Catalytic Methods for Aromatic C–H Amination: An Ideal Strategy for Nitrogen-Based Functional Molecules

Review: 339 refs.

The synthesis of 3-aryl-2-cyclohexenones is a topic of current interest as they are not only privileged structures in bioactive molecules, but they are also relevant feedstocks for the synthesis of substituted phenols or anilines, which are ubiquitous structural elements both in drug design and medicinal chemistry. A simple and sustainable one-pot aerobic double dehydrogenative reaction under mild conditions for the introduction of arenes in the β-position of cyclic ketones has been developed. Starting from the corresponding saturated ketone, this reaction sequence proceeds under relatively low Pd catalyst loading and involves catalytic amounts of electron-transfer mediators (ETMs) under ambient oxygen pressure.

1,1′-Bi(hetero)aryl 2-sulfonamide scaffolds have been widely used as a privileged structure in drug discovery. Herein, we report an efficient rhodium-catalyzed oxidative C–H/C–H cross-coupling between a (hetero)aromatic sulfonamide and a (hetero)arene to afford ortho-sulfonamido bi(hetero)aryls. This methodology features broad substrate scope, good functional group tolerance, and relatively inexpensive catalyst (without the use of RhCp*). A wide range of (hetero)arenes such as thiophenes, benzothiophenes, pyrroles, furans, benzofuran, indolizine, and simple arenes can engage in this transformation. This protocol also provides a facile route to bi(hetero)aryl sultams and dibenzo[b,d]thiophene 5,5-dioxides through further intramolecular cyclization, indicating its potential application in materials exploitation.

The development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both a N-H and C-H bond, is described. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. Mechanistic investigations indicate that the reaction proceeds via nucleophilic attack of the phthalimide on an aromatic radical cation, as opposed to the electrophilic aromatic amination that has been reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted aniline derivatives is demonstrated.

The oxidative cross-coupling of carbon-hydrogen (C-H) and nitrogenhydrogen (N-H) bonds to form carbon-nitrogen (C-N) bonds is an important synthetic advance, as amine and amide functional groups are ubiquitous in biologically active molecules. This technique is orthogonal to conventional amination techniques, which rely on electrophilic nitration/reduction strategies or metal catalyzed coupling of prefunctionalized arenes. This dissertation’s main focus is on the development of oxidative methods for constructing N-arylamines and amides via tandem C-H/N-H bond activation and increasing synthetic efficiency for total synthesis of an inhibitor of botulinum neurotoxin via direct C–H functionalization. The first manuscript, “Metal-Free Intermolecular Oxidative C-N Bond Formation via Tandem C-H and N-H Bond Functionalization,” is focused on the development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both an N-H and a C-H bond. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. The second manuscript, “I(III)-Mediated Regioselective C-H Bond Amination of 2-Arylpyridine Derivatives,” is focused on the development of a novel, useful and economical process for the direct amination of 2-phenylpyridine derivatives. This process requires cheap and commercially available copper triflate and works for a variety of different 2-phenyl- pyridine derivatives. The third manuscript, “Increasing synthetic efficiency via direct C–H functionalization: formal synthesis of an inhibitor of botulinum neurotoxin,” is focused on designing an efficient scheme for the synthesis of one of the best known inhibitors of botulinum neurotoxin serotype A (BoNTA). The synthetic route involves two palladium catalyzed C–H functionalization reactions, formally activating three C– H bonds.

Functionality development as a survival strategy for fine ceramics

The activation and valorization of inert molecules (e.g., dinitrogen (N2), alkanes, and alkenes) for the synthesis of nitrogen-containing organic compounds have long been a highly sought-after goal in chemistry. However, it remains a formidable challenge, stemming from the inherent chemical inertness of the robust N ≡ N and C-H bonds, as well as the competitive adsorption and activation of reactants. Consequently, examples of direct C-N bond formation using N2 and alkanes/alkenes as feedstocks remain exceptionally scarce. Herein, we report that sodium hydride supported on magnesium oxide (NaH/MgO) possesses unique multiple reactive sites, which enable the conversion of N2 and unactivated arenes and facilitate C-N bond formation. The synergistic interplay between sodium, magnesium, and hydride species at the NaH/MgO interface plays a pivotal role in the reduction of N2 to NHx species. These reactive NHx intermediates then deprotonate the aryl C-H bond, attack the alkali-interacted aryl ring, and drive the formation of sodium anilide on the surface. Subsequent protonation of sodium anilide yields aniline with high selectivity (>90%). This work demonstrates the feasibility of transforming N2 and simple arenes into key nitrogen-containing organic compounds via a solid surface-mediated process, thereby opening ample room for developing heterogeneous catalysts for the transformation of N2 and organic substrates.

The present paper deals with characterization of an aminated glassy carbon electrode (GCE) surface obtained by electrooxidation of ammonium carbamate in its aqueous solution (amination reaction) using electrochemical and XPS methods. From the XPS analysis, it was found that not only the primary amine group (i.e., aniline-like aromatic amine moiety) but also other N-containing functional groups (i.e., the secondary amine-like moieties containing pyrrole-type nitrogen and quaternary amine-like moieties containing graphitic quaternary nitrogen) are introduced onto the GCE surface during the amination reaction. Moreover, the presence of the primary and secondary amine groups was ascertained based on the difference in the reactivity of a Michael reaction-type addition reaction of amine groups introduced onto the GCE surface with quinone compounds having a carbonyl group and a C═C double bond (i.e., in this case, 1,2-benzoquinone which is in situ prepared by the electrooxidation of catechol) and on the electrochemical redox response of the introduced benzoquinones. This electrochemical treatment of aminated GCE with catechol led to catechol-grafted aminated GCE which indicated two surface redox couples (i.e., the Ia/Ic and IIa/IIc couples with formal potentials of E(0)'(Ia/Ic) = ca. 0.17 V and E(0)'(IIa/IIc) = ca. 0.03 V vs Ag|AgCl|KCl(sat.) in phosphate buffer solution (pH 7)). From the electrochemical behavior of catechols grafted onto the maleimide-treated aminated GCE and on the methylamine-treated GCE, it was found that the catechol associated with the primary amine groups gave the IIa/IIc redox peaks, while the catechol bound to the secondary amine groups gave the Ia/Ic redox peaks. Further electrochemical measurements and quantum chemical calculations concluded that the IIa/IIc redox peaks are ascribed to the surface-redox reaction of the 1,2-dihydroxybenzene/1,2-benzoquinone couple, while those of the 1,2-dihydroxybenzene/1,2-benzoquinone and the N-(4'-hydroxyphenyl)-p-aminophenol/indophenol couples can be associated with the Ia/Ic redox peaks.

C,C-Palladacycles are an important class of organometallic compounds in which palladium is σ-bonded to two carbon atoms. They have three notable features that make them attractive in organic synthesis and organometallic chemistry: (1) C,C-Palladacycles are reactive intermediates that can be accessed via Pd(0)-catalyzed C-H activation of organic halides. Compared to Pd(II)-catalyzed heteroatom-directed C-H activation, C-H activation catalyzed by Pd(0) has some distinct advantages. In this type of catalytic reaction, the halo groups of readily available organic halides act as traceless directing groups. Furthermore, this strategy avoids the use of stoichiometric external oxidants. (2) C,C-Palladacycles have differentiated reactivities from common open-chain Pd(II) species. In particular, C,C-palladacycles have high reactivity toward electrophiles including alkyl halides. This unique reactivity can be utilized to develop novel reactions. (3) C,C-Palladacycles have two C-Pd bonds, providing a unique platform for developing novel reactions.Although a number of reactions of C,C-palladacycles had been developed prior to our work, the scope was largely limited to intramolecular cyclization reactions. Although Catellani reactions are intermolecular reactions of C,C-palladacycles, only one of the C-Pd bonds is functionalized. Our laboratory has sought to develop intermolecular difunctionalization reactions of C,C-palladacycles that exploit their unique reactivity and open new possibilities in organic synthesis. Aiming to develop synthetically useful reactions, we primarily focus on ring-forming reactions. In this Account, we summarize our laboratory's efforts to exploit intermolecular difunctionalization reactions of C,C-palladacycles that are obtained through Pd(0)-catalyzed C-H activation. We have developed a wide array of new reactions that represent facile and efficient methods for the synthesis of cyclic organic compounds, including functional materials and drug molecules. A range of C,C-palladacycles have been studied, including C(aryl),C(aryl)-palladacycles from 2-halobiaryls, C(aryl),C(alkyl)-palladacycles from ortho-iodo-tert-butylbenzenes or ortho-iodoanisole derivatives, and those obtained by cascade reactions. C,C-Palladacycles have been found to react with a variety of oxidants to furnish Pd(IV) intermediates, such as alkyl halides, aryl halides, diazo compounds, and N,N-di-tert-butyldiaziridinone, ultimately affording various cyclic structures, including 5-10-membered rings, carbo- and azacycles, spirocycles, and fused rings. Furthermore, novel reactivity of C,C-palladacycles has been discovered. For example, we found that C,C-palladacycles have unusually high reactivity toward disilanes, which can be leveraged to disilylate a variety of C,C-palladacycles with very high efficiency. These results should provide inspiration to develop other C-Si bond-forming reactions in the future. We hope that this Account will stimulate further research into the rich chemistry of C,C-palladacycles, in particular reactions that find practical applications in the synthesis of bioactive and functional molecules and those that advance the state of the art in C-H functionalization.

Review: [47 refs.

Privileged chiral catalysts in asymmetric Morita-Baylis-Hillman/aza-Morita-Baylis-Hillman reaction

Sustainable afterglow room temperature phosphorescence (RTP) materials, especially afterglow RTP structural materials, are crucial but remain difficult to achieve. Here, an oxidation strategy is developed to convert lignin to afterglow materials with a lifetime of ~ 408 ms. Specifically, lignin is oxidized to give aromatic chromophores and fatty acids using H2O2. The aromatic chromophores are locked by a fatty acid-based matrix by hydrogen bonds, triggering enhanced spin orbit coupling and long afterglow emission. More interestingly, motivated by this discovery, an auto fabrication line is built to convert wood (natural structural materials) to wood with afterglow RTP emission (RTP wood) via in situ oxidation of naturally-occurring lignin located in the wood cell walls to oxidized lignin (OL). The as-prepared RTP wood exhibits great potential for the construction of sustainable afterglow furniture. With this research we provide a new strategy to promote the sustainability of afterglow RTP materials and structural materials.

Mechanically strong, cost-efficiency, and sustainable fully wood-derived structural materials by micro/nanoscale design

This study presents the synthesis, crystal structure, and a Hirshfeld-surface analysis of the bioactive compound 5-methyl-1H-pyrazol-3-yl 4-nitro-benzene-sulfonate-(C10H9N3O5S), a pyrazole derivative with pharmacological potential. Pyrazoles are known for diverse bioactivities, and recent research emphasizes their role as a 'privileged structure' in drug design. Here, the asymmetric unit of the title compound contains two distinct mol-ecules, A and B, exhibiting differences in conformation resulting from variation in key torsion angles. These distinctions influence the mol-ecular orientation and inter-molecular inter-actions, with strong N-H⋯N and N-H⋯O hydrogen bonds forming a centrosymmetric tetra-mer stabilized by π-π stacking. Hirshfeld surface analysis readily confirms differing inter-molecular contacts for A and B, primarily involving hydrogen atoms and differences in their close contacts to nitro-gen and oxygen. This study offers further insight into the mol-ecular architecture and potential inter-actions of pyrazole-based drug candidates.

To a large extent, the mechanical properties of polymers are determined by the strength of the physical interactions between chains. Thermoplastic elastomers (TPE’s) make sophisticated use of reversible physical interactions.1 They consist of polymer chains in which strongly interacting segments alternate with weakly interacting segments to give rise to microphase-separated materials with a soft block/hard block morphology. When the hard blocks contain urethane and/or urea groups, strong and specific hydrogen-bonding interactions2 lead to useful properties, such as a high modulus for a given hard block content. In recent years, highly directional physical interactions have been applied in a fundamentally different way to form supramolecular polymers.3 In this novel class of materials, endfunctionalization of unimers with functional groups that associate via noncovalent interactions such as multiple hydrogen bonds4,5 or coordinative bonds6 results in a strong increase of the virtual molecular weight and in concurrent changes of mechanical and rheological properties. The use of directional hydrogen bonding within the hard blocks of TPE’s has been studied by Stadler and co-workers,7 who used telechelic hydrogen-bonded polyisobutylenes with relatively weak end-to-end interactions between urazole groups and between benzoic acid groups. Recently, Bouteiller et al.8 have studied poly(dimethylsiloxane)s with bisurea end groups which aggregate laterally. The authors concluded that aggregation of the end groups into 3-D crystalline domains results in elastomeric behavior, while the formation of hydrogen bonds without crystallization was not sufficient to obtain tensile properties. Similar conclusions were drawn by Rowan et al.,9 who noticed that even very weak end-to end interactions can be used to obtain polymers with film-forming properties when the end groups phase segregate. Here, we study the effect of combining very strong end-toend association via ureidopyrimidinone (UPy) quadruple hydrogen bonding10 and directional lateral aggregation via the urea (U) and urethane (T) hydrogen bonding motifs11 to give supramolecular thermoplastic elastomers with 1-D aggregation of dimerized end groups. Hydroxy-telechelic poly(ethylene butylene) (PEB, Mn ) 3500 g/mol, Mw/Mn ) 1.06, degree of functionalization 1.92) was functionalized with lateral hydrogen-bonding functionalities (UU-PEB-U-U and U-T-PEB-T-U), with end-to-end hydrogenbonding functionalities (UPy-PEB-UPy), and functionalized with both lateral and end-to-end functionalities (UPy-U-PEB-U-UPy and the previously reported5 UPy-T-PEB-T-UPy) (Scheme 1). The resulting materials were characterized with DSC, AFM, dynamic mechanical measurements, and tensile testing. The parent hydroxy-telechelic PEB is a liquid at room temperature which shows purely viscous behavior in oscillatory shear experiments. Incorporation at the chain ends of functional groups capable of lateral aggregation via 3 or 4 hydrogen bonds leads to the formation of elastic solids, with melting points that increases from 45 °C for U-T-PEB-T-U to 129 °C for the U-UPEB-U-U material. The former is a single segment of a segmented, PEB-based poly(urethane-urea) recently reported by Wilkes et al.,2b while the latter material can be considered a PEB analogue of the bisurea-functionalized PDMS reported by Bouteiller.8 In line with the highly directional nature of the hydrogen bonding of UPy moieties, direct functionalization of PEB with the UPy quadruple hydrogen bonding unit in UPyPEB-UPy gives rise to a noticeable increase in viscosity at 40 °C from 10 to 7 × 103 Pa‚s, but it does not lead to the formation of a material with a discernible melting point. The viscosity changes are in line with end-to-end linking of PEB by directional quadruple hydrogen bonds between UPy functional groups, considering that the degree of functionalization of 1.92 of the starting material limits the average number of end-linked unimers to ∼50. A master curve of oscillatory shear experiments on UPy-PEBUPy (Figure 1) confirms the directional end-to-end nature of UPy-UPy hydrogen bonding as the storage and loss moduli show terminal relaxation behavior with slopes of 0.96 and 2.05, demonstrating the absence of long-lived lateral interactions. Nevertheless, the formation of supramolecular polymer chains by linear association of unimers results in an entanglement network with characteristic lifetime of 1 s at 40 °C, evident from a viscoelastic transition at higher frequencies. A dramatic enhancement of mechanical properties was observed when end-to-end and lateral interactions were combined in UPy-U-PEB-U-UPy. In contrast to UPy-PEB-UPy, this material is an elastic solid, with a melting point of 129 °C. The * Corresponding authors. E-mail: r.p.sijbesma@tue.nl; e.w.meijer@tue.nl. Scheme 1. Hydrogen-Bonded Telechelic PEB’s