2-pyridone synthesis using 2-(phenylsulfinyl)acetamide

Article abstract of DOI:10.1021/ol303320c

2-Pyridones were prepared by means of an efficient protocol including the 1,4-addition of 2-(phenylsulfinyl)acetamide to α,β-unsaturated ketones followed by cyclization and sulfoxide elimination.

Full text of DOI:10.1021/ol303320c

ORGANIC
LETTERS
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Vol. XX, No. XX
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2‑Pyridone Synthesis Using
2‑(Phenylsulfinyl)acetamide
Masaya Fujii,† Takuya Nishimura,† Takahiro Koshiba,† Satoshi Yokoshima,‡ and
Tohru Fukuyama*,†,‡
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Graduate School of Pharmaceutical Sciences,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received December 4, 2012
ABSTRACT
2-Pyridones were prepared by means of an efficient protocol including the 1,4-addition of 2-(phenylsulfinyl)acetamide to R,β-unsaturated ketones
followed by cyclization and sulfoxide elimination.
2-Pyridones are found in a wide range of compounds,
including biologically active natural products and medi-
cines (Figure 1).1 Due to the dual properties of an aromatic
ring and an amide, 2-pyridones appear to have many
effective interactions with biological molecules.
† University of Tokyo.
‡ Nagoya University.
(1) (a) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.;
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ꢀ
Boisse, T.; Rigo, B.; Millet, R.; Henichart, J. P. Tetrahedron 2007, 63,
Figure 1. Biologically active natural products and medicines
containing 2-pyridone rings.
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To date, various methods have been developed to con-
struct 2-pyridone rings.2,3 Among them, the methods
employing R,β-unsaturated ketones and 2-substituted
acetamides as substrates proved to be effective in the pre-
paration of a variety of 2-pyridones. These transformations
r
10.1021/ol303320c
XXXX American Chemical Society

involve 1,4-addition of the acetamides to R,β-unsaturated
ketones followed by cyclization and elimination
(Scheme 1).4,5 Since the elimination step usually proceeds
via the E2 mechanism or deprotonation of the less acidic
position, relatively harsh conditions are required.
products. Our method is characterized by the enhanced
acidity of the R-position of the acetamide by the phenyl-
sulfinyl group as well as its facile elimination from the
Michael adduct through sulfoxide elimination. Extensive
efforts have been made to improve our method so that it
could be regarded as the method of choice for certain
2-pyridones. Herein we disclose the scope and limitations
of our 2-pyridone synthesis.
The key reagent, 2-(phenylsulfinyl)acetamide (1),7 was
prepared from commercially available 2-chloroacetamide
(2) in two steps (Scheme 2). A substitution reaction of 2
with benzenethiol in the presence of potassium carbonate
afforded 2-(phenylthio)acetamide (3). The crude product 3
was oxidized with ozone to give, after recrystallization
from methanol, 1 in 77% yield.
Scheme 1. Synthesis of 2-Pyridone
Scheme 2. Preparation of 2-(Phenylsulfinyl)acetamide
Scheme 3 illustrates the typical procedure to synthesize
2-pyridones. Although a strong base such as sodium
hydride was used initially for the Michael addition,
we found that the reaction could be carried out under
much milder conditions similar to the ones used for the
HornerÀWadsworthÀEmmons reactions by Roush and
During the course of our synthetic studies on Lycopo-
dium alkaloids,6 we encountered difficulties in forming
2-pyridone rings from R,β-unsaturated ketones by means
of conventional procedures. Hence, we developed a
novel method to construct 2-pyridone rings using
2-(phenylsulfinyl)acetamide (X = SOPh, Scheme 1) and
successfully applied it to the total synthesis of the natural
Scheme 3. Typical Procedure for 2-Pyridone Synthesis
€
(4) (a) Thesing, J.; Muller, A. Chem. Ber. 1957, 90, 711. (b) Besidsky,
€
Y.; Luthman, K.; Claesson, A.; Fowler, C. J.; Csoregh, I.; Hacksell, U.
J. Chem. Soc., Perkin Trans. 1 1995, 465. (c) Katritzky, A. R.; Belyakov,
S. A.; Sorochinsky, A. E.; Henderson, S. A.; Chen, J. J. Org. Chem. 1997,
€
62, 6210. (d) Grosche, P.; Holtzel, A.; Walk, T. B.; Trautwein, A. W.;
Jung, G. Synthesis 1999, 1961. (e) Carles, L.; Narkunan, K.; Penlou, S.;
Rousset, L.; Bouchu, D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304.
(f) Katritzky, A. R.; Chassaing, C.; Barrow, S. J.; Zhang, Z.; Vvedensky,
V.; Forood, B. J. Comb. Chem. 2002, 4, 249. (g) Labaudiniere, R.; Dereu,
N.; Cavy, F.; Guillet, M.-C.; Marquis, O.; Terlain, B. J. Med. Chem.
1992, 35, 4315. (h) Wang, S.; Yu, G.; Lu, J.; Xiao, K.; Hu, Y.; Hu, H.
Synthesis 2003, 487. (i) Yu, G.; Wang, S.; Wang, K.; Hu, Y.; Hu, H.
Synthesis 2004, 1021. (j) Wang, S.; Cao, L.; Shi, H.; Dong, Y.; Sun, J.;
Hu, Y. Chem. Pharm. Bull. 2005, 53, 67.
(5) Reactions of R,β-unsaturated ketones with 2-cyanoacetamide to
synthesize 3-cyano-2-pyridones have been reported. These methods
involve oxidation of the intermediates: (a) Al Hajjar, F. H.; Jarrar,
A. A. J. Heterocycl. Chem. 1980, 17, 1521. (b) Jain, R.; Roschangar, F.;
Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 3307. Related oxidative
2-pyridone syntheses have also been reported: (c) Wang, S.; Tan, T.; Li,
J.; Hu, H. Synlett 2005, 2658. (d) Li, S.; Wang, S. J. Heterocycl. Chem.
2008, 45, 1875.
(6) (a) Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2009,
11, 5354. (b) Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T.
J. Am. Chem. Soc. 2011, 133, 418.
(7) 2-(Phenylsulfinyl)acetamide was first reported by Durst and co-
workers in 1973: Durst, T.; Tin, K. C.; Marcil, M. Can. J. Chem. 1973,
51, 1704.
B
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revealed that acetic acid was optimum for the cyclization.
After addition of an excess of acetic acid, the reaction
mixture was heated at reflux to promote cyclization and
sulfoxide elimination, giving pyridone 6a in good yield.
Table 1 summarizes the substrate scope of the 2-pyridone
synthesis. R,β-Unsaturated ketones possessing substituents
at the R- or β-position of the ketone could be converted into
2-pyridones (entries 1À3, 5, and 6). Bulky substituents tend
to decrease the yield, perhaps due to the difficulties in the
1,4-addition (entries 3 and 4). In addition, chalcones could
be employed as substrates (entries 7À10). The mild reac-
tion conditions are compatible with a variety of func-
tional groups, including TBS, MOM, Boc, and Ns groups
(entries 11À15). Somewhat base-sensitive benzoate un-
derwent partial hydrolysis to give 72% yield of 6m along
with 7% of debenzoylated product (entry 13).
Table 1. Substrate Scope of the 2-Pyridone Synthesisa
In conclusion, we have demonstrated an efficient
2-pyridone synthesis using 2-(phenylsulfinyl)acetamide.
A variety of functional groups survived the mild reaction
conditions. Since 2-pyridone is ubiquitous in biologically
active molecules, this method is likely to find widespread
use in the synthesis of medicinally relevant compounds.
Acknowledgment. This work was financially supported
by Grants-in-Aid for Scientific Research (20002004,
22590002) from the Japan Society for the Promotion of
Science (JSPS), the Research Foundation for Pharmaceu-
tical Sciences, the Mochida Memorial Foundation for
Medical and Pharmaceutical Research, the Uehara Memo-
rial Foundation, and the Sumitomo Foundation. M.F. is
grateful to the Graduate Program for Leaders in Life
Innovation (GPLLI).
a Reaction conditions: 1 (2 equiv), DBU (3 equiv), LiCl (3 equiv),
MeCN, 50 °C; AcOH (10 equiv), reflux. b Isolated yield. c Deprotected
alcohol (X = OH) was concomitantly obtained in 7% yield.
Masamune.8 Thus, the 1,4-addition proceeded smoothly
by treatment of a mixture of 4a and 1 with DBU and
lithium chloride in acetonitrile at 50 °C.9,10 After the
addition iscomplete, subsequent cyclization was facilitated
by the addition of acid. Screening of a series of acids
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectra for all new com-
pounds. This material is available free of charges via the
Internet at http://pubs.acs.org.
(10) Roush and Masamune reported that the acidity of phosphono-
acetates seems to be enhanced by complexation with a lithium ion.
2-(Phenylsulfinyl)acetamide (1) can form the same type of complex with
a lithium ion, generating the corresponding anion under milder
conditions.
(8) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(9) In the absence of LiCl, the reaction does not proceed at all.
Employing other salts instead of LiCl resulted in low yields (LiBr, LiI,
MgCl2) or no production of the pyridone (NaCl, KCl, ZnCl2). For
details, see Supporting Information.
The authors declare no competing financial interest.
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