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Microwave Chemistry Highlights
A short summary of articles published within the last month on microwave-assisted organic synthesis (MAOS)

Saturday, March 15, 2008
Doris Dallinger
Karl-Franzens-University Graz

Synthesis of α,α-Disubstituted Amino Aldehydes

The group of Stefan Bräse from the University of Karlsruhe has performed optimization studies toward solvent, time, temperature and catalyst loading for the microwave-mediated organocatalytic asymmetric α-amination of disubstituted aldehydes with diethyl azodicarboxylate (Eur. J. Org. Chem. 2008, ASAP. DOI: 10.1002/ejoc.200701167). Optimum conditions in terms of both high yield and enantioselectivity proved to be MeCN as solvent, 50 mol% of L-proline as catalyst, a reaction temperature of 60°C and 30 min reaction time. Importantly, the reaction time could be decreased from several days to only 30 min by applying microwave heating compared to room temperature conditions, with a concomitant increase in yield and enantioselectivity. In particular, improvements for otherwise unreactive starting materials bearing electron-withdrawing R-groups (e.g. F, NO2, CF3) were observed.

Nickel-on-Graphite Catalyzed Cross-Couplings

Carbon-carbon cross-couplings catalyzed by activated Ni(II) mounted on graphite (Ni/Cg) were reported by the group of Bruce Lipshutz from the University of California, Santa Barbara (Org. Lett. 2008, 10, 697. DOI: 10.1021/ol702453q). In addition to the Suzuki coupling of aryl chlorides and tosylates with boronic acids, vinylalanes and vinylzirconocenes were reacted with aryl halides and tosylates. Compared to the corresponding nickel-in charcoal (Ni/C) catalyzed reactions, couplings proceed faster, higher yields are obtained and cleaner reactions are afforded with Ni/Cg as catalyst. In some cases, different chemoselectivities depending on the used catalyst were obtained.

Desulfitative Sonogashira-Type Cross-Coupling

The desulfitative Sonogashira-type cross-coupling of thioether-functionalized pyrazinones 1 and various terminal alkynes was disclosed by Erik Van der Eycken and his group from the University of Leuven (Org. Lett. 2008, 10, 1147. DOI: 10.1021/ol800054b). The reaction proceeded well for both ethylthio-substituted and resin-linked pyrazinones, although longer reaction times (60 and 90 min) compared to the phenylthio-substituted scaffolds are necessary for resin bound reactions. In addition, the desulfitative alkynylation was extended to other (het)aryls such as oxazinones, pyrazines and phenyl thioesters.

Rh(I)-Catalyzed Arylation of Heterocycles via C-H Bond Activation

In order to overcome problems such as substrate scope and functional group tolerance in metal-catalyzed direct arylations and to improve practicability of previously published Rh-catalyzed arylations, the groups of Robert Bergman and Jonathan Ellman from the University of California, Berkeley, have developed a new protocol for the direct arylation of a variety of heterocycles with aryl bromides employing phosphepine ligand 1 (J. Am. Chem. 2008, 130, 2493. DOI: 10.1021/ja0748985). This ligand proved to be the most effective in a ligand screen and coordinates to Rh in a bidentate P-olefin fashion and thus generates an active and temperature stable catalyst. For a greater practicability of the protocol, the air-sensitive ligand 1 can be protected as its HBF4 salt and [RhCl(cod)]2 as air-stable Rh-source can be employed. Thus, reaction mixture preparation in a glovebox is avoided and only an inert atmosphere in the microwave vial is required. In addition, by using THF as low boiling solvent product isolation is simplified.


D. Dallinger, Org. Chem. Highlights 2008, March 15.