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Rhodium-catalysed C(sp(2))-C(sp(2)) bond formation via C-H/C-F activation.

Tian P, Feng C, Loh TP - Nat Commun (2015)

Bottom Line: Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry.The use of readily available gem-difluoroalkenes as electrophiles provides a highly efficient and operationally simple method for the introduction of α-fluoroalkenyl motifs onto (hetero)arenes under oxidant-free conditions.Furthermore, the employment of alcoholic solvent and the in-situ generated hydrogen fluoride are found to be beneficial in this transformation, indicating the possibility of the involvement of hydrogen bond activation mode with regards to the C-F bond cleavage step.

View Article: PubMed Central - PubMed

Affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.

ABSTRACT
Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry. However, the synthetic access to fluoroalkenes was much underdeveloped with previous reported methods suffering from either low step economy or harsh reaction conditions. Here we present a Rh(III)-catalysed tandem C-H/C-F activation for the synthesis of (hetero)arylated monofluoroalkenes. The use of readily available gem-difluoroalkenes as electrophiles provides a highly efficient and operationally simple method for the introduction of α-fluoroalkenyl motifs onto (hetero)arenes under oxidant-free conditions. Furthermore, the employment of alcoholic solvent and the in-situ generated hydrogen fluoride are found to be beneficial in this transformation, indicating the possibility of the involvement of hydrogen bond activation mode with regards to the C-F bond cleavage step.

No MeSH data available.


Related in: MedlinePlus

Proposed method of rhodium-catalysed α-fluoroalkenylation.(a) Oxidative alkenylation through Rh(III)-catalysed C–H activation. (b) Transition-metal-catalysed C–C bond formation through C–F activation. M, metal; TM, transition metal. (c) Base-promoted inter- or intramolecular nucleophilic addition or substitution of gem-difluoroalkenes with heteronucleophiles. X, hetero atom. (d) Pd/Cu-catalysed C–H fluoroalkenylation of heteroarenes. X, Br or CO2H. (e) In this report, oxidant-free Rh(III)-catalysed α-fluoroalkenylation of (hetero)arenes. The hydrogen bonding interaction is believed to promote the cleavage of C–F bond, which, in turn, renders this reaction redox neutral. DG, directing group.
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f1: Proposed method of rhodium-catalysed α-fluoroalkenylation.(a) Oxidative alkenylation through Rh(III)-catalysed C–H activation. (b) Transition-metal-catalysed C–C bond formation through C–F activation. M, metal; TM, transition metal. (c) Base-promoted inter- or intramolecular nucleophilic addition or substitution of gem-difluoroalkenes with heteronucleophiles. X, hetero atom. (d) Pd/Cu-catalysed C–H fluoroalkenylation of heteroarenes. X, Br or CO2H. (e) In this report, oxidant-free Rh(III)-catalysed α-fluoroalkenylation of (hetero)arenes. The hydrogen bonding interaction is believed to promote the cleavage of C–F bond, which, in turn, renders this reaction redox neutral. DG, directing group.

Mentions: Fluorine, ‘small atom with a big ego', due to its intrinsic properties such as small size and high electronegativity in comparison with other halogen atoms, has played a key role in all fields of science12. More specifically, the incorporation of fluorine or fluorine-containing structural motifs into organic molecule brings about substantial improvement in its bioactivity and provides unique chemical and physical properties, thus enabling the widespread use of this strategy in the field of medicinal chemistry345. In this context, fluoroalkenes represent a class of very important molecules owing to their biological properties and also their synthetic potential in synthetic organic chemistry67. Furthermore, as favourable peptide bond mimetics, both electrostatically and geometrically, as well as their resistant nature to enzymatic degradation, the fluoroalkene structural motifs have been attracting increasing interest in medicinal chemistry and drug-discovery research89101112. Albeit their great importance, compared with the development of analogous fluorination and trifluoromethylation methodologies131415161718, the synthetic access to alkenyl fluorides remains largely underdeveloped, with most of the reported protocols suffering from the need of substrate pre-activation or using non-readily available starting materials, low regio- or stereo-selectivity and poor functional group tolerance due to the employment of sensitive reagents192021. By taking advantage of the Pd/Cu-catalysed C–H activation strategy, Hoarau and colleagues2223 reported elegant works on the fluoroalkenylation of heteroarenes either through C–H/C–Br or C–H/CO2H couplings (Fig. 1d). Notwithstanding the advance attained, the development of a new synthetic method, which streamlines the access to fluoroalkene motifs using readily available building blocks while avoiding substrate pre-activation steps, would still be of meaningful importance in both the synthetic organic chemistry and pharmaceuticals development.


Rhodium-catalysed C(sp(2))-C(sp(2)) bond formation via C-H/C-F activation.

Tian P, Feng C, Loh TP - Nat Commun (2015)

Proposed method of rhodium-catalysed α-fluoroalkenylation.(a) Oxidative alkenylation through Rh(III)-catalysed C–H activation. (b) Transition-metal-catalysed C–C bond formation through C–F activation. M, metal; TM, transition metal. (c) Base-promoted inter- or intramolecular nucleophilic addition or substitution of gem-difluoroalkenes with heteronucleophiles. X, hetero atom. (d) Pd/Cu-catalysed C–H fluoroalkenylation of heteroarenes. X, Br or CO2H. (e) In this report, oxidant-free Rh(III)-catalysed α-fluoroalkenylation of (hetero)arenes. The hydrogen bonding interaction is believed to promote the cleavage of C–F bond, which, in turn, renders this reaction redox neutral. DG, directing group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557390&req=5

f1: Proposed method of rhodium-catalysed α-fluoroalkenylation.(a) Oxidative alkenylation through Rh(III)-catalysed C–H activation. (b) Transition-metal-catalysed C–C bond formation through C–F activation. M, metal; TM, transition metal. (c) Base-promoted inter- or intramolecular nucleophilic addition or substitution of gem-difluoroalkenes with heteronucleophiles. X, hetero atom. (d) Pd/Cu-catalysed C–H fluoroalkenylation of heteroarenes. X, Br or CO2H. (e) In this report, oxidant-free Rh(III)-catalysed α-fluoroalkenylation of (hetero)arenes. The hydrogen bonding interaction is believed to promote the cleavage of C–F bond, which, in turn, renders this reaction redox neutral. DG, directing group.
Mentions: Fluorine, ‘small atom with a big ego', due to its intrinsic properties such as small size and high electronegativity in comparison with other halogen atoms, has played a key role in all fields of science12. More specifically, the incorporation of fluorine or fluorine-containing structural motifs into organic molecule brings about substantial improvement in its bioactivity and provides unique chemical and physical properties, thus enabling the widespread use of this strategy in the field of medicinal chemistry345. In this context, fluoroalkenes represent a class of very important molecules owing to their biological properties and also their synthetic potential in synthetic organic chemistry67. Furthermore, as favourable peptide bond mimetics, both electrostatically and geometrically, as well as their resistant nature to enzymatic degradation, the fluoroalkene structural motifs have been attracting increasing interest in medicinal chemistry and drug-discovery research89101112. Albeit their great importance, compared with the development of analogous fluorination and trifluoromethylation methodologies131415161718, the synthetic access to alkenyl fluorides remains largely underdeveloped, with most of the reported protocols suffering from the need of substrate pre-activation or using non-readily available starting materials, low regio- or stereo-selectivity and poor functional group tolerance due to the employment of sensitive reagents192021. By taking advantage of the Pd/Cu-catalysed C–H activation strategy, Hoarau and colleagues2223 reported elegant works on the fluoroalkenylation of heteroarenes either through C–H/C–Br or C–H/CO2H couplings (Fig. 1d). Notwithstanding the advance attained, the development of a new synthetic method, which streamlines the access to fluoroalkene motifs using readily available building blocks while avoiding substrate pre-activation steps, would still be of meaningful importance in both the synthetic organic chemistry and pharmaceuticals development.

Bottom Line: Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry.The use of readily available gem-difluoroalkenes as electrophiles provides a highly efficient and operationally simple method for the introduction of α-fluoroalkenyl motifs onto (hetero)arenes under oxidant-free conditions.Furthermore, the employment of alcoholic solvent and the in-situ generated hydrogen fluoride are found to be beneficial in this transformation, indicating the possibility of the involvement of hydrogen bond activation mode with regards to the C-F bond cleavage step.

View Article: PubMed Central - PubMed

Affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.

ABSTRACT
Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry. However, the synthetic access to fluoroalkenes was much underdeveloped with previous reported methods suffering from either low step economy or harsh reaction conditions. Here we present a Rh(III)-catalysed tandem C-H/C-F activation for the synthesis of (hetero)arylated monofluoroalkenes. The use of readily available gem-difluoroalkenes as electrophiles provides a highly efficient and operationally simple method for the introduction of α-fluoroalkenyl motifs onto (hetero)arenes under oxidant-free conditions. Furthermore, the employment of alcoholic solvent and the in-situ generated hydrogen fluoride are found to be beneficial in this transformation, indicating the possibility of the involvement of hydrogen bond activation mode with regards to the C-F bond cleavage step.

No MeSH data available.


Related in: MedlinePlus