Microwave-assisted solid-phase synthesis

Combinatorial chemistry and solid-phase organic synthesis 

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Table 7.1 Swelling behavior, loss tangents (tan <5), and boiling points for solvents used in microwave-assisted solid-phase synthesis.

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

An efficient microwave-assisted multi-step synthesis of8//-quinazolino [4,3-b] quina-zolin-8-one has been investigated by Besson and co-workers77. The synthesis involved two Niementowski condensations starting from substituted anthranilic acids (Scheme 3.49). Both homogeneous and heterogeneous conditions were studied in an effort to develop a convenient synthesis of the desired compounds. The solventless procedure allowed easier access to the quinazolino[4,3-fi]quinazolin-8-ones and gave better yields than the method performed in the presence of solvents. However, the procedure with solvents would offer the possibility of investigating the microwave-assisted solid-phase synthesis of these quinazolinones, which would faciltate purification of the final products. 

Finaru, A., Berthault, A., Besson, T., Guillaumet, G. and Berteina-Raboin, S., Microwave-assisted solid-phase synthesis of 5-carboxamido-N-acetyltryptamine derivatives, Org. Lett., 2002, 4, 2613-2615. 

The combination of microwave-assisted chemistry and solid-phase synthesis applications is a logical consequence of the increased speed and effectiveness offered by microwave dielectric heating. While this technology is heavily used in the pharmaceutical and agrochemical research laboratories already, a further increase in the use of microwave-assisted solid-phase synthesis both in industry and in academic laboratories can be expected. This will depend also on the availability of modern microwave instrumentation specifically designed for solid-phase chemistry, involving for example dedicated vessels for bottom filtration techniques. 

Austin, R.E., Okonya, J.F., Bond, D.R.S. and Al-Obeidi, F., Microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines, Tetrahedron Lett., 2002, 43, 6169-6171. 

A microwave-assisted solid-phase synthesis of the antimicrobial oxazo-lidinone pharmacophore is described herein as a demonstration of the utility of this emerging technology toward drug discovery.4 The optimization process and full experimental details for the synthesis of a small library of oxazolidinones are exemplified. 

Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin-bound 6-thiopurines <02T7911>, and microwave assisted solid-phase synthesis of 2,6,9-trisubstituted purines <02TL6169> have been described. A resin-capture and release strategy toward combinatorial libraries of 2,6,9-trisubstituted purines has been reported <02JCO183>. Alkylated purines chlorinated at the 6,8- or 2,6,8-positions can be captured onto a solid support and further elaborated by aromatic substitution or via palladium catalyzed crosscoupling reactions <02JA1594>. 

A microwave assisted solid-phase synthesis of trisubstituted 2-(2,6-purin-9-yl)acetamides has been described <05TL2873>. New trisubstituted purin-8-ones 71 have been synthesized starting from cheap and readily available 5-bromouracil 70 <05S2227>. 

Microwave-assisted solid-phase synthesis of purines on an acid-sensitive meth-oxybenzaldehyde (AMEBA)-linked polystyrene has been reported [50]. The heterocyclic scaffold was first attached to the polymer support via an aromatic nucleophilic substitution reaction by conventional heating in l-methyl-2-pyrrolidinone (NMP) in the presence of N,N-diisopropylethylamine. The key aromatic nucleophilic substitution of the iodine with primary and secondary amines was conducted by microwave heating for 30 min at 200 °C in l-methyl-2-pyrrolidone (Scheme 16.28). After reaction the products were cleaved from the solid support by use of trifluoroacetic acid-water at 60 °C. 

Carenbauer, A.L. Cecil, M.R. CzERWiNSKi, A. Darlak, K. Dariak, M. Long, D.W. Valenzuela, F. Barany, G. Microwave Assisted Solid Phase Synthesis on CLEAR Supports Presented at the 19th American Peptide Symposium, San Diego, C.A. 

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