DNA-encoded
library (DEL) technology has emerged as a novel interrogation
modality for ligand discovery in the pharmaceutical industry. Given
the increasing demand for a higher proportion of C(sp3)-hybridized
centers in DEL platforms, a photoredox-mediated cross-coupling and
defluorinative alkylation process is introduced using commercially
available alkyl bromides and structurally diverse α-silylamines.
Notably, no protecting group strategies for amines are necessary for
the incorporation of a variety of amino-acid-based organosilanes,
providing crucial branching points for further derivatization.
The concurrent installation of C−C and C−N bonds across alkene frameworks represents a powerful tool to prepare motifs that are ubiquitous in pharmaceuticals and bioactive compounds. To construct such prevalent bonds, most alkene difunctionalization methods demand the use of precious metals or activated alkenes. We report a metal-free, photochemically mediated imino-alkylation of electronically diverse alkenes to install both alkyl and iminyl groups in a highly efficient manner. The exceptionally mild reaction conditions, broad substrate scope, excellent functional group tolerance, and facile one-pot reaction protocol highlight the utility of this method to prepare privileged motifs from readily available alkene and acid feedstocks. One key and striking feature of this transformation is that an electrophilic trifluoromethyl radical is equally efficient with both electrondeficient and electron-rich alkenes. Additionally, dispersion-corrected density functional theory (DFT) and empirical investigations provide detailed mechanistic insight into this reaction.
A general aminoalkylation of aryl
halides was developed, overcoming
intolerance of free amines in nickel-mediated C–C coupling.
This transformation features broad functional group tolerance and
high efficiency. Taking advantage of the fast desilylation of α-silylamines
upon single-electron transfer (SET) facilitated by carbonate, α-amino
radicals are generated regioselectively, which then engage in nickel-mediated
C–C coupling. The reaction displays high chemoselectivity for
C–C over C–N bond formation. Highly functionalized pharmacophores
and peptides are also amenable.
Highly strained 1,3-disubstituted bicyclo[1.1.1]pentanes
(BCPs)
have been established as bioisosteres of para-disubstituted
benzene because they impart valuable pharmacokinetic properties. Herein,
we demonstrate an energy transfer-mediated protocol for acylboration
of [1.1.1]propellanes that allows the direct construction of various
carbonyl species, such as carbamoyl-, carboxyl-, and acyl-, in tandem
with synthetically versatile pinacol boronate (Bpin) groups onto the
BCP substructure under simple reaction conditions. Moreover, drug-like
molecules containing BCP boronates are further submitted to late-stage
functionalization events. Several important transformations of the
Bpin functional group of BCP boronates, including photoinduced cross-coupling
reactions of BCP-BF3K, derived from BCP-Bpin, were successfully
performed to showcase the synthetic utility. Additionally, diverse
and elaborate mechanistic investigations were performed to provide
mechanistic insights, and a plausible reaction mechanism is proposed.
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