Mass spectrometry of some methyl esters of N-4-pyrimidinylamino acids: Rearrangements of the ions occurring on electron-impact ionization

The electron-impact-induced mass fragmentations of methyl esters of N-(1H-2-oxo-4-pyrimidinyl)ainino acids are reported. The loss of a ·COOCH₃ radical and the elimination of a methanol molecule were observed and possible mechanisms of these processes are proposed. The loss of a ·COOH radical and elimination of water were established, which suggests the rearrangement of the investigated esters into isomeric N-4-pyrimidinylamino acids.     

Nonaqueous diazotization of 5-amino-1-aryl-1H-pyrazole-4-carboxylate esters

5-Amino-1-aryl-1H-pyrazole-4-carboxylate esters are converted to the corresponding desamino, chloro, bromo, iodo, and methylthio esters by processes involving nonaqueous diazotization. Diazotizing agents are alkyl nitrites except in the case of chlorine where nitrosyl chloride is used. Evidence is presented that the latter reagent leads to the formation of cationic rather than radical intermediates.     

Laser flash photolysis studies of alkoxyl radical kinetics using 4-nitrobenzenesulfenate esters as radical precursors

4-Nitrobenzenesulfenate esters were used as precursors for the generation of alkoxyl radicals under laser flash photolysis conditions. The esters were efficiently cleaved using the Nd:YAG third harmonic (355 nm) to produce alkoxyl radicals and the 4-nitrobenzenethiyl radical. Rate constants for beta-scission and 1, 5-hydrogen abstraction reactions of alkoxyl radicals were measured.     

Synthesis of 4-piperidazinethiols as potential antiradiation agents

The free radical addition of thioacetic acid to 1,2-dicarbethoxy-1,2,3,6-tetrahydropyridazines gave high yields of 1,2-dicarbethoxy-4-S-thiolacetoxypiperidazines. The latter compounds served as the key intermediates in the preparation of 4-piperidazinethiols. The thiolacetoxy derivatives were partially hydrolyzed to afford the related 1,2-dicarbethoxy-4-piperidazinethiols. Complete hydrolysis of the thiolacetates gave rise to 4-piperidazinethiols. Finally, lithium aluminum hydride reduction of the thiolacetoxy esters produced a series of 1,2-dimethyl-4-piperidazinethiols. Only 4-piperidazinethiol hydrochloride showed appreciable anti-radiation activity.     

One-electron oxidation of 2-(4-methoxyphenyl)-2-methylpropanoic and 1-(4-methoxyphenyl)cyclopropanecarboxylic acids in aqueous solution. the involvement of radical cations and the influence of structural effects and pH on the side-chain fragmentation reactivity

A product and time-resolved kinetic study on the one-electron oxidation of 2-(4-methoxyphenyl)-2-methylpropanoic acid (2), 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (3), and of the corresponding methyl esters (substrates 4 and 5, respectively) has been carried out in aqueous solution. With 2, no direct evidence for the formation of an intermediate radical cation 2*+ but only of the decarboxylated 4-methoxycumyl radical has been obtained, indicating either that 2*+ is not formed or that its decarboxylation is too fast to allow detection under the experimental conditions employed (k > 1 x 10(7) s(-1)). With 3, oxidation leads to the formation of the corresponding radical cation 3*+ or radical zwitterion -3*+ depending on pH. At pH 1.0 and 6.7, 3*+ and -3*+ have been observed to undergo decarboxylation as the exclusive side-chain fragmentation pathway with rate constants k = 4.6 x 10(3) and 2.3 x 10(4) s(-1), respectively. With methyl esters 4 and 5, direct evidence for the formation of the corresponding radical cations 4*+ and 5*+ has been obtained. Both radical cations have been observed to display a very low reactivity and an upper limit for their decay rate constants has been determined as k < 10(3) s(-1). Comparison between the one-electron oxidation reactions of 2 and 3 shows that the replacement of the C(CH3)2 moiety with a cyclopropyl group determines a decrease in decarboxylation rate constant of more than 3 orders of magnitude. This large difference in reactivity has been qualitatively explained in terms of three main contributions: substrate oxidation potential, stability of the carbon-centered radical formed after decarboxylation, and stereoelectronic effects. In basic solution, -3*+ and 5*+ have been observed to react with -OH in a process that is assigned to the -OH-induced ring-opening of the cyclopropane ring, and the corresponding second-order rate constants (k-OH) have been obtained. With -3*+, competition between decarboxylation and -OH-induced cyclopropane ring-opening is observed at pH >or=10, with the latter process that becomes the major fragmentation pathway around pH 12.     

The synthesis and transition temperatures of benzoate ester derivatives of 2-fluoro-4-hydroxy-and 3-fluoro-4-hydroxybenzonitriles

The synthesis and the liquid-crystal temperatures of sixty 4-cyano-2-fluorophenyl and 4-cyano-3-fluorophylen 4-substituted benzoates are described. The nematic-isotropic liquid transition temperatures of the most of these novel esters are only marginally lower than those of the corresponding esters containing an H-atom in place of the F-substituent. In several instances, the clearing points of the F-substiuted-phenyl esters are higher than those of the non-substituted-phenyl esters. The nematic ranges of several of the new esters are markedly broader than those of the analogous non-F-substituted-phenyl esters.     

Synthesis of tert-butyl peresters from aldehydes by Bu4NI-catalyzed metal-free oxidation and its combination with the Kharasch-Sosnovsky reaction

A new tert-butyl peresters synthesis directly from aldehydes and TBHP was developed via Bu(4)NI-catalyzed aldehyde C-H oxidation. Mechanistic studies suggest that the protocol proceeds via a radical process. Combining the method with the Kharasch-Sosnovsky reaction offers a practical approach for the synthesis of allylic esters from simple aldehydes and alkenes via a two-step one-pot procedure.     

BF2-Chelates of N-Acylhydrazones as Versatile Coupling Partners in Photoredox Promoted Reactions

Five-membered difluoroboryl chelate complexes are competent substrates for radical reactions with various radical precursors including potassium trifluoroborates, bis(catecholato)siliconates, 4-alkyl-substituted Hantzsch esters, dihydroquinazolinones, esters of N-hydroxyphthalimide, Katritzky salts, alkyl iodides and thiols. Using these reagents, primary, secondary, and tertiary radicals can be generated under oxidative or reductive conditions and add at the C=N bond of the difluoroboryl chelates leading to hydrazide products.     

A practical method for preparation of 4-hydroxyquinolinone esters

4-Hydroxyquinolinone esters are a common motif for many medicinal agents. Several methods exist for preparation of these compounds, generally involving the use of sodium hydride, which raises significant safety issues and limits their application to large-scale synthesis. In this note a practical, safe, and general method that employs a combination of diisopropylethylamine and sodium tert-butoxide is described. This allows for the synthesis of 4-hydroxyquinolinone esters and amides in good yields.     

A convenient route to 4-carboxy-4-anilidopiperidine esters and acids

The route selection and development of a convenient synthesis of 4-carboxy-4-anilidopiperidines is described. Previous routes were hampered by the low yield of the target esters as well as the inability to convert the esters to the required free acids. Considerations for large-scale production led to a modified synthesis that utilised a tert-butyl ester of 4-carboxy-4-anilidopiperidines which resulted in a dramatic increase in the overall yield of the target N-propionylated- 4-anilidopiperidine-4-carboxylic acids and their corresponding methyl esters. These compounds are now available for use as precursors and reference standards, of particular value for the production of 11C and 18F-labelled 4-carboxy-4-anilidopiperidine radiotracers.     

Facile Construction of Quinoline‐2‐carboxylate Esters through Aerobic Oxidation of Alkyl 4‐Anilinocrotonates Induced by a Radical Cation Salt

A facile construction of quinoline‐2‐carboxylate esters through an aerobic oxidation of alkyl 4‐anilinocrotonates is described. In the presence of dioxygen, sp³ C−H bonds in 4‐anilinocrotonates can easily be oxidized by using a catalytic amount of a radical cation salt, providing a radical intermediate. After further oxidation and domino cyclization, the desired quinoline derivatives were afforded in high yields. This reaction provides a new way to construct the pharmaceutically relevant quinoline skeleton, avoiding harsh reaction conditions and tedious starting material synthesis.     

Photoinduced electron-transfer reaction of α-bromomethyl-substituted benzocyclic β-keto esters with amines: selective reaction pathways depending on the nature of the amine radical cations

Photoinduced electron-transfer reaction of α-bromomethyl-substituted benzocyclic β-keto esters with tertiary amines was investigated. Debrominated β-keto esters and ring-expanded γ-keto esters were obtained as major products. On the basis of mechanistic experiments it was concluded that these products are formed via a reaction sequence of selective carbon–bromine bond cleavage and subsequent competitive hydrogen abstraction and Dowd–Beckwith ring-expansion of the resulting primary alkyl radicals. The characteristic product distribution observed for the type of amine used is rationalized on the basis of selective reaction pathways of generated radical intermediates that depend on the nature of the amine radical cations.     

The synthesis and transition temperatures of ester derivatives of 2-fluoro-4-hydroxy- and 3-fluoro-4-hydroxybenzonitriles also incorporating aliphatic ring systems

The synthesis and liquid-crystal transition temperatures of forty ester derivatives of 2-fluoro-4-hydroxybenzonitrile and 3-fluoro-4-hydroxybenzonitrile are reported. The esters contain the trans-1,4-disubstituted cyclohexane or the 1,4-disubstituted bicyclo[2.2.2]octane rings (some contain an additional phenyl ring). Many of the novel F-substituted esters exhibit substantially higher nematic-isotropic transition temperatures than the corresponding unsubstituted esters. The order of clearing points of these laterally substiuted esters differing only in the presence of a benzene ring and the above-mentioned rings id established.     

The synthesis and liquid crystal properties of some 4-n-nonylphenyl esters of 3-(4'-n-alkoxybiphenylyl)- and 3-(4'-n-alkoxybiphenylyl)-3-methyl-propanoic acids and their laterally fluorinated analogues

A number of 4-n-nonylphenyl esters and mono- and di-fluorinated 4-n-nonylphenyl esters derived from 3-(4'-n-alkoxybiphenylyl)propanoic acids (II) have been synthesized and their thermotropic liquid crystal properties assessed with a view to obtaining tilted smectic phases for possible use in ferroelectric display devices. Many of these compounds exhibit wide temperature range S_C and S_I/F phases, but none gave the ideal phase sequence S_C-S_A-N-I mainly because the structure of these compounds was not conducive to the formation of the nematic phase. To try to alleviate this problem a series of 4-n-nonylphenyl esters based on 3-(4'-n-alkoxybiphenylyl)-3-methylpropanoic acid was prepared, where a lateral methyl group was incorporated in the β-position of the -CH₂CH₂CO₂- linkage. Incorporation of the lateral methyl group encouraged the formation of a nematic phase at the expense of both the smectic A phase and tilted smectic phases.     

Reaction of 2-trifluoromethyl-4H-3,1-benzoxazin-4-one derivatives with carboethoxymethylenetriphenylphosphorane

Treatment of a series of 2-trifluoromethyl-4H-3,1-benzoxazin-4-one derivatives 1 with carboethoxymethyl-enetriphenylphosphorane 2 yielded the phosphoranes 3 in boiling toluene solution. Thermolysis of these phosphoranes 3 gave esters 6.     

DPPH (= 2,2‐Diphenyl‐1‐picrylhydrazyl = 2,2‐Diphenyl‐1‐(2,4,6‐trinitrophenyl)hydrazyl) Radical‐Scavenging Reaction of Protocatechuic Acid Esters (= 3,4‐Dihydroxybenzoates) in Alcohols: Formation of Bis‐alcohol Adduct

Protocatechuic acid esters (= 3,4‐dihydroxybenzoates) scavenge ca. 5 equiv. of radical in alcoholic solvents, whereas they consume only 2 equiv. of radical in nonalcoholic solvents. While the high radical‐scavenging activity of protocatechuic acid esters in alcoholic solvents as compared to that in nonalcoholic solvents is due to a nucleophilic addition of an alcohol molecule at C(2) of an intermediate o‐quinone structure, thus regenerating a catechol (= benzene‐1,2‐diol) structure, it is still unclear why protocatechuic acid esters scavenge more than 4 equiv. of radical (C(2) refers to the protocatechuic acid numbering). Therefore, to elucidate the oxidation mechanism beyond the formation of the C(2) alcohol adduct, 3,4‐dihydroxy‐2‐methoxybenzoic acid methyl ester ( 4 ), the C(2) MeOH adduct, which is an oxidation product of methyl protocatechuate ( 1 ) in MeOH, was oxidized by the DPPH radical (= 2,2‐diphenyl‐1‐picrylhydrazyl) or o‐chloranil (= 3,4,5,6‐tetrachlorocyclohexa‐3,5‐diene‐1,2‐dione) in CD₃OD/(D₆)acetone 3 : 1). The oxidation mixtures were directly analyzed by NMR. Oxidation with both the DPPH radical and o‐chloranil produced a C(2),C(6) bis‐methanol adduct ( 7 ), which could scavenge additional 2 equiv. of radical. Calculations of LUMO electron densities of o‐quinones corroborated the regioselective nucleophilic addition of alcohol molecules with o‐quinones. Our results strongly suggest that the regeneration of a catechol structure via a nucleophilic addition of an alcohol molecule with a o‐quinone is a key reaction for the high radical‐scavenging activity of protocatechuic acid esters in alcoholic solvents.     

4'-substituted-4-biphenylyloxenium ions: reactivity and selectivity in aqueous solution

Azide trapping shows that the 4'-substituted-4-biphenylyloxenium ions 1b-d are generated during hydrolysis of 4-aryl-4-acetoxy-2,5-cyclohexadienones, 2c and 2d, and O-(4-aryl)phenyl-N-methanesulfonylhydroxylamines, 3b and 3c. In addition, the 4'-bromo-substituted ester, 2d, undergoes a kinetically second-order reaction with N3- that accounts for a fraction of the azide adduct, 5d. Since both first-order and second-order azide trapping occurs simultaneously in 2d, the second-order reaction is not enforced by the short lifetime of 1d, which has similar azide/solvent selectivity to the unsubstituted ion, 1a. In contrast the 4'-CN and 4'-NO2 ions 1e and 1f cannot be detected by azide trapping during the hydrolysis of the dichloroacetic acid esters 2e' and 2f' even though 18O labeling experiments show that a fraction of the hydrolysis of both esters occurs through C(alkyl)-O bond cleavage. These esters exhibit only second-order trapping by azide. Correlations of the azide/solvent selectivities of 1a-d with the calculated relative driving force for hydration of the ions (DeltaE of eq 4) determined at the pBP/DN//HF/6-31G and BP/6-31G//HF/6-31G levels of theory suggest that 1e and 1f have lifetimes in the 1-100 ps range. Ions with these short lifetimes are not in diffusional equilibrium with nonsolvent nucleophiles, and must be trapped by such nucleophiles via a preassociation mechanism. The second-order trapping that is observed in these two cases is enforced by the short lifetime of the cations, and may occur by a concerted S(N)2' mechanism or by internal azide trapping of an ion sandwich produced by azide-assisted ionization. Comparison of azide/solvent selectivities of the oxenium ions 1a-c with the corresponding biphenylylnitrenium ions 8a-c shows that 4'-substituent effects on reactivity in both sets of ions are similar in magnitude, although the nitrenium ions are ca. 30-fold more stable in an aqueous environment than the corresponding oxenium ions. The magnitude of the 4'-substituent effects for electron-donating substituents suggest that both sets of ions are more accurately described as 4-aryl-1-imino-2,5-cyclohexadienyl or 4-aryl-1-oxo-2,5-cyclohexadienyl carbocations. Calculated structures of the oxenium ions are also consistent with this interpretation.     

Synthesis and biological evaluations of some Schiff-base esters of ferrocenyl aniline and simple aniline

The synthesis and biological studies of some long chain esters containing Schiff bases and their ferrocenyl analogues were carried out. The 4-amino ferrocene was prepared by the reported method. Long chain esters were synthesized by the condensation of different aliphatic acids with the corresponding aldehyde. The esters were then reacted with aniline as well as with 4-aminophenyl ferrocene to give corresponding Schiff bases. All the synthesized compounds were analyzed by elemental, FTIR and proton NMR studies, were also investigated for a range of biological activities. Determined by crown gall tumor inhibition assay. Antioxidant and DNA protective activities were determined by DPPH free radical scavenging assay and OH radical induced oxidative DNA damage assay, respectively. Among all test compounds, o-hydroxy-p-n-octadecanoyloxy-benzylidine-p-ferrocenyl aniline (FA2.1: a ferrocene containing Schiff base) showed highest antitumor, DPPH free radical scavenging and DNA protective activities.     

Synthesis of some 2-alkyl-4-quinolone and 2-alkyl-4-methoxyquinoline alkaloids

Acid-catalyzed condensation of a series of 3-oxoalkanoic acid esters with aniline affords the corresponding 2-alkyl-4-quinolones in good yield. Treatment of these compounds with methyl iodide affords 2-alkyl-4-methoxyquinolines and 2-alkyl-N-methylquinolones. Three of the compounds are naturally-occurring alkaloids which are synthesized here for the first time.     

Some novel liquid crystalline derivatives of 4-carboxyphthalimide

A series of novel esters of 4-carboxyphthalimides has been prepared. Differential scanning calorimetry and polarizing optical microscopy studies reveal that N-substituted 4-cholesteryloxycarboxyphthalimides exhibit a chiral nematic (cholesteric) phase in the range 120-205°C. Unexpectedly, esters containing well-known mesogenic groups such as 4-cyano- or 4-methoxy-phenyl do not form liquid crystal phases.