Tomislav Rovis

Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

The functionalization of C(sp3 )-H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3 )-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.

Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic meso-Anhydrides

The enantioselective desymmetrization of cyclic meso-anhydrides with benzyl trifluoroborates under nickel-photoredox catalysis is described. The reaction tolerates a variety of sterically and electronically different trifluoroborates, as well as structurally unique cyclic anhydrides. The trans isomer of the keto-acid products is also observed at varying levels dependent on the trifluoroborate identity and relative catalyst loading. A mechanism involving decarbonylation and Ni-C bond homolysis of a NiII adduct is proposed. This feature allows access to a trans keto-acid as the major product in high enantioselectivity from a cis meso anhydride.

N-Heterocyclic Carbene and Chiral Bronsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation

A chiral NHC/Brønsted acid cooperative catalysis system has been developed for asymmetric annulation of functionalized benzaldehydes and activated ketones through dearomative generation of dienolate.

Ir(III)-Catalyzed Carbocarbation of Alkynes through Undirected Double C–H Bond Activation of Anisoles

A novel, electron-deficient cyclopentadienyl iridium(III) catalyst enables sequential cleavage of arene C(sp2)-H and methoxy C(sp3)-H bonds of anisoles, generating reactive metalacycles that insert difluoroalkynes to afford chromenes under mild reaction conditions. This transformation is an arylalkylation of an alkyne-a carbocarbation-via a nonchelate-assisted cleavage of two C-H bonds.

Experimental and Computational Gas Phase Acidities of Conjugate Acids of Triazolylidene Carbenes: Rationalizing Subtle Electronic Effects

In recent years, triazolylidene carbenes have come to the forefront as important organocatalysts for a wide range of reactions. The fundamental properties of these species, however, remain largely unknown. Herein, the gas phase acidities have been measured and calculated for a series of triazolium cations (the conjugate acids of the triazolylidene carbenes) that have not been heretofore examined in vacuo. The results are discussed in the context of these species as catalysts. We find correlations between the gas phase acidity and selectivity in two Umpolung reactions catalyzed by these species; such correlations are the first of their kind. We are able to use these linear correlations to improve reaction enantioselectivity. These results establish the possibility of using these thermochemical properties to predict reactivity in related transformations.

Direct α-alkylation of primary aliphatic amines enabled by CO 2 and electrostatics

AbstractPrimary aliphatic amines are important building blocks in organic synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Experimental and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermolecular HAT by an electrostatically accelerated interaction between the in situ-generated negatively charged carbamate and the positively charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissociation energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.CO2 can be used as an activator for the direct transformation of abundant and unprotected primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen-atom-transfer catalysis. Electrostatic interactions between the in situ generated alkylammonium carbamate and the positively charged quinuclidinium radical lead to regioselective hydrogen atom abstraction.n

Stereodivergent Rhodium(III)-Catalyzed cis-Cyclopropanation Enabled by Multivariate Optimization

The design of stereodivergent transformations is of great interest to the synthetic community as it allows funneling of a given reaction pathway toward one stereochemical outcome or another by only minor adjustments of the reaction setup. Herein, we present a physical organic approach to invert the sense of induction in diastereoselective cyclopropanation of alkenes with N-enoxyphthalimides through rhodium(III) catalysis. Careful parametrization of catalyst-substrate molecular determinants allowed us to interrogate linear-free energy relationships and establish an intuitive and robust statistical model that correlates an extensive number of data points in high accuracy. Our multivariate correlations-steered mechanistic investigation culminated with a robust and general diastereodivergent cyclopropanation tool where the switch from trans- to cis-diastereoinduction is attributed to a mechanistic dichotomy. Selectivity might be determined by the flexibility of rhodacyclic intermediates derived from ring-opened versus -unopened phthalimides, induced by both their respective ring size and the Sterimol B1 parameter of the CpX ligand on rhodium.

A Photochemical Two-Step Formal [5+2] Cycloaddition: A Condensation–Ring-Expansion Approach to Substituted Azepanes

Seven-membered nitrogen-containing heterocycles are considerably underrepresented in the literature compared to their five- and six-membered analogues. Herein, we report a relatively understudied photochemical rearrangement of N-vinylpyrrolidinones to azepin-4-ones in good yields. This transformation allows for the conversion of readily available pyrrolidinones and aldehydes to densely functionalized azepane derivatives in a facile two step procedure.