis and
reactivity of cycloimmonium salts, has been focused on
developing the Westphal reaction in solid-phase.16 The only
precedent in the literature has been the preparation of poly-
quinoliziniums as cation-exchange resins, through Westphal
reaction of poly-2-methyl-5-vinylpyridine-divinylbenzene or
Scheme 2
(10) Isacsson, J.; Westman, G. Tetrahedron Lett. 2001, 42, 3207.
(11) Deng, Y.; Hlasta, D. J. Org. Lett. 2002, 4, 4017.
(12) (a) Pastor, J.; Siro, L.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J. J.; Rodrigo,
M. M.; Ballesteros, M.; Alvarez-Builla, J. Bioorg. Med. Chem. Lett. 1995,
5, 3043. (b) Molina, A.; Vaquero, J. J.; Garc´ıa-Nav´ıo, J. L.; Alvarez-Builla,
J.; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M. J. Org. Chem. 1999,
64, 3907. (c) Fontana, A.; Benito, E. J.; Mart´ın, M. J.; Sa´nchez, N.; Alajar´ın,
R.; Vaquero, J. J.; Alvarez-Builla, J.; Lambel-Giraudet, S.; Leonce, S.;
Pierre´, A.; Caignard, D. Bioorg. Med. Chem. Lett. 2002, 12, 2611.
(13) Westphal, O.; Jahn, K.; Heffe, W. Arch. Pharm. (Weinheim, Ger.)
1961, 294, 37.
(14) Baranova, N.; Sheinkman, A. K.; Kost, A. N. Khim. Geterotsikl.
Soedin. 1970, 8, 1148; Chem. Abstr. 1971, 75, 63840.
(15) Mat´ıa, M. P.; Garc´ıa Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-Builla, J.
J. Heterocycl. Chem. 1990, 27, 661.
(16) (a) Vaquero, J. J.; Alvarez-Builla, J. AdV. Nitrogen Heterocycl. 2000,
4, 159. (b) Mart´ınez-Barrasa, V.; Burgos, C.; Izquierdo, M. L.; Alvarez-
Builla, J.; Vaquero, J. J. Tetrahedron Lett. 1999, 40, 4115. (c) D´ıaz, A.;
Mat´ıa, M. P.; Ezquerra, J.; Garc´ıa Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-
Builla, J. J. Org. Chem. 1994, 59, 8294.
4058
Org. Lett., Vol. 5, No. 22, 2003