Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp²)–C(sp³) Cross-Coupling Methods by Library Synthesis

Abstract

Despite recent advances in the field of C­(sp2)–C­(sp3) cross-couplings and the accompanying increase in publications, it can be hard to determine which method is appropriate for a given reaction when using the highly functionalized intermediates prevalent in medicinal chemistry. Thus a study was done comparing the ability of seven methods to directly install a diverse set of alkyl groups on “drug-like” aryl structures via parallel library synthesis. Each method showed substrates that it excelled at coupling compared with the other methods. When analyzing the reactions run across all of the methods, a reaction success rate of 50% was achieved. Whereas this is promising, there are still gaps in the scope of direct C­(sp2)–C­(sp3) coupling methods, like tertiary group installation. The results reported herein should be used to inform future syntheses, assess reaction scope, and encourage medicinal chemists to expand their synthetic toolbox.

Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates

“…Notably, coupling of the methylcyclopropane fragment with aryl halides is virtually unreported in the present literature, with a single example producing arylated product in 6% yield. 41 We next examined 1-phenylcyclopropane 17d. The BF 3 K analogue of this substrate was shown previously to couple using cata-CXium A G2 precatalyst, Cs 2 CO 3 in PhMe/H 2 O at 95 C, 39 conditions which returned only starting materials when applied to the coupling of the Bpin substrate 17d.…”

A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides

“…Celebrex (46, 87% yield), Navoban (47, 52% yield), Skelaxin (48, 87% yield), and Dogmatil (49, 73% yield) were all expediently converted to complex N-alkyl analogs using various bromide coupling partners, with basic and oxidation-prone 67 tertiary amines notably tolerated in several cases. 68 Given the prevalence of heterocyclic Nnucleophiles in drug candidates, this platform should provide medicinal chemists facile access to diverse pharmaceutical analogs via modular, late-stage N-alkylation.…”

Palladium‐Catalyzed Cross‐Coupling of Alkenyl Carboxylates

“…Many of these reactions occur at room temperature with no need for inert atmosphere, use water as a co‐solvent, and do not require exogenous base. This process takes advantage of the broad functional‐group tolerance common to many Pd catalyzed reactions to functionalize multiple pharmaceutically relevant heterocycles. The success of this method is in stark contrast to the general perception that Pd catalysts are less reactive or inert toward many C(sp 2 )−O electrophiles …”