Radical Chlorination of Non-Resonant Heterobenzylic C-H Bonds and High-Throughput Diversification of Heterocycles.

Site-selective functionalization of the heterobenzylic C(sp3)-H bonds of pyridines and related heteroaromatic compounds presents challenges associated with the basic nitrogen atom and the variable reactivity among different positions on the heteroaromatic ring. Methods for functionalization of 2- and 4-alkylpyridines are increasingly available through polar pathways that leverage resonance stabilization of charge build-up at these positions. In contrast, functionalization of 3-alkylpyridines is largely inaccessible. Here, we report a photochemically promoted method for chlorination of non-resonant heterobenzylic C(sp3)-H sites in 3-alkylpyridines and related alkylheteroaromatics. Density functional theory calculations show that the optimal reactivity reflects a balance between the energetics of the two radical-chain propagation steps, with the preferred reagent consisting of an N-chlorosulfonamide. The operationally simple chlorination protocol enables access to heterobenzylic chlorides which serve as versatile intermediates in C-H cross-coupling reactions between heteroaromatic building blocks and diverse oxidatively sensitive nucleophiles using high-throughput experimentation.

Reductive alkyl-alkyl coupling from isolable nickel-alkyl complexes.

The selective cross-coupling of two alkyl electrophiles to construct complex molecules remains a challenge in organic synthesis.1,2 Known reactions are optimized for specific electrophiles and are not amenable to interchangeably varying electrophilic substrates that are sourced from common alkyl building blocks, such as amines, carboxylic acids, and halides.3-5 These limitations restrict the types of alkyl substrates that can be modified and, ultimately, the chemical space that can be explored.6 Here we report a general solution to these limitations that enables a combinatorial approach to alkyl-alkyl cross-coupling reactions. This methodology relies on the discovery of unusually persistent Ni(alkyl) complexes that can be formed directly by oxidative addition of alkyl halides, redox-active esters, or pyridinium salts. The resulting alkyl complexes can be isolated or directly telescoped to couple with a second alkyl electrophile, which represent cross-selective reactions that were previously unknown. The utility of this synthetic capability is showcased in the rapid diversification of amino acids, natural products, pharmaceuticals, and drug-like building blocks by various combinations of dehalogenative, decarboxylative, or deaminative coupling. In addition to a robust scope, this work provides insights into the organometallic chemistry of synthetically relevant Ni(alkyl) complexes through crystallographic analysis, stereochemical probes, and spectroscopic studies.

Development of High-Throughput Experimentation Approaches for Rapid Radiochemical Exploration.

Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies for radiolabeling, the optimization of these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be a powerful approach for optimizing reactions in many areas of chemical synthesis. However, to date, HTE has rarely been applied to radiochemistry. This is largely because of the short lifetime of common radioisotopes, which presents major challenges for efficient parallel reaction setup and analysis using standard equipment and workflows. Herein, we demonstrate an effective HTE workflow and apply it to the optimization of copper-mediated radiofluorination of pharmaceutically relevant boronate ester substrates. The workflow utilizes commercial equipment and allows for rapid analysis of reactions for optimizing reactions, exploring chemical space using pharmaceutically relevant aryl boronates for radiofluorinations, and constructing large radiochemistry data sets.

Persistent organonickel complexes as general platforms for Csp2-Csp3 coupling reactions.

The importance of constructing Csp2-Csp3 bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl-aryl couplings, including those that were previously unknown. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for C(sp2)-C(sp3) coupling. Aryl, heteroaryl or vinyl complexes of Ni can be inexpensively prepared on a multigram scale by mild electroreduction from the corresponding C(sp2) electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to micromole scales by integrating soluble battery chemistries as redox initiators, enabling a high-throughput exploration of substrate diversity.

Diastereoselective Reductive Etherification Via High-Throughput Experimentation: Access to Pharmaceutically Relevant Alkyl Ethers.

This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.

Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation.

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

Nickel-Catalyzed Electroreductive Coupling of Alkylpyridinium Salts and Aryl Halides.

An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions. Mechanistic insights were critical to enhance the efficiency of coupling using secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches.

Unlocking the Potential of High-Throughput Experimentation for Electrochemistry with a Standardized Microscale Reactor.

Organic electrochemistry has emerged as an enabling and sustainable technology in modern organic synthesis. Despite the recent renaissance of electrosynthesis, the broad adoption of electrochemistry in the synthetic community, and especially in industrial settings, has been hindered by the lack of general, standardized platforms for high-throughput experimentation (HTE). Herein, we disclose the design of the HTe - Chem, a high-throughput microscale electrochemical reactor that is compatible with existing HTE infrastructure and enables the rapid evaluation of a broad array of electrochemical reaction parameters. Utilizing the HTe - Chem to accelerate reaction optimization, reaction discovery, and chemical library synthesis is illustrated using a suite of oxidative and reductive transformations under constant current, constant voltage, and electrophotochemical conditions.

Ni-Catalyzed C-H Arylation of Oxazoles and Benzoxazoles Using Pharmaceutically Relevant Aryl Chlorides and Bromides.

This manuscript details the development of the nickel-catalyzed arylation of oxazoles and benzoxazoles with aryl halides. A series of aryl, heteroaryl, and druglike electrophiles relevant to pharmaceutical applications were surveyed. The desired arylated products were obtained in synthetically useful yields using electronically and structurally varied aryl halides. The use of microscale high-throughput experimentation was essential for both the rapid identification of optimal reaction parameters and the investigation of the aryl halide scope.

Nickel-Catalyzed Coupling of Azoles with Aromatic Nitriles.

This manuscript describes the Ni-catalyzed coupling of azoles with aromatic nitriles. The use of BPh3 promotes these arylations with electronically diverse azoles and benzonitriles. While the nickel catalyst is necessary for the arylations of phenyl oxazoles, arylation of benzoxazoles with some nitriles affords the arylated products even in the absence of the Ni catalyst albeit in lower yield than the catalyzed process. The Ni-catalyzed process exhibits higher rates and a broader scope than the uncatalyzed transformation.

Palladium Catalyzed Arylation and Benzylation of Nitroarenes Using Aryl Sulfonates and Benzyl Acetates.

Pd-catalyzed arylation or benzylation of nitroazoles using aryl sulfonates or benzyl acetates is described. Electronically varied aryl tosylates and mesylates, as well as benzyl acetates, afford the arylated and benzylated products. Arylation of nitrobenzene is also reported. The relative rate for the arylation of halides is greater than that of tosylates using the reported reaction parameters. These studies enhance the scope of electrophiles for nitroarene arylations and benzylations, which was hitherto limited to the use of halide electrophiles.

Nickel-Catalyzed Decarboxylative Arylation of Azoles with Perfluoro- and Nitrobenzoates.

This manuscript describes a Ni-catalyzed method for the direct arylation of azoles using benzoates. Perfluorophenyl and 2-nitrobenzoates participate in these reactions to afford the corresponding products in modest to good yields. The efficiency of the arylations with perfluorobenzoates is highly dependent on both the degree and position of fluorine atoms in the benzoates.

Nickel-catalyzed decarboxylative cross-coupling of perfluorobenzoates with aryl halides and sulfonates.

A Ni-catalyzed method for the coupling of perfluorobenzoates with aryl halides and pseudohalides is described. Aryl iodides, bromides, chlorides, triflates, and tosylates participate in these transformations to afford the products in good yields. Penta-, tetra-, and trifluorinated biaryl compounds are obtained using these newly developed Ni-catalyzed decarboxylative cross-coupling reactions.

Palladium-Catalyzed Intra- and Intermolecular C-H Arylation Using Mesylates: Synthetic Scope and Mechanistic Studies.

This paper describes the development of Pd-catalyzed inter- and intramolecular direct arylation using mesylates. Furthermore, a sequential mesylation/arylation protocol using phenols as substrates is described. These transformations are general with respect to the electronics of the C-H substrates and allow for the synthesis of diverse heterocyclic motifs in good yields. Both arenes and heteroarenes efficiently participate in these reactions. Preliminary mechanistic studies are presented for both inter- and intramolecular arylations.

Nickel-Mediated Synthesis of Isoindolinones at Room Temperature.

This communication describes a method for the Ni(cod) 2-mediated intramolecular arylation of alkyl C-H bonds adjacent to the nitrogen atom in benzamide substrates. The transformation proceeds at room temperature and exhibits selectivity for functionalization of more substituted C-H bonds. The yields of the desired isoindolinone products are higher with benzamide substrates containing tertiary alkyl groups on the nitrogen atom than with those bearing primary or secondary alkyls. The results described herein suggest a mechanism involving radical intermediates for these reactions.

Nickel or phenanthroline mediated intramolecular arylation of sp3 C-H bonds using aryl halides.

The development of the intramolecular arylation of sp(3) C-H bonds adjacent to nitrogen using aryl halides is described. Arylation was accomplished using either Ni(COD)2 or 1,10-phenanthroline in substoichiometric amounts, and the reaction conditions were applied to a variety of electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates.

Palladium-catalyzed intramolecular C-H arylation of arenes using tosylates and mesylates as electrophiles.

This paper describes a method for the palladium catalyzed intramolecular C-H arylation using tosylates and mesylates as electrophiles. The transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally, a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented.