Philippe Franck

Dual effect of halides in the Stille reaction: in situ halide metathesis and catalyst stabilization.

Halide anions can increase or decrease the transmetallation rate of the Stille reaction through in situ halide metathesis. Although the influence of the halogen present in oxidative addition complexes on the transmetallation rate with organostannanes was already known, the application of in situ halide metathesis to accelerate cross-coupling reactions with organometallic reagents is not described in the literature yet. In addition a second unprecedented role of halides was discovered. Halide anions stabilize the [Pd(0)(L)(2)] catalyst in Stille reactions, by means of [Pd(0)X(L)(2)](-) formation (X=Cl, I), hereby preventing its leaching from the catalytic cycle. Both arene (iodobenzene) and azaheteroarene (2-halopyridine, halopyrazine, 2-halopyrimidine) substrates were used.

Amine Activation: Synthesis of N-(Hetero)arylamides from Isothioureas and Carboxylic Acids

A novel method for N-(hetero)arylamide synthesis based on rarely explored amine activation, rather than classical acid activation, is reported. The activated amines are easily prepared using a three-component reaction with commercial reagents. The new method shows a broad scope including challenging amides not (efficiently) accessible via classical protocols.

2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors

New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.

Concise Xanthine Synthesis through a Double-Amidination Reaction of a 6-Chlorouracil with Amidines using Base-Metal Catalysis.

A new and concise route towards xanthines through a double-amidination reaction is described; consecutive intermolecular C-Cl and intramolecular oxidative C-H amidination. N-uracil amidines are obtained through SN AE on a 6-chlorouracil with amidines. Direct Cu-catalyzed oxidative C-H amidination on these N-uracil amidines yields polysubstituted xanthines. Sustainable oxidants, tBu2 O2 or O2 , can be used in this oxidase-type reaction. The protocol allows for the introduction of N1, N3, N7, and C8 substituents during the xanthine-scaffold construction, thus avoiding post-functionalization steps. Both 6-chlorouracils and amidines are readily available commercially or through synthesis.