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Fast and accurate prospective predictions of the regioselectivity can significantly reduce the time and resources spent on unproductive transformations in the pharmaceutical industry. Density functional theory (DFT) reaction modeling through transition state theory (TST) and machine learning (ML) methods have been widely used to predict reaction outcomes such as selectivity. However, TST reaction modeling and ML methods are either time-consuming or data dependent. Herein, we introduce a prototype seamlessly bridging machine learning and TST modeling by triggering the resource-intensive but much less domain sensitive DFT calculation only on less confident ML predictions. The proposed workflow was trained and tested on both Pfizer internal dataset and USPTO public dataset to predict regioselectivity for SNAr reactions. Our method is accurate and fast which achieves 96.3% and 94.7% accuracy predicting the correct major product on Pfizer and USPTO datasets, respectively, in a fraction of conventional TST computing time.

A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tert-butyl isocyanide as a CO source. The intermediate 1,2-diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis- vs monoinsertion product.

Several classes of enantioselective silylations of C-H bonds have been reported recently, but little mechanistic data on these processes are available. We report mechanistic studies on the rhodium-catalyzed, enantioselective silylation of aryl C-H bonds. A rhodium silyl dihydride and a rhodium norbornyl complex were prepared and determined to be interconverting catalyst resting states. Kinetic isotope effects indicated that the C-H bond cleavage step is not rate-determining, but the C-H bond cleavage and C-Si bond-forming steps together influence the enantioselectivity. DFT calculations indicate that the enantioselectivity originates from unfavorable steric interactions between the substrate and the ligand in the transition state leading to the formation of the minor enantiomer.

The functionalization of unactivated C(sp(3))-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond β to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of unactivated C(sp(3))-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.

We describe an enantioseleclive silylation of cyclopropanes catalyzed by a rhodium precursor and the bisphosphine (S)-DTBM-SEGPHOS. (Hydrido)silyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C-H bonds in high yields with high enantiomeric excesses in the presence of the rhodium catalyst. The resulting enantioenriched oxasilolanes are suitable substrates for Tamao-Fleming oxidation to form cyclopropanols with conservation of the ee from the C-H bond silylation. Preliminary mechanistic data suggest that C-H cleavage is likely to be the turnover-limiting and enantioselectivity-determining step.

Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C-H bonds in high yields and with high enantiomeric excesses in the presence of a rhodium catalyst derived from a rhodium precursor and the bisphosphine (S)-DTBM-SEGPHOS. The resulting enantioenriched oxasilolanes are suitable substrates for the Tamao-Fleming oxidation to form cyclopropanols with conservation of the ee value from the C-H silylation. Preliminary mechanistic data suggest that C-H cleavage is likely to be the turnover-limiting and enantioselectivity-determining step.

The hydrosilylation of symmetrical benzophenones (II) and (X) with diethylsilane followed by Rh-catalyzed asymmetric intramolecular silylation gives rise to chiral benzoxasiloles (IV) and (XI), respectively.

We report a Rh-catalyzed, enantioselective silylation of arene C–H bonds directed by a (hydrido)silyl group. (Hydrido)silyl ethers that are formed in situ by hydrosilylation of benzophenone or its derivatives undergo asymmetric C–H silylation in high yield with excellent enantioselectivity in the presence of [Rh(cod)Cl]2 and a chiral bisphosphine ligand. The stereoselectivity of this process also allows enantioenriched diarylmethanols to react with site selectivity at one aryl group over the other. Enantioenriched benzoxasiloles from the silylation process undergo a range of transformations to form C–C, C–O, C–I, or C–Br bonds.