- Regioselective multicomponent sequential synthesis of hydantoins
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The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry. The Royal Society of Chemistry 2012.
- Olimpieri, Francesca,Bellucci, Maria Cristina,Marcelli, Tommaso,Volonterio, Alessandro
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p. 9538 - 9555
(2013/01/16)
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- The Reaction between Acyl Halides and Alcohols: Alkyl Halide vs. Ester Formation
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In the reaction between an acyl halide and an alcohol the thermodynamically favoured products are the free carboxylic acid and the alkyl halide.The initial reaction is, generally, the formation of an ester and HHal.When the alcohol is very prone to yield an alkyl cation upon protonation by HHal, formed H2O exhibited a superior reactivity and competed successfully with the alcohol for the acyl halide making, therefore, ester formation practically confined to a triggering role.But, in those cases where the cation is less easily formed, ester formation was favoured and, consequently, became the necessary elementary step towards alkyl halide formation.Tis final product, on the other hand, might be extremely slow to form in an SN2 reaction between the protonated ester function and the halide ion.In these instances, therefore, as well as in the cases when a basic solvent competes for the proton of HHal, the ester is the final product.A notable exception of the situation above outlined, is given by α-hydroxy-α-phenylbenzeneacetic acid (2y), which appears to undergo direct chlorine-hydroxyl interchange through a quaternary intermediate (E), in the end collapsing to α-chloro-α-phenyl-benzeneacetic acid (4y).Different systems were compared using CH2Cl2 as a solvent under strictly similar conditions.Some 28 different substrates were tested for reaction with AcCl (1a), whereas the action of eight acyl halides (a) against (RS)-α-methylbenzenemethanol (2n) and α-phenylbenzenemethanol (2p), as well as the effect of five different solvents on the reaction between two alcohols (2p and 2-methyl-2-propanol, 2c) with 1a, were observed.
- Strazzolini, Paolo,Giumanini, Angelo G.,Verardo, Giancarlo
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p. 217 - 254
(2007/10/02)
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- Nucleophilic substitution in diphenylmethyl derivatives. I. Formolysis of diarylmethyl derivatives: an α-substituent effect
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The reactions of formic acid with and without addition of sodium formate with diphenylmethanol (4) and chlorodiphenylmethane (3) were compared to those with hydroxydiphenylacetic (benzilic) acid (12a) and chlorodiphenylacetic acid (14a).Formic acid did not favour any SN1-type reaction on 4, but a strong catalysis by iodide ion was observed.Sodium formate rapidly performed the substitution of the chlorine in 3.A similar outcome was obtained with chloro acid 14a, but the rationalization of the results is different.Chloro acid 14a and its methyl ester 14b were prompt to react, but the equilibria were shiftet to α-formyloxy products 13 only by the addition of HCOONa.HCOOH was unable to perform any reduction on either 3 or 4 or 12a and 14a, a fact which was taken as evidence for concerted substitution mechanism on ion pairs or betaine 15.Mechanistic implications are drawn.
- Strazzolini, Paolo,Giumanini, Angelo G.,Verardo, Giancarlo
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- Nucleophilic substitution in diphenylmethyl derivatives. II. Methanolysis of α substituents of diphenylacetic acid and its derivatives
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The nucleophilic displacement of α substituents of diphenylacetic acid and its methyl ester by MeOH under a variety of experimental conditions allowed us to establish that the reaction occurs rapidly in one of the following structural combinations: (a) carboxylate anion and a good leaving group; (b) carboxylic group and a less reactive leaving group; (c) methyl ester and a proton-activated, poor leaving group.The importance of internal hydrogen bonding (case b) was the governing factor in the outcome of the reaction of hydroxydiphenylacetic acid (3a) and its methyl ester 3b with acetyl chloride.The key intermediate in substitution at the α carbon is thought to be a carbocation stabilized both by the attached phenyl groups and, to a smaller extent, by the carboxyl group.
- Strazzolini, Paolo,Poiana, Marco,Verardo, Giancarlo,Giumanini, Angelo G.
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p. 283 - 289
(2007/10/02)
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