Maria Grazia Cabiddu

Metallation reactions XXII: Regioselective metallation of (trifluoromethyl)(alkylthio) benzenes

Abstract The metallation reactions of (trifluoromethyl)(alkylthio)benzenes with organolithium reagents and with the butyllithium/potassium tert -butoxide superbasic mixture are here described. The results, according to the theoretical calculations of energy minima, show the monometallation regiochemistry is directed by the sulphur atom. On the other side, the bimetallation, that can be performed only on methylthio derivatives, depends on the organometallic reagent employed. Using butyllithium the stronger coordinative power of sulphur prevails and products metallated in ortho and alpha positions to this atom are mainly formed. With the more basic sec -butyllithium and with the superbase, because of mutual competition between the thioalkyl and trifluoromethyl groups, mixtures of products, coming from metallation in the ortho position to the trifluoromethyl group and in the alpha position of the thiomethylic group, are obtained. In addition, products coming from substitution ortho,alpha to the thiomethyl group are also formed. All mono- and bimetallated intermediates showed to be good synthons for the synthesis of fluoro- and (trifluoromethyl)-substituted benzothiophenes and (trifluoromethyl)benzenes substituted on the thioalkylic chain and/or on the ring.

Addition of 1,3-Benzoxathiole 3-Oxide Anion to Azomethines under Varying Reaction Conditions

The reaction of benzoxathiole 3-oxide with LDA in THF gave an anion which was reacted with azomethines under varying conditions of temperature and solvent. At −78 °C in THF, the two diastereomers resulting from a trans addition were mainly obtained, while at temperatures higher than −40 °C, or upon increasing the solvent polarity, only one trans and one cis diastereomer were obtained. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

METALATION REACTIONS. XXIV. METALATION OF (VINYLTHIO)BENZENE

The addition of organolithium compounds to (vinylthio)benzene (1) and then an electrophilic quenching followed by a further metalation/electrophilic quenching is a general method to prepare in one pot (alkylthio)benzenes ortho,alpha-substituted with equal or different groups. The direct dimetalation of 1 affords the ortho, alpha-dilithiated species 15 besides other by-products. Starting from 15 it is possible to obtain in one step ortho,alpha-substituted (vinylthio)benzenes and heterocyclic compounds.

A re-examination of the methylenation reaction

A re-examination of the methylenation reaction of 1-hydroxy-2-mercapto-, 1,2-dihydroxy- and 1,2-dimercapto-substituted benzenes by bromochloromethane with cesium carbonate shows that these substrates give mixtures of five- and ten-membered benzocondensed heterocyclic compounds and in some cases even dibenzodioxines.

Anion reaction of 1,3-benzoxathiole-3-oxide with several electrophilic compounds

Abstract The reaction of benzoxathiole-3-oxide with LDA in THF or THF/hexane or THF/HMPA gave a carbanion which was reacted with methyl iodide, aromatic aldehydes or carbon dioxide. The conformational stability (α-diastereoselectivity) of the carbanion and the asymmetric induction due to the prochiral electrophiles (β-diastereoselectivity) was studied. The temperature and the solvent effects on the α- and β-diastereoselectivity are discussed.

Metallation reactions. XXVI. α,α′-Dimetallation of 1,2-bis(methylthiobenzene)

Abstract α,α′-Dimetallation of bis(methylthio)benzene (1) with butyllithium or with superbases gives 2 with good yield. This species allows the simultaneous introduction of two electrophiles in thiomethyl groups. Alternatively it was possible to functionalize these groups with two different electrophiles by two successive one-flask monometallations. Compound 2 rise to gives heterocyclic compounds.

Metallation reactions XXVII.: Metallation of (methylthio)anilines☆

Abstract The metallation reactions of (methylthio)anilines with organolithium reagents and with the butyllithium–potassium tert-butoxide superbasic mixture are here described. The results show that the para isomer when treated with butyllithium gave a mixture of products with no selectivity. Using tert-butyllithium or superbases we obtained the substitution of the thiomethyl hydrogen. Moreover, superbase allowed to prepare the disubstituted product with the new groups in the thiomethyl and in ortho to this group. On the other side, both ortho and meta isomers were lithiated at the thiomethyl carbon by butyllithium and the other reagents. Starting from the unalkylated amine we prepared through three successive one-pot monometallations N,N-disubstituted amines with equal or different groups and bearing an alkylthio chain as long as wanted.

METALATION REACTIONS. PART XVII. DILITHIATION OF PHENYL ISOPROPYL SULPHONE

Abstract The general utility of dimetalation reactions of phenyl iso-propyl sulphone for the preparation of ortho,alpha-substituted aryl sulphones is described. All the products were obtained in satisfactory yields.

Synthesis of new compounds with promising antiviral properties against group A and B Human Rhinoviruses

The human common cold, which is a benign disease caused by the Rhinoviruses, generally receives palliative symptomatic treatments, since no specific therapy against any of these viruses currently exists. In this work, some original synthetic compounds were produced and tested, in order to find non-toxic substances with an improved protection index (PI) for infected cells, as compared to reference drugs such as Pirodavir. We designed a series of novel molecules with a double oxygen in the central hydrocarbon chain and some modifications of the lateral methylisoxazole and propoxybenzoate moieties of lead compound 6602 (ethyl 4-{3-[2-(3-methyl-1,2-isoxazol-5-yl)ethoxy]propoxy}benzoate). It was found that most of these substances were actually less toxic than Pirodavir; in addition, the new molecule indicated as 8c was more than 30 times less toxic than Pirodavir, about twice as active on the group A strain of Rhinovirus HRV14, and even four times more effective on the group B strain HRV39, as compared to Pirodavirs PI.

An unusual behaviour of N-(tert-butoxycarbonyl)- and N-pivaloyl-(methylthio)anilines in metallation reactions

Abstract The metallation reaction of N-Boc-and N-Piv-(methylthio)anilines are here described. The results show that N-Boc derivatives are metallated only by superbases to give products substituted at the thiomethylic group. N-Piv derivatives show a different behaviour: ortho-derivative is metallated by both butyllithium and superbase at the thiomethylic carbon atom, while para-derivative is metallated in ortho to the N-Piv group by butyllithium and at the thiomethylic carbon atom by superbase. The meta-derivative is metallated only by superbase at the thiomethylic carbon atom.