General cross-coupling reactions with adaptive dynamic homogeneous catalysis

Prieto Kullmer C.N., Kautzky J.A., Krska S.W., Nowak T., Dreher S.D., MacMillan D.W.

Reaction generality is crucial in determining the overall impact and usefulness of synthetic methods. Typical generalization protocols require a priori mechanistic understanding and suffer when applied to complex, less understood systems. We developed an additive mapping approach that rapidly expands the utility of synthetic methods while generating concurrent mechanistic insight. Validation of this approach on the metallaphotoredox decarboxylative arylation resulted in the discovery of a phthalimide ligand additive that overcomes many lingering limitations of this reaction and has important mechanistic implications for nickel-catalyzed cross-couplings.

Qin Y., Sun R., Gianoulis N.P., Nocera D.G.

Photoredox-mediated nickel-catalyzed cross-couplings have evolved as a new effective strategy to forge carbon-heteroatom bonds that are difficult to access with traditional methods. Experimental mechanistic studies are challenging because these reactions involve multiple highly reactive intermediates and perplexing reaction pathways, engendering competing, but unverified, proposals for substrate conversions. Here, we report a comprehensive mechanistic study of photoredox nickel-catalyzed C-S cross-coupling based on time-resolved transient absorption spectroscopy, Stern-Volmer quenching, and quantum yield measurements. We have (i) discovered a self-sustained productive Ni(I/III) cycle leading to a quantum yield Φ > 1; (ii) found that pyridinium iodide, formed in situ, serves as the dominant quencher for the excited state photocatalyst and a critical redox mediator to facilitate the formation of the active Ni(I) catalyst; and (iii) observed critical intermediates and determined the rate constants associated with their reactivity. Not only do the findings reveal a complete reaction cycle for C-S cross-coupling, but the mechanistic insights have also allowed for the reaction efficiency to be optimized and the substrate scope to be expanded from aryl iodides to include aryl bromides, thus broadening the applicability of photoredox C-S cross-coupling chemistry.

Zhang J., Wang S., Zhang Y., Feng Z.

Lavagnino M.N., Liang T., MacMillan D.W.

Significance Copper-catalyzed carbon–nitrogen bond formation has the potential to provide efficient synthetic access to medicinally relevant organic molecules, but broad use of the coupling has been hampered by the requirement for an energetically challenging substrate activation step (oxidative addition into an aryl halide). Here we report a mechanistic alternative that circumvents oxidative addition by cooperatively employing photochemically generated silicon-centered radicals and copper to activate aryl halides via a one-electron pathway. This dramatically increases the range of accessible products, thereby allowing room-temperature synthesis of a diverse electronic and steric range of products traditionally considered inaccessible via copper catalysis due to the prohibitively high barrier for direct copper oxidative addition.

Till N.A., Tian L., Dong Z., Scholes G.D., MacMillan D.W.

The combined use of reaction kinetic analysis, ultrafast spectroscopy, and stoichiometric organometallic studies has enabled the elucidation of the mechanistic underpinnings to a photocatalytic C-N cross-coupling reaction. Steady-state and ultrafast spectroscopic techniques were used to track the excited-state evolution of the employed iridium photocatalyst, determine the resting states of both iridium and nickel catalysts, and uncover the photochemical mechanism for reductive activation of the nickel co- catalyst. Stoichiometric organometallic studies along with a comprehensive kinetic study of the reaction, including rate-driving force analysis, unveiled the crucial role of photocatalysis in both initiating and sustaining a Ni(I)/Ni(III) cross-coupling mechanism. The insights gleaned from this study further enabled the discovery of a new photocatalyst providing a >30-fold rate increase.

Escobar R.A., Johannes J.W.

While carbon-heteroatom cross-coupling reactions have been extensively studied, many methods are specific and limited to a particular set of substrates or functional groups. Reported here is a general method that allows for C-O, C-N and C-S cross-coupling reactions under one general set of conditions. We propose that an energy transfer pathway, in which an iridium photosensitizer produces an excited nickel(II) complex, is responsible for the key reductive elimination step that couples aryl bromides, iodides, and chlorides to 1° and 2° alcohols, amines, thiols, carbamates, and sulfonamides, and is amenable to scale up via a flow apparatus.

Sun R., Qin Y., Nocera D.G.

We establish self-sustained Ni(I/III) cycles as a potentially general paradigm in photoredox Ni-catalyzed carbon-heteroatom cross-coupling reactions by presenting a strategy that allows us to recapitulate photoredox-like reactivity in the absence of light across a wide range of substrates in the amination, etherification, and esterification of aryl bromides, the latter of which has remained, hitherto, elusive under thermal Ni catalysis. Moreover, the accessibility of esterification in the absence of light is especially notable since previous mechanistic studies on this transformation under photoredox conditions have unanimously invoked energy transfer-mediated pathways.

Diccianni J.B., Diao T.

Advances in nickel-catalyzed cross-coupling reactions have expanded the chemical space of accessible structures and enabled new synthetic disconnections. The unique properties of Ni catalysts facilitate the activation of traditionally inert substrates, tolerate alkyl coupling partners that undergo decomposition via β-hydride (β-H) elimination with Pd, and enable stereoconvergent cross-couplings. The radical pathways accessed by Ni catalysts have been merged with photoredox and electrochemical catalysis to achieve new reactivity. The growing utility of Ni catalysis is, in no small part, due to advances in our fundamental understanding of the properties of Ni catalysts and the mechanisms by which the reactions occur. This review highlights recent important contributions to the field with an emphasis on studies that have afforded mechanistic insight.

Dorel R., Grugel C.P., Haydl A.M.

The Pd-catalyzed coupling of aryl (pseudo)halides and amines is one of the most powerful approaches for the formation of C(sp2 )-N bonds. The pioneering reports from Migita and subsequently Buchwald and Hartwig on the coupling of aminostannanes and aryl bromides rapidly evolved into general and practical tin-free protocols with broad substrate scope, which led to the establishment of what is now known as the Buchwald-Hartwig amination. This Minireview summarizes the evolution of this cross-coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well-established methodology.

Ahneman D.T., Estrada J.G., Lin S., Dreher S.D., Doyle A.G.

A guide for catalyst choice in the forest Chemists often discover reactions by applying catalysts to a series of simple compounds. Tweaking those reactions to tolerate more structural complexity in pharmaceutical research is time-consuming. Ahneman et al. report that machine learning can help. Using a high-throughput data set, they trained a random forest algorithm to predict which specific palladium catalysts would best tolerate isoxazoles (cyclic structures with an N–O bond) during C–N bond formation. The predictions also helped to guide analysis of the catalyst inhibition mechanism. Science , this issue p. 186

Ruiz-Castillo P., Buchwald S.L.

Pd-catalyzed cross-coupling reactions that form C-N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C-N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

Shaw M.H., Twilton J., MacMillan D.W.

In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon-carbon and carbon-heteroatom bonds.

Oderinde M.S., Frenette M., Robbins D.W., Aquila B., Johannes J.W.

Ni-catalyzed cross-couplings of aryl, benzyl, and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox catalyst. Highly chemoselective C-S cross-coupling was achieved versus competitive C-O and C-N cross-couplings. This C-S cross-coupling method exhibits remarkable functional group tolerance, and the reactions can be carried out in the presence of molecular oxygen. Mechanistic investigations indicated that the reaction proceeded through transient Ni(I)-species and thiyl radicals. Distinct from nickel-catalyzed cross-coupling reactions involving carbon-centered radicals, control experiments and spectroscopic studies suggest that this C-S cross-coupling reaction does not involve a Ni(0)-species.

Ghosh A.K., Brindisi M.

The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many derivatives are specifically designed to make drug-target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chemistry.

Vitaku E., Smith D.T., Njardarson J.T.

Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of U.S. FDA approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle. In this review we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: (1) three- and four-membered heterocycles, (2) five-, (3) six-, and (4) seven- and eight-membered heterocycles, as well as (5) fused, (6) bridged bicyclic, and (7) macrocyclic nitrogen heterocycles. Each section reveals the top nitrogen heterocyclic structures and their relative impact for that ring type. For the most commonly used nitrogen heterocycles, we report detailed substitution patterns, highlight common architectural cores, and discuss unusual or rare structures.

Li J., Wang P., Bai B., Xiao Y., Wan Y., Yan Y., Li F., Song G., Li G., Wang C., Zhang X., Dong J., Kang T., Xue D.

Xu X., Chen S., Liu Q., Cao X., Zhao Z., Chen J., Yao Y., Yang C., Sun K.

Nikitin M., Ötvös S.B., Ghosh I., Philipp M., Gschwind R., Kappe C.O., König B.

Düker J., Philipp M., Lentner T., Cadge J.A., Lavarda J.E., Gschwind R.M., Sigman M.S., Ghosh I., König B.

Morozkov G.V., Troickiy A.A., Averin A.D., Mitrofanov A.Y., Abel A.S., Beletskaya I.P.

Photoredox-catalyzed phosphonylation of bromo-substituted 1,10-phenanthrolines under visible light irradiation was studied. The reaction was shown to proceed under mild conditions with Eosin Y as a photocatalyst in DMSO under blue light irradiation. It is transition-metal-free and affords the target phosphonate-substituted 1,10-phenanthrolines in moderate yields (26–51%) in 22 to 40 h. The rate and selectivity of the reaction depend largely on the position of the bromine atom, as well as on the nature and position of other substituents in the 1,10-phenanthroline core.

Luo F., Wang W., Xiang C., Zeng L., Zhang C., Zhang J., Zhang X., Shao J., Zhu H.

D’Andrea L., Steinmann C.

Pd EnCat™ 30 is a palladium catalyst broadly used in several hydrogenation and cross-coupling reactions. It is known for its numerous beneficial features, which include high-yielding performance, easy recovery, and reusability. However, the available data regarding its recyclability in Suzuki coupling reactions are limited to a few reaction cycles and, therefore, fail to explore its full potential. Our work focuses on investigating the extent of Pd EnCat™ 30 reusability in Suzuki cross-coupling reactions by measuring its performance according to isolated yields of product. Our findings demonstrate that Pd EnCat™ 30 can be reused over a minimum of 30 reaction cycles, which is advantageous in terms of cost reduction and more sustainable chemical production.

Song G., Song J., Li Q., Kang T., Dong J., Li G., Fan J., Wang C., Xue D.

Egorov M.P., Ananikov V.P., Baskir E.G., Boganov S.E., Bogdan V.I., Vereshchagin A.N., Vil’ V.A., Dalinger I.L., Dilman A.D., Eliseev O.L., Zlotin S.G., Knyazeva E.A., Kogan V.M., Kononov L.O., Krayushkin M.M., et. al.

A key goal of organic chemistry is to develop new principles for the control of reactions, which can be used to create promising materials demanded in all fields of scientific research and industry. This review is an overview of the scientific advances, which have been made by the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences in the past decade within the framework of current trends in organic chemistry. The review covers the results, which are significant for fundamental research and hold great promise for the application in different areas, from the production of materials, petrochemistry, and chemical ecology to medicine, agriculture, and food industry.

Chugh V., Wu J., Leutzsch M., Randel H., Weyhermüller T., Auer A.A., Farès C., Werlé C.

Sripada A., Chong E., Wu H., An J., Hurtak J., Haddad N., Lei Z.

Beil S.B., Bonnet S., Casadevall C., Detz R.J., Eisenreich F., Glover S.D., Kerzig C., Næsborg L., Pullen S., Storch G., Wei N., Zeymer C.

Chen P., Hsu S., Chen C., Fu J., Hou D.

Alamer B., Sagadevan A., Bodiuzzaman M., Murugesan K., Alsharif S., Huang R., Ghosh A., Naveen M.H., Dong C., Nematulloev S., Yin J., Shkurenko A., Abulikemu M., Dong X., Han Y., et. al.

Cagan D.A., Bím D., Kazmierczak N.P., Hadt R.G.