AI-driven robotic chemist for autonomous synthesis of organic molecules.

The automation of organic compound synthesis is pivotal for expediting the development of such compounds. In addition, enhancing development efficiency can be achieved by incorporating autonomous functions alongside automation. To achieve this, we developed an autonomous synthesis robot that harnesses the power of artificial intelligence (AI) and robotic technology to establish optimal synthetic recipes. Given a target molecule, our AI initially plans synthetic pathways and defines reaction conditions. It then iteratively refines these plans using feedback from the experimental robot, gradually optimizing the recipe. The system performance was validated by successfully determining synthetic recipes for three organic compounds, yielding that conversion rates that outperform existing references. Notably, this autonomous system is designed around batch reactors, making it accessible and valuable to chemists in standard laboratory settings, thereby streamlining research endeavors.

Direct C-H cross-coupling approach to heteroaryl coumarins.

A Pd-catalyzed direct cross-coupling of 3-bromocoumarins with heteroarenes provided an efficient route to synthesizing 3-heteroarylcoumarins. The reaction scope for the transformation was fairly broad, affording modest to good yields of various 3-heteroarylcoumarin scaffolds, which are privileged structures and prevalent motifs in many biologically active compounds and fluorophores.

Direct Phosphonation of Quinolinones and Coumarins Driven by the Photochemical Activity of Substrates and Products.

Light-promoted phosphonation of quinolinones and coumarins was developed without the need for an external photocatalyst. Investigations support a mechanism whereby both starting materials and products act as photosensitizers upon excitation using compact fluorescent light sources to photochemically promote the dissociation of the N-O bond in the pyridinium salt by a single electron transfer pathway. A wide range of quinolinone and coumarin substrates can be utilized in the phosphonation process under mild reaction conditions.

Unraveling innate substrate control in site-selective palladium-catalyzed C-H heterocycle functionalization.

Understanding the regioselectivity of C-H activation in the absence of directing groups is an important step towards the design of site-selective C-H functionalizations. The Pd(ii)-catalyzed direct arylation of chromones and enaminones provides an intriguing example where a simple substitution leads to a divergence in substrate-controlled site-selectivity. We describe computational and experimental studies which reveal this results from a switch in mechanism and therefore the selectivity-determining step. We present computational results and experimentally measured kinetic isotope effects and labelling studies consistent with this proposal. The C-H activation of these substrates proceeds via a CMD mechanism, which favors more electron rich positions and therefore displays a pronounced kinetic selectivity for the C3-position. However, C2-selective carbopalladation is also a competitive pathway for chromones so that the overall regiochemical outcome depends on which substrate undergoes activation first. Our studies provide insight into the site-selectivity based on the favorability of two competing CMD and carbopalladation processes of the substrates undergoing coupling. This model can be utilized to predict the regioselectivity of coumarins which are proficient substrates for carbopalladation. Furthermore, our model is able to account for the opposite selectivities observed for enaminone and chromone, and explains how a less reactive coupling partner leads to a switch in selectivity.

AgSbF6-controlled diastereodivergence in alkyne hydroarylation: facile access to Z- and E-alkenyl arenes.

AgSbF6-controlled diastereodivergent hydroarylation reactions were developed. Unprecedented and remarkable switching of the E/Z-stereoselectivity could be obtained by adjusting the AgSbF6 loading.

One-pot catalysis of dehydrogenation of cyclohexanones to phenols and oxidative Heck coupling: expedient synthesis of coumarins.

One-pot reactions leading to highly functionalized coumarins have been developed via a Pd(II)-catalyzed dehydrogenation-oxidative Heck-cyclization process.

Regioselective palladium-catalyzed olefination of coumarins via aerobic oxidative Heck reactions.

Pd-catalyzed oxidative Heck reactions of coumarins were developed via simultaneous C-H functionalization at the C3 position of coumarins under aerobic conditions.

Regioselective palladium-catalyzed direct cross-coupling of coumarins with simple arenes.

An efficient method for the C4-regiocontrolled C-H functionalization of coumarins to enable facile oxidative cross-couplings with simple arene components is disclosed.