Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products
This paper presented the efficiency of different Pd-based catalytic systems in a series of SM reactions of 4,5-dibromo-2-methylpyridazin-3(2<i>H</i>)-one with ferroceneboronic acid, ferrocene-1,1′-diboronoc acid, and its <i>bis</i>-pinacol ester. In addition to the disubstitu...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Catalysts |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4344/12/6/578 |
| _version_ | 1797489030590365696 |
|---|---|
| author | Nour-Eddine El Alaoui Mohammed Boulhaoua Dániel Hutai Rita Oláh-Szabó Szilvia Bősze Ferenc Hudecz Antal Csámpai |
| author_facet | Nour-Eddine El Alaoui Mohammed Boulhaoua Dániel Hutai Rita Oláh-Szabó Szilvia Bősze Ferenc Hudecz Antal Csámpai |
| author_sort | Nour-Eddine El Alaoui |
| collection | DOAJ |
| description | This paper presented the efficiency of different Pd-based catalytic systems in a series of SM reactions of 4,5-dibromo-2-methylpyridazin-3(2<i>H</i>)-one with ferroceneboronic acid, ferrocene-1,1′-diboronoc acid, and its <i>bis</i>-pinacol ester. In addition to the disubstituted product, these transformations afford substantial amounts of isomeric 4- and 5-ferrocenyl-2-methylpyridazin-3(2<i>H</i>)-ones, and a unique asymmetric bi-pyridazinone-bridged ferrocenophane with a screwed molecular architecture. The reactions of phenylboronic acid, conducted under the conditions, are proven to be the most reductive in the conversions of ferroceneboronic acid, and produce 2-methyl-4,5-diphenylpyridazin-3(2<i>H</i>)-one as single product, supporting our view about solvent-mediated hydrodehalogenations that are supposed to proceed via the assistance of the ferrocenyl group present in the reaction mixture, or attached to the bromo-pyridazinone scaffold, which is constructed in the first SM coupling of the heterocyclic precursor. A comparative DFT modelling study on the structures and possible transformations of relevant bromo-, ferrocene- and phenyl-containing carbopalladated intermediate pairs was carried out, providing reasonable mechanisms suitable to account for the apparently surprising regioselectivity of the alternative hydrodebromination processes, and for the formation of the ferrocenophane product. Supporting the results of DFT modelling studies, the implication of DMF as a hydrogen transfer agent in the hydrodebromination reactions is evidenced by deuterium labelling experiments using the solvent mixtures DMF-d<sub>7</sub>–H<sub>2</sub>O (4:1) and DMF–D<sub>2</sub>O (4:1). The organometallic products display antiproliferative effects on human malignant cell lines. |
| first_indexed | 2024-03-10T00:11:41Z |
| format | Article |
| id | doaj.art-0118aa87d2af4db4a8a029810811276c |
| institution | Directory Open Access Journal |
| issn | 2073-4344 |
| language | English |
| last_indexed | 2024-03-10T00:11:41Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Catalysts |
| spelling | doaj.art-0118aa87d2af4db4a8a029810811276c2023-11-23T15:58:43ZengMDPI AGCatalysts2073-43442022-05-0112657810.3390/catal12060578Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone ProductsNour-Eddine El Alaoui0Mohammed Boulhaoua1Dániel Hutai2Rita Oláh-Szabó3Szilvia Bősze4Ferenc Hudecz5Antal Csámpai6Department of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University (ELTE), H-1117 Budapest, HungaryDepartment of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University (ELTE), H-1117 Budapest, HungaryDepartment of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University (ELTE), H-1117 Budapest, HungaryELKH-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University (ELTE), Budapest Pázmány P. Sétány 1/A, H-1117 Budapest, HungaryELKH-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University (ELTE), Budapest Pázmány P. Sétány 1/A, H-1117 Budapest, HungaryDepartment of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University (ELTE), H-1117 Budapest, HungaryDepartment of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University (ELTE), H-1117 Budapest, HungaryThis paper presented the efficiency of different Pd-based catalytic systems in a series of SM reactions of 4,5-dibromo-2-methylpyridazin-3(2<i>H</i>)-one with ferroceneboronic acid, ferrocene-1,1′-diboronoc acid, and its <i>bis</i>-pinacol ester. In addition to the disubstituted product, these transformations afford substantial amounts of isomeric 4- and 5-ferrocenyl-2-methylpyridazin-3(2<i>H</i>)-ones, and a unique asymmetric bi-pyridazinone-bridged ferrocenophane with a screwed molecular architecture. The reactions of phenylboronic acid, conducted under the conditions, are proven to be the most reductive in the conversions of ferroceneboronic acid, and produce 2-methyl-4,5-diphenylpyridazin-3(2<i>H</i>)-one as single product, supporting our view about solvent-mediated hydrodehalogenations that are supposed to proceed via the assistance of the ferrocenyl group present in the reaction mixture, or attached to the bromo-pyridazinone scaffold, which is constructed in the first SM coupling of the heterocyclic precursor. A comparative DFT modelling study on the structures and possible transformations of relevant bromo-, ferrocene- and phenyl-containing carbopalladated intermediate pairs was carried out, providing reasonable mechanisms suitable to account for the apparently surprising regioselectivity of the alternative hydrodebromination processes, and for the formation of the ferrocenophane product. Supporting the results of DFT modelling studies, the implication of DMF as a hydrogen transfer agent in the hydrodebromination reactions is evidenced by deuterium labelling experiments using the solvent mixtures DMF-d<sub>7</sub>–H<sub>2</sub>O (4:1) and DMF–D<sub>2</sub>O (4:1). The organometallic products display antiproliferative effects on human malignant cell lines.https://www.mdpi.com/2073-4344/12/6/578Suzuki–Miyaura couplingferroceneferrocenophanehydrodehalogenationDFT-supported reaction mechanismtransmetalation |
| spellingShingle | Nour-Eddine El Alaoui Mohammed Boulhaoua Dániel Hutai Rita Oláh-Szabó Szilvia Bősze Ferenc Hudecz Antal Csámpai Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products Catalysts Suzuki–Miyaura coupling ferrocene ferrocenophane hydrodehalogenation DFT-supported reaction mechanism transmetalation |
| title | Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products |
| title_full | Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products |
| title_fullStr | Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products |
| title_full_unstemmed | Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products |
| title_short | Synthetic and DFT Modeling Studies on Suzuki–Miyaura Reactions of 4,5-Dibromo-2-methylpyridazin-3(2<i>H</i>)-one with Ferrocene Boronates, Accompanied by Hydrodebromination and a Novel Bridge-Forming Annulation In Vitro Cytotoxic Activity of the Ferrocenyl–Pyridazinone Products |
| title_sort | synthetic and dft modeling studies on suzuki miyaura reactions of 4 5 dibromo 2 methylpyridazin 3 2 i h i one with ferrocene boronates accompanied by hydrodebromination and a novel bridge forming annulation in vitro cytotoxic activity of the ferrocenyl pyridazinone products |
| topic | Suzuki–Miyaura coupling ferrocene ferrocenophane hydrodehalogenation DFT-supported reaction mechanism transmetalation |
| url | https://www.mdpi.com/2073-4344/12/6/578 |
| work_keys_str_mv | AT noureddineelalaoui syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts AT mohammedboulhaoua syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts AT danielhutai syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts AT ritaolahszabo syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts AT szilviabosze syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts AT ferenchudecz syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts AT antalcsampai syntheticanddftmodelingstudiesonsuzukimiyaurareactionsof45dibromo2methylpyridazin32ihionewithferroceneboronatesaccompaniedbyhydrodebrominationandanovelbridgeformingannulationinvitrocytotoxicactivityoftheferrocenylpyridazinoneproducts |