Bond Amination Research Articles

Facile synthesis, physiochemical characterization and bio evaluation of sulfadimidine capped cobalt nanoparticles.

Due to their less expensive, environment friendly nature, and their natural abundance of cobalt have attained more significant attention for the synthesis of cobalt nanoparticles. In the present study, we report the facile synthesis of cobalt nanoparticles using a straight forward chemical reduction approach of cobalt chloride with sodium borohydride and capping of sulfadimidine. sulfadimidine has strong capping eligibility on the surface of nanoparticles due to its chemical stability and is an applicable as stabilizer due to the existence of an amine bond. The as-synthesized sulfadimidine stabilized cobalt nanoparticles (Co-SD NPs) were characterized by using various spectroscopic and microscopic analysis like UV–Visible spectroscopy (UV–Vis), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), High-Resolution Transmission electron microscopy (HR-TEM), and Fourier-transform infrared spectroscopy (FT-IR). The XRD analysis exhibited the triclinic crystal structure of the as-synthesized cobalt nanoparticles and FT-IR analysis confirmed the capping of sulfadimidine via monodentate interaction. The HR-TEM analysis displayed the size of the cobalt nanoparticles approximately 3–5 nm. The antibacterial properties of the sulfadimidine stabilized cobalt nanoparticles (Co-SD NPs) were tested against various bacterial strains such as Klebsiella pneumonia (KP), Escherichia coli (EC) and Pseudomonas syringae (PS) by using agar disc diffusion approach. The results of sulfadimidine capped cobalt nanoparticles displayed the enhanced biological properties against the tested gram-negative bacteria.

Front Cover Picture: Enantioselective Desymmetrization of 1,3‐Disubstituted Adamantane Derivatives via Rhodium‐Catalyzed C−H Bond Amination: Access to Optically Active Amino Acids Containing Adamantane Core (Adv. Synth. Catal. 6/2021)

The front cover picture illustrates that starting from the tetrahedron as a source, a road splits into two. On the left side of the road, alpha-amino acid derived from methane is passing. On the right side of the road, amino acid containing the adamantane core derived from adamantane is passing. Hoping that optically active amino acids containing the adamantane core are useful as large analogs of alpha-amino acids, their preparation by an enantioselective desymmetrization of 1,3-disubstituted adamantane derivatives via rhodium-catalyzed C–H bond amination was examined. Details can be found in the Full Paper by Risa Yasue and Kazuhiro Yoshida (R. Yasue, K. Yoshida, Adv. Synth. Catal. 2021, 363, 1662–1671; DOI: 10.1002/adsc.202001419).

Synthesis of 1H-Indazoles via Silver(I)-Mediated Intramolecular Oxidative C-H Bond Amination.

We described a silver(I)-mediated intramolecular oxidative C–H amination that enables the construction of assorted 1H-indazoles that are widely applicable in medicinal chemistry. The developed amination was found to be efficient for the synthesis of a variety of 3-substituted indazoles that are otherwise difficult to be synthesized by other means of C–H aminations. Preliminary mechanistic studies suggested that the current amination proceeds via single electron transfer (SET) mediated by Ag(I) oxidant.

Metabolically stable neurotensin analogs exert potent and long-acting analgesia without hypothermia

The endogenous tridecapeptide neurotensin (NT) has emerged as an important inhibitory modulator of pain transmission, exerting its analgesic action through the activation of the G protein-coupled receptors, NTS1 and NTS2. Whereas both NT receptors mediate the analgesic effects of NT, NTS1 activation also produces hypotension and hypothermia, which may represent obstacles for the development of new pain medications. In the present study, we implemented various chemical strategies to improve the metabolic stability of the biologically active fragment NT(8−13) and assessed their NTS1/NTS2 relative binding affinities. We then determined their ability to reduce the nociceptive behaviors in acute, tonic, and chronic pain models and to modulate blood pressure and body temperature. To this end, we synthesized a series of NT(8−13) analogs carrying a reduced amide bond at Lys8-Lys9 and harboring site-selective modifications with unnatural amino acids, such as silaproline (Sip) and trimethylsilylalanine (TMSAla). Incorporation of Sip and TMSAla respectively in positions 10 and 13 of NT(8−13) combined with the Lys8-Lys9 reduced amine bond (JMV5296) greatly prolonged the plasma half-life time over 20 h. These modifications also led to a 25-fold peptide selectivity toward NTS2. More importantly, central delivery of JMV5296 was able to induce a strong antinociceptive effect in acute (tail-flick), tonic (formalin), and chronic inflammatory (CFA) pain models without inducing hypothermia. Altogether, these results demonstrate that the chemically-modified NT(8−13) analog JMV5296 exhibits a better therapeutic profile and may thus represent a promising avenue to guide the development of new stable NT agonists and improve pain management.

Construction of α-Alkylated Amines by Iridium Complex-Catalyzed One-Step Transfer Hydrogenation of C=C and C=N Bonds

AbstractHydrogenation of C=C bond and reductive amination are important transformations utilized in chemistry. An environmentally friendly, efficient, and facile one-pot transfer hydrogenation of C=C bond of enones and reductive amination of C=N bond of imines are reported using iridium complex as catalysts and formic acid as hydrogen source in aqueous medium. In this catalytic system, a wide range of α-alkylated amines were obtained in excellent yields by one-pot transfer hydrogenation of C=C bond and reductive amination. The practical application of this protocol is characterized by gram-scale transformation.

Enantioselective Desymmetrization of 1,3‐Disubstituted Adamantane Derivatives via Rhodium‐Catalyzed C−H Bond Amination: Access to Optically Active Amino Acids Containing Adamantane Core

AbstractIn order to synthesize optically active amino acids containing the adamantane core, an enantioselective desymmetrization of adamantanes via rhodium‐catalyzed C−H bond amination was examined. After investigating various conditions, it was found that the coupling reaction between disubstituted adamantane and aryloxysulfonamide was catalyzed by Rh2(S‐TCPTTL)4 to furnish the desired products having up to 85% ee (e.r.=92.4: 7.6) (>99% ee after recrystallization). The synthetic utility of the enantioenriched products as chiral building blocks was demonstrated by transforming one of them into a dipeptide derivative and a Schiff‐base ligand. The absolute configuration of one of the amino acid derivatives was determined unambiguously by X‐ray single‐crystal structure analysis.magnified image

Copper-Catalyzed Intramolecular Amination of C(sp3)-H Bond of Secondary Amines to Access Azacycles.

The cross-coupling of C-N bond directly from inert C-H bonds is an ideal approach to synthesize saturated azacycles due to its high efficiency and atom economy. In this article, a copper-catalyzed intramolecular amination via the cross coupling of C(sp3)-H and N-H bonds of secondary amine has been reported, which exhibit excellent chemo- and regioselectivity, extensive substrate scope, and functional group tolerance in good to excellent yield, offering an efficient pathway to build nitrogen-containing heterocycle skeletons.

Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands.

The trityl-substituted bisoxazoline (TrHBOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI2(py)4 followed by potassium graphite reduction afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct (TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

Selective cleavage and reconstruction of C–N/C–C bonds in saturated cyclic amines: tunable synthesis of lactams and functionalized acyclic amines

Selective cleavage of C–N/C–C bonds in saturated cyclic amines for the tunable synthesis of lactams and functionalized acyclic amines under the promotion of oxoammonium salt and TBHP in the presence of different additives have been developed.

Direct intramolecular C(sp3)–H bond sulfonamidation to synthesize benzosultam derivatives under metal-free conditions

An efficient intramolecular C(sp3)–H bond amination under metal-free conditions has been developed to provide a straightforward method for the synthesis of 5-membered cyclic sulfonamides (benzosultams).

Rh(iii)-Catalyzed sulfonylamination of α-indolyl alcohols via Csp2–Csp3 bond cleavage

A Rh(iii)-catalyzed beta-carbon amination of α-aryl alcohols with sulfonyl azides has been developed. This transformation features unstrained Csp2–Csp3 σ bond amination via C–C bond cleavage, and provides a direct approach to complex 2-aminoindoles.

Redox-neutral functionalization of α-Csp3–H bonds of secondary cyclic amines: a highly atom-economical strategy forN-arylation/formal cross-dehydrogenative couplings

An efficient redox-neutral method has been developed for α-Csp3–H functionalization of secondary cyclic aminesviaconcurrentN-arylation/formal cross dehydrogenation coupling (CDC) with sp2-C–H and sp3-C–H bonds of arenes and ketones, respectively.

Copper(ii) ions supported on functionalized graphene oxide: an organometallic nanocatalyst for oxidative amination of azoles via C–H/C–N bond activation

Graphene oxide (GO) was chemically modified with para-aminobenzoic acid (PABA) to immobilize copper(ii) ions on its surface and used as a nanocatalyst for the oxidative C (sp2)–H bond amination reaction.

A soluble iron(ii)-phthalocyanine-catalyzed intramolecular C(sp3)–H amination with alkyl azides

Herein, we describe a soluble iron(II)-phthalocyanine, [FeII(tBu4Pc)(py)2] (Pc = phthalocyaninato(2-)), as an effective catalyst in intramolecular C(sp3)-H bond amination, with alkyl azides as the nitrogen source, to afford the amination products in moderate to excellent yields with a broad substrate scope.

Piloty’s acid and its hydrazide analogue: Insights from the density functional theory and vibrational spectroscopy on the conformational stability and chemical reactivity

N-hydroxybenzenesulfonamide (commonly known as Piloty’s acid) is considered a major source for nitroxyl (HNO) species which has potential biological and medicinal applications. In the present study, the conformational preferences and chemical reactivity of Piloty’s acid (PA) and its hydrazide analogue (benzenesulfonylhydrazide, BSH) were studied using spectroscopic and computational tools. Six stable conformations of each molecule were theoretically identified, and their structures were fully optimized at the DFT-B3LYP and MP2 levels. Both molecules in their most stable forms adopt the anti configuration with the NH bond of the secondary amine pointing away from the terminal hydroxyl and amine moieties in the acid and hydrazide molecules, respectively. Three stable gauche states facilitated by weak intramolecular interactions of the SO⋯HO and SO⋯HN types arise due to the internal rotation about the SN linkage. Reliable assignments of the vibrational modes and the calculated reaction coordinates support a two-step mechanistic pathway of the Piloty’s acid dissociation leading to the production of the nitroxyl (HNO) intermediate with moderate transition state barriers. Frontier molecular orbitals distributions, molecular electrostatic potential maps and condensed Fukui functions analysis of the molecules were employed to elucidate the agility of PA to dissociate to produce HNO and the absence of such a dissociation of BSH that would produce diazene (N2H2).

Intramolecular C(sp₃)-H Bond Amination Strategies for the Synthesis of Saturated N-containing Heterocycles.

The selective functionalization of C(sp³)-H bonds via intramolecular amination reactions represents a very attractive strategy for the construction of saturated N-containing heterocycles (SNHets). Over the past de- cades, the chemical community has devoted its efforts towards expanding the synthetic toolbox with the aim of facilitating access to these key fragments in a controllable, reproducible and efficient manner. This review covers selected examples of the most recent advances in intramolecular C(sp³)-N bond-forming reactions by three main approaches: (1) the Hofmann-Löffler-Freytag (HLF) reaction; (2) transition-metal-catalyzed nitrene C(sp³)-H inser- tion; and (3) transition-metal-catalyzed ligand-assisted C(sp³)-N bond-forming reactions via a reductive elimination step. We will discuss reactivity, selectivity and the major mechanistic insights into these transformations.

Catalytic asymmetric addition of an amine N–H bond across internal alkenes

Hydroamination of alkenes, the addition of the N-H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy1-3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes2-4; only a few examples occur by the direct addition of the N-H bond of amines across unactivated internal alkenes5-7, including photocatalytic hydroamination8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity10-13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N-H bonds of other reagents, as well as O-H and C-H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.

Impact of Cholesterol Concentration and Lipid Phase on Structure and Fluctuation of Amyloid Precursor Protein.

Elevated levels of cellular cholesterol have been identified as one factor contributing to the onset of Alzheimer's disease (AD). Specific interaction between cholesterol and the amyloid precursor protein (APP), investigated via NMR experiments and computational studies, has been proposed to play a critical role in the processing of APP by secretases and the biogenesis of amyloid-β (Aβ) protein. We present all-atom molecular dynamics simulations of the 40-residue congener of the C-terminal domain of APP, C9916-55 (C99), in cholesterol-enriched DMPC lipid bilayers. We investigated the effect of cholesterol concentration on the conformational ensemble of wild-type C99 and C99-cholesterol associations at the low pH of endosomal environments, at which residues E22 and D23 are neutral. C99 was also characterized in liquid ordered domains for Dutch (E22Q) and Iowa (D23N) Familial AD mutants at low pH and for the wild-type sequence using protonation states characteristic of neutral pH. Our results reproduce the equilibrium constant of past NMR characterizations of the C99-cholesterol interaction but are not consistent with the C99-cholesterol binding hypothesis. We find that the lifetimes of both DMPC and cholesterol complexed with C99 display a power-law distribution of residence lifetimes. Longer-lived C99-DMPC and C99-cholesterol complexes are primarily stabilized by salt bridges and hydrogen bonds of lysine amines to phosphate and hydroxyl groups. Nevertheless, specific interfaces for C99-cholesterol association which are not present for DMPC can be identified. Changes to C99-cholesterol interfaces are found to depend on C99 tilt angle and orientation of the juxtamembrane domain of C99 containing residues E22 and D23. These observations support a more nuanced view of the C99-cholesterol interaction than has previously been suggested. We propose that cholesterol modulates the conformation and activity of C99 and other small transmembrane proteins indirectly through induction of the liquid ordered phase and directly through hydrogen bonding. This suggests a critical role for membrane heterogeneity introduced by cholesterol in modulating the structural ensemble of C99 and the production of Aβ.

Cu(II)-Catalyzed Phosphonocarboxylative Cyclization Reaction of Propargylic Amines and Phosphine Oxide with CO2.

Compounds bearing organophosphorus motifs and 2-oxazolidinone have found numerous applications in pharmaceutical chemistry, homogeneous catalysis, and organic materials. Here, we describe an efficient and selective protocol for straightforward access to a series of 5-((diarylphosphoryl)methyl)oxazolidin-2-ones via the copper-catalyzed difunctionalization of the C≡C bond of propargylic amines with CO2 and phosphine oxide. Notably, copper catalysis is a sustainable and benign catalytic mode. This reaction proceeds under mild reaction conditions, which is operationally simple and scalable with a broad scope, exclusive selectivity, and good functional group compatibility. Mechanistic studies suggest a one-pot tandem cyclization/radical addition sequence, along with the phosphorylation/cyclization scheme.

Molecular dynamics simulation of amine groups formation during plasma processing of polystyrene surfaces

Plasma treatment and plasma polymerization processes aiming to form amine groups on polystyrene surfaces were studied in-silico with molecular dynamics simulations. The simulations were compared with two experiments, (i) plasma treatment in N2/H2 bipolar pulsed discharge and (ii) plasma polymerization in cyclopropylamine/Ar radio frequency (RF) capacitively coupled discharge. To model favorable conditions for the incorporation of primary amine groups, we assumed the plasma treatment as the flux of NH2 radicals and energetic NH3 ions, and the plasma polymerization as the flux of cyclopropylamine molecules and energetic argon ions. It is shown in both the simulation and the experiment that the polystyrene treatment by the bipolar pulsed N2/H2 plasmas with an applied voltage of about ±1 kV formed a nitrogen-rich layer of a thickness of only a few nm. The simulations also showed that, as the NH3 incident energy increases, the ratio of primary amines to the total number of N atoms on the surface decreases. It is because the energetic ion bombardment brakes up N–H bonds of primary amines, which are mostly brought to the surface by NH2 radical adsorption. Our previous experimental work on the CPA plasma polymerization showed that increased RF power invested in the plasma leads to the deposition of films with lower nitrogen content. The MD simulations showed an increase of the nitrogen content with the Ar energy and a limited impact of the energetic bombardment on the retention of primary amines. Thus, the results highlighted the importance of the gas-phase processes on the nitrogen incorporation and primary amines retention in the plasma polymers. However, the higher energy flux towards the growing film clearly decreases amount of hydrogen and increases the polymer cross-linking.