Insights into the bromination of 3-aryl-5-methyl-isoxazole-4-carboxylate: Synthesis of 3-aryl-5-bromomethyl-isoxazole-4-carboxylate as precursor to 3-aryl-5-formyl-isoxazole-4-carboxylate

Results of the detailed investigations on the bromination of the methyl group of 3-aryl-5-methyl-isoxazole-4-carboxylate a precursor to obtain 3-aryl-5-formyl-isoxazole-4-carboxylate are described. The products generated during the study have been utilized as substrates for the syntheses of isoxazole-fused heterocycles.

Baylis-Hillman reaction assisted synthesis of substituted 5,8-dihydro-isoxazolo[4,5-c]azepin-4-one: A novel isoxazole-annulated heterocycle

The novel synthesis of a new isoxazole-annulated heterocycle namely 5,8-dihydro-isoxazolo[4,5-c]azepin-4-one described herein is based on the reaction of benzyl amine with acetates of Baylis-Hillman adducts generated from 3-aryl-5-formyl-isoxazole-4-carboxylate

Anxiolytic-like effects observed in rats exposed to the elevated zero-maze following treatment with 5-HT2/5-HT3/5-HT4 ligands

The present study examined the effects of administering selective 5-HT antagonists and agonists to rats tested in the elevated zero-maze (EZM) model of anxiety. The EZM paradigm has advantages over the elevated plus-maze (EPM) paradigm with respect to measuring anxiety, yet has been utilized less frequently. Three experiments were conducted each with a diazepam control (0.25, 0.5 and 0.75 mg/kg). In the first experiment, we administered the 5-HT_2C antagonist RS 102221 (0.5, 1.0, and 2.0 mg/kg) and 5-HT_2C agonist MK-212 (0.25, 0.5 and 0.75 mg/kg); in the second experiment, we administered the 5-HT₃ antagonist Y-25130 (0.1, 1.0 and 3.0 mg/kg) and 5-HT₃ agonist SR 57227A (0.1, 1.0 and 3.0 mg/kg), and in the third experiment, we administered the 5-HT₄ antagonist RS 39604 (0.01, 0.1, 1.0 mg/kg) and 5-HT₄ agonist RS 67333 (0.01, 0.1 and 0.5 mg/kg). The administration of 5-HT_2/3/4 subtype antagonists all generated behavioral profiles indicative of anxiolytic-like effects in the EZM, which was apparent from examination of both traditional and ethological measures. While little effect was observed from 5-HT₂ and 5-HT₃ agonists, the 5-HT₄ agonist RS 67333 was found to produce a paradoxical anxiolytic-like effect similar to that produced by the 5-HT₄ antagonist RS 39604. We conclude by discussing the implications of these findings.

Synthesis and crystal structure of triphenyltin-2-(1,2-ethylenedithio) methylene-3-oxo-5-aryl-4-pentenicate

Nine triphenyltin - 2 - (1,2 - ethylenedithio) methylene - 3 - oxo - 5 - aryl - 4 - pentenicates were synthesized. The crystal structure of the title compound 3b (C33H28O3S2Sn) was determined by X - ray diffraction analysis. The crystal belongs to triclinic system, space group P(1)overbar with a = 0.9074 (2) nm, b = 1.6809(3)nm, c = 2.1834(4)nm, alpha =77.57(3)degrees, beta = 88.04(3)degrees, gamma = 89.47(3)degrees, V = 3.2503nm(3), Z = 2, R = 0.0592. In crystal of 3b, there exist intramolecular 0-Sn coordination bonds, with carboxylate group acting as a bidentate ligand: Sn(1)-0(1) = 0.2086(5) and Sn(1)-0(2) = 0.2594nm, having a deformed trigonal bipyramidal geometry.

Crystal structure of poly[[di-mu2-aqua-aquasodium] 4-amino-3,5,6-trichloropyridine-2-carboxylate trihydrate], the sodium salt of the herbicide picloram

In the structure of the title complex [[Na(H2O)3]+ (C6H2Cl3N2O2)-^ . 3(H2O)]n, the Na salt of the herbicide picloram, the cation is a polymeric chain structure, based on doubly water-bridged NaO5 trigonal bipyramidal complex units which have in addition, a singly-bonded monodentate water molecule. Each of the bridges within the chain which lies along the a cell direction is centrosymmetric with Na...Na separations of 3.4807(16) and 3.5109(16)Ang. In the crystal, there are three water molecules of solvation and these, as well as the coordinated water molecules and the amino group of the 4-amino-3,5,6-trichloropicolinate anion are involved in extensive inter-species hydrogen-bonding interactions with carboxyl and water O-atoms as well as the pyridine N-atom. Among these association is a centrosymmetric cyclic tetra-water R4/4(8) ring , resulting in an overall three-dimensional structure.

Dialkyl (3-Aryl- 1,2,4-oxadiazol-5-yl)phosphonates: Synthesis and Thermal Behavior-Evidence for Monomeric Alkyl Metaphosphate

Dialkyl (3-aryl-l,2,4-oxadiazol-5-yl)phosphonate6sa -h have been obtained by 1,3-dipolar cycloaddition of arenenitrile oxides 5a-f to dialkyl phosphorocyanidates (4a and 4b) in yields ranging between 30% and 58%. A standardized method for obtaining cyanidates 4a and 4b has been established. The diethyl thiophosphorocyanidate (4c) is less reactive than 4a and 4b, only the 3-(4'-nitrophenyl) derivative 6i being obtainable. While the IR and NMFt spectra of 6a-i were unexceptional, their UV spectra showed evidence of conjugative interaction in high degrees between the phosphonate and heterocyclic moieties as well as a varying conjugative interaction between the heterocyclic and aryl moieties. The oxadiazoles 6a-h are thermally labile and yield trialkyl phosphates 7 as the only identifiable products. A mechanism based on the intermediacy of monomeric alkyl metaphosphate 11 in the formation of trialkyl phosphate was postulated, and supportive evidence in the form of trapping the metaphosphate with acetophenone has been obtained.

Ethyl 4-(3-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

In the molecular structure of the title compound, C21H25NO4, the dihydropyridine ring adopts a flattened boat conformation while the cyclohexenone ring is in an envelope conformation. In the crystal structure, molecules are linked into a two-dimensional network parallel to (10 (1) over bar) by N-H center dot center dot center dot O and O-H center dot center dot center dot O hydrogen bonds. The network is generated by R-4(4)(30) and R-4(4)(34) graph-set motifs.

Synthetic investigations on illudinine: a new synthesis of methyl 8-methoxy-2,2-dimethyl-7-oxo-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate

A new strategy for the total synthesis of methyl 8-methoxy-2,2-dimethyl-7-oxo-1,2,3,5,6,7-hexahydro-s-indacene-4-carboxylate 4, a key intermediate in the synthesis of illudalanes, is reported. The key step in this strategy is a new method of preparation of indanones from tetralones. Thus, the furfurylidene derivative of 6-methoxy-3,4-dihydronaphthalen-1-(2H)-one is oxidised to the dicarboxylic acid 9a which is cyclodehydrated to methyl 7-methoxy-1-oxoindan-4-carboxylate 10. Similar reactions on the tetrahydronaphthalenone 25, obtained from 6-methoxy-1,2,3,4-tetrahydronaphthalene-7-carbaldehyde 11 by sequential transformations including a regiospecific benzylic oxidation resulted in the hexahydro-s-indacenone 4, thus completing a formal synthesis of illudinine 1.

Studies on the structure of tricyclohexyltin-2-(1,2-dithioethylene)methylene-3-oxo-5-aryl-4-pentenicate

Three title compounds were prepared and the structure of title compound 2 was characterized by IR, H-1 NMR, C-13 NMR, Sn-119 NMR spectroscopy and the crystal structure of compound 2a was determined by X-ray analysis with the final R indices[I >2 sigma (I)] R-1 = 0.0350 and R-2,R-omega = 0.0888. The crystal of compound 2a belongs to triclinic system, space group P1 with a = 1.0598(6) nm, b = 1.307 4(10) nm, c = 1.378 6(10) nm, alpha = 62.666(7)degrees, beta = 72.530(2)degrees, gamma = 80. 680(2)degrees, V = 1.618 0 nm(3), D-x = 1. 444 g (.) cm(-3), Z = 1, F (000) = 728. The bond length of Sn1-O1 is 0. 2076 nm and Sn1 . . . O2 distance is 0.301 3 nm. The coordination about the tin atom can be considered as a distorted tetrahedral. The detail values of H-1 NMR, C-13 NMR, Sn-119 NMR, (2)J(119Sn-1H) and J(119Sn-13C) were obtained. delta (119Sn) = 23.836, (2)J(119Sn-1H) = 88.0 Hz, (1)J(119Sn-13C) = 347.1 Hz, (2)J(119Sn-13C) = 45.6 Hz.

Remodeling of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit composition in hippocampal neurons after global ischemia

Transient global ischemia induces selective delayed cell death, primarily of principal neurons in the hippocampal CA1. However, the molecular mechanisms underlying ischemia-induced cell death are as yet unclear. The present study shows that global ischemia triggers a pronounced and cell-specific reduction in GluR2 [the subunit that limits Ca2+ permeability of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors] in vulnerable CA1 neurons, as evidenced by immunofluorescence of brain sections and Western blot analysis of microdissected hippocampal subfields. At 72 h after ischemia (a time before cell death), virtually all CA1 pyramidal neurons exhibited greatly reduced GluR2 immunolabeling throughout their somata and dendritic processes. GluR2 immunolabeling was unchanged in pyramidal cells of the CA3 and granule cells of the dentate gyrus, regions resistant to ischemia-induced damage. Immunolabeling of the AMPA receptor subunit GluR1 was unchanged in CA1, CA3, and dentate gyrus. Western analysis indicated that GluR2 subunit abundance was markedly reduced in CA1 at 60 and 72 h after the ischemic insult; GluR1 abundance was unchanged in all subfields at all times examined. These findings, together with the previous observation of enhanced AMPA-elicited Ca2+ influx in postischemic CA1 neurons, show that functional GluR2-lacking, Ca2+-permeable AMPA receptors are expressed in vulnerable neurons before cell death. Thus, the present study provides an important link in the postulated causal chain between global ischemia and delayed death of CA1 pyramidal neurons.

2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the Aryl Hydrocarbon Receptor

2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and related compounds are a series of anti-cancer candidate pharmaceuticals (Table 1.), that have been shown to activate the AhR. We show that these compounds are high affinity ligands for the rat AhR, but a quantitative assay for their ability to induce CYP1A1 RNA in H4IIEC3 cells, a measure of activation of the AhR, showed a poor relationship between affinity for the AhR and ability to induce CYP1A1 RNA. 5F 203, an agonist with low potency, was able to antagonise the induction of CYP1A1 RNA by TCDD, while IH 445, a potent agonist, did not antagonise the induction of CYP1A1 RNA by TCDD, and Schild analysis confirmed 5F 203 to be a potent antagonist of the induction of CYP1A1 RNA by TCDD in H4IIEC3 cells. In contrast, several benzothiazoles show potent induction of CYP1A1 RNA in human MCF-7 cells, and 5F 203 is unable to detectably antagonise the induction of CYP1A1 RNA in MCF-7 cells, showing a species difference in antagonism. Evaluation of the antiproliferative activity of benzothiazoles showed that the ability to agonise the AhR correlated with growth inhibition both in H4IIEC3 cells for a variety of benzothiazoles, and between H4IIEC3 and MCF-7 cells for 5F 203, suggesting an important role of agonism of the AhR in the anti-proliferative activity of benzothiazoles.

Zinc mediated azide-alkyne ligation to 1,5- and 1,4,5-substituted 1,2,3-triazoles

A mild method for regioselective formation of 1,5-substituted 1,2,3-triazoles is described. The zinc-mediated reaction works at room temperature and is successful across a wide range of azido/alkynyl substrates. Additionally, the triazole 4-position can be further functionalized through the intermediate aryl-zinc to accommodate a diverse three-component coupling strategy.

Studies on the reduction of the nitro group in 3-aryl-2-methylene-4-nitro-alkanoates afforded by the Baylis-Hillman adducts: Synthesis of 4-aryl-3-methylene-2-pyrrolidinones and 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylates

The formation of substituted 2-pyrrolidinones and indoles by the reduction of the secondary nitro group in appropriate 3-aryl-2-methylene-4-nitroalkanoates afforded by Baylis-Hillman chemistry via different reducing agents is described. The 3-aryl-2-methylene-4-nitroalkanoate obtained from SN2 nucleophilic reaction between the acetate of Baylis-Hillman adducts and ethyl nitroacetate upon reduction with indium-HCl furnishes a mixture of cis and trans substituted phenyl-3-methylene-2-pyrrolidinones. In contrast, similar reductions of analogous substrates derived from nitroethane stereoselectively furnished only the trans substituted phenyl-3-methylene-2-pyrrolidinones. On the other hand the SnCl2.2H2O-promoted reductions of substrates derived from nitro ethylacetate give oxime derivatives while the ones obtained from nitroethane yield a mixture of cis and trans 4-aryl-3-methylene-2-pyrrolidinones. Alternatively, the SnCl2.2H2O-promoted reduction of substituted 2-nitrophenyl-2-methylene-alkanoate furnished from ethyl nitroacetate yields 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylate while indium-promoted reaction of this substrate leads to a complex mixture. Analogous reactions with SnCl2.2H2O of substituted 2-nitrophenyl-2-methylene-alkanoate obtained from nitroethane yield 4-alkyl-3-methylene-2-quinolones in moderate yields

Anhydrous 1:1 proton-transfer compounds of isonipecotamide with picric acid and 3,5-dinitrosalicylic acid: 4-carbamoylpiperidinium 2,4,6-trinitrophenolate and two polymorphs of 4-carbamoylpiperidinium 2-carboxy-4,6-dinitrophenolate

The structures of the anhydrous 1:1 proton-transfer compounds of isonipecotamide (4-carbamoylpiperidine) with picric acid and 3,5-dinitrosalicylic acid, namely 4-carbamoylpiperidinium 2,4,6-trinitrophenolate, C6H13N2O8+ C6H2N3O7- (I) and 4-carbamoylpiperidinium 2-carboxy-4,6-dinitrophenolate, C6H13N2O8+ C7H3N2O7-: two forms, the monoclinic alpha-polymorph (II) and the triclinic beta-polymorph (III) have been determined at 200 K. All compounds form hydrogen-bonded structures, one-dimensional in (II), two-dimensional in (I) and three-dimensional in (III). In (I), the cations form centrosymmetric cyclic head-to-tail hydrogen-bonded homodimers [graph set R2/2(14)] through lateral duplex piperidinium N---H...O(amide) interactions. These dimers are extended into a two-dimensional network structure through further interactions with anion phenolate-O and nitro-O acceptors, including a direct symmetric piperidinium N-H...O(phenol),O(nitro) cation--anion association [graph set R2/1(6)]. The monoclinic polymorph (II) has a similar R2/1(6) cation-anion hydrogen-bonding interaction to (I) but with an additional conjoint symmetrical R1/2(4) interaction as well as head-to-tail piperidinium N-H...O(amide) O hydrogen bonds and amide N-H...O(carboxyl) hydrogen bonds, give a network structure which include large R3/4(20) rings. The hydrogen bonding in the triclinic polymorph (III) is markedly different from that of monoclinic (II). The asymmetric unit contains two independent cation-anion pairs which associate through cyclic piperidinium N-H...O,O'(carboxyl) interactions [graph set R2/1(4)]. The cations also show the zig-zag head-to-tail piperidinium N-H...O(amide) hydrogen-bonded chain substructures found in (II) but in addition feature amide N-H...O(nitro) and O(phenolate) and amide N-H...O(nitro) associations. As well there is a centrosymmetric double-amide N-H...O(carboxyl) bridged bis(cation-anion) ring system [graph set R2/4(8)] in the three-dimensional framework. The structures reported here demonstrate the utility of the isonipecotamide cation as a synthon with previously unrecognized potential for structure assembly applications. Furthermore, the structures of the two polymorphic 3,5-dinitrosalicylic acid salts show an unusual dissimilarity in hydrogen-bonding characteristics, considering that both were obtained from identical solvent systems.

4-(4-Aminophenylsulfonyl)aniline-1,3-5-trinitrobenzene (1/2)

The asymmetric unit of the title co-crystalline 1:2 adduct C12H12N2O2 . 2(C6H3N3O6) contains two independent molecules of bis(4-aminophenyl)sulfone (the drug Dapsone) and four molecules of 1,3,5-trinitrobenzene and is extended into a two-dimensional hydrogen-bonded network structure through amino N-H...O hydrogen-bonding associations with nitro O- atom acceptors. In the two independent Dapsone molecules the inter-ring dihedral angles are 69.0(2) and 63.59(11)deg. Aromatic pi-pi interactions are also found between one of the Dapsone aromatic rings and a trinitrobenzene ring [minimum ring centroid separation 3.576(5)Ang.]. A 4-aminophenyl ring moiety of one of the Dapsone molecules and two nitro groups of a trinitrobenzene are disordered in a 50:50 ratio.