Newsletter Issue 07 Jan-Feb 2009

Highly efficient copper-catalyzed cascade synthesis of quinazoline and quinazolinone derivatives

As we have commented in previous issues of this newsletter, amidines are useful building blocks for the preparation of many 1,3-diazaheterocycles, like imidazoles and pyrimidines. New methods are still being developed because any new broad scope procedure suitable to be applied in parallel is of interest for medicinal chemists. The work of Fu and Jiang (Tsinghua University, Beijing, China) is a good example based in the rediscovered and optimized Ullmann N-arylation. The method involves the coupling of o-carbonylaryl halides (aldehydes or esters) with amidines in the presence of CuI, L-proline as ligand and Cs2CO3 as base in DMF at 110 °C during 16-24 h. The reaction proceeds through an initial condensation of the amidine with the carbonyl group, followed by coupling to the ring. Twenty examples are provided, with yields ranging typically from 80% to 90%. Though the method could be improved by using microwaves, the reaction is easy and constitutes a good addition to the medicinal chemist toolkit.

Chem. Commun., 2008, 6333–6335. See: 10.1039/b814011a

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