Synthesis 2004(13): 2121-2130  
DOI: 10.1055/s-2004-829169
PAPER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Lithiation of Chiral 3-Acylamino-2-alkylquinazolin-4(3H)-ones: Application in Synthesis

Keith Smith*a, Gamal A. El-Hitia, Mohamed F. Abdel-Megeedba Centre for Clean Chemistry, Department of Chemistry, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
Fax: +44(1792)295261; e-Mail: k.smith@swansea.ac.uk;
b Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
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Publication History

Received 14 May 2004
Publication Date:
27 July 2004 (eFirst)

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Abstract

Reaction of 3-amino-2-alkylquinazolin-4(3H)-ones with several chiral acid chlorides was found to be dependent on the molar proportions. When a 1:1 molar mixture was heated under reflux, the corresponding 3-(diacylamino)- derivatives were obtained in poor yields. However, when a 2:1 molar mixture was reacted in refluxing toluene, the 3-acylamino- derivatives were obtained in good yields based on the acid chloride. Lithiation of the 3-acylamino-2-alkyl­quinazolin-4(3H)-ones was achieved by the use of lithium diisopropylamide (LDA) in anhydrous THF at -78 °C and the reaction was regioselective at the carbon α to position 2 of the quinazolin-4(3H)-one moiety. The dilithio reagents thus obtained reacted with electrophiles to give the corresponding 2-substituted derivatives in very good yields. The NMR spectra of the products show the expected diastereotopism for all the CH2 groups and provide evidence for long-range asymmetric induction.

Key words

lithiation - quinazolin-4(3H)-ones - dilithio reagent - asymmetric induction - diastereotopism