Abstract
Microwave heating methods have been combined with the use of solid‐supported catalysts to produce small solution‐phase libraries of medicinally‐relevant compounds. Palladium supported on charcoal (Pd/C) has been used to produce libraries of pyrazole compounds for screening in COX II studies via Suzuki cross coupling reactions, while the same catalyst has been used also to produce styryl‐based nAChR compounds using analogous chemistry. Although the reaction substrates are very different (aryl vs. vinyl), this catalyst system provided consistently good and reliable results. The use of a polystyrene‐supported Ru catalyst for ring‐closing metathesis (RCM) reactions was also evaluated to prepare benzolactam structures for evaluation as factor Xa inhibitors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Shuttleworth, S. J., Allin, S. M., Wilson, R. D. and Nasturica, D., Functionalized polymers in organic chemistry, Part 2, Synthesis, (2000) 1035–1074.
Organ, M. G. and Mallik, D., Optimizing Solution Phase Synthesis Using Solid Phase Techniques, Optimizing Solid‐Phase Chemistry, Marcel‐Dekker, New York, 2001, 315–381.
Ley, S. V., Baxendale, I. R., Bream, R. N., Jackson, P. S., Leach, A. G., Longbottom, D. A., Nesi, M., Scott, J. S., Storer, R. I. and Taylor, S. J., Multi‐step organic synthesis using solid‐supported reagents and scavengers: a new paradigm in chemical library generation, J. Chem. Soc., Perkin Trans., 1 (2000) 3815–4195.
Lidström, P., Tierney, J., Whatey, B. and Westman, J., Microwave assisted organic synthesis – a review, Tetrahedron, 57 (2001) 9225–9283.
Larhed, M. and Hallberg, A., Microwave‐assisted highspeed chemistry: a new technique in drug discovery, Drug Discov. Today, 6 (2001) 406–416.
Kappe, C. O., High‐speed combinatorial synthesis utilizing microwave irradiation, Curr. Opin. Chem. Biol., 6 (2002) 314–320.
Bendale, P. M. and Sun, C.‐M., Rapid microwaveassisted liquid‐phase combinatorial synthesis of 2‐(arylamino)benzimidazoles, J. Comb. Chem., 4 (2002) 359–361.
Larhed, M., Moberg, C. and Hallberg, A., Microwaveaccelerated homogeneous catalysis in organic chemistry, Acc. Chem. Res., 35 (2002) 717–727.
Loupy, A., Microwaves in Organic Synthesis, Wiley‐VCH: Weinheim 2002.
Organ, M. G. and Mayer, S., Synthesis of 4‐(5‐iodo‐3‐methylpyrazolyl) phenylsulfonylamide and its elaboration to a COX II inhibitor library by solution‐phase Suzuki coupling using Pd/C as a solid‐supported catalyst, J. Comb. Chem., 5 (2003) 118–124.
Cavallini, G., Mantegazza, G., Massarini, P. and Tommasini, E., Sull'attività ganglioplegica di alcuni derivati alchilaminici dello stilbene e del difenile, Il Farmaco, 6 (1953) 317–331.
Gotti, C., Fornasari, D. and Clementi, F., Human neuronal nicotinic receptors, Prog. Neurobiol., 53 (1997) 199–237.
Gotti, C., Carbonnelle, E., Moretti, M., Zwart, R. and Clementi, F., Drugs selective for nicotinic receptor subtypes: a real possibility or a dream?, Behav. Br. Res., 113 (2000) 183–192.
Maggi, L., Palma, E., Eusebi, F., Moretti, M., Balestra, B., Clementi, F. and Gotti, C., Selective effect of a 4‐oxystilbene derivative on wild and mutant neuronal chick 7 nicotinic receptor, Br. J. Pharmacol., 126 (1999) 285–295.
Gotti, C., Balestra, B., Moretti, M., Rovati, G. E., Maggi, L., Rossoni, G., Berti, F., Villa, L., Pallavicini, M., and Clementi, F., 4‐Oxystilbene compounds are selective ligands for neuronal nicotinic á‐Bungarotoxin receptors, Br. J. Pharmacol., 124 (1998) 1197–1206.
Organ, M. G., Cooper, T. J., Rogers, L. R., Soleymanzadeh, F. and Paul, T., Synthesis of stereodefined polysubstituted olefins. 1. Sequential intermolecular reactions involving selective, stepwise insertion of Pd(0) intoallylic and vinylic halide bonds. The stereoselective synthesis of disubstituted olefins, J. Org. Chem., 65 (2000) 7959–7970.
Torrado, A., Lopez, S., Alvarez, R. and De Lera, A. R., General synthesis of retinoids and arotinoids via palladiumcatalyzed cross‐coupling of boronic acids with electrophiles, Synthesis, 3 (1995) 285–293.
Suzuki, A., Recent advances in the cross‐coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998, J. Organomet. Chem., 576 (1999) 147–168.
Miyaura, N. and Suzuki, A., Palladium‐catalyzed crosscoupling reactions of organoboron compounds, Chem. Rev., 95 (1995) 2457–2483.
Leadbeater, N. E. and Marco, M., Rapid and amenable suzuki coupling reaction in water using microwave and conventional heating, J. Org. Chem., 68 (2003) 888–892.
Gong, Y. and He, W., Direct synthesis of unprotected 4‐aryl phenylalanines via the Suzuki reaction under microwave irradiation, Org. Lett., 4 (2002) 3803–3805.
Blettner, C. G., Konig, W. A., Stenzel, W. and Schotten, T., Microwave‐assisted aqueous Suzuki cross‐coupling reactions, J. Org. Chem., 64 (1999) 3885–3890.
Larhed, M. and Hallberg, A., Microwave‐promoted palladium‐catalyzed coupling reactions, J. Org. Chem., 61 (1996) 9582–9584.
Bumagin, N. A. and Bykov, V. V., Ligandless palladium 227 catalyzed of arylboronic acids and sodium tetraphenylborate with aryl halides in aqueous media, Tetrahedron, 53 (1997) 14437–14450.
Sakurai, H., Tsukuda, T. and Hirao, Toshikazu, Palladium/ C as reusable catalyst for the coupling reaction of halophenol and arylboronic acids in aqueous media, J. Org. Chem., 67 (2002) 2721–2722.
Heidenreich, R. G., Kohler, K., Krauter, J. G. E. and Pietsch, J., Pd/C as a highly active catalyst for Heck, Suzuki and Sonogashira reactions, Synlett, 7 (2002) 1118–1122.
Leblond, C. R., Andrews, A. T., Sun, Y. and Sowa, J. R., Activation of arylchlorides for Suzuki cross‐coupling by ligandless heterogeneous palladium, Org. Lett., 3 (2001) 1555–1557.
Organ, M. G., Arvanitis, E. A., Dixon, C. E. and Lavorato, D. J., Solution‐phase synthesis of an aminomethyl‐substituted biaryl library via sequential amine N‐alkylation and Suzuki cross‐coupling, J. Comb. Chem., 3 (2001) 473–476.
Leadbeater, N. E. and Marco, M., Ligand‐free palladium catalysis of the Suzuki reaction in water using microwave heating, Org. Lett., 4 (2002) 2973–2976.
Organ, M. G., Xu, J. and N'Zemba, B. M., A General and enantiospecific strategy for the synthesis of CVS 1778 and its analogs: inhibitors of factor Xa, Tetrahedron Lett., 43 (2002) 8177–8180.
Pinto, D. J. P., Orwat, M. J., Wang, S., Fevig, J. M., Quan, M. L., Amparo, E., Cacciola, J., Rossi, K. A., Alexander, R. S., Smallwood, A. M., Luettgen, J. M., Liang, L., Aungst, B. J., Wright, M. R., Knobb, R. M,, Wong, P. C., Wexler, R. R. and Lam, P. Y. S., Discovery of 1‐[3‐(aminomethyl)phenyl]‐N‐[3‐fluoro‐2'‐(methylsulfonyl)‐[1,1'‐biphenyl]‐4‐yl]‐3‐(trifluoromethyl)‐1H‐pyrazole‐5‐carboxamide (DPC423), a highly potent, selective and orallybioavailable inhibitor of blood coagulation factor Xa, J. Med. Chem., 44 (2001) 566–578.
Sanford, M. S., Ulman, M. and Grubbs, R. H., New insights into the mechanism of ruthenium‐catalyzed olefin metathesis reactions, J. Am. Chem. Soc., 123 (2001) 749–750.
Ahmed, M., Barrett, A. G. M., Braddock, D. C., Cramp, S. M. and Procopiou, P. A., A recyclable ‘boomerang’ polymersupported ruthenium catalyst for olefin metathesis, Tetrahedron Lett., 40 (1999) 8657–8662.
Ahmed, M., Arnauld, T., Barrett, A. G. M., Braddock, D. C. and Procopiou, P. A., Second generation recyclable ‘boomerang’ polymer supported catalysts for olefin metathesis: application of Arduengo carbene complexes, Synlett, (2000) 1007–1009.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Organ, M.G., Mayer, S., Lepifre, F. et al. Combining the use of solid‐supported transition metal catalysis with microwave irradiation in solution‐phase parallel library synthesis. Mol Divers 7, 211–227 (2003). https://doi.org/10.1023/B:MODI.0000006826.91512.83
Issue Date:
DOI: https://doi.org/10.1023/B:MODI.0000006826.91512.83