Organic Chemistry Portal
Organic Chemistry Highlights

Microwave Chemistry

Thursday, February 15, 2007
Doris Dallinger
Karl-Franzens-University Graz

One-Pot Cyclization/Suzuki Coupling

Erin DiMauro and Joseph Kennedy from Amgen have developed a microwave protocol for the synthesis of a focused library of 3-amino-imidazopyridines 3 (J. Org. Chem. 2007, 72, 1013. DOI: 10.1021/jo0622072). Starting from 2-aminopyridine-5-boronic acid pinacol ester (1), the imidazopyridine products 3 were obtained via an Ugi-type cyclization, leading to intermediate 2, followed by a Suzuki coupling in a one-pot procedure. Notably, the authors were not successful in performing the reaction sequence in one step nor can be the sequence reversed (first Suzuki then cyclization).

Multidimensional Reaction Screening of o-Alkynyl benzaldehydes

In the course of a multidimensional reaction screening of o-alkynyl benzaldehydes with a variety of catalysts and reactants in order to identify novel chemical transformations, the groups of Aaron Beeler and John Porco Jr. from Boston University have discovered two new reaction pathways where microwave heating is employed (J. Am. Chem. Soc. 2007, 129, 1413. DOI: 10.1021/ja0674744). In the first reaction, o-alkynyl benzaldehyde 1 is reacted with diethyl malonate in dichloroethane (DCE) under Au(OAc)3 catalysis. Via this cycloisomerization/nucleophilic addition sequence, isochromene 2 was obtained as major product along with the ring-opened benzylidenemalonate 3. When MeCN is used as solvent, the ring-opened product 3 is obtained exclusively in 90% yield. The second novel reaction employing microwave heating was the cycloisomerization with subsequent Friedel-Crafts addition and phenol annulation. This sequence is catalyzed by PtCl2 and furnished tetracycle 4 as product.

One-Step Vorbrüggen Glycosylation

Brett Bookser and Nicholas Raffaele from Metabasis Therapeutics have reported on the synthesis of a nucleoside library via the Vorbrüggen glycosylation and subsequent deprotection with NH3/MeOH (J. Org. Chem. 2007, 72, 173. DOI: 10.1021/jo061885l). They were successful in performing this reaction, which is known to be a two-step synthesis (presilylation of the base then reaction with trimethylsilyl triflate activated sugar), in only one step by applying microwave heating at 130 °C for 5 min. An additional advantage of the elevated temperature is that otherwise insoluble silylated bases were solubilized under these conditions. For the library synthesis, 48 N-containing bases were reacted with β-D-ribofuranose 1, out of these, 32 yielded single isomers, six provided separable mixtures and seven afforded inseparable regioisomer mixtures. Altogether a set of 58 nucleosides was obtained in poor to good yields.

Synthesis of Pyrazolopyridines via a Three-Component Approach

Valentin Chebanov and coworkers from the National Academy of Sciences of Ukraine and University of Graz have disclosed the microwave-assisted three-component reaction of 3-substituted 5-aminopyrazoles 1, pyruvic acid or ethyl pyruvate 2 and aromatic aldehydes 3 (Tetrahedron 2007, 63, 1229. DOI: 10.1016/j.tet.2006.11.048). By changing the solvent from AcOH, which is used under conventional conditions, to an EtOH/HCl system, product isolation was facilitated and no further recrystallization was necessary. Compared to classical heating, an 8-12 fold decrease in reaction time was possible and higher yields could be obtained for the pyrazolopyridine carboxylic ethyl ester products 4 (R2 = Et).

D. Dallinger, Org. Chem. Highlights 2007, February 15.