Photogeneration of 2-Deoxyribonolactone in Benzophenone−Purine Dyads. Formation of Ketyl−C1′ Biradicals (original) (raw)
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Photochemistry and Photobiology, 1994
Irradiation of ketoprofen in neutral aqueous medium gave rise to 3-ethylbenzophenone as the major photoproduct. Its formation is justified via protonation of a benzylic carbanion or hydrogen abstraction by a benzylic radical. Minor amounts of eight additional compounds were isolated. Four of them are derived from the benzylic radical: 34 1 -hydroperoxyethyl)benzophenone, 3-( 1 -hydroxyethyl)benzophenone, 3-acetylbenzophenone and 2,3-bis-(3-benzoy1phenyl)butane. The other four products involve initial hydrogen abstraction by the excited benzophenone chromophore of ketoprofen: 1,2-bis-(3-ethyIphenyl)-1,2-diphenyl-1,2-ethanediol, 2-(3-benzoylphenyl)-1 -(3-ethyl-pheny1)-1 -phenylpropan-1-01, cu-(3-ethylphenyl)phenylmethanol, 1,2-bis-[3-(2-hydroxycarbonylethyl)phenyl]-1,2-diphenyl-I ,2-ethanediol. The latter process was found to mediate the photoperoxidation of linoleic acid through a type I mechanism, as evidenced by the inhibition produced by the radical scavengers butylated hydroxyanisole and reduced glutathione. The major photoproduct, which contains the benzophenone moiety but lacks the propionic acid side chain, also photosensitized linoleic acid peroxidation. Because lipid peroxidation is indicative of cell membrane lysis, the above findings are highly relevant to explain the photobiological properties of ketoprofen.
J Am Chem Soc, 1979
Although the photochemical behavior of the carbonyl group has received much scrutiny in the past d e~a d e ,~.~ relatively little is known about the photochemistry of the small amount of enol tautomer which exists in equilibrium with the keto In an earlier reportS dealing with the photorearrangement of 4-phenyl-3-chromanone (1) to 4-phenyldihydrocoumarin (2),6 evidence was presented which demonstrated that the enol content can be an overriding factor in determining the quantum efficiency of a photoreaction. As part of our continuing studies dealing with enol photoc h e r n i~t r y ,~~~ we have undertaken an investigation of the excited state behavior of the 4-carbomethoxy-3-chromanone (3) system. W e now report that in extending our studies to this system, we have discovered an unusual solvent effect which controls the product distribution. In addition, we have uncovered a n unprecedented photodecarbonylation reaction which can best be explained by invoking the intermediacy of a transient cyclopropanone.
Benzophenone photochemistry and Repercussions on ketoprofen’s pharmacovigilance
2018
Ketoprofen (KTP), a prominent member of the AINS arylpropionic acids is known for inducing photosensitized skin reactions, especially after topical administration. In this connection, the dispensation of Ketum gel in France was suspended for a time in 2009. Within this context, MOCL (Medicinal Organic Chemistry Laboratory) realm of activities has been dedicated over the last decade or so, to fostering drug science through the discovery of new chemical entities of therapeutic relevance with a special accent on sustainable development and green chemistry, basing its main approach on biodiversity, green chemistry and development of hemisynthetic processes, using biometric catalysis. Photochemistry is especially suited for this purpose and easily amenable to green chemistry. Along this line, the photochemical behavior of benzophenone and some structurally related analogs was studied to discover which photochemical events are responsible of the photosensibilization sideeffects noted for ...
Articles Mechanism of Photoinduced Decomposition of Ketoprofen
UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen. a Abbreviations: NSAID, nonsteroidal antiinflammatory drug; KP, ketoprofen; ROS, reactive oxygen species; ISC, intersystem crossing; DFT, density functional theory; CNDO/S, complete neglect of differential overlap-singles excitations; ZPE, zero-point vibrational energy; IEFPCM, integral equation formalism of the polarized continuum model; TD-DFT, time-dependent density functional theory; LDA, local density approximation.
Photochemical decomposition of 1-alkoxy-2-azidophenazines. Addition of nitrenes to azides
J Org Chem, 1991
literature data.% IR and HRMS could not be taken, due to the instability of this compound. Ethyl 3 4 l-Hydroxypropyl)-2,4-pentadienoate ((E)-l8b) and Corresponding Lactone (Z)-lBb. The above procedure, using 796.0 mg (2.78 mmol) of l-(phenylsulfinyl)-2,2,2-triethoxyethane,' 137.5 mg (1.40 "01) of hexa-2,3-dien-l-ol, a catalytic amount of 2,4,6-trimethylbenzoic acid, and 2.0 mL of methylene chloride, yielded a crude mixture of (E)-l8b and (Z)-18b (31) as a brown oil. Subsequent purification via short-path column chromatography (silica gel, eluting solvent diethyl ether/ pentane (1:199,1:49, 1:9,1:4)) followed by purification via PTLC (2 X 1500 pm, eluting solvent diethyl ether/hexanes (1.51), extraction Hz, 1 H). '3C NMR (CDCl3) 6 14.2,60.0,62.5, 116.1,119.5, 131.5, solvent methylene chloride) yielded compounds (Q-18b (74.2 mg, 29%) as a yellow oil and (2)-18b (23.7 mg, 12%) 88 a yellow oil. Ester (E)-18b IR (CHCI,, cm-') 3601,3519 (br), 1702; ' H Nh4R (m, 2 H), 1.80 (m, 1 H), 4.18 (qd, J = 7.2,2.3 Hz, 2 H), 4.61 (m,
Photochemical dehydrogenation of 3,4-dihydro-2-pyridones
Photochemical & Photobiological Sciences, 2009
Photochemical dehydrogenation of various substituted 3,4dihydro-2-pyridones was achieved in a very efficient way by employing 10-15 mol% of photo-induced electron transfer sensitizers like 9-cyanoanthracene, 9-cyanophenanthrene and 1-cyanonaphthalene in presence of molecular oxygen, for the first time. The 2-pyridone nucleus is the building block for a wide variety of bioactive molecules. 1 The functionalized 2-pyridones are of significant interest in medicinal chemistry and are being used as antibiotic, 2 antifungal, 3 antiviral, 4 antitumor, 5 anti-HIV, 6 psychotherapeutic 7 and cardiotonic agents. 8 A number of methods are available in literature for the synthesis of 2-pyridones. 9-11 The dehydrogenation of 3,4-dihydro-2-pyridones (3,4-DH-2-P) to get 2-pyridones seems to be a very significant reaction for organic chemists and quite a large number of methods are available. 12,13 But almost all the methods suffer from both the use of drastic conditions and poor yields. Strong oxidants like H 2 SO 4 , 12a HNO 3 , 12b CrO 3-acetic acid, 12c DDQ, 12d MnO 2 12d were used under refluxing conditions to bring about the transformation in moderate to good yield. NBS-peroxide assisted transformation, 13a metal catalysts like Cu(OAc) 2-Pb(OAc) 4 , 13a Pd-C 13b gave only 30-50% of the dehydrogenated product. There is no photochemical approach for that dehydrogenation process although the photochemistry of pyridones have been studied. 14-15 In continuation of our work on the synthesis of heterocycles 16 and photochemical studies, 17 here we describe a very simple and efficient way for the photochemical dehydrogenation of various substituted 3,4-dihydro-2-pyridones to get 2-pyridones in excellent yields using photoinduced electron transfer (PET) sensitizers like 9-cyanoanthracene (9-CA), 9-cyanophenantherene (9-CP) and 1-cyanonapthalene (1-CN). Initially, we have prepared highly substituted 3,4-DH-2-P (1-7) by treating the enaminoesters/enaminonitriles with acrylates in the presence of sodium hydride at room temperature, and 8-9 as reported by Smirez et al. 18 Thus synthesized 3,4-DH-2-Ps were then subjected to photochemical dehydrogenation using different PET sensitizers 19,20 (Scheme 1; Table 1). A solution of 3,4-DH-2-P 1 (2 mmol) and PET sensitizer (10 mol%) 21 dissolved in acetonitrile (25 mL) was irradiated with 450 W medium pressure Hg lamp (Pyrex filter) under aerated conditions. ‡ The progress of the reaction can be conveniently monitored by GC (Fig. 1). 22 The product 2-pyridone 10 was isolated in excellent yield (Table 1) and there was no side reaction to be identified.
Organic Letters, 2003
Air-and moisture-sensitive reactions were performed in flame-dried round bottom flasks fitted with rubber septa under a positive pressure of argon. Air-and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation below 35 ºC at ca. 20 mm Hg. Flash column chromatography was performed as described by Still et al. employing silica gel Merck 60 (230-400 mesh). 1 Thin layer chromatography was performed using aluminum plates with silica gel Merck 60 F 250. Materials. Commercial reagents and solvents were used as received with the following exceptions: THF was distilled from sodium/benzophenone; dichloromethane was distilled from P 2 O 5 ; triethylamine and diisopropylamine were distilled from calcium hydride; pyridine was distilled from KOH. The molarity of n-butyllithium solutions was determined by tritation using diphenylacetic acid as an indicator. Instrumentation. Proton and carbon-13 nuclear magnetic resonance (1 H NMR or 13 C NMR) spectra were recorded with a Bruker AM500 (500 MHz), a Bruker WM250 (250 MHz) or a Varian (200 MHz) NMR spectrometer; chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent. Melting points were recorded with a Büchi apparatus and are uncorrected. Mass spectra (MS) and High Resolution Mass Spectra (HRMS) were recorded with a Kratos MS-50 and a Hewlett Packard 59970MS spectrometer, using Electronic Impact (EI, 75 eV) or FAB with Xe 0 using 2-methoxyethyl disulfide as matrix. Experimental Section Preparation of starting tosylstilbenoids: p-Anisaldehyde, 3,4,5-trimethoxybelzaldehyde and p-tolualdehyde were purchased from Aldrich Co, and used without purification. Methyl N-methoxymethyl-4-(p-tosylmethyl)pyrrole-2-carboxylate was prepared according to a published procedure. 2 p-Methoxybenzyl p-tolyl sulfone and p-methylbenzyl p-tolyl sulfone were synthesised using Otto´s method. 3 Tosylstilbenoids 11 and 15 were obtained by condensation of aldehydes with benzyl sulfones. 4 5-[1-Hydroxy-2-[4-(methoxycarbonyl)-1-(methoxymethyl)-1H-pyrrole-2-yl]-2-[(4-methylphenyl)sulfonyl]ethyl]-1-methyl-1H-pyrrole-3carboxylic acid, methyl ester was prepared by the condensation of a sulfonyl α-anion with a pyrrole carbaldehyde. 5
Journal of Chemical Crystallography, 2010
The title compounds C 11 H 16 Cl 2 O 3 (III) and C 11 H 16 Br 2 O 3 (IV) have been prepared from (S)-Limonen. Their crystal structure and absolute configuration have been determined by X-ray analysis which confirmed the 1 0 S absolute configuration at the cyclopropyl moiety, in agreement with the known absolute configuration of the starting material. Both (III) and (IV) are orthorhombic, space group P2 1 2 1 2 1 with a = 7.2558(4) Å (for III) 7.4058(6) Å (for IV), b = 9.7885(5) Å (for III) 9.7459(7) Å (for IV), c = 17.7551(10) Å (for III) 18.0354(14) Å (for IV), a = 90°, b = 90°, c = 90°and Z = 4.
Photochemistry and Photobiology, 1998
Diclofenac and meclofenamic acid are two structurally related nonsteroidal anti-inflammatory drugs with some photosensitizing potential. Their photochemistry involves cyclization to monohalogenated carbazoles. In principle, photocyclization could occur by photodehalogenation, followed by intramolecular radical addition, or by 6.rr electrocyclization and subsequent dehydrohalogenation of the intermediate dihydrocarbazoles. Previously, it has been assumed that the reaction follows the first pathway and that the key species associated with phototoxicity are the resulting aryl radicals. In the present work, we have performed photophysical and photochemical studies on 2,6-dichlorodiphenylamine (la). This is a suitable model compound because since it contains the active chromophore present in diclofenac and meclofenamic acid, and its photoreactivity should be relevant to the understanding of the photobiological properties of both drugs. Our results clearly show that the first photochemical reaction is a very rapid 6a-electrocyclization, and hence no radicals are formed at this stage. Instead, cleavage of the carbon-halogen bond occurs in the l-chlorocarbazole photoproduct 2a. The reduced lifetime of the 2a triplet (as compared with the unsubstituted carbazole) and the observed reaction quenching by oxygen are in agreement with the reaction occurring from the excited triplet state. Overall, the above results suggest that the potential phototoxicity of diclofenac and meclofenamic acid is due to a photobiologically active photoproduct that is able to generate radicals upon photolysis, rather than to the parent drug.