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Organic Chemistry Highlights

Microwave Chemistry

Friday, July 15, 2005
Bimbisar Desai
Karl-Franzens-University Graz

Regioselective Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-Benzoxazines

A recent publication by Wei-Min Dai and co-workers from the Hong Kong University of Science and Technology (Tetrahedron 2005, 61, 6879. DOI: 10.1016/j.tet.2005.04.072) describes a regioselective one-pot synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines. The use of a base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) is critical for achieving a regioselective O-alkylation of 2-aminophenols with 2-bromoalkanoates to give an acyclic intermediate, which subsequently undergoes an intermolecular amidation reaction to furnish the desired 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines. The desired products possessing alkyl, aryl, halogen, nitro, sulfonyl group, and ring structures have been prepared in 13-82 % yields respectively. Microwave heating was necessary to induce the annulation reaction, for acyclic intermediates bearing an electron-withdrawing group.

Multicomponent Synthesis of 1,3-Diazabicyclo[3.1.0]hex-3-enes

Francesco Risitano and co-workers from the UniversitÓ Vill. S. Agata, Italy (Synlett 2005, 1633. DOI: 10.1055/s-2005-869859) have reported on a synthesis of bridgehead aziridines with high yields and excellent diastereocontrol by a three component reaction of an aldehyde, phenacyl chloride and ammonium acetate in acetic acid. As opposed to 2-3 hours of traditional conductive heating, 5-10 minutes of microwave irradiation at 90 ░C afforded the stereodefined bridgehead aziridines in 35-92 % isolated yields.

Intramolecular Suzuki-Miyaura Reaction Leading to Macrocycles

The formation of a 15-membered meta, meta-cyclophane, biphenomycin B, featuring a key microwave-induced intramolecular Suzuki-Miyaura reaction step, has been demonstrated by Renaud LÚpine and Jieping Zhu from the Institute de Chimie des Substances Naturelles, France (Org. Lett. 2005, 7, 2981. DOI: 10.1021/ol050949w). Controlled microwave heating has been utilized to increase the cyclization efficiency in the key C-C coupling reaction of the tripeptide precursor. The study of solvent effect, taking into account the advantage of best ligand-base combination, found the toluene-water solvent system in the presence of TBAB (tetrabutylammonium bromide) as an additive, to give best yields (50 %) as compared to MeCN and DMSO under identical conditions. The choice of 2-(2┤,6┤-dimethoxybiphenyl)dicyclohexylphosphine as the ligand, in comparison with ligandless conditions has favoured higher efficiency of cyclization in the key Suzuki Miyaura reaction step.

Grignard Reaction of Aryl Chlorides

Mats Larhed and co-workers from Uppsala University, Sweden (Synlett 2005, 1596. DOI: 10.1055/s-2005-869856) have described a safe, productive and reproducible lab-scale protocol for fast generation of Grignard reagents from reluctant aryl chlorides and bromides under controlled microwave heating. The Grignard reagents prepared in this way have been used as precursors to promote a subsequent microwave-assisted Kumada coupling, toward the synthesis of a novel HIV-1 protease inhibitor. The microwave-induced (150 ░C for 1 hour) Grignard formation in most of the aryl chlorides was initiated using only catalytic amounts of iodine as the sole activator.

B. Desai, Org. Chem. Highlights 2005, July 15.