Donatella Giomi

Study on direct benzoannelations of pyrrole and indole systems by domino reactions with 4,5-dicyanopyridazine

Abstract The title pyridazine 1 was found to undergo hetero Diels–Alder [4+2] cycloadditions on the C(2)–C(3) double bond of pyrrole and indole systems; spontaneous loss of nitrogen from the primary adducts, followed by oxidation processes, afforded the corresponding fully aromatic benzoannelated skeletons in modest and reasonable yields, respectively. Competitive attacks of the same systems at the strongly electrophilic C-4 carbon of 1 , leading to substitution products, were evidenced.

Reactions of 4,5-dicyanopyridazine with alkynes and enamines: A new straightforward complementary route to 4-mono- and 4,5-disubstituted phthalonitriles

The preparation of the 1,2-dicyanobenzenes 6a-m in fairly good to excellent yields by one-pot procedures based on [4 + 2] cycloaddition processes of the title compound 1 with acetylenic or enamine dienophiles, is reported; some features of this new synthetic strategy are emphasized.

Hetero Diels-Aler reactions of 4,5-dicyanopyridazine with alkenes

Abstract The behaviour of the title compound 1 with some linear and cyclic olefins has been investigated. Except for the reaction with diphenylcyclopropenone 22, affording 24 and 26 through cyclization processes of the primary Michael adduct 23, a remarkable reactivity as azadiene was observed. The structures of the resulting dicyanocyclohexa-1,3-dienes, aromatic phthalonitriles, and polycyclic bis-adducts were established on the basis of spectral data.

4-Nitroisoxazoles as nitroalkene heterodienes: diastereoselective synthesis of spiro tricyclic nitroso acetals by thermal reactions with ethyl vinyl ether

Abstract A few 4-nitroisoxazoles were found to undergo highly diastereoselective pericyclic homodomino processes with the title enol ether affording 1,6,9-trioxa-5,9a-diazacyclopenta[d]indenes through bicyclic nitronates as key intermediates. Formation of isoxazolo–oxepine systems is also reported together with a domino reaction with the above reagent and methyl acrylate. Two X-ray analyses of compounds 8 and 13 were carried out to firmly establish their stereochemistry.

Phthalonitriles by hetero Diels-Alder reactions of 4,5-dicyanopyridazine with enamines: isolation and characterization of unprecedented intermediates

Abstract The title conversions were shown to involve as key intermediates new dicyanodiene systems, that can be isolated in high yields under mild conditions; their structures, inferred from analytical and spectral data, were confirmed by an X-ray study. Some improvements for the synthetic methodology connected with this finding are discussed.

Recent Syntheses and Biological Activity of Lentiginosine and its Analogues

(+)-Lentiginosine, a natural trans-1,2-dihydroxyindolizidine belonging to the class of iminosugars, is a potent inhibitor of amyloglucosidase, and a good inhibitor of Hsp90. The non-natural enantiomer, (-)-lentiginosine, induces apoptosis on tumor cells of different origin and is poorly cytotoxic towards non-transformed cells. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review is an update of a previous survey and summarizes the most recent achievements on biological studies as well as total syntheses of lentiginosine and trans-1,2-dihydroxyindolizidine analogues.

[4+2]- and [2+4]-cycloaddition processes of 4,5-dicyanopyridazine with 2,3-dimethylbuta-1,3-diene

Abstract The title compounds afforded under relatively mild conditions the polycyclic systems 3a, 4, and 5 through alternative concomitant cycloadditions; the reactivity of the dicyanopyridazine system was critically influenced by the presence of methyl groups at the 3 and 6 positions. The skeleton of 3a and the stereochemistry of 5 were established by X-ray experiments.

[2+4] Cycloaddition reactions of 4-Nitro-3-phenylisoxazole with Carbo- and heterodienes

Abstract The title compound 4 reacted as a dienophile with open-chain and cyclic carbodienes as well as the 1-azadiene 16, to yield different polynuclear isoxazole systems. On the contrary, it gave rise preferentially to a Michael-type reaction with the dimethyluracil derivative 19 affording the cine-substitution product 23, whose structure was determined by an X-ray analysis. Some mechanistic features and synthetic opportunities are emphasized.

Reactivity and Synthetic Applications of 4,5-Dicyanopyridazine: An Overview

Despite the poor reputation of electron-deficient pyridazines in intermolecular Hetero Diels-Alder (HDA) reactions, 4,5-dicyanopyridazine (DCP) showed a surprising reactivity as a heterocyclic azadiene in inverse electron-demand HDA processes with different dienophiles. The use of alkenes, alkynes and enamines as 2π electron counterparts afforded dicyanocyclohexa-1,3-dienes and substituted phthalonitriles, respectively, while the use of suitable bis-dienophiles provides a general strategy for the one-pot synthesis of polycyclic carbo- and hetero-cage systems through pericyclic three-step homodomino processes. HDA reactions with heterocyclic dienophiles allowed direct benzoannelation: in particular, pyrrole and indole derivatives were converted to dicyano-indoles and -carbazoles. In addition an unprecedented reactivity of DCP as a very reactive heterocyclic electrophile at the C-4 carbon was also evidenced: by changing the experimental conditions, cyanopyrrolyl- and cyanoindolyl-pyridazines were obtained through reactions of pyrrole and indole systems as carbon nucleophiles in formal SNAr2 processes where a CN group of DCP acts as leaving group. Thus, careful control of the reaction conditions allows exploitation of both pathways for the synthesis of different classes of heterocyclic derivatives.

Synthesis of 1,2-Dihydroxyindolizidines from 1-(2-Pyridyl)-2-propen-1-ol

1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available picolinaldehyde, resulted a good starting material for the synthesis of the indolizidine skeleton. In particular, a simple process involving bromination, reduction, and nucleophilic substitution (via elimination and addition) allowed an easy conversion of the starting material into (±)-lentiginosine in ~27% overall yield.