Synthetic entries to substituted bicyclic pyridones

Organic Letters

Volumn 9, Issue 25, 2007, Pages 5175-5178

  Cheng, Dachen ^a   Croft, Laura ^a   Abdi, Muna ^a   Lightfoot, Andrew ^b   Gallagher, Timothy ^a  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

FUSED HETEROCYCLIC RINGS; IODINE DERIVATIVE; PYRIDONE DERIVATIVE;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; ISOMERISM; SYNTHESIS;

HETEROCYCLIC COMPOUNDS, 2-RING; IODINE COMPOUNDS; ISOMERISM; MOLECULAR STRUCTURE; PYRIDONES;

EID: 37249006235     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol701689z     Document Type: Article

References (19)

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10. Hehemann, D. G.; Winnik, W. J. Heterocycl. Chem. 1994, 31, 393-396.
11. The primary chloride corresponding to 6 was isolated in 5% yield using a shorter reaction time (15 min), and it was then shown that this chloride cyclizes to give 2a under the microwave reaction conditions used.
12. Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459-7462.
13. 1H NMR but was not fully characterized. Debenzylation of this intermediate occurred on treatment with NaOH, and the apparently facile nature of this step may be associated with the enhanced leaving group ability of a 2-aminopyridine. The structure of 15 was confirmed by an alternative synthesis by reaction of 5 with pyrrolidine. See Supporting Information.
14. Even under forcing conditions, we have not observed N-mesylation of 11 which limits our ability to deactivate the exo-amino function.
15. For reviews of regioselective lithiation of pyridines, see: (a) Quéguiner, G.; Marais, F.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187-304.
16. (b) Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4059-4090.
17. Altenbach, R. J.; Black, L. A.; Chang, S.-J.; Cowart, M. D.; Faghih, R.; Gfesser, G. A.; Ku, Y.-Y.; Liu, H.; Lukin, K. A.; Nersesian, D. L.; Pu, Y.-M.; Sharma, P. N.; Bennani, Y. L. WO 2004043458, 2004. (10) Reaction of 16 with 4-iodopyridine gave the corresponding 3-(4-pyridyl) adduct in 93% yield. Nucleophilic displacements on 2,6-difluoropyridine 3-carboxylates have been studied (Hirokawa, Y.; Horikawa, T.; Kato, S. Chem. Pharm. Bull. 2000, 48, 1847-1853). In our hands, nucleophilic substitution of 17 shows only moderate regioselectivity (8-2:1) depending on the nature of the aryl moiety. In the case of 17a, the minor (of a 2:1 mixture) regioisomer (not shown) was converted to the corresponding C(9)-arylated bicyclic pyridone using the same methodology. See Supporting Information.
18. Schlosser, M.; Rausis, T. Eur. J. Org. Chem. 2004, 1018-1024.
19. Regioisomeric iodopyridines 20 and 21 show significant volatility and care must be taken during work-up and purification.