Base-Free Cross-Couplings of Aryl Diazonium Salts in Methanol: PdII -Alkoxy as Reactivity-Controlling Intermediate.

Pd-catalyzed cross-coupling reactions of aryl diazonium salts are generally assumed to proceed via cationic PdII intermediates which in turn would be highly reactive in the subsequent transmetalation step. Contrary to this belief, we herein report our observation and rationalization of opposing reactivities of ArN2+ in Suzuki (=effective) and Stille (=ineffective) cross-couplings in MeOH. Our systematic experimental and computational studies on the roles of transmetalating agent, solvent, base and the likely involvement of in situ formed diazoether derivatives challenge the currently accepted mechanism. Our data suggest that the observed solvent dichotomy is primarily due to PdII -methoxy intermediates being formed, which are unreactive with arylstannanes, but highly reactive with arylboronic acids, complementing the Suzuki "Pd-oxy" mechanism with the direct demonstration of transmetalation of a PdII -alkoxy complex. Lewis acids were found to circumvent this reactivity divergence, promoting efficient couplings regardless of the employed conditions or coupling partners.

Technology Trends of Catalysts in Hydrogenation Reactions: A Patent Landscape Analysis.

The purpose of this review is to present an overview of the patent landscape for catalysts used in hydrogenation reactions. Based on patent data extracted from PatBase®, we use predefined patent classifications as well as a keyword-based search for our analyses. The results indicate that the number of patent families that protect heterogeneous catalysts grows twice as fast as that for their homogeneous counterparts. Furthermore, the data show a shift towards abundant and non-toxic elements in heterogeneous catalysis, while the noble metals continue to dominate the patent landscape of homogeneous catalysis. A subsequent geographical analysis reveals that the high growth rates in heterogeneous catalysis, especially for nickel and iron, are driven by China. Conversely, patenting activities with regard to homogeneous catalysts mainly take place in the USA, the EU, and Japan. The subsequent keyword-based search illustrates the continuous industrial relevance of enantioselective hydrogenation and transfer hydrogenation, as well as the rapidly increasing body of patents in hydrodeoxygenation. Setting these finding into context, we present and apply two concepts that are commonly used in patent analyses, namely the technology life cycle and the S-curve. We conclude that hydrogenation catalysis has not reached its peak economic relevance yet and will continue to spark valuable patents and innovations in the future.

Visible-Light-Mediated Charge Transfer Enables C-C Bond Formation with Traceless Acceptor Groups.

The development and application of traceless acceptor groups in photochemical C-C bond formation is described. This strategy was enabled by the photoexcitation of electron donor-acceptor (EDA) complexes with visible light. The traceless acceptors, which were readily prepared from amino acid and peptide feedstocks, could be used to alkylate a wide range of heteroarene and enamine donors under metal- and peroxide-free conditions. The crucial role of the EDA complexes in the mechanism of these reactions was explored through combined experimental and computational studies.

Deaminative Borylation of Aliphatic Amines Enabled by Visible Light Excitation of an Electron Donor-Acceptor Complex.

A deaminative strategy for the borylation of aliphatic primary amines is described. Alkyl radicals derived from the single-electron reduction of redox-active pyridinium salts, which can be isolated or generated in situ, were borylated in a visible light-mediated reaction with bis(catecholato)diboron. No catalyst or further additives were required. The key electron donor-acceptor complex was characterized in detail by both experimental and computational investigations. The synthetic potential of this mild protocol was demonstrated through the late-stage functionalization of natural products and drug molecules.

Ligand-Enabled Enantioselective Csp3 -H Activation of Tetrahydroquinolines and Saturated Aza-Heterocycles by RhI.

The first rhodium(I)-catalyzed enantioselective intermolecular Csp3 -H activation of various saturated aza-heterocycles including tetrahydroquinolines, piperidines, piperazines, azetidines, pyrrolidines, and azepanes is presented. The combination of a rhodium(I) precatalyst and a chiral monodentate phosphonite ligand is shown to be a powerful catalytic system to access a variety of important enantio-enriched heterocycles from simple starting materials. Notably, the Csp3 -H activation of tetrahydroquinolines is especially challenging due to the adjacent Csp2 -H bond. This redox-neutral methodology provides a new synthetic route to α-N-arylated heterocycles with high chemoselectivity and enantioselectivity up to 97 % ee.

Redox-Neutral Manganese(I)-Catalyzed C-H Activation: Traceless Directing Group Enabled Regioselective Annulation.

A strategy is reported in which traceless directing groups (TDGs) are used to promote the redox-neutral MnI -catalyzed regioselective synthesis of N-heterocycles. Alkyne coupling partners bearing a traceless directing group, which serves as both the chelator and internal oxidant, were used to control the regioselectivity of the annulation reactions. This operationally simple approach is highly effective with previously challenging unsymmetrical alkyne systems, including unbiased dialkyl alkynes, with perfect regioselectivity. The simple conditions and the ability to carry out synthesis on a gram scale underscore the usefulness of this method. The application of this strategy in the concise synthesis of the bioactive compound PK11209 and the pharmaceutical moxaverine is also described.

Deaminative Strategy for the Visible-Light-Mediated Generation of Alkyl Radicals.

A deaminative strategy for the visible-light-mediated generation of alkyl radicals from redox-activated primary amine precursors is described. Abundant and inexpensive primary amine feedstocks, including amino acids, were converted in a single step into redox-active pyridinium salts and subsequently into alkyl radicals by reaction with an excited-state photocatalyst. The broad synthetic potential of this protocol was demonstrated by the alkylation of a number of heteroarenes under mild conditions.

Manganese(I)-Catalyzed Regioselective C-H Allenylation: Direct Access to 2-Allenylindoles.

A MnI -catalyzed regioselective C-H allenylation is reported that allows a broad range of 2-allenylindoles to be synthesized regioselectively on a gram scale under simple conditions. Notably, a highly efficient chirality transfer was observed (up to 93 % ee) in this transformation. This procedure was further found to allow, for the first time, the direct preparation of ketones by MnI -catalyzed C-H activation. Mechanistic investigations revealed that the precoordination of the oxygen atom to the manganese center as well as the congested tertiary carbon atom in the propargylic carbonates play a crucial role.

Manganese-catalyzed allylation via sequential C-H and C-C/C-Het bond activation.

Manganese-catalyzed sequential C-H and C-C/C-Het bond activation to synthesize allylic alcohols, allylated arenes, functionalized cyclopentenes and skipped dienes is reported. This protocol can be readily scaled up and various coupling partners are applied in manganese catalysis for the first time. Moreover, manganese-catalyzed alkenyl C(sp2)-H activation is also shown. Complimentary to the standard solution-based protocols, these reactions also proceed efficiently under neat conditions, which is unprecedented for abundant metal catalyzed C-H activation reactions.

Cobalt-Catalyzed C-H Thiolation through Dehydrogenative Cross-Coupling.

A cobalt-catalyzed dehydrogenative cross-coupling of thiols and indoles is reported. Using a cooperative reaction system, a new mode of action for the cobalt-catalyzed C-heteroatom bond formation was found. The directed C-H activation catalysis overrides an undirected thiolation of indole in the 3-position that occurs in the absence of cobalt. Mechanistic studies indicate a sequence of C-H activation, thiolate transfer, and reductive elimination.