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Organic Chemistry Highlights

Microwave Chemistry

Thursday, December 15, 2004
C. Oliver Kappe
Karl-Franzens-University Graz

Hiyama Couplings

Somewhat related to the well-known Suzuki cross-coupling reaction involving organoboron reagents, is the so-called Hiyama coupling of organosilanes with halides and triflates to form unsymmetrical biaryl compounds. Seganish and DeShong from the University of Maryland have described rapid, microwave-promoted Hiyama couplings of bis(catechol) silicates with aryl bromides (Org. Lett. 2004, 6, 4379. DOI: 10.1021/ol048044q) . Suitable reaction conditions entailed the use of 5 mol% of Pd2(dba)3 as a palladium source, 5 mol% of 2-(dicyclohexylphosphanyl)biphenyl as ligand, and 1.5 equivalents of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran as solvent. Exposure of the reaction mixture to microwave irradiation at 120C for 10 minutes typically provided good yields of biaryl coupling products for a wide range of substrates. The only functional group that was found to fail in the coupling studies was the amino group, probably as a result of catalyst poisoning.

Sonogashira/Heteroannulation Strategies

Hopkins and Collar have reported a one-pot Sonogashira/heteroannulation strategy for the synthesis of 6-substituted-5H-pyrrolo[2,3-b]pyrazines (Tetrahedron Lett. 2004, 45, 8631. DOI: 10.1016/j.tetlet.2004.09.152) . The reaction could either be performed in a two-step protocol, by first performing a classical Sonogashira coupling on 2-amino-3-chloropyrazine, followed by base-induced cyclization (reaction a), or in a one-step method by reacting the corresponding sulfonamide, N-(3-chloropyrazin-2-yl)-methanesulfonamide, directly with terminal acetylenes in the presence of suitable palladium catalyst (3 mol%) (reaction b). The microwave conditions (150 C, 20 minutes) tolerated much functional diversity (both electron-withdrawing and electron-donating substituents). Halogens as well as cyano groups were also tolerated, along with silyl protecting groups.

β-Glycosylamine Synthesis

Bajugam and Flitsch have described (Org. Lett. 2004, 6, 4001. DOI: 10.1021/ol048342n) . the synthesis of glycosylamines from mono-, di-, and trisaccharides via direct microwave-assisted Kochetkov amination. The reaction was found to be effective with only 5-fold excess (w/w) of ammonium carbonate over sugar compared to 40-50-fold excess needed under thermal conditions. All transformations were completed within 90 minutes in dimethylsulfoxide as solvent while maintaining the vessel temperature at an apparent 40C, using the "heating-while-cooling" technique.

4-Thiazolidinones via Multicomponent Chemistry

Miller and co-workers reported a one-pot protocol for the preparation of thiazolidin-4-ones by condensation of aromatic aldehydes, amines and mercaptoacetic acid in ethanol (Synlett 2004, 2357. DOI: 10.1055/s-2004-832811) . The optimized procedure involved microwave irradiation of a mixture of amine hydrochloride, aldehyde and mercaptoacetic acid (molar ratio 1:2:3) in the presence of 1.25 equivalents of N,N-diisopropylethylamine (DIEA) base in ethanol at 120 C for 30 minutes at atmospheric pressure.

Cu(I)-Catalyzed Azide-Acetylene Ligations ("Click Chemistry")

We have exploited a microwave-assisted version of the copper(I)-catalyzed azide-acetylene ligation process ("click chemistry") for the preparation of 6-(1,2,3-triazol-1-yl)-dihydropyrimidones (J. Comb. Chem. 2004, 6, 884. DOI: 10.1021/cc0498938) . Here a suitable heterocyclic azide intermediate (obtained by microwave-assisted azidation) was treated with phenyl acetylene in N,N-dimethylformamide employing 2 mol% copper(II) sulfate/sodium ascorbate as catalyst precursor. After completion of the cycloaddition process the triazole product can be precipitated in high yield (73%) and purity by addition to ice/water. For the model reaction displayed in the Scheme below full conversion at room temperature required one hour. By carrying out the same reaction utilizing controlled microwave heating at 80 C, complete conversion was achieved within 1 minute. A library of twenty seven 6-(1,2,3-triazol-1-yl)-dihydropyrimidones was prepared with 4 points of diversity.

For certain substrates, Fokin, Van der Eycken and co-workers discovered that the azidation and ligation step can be carried out in a one-pot fashion, thereby simplifying the overall protocol (Org. Lett. 2004, 7, 4223. DOI: 10.1021/ol048341v) . This procedure eliminates the need to handle organic azides, as they are generated in situ.

Recent Reviews:

Kappe, C. O. "Controlled Microwave Heating in Modern Organic Synthesis", Angew. Chem. Int. Ed. 2004, 43, 6650. DOI: 10.1002/anie.200400655 (> 400 references).

C. O. Kappe, Org. Chem. Highlights 2004, December 15.