Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to -butyl 3-oxo-3-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor (), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by -butyllithium, participated in umpolung reactivity via 1,2-addition to -butyl 4-oxopiperidine-1-carboxylate (-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures.

Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings.

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura crosscouplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates.

Total Synthesis of Kadcoccinic Acid A Trimethyl Ester.

The first total synthesis of the trimethyl ester of kadcoccinic acid A is described. The central structural element of our synthesis is a cyclopentenone motif that allows the assembly of the natural product skeleton. A gold(I)-catalyzed cyclization of an enynyl acetate led to efficient construction of the cyclopentenone scaffold.

Palladium-Catalyzed Asymmetric Allylic Fluoroalkylation/Trifluoromethylation.

The first palladium-catalyzed asymmetric allylic trifluoromethylation is disclosed. The methodology evokes a fundamental principle by which the synergistic interplay of a leaving group and its subsequent activation of the nucleophilic trifluoromethyl group enabled the reaction. Allyl fluorides have been shown to be superior precursors for generation of π-allyl complexes, which lead to trifluoromethylated products with high selectivities and functional group tolerance.

3d Transition Metals for C-H Activation.

C-H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C-H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C-H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative.

Enantio- and Diastereoselective Synthesis of Chiral Allenes by Palladium-Catalyzed Asymmetric [3+2] Cycloaddition Reactions.

A protocol for the asymmetric synthesis of highly substituted chiral allenes with control of point and axial chirality has been developed. A palladium-catalyzed [3+2] cycloaddition using readily available racemic allenes gives access to densely functionalized chiral allenes with excellent yields and functional group tolerance. The catalytic asymmetric protocol utilizes a broad range of allenyl TMM (trimethylenemethane) donors to form cyclopentanes, pyrrolidines, and spirocycles with very good control of regio-, enantio-, and diastereoselectivity.

Cobalt-catalyzed C-H cyanations: Insights into the reaction mechanism and the role of London dispersion.

Carboxylate-assisted cobalt(III)-catalyzed C-H cyanations are highly efficient processes for the synthesis of (hetero)aromatic nitriles. We have now analyzed the cyanation of differently substituted 2-phenylpyridines in detail computationally by density functional theory and also experimentally. Based on our investigations, we propose a plausible reaction mechanism for this transformation that is in line with the experimental observations.

Asymmetric Iron-Catalyzed C-H Alkylation Enabled by Remote Ligand meta-Substitution.

Highly enantioselective iron-catalyzed C-H alkylations by inner-sphere C-H activation were accomplished with ample scope. High levels of enantiocontrol proved viable through a novel ligand design that exploits a remote meta-substitution on N-heterocyclic carbenes within a facile ligand-to-ligand H-transfer C-H cleavage.

Mild Cobalt(III)-Catalyzed Allylative C-F/C-H Functionalizations at Room Temperature.

Sustainable, cobalt-catalyst enabled, synthetically significant C-F/C-H functionalizations were achieved with an ample substrate scope at an ambient temperature of 25 °C, thereby delivering perfluoroallylated heteroarenes. Detailed experimental and computational mechanistic studies on the C-F/C-H functionalizations provided strong support for a facile C-F cleavage.

Full Selectivity Control in Cobalt(III)-Catalyzed C-H Alkylations by Switching of the C-H Activation Mechanism.

Selectivity control in hydroarylation-based C-H alkylation has been dominated by steric interactions. A conceptually distinct strategy that exploits the programmed switch in the C-H activation mechanism by means of cobalt catalysis is presented, which sets the stage for convenient C-H alkylations with unactivated alkenes. Detailed mechanistic studies provide compelling evidence for a programmable switch in the C-H activation mechanism from a linear-selective ligand-to-ligand hydrogen transfer to a branched-selective base-assisted internal electrophilic-type substitution.

Ruthenium(II)-Catalyzed C-H Oxygenations of Reusable Sulfoximine Benzamides.

C-H oxygenations of synthetically meaningful sulfoximine benzamides were accomplished by a versatile ruthenium catalysis regime. The ruthenium(II) catalyst was characterized by excellent mono- and chemoselectivity as well as positional selectivity via facile base-assisted intramolecular electrophilic substitution-type (BIES) C-H activation. The synthetic utility of the approach was reflected by high functional group tolerance and sulfoximine removal in a traceless fashion.

Mild C-H/C-C Activation by Z-Selective Cobalt Catalysis.

Cationic cobalt complexes enable unprecedented cobalt-catalyzed C-H/C-C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C-H/C-C cleavage at room temperature, and delivered Z-alkenes with excellent diastereocontrol.

Single-Component Phosphinous Acid Ruthenium(II) Catalysts for Versatile C-H Activation by Metal-Ligand Cooperation.

Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs.

N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C-H tert-Alkylation with Removable Auxiliaries.

Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations.

Manganese-catalyzed synthesis of cis-β-amino acid esters through organometallic C-H activation of ketimines.

Manganese-catalyzed CH functionalization reactions of ketimines set the stage for the expedient synthesis of cis-β-amino acid esters through site- and regioselective alkene annulations. The organometallic CH activation occurred efficiently with high functional group tolerance, delivering densely functionalized β-amino acid derivatives with ample scope.