Concise Entries to 4-Halo-2-pyridones and 3-Bromo-4-halo-2-pyridones

Dedicated to Professor Steven Ley on the occasion of his 70^th birthday

Abstract

Methods for the synthesis of both simple 4-halo-2-pyridones and more functionalized 3,4-di- and (3,4,5-tri)-halo-2-pyridones are described that are based on a combination of Sandmeyer and regioselective (copper-mediated) halogenation, with a 2-chloro or a 2-benzyl­oxy moiety serving as a masked 2-pyridone.

Key words

polyhalopyridone - pyridines - Sandmeyer reaction - halogenation

• References and Notes

• 1 For a recent review on (–)-cytisine synthesis and applications, see: Rouden J, Lasne M.-C, Blanchet J, Baudoux J. Chem. Rev. 2014; 114: 712
• 2 Ishiuchi K, Kubota T, Ishiyama H, Hayashi S, Shibata T, Kobayashi J. Tetrahedron Lett. 2011; 52: 289
• 3 SciFinder indicates that simple 4-halopyridones are commercially available together with a variety of different methods for synthesis available primarily within the patent literature. Some of the results reported here draw on that patent literature, but our goal has been to define generally applicable methods, rather than different procedures for each specific case.

Key references to 2,4-dihalopyridines and 4-halo-2-pyridones. For 2,4-dichloropyridine (from 2-chloro-4-iodopyridine), see:
• 4a Marzi E, Bigi A, Schlosser M. Eur. J. Org. Chem. 2001; 1371 ; and references therein

For 4-chloro-2-pyridone, see:
• 4b Graf R, Lederek-Ponzer E, Freiberg L. Ber. Dtsch. Chem. Ges. 1931; 64: 21

For 4-bromo and 4-iodo-2-pyridones, see:
• 4c Hadida R, Grootenhuis PD. J, Zhou J, Bear B, Miller M, McCartney J. WO 2008141119, 2008
• 4d Claremon DA, Zhuang L, Leftheris K, Tice CM, Xu Z, Ye Y, Singh SB, Cacatian S, Zhao W, Himmelsbach F. WO 2009134400, 2009
• 4e Renz M, Schuehle M, Xu Z. US 20100331320, 2010
• 4f Roth GJ, Fleck M, Neubauer H, Nosse B. US 20120214782, 2012
• 5a Leznoff CC, Svirskaya PI, Yedidia V, Miller JM. J. Heterocycl. Chem. 1985; 22: 145
• 5b We have described an alternative route to 1 (X = F, see ref. 6), because of issues encountered with the separation of 4-and 5-nitropyridines.^5a This alternative employed 4-fluoro-2-methoxypyridine, which is also prepared from 3.
• 5c 4-Bromo-2-pyridone has also been prepared by O-demethylation (using TMSI) of 4-bromo-2-methoxypyridine: Litchfield J, Sharma R, Atkinson K, Filipski KJ, Wright SW, Pfefferkorn JA, Tan B, Kosa RE, Steven B, Tu M, Kalgutkar AS. Bioorg. Med. Chem. Lett. 2010; 20: 6262
• 6 Durkin P, Magrone P, Matthews S, Dallanoce C, Gallagher T. Synlett 2010; 2789
• 7 The 3,4-dibromopyridone 2 (X = Br) has commercial suppliers listed with SciFinder but there is no literature describing the synthesis of this derivative.

This procedure had previously been applied to a 2-chloroquinoline:
• 8a Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Shibata S, Sata Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Miyamoto M, Tojo H, Baba A, Sasaki S. Bioorg. Med. Chem. 2012; 20: 5496

See also:
• 8b Roth GJ, Fleck M, Heine N, Kley J, Lehmann-Lintz T, Neubauer H, Nosse B. US 20120214785, 2012 ; as applied to 4-iodo-2-pyridone
• 9 Attempts to achieve Balz–Schiemann fluorination of 3 under various conditions (as well as in situ conversion into 1a) failed but this may also reflect the likely high volatility of 4a. See: Scott D, Kuduk SD, DiPardo RM, Bock MG. Org. Lett. 2005; 7: 577
• 10 Yoneda N, Fukuhara T. Tetrahedron 1996; 52: 23
• 11 Hydrolysis using NaOH in MeOH at 170 °C has also been reported. See: Searls T, McLaughlin W. Tetrahedron 1999; 55: 11985
• 12 This transformation has also been reported in the patent literature using BnOH and NaH in dioxane at 160 °C: Bahmanyar S, Bates RJ, Blease K, Calabrese AA, Daniel TO, Delgado M, Elsner J, Erdman P, Fahr B, Ferguson G, Lee B, Nadolny L, Packard G, Papa P, Plantevin-Krenitsky V, Riggs J, Rohane P, Sankar S, Sapienza J, Satoh Y, Sloan V, Stevens R, Tehrani L, Tikhe J, Torres E, Wallace A, Whitefield BW, Zhao J. WO 2010027500, 2010
• 13 A control experiment involving exposure of 7b to CuBr₂ (MeCN, r.t., as in Scheme 5) failed to give a tribrominated derivative such as 7c. Both 7b and 7c can be prepared in higher yield starting from 7d (see ref. 16).

For studies associated with copper-mediated halogenation, see:
• 14a Menini L, da Cruz Santos JC, Gusevskaya EV. Adv. Synth. Catal. 2008; 350: 2052

N-Bromosuccinimide will also achieve this transformation:
• 14b Morgentin R, Pasquet G, Boutron P, Jung F, Lamorlette M, Maudet M, Plé P. Tetrahedron 2000; 64: 2772
• 15 When CuI was used in this reaction, we saw a less efficient transformation (24% yield based on 28% conversion, see Supporting Information) to give the 3-iodo analogue of 7d. With CuCl₂, no reaction with 6 was observed.
• 16 Reaction of 7d with CuBr₂ under these conditions gave a mixture of 7b and 7c in 54% and 33% isolated yields, respectively (see Supporting Information).
• 17 McNamara DJ, Cook PD, Allen LB, Kehoe MJ, Holland CS, Teepe AG. J. Med. Chem. 1990; 33: 2006