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Development of scalable processes for C­(sp3)–H oxidative carbonylation of alkylamines is reported to provide convenient access to the β-lactam scaffol d. A study of the kinetics of the process revealed that the reaction is CO-limited even at elevated pressures and that there is an optimal CO concentration for the most effective outcomethis understanding led to an increase in the turnover number from 7 to 420 in the optimized process. Two scalable processes were then developed: a batch process, characterized by a very low catalyst loading, and a continuous process for an oxidative C–H carbonylation reaction that uses a copper-tube-flow reactor as a heterogeneous source of Cu2+ oxidant. The continuous process was tested on oxidative carbonylation of several alkylamines, yielding very good results with virtually no optimization required. This study thereby builds upon the utility of flow chemistry applications to oxidative carbonylations and scalable metal-catalyzed processes more generally. more...

In this work, we report the synthesis of a room-temperature-stable electride (RoSE) reagent, namely K+(LiHMDS)e− (1) (HMDS: 1,1,1,3,3,3-hexamethyldisilazide), from accessible starting materials (potassium metal and LiHMDS) via mechanochemical ball milling at 20 mmol scale. Despite its amorphous nature, the presence of anionic electrons in 1, key diagnostic criteria for an electride, was confirmed by both experimental and computational studies. Therefore, by definition, 1 is an electride. Utilizing its anionic electrons, electride reagent 1 exhibited a versatile reactivity profile that includes (1) mediation of C–H activation and C–C coupling of benzene and pyridine and (2) mediation of solvent-free Birch reduction. This work proves the concept of facile mechanochemical synthesis of a room-temperature-stable electride, and it introduces electride 1 to the synthetic chemistry community as a versatile reagent. more...

Platinum group metal (PGM)-based catalysts are known to be highly active in the total combustion of lower hydrocarbons. However, through an alternative catalyst design reported in this paper by isolating PGM-based active sites in a tungsten phosphate matrix, we present a class of catalysts for selective oxidation of n-butane, propane, and propylene that do not contain Mo or V as redox-active elements. Two different catalyst concepts have been pursued. Concept A: isolating Ru-based active sites in a tungsten phosphate matrix coming upon as ReO3-type structure. Concept B: dilution of PGM-based active sites through the synthesis of X-ray amorphous Ru tungsten phosphates supported on SiO2. Using a high-throughput screening approach, model catalysts over a wide compositional range were evaluated for C3 and C4 partial oxidation. Bulk crystalline and supported XRD amorphous phases with similar Ru/W/P compositions showed comparable performance. Hence, for these materials, composition is more crucial than the degree of crystallinity. Further studies for optimization on second-generation supported systems revealed even better results. High selectivity for n-butane oxidation to maleic anhydride and propane oxidation to an acrolein/acrylic acid has been achieved. more...

Transition metal-catalysed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes (i.e. ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compounds allowing in situ transformation towards numerous functional groups and organic compounds, including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the organic chemistry toolbox. This review discusses all known transition metal-catalysed carbene- and nitrene transfer reactions towards carbon monoxide and isocyanides and in situ transformation of the heteroallenes hereby obtained, with a special focus on the general mechanistic considerations. more...

In this study, we report the synthesis of unsubstituted 1,2-benzothiazines through a redox-neutral Rh(III)-catalyzed C–H activation and [4+2]-annulation of S–aryl sulfoximines with vinylene carbonate. Notably, the introduction of an N-protected amino acid ligand significantly enhances the reaction rate. The key aspect of this redox-neutral process is the utilization of vinylene carbonate as an oxidizing acetylene surrogate and an efficient vinylene transfer agent. This vinylene carbonate enables the cyclization with the sulfoximine motifs, successfully forming a diverse array of 1,2-benzothiazine derivatives in moderate to good yields. Importantly, this study highlights the potential of Rh(III)-catalyzed C–H activation and [4+2]-annulation reactions for the synthesis of optically pure 1,2-benzothiazines with high enantiomeric purity. more...

The factors determining the catalytic performance of a recently discovered system for direct intermolecular alkyne hydroarylations, comprising a gold(I) complex of general formula LAuX (L = neutral ligand; X = weakly coordinating counteranion) and an ionic liquid as solvent, have been investigated. In particular, the effect of the ionic liquid anion, cation, and of the electronic and steric properties of the neutral ligand L have been considered. The results of the investigation shed some light in particular on the role of the anion, which is multiform and can potentially influence the catalytic performance in many respects, and on the role of the neutral ligand, which should be a relatively poor electron donor but not so much as to compromise the stability of the catalyst. Knowledge of the factors affecting catalytic performance will speed up the optimization of this catalytic system, in the case of direct alkyne hydroarylations with different substrates, and will also facilitate the extension of its application to other reactions. more...

Ni(II), Pd(II), and Pt(II) complexes [M(Y-terpy)X] (X = Cl or Br) containing the tridentate N^C^N-cyclometalating 2,3′:5′,2″and 2,2′:4′,2″ stereoisomers of the well-known tridentate N^N^N ligand 2,2′:6′,2″-terpyridine (terpy) were synthesised in moderate to good yields through C–H activation. For the Pt complexes, the phenyl ethynide derivatives [Pt(Y-terpy)(C≡CPh)] were also obtained under Sonogashira conditions. In contrast to this, C^N^N cyclometalated complexes using the 2,2′:6′,3″- and 2,2′:6′4″-terpy isomers were not obtained. Comparison of the N^C^N complexes of the cyclometalated 2,3′:5′,2″- and 2,2′:4′,2″-terpy ligands with complexes [M(dpb)Cl] of the prototypical N^C^N cyclometalating ligand dpb− (Hdpb = 2,6-diphenyl-pyridine) showed higher potentials for the terpy complexes for the ligand-centred reductions in line with the superior π-accepting properties of the terpy ligands compared with dpb. Metal-centred oxidations were facilitated by the dpb ligand carrying a central σ-donating phenyl group instead of a metalated pyridine moiety. The same trends were found for the long-wavelength absorptions and the derived electrochemical and optical band gaps. The lower σ-donating capacities of the cyclometalated terpy derivatives is also confirmed by a reduced trans influence in the structure of [Ni(2,3′:5′,2″-terpy)Br0.14/OAc0.86]. Attempts to re-crystallise some poorly soluble Pd(II) and Pt(II) complexes of this series under solvothermal conditions (HOAc) gave two structures with N-protonated cyclometalated pyridine moieties, [Pt(2,3′:5′,2″-terpyH)Cl].Cl and [Pd(2,3′:5′,2″-terpyH)Cl2]. more...

ispartof: ACS SUSTAINABLE CHEMISTRY & ENGINEERING vol:10 issue:11 pages:3766-3776 status: published

The development of energy-efficient catalytic processes for the selective conversion of hydrocarbons to higher-value chemicals has been a topic of broad interest in both academia and industry. Achieving such a goal requires fundamental advancements in understanding reaction mechanisms, the effects of reaction conditions, structure-activity correlation based on catalytic identity, as well as probing new catalyst designs. Hydrogen–deuterium exchange (H/D exchange) is a commonly used method for studying catalytic activation of C–H(D) bonds by transition metal complexes. A series of Lewis acid additives were studied for H/D exchange of toluene-d8 with weak acetic acid (HOAc) using (RPNP)Rh(X) complexes (R = phosphine substituents including cyclohexyl, isopropyl and tert-butyl; X = trifluoroacetate or acetate) as the pre-catalysts. Cu(II) and Ag(I) salts were found to benefit Rh-mediated C–H(D) activation of toluene with meta-para selectivity by facilitating the conversion to active (RPNP)Rh species and stabilizing the Rh catalysts from decomposition to inactive Rh(s). In contrast, non-oxidizing Lewis acid additives, such as B(OMe)3 or NaOAc, were not effective at facilitating Rh-catalyzed toluene C–H activation. C–H acetoxylation was studied as potential route for conversion of benzene to phenol (after hydrolysis). Using an air-recyclable Cu(II) salt for benzene C–H acetoxylation could potentially lead to a coproduct-free synthetic route for phenol production. Since all of the coproducts are used for recycling of the Cu(II) salt, the overall reaction is the conversion of benzene and dioxygen to phenol. Simple Cu(II) carboxylate salts (e.g., Cu(OAc)2, Cu(OPiv)2, and Cu(OHex)2) were found to be active for C–H acetoxylation of non-activated arenes (i.e., benzene and toluene), as well as related functionalization with OPiv and OHex ester groups (OPiv = pivalate; OHex = 2-ethylhexanoate), with over 80% yield (based on Cu). Combined experimental and computational studies indicate that the arene C–H functionalization likely occurs by a non-radical Cu(II)-mediated organometallic pathway. The presence of water and/or dioxygen during the reaction was found to switch the reaction mechanism to radical pathways. The Cu(II) salts used in the reaction can be isolated, recycled, and reused with little change in reactivity. Also, the Cu(II) salts can be regenerated in situ using O2 and, after the removal of the generated water, the arene C–H acetoxylation and related esterification reactions can be continued. Catalytic oligomerization for upgrading ethylene to higher olefins is an important commercial method for production of linear α-olefins. By using alkylaluminum(III) compounds or other Lewis acid additives, Ni(II) complexes of the type (RPBP)NiBr (R = tBu or Ph) show activity to produce butenes and higher olefins. (PhPBP)NiBr achieved an optimized turnover frequency (TOF) of 640 mol(ethylene)/{mol(Ni)·s} for the formation of butenes with 41(1)% selectivity for 1-butene. The complex (tBuPBP)NiBr provided a TOF of 68 mol(ethylene)/{mol(Ni)·s} for butenes production with 87.2(3)% selectivity for 1-butene. Using methylaluminoxane as co-catalyst and (tBuPBP)NiBr as the precatalyst, ethylene oligomerization to form C4 through C20 products was achieved while the use of (PhPBP)NiBr as the precatalyst retained selectivity for C4 products. Combined experimental and computational studies point to a mechanism that involves a cooperative B/Ni activation of ethylene to form a key 6-membered borametallacycle intermediate. Thus, a cooperative activation of ethylene by the Ni–B unit of the (RPBP)Ni catalysts is proposed as a key element of the Ni catalysis. In addition, under some conditions, the (RPBP)Ni catalysts can operate without solvent to upgrade ethylene in solid-gas phase reactions. Previously, we have demonstrated the use of "capping arene" ligands to modulate stoichiometric and catalytic reactions, in which the reactivity can be tuned by adjusting the distance between metal center and the capping arene moiety. In recent efforts, as an extension of the “capping arene” ligands, we are seeking to use a Sb-moiety that can modulate electron density at the transition metal center as a function of the Sb oxidation state. Thus, the possible transformation of Sb–M bonds between L-, X- and Z-type bonding modes offers potential redox flexibility at the transition metal center that could influence the energetics of reactions that involve redox state changes at the transition metal. A series of Sb(III)- and Sb(V)-based preligands with L-type 8-quinolinyl donors have been synthesized and used for coordinate to late transition-metals such as Rh, Pt, Pd, Ir, Ru, Ag, and Cu. The solid-state structure of some complexes was confirmed via X-ray crystallography, which included an example of Z-type complex with a Pt→Sb interaction. One example of the Rh–Sb complexes was found to be active for H/D exchange of benzene-d6 with HOAc, and slow aerobic benzene alkenylation with propylene was observed. more...

This work demonstrates the influence of the catalyst and alkyne nature on the regioselectivity of rhodium-catalyzed annulation of alkoxy-substituted benzoic acids (such as 3-methoxybenzoic, 3,4-dimethoxybenzoic, and piperonylic acids) with alkynes. Here, X-ray diffraction and DFT calculation data gave evidence that the observed regioselectivity is provided by both steric and coordination effects of methoxy groups. The latter is the result of weak non-covalent C–H⋯O interactions with the supporting ligand rather than with the rhodium atom. We believe that these results are also valid for other reactions of the C-H activation of methoxy-substituted arene compounds. more...

Nickel is a widely abundant and inexpensive metal. Catalysts are substances that remain unconsumed and increase the rate of reactions by reducing the activation energy barrier, often by providing an alternative route. The main goal of this study is to prepare Ni(II) complexes that can promote a catalytic aerobic oxidation reaction by breaking allylic C-H bonds. Based on previous studies, allylnickel N-heterocyclic carbene complexes react with molecular oxygen to give useful carbonyl compounds with a Ni(II)-OH by-product, which undergoes dimerization. In order to achieve catalysis, dimerization of the Ni(II)-OH should be prevented and C-H activation has to be achieved to complete the cycle. This project attempts to promote C-H activation via a Ni-OH moiety utilizing two different strategies that are described in Chapters 2 and 3, respectively. A known tridentate ligand structure proposed to inhibit dimer formation was targeted, which includes an imidazolium salt precursor that contains a hemilabile picolyl group. Studies on synthesizing a Ni(II)-OH monomer were conducted to test its ability toward C-H activation. No success was seen due to the instability of the intermediate leading to the formation of a bis-ligated Ni complex. A new allyl ligand N-8-quinolinyl-4-pentenamide with a bidentate directing group was chosen as an alternative approach. Preliminary studies indicated the formation of a dynamic paramagnetic complex with an unknown structure and a presumed bis-ligated by-product. Catalytic studies were done to test the ability of the unknown complex to activate allylic C-H bonds, but no success was achieved due to a competing reaction of the base with the ligand. more...

This work reports on dye sensitized photoanodes for C-H activation in organic substrates, assembled by vacuum sublimation of a commercially available quinacridone (QNC) dye in the form of nanosized rods onto Fluorine doped tin oxide (FTO), TiO2 and SnO2 slides. The photoanodes display extended absorption in the visible (450-600 nm) and ultrafast photoinduced electron injection (1 ps, as revealed by transient absorption spectroscopy) of the QNC dye into the semiconductor. The proton-coupled electron-transfer reactivity of QNC is exploited for generating a nitrogen-based radical as its oxidized form, which is competent in C-H bond activation. In particular, the key reactivity parameter is the bond dissociation free energy (BDFE) associated with the N•/N-H couple in QNC of 80.5±2.3 kcalmol-1, which enables hydrogen atom abstraction from allylic or benzylic C-H moieties. A photoelectrochemical response is indeed observed for organic substrates characterized by C-H bonds with BDFE below the 80.5 kcalmol-1 threshold, such as γ-terpinene, xanthene, dihydroanthracene. This work opens a rationale and mechanistically oriented design of dye-sensitized photoelectrodes for selective organic transformations. more...

Chemical reactions on surfaces play a central role both for our daily life and industrial purposes, including the storage and release of energy, as well as the formation of new materials. To achieve high efficiency, catalysis lies in the heart of chemical reactions as it plays a critical role in accelerating the chemical transformation to target products. However, environmental issues arise as the applications of catalytic technologies and current synthetic approaches such as pollution from undesirable byproducts and massive emission of carbon dioxides due to the usage of fossil fuels. This calls for developing improved strategies for fabricating new materials with highly efficient catalytic properties. In recent years, on-surface chemical reactions have also been used to synthesize new low-dimensional materials with atomic precision, by coupling molecules into nanostructures. It is crucial to not only obtain high activity for chemical reactions, but also achieve distinct selectivity towards desired products. For this purpose, understanding mechanisms of target chemical reactions and origins of catalysts’ activity are of great significance to facilitate chemical processes. In this thesis, three types of chemical reactions are investigated within the framework of density functional theory (DFT), in which chemical reactions relevant for both heterogeneous catalysis and electrochemical synthesis are considered on two-dimensional transition metal carbides (2D MXenes), and chemical reactions for synthesizing organic nanostructures are studied on metal surfaces. Focusing on one of the most fundamental chemical reaction, C(sp3)-H activation, we demonstrate that MXenes can serve as highly efficient heterogeneous catalysts and exhibit high activity. The thermally triggered C-H activations are shown to follow the “radical-like” mechanism on MXenes, in which O terminations serve as active sites. By adopting the hydrogen affinity (EH) as a descriptor, both the geometry configuration and the catalytic activity of MXenes can be quantitatively characterized. In the context of on-surface synthesis, we theoretically propose reaction mechanisms of two types of chemical reactions on surface. A new strategy for constructing C-C bonds via the desulfonylation reaction was achieved experimentally for the first time by collaborators. With DFT calculations, an observed discrepancy between Ag(111) and Au(111) is ascribed to interactions between surfaces and molecules. Secondly, the formation mechanism of the 2D biphenylene network (BPN), a recently realized carbon allotrope formed by intermolecular HF zipping on Au(111), has been computationally investigated. With the tool of DFT calculations, a single Ni atom catalyst supported by Ti3C2T2 MXenes for electrochemical nitrogen reduction has been theoretically proposed. Such single atom catalyst (SAC) is computationally screened from three aspects including stability, activity, and selectivity. Our theoretical results show that not only the catalytic performance of the Ni SAC predicted by screening criteria can be verified, but also a H rich environment can be beneficial for the electrochemical nitrogen reduction on such SACs. In summary, first-principles calculations have been performed to evaluate the catalytic performance of 2D MXenes towards C-H activation, unravel formation mechanisms of organic materials synthesized via on-surface reactions, and design effective catalysts towards the synthesis of ammonia. It is anticipated that this thesis can pave the way for the rational design of high-efficient catalysts for various reactions and shed lights on developing synthetic strategies of unprecedented organic materials. more...

The first part of this dissertation deals with the design and synthesis of silvestrol and rocaglamide derivatives exhibiting antiviral properties. These two natural products, which belong to the Flavagline group, were isolated from different species of the genus Aglaia. Due to their activity as selective translation inhibitors, they found application in previous medicinal chemistry research primarily as lead structures in cancer research, but later antiviral activity against a variety of RNA viruses was also demonstrated. In the present dissertation, several strategies for the total synthesis of this class of natural products were elaborated on the basis of previous work. This allowed the preparation of a library of 40 derivatives in total. The biological testing of 27 of these compounds against hepatitis E, which was carried out by collaborators at the Ruhr University Bochum, revealed new structure-activity relationships and confirmed that the correlations established in cancer research are also applicable to the antiviral properties. In addition, it was possible to identify candidates that exhibited both higher antiviral activity and proportionally lower cytotoxicity than both natural products. The second part of this dissertation deals with the development of novel synthetic methodologies in the field of radical chemistry. Based on a MINISCI-type decarboxylation, an access to synthetically useful alkoxyamines was established. The relevance of this method was demonstrated by its application in the context of a new total synthesis approach for (±)-indatraline. Studies on the reactivity of a polymer-bound bis(azido)iodiate(I) complex, which releases the highly explosive iodine azide in a controlled manner, enabled the elucidation of several previously unknown radical mechanisms. Furthermore, several methods have been developed to generate bromine azide from stable precursors in situ for the use in organic solvents to accomplish 1,2-functionalization of alkenes and chemoselective oxidation of secondary alcohols. Bundesministerium für Bildung und Forschung/SILVIR/16GW0202/EU more...

This work discusses an enantioselective total synthesis of Ervatamia alkaloids. It relies on an enzyme-catalyzed desymmetrization approach for the installation of chirality. The indole moiety is introduced by a palladium catalyzed C-H activation at a cyclopropane. The cyclopropane is converted into the cyclohepta[b]indole structure of the natural products by a divinylcyclopropane-cycloheptadiene rearrangement. The piperidine moiety is closed by Heck-reaction. published more...

The chemistry of lanthanides is limited to one electron transfer reactions due to the difficulty of accessing multiple oxidation states. Here we report that a redox-active ligand combining three siloxides with an arene ring in a tripodal ligand can stabilize cerium complexes in four different redox states and can promote multielectron redox reactivity in cerium complexes. Ce(iii) and Ce(iv) complexes [(LO3)Ce(THF)] (1) and [(LO3)CeCl] (2) (LO3 = 1,3,5-(2-OSi((OBu)-Bu-t)(2)C6H4)(3)C6H3) were synthesized and fully characterized. Remarkably the one-electron reduction and the unprecedented two-electron reduction of the tripodal Ce(iii) complex are easily achieved to yield reduced complexes [K(2.2.2-cryptand)][(LO3)Ce(THF)] (3) and [K-2{(LO3)Ce(Et2O)(3)}] (5) that are formally "Ce(ii)" and "Ce(i)" analogues. Structural analysis, UV and EPR spectroscopy and computational studies indicate that in 3 the cerium oxidation state is in between +II and +III with a partially reduced arene. In 5 the arene is doubly reduced, but the removal of potassium results in a redistribution of electrons on the metal. The electrons in both 3 and 5 are stored onto d-bonds allowing the reduced complexes to be described as masked "Ce(ii)" and "Ce(i)". Preliminary reactivity studies show that these complexes act as masked Ce(ii) and Ce(i) in redox reactions with oxidizing substrates such as Ag+, CO2, I-2 and S-8 effecting both one- and two-electron transfers that are not accessible in classical cerium chemistry. more...

A dehydrogenative functionalization of styryl carbon-carbon double bonds with triflamide is described via dual visible-light photoredox/cobaloxime catalysis. A range of allylic triflamides (20 examples) were isolated in moderate to good yields (up to 88%) under stoichiometric acceptorless conditions. Dedicated labelling, as well as spectroscopic experiments, enabled to shed light on the concatenated photo- and chemo-catalytic cycles. (Figure presented.). more...

In recent years, transition-metal-catalyzed C–H functionalization has emerged as a potentially greener alternative to classic cross-couplings and as a powerful tool to access complex functional molecules with improved step-economy. This short account relates our experience of industrial collaborations in C(sp3)–H bond activation, which were key to the development of this topic in our group. The synthesis of the antianginal drug Ivabradine led us to develop a general approach to benzocyclobutenes, which were further employed in pericyclic reactions. A follow-up study led us to discover a new method to construct arylcyclopropanes via double C–H activation and the coupling of two alkyl groups. Finally, targeting the herbicide Indaziflam contributed to develop C(sp3)–H activation as a powerful tool to access a variety of relevant indane motifs. We hope that these successful stories will help to stimulate further fruitful Industry-Academia collaborations in the field of synthetic chemistry. more...

Catalytic C‒H functionalization has become a powerful strategy in organic synthesis due to the improved atom-, step- and resource economy in comparison with cross-coupling or classical organic functional group transformations. Despite the significant advances in the metal-catalyzed C‒H activations, recent developments in the field of metallaphotoredox catalysis enabled C‒H functionalizations with unique reaction pathways under mild reaction conditions. Given the relative earth-abundance and cost-effective nature, nickel catalysts for photoredox C‒H functionalization have received significant attention. In this review, we highlight the developments in the field of photoredox nickel-catalyzed C‒H functionalization reactions with a range of applications until summer 2021. more...

Ruthenium(II)-catalyzed enantioselective C–H functionalization reactions of sulfoximines with sulfoxonium ylides are described. The combination of [RuCl2(p-cymene)]2 and a pseudo-C 2-symmetric binaphthyl monocarboxylic acid furnished the S-chiral products in 76:24 to 92:8 er. more...

Several valuable biologically active molecules can be obtained through C–H activation processes. However, the use of expensive and not readily accessible catalysts complicates the process of pharmacological application of these compounds. A plausible way to overcome this issue is developing and using cheaper, more accessible, and equally effective catalysts. First-row transition (3d) metals have shown to be important catalysts in this matter. This review summarizes the use of 3d metal catalysts in C–H activation processes to obtain potentially (or proved) biologically active compounds. more...

The site-selective chemical diversification of biomolecules constitutes an unmet challenge of capital importance within medicinal chemistry and chemical biology. The functionalization of otherwise unreactive C-H bonds holds great promise for reducing the reliance on existing functional groups, thereby streamlining chemical syntheses. Over the last years, a myriad of peptide labelling techniques featuring metal-catalyzed C-H functionalization reactions have been developed. Despite the wealth of reports in the field, the site-selective modification of both phenylalanine (Phe) and tyrosine (Tyr) compounds upon metal catalysis remain comparatively overlooked. This review highlights these promising tagging strategies, which generally occur through the formation of challenging 6-membered metallacycles and enable the late-stage diversification of peptides in a tailored fashion. A. Correa is grateful to Ministerio de Ciencia e Innovacion (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT1033-16) for financial support. He also kindly acknowledges the GEQO group of the RSEQ for the GEQO Young Research Award 2019. Likewise, he sincerely thanks all co-workers for their dedication and invaluable contribution. more...

Transition metal-catalyzed aerobic oxidative reactions using molecular oxygen as the terminal oxidant play a significant role in organic synthesis. Benzoquinone (BQ) has been widely used as an electron-transfer mediator (ETM) in biomimetic palladium-catalyzed aerobic oxidative reactions, but always together with an ETM between O2 and BQ, such as a macrocyclic metal complex. Herein, we report on a heterogeneous palladium-catalyzed allenic C(sp3)-H arylation with only catalytic amounts of BQ under air without the need of an additional ETM. A range of multisubstituted 1,3-dienes were synthesized under mild reaction conditions. Mechanistic studies reveal the bifunctional role of BQ as a ligand for reductive elimination and as an ETM between Pd(0) and O2. This new regime of oxidation has important implications for further development of other transition metal-catalyzed aerobic oxidative reactions. more...

Enantioselective C-H functionalization is a powerful tool for synthesizing chiral molecules. In the past few years, the combination of high-valent group 9 metals with achiral Cp-x ligands and chiral carboxylic acids (CCA) has emerged as a promising catalytic system to enable selective cleavage and functionalization of enantiotopic C-H bonds. This Perspective summarizes the background, catalyst design, and applied reactions in detail, followed by a discussion of future directions. more...

A simple method has been developed for the synthesis of ­3-(2-oxo-2-phenylethylidene)-3,4-dihydroquinoxalin-2(1H)-one and ­3-aryl-quinoxalin-2(1H)-one derivatives through C–H activation of quinoxalin-2(1H)-ones by peroxides and iodide. In this protocol, the per­oxide (TBPB) serves as both the radical initiator and aryl source, realizing arylation of quinoxalin-2(1H)-one in a one-step reaction. The methodology has the advantages of being a metal-free strategy and having broad functional group tolerance. more...

The dehydrogenative coupling of 2-(acetylamino)-1,1'-biphenyls with internal alkynes proceeds regioselectively under rhodium catalysis to afford the corresponding 7-phenylindole derivatives. ....

Natural and synthetic β-lactam derivatives constitute an interesting class of compounds due to their diverse biological activity. Mostly used as antibiotics, they were also found to have antitubercular, anticancer and antidiabetic activities, among others. In this investigation, six new 3,3-dichloro-β-lactams prepared in a previous work were evaluated for their hemolytic and cytotoxic properties. The results showed that the proposed compounds have non-hemolytic properties and exhibited an interesting cytotoxic activity toward squamous cell carcinoma (A431 cell line), which was highly dependent on the structure and concentration of these β-lactams. Among the molecules tested, 2b was the most cytotoxic, with the lowest IC50 values (30–47 µg/mL) and a promising selectivity against the tumor cells compared with non-tumoral cells. more...

V zadnjih letih prihaja na področju organske sinteze do intenzivnega razvoja reakcij C−H aktivacije, saj ne potrebujejo predfunkcionalizacije, ker poteče direktna prekinitev nereaktivne C−H vezi, kar zmanjša število reakcijskih stopenj in preprečuje nastanek velikega števila stranskih produktov. Reakcije za katalizatorje večinoma uporabljajo plemenite 4d in 5d prehodne kovine zaradi njihovih dobrih katalitskih lastnosti. Med reakcijami C−H aktivacije pa je pozornost vedno bolj usmerjena proti okolju prijaznejšim reakcijam, kataliziranim s 3d prehodnimi kovinami. Te so namreč v primerjavi s plemenitimi kovinami manj strupene, lažje dostopne in cenejše. V svojem diplomskem delu bom najprej v uvodu povzela tradicionalne reakcije križnega spajanja in splošno predstavila C−H aktivacijo. V nadaljevanju bom predstavila vsako 3d prehodno kovino posebej in opisala kako katalizira eno reakcijo tvorbe C−C in eno reakcijo tvorbe C−Het vezi. In recent years, there has been an intensive development of C−H activation reactions in the field of organic synthesis, as they do not require pre-functionalization, because direct cleavage of unreactive C−H bond takes place, which reduces the number of reaction steps and prevents the formation of a large number of side products. Reactions mostly use noble 4d and 5d transition metals for catalysts because of their good catalytic properties. Among C−H activation reactions, attention is increasingly directed towards more environmentally friendly reactions, catalyzed by 3d transition metals. Compared to precious metals, these are less toxic, easier to access and cheaper. In my thesis, I will first summarize the traditional cross-coupling reactions in the introduction and give a general presentation of C−H activation. Then, I will present each 3d transition metal separately and describe how it catalyzes one C−C bond formation reaction and one C−Het bond formation reaction. more...

The effect of HClO4 on the reactivity and selectivity of the catalyst systems 1,2/H2O2/AcOH, based on nonheme iron complexes of the PDP families, [(Me2OMePDP)FeIII(μ-OH)2FeIII(MeOMe2PDP)](OTf)4 (1) and [(NMe2PDP)FeIII(μ-OH)2FeIII(NMe2PDP](OTf)4 (2), toward oxidation of benzylideneacetone (bna), adamantane (ada), and (3aR)-(+)-sclareolide (S) has been studied. Adding HClO4 (2–10 equiv. vs. Fe) has been found to result in the simultaneous improvement of the observed catalytic efficiency (i.e., product yields) and the oxidation regio- or enantioselectivity. At the same time, HClO4 causes a threefold increase of the second-order rate constant for the reaction of the key oxygen-transferring intermediate [(Me2OMePDP)FeV=O(OAc)]2+ (1a), with cyclohexane at −70 °C. The effect of strong Brønsted acid on the catalytic reactivity is discussed in terms of the reversible protonation of the Fe=O moiety of the parent perferryl intermediates. more...

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior INCT – Instituto nacional de ciência e tecnologia (Antigo Instituto do Milênio) Outra Agência This work presents the construction and development of a new methodology for the obtention of modified naphthoquinoidal compounds via a C(sp2)–H activation process. In this context, the intrinsic direction capability of the carbonyls, present in naphthoquinones, was explored towards arylation and annulation reactions mediated by ruthenium catalysis. After a sequence of failed results, we expanded this study to the use of directing groups added to the quinoidal structure. The optimization of this method led to the formation of polycyclic quinones, in moderate to optimum yields, from their respective substrates, using a ruthenium-catalyzed double-annulation reaction via a C(sp2)–H activation process, in the presence of an internal alkyne, copper-II acetate and sodium pivalate. Two scope sets were developed, and for the first one, several alkynes were obtained through a Sonogashira-type reaction, and subsequentially applied to the optimized methods, from which eleven double-annulated products were achieved and properly characterized. A second scope was developed using quinoidal compounds previously synthesized after sequential methods of structural modifications, from which seven products were successfully obtained. A complementary study was performed, in which nonsymmetrical alkynes, alkenes and alkyl-substituted alkynes were explored, leading to a mixture of regioisomers. From this method, a total of twenty new compounds were successfully obtained, from which fourteen had their structures corroborated via X-ray diffraction studies. A mechanism was proposed using literature studies and computational data based on relative energies. After obtaining the final products, biological assays were performed to evaluate the antitumoral activity of each derivative against HL-60 cancer cell lines, amongst six other cancer cell lines, however, presenting low activities. The results presented here were published in the Chemistry – A European Journal, furthermore, several review articles were produced using the general knowledge gathered along the development of this presented thesis. Este trabalho apresenta a construção e desenvolvimento de uma nova metodologia para obtenção de compostos naftoquinoidais modificados via processos de ativação de ligação C(sp2)–H. Nesse contexto, foi explorada a capacidade de direção intrínseca das carbonilas, presentes nas naftoquinonas, em reações de arilação e anelação catalisadas por rutênio. Após sequenciais resultados negativos, expandiu-se para o uso de grupos diretores adicionados à estrutura quinoidal. A otimização do método levou à formação de quinonas policíclicas, com rendimentos moderados a ótimos, a partir de seus respectivos substratos, utilizando uma reação de anelação dupla catalisada por rutênio via um processo de ativação de ligação C(sp2)–H, na presença de um alcino interno, acetato de cobre-II e pivalato de sódio. Dois escopos foram desenvolvidos, e para o primeiro deles, diversos alcinos foram obtidos através de uma reação tipo Sonogashira, e subsequencialmente aplicados aos métodos otimizados, de onde onze produtos duplamente anelados foram obtidos e devidamente caracterizados. Um segundo escopo foi desenvolvido utilizando-se compostos quinoidais previamente sintetizados após sequenciais métodos de modificação estrutual, de onde sete produtos foram obtidos com sucesso. Um estudo complementar foi feito, onde foram explorados alcinos não-simétricos, alcenos e alcinos alquílicos, levando à formação de uma mistura de dois regioisômeros. A partir deste novo método, um total de vinte novos compostos foram obtidos com sucesso, dentre os quais quatorze tiveram suas estruturas corroboradas via difração de raios-X. Um mecanismo pôde der proposto com base em estudos da literatura e cálculos computacionais de energias relativas. Após a obtenção dos produtos finais, testes biológicos foram feitos para avaliar a atividade antitumoral de cada derivado contra a linhagem de célula cancerígena HL-60, dentre outras seis linhagens, porém com baixa atividade. Os resultados aqui apresentados foram publicados na Chemistry – A European Journal, além disso, vários artigos de revisão foram também produzidos a partir do conhecimento geral adquirido ao longo do desenvolvimento desta tese. more...

Transition metal-catalysed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes (i.e. ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compounds allowing in situ transformation towards numerous functional groups and organic compounds, including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the organic chemistry toolbox. This review discusses all known transition metal-catalysed carbene- and nitrene transfer reactions towards carbon monoxide and isocyanides and in situ transformation of the heteroallenes hereby obtained, with a special focus on the general mechanistic considerations. more...

A new solvent/ligand-controlled switchable C–H arylation of 1-methyl-4-nitro-1H-indazole catalyzed by Pd(OAc)2 was achieved. A bidentate ligand in DMA promoted the activation at C7 position, while a phosphine ligand in H2O oriented the arylation at C3 position. The C3 and C7 arylation products were obtained in moderate to good yields and with high regioselectivity. more...

Two indoles linked by a C–C bond have recently emerged as promising scaffolds in medicinal chemistry. Their synthesis, however, involves a multitude of reaction steps. So far, the direct C–H/C–H cr... more...

A manganese/NaOPh co-catalyzed C2-selective C–H conjugate addition of indoles to α,β-unsaturated carbonyls has been developed. The reaction features very high atom economy in which no stoichiometric reagents/additives were employed. The crucial role of sodium phenolate (NaOPh) as a synergetic catalyst was revealed in the reaction screening process and mechanistic experiments. more...

Over the last few decades, significant efforts have been put forth towards the C−H bond group functionalization by transition-metalcatalysis and organocatalysis. Several efficient strategies to convert C-H bond to other groups C-C, C-N, C-O bonds have been implemented. The most attractive C-H bond functionalization was the C-H heterocyclic compounds activation that is practical method in organic synthesis. The new C–C, C–N and C–O bond as formed from the C-H bond activation by two diverse ways metal catalysis and/or organocatalysis. The most important is the synthesis of new bioactive heterocyclic compounds by easy and less expensive materials. In this review, we will cover most of the syntheses of heterocyclic derivatives by the functionalization of C-H bond in metal and organocatalytic reagents. more...

Although there is evidence that catalytic active sites can restructure under reaction conditions, their optimal reconstruction to provide the lowest activation barrier is still unclear. Here, we sh... more...

Intramolecular hydroarylation via C-H activation is one of the most powerful methods to synthesize carbo- and heterocyclic compounds, whereas we still have room for developing a highly enantioselective variant of the reaction. Here we describe Ir-catalyzed enantioselective intramolecular hydroarylation of m-allyloxyphenyl ketones. The enantioselective cyclization was efficiently catalyzed by a cationic iridium complex coordinated with a conventional chiral bisphosphine ligand to give benzofurans in high yields with high enantioselectivity. A carbonyl group of ketones functioned as an effective directing group for the C-H activation. In terms of synthetic utility, we also achieved one-pot synthesis of chiral 3-substituted dihydrobenzofurans from readily available allylic carbonates and m-hydroxyacetophenones via sequential Pd-catalyzed allylic substitution and Ir-catalyzed intramolecular hydroarylation. more...

Catalytic methods for the direct introduction of hydrogen isotopes into organic molecules are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metabolism, and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Here, we show that a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C–H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH(3)OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic experiments, including deuterium kinetic isotope effects, determination of kinetic orders, and identification of the catalyst resting state, support C–H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle. more...

[FeIII(OH)(tpena)]+ (tpena- = N,N,N′-tris(2-pyridylmethyl)ethylenediamine-N′-acetate) catalytically activates H2O2 with the concomitant formation of the active oxidants [FeIV(O)(tpena)]+ and HO• in aqueous solutions at pH 8. A kinetic model is used to demonstrate that the activation of [FeIII(OH)(tpena)]+ by H2O2 proceeds by the formation of [FeIII(OOH)(tpena)]+. Two previously unreported reactions of [FeIII(OOH)(tpena)]+, the first with another H2O2 molecule to afford [FeIII(OH)(tpena)]+, O2•-, and HO• and the second, and dominant, with [FeIII(OH)(tpena)]+ to yield 2 equiv of [FeIV(O)(tpena)]+ and H2O, are found to be the major pathways for the formation of HO• and [FeIV(O)(tpena)]+, respectively. The production of HO• was quantified by a chemiluminescence method showing that [FeIV(O)(tpena)]+ is produced in much larger yields than HO•. The generation of HO• compromises the stability of [FeIII(OH)(tpena)]+ unless an external substrate is present that can outcompete [FeIII(OH)(tpena)]+ for HO•. Significantly, we demonstrate that the reaction commonly assumed to occur in the decay of nonheme iron(III)hydroperoxides, homolytic O-O bond cleavage, is of minor significance for the generation of HO• and the iron(IV)oxo complex. The production of both a reactive high-valent iron-oxo species and HO• under mild, aqueous ambient conditions represents a significant contribution to the current state of the art for biomimetic nonheme chemistry in water. more...

Producción Científica, The functionalization of simple arenes without coordinating directing groups is a challenge. Besides facing the task of cleaving the sluggish C-H bond, the process is hampered by the weak coordinating ability of the arene π-system to the metal, which results in reactions that need a large excess of the reactant arene. Using a well-defined palladium complex with the ligand [2, 2’-bipyridin]-6(1H)-one, we have found that the use of a moderately coordinating solvent allows a decrease of the amount of arene used. Moreover, for the least coordinating arenes, the co-solvent produces a significant accelerating effect by altering the concentration and relative stability of relevant metal species in the catalytic cycle as well as the catalyst resting state. t-Butyl methyl ketone (pinacolone) is one of the most effective co-solvents: Even if the ketone C-H bond cleaves easily, the final products are determined by the reductive elimination step (the product-forming step) so the target biaryl products are selectively observed., MINECO -AEI (grant CTQ2016-80913-P), MICINN-AEI (grant PID2019-111406GB-I00), Junta de Castilla y Leoń (grant VA224P20) more...

Despite advances in the synthesis of polysubstituted cyclopentadienyl metal complexes, the rapid access to a library of monosubstituted Cp bearing metal complexes remains challenging. A convenient and general method to access a broad range of monosubstituted cyclopentadienyl rhodium(I) and iridium(I) complexes is reported. The process involves a direct nucleo-metalation of fulvenes with widely available metal precursors, affording a set of CpRhI(olefin)(2) and CpIrI(olefin)(2) complexes in high yields. A broad range of oxygen-, nitrogen-, and carbon-based nucleophiles were found competent for the process and offer good tuning abilities of the cyclopentadienyl portion. more...

A ruthenium-catalyzed electrochemical dehydrogenative C(sp2)−H acyloxylation of aniline derivatives with carboxylic acids has been developed. Electric current is used to recycle the active ruthenium-based catalyst and promote H2 evolution. This method significantly expands the scope and enhances the selectivity of metal-electron catalyzed mono- and di-acyloxylations, which remain challenged. Our findings allowed mono-selectivity in broadly effective late-stage diversification of structurally complex drugs and natural product molecules, tolerating drugs, natural products and amino acids. The method and its underlying strategy are expected to have widespread uses in functional aniline synthesis and drug discovery process. more...

Organoboron compounds are essential reagents in modern C−C coupling reactions. Their synthesis via catalytic C−H borylation by main group elements is emerging as a powerful tool alternative to transition metal based catalysis. Herein, a straightforward metal‐free synthesis of aryldifluoroboranes from BF3 and heteroarenes is reported. The reaction is assisted by sterically hindered amines and catalytic amounts of thioureas. According to computational studies the reaction proceeds via frustrated Lewis pair (FLP) mechanism. The obtained aryldifluoroboranes are further stabilized against destructive protodeborylation by converting them to the corresponding air stable tetramethylammonium organotrifluoroborates., C−H activation: Indoles, pyrroles and indolenines undergo C−H borylation by boron trifluoride with assistance of base and thiourea additives. more...

Heterogeneous single-site catalysts contain spatially isolated, well-defined active sites. This allows not only their easy recovery by solid-liquid separation but also the detailed active site design similar to homogeneous catalysts. Here, heterogeneous Pd(II) single-site catalysts were assembled, based on mesoporous metal oxide-bisphosphonate materials as supports. This new family of hybrid organic-inorganic materials with tunable porosity was further functionalized with thioether ligands containing S,O-binding sites that enhance the activity of Pd(II) for C-H activation reactions. The structures of the resulting Pd(II) single-site catalysts were carefully analyzed via solid-state NMR spectroscopy, via texture analysis by N2 physisorption, infrared spectroscopy, and transmission electron microscopy. Furthermore, the immediate environment of the isolated Pd(II) active sites was studied with X-ray absorption spectroscopy. A clear relationship between the thioether ligand surface density and catalyst activity could be established. Significantly higher yields were obtained using highly porous metal oxide-bisphosphonate materials as supports compared to materials with lower porosities, such as conventional metal oxides, indicating that the high surface area facilitates the presence of isolated, well-accessible S,O-supported Pd(II) active sites. A wide scope of model substrates, including industrially relevant arenes, can be converted with high yields by the optimal heterogeneous Pd catalyst. ispartof: ACS APPLIED MATERIALS & INTERFACES vol:12 issue:42 pages:47457-47466 ispartof: location:United States status: published more...

The importance of fluorinated products in pharmaceutical and medicinal chemistry has necessitated the development of synthetic fluorination methods, of which direct C–H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C–H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal catalysis and photochemistry. Where transition metal catalysis provides one strategy for C–H bond activation, transition-metal-free photochemical C–H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods. One exciting development in C–F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this review, we highlight photosensitized C–H fluorination as a recent strategy for the direct and remote activation of C–H (especially C(sp3)–H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of reactions. more...

A computational approach has been developed to automatically generate and analyse the structures of the intermediates of palladium-catalysed carbon–hydrogen (C–H) activation reactions as well as to predict the final products. Implemented as a high-performance computing cluster tool, it has been shown to correctly choose the mechanism and rationalise regioselectivity of chosen examples from open literature reports. The developed methodology is capable of predicting reactivity of various substrates by differentiation between two major mechanisms – proton abstraction and electrophilic aromatic substitution. An attempt has been made to predict new C–H activation reactions. This methodology can also be used for the automated reaction planning, as well as a starting point for microkinetic modelling. more...

A facile and convenient synthesis of the chiral phthalide framework catalyzed by cationic iridium was developed. The method utilized cationic iridium/bisphosphine-catalyzed asymmetric intramolecular carbonyl hydroacylation of 2-keto benzaldehydes to furnish the corresponding optically active phthalide products in good to excellent enantioselectivities (up to 98% ee). The mechanistic studies using a deuterium-labelled substrate suggested that the reaction involved an intramolecular carbonyl insertion mechanism to iridium hydride intermediate. In addition, we investigated the kinetic isotope effect (KIE) of intramolecular hydroacylation with deuterated substrate and determined that the C-H activation step is not included in the turnover-limiting step. more...