Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group
Abstract Transition-metal-catalyzed C-H alkylation of heteroaromatics with alkenes represents an atom-economical and cost-effective strategy for accessing industrially and pharmaceutically relevant compounds. However, the selective C5-H alkylation of biomass-derived furfural and its isosteric analog...
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Nature Portfolio
2025-08-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01653-5 |
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| author | Olga V. Khazipova Oleg V. Khazipov Konstantin E. Shepelenko Alexey S. Kashin Yu Zhang Victor M. Chernyshev Valentine P. Ananikov |
| author_facet | Olga V. Khazipova Oleg V. Khazipov Konstantin E. Shepelenko Alexey S. Kashin Yu Zhang Victor M. Chernyshev Valentine P. Ananikov |
| author_sort | Olga V. Khazipova |
| collection | DOAJ |
| description | Abstract Transition-metal-catalyzed C-H alkylation of heteroaromatics with alkenes represents an atom-economical and cost-effective strategy for accessing industrially and pharmaceutically relevant compounds. However, the selective C5-H alkylation of biomass-derived furfural and its isosteric analog, thiophene-2-carboxaldehyde, highly challenging yet industrially vital substrates, has remained elusive. Herein, we disclose a Ni/NHC-catalyzed strategy for the C5-H alkylation of furan- and thiophene-2-carboxaldehydes with styrenes and norbornene, enabled by a readily installable and recyclable N-PMP (p-methoxyphenyl) imine protecting group. This method also achieves selective C5-H alkenylation with internal alkynes. Mechanistic studies suggest that C-H alkylation proceeds via a ligand-to-ligand hydrogen transfer (LLHT) pathway. The N-PMP imine group effectively suppresses undesirable benzoin condensation of these reactive aldehydes and prevents NHC trapping in Breslow intermediates, a major catalyst deactivation pathway. The protecting group is efficiently cleaved under acid hydrolysis, yielding C5-functionalized aldehydes, while the liberated anisidine can be recycled for imine substrate preparation. This work also highlights the largely unexplored potential of the N-aryl imine group as the protecting group for distal C(sp²)-H functionalization of heteroaromatic aldehydes under Ni catalysis. |
| format | Article |
| id | doaj-art-bf1b7f3d3d484f07b65cfc7b6f1d27a5 |
| institution | Kabale University |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-bf1b7f3d3d484f07b65cfc7b6f1d27a52025-08-24T11:12:19ZengNature PortfolioCommunications Chemistry2399-36692025-08-018111310.1038/s42004-025-01653-5Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting groupOlga V. Khazipova0Oleg V. Khazipov1Konstantin E. Shepelenko2Alexey S. Kashin3Yu Zhang4Victor M. Chernyshev5Valentine P. Ananikov6Platov South-Russian State Polytechnic University (NPI)Platov South-Russian State Polytechnic University (NPI)Platov South-Russian State Polytechnic University (NPI)Zelinsky Institute of Organic Chemistry, Russian Academy of SciencesGuangzhou Institute of Energy Conversion, Chinese Academy of SciencesPlatov South-Russian State Polytechnic University (NPI)Platov South-Russian State Polytechnic University (NPI)Abstract Transition-metal-catalyzed C-H alkylation of heteroaromatics with alkenes represents an atom-economical and cost-effective strategy for accessing industrially and pharmaceutically relevant compounds. However, the selective C5-H alkylation of biomass-derived furfural and its isosteric analog, thiophene-2-carboxaldehyde, highly challenging yet industrially vital substrates, has remained elusive. Herein, we disclose a Ni/NHC-catalyzed strategy for the C5-H alkylation of furan- and thiophene-2-carboxaldehydes with styrenes and norbornene, enabled by a readily installable and recyclable N-PMP (p-methoxyphenyl) imine protecting group. This method also achieves selective C5-H alkenylation with internal alkynes. Mechanistic studies suggest that C-H alkylation proceeds via a ligand-to-ligand hydrogen transfer (LLHT) pathway. The N-PMP imine group effectively suppresses undesirable benzoin condensation of these reactive aldehydes and prevents NHC trapping in Breslow intermediates, a major catalyst deactivation pathway. The protecting group is efficiently cleaved under acid hydrolysis, yielding C5-functionalized aldehydes, while the liberated anisidine can be recycled for imine substrate preparation. This work also highlights the largely unexplored potential of the N-aryl imine group as the protecting group for distal C(sp²)-H functionalization of heteroaromatic aldehydes under Ni catalysis.https://doi.org/10.1038/s42004-025-01653-5 |
| spellingShingle | Olga V. Khazipova Oleg V. Khazipov Konstantin E. Shepelenko Alexey S. Kashin Yu Zhang Victor M. Chernyshev Valentine P. Ananikov Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group Communications Chemistry |
| title | Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group |
| title_full | Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group |
| title_fullStr | Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group |
| title_full_unstemmed | Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group |
| title_short | Ni/NHC-catalyzed C5-H alkylation and alkenylation of challenging furan(thiophene)-2-carboxaldehydes enabled by recyclable imine protecting group |
| title_sort | ni nhc catalyzed c5 h alkylation and alkenylation of challenging furan thiophene 2 carboxaldehydes enabled by recyclable imine protecting group |
| url | https://doi.org/10.1038/s42004-025-01653-5 |
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