Chemoselective Copper-Catalyzed Ullmann-Type Coupling of Oxazolidinones with Bromoiodoarenes

We describe the highly selective copper-catalyzed Ullmann-type coupling of bromoiodoarenes with oxazolidinones. 3,4,7,8-Tetramethyl-1,10-phenanthroline (Me₄Phen) was identified as an optimal ligand promoting the desired C–N bond formation, while minimizing the competitive bromo–iodo exchange pathway that leads to formation of iodo-substituted and bis-coupled side products. The developed method is highly selective with a >98:2 ratio of the bromo- vs iodo-substituted compounds obtained in the isolated products

Heteroarylation of Azine <i>N</i>-Oxides

Azine <i>N</i>-oxides undergo highly regioselective metalation with TMPZnCl·LiCl under mild conditions. A palladium-catalyzed Negishi cross-coupling reaction of the resulting organozinc species with heteroaromatic bromides provides heterobiaryls specifically oxidized at one nitrogen position in up to 95% yield

Practical Synthesis of a 6‑Triazolylazabicyclo[3.1.0]hexane

We describe a practical, scalable synthesis of an advanced heterocyclic intermediate, (1<i>R</i>,5<i>S</i>,6<i>s</i>)-6-(4<i>H</i>-1,2,4-triazol-4-yl)-3-azabicyclo­[3.1.0]­hexane. A robust synthetic sequence based on a Kulinkovich–de Meijere pyrroline cyclopropanation followed by transamination of <i>N</i>,<i>N</i>′-dimethylformamide azine with the resultant amine was developed to supply >18 kg of the target triazolyl azabicycle with 98 wt % purity in its free base form. Reaction conditions and isolation methods for the key 1,2,4-triazole formation step were explored to minimize undesired reaction pathways and to increase the purity of the product. Additionally, at several stages different freebasing methods were implemented that addressed the high water solubility of the associated nitrogen-rich compounds

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the <i>E</i>/<i>Z</i> Selectivities

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately <i>Z</i>-selective in neat tetrahydrofuran (THF) and <i>E</i>-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of <i>E</i>,<i>E</i>-, <i>E</i>,<i>Z</i>-, and <i>Z</i>,<i>Z</i>-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for <i>E</i> and <i>Z</i> isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in <i>N</i>,<i>N</i>-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing <i>E</i> and <i>Z</i> isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures

Highly Diastereoselective α‑Arylation of Cyclic Nitriles

A highly diastereoselective α-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl•LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles

Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals

Palladium-Catalyzed Site-Selective Amidation of Dichloroazines

A highly site-selective amidation reaction of substituted 2,4-dichloroazines is reported. Palladium acetate/1,1′-bis­(diphenylphosphino)­ferrocene (dppf) was identified as the optimal catalyst system, producing >99:1 C-2/C-4 selectivity for most examples. The generality of this transformation was demonstrated through a survey of a diverse amide/substituted 2,4-dichloroazine scope, leading to the preparation of the desired C-2 amidated products in good to excellent yields

Palladium-Catalyzed Site-Selective Amidation of Dichloroazines

A highly site-selective amidation reaction of substituted 2,4-dichloroazines is reported. Palladium acetate/1,1′-bis­(diphenylphosphino)­ferrocene (dppf) was identified as the optimal catalyst system, producing >99:1 C-2/C-4 selectivity for most examples. The generality of this transformation was demonstrated through a survey of a diverse amide/substituted 2,4-dichloroazine scope, leading to the preparation of the desired C-2 amidated products in good to excellent yields

An Efficient Through-Process for Chk1 Kinase Inhibitor GDC-0575

We report an efficient route to prepare Chk1 kinase inhibitor GDC-0575 from 5-bromo-4-chloro-3-nitro-7-azaindole featuring a sequence of nucleophilic aromatic substitution, hydrogenative nitro-reduction, and a robust, high-yielding end-game involving deprotection–crystallization steps. The developed route was demonstrated on 10 kg scale in 30% overall yield to provide the target API in >99.8 A % HPLC purity