- Microwave-Assisted Synthesis of 2-Substituted 2-Thiazolines and 5,6-Dihydro-4 H -1,3-thiazines
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An efficient and general method for the synthesis of 2-substituted thiazolines and 5,6-dihydro-4 H -1,3-thiazines is developed via microwave-assisted ring closure of ω-thioamidoalcohols promoted by ethyl polyphosphate (PPE). The cyclization reaction involves an S N 2-type mechanism and features the advantages of very short reaction times, high yields and a predictable stereochemical outcome. The acyclic precursors are prepared in high overall yields by an improved diacylation-thionation-saponification sequence from commercially available ω-amino alcohols. The whole process is metal-free and operationally simple.
- Bisceglia, Juan A.,Kilimciler, Natalia B.,Mancinelli, Michele,Mollo, María C.,Orelli, Liliana R.
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p. 1666 - 1679
(2020/06/01)
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- N-nitrosotolazoline: Decomposition studies of a typical N-nitrosoimidazoline
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N-Nitrosotolazoline (N-nitroso-2-benzylimidazoline), a N-nitrosated drug typical of N-nitrosoimidazolines, reacts readily with aqueous acid, nitrous acid, or N-acetylcysteine to produce highly electrophilic diazonium ions capable of alkylating cellular nucleophiles. The kinetics and mechanism of the acidic hydrolytic decomposition of N-nitrosotolazoline have been determined in mineral acids and buffers. The mechanism of decomposition in acidic buffer is proposed to involve the rapid reversible protonation of the imino nitrogen atom followed by slow general base-catalyzed addition of H2O to the 2-carbon of the imidazoline ring to give a tetrahedral intermediate, which is also a α-hydroxynitrosamine. Rapid decomposition of this species gives rise to the diazonium from which the products are derived by nucleophilic attack, elimination, and rearrangement. The proposed mechanism is supported by the observations of general acid catalysis, a negligible deuterium solvent kinetic isotope effect (kH/kD - 1.15) and ΔS≠ = -34 eu. In phosphate buffer at 30°C, the half-lives of N-nitrosotolazoline range from 5 min at pH 3.5 to 4 h at pH 6. The main reaction product of the hydrolytic decomposition is N-(2-hydroxyethyl)phenylacetamide. This and other products are consistent with the formation of a reactive diazonium ion intermediate. N-Nitrosotolazoline nitrosates 50 times more rapidly than tolazoline and results in a set of products derived from reactive diazonium ions but different from those produced from the hydrolytic decomposition of the substrate. N-Acetylcysteine increases the decomposition rate of N-nitrosotolazoline by 25 times at pH 7 and results in both N-denitrosation and induced decomposition to produce electrophiles. These data suggest that N-nitrosotolazoline shares the chemical properties of many known direct-acting mutagens and carcinogens.
- Loeppky, Richard N.,Shi, Jianzheng
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p. 308 - 318
(2008/12/22)
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- A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug
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Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-(N-nitroso-2-imidazolinyl) benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37°C (kobs = 6.25 × 10-5 s-1 in 0.5 M acetate buffer with a 10 * [NO2-] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations 3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.
- Loeppky, Richard N.,Shi, Jianzheng,Barnes, Charles L.,Geddam, Sailaja
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p. 295 - 307
(2008/12/22)
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