Exploiting hydrazones to improve the efficiency of 6π-electrocyclization reactions of 1-azatrienes

The greater geometric lability of hydrazones compared to that of oxime ethers is used as a basis to overcome the reluctance of Z-oxime ether azatrienes to undergo electrocyclization toward the synthesis of borylated (heteroaromatic) pyridines and ring-fused analogues. Such hydrazones now allow access to previously inaccessible tri- and tetrasubstituted 3-borylpyridines in high yields

Synthesis of bifunctional thiophenes via Fiesselmann condensation of ynone trifluoroborate salts

Ynone trifluoroborate salts undergo a base-promoted condensation reaction with alkylthiols to generate thiophene boronates with complete regiocontrol. The products are isolated in high yield and can be further derivatized through conventional C-B bond functionalization reactions

Design and synthesis of novel pyrazole based heterotricycles and their derivatization via automated library synthesis

Small molecule heterocycles bearing orthogonal functionality have the potential to deliver diverse structural motifs that aid the drug discovery effort. This work highlights how a readily assembled N ‐hydroxyethyl pyrazole trifluoroborate offers rapid access to architecturally distinct 5‐6‐6 and 5‐7‐6 fused tricyclic compounds. This chemistry is not only amenable to single compound synthesis, but also to high throughput experimentation. It enables easy access to diverse compound arrays with varying physchem and ADME profiles by fully automated library synthesis. The combination of the high throughput experimentation with rapid testing of the compounds in an integrated physchem and ADME profiling workflow allows accelerated design of novel lead compounds in drug discovery projects

Synthesis and Modular Reactivity of Pyrazole 5-Trifluoroborates: Intermediates for the Preparation of Fully-Functionalized Pyrazoles.

The regioselective condensation of hydrazines and ynone trifluoroborates provides access to a range of pyrazole 5-trifluoroborates. The stability of the borate unit allows chemoselective halogenation of the heteroaromatic ring, thereby delivering pyrazole scaffolds that allow orthogonal functionalization at C5 and C4. The modular reactivity of these intermediates is exemplified by cross-coupling reactions, enabling regiocontrolled synthesis of fully-functionalized pyrazole derivatives

Pyrimidin‐6‐yl trifluoroborate salts as versatile templates for heterocycle synthesis

We report a novel and general method to access a highly under‐studied privileged scaffold – pyrimidines bearing a trifluoroborate at C4, and highlight the broad utility of these intermediates in a rich array of downstream functionalization reactions. This chemistry is underpinned by the unique features of the trifluoroborate group; its robustness provides an opportunity to carry out chemoselective reactions at other positions on the pyrimidine while providing a pathway for elaboration at the C‐B bond when suitably activated

Streamlining bioactive molecular discovery through integration and automation

The discovery of bioactive small molecules is generally driven via iterative design–make–purify–test cycles. Automation is routinely harnessed at individual stages of these cycles to increase the productivity of drug discovery. Here, we describe recent progress to automate and integrate two or more adjacent stages within discovery workflows. Examples of such technologies include microfluidics, liquid-handling robotics and affinity-selection mass spectrometry. The value of integrated technologies is illustrated in the context of specific case studies in which modulators of targets, such as protein kinases, nuclear hormone receptors and protein–protein interactions, were discovered. We note that to maximize impact on the productivity of discovery, each of the integrated stages would need to have both high and matched throughput. We also consider the longer-term goal of realizing the fully autonomous discovery of bioactive small molecules through the integration and automation of all stages of discovery

Design and synthesis of fused pyridine building blocks for automated library generation

We demonstrate that a diboration‐electrocyclization sequence provides access to a range of pyridine fused small molecule boronic ester building blocks, and that these are amenable to high throughput synthesis leading to biaryl and ether linked compound libraries. Moreover, the implementation of an integrated physchem and ADME profiling workflow allows accelerated design of novel lead compounds for application in drug discovery projects

A palladium-catalyzed domino reaction to access 3-amino-2H-indazoles from hydrazines and 2-halobenzonitriles

The development of a novel selective synthesis of 3-amino-2H-indazoles from readily available 2-halobenzonitriles is presented. The reaction proceeds through a domino reaction sequence, consisting of a regioselective palladium-catalyzed coupling of monosubstituted hydrazines with 2-halobenzonitriles, followed by an intramolecular hydroamination through a 5-exo-dig cyclization and subsequent isomerization to directly afford a wide variety of substituted 2H-indazole analogues in good to excellent yields