Site-Selective C-H Amination of Phenol-Containing Biomolecules.

A C-N bond-forming cross-dehydrogenative coupling of a collection of Tyr-containing peptides and estrogens with heteroarenes is described. This oxidative coupling is distinguished by its scalability, operational simplicity, and air tolerance and enables the appendance of phenothiazines and phenoxazines in phenol-like compounds. When incorporated into a Tb(III) metallopeptide, the Tyr-phenothiazine moiety acts as a sensitizer for the Tb(III) ion, providing a new tool for the design of luminescent probes.

Late-Stage C-H Acylation of Tyrosine-Containing Oligopeptides with Alcohols.

The selective tagging of amino acids within a peptide framework while using atom-economical C-H counterparts poses an unmet challenge within peptide chemistry. Herein, we report a novel Pd-catalyzed late-stage C-H acylation of a collection of Tyr-containing peptides with alcohols. This water-compatible labeling technique is distinguished by its reliable scalability and features the use of ethanol as a renewable feedstock for the assembly of a variety of peptidomimetics.

Pd-Catalyzed C(sp2 )-H Alkoxycarbonylation of Phenethyl- and Benzylamines with Chloroformates as CO Surrogates.

The site-selective functionalization of C-H bonds within a complex molecule remains a challenging task of capital synthetic importance. Herein, an unprecedented Pd-catalyzed C(sp2 )-H alkoxycarbonylation of phenylalanine derivatives and other amines featuring picolinamide as the directing group (DG) is reported. This oxidative coupling is distinguished by its scalability, operational simplicity, and avoids the use of toxic carbon monoxide as the C1 source. Remarkably, the easy cleavage of the DG enables the efficient assembly of isoindolinone compounds. Density Functional Theory calculations support a PdII /PdIV catalytic cycle.

On the Mechanism of Cross-Dehydrogenative Couplings between N-aryl Glycinates and Indoles: A Computational Study.

Despite the widespread use of cross-dehydrogenative couplings in modern organic synthesis, mechanistic studies are still rare in the literature and those applied to α-amino carbonyl compounds remain virtually unexplored. Herein, the mechanism of Co-catalyzed cross-dehydrogenative couplings of N-aryl glycinates with indoles is described. Density functional theory studies supported the formation of an imine-type intermediate as the more plausible transient electrophilic species. Likewise, key information regarding the role of the N-aryl group and free NH motif within the reaction outcome has been gained, which may set the stage for further developments in this field of expertise.

Cu-Catalyzed Site-Selective C(sp2)-H Radical Trifluoromethylation of Tryptophan-Containing Peptides.

Site-selective functionalization of C-H bonds within a peptide framework poses a challenging task of paramount synthetic relevance. Herein, we report an operationally simple C(sp2)-H trifluoromethylation of tryptophan (Trp)-containing peptides. This fluorination technique is characterized by its chirality preservation, tolerance of functional groups, and scalability and exhibits chemoselectivity for Trp residues over other amino acid and heterocyclic units. As a result, it represents a sustainable tool toward the late-stage peptide modification and protein engineering.

Site-selective aqueous C-H acylation of tyrosine-containing oligopeptides with aldehydes.

The development of useful synthetic tools to label amino acids within a peptide framework for the ultimate modification of proteins in a late-stage fashion is a challenging task of utmost importance within chemical biology. Herein, we report the first Pd-catalyzed C-H acylation of a collection of Tyr-containing peptides with aldehydes. This water-compatible tagging technique is distinguished by its site-specificity, scalability and full tolerance of sensitive functional groups. Remarkably, it provides straightforward access to a high number of oligopeptides with altered side-chain topology including mimetics of endomorphin-2 and neuromedin N, thus illustrating its promising perspectives toward the diversification of structurally complex peptides and chemical ligation.

Pd-catalyzed site-selective C(sp2)-H radical acylation of phenylalanine containing peptides with aldehydes.

The site-selective functionalization of C-H bonds within a peptide framework remains a challenging task of prime synthetic importance. Herein, the first Pd-catalyzed δ-C(sp2)-H acylation of Phe containing peptides with aldehydes is described. This oxidative coupling is distinguished by its site-specificity, tolerance of sensitive functional groups, scalability, and enantiospecificity and exhibits entire chemoselectivity for Phe motifs over other amino acid units. The compatibility of this dehydrogenative acylation platform with a number of oligopeptides of high structural complexity illustrates its ample opportunities for the late-stage peptide modification and bioconjugation.

Site-Selective Cu-Catalyzed Alkylation of α-Amino Acids and Peptides toward the Assembly of Quaternary Centers.

The CuI -catalyzed selective α-alkylation of α-amino acid and peptide derivatives with 2-alkyl-1,3-dioxolanes is reported. This oxidative coupling is distinguished by its site-specificity, high diastereoselectivity, and chirality preservation and exhibits absolute chemoselectivity for N-aryl glycine motifs over other amino acid units. Collectively, the method allows for the assembly of challenging quaternary centers, as well as compounds derived from natural products of high structural complexity, which may provide ample opportunities for late-stage functionalization of peptides.

Iron-catalyzed C(sp3)-H functionalization of N,N-dimethylanilines with isocyanides.

An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp3)-H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.

Co-Catalyzed C(sp3)-H Oxidative Coupling of Glycine and Peptide Derivatives.

Cobalt-catalyzed selective α-alkylation and α-heteroarylation processes of α-amino esters and peptide derivatives are described. These cross-dehydrogenative reactions occur under mild conditions and allow for the rapid assembly of structurally diverse α-amino carbonyl compounds. Unlike enolate chemistry, these methods are distinguished by their site-specificity, occur without racemization of the existing chiral centers, and exhibit total selectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modifications.

Selective C(sp2)-H Halogenation of "Click" 4-Aryl-1,2,3-triazoles.

Selective bromination reactions of "click compounds" are described. Electron-neutral and electron-deficient arenes selectively undergo unprecedented Pd-catalyzed C-H ortho-halogenations assisted by simple triazoles as modular directing groups, whereas electron-rich arenes are regioselectively halogenated following an electrophilic aromatic substitution reaction pathway. These C-H halogenation procedures exhibit a wide group tolerance, complement existing bromination procedures, and represent versatile synthetic tools of utmost importance for the late-stage diversification of "click compounds". The characterization of a triazole-containing palladacycle and density functional theory studies supported the mechanism proposal.

Triazole-Directed Pd-Catalyzed C(sp(2))-H Oxygenation of Arenes and Alkenes.

Selective Pd-catalyzed C(sp(2))-H oxygenation of 4-substituted 1,2,3-triazoles is described. Unlike previous metal-catalyzed C-H functionalization events, which preferentially occur at the activated heterocyclic C-H bond, the regioselective oxygenation of the arene/alkene moiety is now achieved featuring the unconventional role of a simple triazole scaffold as a modular and selective directing group.

Iron-catalyzed direct α-arylation of ethers with azoles.

The direct α-arylation of cyclic and acyclic ethers with azoles has been achieved, which features a novel iron-catalyzed cross-dehydrogenative coupling (CDC) process. This practical oxidative method allowed the efficient C2-alkylation of a variety of (benzo)azoles constituting straightforward access to heterocycles of utmost medicinal significance and highlighting the convenient use of feedstock substrates and iron catalysts. A preliminary mechanism supported by DFT calculations is discussed as well.

Metal-catalyzed reductive coupling reactions of organic halides with carbonyl-type compounds.

Metal-catalyzed reductive coupling reactions of aryl halides and (pseudo)halides with carbonyl-type compounds have undergone an impressive development within the last years. These methodologies have shown to be a powerful alternate strategy, practicality aside, to the use of stoichiometric, well-defined, and, in some cases, air-sensitive organometallic species. In this Minireview, the recent findings in this field are summarized, with particular emphasis on the mechanistic interpretation of the results and future aspects of this area of expertise.

Ni-catalyzed direct reductive amidation via C-O bond cleavage.

A novel Ni-catalyzed reductive amidation of C(sp(2))-O and C(sp(3))-O electrophiles with isocyanates is described. This umpolung reaction allows for an unconventional preparation of benzamides using simple starting materials and easy-to-handle Ni catalysts.

Ni-catalyzed carboxylation of C(sp2)- and C(sp3)-O bonds with CO2.

In recent years a significant progress has been made for the carboxylation of aryl and benzyl halides with CO2, becoming convenient alternatives to the use of stoichiometric amounts of well-defined metal species. Still, however, most of these processes require the use of pyrophoric and air-sensitive reagents and the current methods are mostly restricted to organic halides. Therefore, the discovery of a mild, operationally simple alternate carboxylation that occurs with a wide substrate scope employing readily available coupling partners will be highly desirable. Herein, we report a new protocol that deals with the development of a synergistic activation of CO2 and a rather challenging activation of inert C(sp(2))-O and C(sp(3))-O bonds derived from simple and cheap alcohols, a previously unrecognized opportunity in this field. This unprecedented carboxylation event is characterized by its simplicity, mild reaction conditions, remarkable selectivity pattern and an excellent chemoselectivity profile using air-, moisture-insensitive and easy-to-handle nickel precatalysts. Our results render our method a powerful alternative, practicality and novelty aside, to commonly used organic halides as counterparts in carboxylation protocols. Furthermore, this study shows, for the first time, that traceless directing groups allow for the reductive coupling of substrates without extended π-systems, a typical requisite in many C-O bond-cleavage reactions. Taking into consideration the limited knowledge in catalytic carboxylative reductive events, and the prospective impact of providing a new tool for accessing valuable carboxylic acids, we believe this work opens up new vistas and allows new tactics in reductive coupling events.

Ni-catalyzed direct carboxylation of benzyl halides with CO2.

A novel Ni-catalyzed carboxylation of benzyl halides with CO(2) has been developed. The described carboxylation reaction proceeds under mild conditions (atmospheric CO(2) pressure) at room temperature. Unlike other routes for similar means, our method does not require well-defined and sensitive organometallic reagents and thus is a user-friendly and operationally simple protocol for assembling phenylacetic acids.