Transition Metal-catalyzed Reactions Research Articles

Selectivity in Transition Metal-catalyzed Cyclizations: Insights from Experiment and Theory.

Transition metal-catalyzed cycloisomerization reactions offer a powerful tool for the synthesis of complex cyclic organic molecules from acyclic precursors. In addition to ring formation, these processes can result in the generation of new stereocentres at the site of ring formation; understanding the origins of stereoselectivity enables the use of cycloisomerization chemistry in synthesis, and promotes the design of new reactions. In this article, some recent developments from our groups in regio- and stereoselective cycloisomerization reactions are discussed. Alongside experimental observations, crucial to developing a robust understanding of selectivity has been the use of computation to explore theoretical reaction pathways, which provides an exceptional level of insight into selectivity. In its most valuable form, this correlation between experiment and theory enables the design of improved catalyst systems exhibiting both enhanced reactivity, and selectivity.

Transition-Metal-Catalyzed Decarbonylative Coupling Reactions: Concepts, Classifications, and Applications.

Transition metal-catalyzed decarbonylative coupling reactions have emerged as a powerful alternative to conventional cross-coupling protocols due to the advantages associated with the use of carbonyl-containing functionalities as coupling electrophiles instead of commonly used organohalides or sulfates. A wide variety of novel transformations based on this concept have been successfully achieved, including decarbonylative carbon-carbon and carbon-heteroatom bond forming reactions. In this Review, we summarize the recent progress in this field and present a comprehensive overview of metal-catalyzed decarbonylative coupling reactions with carbonyl derivatives.

Investigation of transition metal-catalyzed nitrene transfer reactions in water

Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new CN bonds into relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and chemoselective CH bond amination reactions in aqueous media. The unexpected ability to employ water as the solvent in these reactions is advantageous in that it eliminates toxic solvent use and enables reactions to be run at increased concentrations with lower oxidant loadings. Using water as the reaction medium has potential to expand the scope of nitrene transfer to encompass a variety of biomolecules and highly polar substrates, as well as enable pH control over the site-selectivity of CH bond amination.

Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs.

New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand in nearly every sector of chemical industry. The asymmetric construction of quaternary C-F stereogenic centers is the most synthetically challenging and, consequently, the least developed area of research. As a reflection of this apparent methodological deficit, pharmaceutical drugs featuring C-F stereogenic centers constitute less than 1% of all fluorine-containing medicines currently on the market or in clinical development. Here we provide a comprehensive review of current research activity in this area, including such general directions as asymmetric electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, asymmetric elaboration of fluorine-containing substrates via alkylations, Mannich, Michael, and aldol additions, cross-coupling reactions, and biocatalytic approaches.

Allenylic Carbonates in Enantioselective Iridium-Catalyzed Alkylations.

An enantioconvergent C(sp3)-C(sp3) coupling between racemic allenylic electrophiles and alkylzinc reagents has been developed. An Ir/(phosphoramidite,olefin) catalyst provides access to highly enantioenriched allenylic substitution products (93-99% ee) with complete regiocontrol (>50:1 rr in all cases) over the corresponding 1,3-diene isomers which are obtained predominantly when other metal catalysts are emplyed. The synthetic utility of the products obtained was highlighted in a variety of stereoselective transition metal-catalyzed difunctionalization reactions. Furthermore, a combination of experimental and theoretical studies provide support for a putative reaction mechanism wherein enantiodetermining C-C coupling occurs via nucleophilic attack on a highly planarized aryl butadienylium π-system that is coordinated to the Ir center in an η2-fashion.

Renaissance of Sandmeyer-Type Reactions: Conversion of Aromatic C-N Bonds into C-X Bonds (X = B, Sn, P, or CF3).

The Sandmeyer reaction represents an important organic transformation that converts an arylamine to an aryl halide using Cu(I) halide via a diazonium salt intermediate. The reaction was first reported by Sandmeyer in 1884, and a number of named reactions closely related to it have been developed and widely applied in organic synthesis throughout the 20th century. These include the Pschorr reaction for the synthesis of biaryl tricycles, the Gomberg-Bachmann reaction for biaryl formations, the Balz-Schiemann reaction for C-F bond formations, and the Meerwein reaction for arylation of α,β-unsaturated carbonyl compounds. However, all these reactions were discovered before 1940. In 1977, Doyle and co-workers reported an organic phase diazotization process, and Kikukawa and Matsuda used aryldiazonium salts in transition metal-catalyzed cross-coupling reactions. However, completely new processes involving diazonium salts have been seldom reported since then, although aryldiazonium salts are widely utilized in modern organic synthesis. In the past few years, diazonium salt chemistry has been revisited and become a fast-growing research topic. Several novel transformations based on diazonium salts have been developed and have been practiced in organic synthesis. In 2010, we reported a direct conversion of arylamines to pinacol boronates through the reaction of in situ generated aryl diazonium salts with B2pin2. This new strategy is under metal-free conditions and thus completely avoids contamination by transition metals in the boron products. From readily available arylamines various functionalized arylboronates, some of which are difficult to access by other methods, can be easily obtained with this reaction. Mechanistic investigations indicate the reaction likely follows a radical mechanism, which is similar to traditional Sandmeyer-type reactions. Subsequently, modified reaction conditions for this transformation appeared in the literature, which include light-induced reactions, aqueous-phase diazotization methods, and reactions with aryltriazenes as the arene diazonium salt surrogates. In addition to the borylation, we have also demonstrated the corresponding stannylation and phosphorylation of arylamines with similar Sandmeyer-type approaches. The stannylation of arylamines was achieved by the reaction of in situ generated diazonium salts with a distannane reagent, while phosphorylation is the reaction of arylamines with trimethyl phosphite in the presence of tert-butyl nitrite (t-BuONO). With the sequential borylation and stannylation approaches, the aromatic compounds bearing two amino groups are easily converted into trimethylstannyl arylboronates, which can be further used in consecutive Stille and Suzuki-Miyaura cross-couplings. Finally, direct conversion of the amino group of arylamines to the trifluoromethyl group has been developed through aryl diazonium salts almost simultaneously by several groups. These reactions represent a novel strategy to achieve trifluoromethylation of aromatic compounds. These developments show the revivification of this age-old chemistry, and this Account will summarize the Sandmeyer reaction-related transformations that have been developed since 2010.

RECENT ADVANCES IN SULTONE SYNTHESIS

This microreview summarizes recent advances in sultone synthesis, focusing on the transition metal-catalyzed reactions reported from 2012 to 2017.

Striving to exploit alkyl electrophiles: challenge and choice in transition metal-catalyzed cross-coupling reactions of sulfones

Transition metal-catalyzed cross-coupling reactions of alkyl sulfones as crystalline and readily available alkyl electrophiles via a radical process are highlighted.

Mechanism and reactivity of catalytic propargylic substitution reactions via metal–allenylidene intermediates: a theoretical perspective

The mechanism and reactivity of transition metal-catalyzed propargylic substitution reactions are summarized from a theoretical point of view.

Chiral proton-transfer shuttle catalysts for carbene insertion reactions.

Transition metal-catalyzed carbene insertion into X-H bonds (X = N, O, S, and C) represents a typical carbene transfer reaction and has been widely used in organic synthesis. The enantioselectivity-determining step in some of these insertion reactions is the proton transfer of active intermediates such as ylides, metal enolates, or free enols. Since most of the traditional chiral transition metal catalysts tend to dissociate from these active intermediates and cannot be involved in the proton-transfer step, enantiocontrol of these insertion reactions has long been a challenging task. Since 2011, we have developed chiral spiro phosphoric acids as chiral proton-transfer shuttle (CPTS) catalysts, which have been proven to be efficient catalysts for the proton transfer of active intermediates in carbene insertion reactions. Upon combining with achiral dirhodium catalysts, the CPTS catalysts accomplish highly enantioselective insertions of N-H, S-H, and C-H bonds. Herein, a number of important chiral building blocks, including α-amino acid derivatives, α-amino ketones, α-thioesters, and α,α-diaryl acetates, were prepared with high yields and high enantioselectivities through these insertion reactions.

Recent advances in sultone synthesis (microreview)

This microreview summarizes recent advances in sultone synthesis, focusing on the transition metal-catalyzed reactions reported from 2012 to 2017.

2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles: An Overview on Synthetic Strategies and Biological Activity.

2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles represent an important class of ATP-competitive protein kinase inhibitors, offering the possibility of multiple interactions with different regions of the target enzyme. The necessity of exploring the effects of diverse chemical decorations around the imidazole core prompted the design of several synthetic routes aimed at achieving both efficiency and flexibility. Additionally, the optimization of established protocols and the extensive use of transition metal-catalyzed cross-coupling reactions have been broadening the spectrum of preparative methodologies within the last decade. This review summarizes the progress in the development of synthetic strategies leading to 2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and 1-alkyl-2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and offers a glance at the biological activities of this class of compounds.

Development of highly electron-deficient and less sterically-hindered phosphine ligands possessing 1,3,5-triazinyl groups

Highly electron-deficient and less sterically-hindered phosphine ligands with two or three 1,3,5-triazinyl groups on the phosphorus atoms have been synthesized and examined in transition metal-catalyzed reactions for the first time. Due to the lack of any hydrogens or substituents at ortho-positions of the 1,3,5-triazine towards the phosphorous atom, it is considered that the steric hindrance of the tris(triazinyl)phosphine ligand to a metal center is least among triarylphosphine ligands. In the Stille coupling of aryl iodides, these electron-poor phosphine ligands provided good product yields compared to hitherto well-known phosphine ligands.

Regioselective Direct C-Alkenylation of Indoles.

The direct introduction of alkenyl groups into the indole framework avoiding its preliminary functionalization can be carried out using different synthetic strategies. Transition-metal complexes facilitate the C-H activation of indoles or alkenes allowing an efficient Csp2 - Csp2 bond formation. The hydroindolation of alkynes catalyzed by the same metal complexes or various acidic promoters can also be pursued for the alkenylation process. Conjugate addition of electron-poor alkenes and direct condensation of carbonyl derivatives with indoles are also of interest for this purpose. The regiochemical control can be exploited using the intrinsic C-3 reactivity of the indole ring. The introduction of a suitable directing group at the nitrogen atom allows the preparation of C-2 alkenylated derivatives by transition metal catalyzed reactions. This review collects the fundamental contributions in this field reported in literature during the last fifteen years.

Conjugated Trimeric Scaffolds Accessible from Indolyne Cyclotrimerizations: Synthesis, Structures, and Electronic Properties.

We report the design and synthesis of a new class of indole-based conjugated trimers. The targeted compounds are accessed from in situ generated, highly reactive indolyne intermediates using Pd-catalyzed cyclotrimerization reactions. By harnessing three indolyne isomers, six isomeric indole trimers are accessible, none of which have been previously synthesized. Using computational analysis, we describe the structural and photophysical properties of these unique compounds. This study showcases the use of indolynes in transition metal-catalyzed reactions, while providing access to a new class of conjugated trimers, including highly bent heteroaromatic compounds. Computations indicate that, despite differences in planarity between the molecules, the photophysical properties of each trimer are derived from the N-methylindole building block. Excited state behavior follows predicable patterns.

Engaging Radicals in Transition Metal-Catalyzed Cross-Coupling with Alkyl Electrophiles: Recent Advances

Transition metal-catalyzed cross-coupling reactions have created an epoch in modern synthetic organic chemistry, offering a variety of insights into retrosynthetic tactics for synthesizing targeted complex molecules in medicine and materials-based applications. Despite numerous types of combinations of nucleophiles, electrophiles, and transition metal catalysts available for the cross-coupling reactions, construction of covalent bonds that include sp3-hybridized carbon(s) remains a challenge because of the inherent diverse reactivity of the alkyl species (i.e., alkyl halides and alkyl metals) involved in the catalytic cycle. Methods for leveraging alkyl radicals have recently emerged, which will aid in the realization of this goal. This perspective highlights and discusses recent advances in transition metal-catalyzed cross-coupling reactions that engage alkyl radicals for C(sp3)–N and C(sp3)–Si bond formation with alkyl halides as well as use of carboxylic acid derivatives as surrogates of alkyl halides ...

Development of Robust, Scaleable Catalytic Processes through Fundamental Understanding of Reaction Mechanisms

Homogenous transition metal-catalyzed reactions have become a mainstay in organic synthesis and are frequently employed in the discovery and manufacture of modern pharmaceutical compounds. Due to the complex, multi-variant nature of these transformations, the pharmaceutical industry primarily relies on parallel experimentation, such as high-throughput (HTP) screening and design of experiments approaches, to identify and optimize conditions for metal-mediated reactions. Although useful for rapid reaction development, these methods have limitations and may fail to provide critical data for the successful scale-up and implementation of these complex multi-step processes. Due to these limitations, it may be necessary to also evaluate a fundamental mechanism-focused approach towards reaction development. In this article, we review several important lessons from our laboratories at Bristol-Myers Squibb where a combination of HTP screening and mechanistic understanding revealed new insights into known catalytic transformations and facilitated the development of robust, reliable catalytic processes to support the bulk production of pharmaceutical targets.

New Approaches for Biaryl-Based Phosphine Ligand Synthesis via P═O Directed C–H Functionalizations

Given the important influence of phosphine ligands in transition metal-catalyzed reactions, chemists have searched for straightforward and efficient methodologies for the synthesis of diverse phosphine ligands. Although significant progress has been made in this aspect over the past decades, the development of new phosphorus-containing ligands with properties superior to their predecessors remains a central task for chemists. Recently, researchers have demonstrated that biphenyl monophosphine ligands function as highly efficient ligands for transition-metal-catalyzed organic transformations, especially for reactions where chelating bisphosphine ligands cannot be used. In 1998, Buchwald introduced a new class of air-stable phosphine ligands based on the dialkylbiaryl phosphine backbone. These ligands have been successfully used for a wide variety of palladium-catalyzed carbon-carbon, carbon-nitrogen, and carbon-oxygen construction processes as well as serving as supporting ligands for a number of other reactions. At the same time, the use of the biphenyl monophosphine ligands often allows reactions to proceed with short reaction times and low catalyst loadings and under mild reaction conditions. However, the synthesis of chiral biphenyl monophosphine ligands, especially those the chirality of which is due to biaryl axial chirality, is very limited. In this Account, we summarize our methodologies for the synthesis of this kind of biphenyl monophosphine ligands including the P═O directed C-H functionalization, P═O directed diastereoselective C-H functionalization, P═O directed enantioselective C-H functionalization, and metal-free diastereoselective radical oxidative C-H amination under mild reaction conditions. With these methods, a series of biphenyl phosphine ligand precursors containing achiral or axially chiral centers and precursors possessing both axial chirality and a chirogenic phosphorus center with different electronic properties and steric effect have been obtained under different reaction conditions. For the preparation of chiral biphenyl monophosphine ligands, which not only possess axial chirality but in many cases also possess chirality at phosphorus, the primary means of introducing chirality is through the use of the menthyl phenylphosphinate. As a chiral auxiliary group, the menthyl phenylphosphinate has some unique features: (i) it is easy to prepare; (ii) the products contain both axial chirality and central chirality on the phosphorus atom; (iii) the menthyl group could easily be transformed into other functional groups, which is crucial for the diversity of the corresponding biphenyl ligands. In our reaction, the P═O group not only acts as the directing group but also facilitates the construction of the phosphine ligands. In addition, the application of these products in asymmetric catalysis has also been studied with good results obtained in some reactions. The further application of these ligands, especially the chiral biphenyl monophosphine ligands in catalysis reactions is underway in our laboratory, and we hope different kinds of reactions will be achieved with these ligands.

Synthesis and Catalytic Applications of a Triptycene-Based Monophosphine Ligand for Palladium-Mediated Organic Transformations.

1-Methoxy-8-(diphenylphosphino)triptycene (1), featuring high structural rigidity and steric bulkiness around the phosphine functionality, was synthesized as a new chiral monophosphine ligand for transition metal-catalyzed reactions. In the presence of 5–10 mol ppm (i.e., 0.0005–0.001 mol %) Pd(OAc)2 and 1 (2 equiv for Pd), Suzuki–Miyaura cross-coupling reactions of aryl bromides and arylboronic acids proceeded effectively under mild atmospheric conditions to give the corresponding biaryl compounds in a high yield. The single-crystal X-ray analysis of a Pd(II) complex of 1 revealed its coordination structure, in which two homochiral molecules form a dimer, suggesting that triptycene could provide a chiral environment for asymmetric organic transformations. In fact, optically active 1 obtained by optical resolution showed good enantioselectivity in the palladium-catalyzed asymmetric hydrosilylation of styrene, which represents, for the first time, the asymmetric catalytic activity of triptycene-based monophosphine ligands.

Design and Synthesis of Porphyrin Oligomers and Porphyrinoids Via Suzuki-Miyaura Reaction

In view of multi-porphyrin arrays and new porphyrinoids, whih has potential applications in optoelectronic devices, sensors, photovoltaic devices, non-linear optical(NLO) materials, photodynamic therapy (PDT) pigments, light-harvesting models, and host-guest chemistry. Both the manipulation of interporphyrinic interaction and design of new structural porphyrinods are often essential to achieve desirable electronic and photophysical properties. Recently, the Osuka group developed a transition metal-catalyzed coupling reaction that has been proven to be very useful to construct multiporphyrinic systems. Till now we have adopted this strategy and prepared many heterocycles bridged β-to-β porphyrin arrays, including direct-bridged β-to-β porphyrin nanorings[ 1 ], earring porphyrins[ 3 ]. The experiment results indicated that the building blocks will remarkably affect the target molecules. As the bridge is thienylene, the main products is cyclic dimer, trimer, when the bridge is pyridylene, there are trace cyclic products are obtained. when the bridge is free base or Zn(II) porphyrin, bigger loop are formed, while Ni(II)porphyrin is used, the products is much simple. As to synthesis of porphyrin nanobarrel, if the porphyrin monomer is free base or Zn(II) porphyrin, no porphyrin barrel is obtained, which means that only ruffled Ni(II)porphyrin monomers can be used to synthesis porphyrin barrels. Synthesis of direct linked porphyrin nanorings is affected by the meso-substituent on porphyrin, when the substituent is aryl, only trimer and twinned pentamer can be prepared, when the substituent is alkyl, tetramer and twinned heptamer can be obtained.The photophysical study revealed that these porphyrin arrays and porphyrinoids exhibit either longer fluorescent lifetime, larger two photon absorption values or Near-infrared absorptions. Some new porphyrin arrays or porphyrinnoids recently have been constructed through Pd-catalyzed cross-coupling reactions (Figure 1), further study on their properties is underway in our lab. Figure 1. Crystals of earring porphyrins and multi-porphyrin arrays