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1.
Org Biomol Chem ; 21(31): 6325-6341, 2023 Aug 09.
Article in English | MEDLINE | ID: mdl-37337777

ABSTRACT

Examples of carbon-carbon bond-forming cyclisation reactions, involving allyl cations generated by the thermal ring-opening of halocyclopropanes, have been scarcely reported. In this contribution, we are describing the results of a study conducted with N-dihalocyclopropylamide substrates, designed as precursors of cyclic iminium intermediates that were aimed at participating in intramolecular reactions with electron-rich aromatic groups. Competitive side-reactions were identified, and access to the desired polycyclic products was carefully evaluated. The results were found to be strongly dependent on the substitution pattern of the nucleophilic aromatic moieties, as well as on the sizes of the rings of the target products. In spite of the rather moderate yields generally obtained, this approach represents a particularly short and inexpensive route to various interesting nitrogen-containing polycyclic systems, namely benzoindolizidine, benzoquinolizidine, piperidinobenzoazepane and azepanoisoquinoline compounds.

2.
Molecules ; 27(17)2022 Aug 23.
Article in English | MEDLINE | ID: mdl-36080141

ABSTRACT

The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol. The products were obtained with high (E) stereoselectivity but as two regioisomers. The ratios of isomers were found to be dependent on the nature of the allylbenzene partner and were rationalised by electronic effects exercising a determining influence in the ß-hydride elimination step. In addition, the cytotoxic effects of all the Heck reaction products were evaluated against MCF-7 and MDA-MB-231 human breast cancer cells, with unpromising results. Among all, compound 7d exhibited weak cytotoxic activity towards MCF-7 cell lines with IC50 values of 47.92 µM in comparison with tamoxifen and was considered to have general toxicity (SI value < 2).


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , Humans , MCF-7 Cells , Palladium/chemistry , Palladium/pharmacology , Structure-Activity Relationship , Tamoxifen/pharmacology
3.
Org Biomol Chem ; 15(25): 5364-5372, 2017 Jun 27.
Article in English | MEDLINE | ID: mdl-28617508

ABSTRACT

A series of 6,6-dihalo-2-azabicyclo[3.1.0]hexane and 7,7-dihalo-2-azabicyclo[4.1.0]heptane compounds were prepared by the reaction of dihalocarbene species with N-Boc-2,3-dihydro-1H-pyrroles or -1,2,3,4-tetrahydropyridines. Monochloro substrates were synthesised as well, using a chlorine-to-lithium exchange reaction. The behaviour of several aldehydes and ketones under reductive amination conditions with deprotected halogenated secondary cyclopropylamines was investigated, showing that this transformation typically triggers cyclopropane ring cleavage to give access to interesting nitrogen-containing ring-expanded products.

4.
Chemistry ; 21(14): 5584-93, 2015 Mar 27.
Article in English | MEDLINE | ID: mdl-25703453

ABSTRACT

A series of substituted 3-azabicyclo[4.1.0]hept-4-ene derivatives were prepared and analysed by cyclic voltammetry. Preparative aerobic electrochemical oxidation reactions were then carried out. Three original endoperoxides were isolated, characterised and subjected to antimalarial and cytotoxicity activity assays.

5.
Chemistry ; 19(35): 11759-67, 2013 Aug 26.
Article in English | MEDLINE | ID: mdl-23852657

ABSTRACT

The acid-catalysed thermal rearrangements of a family of N-aryl 2-azabicyclo[3.1.0]hexanes is described. These substrates, designed in such a way that the aromatic system is conjugated with an alkene group located at the ortho position relative to the nitrogen atom, have been prepared by using an intramolecular Kulinkovich-de Meijere reaction. The rearrangements can then be conducted either under standard thermal conditions or with microwave activation. Depending on the conditions applied and the substitution pattern, dihydroquinoline or polycyclic aminocyclobutane derivatives can be obtained. A mechanistic discussion is provided, with the proposition of the initial protonation of the aminocyclopropane moiety to give an iminium intermediate. By analogy with related intermolecular reactions, the involvement of electrocyclic reactions among the series of elementary steps that follow is put forward.


Subject(s)
Cyclobutanes/chemistry , Hexanes/chemical synthesis , Catalysis , Hexanes/chemistry , Molecular Dynamics Simulation , Stereoisomerism , Titanium
6.
Chem Commun (Camb) ; 48(41): 5031-3, 2012 May 21.
Article in English | MEDLINE | ID: mdl-22491158

ABSTRACT

The behaviour of thioamides under Kulinkovich-type conditions is compared with the known reactivity of carboxylic amides. Dramatic differences are disclosed.

7.
Org Biomol Chem ; 8(24): 5591-601, 2010 Dec 21.
Article in English | MEDLINE | ID: mdl-20938514

ABSTRACT

This contribution describes the synthesis of several novel bicyclic α-amino endoperoxides, including CF(3)-substituted compounds, prepared by the aerobic electrochemical oxidation of a family of bicyclic aminocyclopropanes. These, in turn, are readily synthesised by a titanium-mediated intramolecular cyclopropanation process (Kulinkovich-de Meijere reaction), starting from N-alkenyl amides that contain a vic-disubstituted double bond, with high diastereoselectivity. An evaluation of the biological activities of several of the molecules produced, against the parasite Plasmodium falciparum, is also presented.


Subject(s)
Amines/chemistry , Antimalarials/chemical synthesis , Cyclopropanes/chemical synthesis , Peroxides/chemistry , Amides/chemistry , Crystallography, X-Ray , Cyclopropanes/pharmacology , Models, Molecular , Molecular Structure , Oxidation-Reduction , Plasmodium falciparum/drug effects , Structure-Activity Relationship
9.
Org Biomol Chem ; 1(17): 3007-9, 2003 Sep 07.
Article in English | MEDLINE | ID: mdl-14518121

ABSTRACT

1,2-Disubstituted olefins bearing an acetamide group were found to undergo intramolecular Kulinkovich-de Meijere cyclopropanation in moderate yield but almost complete diastereoselectivity.

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