ABSTRACT
Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.
Subject(s)
Azoles/chemistry , Chemistry Techniques, Synthetic/methods , Stereoisomerism , Catalysis , Molecular Structure , Triazoles/chemistryABSTRACT
A mild cobalt-catalyzed Negishi-type cross-coupling of various functionalized dialkylzinc reagents with primary and secondary alkyl iodides in acetonitrile is reported using a combination of 20% CoCl2 and chelating nitrogen ligands. The method allows the construction of molecules with alkyl chains bearing sensitive functional groups at room temperature.
ABSTRACT
A combination of 10 % CoCl2 and 20 % 2,2'-bipyridine ligands enables cross-coupling of functionalized primary and secondary alkylzinc reagents with various (hetero)aryl halides. Couplings with 1,3- and 1,4-substituted cycloalkylzinc reagents proceeded diastereoselectively leading to functionalized heterocycles with high diastereoselectivities of up to 98:2. Furthermore, alkynyl bromides react with primary and secondary alkylzinc reagents providing the alkylated alkynes.
ABSTRACT
A cobalt-catalyzed acylation reaction of various primary, secondary and tertiary alkyl, benzyl and (hetero)aryl S-pyridyl thioesters with (hetero)arylzinc pivalates is reported. The thioesters were prepared directly from the corresponding carboxylic acids under mild conditions, thus tolerating sensitive functional groups. Acylations of α-chiral S-pyridyl esters proceeded with very high stereoretention leading to optically enriched α-chiral ketones.
ABSTRACT
A practical nickel-catalyzed cross-coupling of (hetero)aryl or alkynylzinc pivalates with various unsaturated nonaflates or triflates is described. Organozinc pivalates allow these cross-couplings to take place with high yields and a low catalyst loading (0.5 mol %). Couplings with ( E)- and ( Z)-alkenyl triflates proceed with retention of configuration.