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.     

Stereochemical and mechanistic aspects of dioxygenase-catalysed benzylic hydroxylation of indene and chromane substrates

Toluene dioxygenase (TDO)-catalysed benzylic hydroxylation of indene substrates (8, 16 and 17), using whole cell cultures of Pseudomonas putida UV4, was found to yield inden-1-ol (14 and 22) and indan-1-one bioproducts (15 and 23). The formation of these bioproducts is consistent with the involvement of carbon-centred radical intermediates. TDO-catalysed oxidation of indenes 8 and 16 also gave cis-diols 13 and 18 respectively. TDO and naphthalene dioxygenase (NDO), used as both whole-cell preparations and as purified enzymes, were found to catalyse the benzylic hydroxylation of chromane 30, deuteriated (+/-)-chromane 30D and enantiomers (4S)-30D and (4R)-30D to yield (4R)- and (4S)-chroman-4-ols 31/31D respectively. The mechanism of benzylic hydroxylation of chromane 30/30D involves the stereoselective abstraction of a pro-R (with TDO) or a pro-S (with NDO) hydrogen atom at C-4 and a marked preference for retention of configuration.     

Pyridyl groups for protection of the imide functions of uridine and guanosine. Exploration of their displacement reactions for site-specific modifications of uracil and guanine bases

For the protection of the O-4 function of uridine and the O-6 of guanosine, 2-, 3- and 4-hydroxypyridines, 2-pyridinethiol, 6-methyl-2-hydroxy- and 6-methyl-3-hydroxypyridines have been employed. These substituted pyridines gave pyridyl-N-and/or pyridyl-O-substituted derivatives, depending both upon the position of the hydroxyl and methyl groups in the pyridine ring, at the C-4 and the C-6 of the uracil and guanine residues, respectively. These groups were found to be good leaving groups for nucleophilic substitution reactions by amines, thiolates and oximate. If needed, the rate of these substitution reactions could be conveniently increased by almost 1000-fold by conversion of the pyridyl moiety to its methiodide.     

Synthesis and characterization of 2,6-di(quinolin-8-yl)pyridines. New ligands for bistridentate Ru(II) complexes with microsecond luminescent lifetimes

The synthesis of 4-substituted and 4-aryl-substituted 2,6-di(quinolin-8-yl)pyridines is described. The tridentate ligands were prepared via a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction or via a one-step ring-forming reaction generating the central pyridine ring. X-ray crystal structures and 1H NMR shifts are discussed and compared to the corresponding data for a RuII bistridentate complex. Intramolecular stacking of two quinoline units in the RuII complex is suggested by 1H NMR data and also observed in the X-ray structure.     

Derivatives and reactions of glutaconaldehyde—XIII: Regiospecific ring opening of 3-substituted pyridines

A number of nucleophilic ring openings of 3-substituted pyridinium salts have been reinvestigated and summarized. The structure of the resulting stable glutaconaldehyde derivatives was investigated in detail by ¹H NMR. It has been concluded that in general nucleophilic pyridinium ring openings are highly regiospecific. In each case investigated to date a single product was isolated, as a result of attack by the nucleophile at only one of the pyridine α-positions. With the OH ion as the only nucleophile, attack occurs at the pyridine C-2, while larger nucleophiles such as amines and carbanions attack at the pyridine C-6. This was found to be the case for a variety of 3-substituted pyridines such as 3-methyl, 3-methoxy-, 3-cyano-, 3 chloro-pyridine.     

Synthesis of substituted 3,9-diazaspiro[5.5]undecanes via spirocyclization of pyridine substrates

Construction of 3,9-diazaspiro[5.5]undecane derivatives can be easily achieved via intramolecular spirocyclization of 4-substituted pyridines. The reaction entails in situ activation of the pyridine ring with ethyl chloroformate followed by intramolecular addition of an attached β-dicarbonyl nucleophile in the presence of Ti(OⁱPr)₄.     

Interaction of 4,5,7-Trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-<Emphasis Type="Italic">c</Emphasis>]pyridines with Acetic and Trifluoroacetic Anhydrides

The reactions of NH- and N-vinyl-4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo-[3,2-c]pyridines and their 2-substituted derivatives with acetic and trifluoroacetic anhydrides have been studied. Trifluoroacetylation of tetrahydropyrrolo-[3,2-c]pyridines occurs at the α-position of the pyrrole ring, whereas cleavage of the tetrahydropyridine ring with formation of 3-vinylpyrroles occurs with acetic anhydride. 2-Acetyl-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine was synthesized by the Vilsmeier-Haack reaction.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, 751–760. May, 2005.     

Regioselective synthesis of 2-(2-hydroxyaryl)pyridines from the reactions of benzynes with pyridine N-oxides

By modifying the conditions from those in Larock's reported synthesis of 3-(2-hydroxyaryl)pyridines from benzynes, and pyridine N-oxides, we altered the regioselectivity of the reaction toward an efficient synthesis of 2-substituted pyridines. The presence of ethyl propiolate altered the regioselectivity to afford 3-substituted pyridine products instead. We conducted appropriate control experiments that enable a full understanding of the mechanism.     

Chemistry of thienopyridines. VIII. Substitution products derived from thieno[2,3-b] pyridine 7-oxide

Thieno[2,3-b]pyridine (I) was concerted to the N-oxide (II, 53%) by means of hydrogen peroxide and acetic acid. Nitration of II in sulfuric acid gave 4-nitrothieno[2,3-b]pyridine 7-oxide (III, 50%), while nitration in acetic acid formed the isomeric 5-nitrothieno[2,3-b]pyridine 7-oxide (IV, 54%). Compounds III and IV were reduced to the corresponding 4- and 5-aminothieno[2,3-b]pyridines, respectively. Treatment of III with acetyl chloride gave 4-chlorothieno-[2,3-b]pyridine 7-oxide (XI, 81%), convertible in two steps to 4-(N-substituted amino)thieno-[2,3-b]pyridines (especially of the 4-dialkylaminoalkylamino type) for screening as potential antimalarial drugs. 4-Aminothieno[2,3-b]pyridine reacted with aromatic aldehydes to give Schiff's bases and other products. Mechanisms for some of the reactions are suggested. NMR spectral data are reported for various 4-substituted thieno[2,3-b]pyridine compounds.     

Palladium-catalyzed regioselective silaboration of pyridines leading to the synthesis of silylated dihydropyridines

The addition of silylboronic esters to pyridine takes place in toluene at 50 °C in the presence of a palladium catalyst to give N-boryl-4-silyl-1,4-dihydropyridines in high yield. The regioselective 1,4-silaboration also proceeds in the reaction of 2-picoline and 3-substituted pyridines, whereas 4-substituted pyridines undergo 1,2-silaboration to give N-boryl-2-silyl-1,2-dihydropyridines regioselectively.     

Pyridine N-sulfides. Benzisothiazolo[2,3-a]pyridinium tetrafluoroborates and benzothiopheno[3,2-b]pyridines. Novel heterocyclic systems

2-(2-Mercaptophenyl)pyridines are prepared from the corresponding phenols and oxidized with N-chloro-succinimide and silver tetrafluoroborate to benzisothiazolo[2,3-a]pyridine salts ( 4 ). The latter do not rearrange thermally or photochemically to benzothiopheno[3,2-b)pyridines ( 19 ) and are attacked by nucleophiles at sulfur rather than in the pyridine ring, to give the original 2-(2-mercaptophenyl)pyridine back in a reaction involving a dismutation. 19 is prepared by rearranging O-[2-(3-bromo-2-pyridyl)-4-nitrophenyl]dimethylthio-carbamate to the S-aryl compound and heating the latter with strong base.     

Reactions of pyridinium or isoquinolinium ketene dithioacetals with aromatic N-imines and S-imines

Reactions of ketene dithioacetals, 1-[1-substituted 2,2-bis(methylthio)ethenyl]pyridinium 1a-i or -isoquinolinium 2a,b iodides with aromatic N-imines, 1-aminopyridinium 3a-1,1 -aminoquinolinium ( 4 ), and 2-amino-isoquinolinium ( 5 ) mesitylene sulfonates gave the corresponding 2-methylthioimidazo[1,2-a]pyridines 9a-k , 2-methylthiopyrazolo[1,5-a]pyridines 11a-q , 2-methylthioimidazo[2,1-a]isoquinoline derivatives 10a,b and 2-methylthiopyrazolo[1,5-a]quinoline ( 12 ). The benzoyl compounds, 1-[1-benzoyl-2,2-bis(methylthio)ethenyl]-pyridinium iodides 1g,h,i reacted with N-imine 3a to give the 3-benzoyl-2-methylthioimidazo[1,2-a]pyridines 9h-k . The reaction of pyridinium ketene dithioacetals 1a,f,g (R¹ = COOE_t, COPh, and CN) with substituted pyridinium N-imines having an electron-withdrawing group on the pyridine ring afforded only the corresponding pyrazolo[1,5-a]pyridine derivatives 11j-r in good yields. Reactions of ketene dithioacetals with various S-imines are also described. Possible mechanisms for the formation of 9 and 11 are described.     

Dioxygenase-catalysed oxidation of disubstituted benzene substrates: benzylic monohydroxylation versus aryl cis-dihydroxylation and the meta effect

Biotransformations of a series of ortho-, meta- and para-substituted ethylbenzene and propylbenzene substrates have been carried out, using Pseudomonas putida UV4, a source of toluene dioxygenase (TDO). The ortho- and para-substituted alkylbenzene substrates yielded, exclusively, the corresponding enantiopure cis-dihydrodiols of the same absolute configuration. However, the meta isomers, generally, gave benzylic alcohol bioproducts, in addition to the cis-dihydrodiols (the meta effect). The benzylic alcohols were of identical (R) absolute configuration but enantiomeric excess values were variable. The similar (2R) absolute configurations of the cis-dihydrodiols are consistent with both the ethyl and propyl groups having dominant stereodirecting effects over the other substituents. The model used earlier, to predict the regio- and stereo-chemistry of cis-dihydrodiol bioproducts derived from substituted benzene substrates has been refined, to take account of non-symmetric substituents like ethyl or propyl groups. The formation of benzylic hydroxylation products, from meta-substituted benzene substrates, without further cis-dihydroxylation to yield triols provides a further example of the meta effect during toluene dioxygenase-catalysed oxidations.     

Substituent effect of the coordinated pyridine in a series of pyrazolato bridged dinuclear diiron(II) complexes on the spin-crossover behavior

Two series of pyrazolato bridged dinuclear NCS and NCBH3 diiron(II) complexes with various types of 3- or 4-substituted pyridines, [{Fe(NCS or NCBH3)(X-py)}2(mu-bpypz)2], were prepared and their variable-temperature magnetic susceptibilities were measured. There were found linear correlations of the spin-crossover temperatures Tc not only between the NCS and NCBH3 complexes with the corresponding substituted pyridines, but also between the Tc and the Hammett constants, supporting the electronic substituent effect of the coordinated pyridine rather than a steric effect. The ligand field and the interelectronic repulsion parameters together with the thermodynamic data and/or cooperativity factor were discussed in relation with their spin-crossover behavior.     

Electron ionization mass spectrometric study of 1,4-dihydro-4-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)pyridines

Using the accurate masses obtained from a time-of-flight instrument and the tandem mass spectrometric (MS/MS) data from an ion trap instrument, electron ionization mass spectra of a series of 1,4-dihydro-4-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)pyridines are reported and rationalized. Two sets of fragmentation pathways are proposed. One involves the formation of fragment ions containing the 1,4-dihydropyridine structure, and the other of ions containing a pyridine ring.     

Estimation of the total range of 1J(CC) couplings in heterocyclic compounds: pyridines and their N-oxides, the experimental and DFT studies

A very large set of one-bond spin-spin carbon carbon coupling constants, 1J(CC), has been measured for 32 variously mono- and disubstituted pyridine N-oxides and for 14 substituted pyridines. The N-oxides studied were 2-, 3- and 4-monosubstituted isomers, and a series of disubstituted compounds. A variety of substituents has been employed (CH3, COCH3, C5H4NO, CN, F, Br, Cl, OH, OCH3, NH2, N(CH3)2 and NO2), which allowed us to study substituent effects thoroughly. Good linear relationships between 1J(C3C4) in 3- and/or 4-substituted pyridine N-oxides and 1J(CipsoCortho) in benzenes and between 1J(C2C3) in 2- and/or 3-substituted pyridine N-oxides and 1J(CipsoCortho) in benzenes have been found. An analogous linear relationship has been observed between 1J(C3C4) in 3- and/or 4-substituted pyridines and 1J(CipsoCortho) in benzenes. It has been also concluded that, by analogy to 1J(CC) couplings in substituted benzenes, those in pyridines and their N-oxides are the substituent electronegativity dependent. The estimated total range covered by 1J(CC), couplings in substituted compounds varies, in the case of 1J(C2C3) couplings for example, from 25 Hz in 2-lithiopyridine N-oxide to ca. 100 Hz in 2,3-difluoropyridine N-oxide and from 18 Hz in 2-lithiopyridine to 92 Hz in 2,3-difluoropyridine. The DFT calculations have been carried out for the parent compounds and for a set of their 2-lithio, and variously substituted fluoro derivatives. The DFT data reproduced very well the experimental coupling values and revealed that the Fermi contact contribution is the dominating factor which governs the magnitude of the CC coupling across one bond.     

In search of oligo(2-thienyl)-substituted pyridine derivatives: a modular approach to di-, tri- and tetra(2-thienyl)pyridines

Herein, we describe our attempts to systematically prepare a series of oligo(2-thienyl)-substituted pyridine derivatives. The crucial starting material, a β-alkoxy-β-ketoenamide, is easily available on a large scale by the reaction of lithiated methoxyallene with thiophene-2-carbonitrile and thiophene-2-carboxylic acid. This three-component reaction is followed by intramolecular cyclization to yield the suitably functionalized 2,6-di(2-thienyl)-substituted pyridine derivates. The two oxygen atoms allow the programmed activation of positions C-3, C-4, or C-5 of the pyridine ring to perform palladium-catalyzed coupling reactions with thiophene-2-boronic acid or 2-(tributylstannyl)thiophene, and alternatively, reductive removal of groups. With this concept, we were able to prepare five pyridine derivatives with 2-thienyl substituents in the 2,6-, 2,3,6-, 2,4,6-, 2,3,4,6-, and 2,3,5,6-positions. 2,3,4,5,6-Penta(2-thienyl)pyridine was not available with our methods. The UV/Vis and fluorescence spectra of all pyridines were recorded and showed a dependence on the substitution pattern and protonation state. For the protonated 2,3,5,6-tetra(2-thienyl)-substituted pyridine, a Stokes shift of about 180 nm with an emission at 515 nm was observed.     

Triazolopyridines. Part 8.1 Nucleophilic substitution reactions of 5-bromo[1,2,3]triazolo[5,1-a]isoquinoline and 7-bromo[1,2,3]-triazolo[1,5-a]pyridine

Nucleophilic substitution of 5-bromotriazoloisoquinoline (3) and of 7-bromo-3-methyltriazolopyridine (6) proceeds readily to give a range of 5-substituted triazoloisoquinolines (4a)-(4e), and of 7-substituted triazolopyridines (7a)-(7h) respectively. Triazoloisoquinolines have been converted into 1,3-disubstituted isoquinolines (11)-(13), (15), and (16), and triazolopyridines into 2,6-disubstituted pyridines (17)-(19). Of secondary amine nucleophiles, only piperidine reacted with 7-bromo-3-methyltriazolopyridine (6) to give the 7-substituted derivative (7g). A second product in this reaction was a 2,6-disubstituted pyridine (8); the similar compounds (20)-(24) were the only products when morpholine or N-acetylpiperazine were used. The reaction between 7-bromotriazolopyridine (9) and piperidine or morpholine gave in high yield the 2,6-disubstituted pyridines (25) and (26).     

Synthesis and Spectroscopic Characterization of Group 6 Pentacarbonyl(4-substituted pyridine)metal(0) Complexes

Carbonyl-metal (M:Cr, Mo, W) derivatives of 4-substituted pyridines [4-methylpyridine (4-mp), 4-tert-butylpyridine (4-tbp) and 4-dimethylaminopyridine (4-dmap)] where the metal center is bonded to the nitrogen atom of the substituted pyridine ring are described. The organometallic complexes, M(CO)₅L, were synthesized by either the direct reaction of the metal hexacarbonyls or by the thermal substitution of M(CO)₅(THF) with the pyridine ligands; 4-methylpyridine (1), 4-tert-butylpyridine (2), 4-dimethylaminopyridine (3). The reported complexes were purified by column chromatography and recrystallization. The complexes were all characterized in solution by elemental analysis, MS, ir , ¹H-nmr and ¹³C-nmr spectroscopies.     

NMR and theoretical study on interactions between diperoxovanadate complex and 4-substituted pyridines

To understand the substituting group effects of organic ligands on the reaction equilibrium, the interactions between diperoxovanadate complex [OV(O2)2(D2O)]-/[OV(O2)2(HOD)](-) and a series of 4-substituted pyridines in solution were explored using multinuclear (1H, 13C, and 51V) magnetic resonance, DOSY, and variable temperature NMR in 0.15 mol/L NaCl ionic medium for mimicking the physiological condition. Some direct NMR data are given for the first time. The reactivity among the 4-substituted pyridines is pyridine > isonicotinate > N-methyl isonicotinamide > methyl isonicotinate. The competitive coordination results in the formation of a series of new six-coordinated peroxovanadate species [OV(O2)2L](n-) (L = 4-substituted pyridines, n = 1 or 2). The results of density functional calculations provide a reasonable explanation on the relative reactivity of the 4-substituted pyridines. Solvation effects play an important role in these reactions.