Transition Metal-catalyzed Reactions Research Articles

Copper's rapid ascent in visible-light photoredox catalysis.

Visible-light photoredox catalysis offers a distinct activation mode complementary to thermal transition metal catalyzed reactions. The vast majority of photoredox processes capitalizes on precious metal ruthenium(II) or iridium(III) complexes that serve as single-electron reductants or oxidants in their photoexcited states. As a low-cost alternative, organic dyes are also frequently used but in general suffer from lower photostability. Copper-based photocatalysts are rapidly emerging, offering not only economic and ecological advantages but also otherwise inaccessible inner-sphere mechanisms, which have been successfully applied to challenging transformations. Moreover, the combination of conventional photocatalysts with copper(I) or copper(II) salts has emerged as an efficient dual catalytic system for cross-coupling reactions.

Efficient Enantioselective Syntheses of Chiral Natural Products Facilitated by Ligand Design.

The employment of enantioselective transition-metal-catalyzed transformations as key steps in asymmetric natural product syntheses have attracted considerable attention in recent years owing to their versatile synthetic utilities, mild conditions and high efficiency in chirality generation. The chiral catalysts or supporting ligands are believed to be crucial for the requisite reactivity and enantioselectivity. Therefore, the rational design of chiral ligands is at the heart of developing new asymmetric transition-metal catalyzed reactions and provides an avenue to the asymmetric synthesis of natural products. Our group has been engaged in the development of transition-metal-catalyzed enantioselective cross-coupling, cyclization and other related reactions and the application of these methodologies to natural product syntheses. In this account, we summarized our recent synthetic efforts towards the efficient total syntheses of several different types of natural products including terpenes, alkaloids and polyketides facilitated by the design of a series of versatile P-chiral phosphorous ligands.

DECORATION OF 1,3-OXAZOLE BY ALKYL SUBSTITUENTS V IA CH ACTIVATION

Microreview describes recent advances in the synthesis of alkyl-substituted 1,3-oxazoles via CH activation reaction. The latest selected examples (2008–2018) on the synthesis of alkyl-substituted oxazoles by transition metal-catalyzed CH activation reactions as well as metalation with subsequent alkylation are summarized.

The Metal Hydride Problem of Computational Chemistry: Origins and Consequences

Formation and breaking of metal-hydrogen bonds are central to many important catalytic processes such as transition-metal catalyzed ammonia synthesis, hydrogenation reactions, and water splitting, and thus, they require an adequate theoretical description. We studied a data set of all 30 M-H and 30 M+-H bonds of the 3d, 4d, and 5d transition series; 50 of these systems have experimentally known bond dissociation enthalpies (BDE). To probe both the limit of low and high coordination number, we also studied a data set of 19 ML nH complexes. The BDEs were computed using Hartree-Fock (HF), MP2, CCSD, CCSD(T), and 10 diverse density functionals including local, GGA, hybrid GGA, meta hybrid, range-separated, and double hybrids. Our ten most important findings are as follows: (1) HF fails completely to describe the metal hydrogen bond due to its lack of static correlation; (2) this makes post-HF methods such as MP2 and even CCSD(T) perform worse than many density functionals; (3) DFT requires much more HF exchange (∼35% on average) to describe the pure M-H bonds than to describe other metal ligand bonds (0-20%); (4) we design a test to determine if self-interaction error (SIE) is important by correlating DFT errors against a one-electron SIE metric; (5) we show that SIE correlates directly with the DFT errors and thus causes most of the problem; (6) HF-DFT cannot handle these systems because the HF method is too pathological already at the density level; (7) instead, we define and apply a simple metric of electronic abnormality as the difference in PBE energy computed at the self-consistent PBE0 and SVWN densities, and this metric gives appropriate spread and effectively captures density-derived errors; (8) the low electronegativity of the metal enforces a diffuse hydride-like electron density, which make the metal hydrides primary examples of many-electron systems exhibiting SIE already at equilibrium geometries; (9) in the coordinatively saturated ML nH systems, much less HF exchange is required; i.e., the HF exchange requirements vary drastically with coordination number. Accordingly, DFT is unbalanced for any catalytic process involving both M-H and M-L bonds and changing coordination numbers; (10) importantly, the range-separated and double-hybrid functionals CAM-B3LYP and B2PLYP alone perform well for both M-H and M-L systems and in both limits of low and high coordination number, and at least as well as CCSD(T). This lends hope to a balanced treatment of computational chemistry for all types of M-L bonds at variable coordination number, as required for real catalytic reactions.

Breaking Amide C-N Bonds in an Undergraduate Organic Chemistry Laboratory.

An undergraduate organic chemistry laboratory experiment involving the breakage of amide C-N bonds is reported. Whereas amides are typically considered stable species due to well-established resonance effects, this experiment allows students to cleave the amide C-N bond in a nickel-catalyzed esterification process. Moreover, students perform the experiment on the benchtop using a commercially available paraffin wax capsule containing the necessary nickel precatalyst and N-heterocyclic carbene ligand. The laboratory procedure introduces students to several modern topics in organic chemistry that are not otherwise well-represented in typical undergraduate organic chemistry curricula, such as amide bond cleavage, transition metal-catalyzed cross-coupling reactions, and nonprecious-metal catalysis.

Decoration of 1,3-oxazole by alkyl substituents via CH activation (microreview)

Microreview describes recent advances in the synthesis of alkyl-substituted 1,3-oxazoles via CH activation reaction. The latest selected examples (2008–2018) on the synthesis of alkyl-substituted oxazoles by transition metal-catalyzed CH activation reactions as well as metalation with subsequent alkylation are summarized.

Regiodivergent Hydroaminoalkylation of Alkynes and Allenes by a Combined Rhodium and Photoredox Catalytic System.

A rhodium/photoredox dual catalyzed regiodivergent α-allylation of amines is described. As an atom-economic and efficient method, alkynes and allenes are used as allylic electrophile surrogates in this novel protocol. With different reaction conditions, synthetically useful branched or linear homoallylic amines could be synthesized in good to excellent yields and regioselectivity. This straightforward strategy complements the traditional transition-metal catalyzed allylation reactions.

Photo-Modulatable Potential Oscillation during Organic-Phase Iodization Reaction

For an insight into the photo-electrochemical intensification kinetics and its solvent effect during transition-metal catalyzed iodization reaction, photo-modulatable electrochemical potential oscillation was successfully achieved in acetonitrile solvent for the first time. Such an oscillation behavior cannot be observed in a similar iodization reaction system using aqueous solvent, which is different from classical B-Z oscillation or iodine-clock oscillation. The oscillation reaction cannot only be modulated by solar light, but also be coupled with another electrochemical iodization process for promoting reaction efficiency. A possible oscillation mechanism with dynamic equations was proposed to explicit the contribution of acetonitrile as solvent and trace amount of water as one reactant to iodate reactivity and proton activity. As is also demonstrated, the oscillation mechanism may inspire new intensification strategies toward highly-efficient iodization reaction with low energy consumption or high power output.

Recent advances in the synthesis and applications of α-(trifluoromethyl)styrenes in organic synthesis.

α-Trifluoromethylstyrene derivatives are versatile synthetic intermediates for the preparation of more complex fluorinated compounds. Much attention has been paid to these compounds by the organic chemistry community, because they have been successfully utilized in C-F bond activation in a CF3 group, mainly including anionic SN2'-type substitution, cationic SN1'-type substitution, ipso-substitution and defluorinative functionalization with transition metals or photoredox catalysts. In addition, transition metal-catalyzed cycloaddition reactions of α-trifluoromethylstyrenes have been developed for the construction of cycloalkanes and cycloalkenes containing fluoro or trifluoromethyl groups. In this review, we systematically summarized the synthesis of α-trifluoromethylstyrenes and their applications in organic synthetic chemistry, and their mechanisms were also discussed.

Metal-Free Cross-Dehydrogenative Coupling (CDC): Molecular Iodine as a Versatile Catalyst/Reagent for CDC Reactions.

The development of ecofriendly methods for carbon-carbon (C-C) and carbon-heteroatom (C-Het) bond formation is of great significance in modern-day research. Metal-free cross-dehydrogenative coupling (CDC) has emerged as an important tool for organic and medicinal chemists as a means to form C-C and C-Het bonds, as it is atom economical and more efficient and greener than transition-metal catalyzed CDC reactions. Molecular iodine (I2 ) is recognized as an inexpensive, environmentally benign, and easy-to-handle catalyst or reagent to pursue CDCs under mild reaction conditions, with good regioselectivities and broad substrate compatibility. This review presents the recent developments of I2 -catalyzed C-C, C-N, C-O, and C-S/C-Se bond-forming reactions for the synthesis of various important organic molecules by cross-dehydrogenative coupling.

Upgrading Cross-Coupling Reactions for Biaryl Syntheses.

Transition-metal catalyzed cross-coupling reactions have emerged as a powerful tool for constructing biaryl compounds. Aryl halides and aryl metallic reagents (typically prepared from aryl halides) are used as coupling partners. It would be desirable to replace either aryl halide or aryl metallic reagents used in cross-couplings reactions with more readily available surrogates. Oxidative dehydrogenative cross-coupling between two different "inert" aryl C-H bonds represents an ideal system that would revolutionize cross-coupling chemistry. Furthermore, cross-coupling reactions might be improved by developing new catalytic protocols based on cheap transition-metal catalysts or even transition-metal-free systems to decrease costs and avoid the use of heavy metal and noble transition metals. It would be desirable to promote both catalytic systems and replace either or both coupling partners. We have used different strategies to improve cross-coupling reactions for constructing biaryls, which we categorized into four groups as follows. First, we focused on developing methodologies to be applied to easily produced and naturally abundant arenol-based electrophiles in cross-coupling via C-O activation. We have extended coupling partners to aryl carboxylates and arenols. Direct application of arenes as surrogates for organohalides and organometallic reagents avoids the tedious preparation of these reagents from arenes and considerably reduces the cost of starting materials. We have also explored cross-coupling reactions of arenes with various organometallic reagents, such as arylboronic acids, arylsilanes, and aryl Grignard reagents. Second, we summarize oxidative cross-coupling reactions based on C-H activation with aryl metallic reagents. On the basis of the reactivity patterns of different organometallic reagents, we adapted different catalytic systems to achieve effective cross-coupling reactions. Third, we improved a well-developed cross-coupling between arenes and organohalides through a strategy of replacing one coupling partner and using a new catalytic system. We have applied earth-abundant transition metals, such as Fe, and Co, and even developed transition-metal-free catalytic systems. Finally, our ultimate goal is to construct biaryls by cross dehydrogenative arylation between two different arenes. Owing to the structural similarity of both arenes, in particular two substituted benzenes, the greatest challenges are not only achieving regio- and chemo-selective C-H activation reactions but also matching both the reactivities and selectivities of both substrates to avoid homocouplings of either arene. Through our efforts, we have developed and applied four different strategies by introducing directing groups, controlling electronic and steric properties, and using dual directing strategies. We hope our studies will stimulate interest and new thinking on cross-couplings reactions for building carbon-carbon bonds from readily available and inexpensive chemicals from basic petroleum chemistry and nature.

Synthesis of novel diketopyrrolopyrrole-based dyes

Three novel diketopyrrolopyrrole-based molecules for potential application in dye-sensitized solar cells are synthesized starting from a common and easily available key intermediate with a bis-thienyl diketopyrrolopyrrole structure. The synthetic sequence is based upon transition-metal catalyzed coupling reactions involving commercial boronic acid followed by condensation reactions with 2-cyanoacetic acid. Absorption and fluorescence spectra of the molecules are also reported.

Introduction of Diverse Functional Groups to Isoquinolines by Microwave-assisted Transition Metal-catalyzed Coupling Reactions

Diverse functional groups were introduced in isoquinolines under microwave-assisted palladium- or copper-catalyzed coupling reactions, which include functional groups to isoquinoline were achieved with 1-substituted 4- and 7-bromoisoquinolines, arylboronic acids, terminal alkenes, terminal alkynes, and azaheterocycles. 1,4- or 1,7-Disubstituted isoquinolines were obtained in moderate to excellent yields within 1 h under microwave irradiation. The facile functional group modification of isoquinoline core could establish isoquinoline compound library for drug discovery.

Assessment on the double role of the transition metal salts on the acetalization of furfural: Lewis and Brønsted acid catalysts

The conversion of biomass derived to more valuable compounds has attracted growing attention due to the economic and environmental reasons. In special, the furfural deserves highlight because it is a versatile biorefinery platform-molecule and has been used as feedstock to produce fuels and fine chemicals. In this work, we have developed a process to synthesize furfural acetals at room temperature in transition metal-catalyzed reactions using different alcohols. Among the transition metal catalysts, the FeCl3 provided the highest catalytic activity (ca. 90% conversion within 1 h reaction) and highest furfural acetal yield (ca. 94% of 2-(dimethoxymethyl)furan). Effects of main reaction parameters such as e.g. reaction time, catalyst concentration and pH of medium were assessed. Based on experimental results, we conclude that metal salts (i.e., mainly FeCl3 and NiCl2) act as Lewis and Brønsted acid catalysts on these reactions. The reaction scope was successfully extended to the different alcohols. A special attention was paid to assess the effects of catalyst nature on these processes.

Mapping out the key carbon–carbon bond-forming steps in Mn-catalysed C–H functionalization

Detailed understanding of the mechanistic processes that underpin transition metal-catalysed reactions allows for the rational and de novo development of complexes with enhanced activity, efficacy and wider substrate scope. Directly observing bond-cleaving and -forming events underpinning a catalytic reaction is non-trivial as the species that facilitate these steps are frequently short-lived and present at low concentrations. Here, we describe how the photochemical activation of a manganese precatalyst, [Mn(ppy)(CO)4] (ppy = 2-phenylpyridine), results in selective loss of a carbonyl ligand simulating entry into the catalytic cycle for manganese-promoted C–H bond functionalization. Time-resolved infrared spectroscopy (on the ps–ms timescale) allows direct observation of the species responsible for the essential C–C bond formation step and an evaluation of the factors affecting its rate. This mechanistic information prompted the discovery of a new photochemically initiated manganese-promoted coupling of phenylacetylene with 2-phenylpyridine. This study provides unique insight into the mechanistic pathways underpinning catalysis by an Earth-abundant metal, manganese. Although mechanistic understanding can drive new reactivity development, the key bond-forming and -breaking steps in catalytic cycles are often sufficiently fast to elude observation. Here, the authors photochemically produce a key intermediate in Mn-catalysed C–H functionalization, and follow the subsequent steps—spanning processes occurring over seven orders of magnitude in time—using time-resolved infrared spectroscopy.

Photocatalytic Activation of Less Reactive Bonds and Their Functionalization via Hydrogen-Evolution Cross-Couplings.

Cross-coupling reactions have been established as potential tools for manufacture of complex molecular frameworks of diversified interests by connecting two simple molecules through the formation of a carbon-carbon (C-C) or a carbon-heteroatom (C-X) bond. Conventional cross-couplings are transition metal-catalyzed reactions between electrophiles and nucleophiles. Generally, the electrophilic partner is an aryl or alkenyl halide, the nucleophile is an organometallic reagent, and both are obtained from prefunctionalization of their corresponding hydrocarbons. During the past decade, transition metal-catalyzed dehydrogenative cross-couplings between two carbon-hydrogen (C-H) bonds and between one C-H bond and one heteroatom-hydrogen (X-H) bond, which build a C-C and a C-X linkage respectively, have emerged as an attractive strategy in synthetic chemistry. Such straightforward couplings allow use of less functionalized reagents, thus reducing the number of steps to the target molecule and minimizing waste production. However, such reactions involve the use of stoichiometric amounts of sacrificial oxidants such as peroxides, high-valent metals, and iodine(III) oxidants. This leads to low atom economy and possible generation of toxic wastes. Recently, visible light photocatalytic dehydrogenative cross-coupling reactions have received much attention due to their potential in utilizing sunlight as a source of energy making the process appealing. In this approach, metal complexes, organic dyes, or semiconductor quantum dots that absorb visible light are employed as photocatalysts. Upon irradiation, photocatalyst initiates single electron transfer with substrate(s) to generate a radical cation or radical anion of the substrate, which undergoes the desired reaction of interest. In this case, molecular oxygen is utilized as the oxidant with the formation of hydrogen peroxide as the only byproduct. These aspects make the process much greener than the corresponding transition metal-catalyzed dehydrogenative cross-coupling reactions. Research efforts from our group have led to the development of an environmentally benign strategy to construct a C-C bond from two different C-H bonds and to construct a C-X bond from one C-H bond and one X-H bond by visible light photocatalysis. Our approach, photocatalytic hydrogen-evolution cross-coupling reactions, combines a photocatalyst with a proton reduction cocatalyst to create a dual catalyst system. The former catalyst uses light energy as the driving force for the cross-coupling, while the latter catalyst may capture electrons from the substrates or reaction intermediates to reduce the protons eliminated from the reactive scaffolds (C-H/C-H or C-H/X-H bonds) into molecular hydrogen (H2). Thus, without use of any sacrificial oxidant and under mild conditions, our dual catalyst system affords cross-coupling products with excellent yields with generation of an equimolar amount of H2 as the sole byproduct. The photocatalytic hydrogen-evolution cross-coupling is highly step and atom economical and particularly useful for reactions that involve species sensitive to oxidative conditions. This Account highlights the findings from our laboratories on photocatalytic hydrogen-evolution cross-coupling reactions featuring activation and functionalization of C(sp3)-H bonds adjacent to amino groups and to oxygen atoms in ethers, aromatic C(sp2)-H bonds, and several types of X-H bonds. We expect that this strategy for combining photocatalytic activation of C-H and X-H bonds with proton reduction holds significant potential for development of atom economical and environmentally benign transformations.

Transition Metal-Catalyzed Reactions of 3-Aza-2-oxabicyclo[2.2.1]hept-5-enes

Background: Transition metal catalysts are becoming increasingly more important in organic synthesis and are being used to catalyze novel reactions that allow for more efficient synthesis of many pharmaceuticals. Transition metal-catalyzed reactions of 3-aza-2-oxabicyco[2.2.1]hept-5-enes provide efficient synthetic pathways to generate a diverse range of biologically and synthetically useful products. 3-Aza-2- oxabicyclic alkenes undergo three main types of reactions: reductive N-O bond cleavage, C-O bond cleavage, and modification of the alkene component. Objective: The purpose of this review is to summarize and discuss the transition metal-mediated reactions of 3- aza-2-oxabicyclo[2.2.1]hept-5-enes, including the mechanisms of reactions based on the transition metal used, the different stereo- and regiochemical outcomes of reactions with this asymmetrical substrate, and the biological importance of exploring these reactions. Conclusion: It is clear from the review of the topic that a vast amount of work has been done in this area, and transition metals have been used to control the regio- and stereoselective reactions of 3-aza-2-oxabicyclic alkenes to create biologically active and synthetically useful products. The transition metal-catalyzed reactions of 3-aza-2-oxabicyclic alkenes proceed through three general reactions: through cleavage of the N-O bond, cleavage of the C-O bond, and modification of the alkene component. Without the use of transition metals, the substrate would not be activated and these reactions would not be possible. The use of transition metals opens up an array of new reactions that have the ability to create different functional groups with different regio- and stereoselectivities based on the metal and conditions used. The products made through these transition metalcatalyzed reactions can be useful as antibiotics, siderophores, and carbocyclic nucleosides such as noraristeromycin and carbocyclic polyoxin C.

Bismuth-catalyzed synthesis of 2-substituted quinazolinones

The bismuth-catalyzed oxidative condensation of aldehydes with 2-aminobenzamide under aerobic conditions is reported using ethanol as the solvent. Good to excellent isolated yields (68–95%) of the corresponding 2-substituted quinazolinones were obtained under mild reaction conditions with excellent functional group tolerance. The quinazolinones were further functionalized to afford N-allylated quinazolinones, 2-aminopyridine derivatives, and annulated polyheterocyclic compounds via transition-metal catalyzed reactions.

Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions: Discovery, Development and Applications to Target-Directed Synthesis.

The transition metal-catalyzed allylic substitution reaction is a particularly versatile method for the construction of carbon-carbon and carbon-heteroatom bonds. In this regard, the rhodium-catalyzed variant has emerged as a powerful method for the regioselective and stereospecific allylic substitution of chiral nonracemic secondary and tertiary allylic carbonates with a variety of carbon- and heteroatom-based nucleophiles. In addition, recent developments have made the analogous enantioselective process possible using prochiral nucleophiles with achiral allylic electrophiles, which represents a significant advance in this area. In this Perspective, the discovery, development and applications of these conceptually orthogonal strategies to target-directed synthesis are discussed, with a particular emphasis given to those methods developed in our laboratory.

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.