Organic Chemistry Portal
Organic Chemistry Highlights

Microwave Chemistry

Monday, November 15, 2004
C. Oliver Kappe
Karl-Franzens-University Graz

Reductive Aminations and Suzuki-Type Couplings

In the chemistry described below, Coats and a group of researchers from Johnson and Johnson utilized successive reductive aminations and Suzuki cross coupling reactions to prepare a 192-member library of tropanylidene benzamides (Bioorg. Med. Chem. Lett. 2004, 14, 5493. DOI: 10.1016/j.bmcl.2004.09.004) . This series of tropanylidene opioid agonists proved extremely tolerant of structural variation while maintaining excellent opioid activity. For the solution phase preparation of functionalized tropanylidenes the authors simply dispensed 1,2-dichloroethane (DCE) solutions of the bromo N-H precursor to a set of microwave vials, added the aldehydes (3 equiv) and a solution of sodium triacetoxy borohydride in dimethylformamide (2 equiv), and subjected the mixture to microwave irradiation for 6 min at 120 C. Quenching the reductive amination with water and subsequent concentration allowed to directly perform a microwave-assisted Suzuki reaction on the crude products.

Carbasugar Synthesis

A rapid synthesis of carbasugars was reported by Pohl and co-workers from Iowa State University (J. Am. Chem. Soc. 2004, 126, 13188. DOI: 10.1021/ja045522j) starting from a protected D-glucose. Microwave-enhanced iodination of the selectively protected glucose precursor took place in one min in toluene at 60 C in the presence of iodine and triphenylphosphine. Subsequent base-promoted elimination of hydrogen iodide in the presence of DBU required 30 min (DMF, 80 C), and the key Ferrier rearrangement induced by palladium dichloride was also completed within 5 min of microwave irradiation. The development of this series of microwave-assisted transformations significantly shortened the time to form the core carbocyclic structure from a protected glucose.

Negishi Couplings

An application of high-speed Negishi coupling methodology for the preparation of enantiopure 2,2'-diarylated 1,1'-binaphthyls was reported by Putala and co-workers from the Slovak republic (Chem. Commun. 2004, advance article, DOI: 10.1039/b410185e) . Reaction times as short as 40 seconds in some cases were sufficient to achieve complete conversions in the stereoconservative Negishi coupling of commercially available 2,2'-diiodo-1,1'-binaphthyl (DIBN) with arylzinc chlorides. The catalyst loading for typical runs was 5 mol% of Pd(PPh3)4, but could be lowered to 0.5 mol% in some instances without appreciable reduction of coupling efficiency. The formed enantiopure 2,2'-diarylated 1,1'-binaphthyls are of interest in material sciences application. In the same article, the corresponding Negishi alkynations using zinc phenylacetylide and zinc trimethylsilylacetylide were also described.

Multicomponent Synthesis of 2-Pyridones

We have described (Tetrahedron 2004, 60, 8633. DOI: 10.1016/j.tet.2004.05.100) a multicomponent, one-pot, two-step pathway to 3,5,6-substituted 2-pyridones. In the first step equimolar mixtures of a CH-acidic carbonyl compound and N,N-dimethylformamide dimethyl acetal (DMFDMA) were reacted to form the corresponding enamines, either at room temperature or under microwave conditions. After addition of a methylene active nitrile (1 equiv), 2-propanol as solvent and catalytic amounts of piperidine base, the reaction mixture was heated to 100 C for 5 minutes under microwave conditions. In most cases, the desired heterocyclic product precipitated directly after cooling of the reaction mixture and could be collected by filtration.

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