A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs—with varying length, polarity, and rigidity—were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure–activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design–make–test cycles.

Arene amination is achieved by site-selective C–H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amido diethylzincate base that is effective for a wide range of arenes, including non-activated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine and isoquinoline. An analogous C–H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable, diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogs of natural product (–)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.

Direct amination of heteroarenes and arenes has been achieved in a one-pot C–H zincation/copper-catalyzed electrophilic amination procedure. This amination method provides an efficient and rapid approach to access a diverse range of heteroaromatic and aromatic amines including those previously inaccessible using C–H amination methods. The mild reaction conditions and good functional-group compatibility demonstrate its great potential for the synthesis of important and complex amines.

A new approach to access o-haloaminoarenes has been achieved by insertion of arynes into a nitrogen–halide bond (N–X). This transition-metal-free transformation displays a broad substrate scope of arynes, good compatibility with functional groups, and high regioselectivity. Representative transformations of the o-haloaminoarenes are described to highlight their utility for rapid access to diversely functionalized aminoarene derivatives.