One-pot synthesis of 2-pyridones via chemo- and regioselective tandem Blaise reaction of nitriles with propiolates

Article abstract of DOI:10.1021/jo901642t

(Chemical Equation Presented) The Blaise reaction intermediate, generated in situ from Reformatsky reagent and nitrile, reacted with propiolates in a chemo- and regioselective manner to afford 2-pyridone derivatives in good to excellent yields. 2009 Ameri

Full text of DOI:10.1021/jo901642t

pubs.acs.org/joc
substrate, and subsequent hydrolytic cyclization followed by
One-Pot Synthesis of 2-Pyridones via Chemo- and
Regioselective Tandem Blaise Reaction of Nitriles
with Propiolates
oxidative aromatization of the resulting 3,4-dihydropyridones
with use of DDQ,3 molecular oxygen,4 and HNO25 as oxidants
or by eliminative aromatization employing acetoamino and
benzenetriazolyl leaving groups.6 Alternatively, dienaminoe-
sters prepared by the reaction of β-enaminoester with propio-
late can be cyclized to 2-pyridones.7 As an extension, Savarin
and co-workers have recently reported that the reaction of
N-arylated β-enamino ketones with methyl propiolates yielded
the corresponding N-aryl 5-acyl-2-pyridones, which was utilized
as a common template for naphthyridones and quinolines.8 Al-
though these methods are effective for the synthesis of pyri-
done derivatives, it is a prerequisite to prepare R,β-unsaturated
carbonyl substrates or β-enaminocarbonyl derivatives before-
hand from aldehydes or β-ketocarbonyl compounds, res-
pectively. To improve on this, we devised a tandem one-pot
synthesis of various 2-pyridone derivatives from nitriles via the
Blaise reaction intermediate, which is very efficient in yield and
operationally convenient.
Yu Sung Chun,† Ka Yeon Ryu,† Young Ok Ko,†
Joo Yeon Hong,‡ Jongki Hong,‡ Hyunik Shin,*,§ and
Sang-gi Lee*,†
†Department of Chemistry and Nano Science (BK21),
Ewha Womans University, Seoul 120-750, Korea, ‡College of
Pharmacy, Kyung Hee University, Seoul 130-701, Korea, and
§Chemical Development Division, LG Life Sciences,
Ltd./R&D, Daejeon 305-380, Korea
sanggi@ewha.ac.kr;hisin@lgls.com
Received July 29, 2009
The reaction of the Reformatsky reagent with nitrile, the
so-called Blaise reaction, is known to proceed via a zinc
bromide complex of a β-enamino ester.9 Hydrolytic workup
of this reaction intermediate under acidic or basic conditions
provides the corresponding β-keto esters and β-enamino
esters, which have been engineered to build a variety of
molecules.10 Recently, we were intrigued by the possible
tandem use of the Blaise reaction intermediate as a bidendate
organozinc nucleophile having two nucleophilic atoms, i.e.,
the R-carbon and β-nitrogen to the ester group, and found
that the Blaise reaction intermediate acts as a carbon nu-
cleophile toward anhydrides and terminal alkynes to give
R-acylated and R-vinylated β-enaminoesters, respectively.11
The Blaise reaction intermediate, generated in situ from
Reformatsky reagent and nitrile, reacted with propiolates
in a chemo- and regioselective manner to afford 2-pyr-
idone derivatives in good to excellent yields
Pyridones are embedded as common structural units of many
natural products and biologically active compounds.1 As a
result, the development of efficient synthetic methods for this
class of heterocyclic compounds has become a long-stand-
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or malonitrile to an appropriate R,β-unsaturated carbonyl
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Published on Web 09/04/2009
DOI: 10.1021/jo901642t
r
2009 American Chemical Society

Chun et al.
JOCNote
SCHEME 1. A Proposed Mechanism for the Tandem Synthesis
of 2-Pyridone 4a
TABLE 1. Synthesis of 2-Pyridones via Tandem Blaise Reaction with
Propiolatesa
Encouraged by these results, we envisioned that a chemo-
and regioselective reaction of the Blaise reaction intermedi-
ate with propiolates bearing two electrophilic functional
groups, alkyne and ester, would provide a new tandem
synthetic route for 2-pyridone derivatives. Herein we present
the results of our investigation on the development of a
highly efficient one-pot synthesis of 2-pyridone derivatives
via a chemo- and regioselective tandem reaction of the Blaise
reaction intermediate, a zinc bromide complex of β-enamino
ester 2, with propiolates.
To begin our investigation, a Blaise reaction intermediate
2a was prepared in situ by the addition of ethyl bromoacetate
(1.5 equiv) to a solution of benzonitrile 1a (1.0 equiv) and
zinc powder (2.0 equiv, preactivated by using 5.0 mol % of
CH3SO3H) in THF. To our delight, the tandem reaction of
the intermediate 2a with 1.1 equiv of ethyl phenylpropiolate
3a for 3 h afforded the corresponding 2-pyridone 4a in
extremely high 98% yield (Scheme 1).
This result clearly indicated that the Blaise reaction inter-
mediate 2a has an ambivalent nucleophilic nature;both
R-carbon and β-nitrogen can act as nucleophiles. As shown in
Scheme 1, Michael addition of the Blaise reaction intermediate
2a to the propiolate 3a gave the vinyl zinc bromide 5, which was
isomerized to the R-vinylated zinc bromide complex 6 via inter-
and/or intramolecular proton transfer of the acidic R-proton.
Rearrangement of 6 to the Csp3-ZnBr 7, followed by intramo-
lecular cyclization led to the 2-pyridone structure. Careful
monitoring and quenching of the reaction in the early stage
made possible the isolation of appreciable amounts of the
R-vinylated β-enaminoester 8, which supports our proposed
reaction mechanism. The intermediate 8 can also be isolated in
45% yield when the reaction was carried out at 40 °C for 24 h.
We next explored the scope of the tandem Blaise reaction
with propiolates 3 (Table 1).
aThe reaction was carried out on a 7.6-mmol scale of nitrile 1, and
propiolate 3 was added after >98% conversion of nitrile unless other-
wise noted. bIsolated by silica chromatography. cPropiolate 3a was
added at 93% conversion of nitrile.
group with good to excellent yields through the tandem
reaction with ethyl phenylpropiolate. The structures of
2-pyridones are unambigously characterized by spectroscopic
methods and further confirmation was obtained from the
X-ray structure of the 6-ethyl-substituted 2-pyridone 4k
prepared from propionitrile.12 In general, the electronic
properties of nitriles did not affect the reactivity. However,
the sterically more demanding o-methylbenzonitrile showed
diminished reactivity, resulting in a relatively lower yield of
2-pyridone 4e (56%, entry 5, Table 1). Various propiolates
such as aryl and alkyl propiolates have also been investigated
by the tandem reaction of the Blaise reaction intermediate,
prepared from benzonitrile 1a and ethyl bromoacetate
(entries 13-16, Table 1). Tandem reaction with aryl propio-
late having either electron-withdrawing 4-fluoro- or elec-
tron-donating 4-methoxyphenyl groups (3b and 3c) showed
comparable results in providing the corresponding 4,5-dia-
rylated 2-pyridones 4m (92%, entry 13, Table 1) and 4n
(94%, entry 14, Table 1), respectively. The ethyl hexynoate
3d reacted very effectively to afford the corresponding
4-butyl 2-pyridone 4o in 90% yield (entry 15, Table 1). The
sterically more demanding 3e (R2 = cy-C6H11) required
prolonged reaction time (8 h) to achieve high yield of 4p
(entry 16, Table 1). In contrast, the reaction of ethyl propio-
late 3f (R2 = H) resulted in 4q in a poor yield of 18%, which
(12) Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC 742379.
Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: þ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk). For details, see the Supporting Information.
A wide range of aromatic, heteroaromatic, and aliphatic
nitriles could be transformed efficiently to the corresponding
2-pyridones 4a-l (entries 1-12, Table 1) with a 4-phenyl
J. Org. Chem. Vol. 74, No. 19, 2009 7557

Chun et al.
JOCNote
was marginally increased to 35% with 2.2 equiv of 3f even
after 24 h. Significant amounts of the Blaise adduct,
β-enaminoester, were isolated, reflecting facile proton trans-
fer of the acidic acetylenic proton to the Blaise reaction
intermediate (entry 17, Table 1).
In summary, we developed a highly efficient, one-pot
procedure for the synthesis of 2-pyridones through the
tandem reaction of the Blaise reaction intermediate of ni-
triles with propiolates. This methodology not only allows
direct use of nitriles, but also provides quick buildup of high
diversity of pyridone derivatives.
NH4Cl at room temperature and extracted with ethyl acetate
(3 ꢀ 30 mL). The combined organic layer was dried with
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica chromatography
to yield the 2-pyridone 4a (98%, 2.65 g). Yellow solid; mp
208-210 °C; 1H NMR (250 MHz, CDCl3) δ 0.75 (t, J = 7.1
Hz, 3H), 3.80 (q, J = 7.2 Hz, 2H), 6.45 (s, 1H), 7.26-7.41(m,
5H), 7.45-7.52 (m, 5H), 12.21(br s, 1H); 13C NMR (63 MHz,
CDCl3) δ 13.2, 61.2, 114.3, 118.5, 127.2, 128.2, 128.4, 128.7,
128.8, 130.3, 132.9, 138.1, 147.2, 154.0, 163.7, 166.7.
General procedure for the tandem reacton of the Blaise
reaction intermediate of nitrile with propiolate: To a stirred
suspension of commercial zinc dust (10 μm, 1.0 g, 15.3 mmol)
was added methanesulfonic acid (3.7 mg) in anhydrous THF
(4.0 mL). After 10 min of reflux, benzonitrile (0.8 mL,
7.6 mmol) was added all at once. While maintaining reflux
temperature, ethyl bromoacetate (1.26 mL, 11.4 mmol) was
added over 1 h with use of a syringe pump, and the reac-
tion mixture was further heated at reflux for 1 h. To this reac-
tion mixture was added ethyl phenylpropiolate (1.4 mL,
8.4 mmol). After being stirred for 3 h at reflux temperature,
the reaction mixture was quenched with saturated aqueous
Acknowledgment. This work was supported by grants
from the Korea Research Foundation (KRF-2006-312-
C00587) and from the Basic Research Program through
the National Research Foundation of Korea (Nos.
20090070898 and 20090063004) funded by the Ministry of
Education, Science and Technology. We thank Dr. Y. Kim
for X-ray analysis.
Supporting Information Available: Experimental proce-
dure and spectroscopic data and copies of the 1H NMR and
13C NMR spectra for 4a-p and 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
7558 J. Org. Chem. Vol. 74, No. 19, 2009