Benzyl Derivatives Research Articles

(Invited) Synthesis and Stabilization of the Unstable Dimetallofullerenes

The metal-metal (M-M) bonding in dimetallofullerenes presents the peculiar electronic structures as well as the chemical and physical properties.[1-2] For Y and medium-size lanthanides (Gd, Tb, Dy), computations by Shinohara et al. showed that M2@C80 has one unpaired electron occupying the M–M bonding molecular orbitals, and the other electron is delocalized over the carbon cage (Figure 1a).[3] Such molecules are unstable radicals. Recently, we have succeeded in the capture of the elusive M2@C80 (M=Y, Dy) as benzyl derivatives (Figure 1b). The structure was unambiguously determined (Figure 1c, d).[4] In this contribution, the synthesis, separation, and structural characterizations of the elusive M2@C80 will be presented and discussed. [1] A. A. Popov, S. Yang, L. Dunsch, Chem. Rev. 2013, 113, 5989-6113. [2] A. A. Popov, S. M. Avdoshenko, A. M. Pendas, L. Dunsch, Chem. Commun. 2012, 48, 8031-8050. [3] Z. Wang, R. Kitaura, H. Shinohara, J. Phys. Chem. C 2014, 118, 13953-13958. [4] F. Liu, D. S. Krylov, L. Spree, S. M. Avdoshenko, N. A. Samoylova, M. Rosenkranz, A. Kostanyan, T. Greber, A. U. B. Wolter, B. Büchner, A. A. Popov, Nat. Commun. 2017, 8, 16098. Figure 1

α-Substituted Benzylic Complexes of Palladium(II) as Precursors of Palladium Hydrides

The adoption of a pseudoallylic (η3) form makes palladium benzylic derivatives a class of stabilized palladium alkyls that can undergo β-H elimination reactions in a more controlled way. α-(Pentafluorophenylmethyl)benzyl palladium complexes have been studied, and they decompose by β-H elimination to give palladium hydrides that, depending on the auxiliary ligands, can: (a) transmetalate to another palladium atom and, by reductive elimination, give hydrogenated products; this process is favored for a combination of bridging ligands (i.e., halogens) and low coordinating ligands. (b) Be used as a hydride source and get trapped by a diene to give palladium allylic derivatives. The presence of carbon monoxide does not induce a β-H elimination reaction, and only CO insertion into the Pd–benzyl bond to give acyl derivatives is observed.

Versatile Surface Modification of Cellulose Fibers and Cellulose Nanocrystals through Modular Triazinyl Chemistry

The ability to tune the interfacial and functional properties of cellulose nanomaterials has been identified as a critical step for the full utilization of nanocellulose in the development of new materials. Here, we use triazine chemistry in a modular approach to install various functionalities and chemistries onto cellulose fibers and cellulose nanocrystals (CNCs). The surface modification is demonstrated in aqueous and organic media. Octadecyl, monoallyl-PEG, benzyl, and propargyl triazinyl derivatives were grafted onto cellulose/CNCs via aromatic nucleophilic substitution in the presence of base as hydrochloric acid scavenger. The covalent nature and degree of substitution of grafted aliphatic, polymeric, alkyne chains, and aromatic rings were characterized through Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, elemental analysis, and thermogravimetric analysis. In addition, AFM and DLS analysis showed minimal change in the geometry and individualized character of CNCs after...

Synthesis, Reactivity and Stability of Aryl Halide Protecting Groups towards Di-Substituted Pyridines

This paper reports the synthesis and reactivity of different Benzyl derivative protecting groups. The synthesis and stability of Benzyl halides, 4-methoxybenzyl halides, 3,5-dimethoxybenzyl halides, 3,4-dimethoxybenzyl halides, 3,4,5-trimethoxybenzyl halide protecting groups and their reactivity towards nitrogen atom of a di-substituted pyridine ring in formation of pyridinium salts is also reported.

Synthesis and selected properties of nonahalogenated 2-ammonio-decaborate anions and their derivatives substituted at N-centre

New preparative methods for halogenation of the cage producing the corresponding [2-NH3-B10X9]- species (2- to 4-, X = Cl, Br, I) have been developed using halogenations by elemental halogens in a glass pressure vessel. Compared to similar icosahedral species of formulation [1-H3N-B12X11]- (X = Cl, Br), the N-alkylation reactions in 10-vertex series proceed significantly more easily. The reason for this difference is conceivably due to the two orders of magnitude lower basicity of the amino group, with pKa values in the interval from 9.27 to 8.37, and slightly lower steric strain around the reaction centre. Thus methylations with MeI under mild conditions provided the whole series of corresponding quarternary amines of the formulation [2-Me3N-B10X9]- (5-to 7-, X = Cl, Br, I). The effect of the steric strain of the surrounding halogens on the reactivity at the NH3- centre could then be better seen from reactions with bulkier benzyl bromide. Under comparable conditions, these reactions resulted in the ready formation of disubstituted compounds in case of X = Cl (8-), mixture of mono and disubstituted derivatives for X = Br (9-, 10-) or in monosubstited product for X = I (11-) only. Dibenzyl derivative of the nonaiodinated products (12-) could be still obtained, however only under more forcing conditions. The single-crystal X-ray diffraction structures of all three polyhalogenated derivatives 2- to 4- are presented along with that for benzyl derivative 10-, spectral and physicochemical properties of these polyhalogenated systems are outlined along with specific insights into specific properties of the NH3 group.

The Synthesis of (1,3,4-Oxadiazol-2-yl)Acrylic Acid Derivatives with Antibacterial and Protistocidal Activities

A series of new 1,3,4-oxadiazol-2-yl-acrylic acids was synthesized by cyclization of 4-(2-R-hydrazino)- 4-oxo-2-butenic acids, and their antibacterial and protistocidal activities were studied. The p-substituted benzyl derivatives in the Z-form were shown to exhibit a high protistocidal activity, which exceeded that of the reference drug Baycox (toltrazuril) by several times, whereas the 3-hydroxy-2-naphthyl derivative, in addition to a very high protistocidal activity, also exhibited a moderate antibacterial activity.

Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl bromides to produce substituted exo-glycals

Palladium-catalyzed cross-couplings of O-peracylated and O-permethylated 2,6-anhydro-aldose tosylhydrazones with aryl halides were studied under thermic conditions in the presence of LiOtBu and phosphine ligands. The reactions gave the corresponding aryl substituted exo-glycals as mixtures of diastereomers in 11–75% yields. The transformations represent a new access to these types of glycomimetic compounds. The double bond of some aryl substituted exo-glycals was saturated to give good yields of benzylic C-glycosyl derivatives.

Brønsted acid-catalysed regiodivergent phosphorylation of 2-indolylmethanols to synthesize benzylic site or C3-phosphorylated indole derivatives.

A Brønsted acid catalysed regiodivergent phosphorylation of 2-indolylmethanols with diarylphosphine oxides has been established, which provides a brand-new strategy for accessing highly functionalized phosphorus-containing indoles with structural diversity. Under the catalysis of HOTs·H2O, 2-indolylmethanols undergo regioselective benzylic phosphorylation at room temperature to afford benzylic site phosphorylated indoles in good to high yields (29 examples, up to 98% yield), while C3-phosphorylated indoles are obtained in the presence of HOTf under heating conditions (16 examples, up to 83% yield). Preliminary mechanistic studies suggest that C3-phosphorylated indoles are possibly obtained partially from direct C3-phosphorylation and dominantly from a tandem benzylic phosphorylation/[1,3]-P migration/isomerization sequence from 2-indolylmethanols. Furthermore, the acidity of the Brønsted acid and the reaction temperature play a vital role in the [1,3]-P migration of benzylic phosphorylated indoles to form C3-phosphorylated indoles. This protocol serves as a good example for regioselective benzylic functionalization of 2-indolylmethanols.

Studies Toward the Synthesis of Caramboxin Analogues

Intrigued by the recent discovery of caramboxin by Brazilian researchers, we present the results from our studies toward the racemic synthesis of caramboxin analogs through the ortho-carboxylation of 3,5-dimethoxy benzyl derivatives. Three different approaches were tested, and the route involving a Vilsmeier-Haack formylation followed by a Lindgren oxidation provide a potential intermediate for the synthesis of several caramboxin analogs.

Asymmetric synthesis via stereospecific C-N and C-O bond activation of alkyl amine and alcohol derivatives.

This perspective showcases our development of benzylic and allylic amine and alcohol derivatives as electrophiles for stereospecific, nickel-catalyzed cross-coupling reactions, as well as the prior art that inspired our efforts. The success of our effort has relied on the use of benzyl ammonium triflates as electrophiles for cross-couplings via C-N bond activation and benzylic and allylic carboxylates for cross-couplings via C-O bond activation. Our work, along with others' exciting discoveries, has demonstrated the potential of stereospecific, nickel-catalyzed cross-couplings of alkyl electrophiles in asymmetric synthesis, and enables efficient generation of both tertiary and quaternary stereocenters.

Substrate switchable Suzuki-Miyaura coupling for benzyl ester vs. benzyl halide.

Two reaction conditions were developed to accomplish the substrate switchable Suzuki–Miyaura coupling of benzyl derivatives and arylboronic acid derivatives. Under conditions for esters, benzyl esters such as carbonates and acetates reacted with arylboronic acids to afford the corresponding diarylmethanes. However, the benzyl halides did not react under the same conditions. On the other hand, benzyl halides such as bromides and chlorides furnished diarylmethanes under conditions for halides, under which benzyl ester substrates did not react, in which water was found to play an important role. This switching system was tested using the intermolecular/intramolecular competitive reactions, during which the desired products could be synthesized by selecting the appropriate reaction conditions.

An Optimized Synthesis, Molecular Structure and Characterization of Benzylic Derivatives of 1,2,4-Triazin-3,5(2H,4H)-dione.

4-Benzyl-1,2,4-triazin-3,5(2H,4H)-dione (3-benzyl-6-azauracil, 2), and 2,4-dibenzyl-1,2,4-triazin-3,5(2H,4H)-dione (1,3-dibenzyl-6-azauracil, 3) were synthesized by the reaction of 1,2,4-triazin-3,5(2H,4H)-dione (6-azauracil, 1) with benzyl bromide and potassium carbonate in dry acetone via the 18-crown-6-ether catalysis. In these reaction methods, we developed more convenient and efficient methodologies to afford compounds 2 and 3 in good yields. These compounds were characterized by 1H- and 13C-NMR, MS spectrum, IR spectroscopy and elemental analysis. The structure of 2 was verified by 2D-NMR measurements, including gHSQC and gHMBC measurements. A single-crystal X-ray diffraction experiment indicated that compound 3, with the molecular formula C17H15N3O2, crystallized from a CH3OH/CH2Cl2 diffusion solvent system in a monoclinic space group P21/c with a = 13.7844(13), b = 8.5691(8), c = 13.0527(12) Å, β = 105.961(2)°, V = 1482.3(2) Å3, Z = 4, resulting in a density Dcalc of 1.314 g/cm3. The crystal structure of compound 3 is tightly stabilized by contact with five other molecules from the six short contacts formed by intermolecular C−O···H−Car, C−H···Car, and weakly π···π stacking interactions. The dihedral angle 31.90° is formed by the mean planes of the benzene rings of the N-2 and N-4 benzyl groups.

Chemical Modification of Oligo(Hexamethylene Guanidine): Synthesis of Alkylated Derivatives and Their Estimated Activity Against Mycobacterium Smegmatis

It was found that oligo(hexamethylene guanidine) (OHMG) reacted very slowly with unactivated high-molecular-mass alkyl halides (dodecyl chloride), possibly due to steric hindrance and the low nucleophilicity of the guanidine moiety. Therefore, this alkyl halide could not be used to modify OHMG under conventional conditions. Ethylation of OHMG was much more facile. However, the substitution in the derivatives was broadly scattered (under ordinary conditions and reagent ratios). It was shown simultaneously that the antibacterial activity of the alkylated derivatives was less than that of the starting OHMG hydrochloride. Benzyl chloride reacted readily with OHMG to produce derivatives with the desired degree of substitution. It was found that benzyl derivatives with 0.2 degree of substitution were more active against mycobacteria than the starting hydrochloride with the activity gradually diminishing if the degree of substitution was increased further. The increased activity may have been related to the optimum increase of OHMG hydrophobicity and/or steric structure. The rather high antibacterial activities of the benzyl derivatives against Mycobacterium smegmatis strain ATCC 607 made them promising for further development and studies of the properties of alkylated OHMG derivatives to discover more active derivatives, including against M. smegmatis. The most obvious candidates could become the methylcarboxy-substituted OHMG derivatives.

N′-mono- and N, N′-diacyl derivatives of benzyl and arylhydrazines as contact insecticides against adult Anopheles gambiae

New public health insecticides are urgently required to prevent the spread of vector-borne disease. With the goal of identifying new K+-channel-directed mosquitocides, analogs of the RH-5849 family of diacyl t-butylhydrazines were synthesized and tested for topical toxicity against adult Anopheles gambiae, the African vector of malaria. In total, 80N′-monoacyl and N, N′-diacyl derivatives of benzyl- and arylhydrazines were prepared. Three compounds (2bo, 2kb, 3ab) were identified that were more toxic than RH-5849 and RH-1266. The potencies of these compounds to block K+ currents in An. gambiae and human Kv2.1 channels were assessed to address their possible mechanism of mosquitocidal action. Selectivity for inhibition of An. gambiae Kv2.1 vs human Kv2.1 did not exceed 3-fold. Furthermore, no correlation was seen between the potency of insecticidal action and K+ channel blocking potency. These observations, combined with the minimal knockdown seen with 2bo near its LD50 value, suggests a mode of action outside of the nervous system.

Photoelectrochemical Oxidation of Benzylic Alcohol Derivatives on BiVO4/WO3 under Visible Light Irradiation

AbstractThe photo‐assisted electrochemical oxidation of benzylic alcohol derivatives was achieved with excellent yields up to 97 % at low applied potential under visible light irradiation (>420 nm) by using a BiVO4/WO3 photoelectrode in aprotic organic media. The faradaic efficiencies for the oxidation of 1‐phenylethyl alcohol was very high (>99 %) in 0.1 M Bu4NBF4/MeCN. The applied potentials for the oxidation of benzylic alcohols (approximately +0.7 V vs. SHE) were considerably lower than those of the Pt electrodes (approximately +1.9 V vs. SHE). The turnover number of moles of oxidation product per moles of BiVO4 was approximately 1200.

Mechanism and Origins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki-Miyaura Coupling with Benzylic Esters: AComputational Study.

Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp3)-O cleavage. The SIMes ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy3) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand-controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an SN2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy3 ligand, the nickel-ligand interaction involves mainly σ-donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy3 ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side SN2-type oxidative addition delivers the stereoinversion.

Electrochemical behavior of N‐oxyphthalimides: Cascades initiating self‐sustaining catalytic reductive N―O bond cleavage

AbstractN‐oxyphthalimides are stable and easily accessible compounds that can produce oxygen radicals upon 1‐electron reduction. We present a systematic study of electrochemical properties of N‐oxyphthalimide derivatives (PI‐ORs) in DMF by cyclic voltammetry. In all cases, electron transfer to the substrate leads to decomposition of the intermediate radical anion via the N―O bond cleavage. In the case of benzyloxyphthalimide or its derivatives containing electron‐donating substituents, reductive electron transfer induces the chain decomposition of the substrate to phthalimide (PI) radical‐anion and the corresponding carbonyl compound. The PI radical‐anion product is a powerful reductant that can transfer an electron to the reactant PI‐OR, thus establishing a catalytic cycle for reductive N―O scission. This self‐catalytic process is reflected in a considerable decrease in the reduction current for the substrate (<1e‐/molecule). By contrast, reductive fragmentations of benzyl derivatives containing electron‐withdrawing substituents in the aromatic ring or at the benzylic position, as well as tosyl and alkyl derivatives, occur via a 1‐electron mechanism. A sequence of N―O and C―C scissions was engineered to support the intermediacy of O‐centered radicals in these processes.

Facile alkylation of 4-nitrobenzotriazole and its platelet aggregation inhibitory activity

We explored the facile alkylation of 4-nitrobenzotriazole under basic conditions and the synthesized derivatives were tested for their potential ADP induced platelet aggregation inhibition activity in comparison with standard drug ticagrelor (selective P2Y12 inhibitor). The nitro group at 4-position is highly activating toward alkylation reactions (under strong basic conditions) and resulted in formation of degradation product like 3-nitrobenzene-1,2-diamine which make isolation of alkyl products very difficult. We optimized the reaction under mild basic condition (potassium carbonate and DMF) which is devoid of any degradation product. This is perhaps the first report of 4-nitrobenzotriazole derivatives possessing platelet aggregation inhibitory activity. Generally activity increases with increase in length of alkyl chain and 1-alkyl positional isomers were found to be more potent than 2-alkyl isomers. The benzoyl derivative was found to be the most potent [compound 22; (4-Nitro-1H-benzotriazol-1-yl)(phenyl)methanone; IC50=0.65±0.10mM] which may be attributed to electronegative oxygen atom and aromatic ring. Benzyl derivatives [compound 20; 1-Benzyl-4-nitro-1H-benzotriazole; IC50=0.81±0.08mM, compound 21; 2-Benzyl-4-nitro-2H-benzotriazole; IC50=0.82±0.19mM] and sulfonyl derivative [compound 23; 1-[(4-Methylphenyl)sulfonyl]-4-nitro-1H-benzotriazole; IC50=0.82±0.19mM] are also found to be highly active. Furthermore, all compounds possess P2Y12 binding affinity as confirmed by VASP/P2Y12 phosphorylation assay.

Antidepressent Effect of Two New Benzyl Derivatives from Wild Strawberry Fragaria vesca var. nubicola Lindl. ex Hook.f.

Two new benzyl derivatives were isolated from ethyl acetate fraction of wild strawberry, Fragaria vesca var. nubicola Lindl. ex Hook.f. The structures of these compounds were elucidated to be 5-(4-hydroxy-3-methoxyphenethyl)-7-methoxy-2H-chromen-3-ol (1) and 5-(4-hydroxy-3-methoxyphenethyl)-4,7-dimethoxy-2H-chromen-3-ol (2) based on spectroscopic data through IR, UV, 1H-NMR, 13C-NMR along with two dimensional (2D) techniques HMBC, HMQC, and COSY. Both compounds 1 and 2 were studied in tail suspension and forced swim tests for antidepressant like effects. A significant dose dependent antidepressant like effect was observed by causing spontaneous anti-immobility at various test doses upon intraperitoneal administration.

Ferrocenyl, Ruthenocenyl, and Benzyl Oxamniquine Derivatives with Cross-Species Activity against Schistosoma mansoni and Schistosoma haematobium.

Schistosomiasis is a parasitic disease that affects more than 250 million people annually, mostly children in poor, tropical, rural areas. Only one treatment (praziquantel) is available, putting control efforts at risk should resistance occur. In pursuit of treatment alternatives, we derivatized an old antischistosomal agent, oxamniquine (OXA). Four organometallic derivatives of OXA were synthesized and tested against Schistosoma mansoni in vitro and in vivo. Of these, a ferrocenyl derivative, 1, killed larval and adult worms 24 h postexposure in vitro, in contrast to OXA, which lacks in vitro activity against adult worms. A dose of 200 mg/kg of 1 completely eliminated the worm burden in mice. Subsequently, a ruthenocenyl (5) and a benzyl derivative (6) of OXA were synthesized to probe the importance of the ferrocenyl group in 1. Compounds 1, 5, and 6 were lethal to both S. mansoni and S. haematobium adults in vitro. In vivo, at 100 mg/kg, all three compounds revealed S. mansoni worm burden reductions of 76 to 93%, commensurate with OXA. Our findings present three compounds with activity against S. mansoni in vitro, comparable activity in vivo, and high activity against S. haematobium in vitro. These compounds may possess a different binding mode or mode of action compared to OXA and present excellent starting points for further SAR studies.