Remarkable Chichibabin-type cyclotrimerisation of 3-nitrotyrosine, tyrosine and phenylalanine to 3,5-diphenylpyridine derivatives induced by hypochlorous acid

Reaction of 3-nitrotyrosine with HOCl in aqueous phosphate buffer (pH 7.4) leads to a mixture of extractable products, including 3,5-di(4-hydroxy-3-nitrophenyl)pyridine (15% isolated yield) and 3,5-di(4-hydroxy-3-nitrophenyl)-2-(4-hydroxy-3-nitrophenylmethyl)pyridine (3%) arising by a Chichibabin-like pyridine synthesis via N-chloroimine intermediates. Under the same conditions, phenylalanine gives 3,5-diphenylpyridine in 9% isolated yield, while tyrosine leads to 3,5-di(4-hydroxyphenyl)pyridine (3%) and 3-(3-chloro-4-hydroxyphenyl)-5-(4-hydroxyphenyl)pyridine (3%).     

Synthesis and anticonvulsant activity of 3-[3-[(dimethylamino)-methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine

Wolff-Kishner reduction of 3-amino-4-(o-chlorobenzoyl)pyridine ( 3 ) afforded 3-amino-4-(o-chlorobenzyl)pyridine ( 5 ), which on subsequent reaction with triethyl orthoformate and then acetyl hydrazide yielded 1-acetyl-2-[N-[4-(o-chlorobenzyl)pyridin-3-yl]formimidoyl]hydrazone ( 7 ). Cyclization of hydrazone 7 gave 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 8 ), which on Jones oxidation yielded 3-(3-methyl-4H-1,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ). The Mannick reaction of 3-(3-methyl-4H-l,2,4-triazol-4-yl)-4-(o-chlorobenzyl)pyridine ( 9 ) with aqueous formalin and dimethylamine hydrochloride afforded 3-[3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)-pyridine ( 10 ). 3-[3-[(Dimethylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]-4-(o-chlorobenzoyl)pyridine ( 10 ) exhibited good anticonvulsant activity in the subcutaneous pentylenetetrazole anticonvulsant screen indi cating that an appropriately substituted-pyridine ring moiety can serve as a bioisostere of a chlorobenzene ring with respect to anticonvulsant activity.     

吡唑并[1,5-α]吡啶类化合物的合成及其体外受体结合分析

以吡唑并[1,5-α]吡啶-3-甲醛和N-甲酰基哌嗪为原料,经过还原胺化、水解和N-烷基化反应,合成了3-(4-苄基哌嗪-1-基甲基)吡唑并[1,5-α]吡啶、3-[4-(4-氯苄基)哌嗪-1-基甲基]吡唑并[1,5-α]吡啶和3-[4-(4-甲氧基苄基)哌嗪-1-基甲基]吡唑并[1,5-α]吡啶,通过1H NMR、ESI MS等技术手段对中间体及3个目标化合物进行了表征,并通过体外受体结合实验,测定3个目标化合物对多巴胺D4.2受体的亲和常数(Ki)分别为1.6、7.2、65 nmol/L;对D2受体的亲和常数分别为1920、5320和9800 nmol/L;对D3受体的亲和常数分别为1710、4270和5600 nmol/L。结果表明,3-(4-苄基哌嗪-1-基甲基)吡唑并[1,5-α]吡啶对多巴胺D4受体具有较高的亲和性与选择性,是多巴胺D4受体潜在的配基。     

1-Ethyl-1,4-dihydro-4-oxo-7-(pyridinyl)-3-quinolinecarboxylic acids. I. Synthesis of 3- and 4-(3-aminophenyl)pyridine intermediates

A series of substituted 3- and 4-(3-aminophenyl)pyridines has been prepared as intermediates for the synthesis of some 1-alkyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The Hantzsch, Hauser and other pyridine syntheses were used. 4-(3-Aminophenyl)pyridine was prepared via 3-(4-pyridinyl)-2-cyclohexen-1-one using the Semmler-Wolff reaction.     

Metal-assisted in situ formation of a tridentate acetylacetone ligand for complexation of fac-Re(CO)3+ for radiopharmaceutical applications

Reaction of [NEt4]2[ReBr3(CO)3] with 2,4-pentanedione (acac) yields a complex of the type fac-Re(acac)(OH2)(CO)3 (1) under aqueous conditions. 1 was further reacted with a monodentate ligand (pyridine) to yield a fac-Re(acac)(pyridine)(CO)3 complex (2). Complex 1 was found to react with primary amines to generate a Schiff base (imine) in aqueous solutions. When a mixed-nitrogen donor bidentate ligand, 2-(2-aminoethyl)pyridine, that has different coordination affinities for fac-Re(acac)(OH2)(CO)3 was utilized, a unique tridentate ligand was formed in situ utilizing a metal-assisted Schiff base formation to yield a complex fac-Re(CO)3(3[(2-phenylethyl)imino]-2-pentanone) (3). Tridentate ligand formation was found to occur only with the Re-coordinated acac ligand. Reactions of acac with fac-Re(CO)3Br(2-(2-aminoethyl)pyridine) (4) or a mixture of [NEt4]2[ReBr3(CO)3], acac, and 2-(2-aminoethyl)pyridine did not yield the formation of complex 3 in water.     

Fluorinated pyridine derivatives: Part 1. The synthesis of some mono- and bis-quaternary pyridine salts of potential use in the treatment of nerve agent poisoning

Experiments were performed to determine whether F- and CF₃-substituted pyridines undergo quaternization with iodomethane (1:1 molar ratio in THF) and 1,3-diiodopropane (2:1 molar ratio in MeCN). 2-Fluoropyridine and 2-(trifluoromethyl)pyridine did not react with MeI even under prolonged reflux, while 3-fluoropyridine, 3,5-difluoropyridine, 3-(trifluoromethyl)pyridine and 4-(trifluoromethyl)pyridine gave methiodide salts in 28-72% yield. 2-Fluoropyridine did not react with I(CH₂)₃I, 3-fluoropyridine gave the bis-quaternary salt and 3,5-difluoropyridine yielded a mono-quaternary derivative. Both 3- and 4-(trifluoromethyl)pyridine furnished the bis-quaternary products in 53 and 55% yield, respectively. The bis-quaternary salts are potentially useful in the treatment of organophosphorus nerve agent poisoning.     

Enhanced deep-red luminescence of tris(hexafluoroacetylacetonato)samarium(III) complex with phenanthroline in solution by control of ligand coordination

The effect of solvent molecule on the emission properties of Sm(hfa)3(phen)2 (hfa = hexafluoroacetylacetonato, phen = phenanthoroline) was investigated using acetone, acetonitrile, and pyridine. 5G(5/2) --> 5H(9/2) transition intensities in pyridine were found to be larger than those in corresponding acetone and acetonitrile. The radiative rate constant in pyridine (4.8 x 10(2) s(-1)) was 2 times larger than those in acetonitrile (2.6 x 10(2) s(-1)) and acetone (2.3 x 10(2) s(-1)), although the nonradiative transition via vibrational relaxation (k(nr) = 1.7 x 10(4) s(-1)) in pyridine was the same as those in acetone and acetonitrile (k(nr) = 1.8 x 10(4) s(-1)), resulting in the enhanced emission quantum yield of Sm(III) complex in pyridine (2.7%). The coordination structures of Sm(hfa)3(phen)2 in acetonitrile, acetone, and pyridine were estimated by X-ray single-crystal analyses. These results indicate that enhancement of the emission properties in pyridine is due to faster radiative rate related to formation of asymmetrical nine-coordinated structure, Sm(hfa)3(phen)(py) (py = pyridine).     

Platinum(II) complexes containing 2-(alkenyl)pyridines

The ligands 2-(allyl)pyridine(APy), and 2-(1-methallyl)pyridine (1-MAPy) react with [Pt₂X₄(PEt₃)₂] (X = Cl or Br), in acetone solution to give complexes of the type [PtX(PEt₃)L] [PtX₃(PEt₃)], (L = APy or 1-MAPy), which contain a bidentate 2-(alkenyl)pyridine, whereas the same reaction in benzene solution gives trans-[PtBr₂(PEt₃)L], (L = APy or 1-MAPy), which contains a monodentate 2-(alkenyl)pyridine; ¹H NMR spectra indicate that both types of product undergo olefin exchange in solution. The same reaction with 2-(3-methallyl)-pyridine [2-(2-butenyl)pyridine] (3-MAPy), 2-(3,3-dimethylallyl)pyridine [2-(3-methyl-2-butenyl)pyridine] (3,3-DMAPy), and 2-(3-butenyl)pyridine (BPy), in either acetone or benzene solution, gives only trans-[PtBr₂(PEt₃)L]. The reaction of trans-[PtBr₂(PEt₃)L] (L = APy or 3-MAPy) with AgClO₄ gives [PtBr(PEt₃)L]ClO₄. Complexes of the type [PtCl₂L], which contain bidentate 2-(alkenyl)pyridines, result on reaction of L = APy, 3-MAPy, 3,3-DMAPy, BPy, MBPy with [Pt₂Cl₄(C₂H₄)₂].     

Unusual products from the synthesis of 3-(2-phenylethyl)pyridines by the hydrosulfite reduction of nitrosamines

The Overberger hydrosulfite reduction of N-nitroso[(3-phenylmethylamino)methyl]pyridine gave 3-(2-phenylethyl)pyridine and, as determined by nmr, glc and mass spectral studies, about 15% of a mixture which consisted of the 2-, 4-, and 6-(phenylmethyl)-3-methylpyridines, and the 3-[2-, 3-, and 4-(methylphenylmethyl)]pyridines. These by-products resulted from the coupling of an arylmethyl fragment with the opposite aryl group. A concerted reaction is suggested for the ortho couplings and a radical rearrangement for the para couplings. Authentic samples of three of these by-products were prepared for comparison. A similar reduction of (+)-N-nitroso-3-[(phenylethylamino)methyl]pyridine gave (+)3-(2-phenylpropyl)pyridine of undetermined optical purity and by-products which were not examined but whose nmr spectrum indicated them to be of analogous origin.     

Synthesis and reactions of 3-acetyl-6-methyl-2-(methylthio)pyridine

A reaction of methyllithium with 3-cyano-6-methylpyridine-2(1 H)-thione followed by alkylation of the resulting 3-acetylpyridinethione, or a direct reaction of methyllithium with 3-cyano-6-methyl-2-(methylthio)pyridine, afforded 3-acetyl-6-methyl-2-(methylthio)pyridine. The ketone obtained was examined in bromination reactions under various conditions. Bromi-nation in methanol or chloroform, proceeding through the formation of sulfonium bromides, gave substituted 3-(bromoacetyl)pyridine. A reaction of 3-acetyl-6-methyl-2-(methyl-thio)pyridine with N-bromosuccinimide in CCl4 afforded N-(pyridinesulfenyl)succinimide. The bromo ketone was used for the synthesis of various heterocyclic compounds.     

Synthesis and antimicrobial studies of new pyridine derivatives

2-(p-Acetylaminobenzenesulfonylamido)-substituted benzothiazoles were prepared from 2-amino-substituted benzothiazoles and p-acetamidobenzenesulfonyl chloride using a mixture of pyridine and Ac₂O, which formed an electrophilic N-acetyl- pyridinium complex facilitating condensation to give the desired products by removal of HCl. 2-[4-(Substituted benzothiazol-2-yl)aminosulfonylanilino]pyridine-3-carboxylic acids (synthesized from 2-chloropyridine-3-carboxylic acid and the corresponding substituted 2-(p-aminobenzenesulfonylamido)benzothiazole in 2-ethoxyethanol using Cu-powder and K₂CO₃) were then converted to acid chlorides, which on further reaction with piperazine and 4-methoxyphenylpiperazine yielded the corresponding 2-[4-(substituted benzothiazol-2-yl)amino-sulfonyl]anilino-3-(piperazinocarbonyl) pyridine and 2-[4-(substituted benzothiazol-2-yl)amino-sulfonyl]anilino-3-[(4-methoxyphenyl)piperazin-1-yl-carbonyl]pyridine. The structures of the new compounds have been established on the basis of their elemental analyses as well as IR, ¹H NMR, and mass-spectral data. All the compounds have been screened for antimicrobial activity and found to possess considerable antibacterial activity.     

Cooperative ligation,back-bonding,and possible pyridine-pyridine interactions in tetrapyridine-vanadium(II): a visible and X-ray spectroscopic study

The binding of pyridine by V(II) in aqueous solution shows evidence for the late onset of cooperativity. The K(1) governing formation of [V(py)](2+) (lambda(max) = 404 nm, epsilon(max) = 1.43 +/- 0.3 M(-1) cm(-1)) was determined spectrophotometrically to be 11.0 +/- 0.3 M(-)(1), while K(1) for isonicotinamide was found to be 5.0 +/- 0.1 M(-1). These values are in the low range for 3d M(2+) ions and indicate that V(II).py back-bonding is not significant in the formation of the 1:1 complex. Titration of 10.5 mM V(II) with pyridine in aqueous solution showed an absorption plateau at about 1 M added pyridine, indicating a reaction terminus. Vanadium K-edge EXAFS analysis of 63 mM V(II) in 2 M pyridine solution revealed six first-shell N/O ligands at 2.14 A and 4 +/- 1 pyridine ligands per V(II). UV/vis absorption spectroscopy indicated that the same terminal V(II) species was present in both experiments. Model calculations showed that in the absence of back-bonding only 2.0 +/- 0.2 and 2.4 +/- 0.2 pyridine ligands would be present, respectively. Cooperativity in multistage binding of pyridine by [V(aq)](2+) is thus indicated. XAS K-edge spectroscopy of crystalline [V(O(3)SCF(3))(2)(py)(4)] and of V(II) in 2 M pyridine solution each exhibited the analogous 1s --> (5)E(g) and 1s --> (5)T(2g) transitions, at 5465.5 and 5467.5 eV, and 5465.2 and 5467.4 eV, respectively, consistent with the EXAFS analysis. In contrast, [V(py)(6)](PF(6))(2) and [V(H(2)O)(6)]SO(4) show four 1s --> 3d XAS transitions suggestive of a Jahn-Teller distorted excited state. Comparison of the M(II)[bond]N(py) bond lengths in V(II) and Fe(II) tetrapyridines shows that the V(II)[bond]N(py) distances are about 0.06 A shorter than predicted from ionic radii. For [VX(2)(R-py)(4)] (X = Cl(-), CF(3)SO(3)(-); R = 4-Et, H, 3-EtOOC), the E(1/2) values of the V(II)/V(III) couples correlate linearly with the Hammett sigma values of the R group. These findings indicate that pi back-bonding is important in [V(py)(4)](2+) even though absent in [V(py)](2+). The paramagnetism of [V(O(3)SCF(3))(2)(py)(4)] in CHCl(3), 3.8 +/- 0.2 mu(B), revealed that the onset of back-bonding is not accompanied by a spin change. Analysis of the geometries of V(II) and Fe(II) tetrapyridines indicates that the ubiquitous propeller motif accompanying tetrapyridine ligation may be due to eight dipole interactions arising from the juxtaposed C-H edges and pi clouds of adjoining ligands, worth about -6 kJ each. However, this is not the source of the cooperativity in the binding of multiple pyridines by V(II) because the same interactions are present in the Fe(II)-tetrapyridines, which do not show cooperative ligand binding. Cooperativity in the binding of pyridine by V(II) is then assigned by default to V(II)-pyridine back-bonding, which emerges only after the first pyridine is bound.     

(1-Adamantanethio)pyridines and tetrahydropyridines from the reaction of 1-adamantanethiol with pyridine I-oxide in acetic anhydride

The reaction of pyridine 1-oxide with 1-adamantanethiol in acetic anhydride produced a mixture of 2- and 3-(1-adamantanethio)pyridines, 1-aeetyl-2-(1-adamantanethio)-3-hydroxy-4-acetoxy-1,2,3,4-telrahydropyridine and the corresponding 3-acetoxyderivative. Pure substances were separated by means of column chromatography on alumina. The tetrahydropyridines were identified by means of their proton magnetic and mass spectra. 4-(1-Adamantanethio)pyridine was synthesized from 4-chloropyridinc and 1-adamantanethiol. The three isomeric (1-adamantanethio)-pyridines were, each, cleaved by concentrated hydrochloric acid to give 1-chloroadamantane and the corresponding pyridinethiol.     

Die Reaktion von 4,6-Dinitroisophthalaldehyd und 4,6-Dinitroisophthalonitril mit Pyridin

The reaction of 4,6-dinitroisophthalaldehyde and 4,6-dinitroisophthalonitrile with pyridine 4, 6-Dinitroisophthalaldehyde ( 4 ) gives on reaction with pyridine 4,6-diformyl-3-(1′-pyridinio)-1-phenolate ( 5 ), whereas 4,6-dinitroisophthalonitrile ( 7 ) gives under the same conditions one main product: 3-(1′)-pyridinio-4, 6-dicyano-1-phenolate ( 10 ) and two side products: 2-(1′-pyridinio)-4, 6-dicyano-3-nitro-1-phenolate ( 11 ) and 4, 6-dicyano-3-nitro-1-phenol ( 12 ). The new structures were elucidated by ¹H-NMR. and ¹³C-NMR. spectroscopy.     

Microwave activation in the synthesis of nitrogen heterocycles, N-oxides of pyridine series

Oxidation of heterocycles of the pyridine series under conditions of microwave irradiation was studied. It is established that oxidation of pyridine and 4-methylpyridine with hydrogen peroxide results in the corresponding N-oxides, and oxidation of 3-(piperidin-2-yl)pyridine gives δ-oximino-δ-(pyridyl-3-N-oxide)-valeric acid.     

Logistic flexibility in the preparation of isomeric halopyridinecarboxylic acids

Although there are many conceivable ways to funtionalize, and specifically carboxylate, 2-chloro-4-(trifluoromethyl)pyridine optionally at all three vacant positions, it is more straightforward to prepare only the 2-chloro-4-(trifluoromethyl)pyridine-3-carboxylic acid (1) from this precursor and the other 6-chloro-4-(trifluoromethyl)pyridine-2- and -3-carboxylic acids (2 and 3) from a different one, viz. 5-bromo-2-chloro-4-(trifluoromethyl)pyridine. In the same manner, it proved more convenient to convert 5-chloro-2-(trifluoromethyl)pyridine in only two of the corresponding acids (6 and 7) and to make the third one (8) from 3-bromo-5-chloro-2-(trifluoromethyl)pyridine as an alternative starting material. All model substrates for functionalization were readily accessible from the correspondingly substituted chloroiodopyridine through heavy halogen displacement by in situ generated (trifluoromethyl)copper.     

Au(i)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to provide pyrazolo[1,5-a]pyridines

Pyrazolo[1,5-a]pyridines and 6-iodopyrazolo[1,5-a]pyridines were synthesized by gold-catalyzed and iodine-mediated cyclization of enynylpyrazoles in good to excellent yields, respectively. The iodinated adducts were further converted to 6-arylpyrazolo[1,5-a]pyridines via Suzuki-Miyaura coupling reaction and 6-cyanopyrazolo[1,5-a]pyridine by Ullmann condensation reaction. One of the cyclization adducts, 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine, was converted to a p38 kinase inhibitor, 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine, in two steps.     

Interaction of 3-amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-methyl-thieno[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridine with Raney nickel

3-Amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-methylthieno[2,3-b]pyridine was synthesized by the reaction of 2(1H)-thioxopyridine-3-carbonitrile with 3-chloromethylisoxazole in the presence of two equivalents of KOH. Boiling of 3-amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-meth-ylthieno[2,3-b]pyridine with Raney nickel results in 4-aminothieno[2,3-b;4,5-b′]dipyridine or 5-(4-amino-2-pyridyl)pyridine depending on the reaction conditions. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 669–670, March, 2008.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

The interplay of metal and supporting ligand in labile coordination to pincer complexes of Ag(I)

The bis(imino)pyridine scaffold provides support for the synthesis and characterization of unique Ag(I) pincer complexes [{ArN=CPh}(2)(NPh)]Ag(+)(OTf)(-) (Ar = 2,5-(t)Bu(2)C(6)H(3)3; 2,6-(i)Pr(2)C(6)H(3) 4). The bonding interactions between the cation-anion and between the bis(imino)pyridine ligand and the Ag centre are presented. Coordination of pyridine, toluene, 2-butyne and cyclooctene to the Ag centre led to the isolation and crystallographic characterization of labile transient adduct species. Bonding analysis of the adducts revealed conventional ligand-Ag coordination and important unconventional electron donation from the ligand to a π*-orbital of the bis(imino)pyridine group.