69
A. Honraedt, T. Gallagher
Letter
Synlett
(5) (a) Leznoff, C. C.; Svirskaya, P. I.; Yedidia, V.; Miller, J. M. J. Het-
erocycl. Chem. 1985, 22, 145. (b) We have described an alterna-
tive 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. (c) 4-Bromo-2-pyridone has also been prepared by
O-demethylation (using TMSI) of 4-bromo-2-methoxypyri-
dine: Litchfield, J.; Sharma, R.; Atkinson, K.; Filipski, K. J.;
Wright, S. W.; Pfefferkorn, J. A.; Tan, B.; Kosa, R. E.; Steven, B.; Tu,
M.; Kalgutkar, A. S. Bioorg. Med. Chem. Lett. 2010, 20, 6262.
(6) Durkin, P.; Magrone, P.; Matthews, S.; Dallanoce, C.; Gallagher,
T. Synlett 2010, 2789.
NH2
X
X
Br
Br
Br
O
t-BuONO
HCl
CuCl2 or CuI
MeCN, r.t.
MeOH
reflux
N
OBn
N
OBn
N
H
7e X = Cl (86%)
7f X = I (55%)
7d
10 X = Cl (96%)
11 X = I (89%)
F
NH2
Br
Br
HCl
t-BuONO
7d
7d
HF, py
MeOH
reflux
N
H
O
N
O
(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.
H
12 (59%)
13 (78%)
Scheme 6 4-Substituted 3-bromo-2-pyridones
(8) This procedure had previously been applied to a 2-chloroquino-
line: (a) 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: (b) Roth, G. J.; 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, S. D.; DiPardo, R. M.; Bock, M. G. Org. Lett.
2005, 7, 577.
In summary, generally applicable methods for the syn-
thesis of the range of 4-halo-2-pyridones 1a–d and a series
of di- and trihalo-2-pyridones 8–12 have been developed.
Acknowledgment
We thank the University of Bristol for financial support.
(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.
Supporting Information
Experimental procedures, full characterization of compounds, and
copies of 1H and 13C NMR spectra are available online at
(12) This transformation has also been reported in the patent litera-
ture using BnOH and NaH in dioxane at 160 °C: Bahmanyar, S.;
Bates, R. J.; Blease, K.; Calabrese, A. A.; Daniel, T. O.; 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, B. W.;
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 start-
ing from 7d (see ref. 16).
(14) For studies associated with copper-mediated halogenation, see:
(a) Menini, L.; da Cruz Santos, J. C.; Gusevskaya, E. V. Adv. Synth.
Catal. 2008, 350, 2052. N-Bromosuccinimide will also achieve
this transformation: (b) 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 Sup-
porting Information) to give the 3-iodo analogue of 7d. With
CuCl2, no reaction with 6 was observed.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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 commer-
cially 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.
(4) Key references to 2,4-dihalopyridines and 4-halo-2-pyridones.
For 2,4-dichloropyridine (from 2-chloro-4-iodopyridine), see:
(a) Marzi, E.; Bigi, A.; Schlosser, M. Eur. J. Org. Chem. 2001, 1371;
and references therein. For 4-chloro-2-pyridone, see: (b) Graf,
R.; Lederek-Ponzer, E.; Freiberg, L. Ber. Dtsch. Chem. Ges. 1931,
64, 21. For 4-bromo and 4-iodo-2-pyridones, see: (c) Hadida, R.;
Grootenhuis, P. D. J.; Zhou, J.; Bear, B.; Miller, M.; McCartney, J.
WO 2008141119, 2008. (d) Claremon, D. A.; Zhuang, L.;
Leftheris, K.; Tice, C. M.; Xu, Z.; Ye, Y.; Singh, S. B.; Cacatian, S.;
Zhao, W.; Himmelsbach, F. WO 2009134400, 2009. (e) Renz, M.;
Schuehle, M.; Xu, Z. US 20100331320, 2010. (f) Roth, G. J.; Fleck,
M.; Neubauer, H.; Nosse, B. US 20120214782, 2012.
(16) Reaction of 7d with CuBr2 under these conditions gave a
mixture of 7b and 7c in 54% and 33% isolated yields, respec-
tively (see Supporting Information).
(17) McNamara, D. J.; Cook, P. D.; Allen, L. B.; Kehoe, M. J.; Holland, C.
S.; Teepe, A. G. J. Med. Chem. 1990, 33, 2006.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 67–69