ABSTRACT
An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct.
Subject(s)
Lithium/chemistry , Nitriles/chemistry , Nitriles/chemical synthesis , Organometallic Compounds/chemistry , Catalysis , Chemistry Techniques, Synthetic , Indicators and Reagents/chemistryABSTRACT
A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , HIV/enzymology , Acylation , Catalysis , Copper/chemistry , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemistry , Humans , Ligands , Stereoisomerism , Sulfonamides/chemistryABSTRACT
The key Pd-catalyzed cross-coupling of aryl bromides or triflates and cyclopropylmagnesium bromide in the presence of substoichiometric amounts of zinc bromide produces cyclopropyl arenes in good to excellent yields. The cross-coupling of other alkyl, cycloalkyl, and aryl Grignard reagents with aryl bromides under the same conditions gives the corresponding substituted arenes in good yields.
Subject(s)
Bromides/chemistry , Calixarenes/chemical synthesis , Hydrocarbons, Brominated/chemistry , Organometallic Compounds/chemistry , Palladium/chemistry , Zinc Compounds/chemistry , Calixarenes/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
Reaction of 4-bromo-NH-1,2,3-triazoles 2 with alkyl halides in the presence of K(2)CO(3) in DMF produced the corresponding 2-substituted 4-bromo-1,2,3-triazoles 5 in a regioselective process. Subsequent Suzuki cross-coupling reaction of these bromides provided an efficient synthesis of 2,4,5-trisubstituted triazoles 3. In addition, reduction of the bromotriazoles by hydrogenation furnished an efficient synthesis of 2,4-disubstituted triazoles 8.
