Sonogashira cross-coupling reaction in 4-chloro-2-trichloromethylquinazoline series is possible despite a side dimerization reaction

• Published in: Tetrahedron Vol. 69; no. 14; pp. 2987 - 2995
• Main Authors: Kieffer, Charline, Verhaeghe, Pierre, Primas, Nicolas, Castera-Ducros, Caroline, Gellis, Armand, Rosas, Roselyne, Rault, Sylvain, Rathelot, Pascal, Vanelle, Patrice
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 08.04.2013; Elsevier
• Subjects: Chemical Sciences; Chemistry; Chemistry, Organic; Organic chemistry; Physical Sciences; Quinazoline ring; Reductive homocoupling reaction; Science & Technology; Sonogashira cross-coupling reaction; Trichloromethyl group; Trichloromethyl group; Sonogashira cross-coupling reaction; Reductive homocoupling reaction; Quinazoline ring; ANTIPLASMODIAL ACTIVITY; ACETYLENES; ALKYNES; IDENTIFICATION; DERIVATIVES
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2013.01.094

We studied the Sonogashira coupling reaction between 4-chloro-2-trichloromethylquinazoline and various terminal alkynes, mainly in phenylacetylene series. A brief review of the literature shows that mono- or polybromo/chloromethylated substrates, especially in aromatic series, are very rarely compatible with the achievement of Sonogashira reactions. Thus, although the 4-chloroquinazoline scaffold is a very good substrate for this palladium-catalyzed reaction, the typical behavior of the trichloromethyl group in reductive media leads to the competitive formation of undesirable reduced homodimers in high yields. However, by closely examining all the Sonogashira reaction parameters, we developed a specific operating procedure, using Pd(OAc)2, Cs2CO3, and DMF, which resulted in the synthesis of 14 original coupling products in 10–70% yield, depending on the alkyne used. [Display omitted]