An experimental and theoretical study of reaction mechanisms between nitriles and hydroxylamine.

The industrially relevant reaction between nitriles and hydroxylamine yielding amidoximes was studied in different molecular solvents and in ionic liquids. In industry, this procedure is carried out on the ton scale in alcohol solutions and the above transformation produces a significant amount of unexpected amide by-product, depending on the nature of the nitrile, which can cause further analytical and purification issues. Although there were earlier attempts to propose mechanisms for this transformation, the real reaction pathway is still under discussion. A new detailed reaction mechanistic explanation, based on theoretical and experimental proof, is given to augment the former mechanisms, which allowed us to find a more efficient, side-product free procedure. Interpreting the theoretical results obtained, it was shown that the application of specific imidazolium, phosphonium and quaternary ammonium based ionic liquids could decrease simultaneously the reaction time while eliminating the amide side-product, leading to the targeted product selectively. This robust and economic procedure now affords a fast, selective amide free synthesis of amidoximes.

Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo.

A novel adenosine A(3) receptor antagonist (SSR161421) was characterized by both receptor binding assays and pharmacological tests. Binding studies on cloned human adenosine receptors showed that SSR161421 has high affinity for adenosine hA(3) receptors (K(i)=0.37 nM) with at least 1000-fold selectivity compared to hA(1), hA(2A) and hA(2B) receptors. The receptor antagonist nature of SSR161421 was determined in a functional study on Chinese hamster ovarian cells (CHO) cells expressing human adenosine A(3) receptors. SSR161421 competitively antagonized the effect of 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) on cAMP production with a pA2 value in a luciferase reporter gene construct. In mice, intravenously administered SSR161421 inhibited the N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride (AB-MECA) induced increase in plasma histamine levels (ED(50)=2.0mg/kg) and the Cl-IB-MECA evoked plasma extravasation (ID(50)=2.9 mg/kg) and oedema formation (ID(50)=4.6 mg/kg) in mouse ear.

Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models.

The effects of a novel adenosine A(3) receptor antagonist, SSR161421, were examined on both antigen per se and adenosine receptor agonist-increased airway responses in antigen-sensitized guinea pigs. Adenosine (10(-5)M) and AB-MECA [N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride] (10(-7)M) increased the antigen response up to 61 ± 3.0% and 88 ± 5.2% of maximal contraction, respectively. The agonists of adenosine A(1) and A(2) adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5'-N-ethylcarboxamidoadenosine], R-PIA [N(6)-R-phenylisopropyladenosine], and CGS21680 (10(-7)M) were ineffective. In vivo intravenous adenosine (600 µg/kg) and AB-MECA (30 µg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214 ± 13.0% and 220 ± 15.2%, respectively. SSR161421 in vitro (IC(50)=5.9 × 10(-7)M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED(50)=0.008 mg/kg) or oral (ED(50)=0.03 mg/kg) administration in sensitized guinea pigs. Antigen itself could evoke tracheal contraction in vitro and bronchoconstriction in vivo in antigen-sensitized guinea pigs. SSR161421 (3 × 10(-6)M) decreased the AUC of the antigen-induced contraction-time curve to 20.8 ± 5.4% from the 100% control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC(50) values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.

Design and application of new imidazolylsulfonate-based benzyne precursor: an efficient triflate alternative.

Several o-(trimethylsilyl)aryl imidazolylsulfonates were synthesized in a simple process and successfully applied in cycloadditions involving benzyne intermediates. The precursor offers an efficient alternative for generating benzynes compared to widely used ortho TMS triflates under similar reaction conditions. With the utilization of this new precursor, the formation of potentially genotoxic trifluoromethanesulfonate side product is eliminated. The applicability of the new benzyne precursor was demonstrated in different types of cycloaddition reactions to prepare heterocyclic molecules.

Dual luminescence properties of differently benzo-fused N-phenylphenanthridinones.

The photophysics of some newly prepared N-arylphenanthridinone derivatives have been investigated. It has been demonstrated how the luminescence properties are influenced by the size of the aromatic ring system. It has been shown that the replacement of the phenyl group in N-phenyphenanthridinone (PP) by an alpha-naphthyl or beta-naphthyl group (alphaNP and betaNP, respectively), influences the fluorescence spectra very differently. For alphaNP, the long-wavelength (LW) emission, which is well observable in case of PP, disappears, while for betaNP, the intensity of LW emission increases compared to the short-wavelength (SW) fluorescence. The rotation of the alpha-naphthyl group to the coplanar geometry, which is a requirement of the formation of the LW state, is strongly hindered, resulting in the lack of LW emission. In respect of steric hindrance, the beta-napthyl group is similar to phenyl, however, it decreases the energy of the LW state more as a consequence of its better electron donating character and the more extended conjugation of the coplanar system. This causes the increase of the LW/SW fluorescence ratio. The benzo-fusing on the phenanthridinone moiety results in a 6-7 kcal mol(-1) decrease in the SW singlet energy, however, surprisingly the LW state energy also decreases in almost the same manner. The phenomenon shows that the entire benzo-phenanthridinone group is strongly involved in both transitions. As a consequence, the benzo-fused N-aryl derivatives also show dual luminescence. The dipole moments of the LW state of betaNP and betaNBiP (6-naphthalen-2-yl-6H-benzo[i]phenanthridin-5-one) proved to be bigger by 30 and 50%, than that of the SW state, respectively. MO calculation indicates that in the SW --> LW reaction not only the size but the direction of the excited state dipole also changes significantly. In apolar solvents, the dominant deactivation process of the examined molecules is intersystem crossing. In polar solvents, where the LW emission energy is smaller, internal conversion becomes more significant than the other processes, resulting in low fluorescence yield.

Valence Bond Isomerization of Fused [1,2,3]Triazolium Salts with Bridgehead Nitrogen Atom. Fused Azolium Salts. 19(,).

[1,2,3]Triazolo[1,5-a]quinolinium (7), [1,2,3]triazolo[1,5-b]isoquinolinium (8), and [1,2,3]triazolo[1,5-a]pyrazinium salts (9) when heated in trifluoroacetic acid and/or 1,2-dichlorobenzene undergo valence bond isomerization to ring-opened reactive intermediates (e.g., 8 gave 13) which can participate in (i) electrophilic substitution as nitrenium cations to yield pyrazole- and indazole-fused new heterocycles (e.g., from 13, 14, and 15 are formed), (ii) pseudoelectrocyclization (e.g., intermediate 19c leads to the pyrazolo[3,4-b]pyrazine 21), or (iii) in nucleophilic addition as carbenium cations (e.g., 1 gave the methoxy-substituted adduct 22 when heated in methanol). Comparison of these and some recent results reveals that this ring opening of fused [1,2,3]triazolium salts is a general phenomenon and is closely related to the well-known retro-electrocyclizations (called "1,5-dipolar cyclizations") of neutral fused [1,2,3]triazoles and tetrazoles.