Photochemical Reactions. Part 67. photochemistry of saturated aliphatic and cyclic β-keto sulfoxides (Cα?S)- and α-cleavage – A new case of photostereomutation

The photochemical behaviour of saturated aliphatic ( 2, 4 , and 5 ) and bicyclic ( 18 and 19 ) β-keto sulfoxides has been studied. Photostereomutation of the sulfoxide group was observed on irradiation of 4a, 4b, 18 , and 19 . Most likely an internal energy transfer from the excited carbonyl to the sulfoxide group is operating on direct irradiation of such compounds. Prolonged photolysis of an aliphatic β-keto sulfoxide, which is nonalkylated a t the α-carbon ( 2 ), yielded a product due to preferential (C_α-S)-cleavage ( 24 ). Mono- ( 4 ) and dialkylated- ( 5 , 6 , and 8 )analogues primarily afforded products due to α-cleavage ( 26–31 and 32 ). The carboxylic acid S-methylesters ( 26–31 ) were exclusively formed by an intermolecular path. Prolonged irradiation of the bicyclic β-keto sulfoxides 18 and 19 favored the formation of a desulfurized compound 34 due to initial ( C_α-S )-cleavage.     

Polarographic study of alkyl benzimidazolyl sulfoxide and the corresponding suldife and sulpfone

2-(5-Methylbenzimidazolyl) 1-(2-pyridyl)ethyl sulfide, 2-(5-methylbenzimidazolyl) 1-(2-pyridyl)ethyl sulfoxide and 2-(5-methylbenzimidazolyl) 1-(2-pyridyl-1-oxide)ethyl sulfone are reduced at a dropping mercury electrode in aqueous ethanol. Coulometric experiments at a mercury pool prove that 2-ethylpyridine and 2-mercapto-5-methylbenzimidazole are formed in the reduction process of the sulfide and the sulfoxide. Coulometric reduction of the sulfone results in some conversion of the pyridine-1-oxide group together with a reductive fission of the ethyl—sulfonyl bond. One of these fission products methyl undergoes secondary reactions. The concentration of 2-benzimidazolyl 2-pyridyl methyl sulfoxide in a pharmaceutical formulation has been determined by differntial pulse polarogarphy.     

Photosensitized oxidation of alkyl phenyl sulfoxides. C-S bond cleavage in alkyl phenyl sulfoxide radical cations

The 3-cyano-N-methylquinolinium perchlorate (3-CN-NMQ(+)ClO4(-))-photosensitized oxidation of phenyl alkyl sulfoxides (PhSOCR1R2R3, 1, R1 = R2 = H, R3 = Ph; 2, R1 = H, R2 = Me, R3 = Ph; 3, R1 = R2 = Ph, R3 = H; 4, R1 = R2 = Me, R3 = Ph; 5, R1 = R2 = R3 = Me) has been investigated by steady-state irradiation and nanosecond laser flash photolysis (LFP) under nitrogen in MeCN. Steady-state photolysis showed the formation of products deriving from the heterolytic C-S bond cleavage in the sulfoxide radical cations (alcohols, R1R2R3COH, and acetamides, R1R2R3CNHCOCH3) accompanied by sulfur-containing products (phenyl benzenethiosulfinate, diphenyl disulfide, and phenyl benzenethiosulfonate). By laser irradiation, the formation of 3-CN-NMQ(*) (lambda(max) = 390 nm) and sulfoxide radical cations 1(*+) , 2(*+), and 5(*+) (lambda(max) = 550 nm) was observed within the laser pulse. The radical cations decayed by first-order kinetics with a process attributable to the heterolytic C-S bond cleavage leading to the sulfinyl radical and an alkyl carbocation. The radical cations 3(*+) and 4(*+) fragment too rapidly, decaying within the laser pulse. The absorption band of the cation Ph2CH(+) (lambda(max) = 440 nm) was observed with 3 while the absorption bands of 3-CN-NMQ(*) and PhSO(*) (lambda(max) = 460 nm) were observed just after the laser pulse in the LFP experiment with 4. No competitive beta-C-H bond cleavage has been observed in the radical cations from 1-3. The C-S bond cleavage rates were measured for 1(*+), 2(*+), and 5(*+). For 3(*+) and 4(*+), only a lower limit (ca. >3 x 10(7) s(-1)) could be given. Quantum yields (Phi) and fragmentation first-order rate constants (k) appear to depend on the structure of the alkyl group and on the bond dissociation free energy (BDFE) of the C-S bond of the radical cations determined by a thermochemical cycle using the C-S BDEs for the neutral sulfoxides 1-5 obtained by DFT calculations. Namely, Phi and k increase as the C-S BDFE becomes more negative, that is in the order 1 < 5 < 2 < 3, 4, which is also the stability order of the alkyl carbocations formed in the cleavage. An estimate of the difference in the C-S bond cleavage rate between sulfoxide and sulfide radical cations was possible by comparing the fragmentation rate of 5(*+) (1.4 x 10(6) s(-1)) with the upper limit (10(4) s(-1)) given for tert-butyl phenyl sulfide radical cation (Baciocchi, E.; Del Giacco, T.; Gerini, M. F.; Lanzalunga, O. Org. Lett. 2006, 8, 641-644). It turns out that sulfoxide radical cations undergo C-S bond breaking at a rate at least 2 orders of magnitude faster than that of corresponding sulfide radical cations.     

Synthesis and characterization of ruthenium(ii) complexes of 5-hydroxyflavones

Bis(dimethyl sulfoxide)bis(flavonato)ruthenium(II) complexes, RuL₂(DMSO)₂, were synthesized by the reaction of dichlorotetrakis(dimethyl sulfoxide)ruthenium(II) with the sodium salts of 5-hydroxyflavone, 5-hydroxy-4′-methoxyflavone and 5-hydroxy-3′,4′,5′,7-tetramethoxyflavone, ( L ). The complexation was followed by ¹H nmr spectroscopy. The 1:1 kinetically favoured tris(dimethyl sulfoxide)chloroflavonatoruthenium(II) complexes, RuLCl(DMSO)₃, were initially formed and then transformed into the thermodynamically more stable ones. Each one of these complexes, by reacting with another equivalent of lig-and L, also gave rise to a mixture of 1:2 kinetic species, from which the 1:2 thermodynamically more stable bis(dimethyl sulfoxide)bis(flavonato)ruthenium(II) complexes, RuL₂(DMSO)₂, were formed. The complexes were characterized by extensive studies involving ¹H, ¹³C nuclear magnetic resonance, infrared and ultraviolet-visible spectroscopy, mass spectrometry, cyclic voltammetry and elemental analysis. Such 1:2 complexes exhibited properties of two nonequivalent flavonate ligands and also of two non-equivalent dimethyl sulfoxide ligands; one of these dimethyl sulfoxide ligands is considered to be S-bonded and the other O-bonded. Also two quasireversible one-electron redox steps were observed at 0.53 to 0.57 and 0.44 to 0.41 V (vs Saturated Calomel Electrode). The spectroscopic results obtained allow for the discussion of stereochemistry of each bis(dimethyl sulfoxide)bis(flavonato)ruthenium(II) complex and to postulate its possible structure as one corresponding to the more anisochronous species.     

Intriguing Influence of the Solvent on the Regioselectivity of Sulfoxide Thermolysis in β‐Amino‐α‐sulfinyl Esters

The sulfoxide thermolysis of the diastereoisomeric methyl (3R,4aS,10aR)‐6‐methoxy‐1‐methyl‐3‐(phenylsulfinyl)‐1,2,3,4,4a,5,10,10a‐octahydrobenzo[g]quinoline‐3‐carboxylates 3a and 3′b in toluene yields, by loss of benzenesulfenic acid, an almost 1 : 1 mixture of the vinylogous urethane 2b and the isomeric α‐aminomethyl enoate 2a . When this elimination is performed in acetic acid, the enoate 2a is formed rather selectively. The same solvent effects on the regioselectivity of the elimination of benzenesulfenic acid are observed with a simple sulfoxide of ethyl piperidine‐3‐carboxylate ( 7 ).     

Alkatrienyl Sulfoxides and Sulfones. Part I. 3-Methyl-1,2,4-pentatrienyl Phenyl Sulfoxide-Synthesis and Electrophile-Induced Cyclization Reactions

A method for the synthesis of the 3-methyl-1,2,4-pentatrienyl phenyl sulfoxide 3 by [2,3]-sigmatropic rearrangement of the 3-methyl-1-penten-4-yn-3-yl benzenesulfenate 2 , formed in the reaction of the 3-methyl-1-pentene-4-yn-2-ol 1 with phenylsulfenyl chloride has been created. Possibilities and restrictions of the five-membered heterocyclization in electrophile-induced reactions leading to the synthesis of the 5H-1,2-oxathiol-2-ium salts 5 , 7 , and 8 have been explored. Chlorination of the sulfoxide 2 proceeded with formation of the (E)-2-chloro-3-methylene-1,4-pentadienyl phenyl sulfoxide 4 , while the bromination afforded the 4-bromo-5H-1,2-oxathiol-2-ium bromide 5 , which after reflux in 1,2-dichloroethane eliminated hydrogen bromide and was transformed into the (E)-2-bromo-3-methylene-1,4-pentadienyl phenyl sulfoxide 6 .     

Reactive oxygen species produced upon photoexcitation of sunscreens containing titanium dioxide (an EPR study)

Commercial sunscreen products containing titanium dioxide were irradiated with lambda>300 nm and the formation of oxygen- (.OH, O2.-/.OOH) and carbon-centered radicals was monitored by EPR spectroscopy and spin trapping technique using 5,5-dimethyl-1-pyrroline N-oxide, alpha-phenyl-N-tert-butylnitrone (PBN), alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone as spin traps, and free nitroxide radical 4-hydroxy-2,2,6,6-tetramethylpiperidine N-oxyl. The photoinduced production of singlet oxygen was shown by 4-hydroxy-2,2,6,6-piperidine. The generation of reactive oxygen radical species upon irradiation of sunscreens significantly depends on their composition, as the additives present (antioxidants, radical-scavengers, solvents) can transform the reactive radicals formed to less harmful products. The continuous in situ irradiation of titanium dioxide powder, recommended for cosmetic application, investigated in different solvents (water, dimethyl sulfoxide, isopropyl myristate) resulted in the generation of oxygen-centered reactive radical species (superoxide anion radical, hydroxyl and alkoxyl radicals).     

The photochemistry of 6‐phenanthridinecarbonitrile I. Product analysis

When 6‐phenanthridinecarbonitrile ( 3 ) is irradiated at 2537 Å in neutral 9:1 2‐propanol/water, three major products are formed. These are dimethyl‐(6‐phenanthridinyl)methanol ( 4 ), phenanthridine ( 5 ) and 6,6′‐biphenanthridine ( 6 ). When benzophenone is present in the reaction mixture, diphenyl‐(6‐phenanthridinyl)‐methanol is also formed. 6‐Phenanthridinyl radical which is common to the formation of all these products, is formed by a monophotonic process involving hydrogen atom abstraction from an alcohol molecule by an excited state of 3 . Unlike what is generally found with other nitrogen‐heterocycles, the photochemistry of 3 appears to involve only a π,π* singlet state. The fluorescence of 3 is quenched with the triplet quencher cis/trans‐piperylene as a function of the concentration of the diene without the accompaniment of an exci‐plex emission.     

Approaches to 1H-Cyclopropa[l]phenanthrenes. Eliminations with 1a,9b-Dihydro-1H-cyclopropa[l]phenanthrene Derivatives

Base-induced elimination of the sulfonium salt 2i in the presence of furan affords the addition products 7 and 8 , derived from 1H-cyclopropa[l]phenanthrene ( 1 ) and the isomeric cyclopropene 5a (Scheme 3). Upon oxidation, the selenide 2c yields phenanthrene-9-methanol ( 9 ), presumably via 1 . No evidence for the intermediate 1 is obtained from sulfoxide pyrolysis with 2e , which leads to products formed by radical pathways (Scheme 5). Reductive elimination of the disulfone 3b gives half-reduction to monosulfone 2g and complete reduction to cyclopropane 2 as well as 9-methylphenanthrene ( 15 ), but no evidence for the intermediate 1 .     

Prior ligand exchange,followed by ligand coupling in the reaction of 2-pyridyl 2-thienyl sulfoxide with 2-thienyllithium or 2-selenophenyllithium

2-Pyridyl 2-thienyl sulfoxide was found to react with variously substituted 2-thienyllithiums and 2-selenophenyllithium, exclusively affording 2-(2-pyridyl)thiophenes and 2-(2-pyridyl)-selenophene and the disulfides derived from the substituted thiophenes and selenophene. Apparently, ligand exchange precedes ligand coupling. The coupling product always involved the pyridine nucleus, but no bithienyl-type products were formed.     

Natural phenolic compounds in the reaction with a nitrogen-centered radical in an aprotic solvent

Kinetics and mechanism of the reaction of vegetable phenols (PhOH) with 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH?) in a polar aprotic solvent, dimethyl sulfoxide, were studied. The reaction of natural phenols with DPPH? in dimethyl sulfoxide occurs in two stages. In the first stage, a proton-coupled electron transfer (PCET) occurs from a PhOH molecule to DPPH? to give primary transformation products, phenoxyl radicals (PhO?) and diphenyl hydrazine (DPPH–H), and in the second, the hydrazyl radical is consumed in the reaction with PhO? transformation products, enolized dimers, which is confirmed by NMR spectroscopy. A relationship was revealed between the antiradical activity of phenols in the reaction with DPPH? (ln k) and the ionization potential of the phenolates being formed.     

S-demethylation of nitrogen heterocycles

When 3-chloro-4,5-diaminopyridazine ( 2 ) was treated with sodium methylmercaptide in refluxing N,N-dimethylformamide, two heterocycles were formed and isolated, neither of which was the expected 3-methylthio-4,5-diaminopyridazine ( 3 ). A thorough spectral analysis of these heterocycles showed them to be 4-methylthioimidazo[4,5-d]pyridazine ( 5 ) and imidazo[4,5-d]pyridazine-4-thione ( 6 ). N,N-Dimethylformamide was found to provide the one carbon unit required for the formation of 5. The origin of 6 was shown to be a result of S-demethylation of 5. S-Demethylation of 3 could also be effected with sodium methylmercaptide in methyl sulfoxide without the occurrence of annulation. In methyl sulfoxide the process of demethylation was accelerated and occurred at lower temperature.     

Efficient Synthesis of Tetrahydropyrimidines and Pyrrolidines by a Multicomponent Reaction of Dialkyl Acetylenedicarboxylates (=Dialkyl But‐2‐ynedioates), Amines,and Formaldehyde in the Presence of Iodine as a Catalyst

Iodine was explored as an efficient catalyst for the synthesis of tetrahydropyrimidines 4 and pyrrolidines 5 by a multicomponent reaction of dialkyl acetylenedicarboxylates (=dialkyl but‐2‐ynedioates) 1 , amines 2 , and HCHO 3 at room temperature (Scheme). When the molar ratios of these substrates were 1 : 2 : 4 and 1 : 1 : 4, tetrahydropyrimidines and pyrrolidines were formed, respectively. The products were obtained in high yields (73–85%) within a short period of time (25–35 min).     

Inclusion of volatile guests by a tetrapedal host: structure and kinetics

The host compound tetra(3-hydroxy-3,3-diphenyl-2-propynyl)ethene, TET, forms inclusion compounds with acetone, dimethyl sulfoxide, dioxane and pyridine. All the structures were successfully solved in the triclinic space group P1[combining macron]. We found variable host : guest ratios for the acetone (TET.ACE, H : G = 1 : 4), dimethyl sulfoxide (TET.DMSO, H : G = 1 : 4) and pyridine compounds (TET.PYR, H : G = 1 : 5). Solutions of the host compound and dioxane formed TET.2DIOX, H : G = 1 : 2 when left to crystallise at room temperature, whereas TET.4DIOX, H : G = 1 : 4 was formed during crystal growth at low temperature. We have correlated the structures with their thermal stabilities and kinetics of desolvation.     

Reaction of 5-amino-1-phenylpyrazole-4-carbonitriles with dimethyl acetylenedicarboxylate. Synthesis and structural determination of trimethyl 4,8-dioxo-1-phenyl-4,5,5a,8-tetrahydro-1H-pyrazolo[3,4-e]indolizine-5,5a,6-tricarboxylate derivatives

The reaction of 5-amino-1-phenylpyrazole-4-carbonitriles 1a-c with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave trimethyl 4,5,5a,8-tetrahydro-1-phenyl-4,8-dioxo-1H-pyrazolo[3,4-e]indolizine-5,5a,6-tricarboxylate derivatives 3a-c from the basic solution. The products were formed by a double Michael reaction of 1 with dimethyl acetylenedicarboxylate followed by cyclization to the cyano group. The structure of product 3a was established by X-ray crystallography.     

Novel heterocycles. 10. Reactions of 1,3,2-benzodiazaphosphorin-4(1H)-one 2-oxides

Reactions of 1,3-disubstituted-2,3-dihydro-1,3,2-benzodiazaphosphorin-4 (1 H)-one 2-oxides ( 1 ) with various electrophiles were investigated. The treatment of 1 with aldehydes in the absence of a basic catalyst directlyafforded alcohols 7a-h in good yield. The product from the reaction of 1 with chloral, on treatment with sodium hydride, resulted in the formation of a dichloroepoxide ( 8 ). When 1 was allowed to react with isocyanates or isothiocyanates in the presence of triethylamine, amides 10a-e and thioamide 11 were produced in good yield. Compounds 1a and 1b were readily halogenated on their phosphorus atom by treatment with either carbon tetrachloride or carbon tetrabromide and triethylamine. The P-chloro compound 12a reacted with ethanol to furnish the P-ethoxy derivative 13 and, in an attempt to react 12a with bis (2-chloroethyl) amine, anhydride 14 was formed in high yield. Spectral data for the majority of the products are also discussed.     

Addition of cyclopropyl alkynes to a Brook silene: definitive evidence for a biradical intermediate

The addition of three newly developed mechanistic probes, (trans-2-phenylcyclopropyl)ethyne, (trans,trans-2-methoxy-3-phenylcyclopropyl)ethyne, and (trans,trans-2-methoxy-1-methyl-3-phenylcyclopropyl)ethyne, 1a-c, to a Brook silene, 2-tert-butyl-2-trimethylsiloxy-1,1-bis(trimethylsilyl)-1-silene, 10, was examined. When alkyne 1a was added to silene 10 products derived from a formal ene reaction were obtained. When alkynes 1b-c were added to silene 10, in addition to the typical silacyclobutenes, a variety of silacycloheptenes were obtained in which the cyclopropyl ring had clearly opened. Formal ene-addition products were also produced from the addition of 1b to 10. Based on the relative positions of the phenyl and methoxy substituents within the seven-membered ring of the silacycloheptenes and the known behavior of the alkyne probes under both radical and ionic conditions, it was concluded that a biradical intermediate was formed during the addition of alkynes 1b-c to silene 10. In the addition of alkynes 1a-b to silene 10, the ene products are most likely formed by a competitive pericyclic reaction. We also present a straightforward method for the unambiguous determination of the regiochemistry of silacyclobutenes derived from the cycloaddition of terminal alkynes to silenes.     

Dioxygenase-catalysed oxidation of monosubstituted thiophenes: sulfoxidation versus dihydrodiol formation

Toluene dioxygenase (TDO)-catalysed sulfoxidation, using Pseudomonas putida UV4, was observed for the thiophene substrates 1A-1N. The unstable thiophene oxide metabolites, 6A-6G, 6K-6N, spontaneously dimerised yielding the corresponding racemic disulfoxide cycloadducts 7A-7G, 7K-7N. Dimeric or crossed [4 + 2] cycloaddition products, derived from the thiophene oxide intermediates 6A and 6D or 6B and 6D, were found when mixtures of thiophene substrates 1A and 1D or 1B and 1D were biotransformed. The thiophene sulfoxide metabolite 6B was also trapped as cycloadducts 17 or 18 using stable dienophiles. Preferential dioxygenase-catalysed oxidation of the substituent on the thiophene ring, including exocyclic sulfoxidation (1H-1J) and cis-dihydroxylation of a phenyl substituent (1G and 1N), was also observed. An enzyme-catalysed deoxygenation of a sulfoxide in P. putida UV4 was noticed when racemic disulfoxide cyclo-adducts 7A, 7B and 7K were converted to the corresponding enantioenriched monosulfoxides 8A, 8B and 8K via a kinetic resolution process. The parent thiophene 1A and the 3-substituted thiophenes 1K-1N were also found to undergo ring dihydroxylation yielding the cis/trans-dihydrodiol metabolites 9A and 9K-9N. Evidence is provided for a dehydrogenase-catalysed desaturation of a heterocyclic dihydrodiol (9Kcis/9Ktrans) to yield the corresponding 2,3-dihydroxythiophene (24) as its preferred thiolactone tautomer (23). A simple model to allow prediction of the structure of metabolites, formed from TDO-catalysed bacterial oxidation of thiophene substrates 1, is presented.     

Asymmetric synthesis of rubiginones A(2) and C(2) and their 11-methoxy regioisomers

Convergent enantioselective syntheses of angucyclinone-type natural products rubiginones A(2) (2) and C(2) (1) and their 11-methoxy regioisomers 3 a and 3 b have been achieved by using two domino processes from a common enantiomerically pure 1-vinylcyclohexene 4. Key steps in the synthesis of this diene were the stereoselective conjugate addition of AlMe(3) on (SS)-[(p-tolylsulfinyl)methyl]-p-quinol (9) and the elimination of the beta-hydroxy sulfoxide fragment, after oxidation to sulfone, to recover a carbonyl group. The first domino sequence comprised Diels-Alder reaction with a sulfinyl naphthoquinone followed by sulfoxide elimination. An efficient opposite regioselection in the cycloaddition step was achieved in the convergent construction of the tetracyclic skeleton using a sulfoxide at C-2 or C-3 of the dienophiles 5 or 6, derived from 5-methoxy-1,4-naphthoquinone. The second domino process, triggered by oxygen and sunlight, allowed the transformation of the initial tetracyclic adducts into the final products after B ring aromatization, silyl deprotection and C-1 oxidation.     

Electrospray mass and tandem mass spectrometry identification of ozone oxidation products of amino acids and small peptides

Aqueous ozonation of the 22 most common amino acids and some small peptides were studied by electrospray mass (ESI-MS) and tandem mass spectrometry. After 5 min of ozonation only His, Met, Trp, and Tyr form oxidation products clearly detectable by ESI-MS. For His, the main oxidation product is formed by the addition of three oxygen atoms, His + 30; for Met and Tyr by the addition of one oxygen atom, Met + O and Tyr + O, and for Trp by the addition of two oxygen atoms, Trp + 20. Ozone oxidation occurs rapidly, products are already detected after 30 s of ozonation, and the reactivity order is Met > Trp > Tyr > His. The structures of the oxygen addition products were investigated by electrospray product ion mass spectra, and by comparing these spectra to those of protonated intact amino acids, and when available, to those of model compounds. His + 30 was assigned as 2-amino-4-oxo-4-(3-formylureido)butanoic acid (1) formed by oxidation of the His imidazole ring, Met + O as methionine sulfoxide (2), Trp + 20 as N-formylkynurenine (4), and Tyr + O as a mixture of dihydroxyphenylalanines (7 and 8). Ozonation of peptides show that the same number of oxygen atoms are added as expected from the ozonation of the free amino acids. The product ion mass spectra of both the protonated intact peptides, MH+, and the main ozonation products (M + nO)H+ (n = 1-3) revealed b and y type ions as the main fragments, which allow one to assign the type and location of modified amino acid in the model peptides.