Iridium-Catalysed C–H Borylation of 2-Pyridones; Bisfunctionalisation of CC4

Aurélien Honraedt; Worawat Niwetmarin; Cecilia Gotti; Hugo Rego Campello; Timothy Gallagher

doi:10.1055/s-0036-1591594

Synthesis, Inhaltsverzeichnis

Synthesis 2018; 50(17): 3420-3429
DOI: 10.1055/s-0036-1591594

paper

Iridium-Catalysed C–H Borylation of 2-Pyridones; Bisfunctionalisation of CC4

Aurélien Honraedt

^aSchool of Chemistry, University of Bristol, BS8 1TS, Bristol, UK eMail: hugo.regocampello@bristol.ac.uk eMail: t.gallagher@bristol.ac.uk

,

Worawat Niwetmarin

^aSchool of Chemistry, University of Bristol, BS8 1TS, Bristol, UK eMail: hugo.regocampello@bristol.ac.uk eMail: t.gallagher@bristol.ac.uk

,

Cecilia Gotti

^bCNR, Institute of Neuroscience, Biometra Department, University of Milan, 20129 Milan, Italy

,

Hugo Rego Campello*

^aSchool of Chemistry, University of Bristol, BS8 1TS, Bristol, UK eMail: hugo.regocampello@bristol.ac.uk eMail: t.gallagher@bristol.ac.uk

,

Timothy Gallagher*

^aSchool of Chemistry, University of Bristol, BS8 1TS, Bristol, UK eMail: hugo.regocampello@bristol.ac.uk eMail: t.gallagher@bristol.ac.uk

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Abstract

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Abstract

The high regioselectivity associated with the iridium-catalysed borylation of pyridones has been exploited to provide a very direct and efficient entry to C(10) doubly substituted CC4 variants of cytisine. Two approaches have been evaluated based on (i) C–H activation of cytisine (or an N-substituted derivative) followed by N-alkylation (to enable dimer formation) and (ii) direct C–H activation and borylation of CC4 itself. Both approaches provide access to C(10)-functionalized CC4 derivatives, but direct borylation of CC4 allows for a wider range of functional group interconversions to be tolerated.

Key words

2-pyridone - iridium-catalyzed borylation - C–H functionalization - CC4 - cytisine

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Referenzen

References

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20 We have carried out preliminary pharmacological evaluation (using binding methods obtained as described earlier^[14]) of two ligands 12d and 12g shown in this paper. Ligand 12d had K _i values of 4142 nM at human α4β2; 45610 nM at human α7. Ligand 12g had K _i values of 7360 nM at human α4β2; 45890 nM at human α7. This indicates that these two substitution changes (NHAc and CO₂Me respectively) lead to both a significant reduction of binding affinity at each of α4β2 and α7, as well as a loss of subtype selectivity by one to two orders of magnitude across these two nicotinic receptors, as compared to CC4. Details of a more extensive study to understand the structure-activity relationships involved here will be published in due course.

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