Α-phenyl Group Research Articles

Stereodivergent synthesis of α-fluoro α-azaaryl γ-butyrolactones via cooperative copper and iridium catalysis

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically important α-fluoro γ-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance. Herein, a novel asymmetric [3+2] annulation of α-fluoro α-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization, affording a variety of enantioenriched α-fluoro γ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity (up to 98% yield, generally >20:1 dr and >99% ee). Notably, all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually via simple permutations of two enantiomeric catalysts. In addition, other azaaryl acetates bearing α-methyl, α-chlorine or α-phenyl group were tolerated well in this transformation. Reaction mechanistic investigations were conducted to explore the process of this bimetallic catalysis based on the results of reaction intermediates, isotopic labelling experiments, and kinetic studies.

Direct Aerobic Carbonylation of C(sp²)-H and C(sp³)-H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source.

The direct carbonylation of aromatic sp(2) and unactivated sp(3) C-H bonds of amides was achieved via nickel/copper catalysis under atmospheric O2 with the assistance of a bidentate directing group. The sp(2) C-H functionalization showed high regioselectivity and good functional group compatibility. The sp(3) C-H functionalization showed high site-selectivity by favoring the C-H bonds of α-methyl groups over those of the α-methylene, β- or γ-methyl groups. Moreover, this reaction showed a predominant preference for functionalizing the α-methyl over α-phenyl group. Mechanistic studies revealed that nickel/copper synergistic catalysis is involved in this process.

Structural requirements for substrate in highly enantioselective hydrogenation over the cinchonidine-modified Pd/C

Relationship between substrate structure and enantioselectivity is studied for the asymmetric hydrogenation of 42 different ( E)- α , β -disubstituted acrylic acids (propenoic acids) over cinchonidine-modified Pd/C. The β-phenyl group is indispensable for high enantioselectivity of α-phenylcinnamic acid (2,3-diphenylpropenoic acid, 81% ee), and substitution on this group affects markedly the selectivity. The high ee up to 92% was achieved by the β - p -alkoxyphenyl substitution, and the selectivity is ascribed mainly to stronger interaction of the substrate with the chiral modifier on the catalyst surface. In contrast, substitution on the α-phenyl group does not affect notably the enantioselectivity (80–82% ee) or even the α-phenyl group itself is not indispensable but replaceable with a properly bulky group for the high enantioselectivity.

Ion-size recognition of Group 13 metals (Al3+, In3+) with modified β-diketones

Ion-size recognition of Group 13 metals (Al3+ and In3+) with modified β-diketones, 3-phenylpentane-2,4-dione (α-phenylacetylacetone, HL2) and 1,2-diphenylbutane-1,3-dione (α-phenylbenzoylacetone, HL4), has been studied by the liquid–liquid extraction method and compared with that of pentane-2,4-dione (acetylacetone, HL1) and 1-phenylbutane-1,3-dione (benzoylacetone, HL3). While HL1 and HL3 quantitatively extracted both ions, HL2 and HL4 greatly discriminated Al3+ from In3+: Al3+ was readily extracted into benzene at a pH below 5, while In3+ was entirely unextractable, leading to an effective extraction separation of Al3+ from In3+. This could be ascribed to the large ‘bite size’ (O · · · O distance in the chelate ring) in the indium β-diketonates. The steric repulsions between the α-phenyl group and the terminal methyl or phenyl groups prevent HL2 and HL4 from widening their bite size. In addition, the extraction of Al3+ was greatly influenced by the interligand contact due to its remarkably small ionic radius. The extraction order with HL1 and HL3 is Al3+ > In3+ obeying the common tendency that the metal ion with a smaller ionic radius is more readily extracted, while that with ligands having bulky terminal groups, such as 1,3-diphenylpropane-1,3-dione (dibenzoylmethane, HL5), is the opposite. These steric factors have been evaluated by the investigation of the crystal structures of the complexes of Al3+ and In3+ and by molecular mechanics calculations. The steric factors have been confirmed through extraction behaviors with various kinds of β-diketones.

A new silicon-mediated elimination–rearrangement

Treatment of trimethylsilylethanes bearing α-phenyl groups and β-phenylthio, phenylsulfonyl or cyano groups with LDA causes elimination–rearrangement mediated by the β-carbanionic species. Mechanistic conclusions are based on isotopic labelling experiments, the effects of substituents and approximate kinetics. These suggest that trimethylsilyl is the migrating group, that cleavage of the bond to the leaving group is little advanced in the transition structure and that placing of a substituent to encourage Si–C bond cleavage is mandatory.

Fluorescent Spot Test Method for Specific Detection of β-Lactamases

A simple, sensitive fluorescent spot test method for specific detection of microbial beta-lactamases has been developed, based on the modification of a previously disclosed method (K. C. S. Chen, October 23, 1990, U.S. Patent 4,965,193). The new fluorescence developer used in the present study consisted of 0.5 mM HgCl 2, in 0.5 M sodium citrate buffer, pH 4.5, prepared in 0.5% formaldehyde aqueous solution. A β-lactam substrate solution consisting of a β-lactam antibiotic with an acyl side chain containing an α-amino group and an α-phenyl group, or its derivatives, was incubated with a β-lactamase-producing organism. One volume of the fluorescence developer was added to 4 vol of the incubated β-lactam substrate solution, followed by heating the mixture at 45°C for 10 min. The mixture was spotted on filter paper. Production of fluorophore indicated β-lactamase activity. Each fluorophore was analyzed by TLC and its chemical identity was determined. Using ampicillin as the penicillinase substrate and cephalexin as the cephalosporinase substrate, the new method can be conveniently carried out by using dropping bottles for storing and dispensing the substrate solutions and the fluorescence developer. This modified method also provided more favorable conditions for the penicillinases to remain active during fluorescence development. Therefore, the sensitivity of the test was increased.

Kinetics and mechanisms of nucleophilic displacements with heterocycles as leaving groups. Part 25. X-Ray structure determinations, crystallographic evidence for steric crowding, and correlation with acceleration of rates

X-Ray crystallographic structures are determined for seven N-benzylpyridinium salts including compounds possessing free, five-ring fused, and six-ring fused α-phenyl groups. Significant bond lengths, non-bonding distances, torsional and interplanar angles are determined and compared for the eight structures (the triphenyl derivative was found in two crystal environments). The results show steric overcrowding to an extent that parallels the kinetic displacement rates. However, the steric strain existing in all these molecules is relieved to different extents by different distortions in the different molecules. Nevertheless, crystallographic interatomic distances and angles are shown to be of potential utility in determining the type of mechanistic changes to be undergone, provided the appropriate parameters are selected.

Solution and gas-phase basicities of pyridines with bulky α-substituents

Steric hindrance to solvation of pyridinium cations is largest for two α-t-butyl substituents, less for one t-butyl and one phenyl, less for two α-phenyl groups, and least for one phenyl and one alkyl. The effect of α-phenyl groups is reduced by buttressing. Gas-phase proton affinities of the pyridine determined by dimer dissociation do not correlate with the solution pKa values. Steric accelerations of pyridinium dealkylation show fair correlation with solution pKa; reasons for discrepancies are discussed.

A simple H 1 NMR approach to the conformations of α,β-diarylacrylonitriles

Room temperature 60 MHz NMR data of α,β-diarylacrylonitriles were interpreted in a search for a method for routine stereochemical assignments and to establish the conformational preferences of the β-heterocyclic ring. The conformation of the α-phenyl group differs from that of diaryl ethylenes previously investigated. Solvent effect on the conformations is observed only for pyrrole derivatives.

Vinyl ether hydrolysis. XI. The effect of α-phenyl substitution

The unexpected inability of an α-phenyl group to accelerate the rate of vinyl ether hydrolysis more strongly than an α-methyl substituent, k(CH2=CPhOEt)/k(CH2=CMeOEt) = 0.2 for catalysis by H3O+ at 25 °C, is examined and is found to be the result of two effects: (i) preferential initial state stabilization by phenyl and (ii) weak resonance interaction with the developing alkoxy carbonium ion in the transition state induced by the reactant-like character of the latter. A curved Brønsted relation for the hydrolysis of 3-methoxyindene catalyzed by carboxylic acids and monohydrogen phosphonate anions gives the Marcus theory parameters ΔG0≠ = 3 ± 1 kcal/mol and wr = 12 ± 1 kcal/mol.

Photochemistry of αα′-disbstituted azoalkanes. Part II. Photolytic dechlorination, decomposition, and oxidation of αα′-dichloro- and αα′-diacyloxy-azoalkanes

The photochemistry of a series of αα′-dichloro (III) and αα′-diacyloxy-azoalkanes (IV) with α-phenyl groups has been studied. Irradiation of (III) yields both products of N2 extrusion (RN2R [graphic omitted] R·+ N2+ R·) well known for unsubstituted azoalkanes and a new reaction leading to the loss of 2Cl· and formation of ketazines. In addition, the radical intermediates produced in both photoreactions are susceptible to oxiadation. The dechlorination: N2 extrusion ratio increases with increasing electron donor character of the substituted α-phenyl group. On the other hand irradiation of (IV) gives only N2 extrusion. A sensitization and quantum yield study of αα′-dichloro-(I) and αα′-diacyloxy-azoalkanes (II) without α-phenyl substituents as well as of (III) and (IV) showed that the various photoreactions of the series proceed only with singlet sensitization. The photochemical mechanisms of these reactions are discussed.

Elimination reactions of 1,2-diaryl-1-chloroethanes promoted by sodium ethoxide in ethanol. The kinetic effects of α- and β-phenyl substituents

The kinetics of the elimination reactions of several substituted 1,2-diaryl-1-chloroethanes promoted by sodium ethoxide in ethanol have been studied. On the basis of the kinetic effects of β-phenyl substituents a ρ value of +2·26 has been calculated. This value is slightly less positive than that (+2·50) found in the corresponding elimination from substituted phenylethyl chlorides, thus showing that the introduction of an α-phenyl group does not modify substantially the carbanionic character of the transition state in the elimination reactions of β-phenyl activated substrates. Small kinetic effects are observed for α-phenyl substituents. Electron-withdrawing α-phenyl substituents produce an increase in the reaction rate: it appears therefore that these substituents exert their influence mainly through a favourable interaction with the partial negative charge present on Cβ in the transition state.

Oxidation of 2′-hydroxy-α-phenylchalcones: substituent effects on the course of the Algar–Flynn–Oyamada (AFO) reaction

In alkaline hydrogen peroxide, 2′-hydroxy-α-phenylchalcones with and without a 6′-methoxy-substituent cyclised preferentially at the β-carbon atom to give chromanones. Fusion of a benzene ring at the 5′- and 6′-positions in the chalcone affected the directive influence of the α-phenyl group, and AFO oxidation afforded a 1 : 1 mixture of α- and β-cyclisation products. Products of aerial oxidation of the chalcones were also studied.

SEMISYNTHETIC /9-LACTAM ANTIBIOTICS. III

Structure-activity relationships were examined for a number of α-sulfopenicillins and related compounds. Among the α-sulfopenicillins tested, the α-thienyl and α-(p-aminophenyl) homologues showed the greatest activity against Pseudomonas aeruginosa, and broad spectra comparable to that of α-sulfobenzylpenicillin (1). With the exception of these two homologues, any modification in position or structure of the α-sulfo or α-phenyl group of 1, diminished activity. Relationships between antipseudomonal or antistaphylococcal activity and a negative charge in the acyl side chain are discussed.

Effects of the Nitrone Group in NMR Spectra of α,N-Diphenylnitrones

Abstract The NMR and UV spectra of α,N-diphenylnitrone and its derivatives which have a substituent at the para position of the α-phenyl group and some of which have in addition a methyl substituent at the ortho position of the α-phenyl group were measured. Examination led to the following conclusions. The NMR signal of the ortho protons of the α-phenyl group appears at a very low field. This is mainly attributed to the direct effect of the negatively charged oxygen atom of the nitrone group. Increase in the electron-donating power of the para substituent enhances this effect.

Antipseudomonal activity of alpha-sulfoaminopenicillins.

A series of penicillins characterized by the presence of a sulfoamino or a modified sulfoamino group in the side chain was subjected to in vitro antimicrobial screening tests. Although the most potent members of the series were less active than benzylpenicillin against gram-positive bacteria and comparably active against most gram-negative bacteria, they were, on the average, 8 to 16 times more effective against strains of Pseudomonas aeruginosa. In other comparative laboratory tests against P. aeruginosa, these compounds were about as active as carbenicillin and four to eight times more active than ampicillin. An examination of structure-activity relationships indicated that maximal potency was obtained with penicillins having an alpha-(aromatic or heteroaromatic)-alpha-sulfoaminoacetamido side chain. The compound with an alpha-phenyl group was comparable in activity to those having an alpha-(2- or 3-thienyl) group, whereas any modification in position or structure of the alpha-sulfoamino group reduced activity. Results of studies with a cell-free P. aeruginosa beta-lactamase suggest that the marked inhibitory effects of alpha-sulfoamino penicillins for P. aeruginosa can be attributed, at least in part, to their high degree of resistance to this enzyme. Some derivatives, however, had weak antipseudomonal activity, despite possessing a high degree of beta-lactamase resistance.

Antipseudomonal Activity of α-Sulfoaminopenicillins

A series of penicillins characterized by the presence of a sulfoamino or a modified sulfoamino group in the side chain was subjected to in vitro antimicrobial screening tests. Although the most potent members of the series were less active than benzylpenicillin against gram-positive bacteria and comparably active against most gram-negative bacteria, they were, on the average, 8 to 16 times more effective against strains of Pseudomonas aeruginosa. In other comparative laboratory tests against P. aeruginosa, these compounds were about as active as carbenicillin and four to eight times more active than ampicillin. An examination of structure-activity relationships indicated that maximal potency was obtained with penicillins having an alpha-(aromatic or heteroaromatic)-alpha-sulfoaminoacetamido side chain. The compound with an alpha-phenyl group was comparable in activity to those having an alpha-(2- or 3-thienyl) group, whereas any modification in position or structure of the alpha-sulfoamino group reduced activity. Results of studies with a cell-free P. aeruginosa beta-lactamase suggest that the marked inhibitory effects of alpha-sulfoamino penicillins for P. aeruginosa can be attributed, at least in part, to their high degree of resistance to this enzyme. Some derivatives, however, had weak antipseudomonal activity, despite possessing a high degree of beta-lactamase resistance.

Oxidation by persulphate. Part IV. Silver-catalysed oxidation of primary aliphatic amines

Oxidation of a primary aliphatic amine, RCH2·NH2, by aqueous persulphate under alkaline conditions and in the presence of a catalytic amount of silver nitrate, gave the aldimine, RCH:N·CH2R, which was subsequently hydrolysed to the aldehyde, RCHO, and the original amine, or was hydrogenated to the corresponding secondary amine, (RCH2)2NH. The yield of aldehyde varied from 15 to 95% among C3—C9 amines, and the conversion was favoured by branching in the alkyl chain or by the presence of an α-phenyl group. Under similar conditions, a primary amine of the type R1R2CH·NH2 was converted into the ketone, R1R2CO, without separation of the ketimine. Primary amines of the type R1R2R3C·NH2 were unchanged. Secondary reactions may complicate the oxidations.