Ortho-substituted Benzyl Research Articles

Discovery of 2-(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity.

RORγ is a dual-functional drug target, which involves not only induction of inflammation but also promotion of cancer immunity. The development of agonists of RORγ promoting Th17 cell differentiation could provide a novel mechanism of action (MOA) as an immune-activating anticancer agent. Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742. Interestingly, subtle structural differences of the compounds led to the opposite biological MOA. After rational optimization for structure-activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound 17 that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the in vivo antitumor efficacy of an RORγ agonist.

Novel Strobilurin Derivatives Containing Carboxylate Unit as Potential Antifungal Agents

Background: Due to the extensive use of a single fungicide to control crop diseases, the increase of resistant individuals leads to control failures. The search for molecules with fungicidal activity is still ongoing. Strobilurin is one of the most popularly used fungicides in the agrochemical field. A large number of strobilurin derivatives with both high activity and low toxicity have been developed. Methods: In the present study, a series of novel ortho-substituted benzyl carboxylates were efficiently synthesized by the reaction of (E)-methyl 2-(2-(bromom-ethyl)phenyl)-2-methox-yiminoaceta with various carboxylic acids. Their structures were confirmed and characterized by 1H NMR, 13C NMR, and ESI-MS analysis. Their fungicidal activities against common phytopathogenic fungi from six major cash crops were screened based on the pesticides guidelines for the laboratory bioactivity tests. Results: The primary fungicidal activity test results indicate that all compounds showed a certain inhibitory effect on the growth of 13 plants pathogenic fungi at a concentration of 100 ppm, and Compd. 3 has the most obvious inhibitory effect on all fungi. Further fungicidal activity studies indicate that some of these novel strobilurin derivatives containing carboxylate unit exhibited potential in vitro fungicidal activities at the dosage of 6.25 mg/L-1. Conclusion: A series of the ortho-substituted benzyl carboxylates derivatives containing β- methoxyacrylate moiety were designed and synthesized by modifying the side chain of traditional strobilurin fungicide. Compd. 3, Compd. 2 and Compd. 16 were identified as the most promising candidates for further study.

Selective photooxidation of ortho-substituted benzyl alcohols and the catalytic role of ortho-methoxybenzaldehyde

Abstract It has been recently reported by Palmisano et al. (2015) [1] that the oxidation of 2-methoxybenzyl alcohol (2-MBA) to 2-methoxybenzaldehyde (2-MBAD) proceeds in water under near-UV light with an unexpected catalytic effect of 2-MBAD. In order to investigate the catalytic role of aldehyde in photolytic oxidation of ortho-substituted benzyl alcohols (OSBAs), reactivity runs were carried out with 2-methylbenzyl alcohol (2-MeBA), 2-nitrobenzyl alcohol (2-NBA), 2-hydroxybenzyl alcohol (2-HBA) and 2-chlorobenzyl alcohol (2-ClBA) in the absence and in the presence of their corresponding aldehyde. None of those alcohols showed a measurable oxidation rate even in the presence of their aldehydes but 2-NBA was oxidised very fast, although no corresponding carbonyl product was obtained. The possible catalytic role of 2-MBAD was investigated for the photolytic oxidation of 4-methoxybenzyl alcohol (4-MBA), 4-nitrobenzyl alcohol (4-NBA), 2-ClBA, 2-HBA, 2-MeBA and ferulic acid (FA). The results showed that 2-MBAD acts as a catalyst only for 4-MBA, 2-HBA and FA. The photocatalytic oxidation of OSBAs in the presence of powdered TiO2 has been also carried out in order to investigate the mutual influences, if any, between homogeneous and heterogeneous processes. The reactivity runs were carried out with TiO2 photocatalyst in water and under near-UV irradiation; a home-prepared (HP) TiO2 sample was used along with Degussa P25. HP catalyst showed the best performance: the 2-MBA half-life time was 5 times smaller and the selectivity to aldehyde 13 times higher than in the presence of Degussa P25.

Design, synthesis and biological evaluation of 3′-benzylated analogs of 3′-epi-neoponkoranol as potent α-glucosidase inhibitors

A group of 3′-epi-neoponkoranol analogs with different hydrophobic substituents attached at 3′-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against α-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho-substituted benzyl groups showed best α-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against α-glucosidase enzymes. The strongest α-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3′-attached substituent and particularly the ortho-substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each α-glucosidase.

Theoritical study of the geometrical and electronic properties of N. N'-di(ortho-substituted benzyl) hydrazine

In this paper, we report on a theoretical study of N, N'-di(ortho-substituted benzyl) hydrazine (DBH (R)). The conformational analysis, structural and electronic properties were performed by the method B3LYP/6-31G (d). This study aims to show the interest of the substitution of radicals (R) of the two benzyl groups, then its effect on the physico-chemical properties. The results show that the values of the bonds lengths and angles of the torsion of the compounds studied are comparable to those obtained in the literature. Inductive or mesomeric effect of the substituent (R) has an impact on the length of the bridge bond the N-N, energy Gap, maximum absorption and stability of these compounds.

ChemInform Abstract: Iron‐Catalyzed Ring‐Opening Azidation and Allylation of O‐Heterocycles.

We have established the first catalytic C–C and C–N bond formation reactions of O-heterocycles (e.g., tetrahydrofuran, phthalane, and lactone derivatives) using iron trichloride as a catalyst in the presence of TMSN3 or allylsilanes accompanied by the ring opening of O-heterocycles. The reactions smoothly proceeded at room temperature to give the corresponding primary saturated alcohols from the 2-substituted tetrahydrofurans, ortho-substituted benzyl alcohols from phthalanes, and saturated carboxylic acids from lactones in high yields.

Iron-Catalyzed Ring-Opening Azidation and Allylation of O-Heterocycles

We have established the first catalytic C-C and C-N bond formation reactions of O-heterocycles (e.g., tetrahydrofuran, phthalane, and lactone derivatives) using iron trichloride as a catalyst in the presence of TMSN3 or allylsilanes accompanied by the ring opening of O-heterocycles. The reactions smoothly proceeded at room temperature to give the corresponding primary saturated alcohols from the 2-substituted tetrahydrofurans, ortho-substituted benzyl alcohols from phthalanes, and saturated carboxylic acids from lactones in high yields.

Solvent and Pressure Effects on the Motions of Encapsulated Guests: Tuning the Flexibility of a Supramolecular Host

The supramolecular host assembly [Ga4L6](12-) [1; L = 1,5-bis(2,3-dihydroxybenzamido)naphthalene] contains a flexible, hydrophobic interior cavity that can encapsulate cationic guest molecules and catalyze a variety of chemical transformations. The Ar-CH2 bond rotational barrier for encapsulated ortho-substituted benzyl phosphonium guest molecules is sensitive to the size and shape of the host interior space. Here we examine how changes in bulk solvent (water, methanol, or DMF) or applied pressure (up to 150 MPa) affect the rotational dynamics of encapsulated benzyl phosphonium guests, as a way to probe changes in host cavity size or flexibility. When host 1 is dissolved in organic solvents with large solvent internal pressures (∂U/∂V)T, we find that the free energy barrier to Ar-CH2 bond rotation increases by 1-2 kcal/mol, compared with that in aqueous solution. Likewise, when external pressure is applied to the host-guest complex in solution, the bond rotational rates for the encapsulated guests decrease. The magnitude of these rate changes and the volumes of activation obtained using either solvent internal pressure or applied external pressure are very similar. NOE distance measurements reveal shorter average host-guest distances (~0.3 Å) in organic versus aqueous solution. These experiments demonstrate that increasing solvent internal pressure or applied external pressure reduces the host cavity size or flexibility, resulting in more restricted motions for encapsulated guest molecules. Changing bulk solvent or external pressure might therefore be used to tune the physical properties or reactivity of guest molecules encapsulated in a flexible supramolecular host.

Encapsulated Guest−Host Dynamics: Guest Rotational Barriers and Tumbling as a Probe of Host Interior Cavity Space

The supramolecular host assembly [Ga(4)L(6)](12-) (1; L = 1,5-bis[2,3-dihydroxybenzamido]naphthalene) encapsulates cationic guest molecules within its hydrophobic cavity and catalyzes a variety of chemical transformations within its confined interior space. Despite the well-defined structure, the host ligand framework and interior cavity are very flexible and 1 can accommodate a wide range of guest shapes and sizes. These observations raise questions about the steric effects of confinement within 1 and how encapsulation fundamentally changes the motions of guest molecules. Here we examine the motional dynamics (guest bond rotation and tumbling) of encapsulated guest molecules to probe the steric consequences of encapsulation within host 1. Encapsulation is found to increase the Ph-CH(2) bond rotational barrier for ortho-substituted benzyl phosphonium guest molecules by 3 to 6 kcal/mol, and the barrier is found to depend on both guest size and shape. The tumbling dynamics of guests encapsulated in 1 were also investigated, and here it was found that longer, more prolate-shaped guest molecules tumble more slowly in the host cavity than larger but more spherical guest molecules. The prolate guests reduce the host symmetry from T to C(1) in solution at low temperatures, and the distortion of the host framework that is in part responsible for this symmetry reduction is observed directly in the solid state. Analysis of guest motional dynamics is a powerful method for interrogating host structure and fundamental host-guest interactions.

Probing Persistent Intramolecular C−H···X (X = O, S, Br, Cl, and F) Bonding in Solution Using Benzyl Meldrum’s Acid Derivatives

Persistent intramolecular interactions between acidic C-H hydrogens and a variety of acceptors (X) (X = O, S, Br, Cl, and F) in solution were probed by (1)H NMR experiments, using 5-benzyl Meldrum's acid derivatives. To bring about formation of intramolecular C-H...X bonding, ortho-substituted benzyl Meldrum's acids were designed, for which hydrogen bonding occurred through a six-membered ring. Introduction of substituents on the aromatic moiety and in the tether allowed variation of electronic and steric factors. The superior acidity of Meldrum's acids impacted the ability of the C-H hydrogen to engage in nonclassical C-H...X bonds and drove the conformational properties of benzyl Meldrum's acid, in combination with steric factors, namely A(1,3)-allylic strain. Further understanding of intramolecular C-H...X bonds was gained by characterization of benzyl Meldrum's acids in the solid state, by X-ray analysis, and by the conformation correlated to the observations made in solution.

Correlation analysis of reactivity in the oxidation of substituted benzyl alcohols by 2,2' -bipyridinium chlorochromate

Oxidation of benzyl alcohol and some ortho-, meta- and para-monosubstituted ones by 2,2'-bipyridinium chlorochromate (BPCC) in DMSO leads to the formation of corresponding benzaldehydes. The reaction is first order in both BPCC and the alcohol. The reaction is promoted by hydrogen ions; the hydrogen-ion dependence has the form : k obs = a + b [H + ]. Oxidation of α,α-dideuteriobenzyl alcohol (PhCD 2 OH) has exhibited a substantial primary kinetic isotope effect (k H /k D = 5.60 at 298 K). The reaction has been studied in nineteen organic solvents and the effect of solvent analysed using Taft's and Swain's multi-parametric equations. The rates of oxidation of para- and meta-substituted benzyl alcohols have been correlated in terms of Charton's triparametric LDR equation whereas the oxidation of ortho-substituted benzyl alcohols with tetraparametric LDRS equation. The oxidation of para-substituted benzyl alcohols is more susceptible to the delocalization effect than that of ortho- and meta-substituted compounds, which display a greater dependence on the field effect. The positive value of η suggests the presence of an electron-deficient reaction centre in the rate-determining step. The reaction is subjected to steric acceleration by the ortho-substituents. A suitable mechanism has been proposed.

Correlation of the Rates of Solvolyses of Carbomethoxybenzyl Bromides Using the Grunwald-Winstein Equation

Some years ago, Andrews and co-workers 1,2 studied the effects of ortho-substitution on nucleophilic substitution reactions of benzylic derivatives in 80% aqueous dioxane. They proposed that ortho-groups possessing a nucleophilic center could give intramolecular assistance to reactions; the relatively high reactivity of the ortho isomer has been explained on the assumption that its carboxylic acid group can participate electronically in the activation process by releasing electrons to the vacant p-orbital developing at the reaction center. Although previous workers have carried out some product studies showing intramolecular participation, they show only a profile of the products after completion of reaction. As mentioned above, the solvolyses of orthosubstituted benzyl halides have been less studied kinetically. The extended Grunwald-Winstein equation [eqn.(1)] has been applied to a powerful mechanistic tool for solvolysis reactions. 3 log(k/ko) = lNT + mYX + c (1)

Correlation analysis of reactivity in the oxidation of substituted benzyl alcohols by quinolinium bromochromate

Oxidation of benzyl alcohol and some ortho- meta- and para-monosubstituted ones by quinolinium, bromochromate (QBC) in dimethyl sulphoxide (DMSO) leads to the formation of corresponding benzaldehydes. The reaction is first order each in both QBC and the alcohol. The reaction is promoted by hydrogen ions; the hydrogen-ion dependence has the form k o b s = a + b [H + ]. Oxidation of α,α-dideuteriobenzyl alcohol (PhCD 2 OH) has exhibited a substantial primary kinetic isotope effect (k H /k D = 5.60 at 298 K). The reaction has been studied in nineteen organic solvents and the effect of solvent analysed using Taft's and Swain's multi-parametric equations. The rates of oxidation of para- and meta-substituted benzyl alcohols have been correlated in terms of Charton's triparametric LDR equation whereas the oxidation of ortho-substituted benzyl alcohols with tetraparametric LDRS equation. The oxidation of para-substituted benzyl alcohols is more susceptible to the delocalization effect than that of ortho- and meta-substituted compounds which display a greater dependence on the field effect. The positive value of η suggests the presence of an electron-deficient reaction centre in the rate-determining step. The reaction is subjected to steric acceleration by the ortho-substituents. A suitable mechanism has been proposed.

Correlation analysis of reactivity in oxidation of substituted benzyl alcohols by tetrabutylammonium tribromide

AbstractOxidation of benzyl alcohol and some ortho‐, meta‐ and para‐monosubstituted benzyl alcohols by tetrabutylammonium tribromide (TBATB) in aqueous acetic acid leads to the formation of corresponding benzaldehydes. The reaction is first order each in TBATB and the alcohol. The oxidation of [1,1‐2H2]benzyl alcohol (PhCD2OH) exhibited a substantial kinetic isotope effect. Addition of tetrabutylammonium chloride or potassium bromide did not affect the rate. Tribromide ion has been postulated as the reactive oxidizing species. The reaction rate increases with increase in the polarity of the solvent. The rates of oxidation of meta‐ and para‐substituted benzyl alcohols showed excellent correlation in terms of Charton's triparametric LDR, equation whereas the oxidation of ortho‐substituted benzyl alcohols correlated best with the LDRS equation. The oxidation of para‐substituted benzyl alcohols is more susceptible to the delocalization effect than is the oxidation of ortho‐ and meta‐substituted compounds, which display a greater dependence on the field effect. The positive value of η suggests the presence of an electron‐deficient reaction centre in the rate‐determining step. The reaction is subject to steric acceleration by the ortho‐substituents. A suitable mechanism is proposed. Copyright © 2002 John Wiley & Sons, Ltd.

Oxidation of benzyl alcohol by pyridinium dichromate in acetonitrile. Using the para/meta ratio of substituent effects for mechanism elucidationElectronic supplementary information (ESI) available: Table S1 containing kinetic data for establishing rate laws. See http://www.rsc.org/suppdata/p2/b2/b200742h/

Rate constants were measured for the oxidation reaction of benzyl alcohol and twenty-five ortho-, meta- and para-monosubstituted derivatives in the temperature range 293–323 K at intervals of 10 K. The kinetics were followed spectrophotometrically in dry acetonitrile acidified with trichloroacetic acid (TCA) using pyridinium dichromate (PDC) as oxidising agent under pseudo-first-order conditions with respect to PDC. Benzaldehyde is the only oxidation product and no reaction takes place without TCA. From good linear Eyring plots activation enthalpies Δ‡H° and entropies Δ‡S° are calculated. For ortho-substituted benzyl alcohols high Δ‡H° values and small negative Δ‡S° values point to an ortho effect on the rate-determining step. Using the tetralinear approach to substituent effects, the average value = 1.09 ± 0.05 for the para/meta ratio of inductive or Electra effects is obtained and negative Hammett reaction constants decreasing in magnitude with increasing temperature are found. A mechanism implicating the prior acid-catalysed formation of neutral benzyl hydrogen dichromate ester followed by intramolecular proton transfer is proposed. Modelling of parameter λ in terms of the electrostatic theory showed its experimental value to be consistent with the ratio of electric potentials generated in the immediate vicinity of the nearest chromium atom by dipolar substituents introduced in the aromatic ring on para and meta positions. At a molecular level the oxidative, rate-determining step is suggested to be triggered by the retraction or shrinkage of electron pairs from sigma bonds in Cr2VI species to non-bonding orbitals in unstable CrIV–O–CrVI species. In contrast with past interpretations, an electrochemical approach is used to explain negative values for the Hammett reaction constant.

Sparteine-mediated enantioselective [2,3]-Wittig rearrangement of allyl ortho-substituted benzyl ethers and ortho-substituted benzyl prenyl ethers

The (−)-sparteine-mediated enantioselective [2,3]-Wittig rearrangement of N, N-dialkyl- o-allyloxymethylbenzamides and o-substituted benzyl prenyl ethers has been investigated. Enantiomeric excess up to 60% was observed as for the reaction with N, N-diethyl- o-allyloxymetylbenzamide. From the mechanistic investigations, it was suggested that the stereoinformation was introduced at the deprotonation step. Substoichiometric amount of (−)-sparteine (0.2 equiv.) did not decrease the enantioselectivity. Introduction of functional groups other than carbamoyl group did not enhance the enantioselectivity in this rearrangement.

Transportation (2,3) de Wittig des éthers d'allyle ou crotyle et de benzyle chrome tricarbonyle

The (2,3) Wittig rearrangement of ortho-substituted benzyl tricarbonyl chromium allyl ether occurs with complete stereoselectivity. The ortho-substituted benzyl tricarbonyl chromium E crotyl ether gives exclusively erythro diastereoisomer, the Z isomer gives a mixture (ratio 59 41 ) of threo and erythro diastereoisomers.

Kinetic resolution of (η 6-arene)chromium complexes by a lipase

Tricarbonylchromium complexes of ortho-substituted benzyl alcohol derivatives were kinetically resolved by asymmetric esterification with a lipase.

Mechanism of formation of mercapturic acids from aromatic aldehydes in vivo.

Male adult Wistar rats dosed i.p. with o-substituted benzaldehydes (o-F, o-Cl, and o-Br = V, VI, and VII) excreted mercapturic acids in urine. These acids were identified as N-acetyl-S-(ortho-substituted benzyl)cysteines (I, II, III). The total mercapturic acid excretion as % dose (2.0 mmol/kg, n = 4) was 1.2 +/- 0.4, 6.8 +/- 0.9, and 10.4 +/- 2.0 for V, VI, and VII. p-Cl-benzaldehyde administered in the same dose showed a non-significant urinary thioether excretion. The aim of the investigation was to prove in vivo a postulated metabolic pathway of substituted benzaldehydes via sulphate esters to mercapturic acids. After a single administration of the sodium salts of o- and p-Cl-benzylsulfuric acid a significant increase in mercapturic acid excretion of 21.2 +/- 1.8% and 14.5 +/- 1.2% of dose (2.0 mmol/kg, n = 4) was found. By pretreatment with pyrazole the mercapturic acid excretion increased after administration of o-Cl-benzyl alcohol (IX) whereas a significant decrease was found after administration of o-Cl-benzaldehyde (VI). After simultaneous administration of ethanol with IX and VI an increase in mercapturic acid excretion was observed. After previous administration of pentachlorophenol a significant decrease in urinary mercapturic acid excretion for IX and VI was found. These findings are in accordance with a metabolic pathway of substituted benzaldehydes via benzyl alcohols, subsequently sulphate esters to the corresponding benzylmercapturic acids.

Solvolysis of 9-(ortho-substituted benzyl)fluorene-9-trimethylammonium ions. The effect of steric crowding

The solvolytic reaction of several 9-(ortho-substituted benzyl)fluorene-9-trimethylammonium salts in ethanol at 57.3 °C has been found to give both the substitution and elimination products. The observed rate constant for alkene formation increases when both ortho positions have substituents, kobs(s−1) = 2.35 × 10−5 and 268 × 10−5 for 2-Me and 2,6-diMe compounds, respectively. As well, the magnitude of the observed hydrogen–deuterium isotope effect is dependent on ring substituents, kobsH/kobsD = 1.22 and 2.35 for 2-Me and 2,6-diMe substrates, respectively. The results are discussed in the light of steric acceleration favouring loss of the poor leaving group, which leads to only the second example of a trimethylammonium salt reacting via the E1 mechanism.