Novel 2-pyridone synthesis via nucleophilic addition of malonic esters to alkynyl imines

Article abstract of DOI:10.1021/ol026283c

(Matrix presented) A novel 2-pyridone synthesis via nucleophilic addition of malonic esters to alkynyl imines has been developed. The reaction of dialkylalkyl sodiomalonates with alkynyl imines provided 2-pyridones in good to excellent yields.

Full text of DOI:10.1021/ol026283c

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2755-2757
Novel 2-Pyridone Synthesis via
Nucleophilic Addition of Malonic Esters
to Alkynyl Imines
Iwao Hachiya, Kana Ogura, and Makoto Shimizu*
Department of Chemistry for Materials, Mie UniVersity, Tsu, Mie 514-8507, Japan
mshimizu@chem.mie-u.ac.jp
Received June 3, 2002
ABSTRACT
A novel 2-pyridone synthesis via nucleophilic addition of malonic esters to alkynyl imines has been developed. The reaction of dialkylalkyl
sodiomalonates with alkynyl imines provided 2-pyridones in good to excellent yields.
Nucleophilic addition to imines is one of the most important
carbon-carbon bond formation reactions for the synthesis
of nitrogen-containing compounds. For example, Lewis acid
catalyzed imino aldol reactions of silyl enol ethers with
aldimines are a useful method for the preparation of â-amino
esters, which are readily converted into â-lactams and amino
acids.1 R,â-Unsaturated aldimines are also employed as
electrophiles in not only imino aldol reactions2 but also
Michael reactions.3 We have already reported a double
nucleophilic addition reaction to R,â-unsaturated aldimines
promoted by titanium tetrahalide or aluminum chloride.4 In
these reactions, ketene silyl acetals underwent 1,4- and
subsequently 1,2-addition to R,â-unsaturated aldimines to
give doubly alkylated products in good yields (Scheme 1).
The initial examination was carried out using the addition
of ketene silyl acetal as nucleophile to alkynyl imines5 in
order to obtain a doubly alkylated product possessing a
double bond. However, the reaction of alkynyl imine 1a with
ketene silyl acetal 2 in the presence of TiCl4 proceeded to
give only 1,2-additon adduct 3 in a quantitative yield
(Scheme 2, eq 1).
To facilitate the conjugate addition, dimethyl malonate
anion, which is a stabilized carbon nucleophile and frequently
employed in conjugate addition reactions, was used as a
nucleophile.6 The reaction of dimethyl sodiomalonate pre-
pared from dimethyl malonate with sodium hydride in THF
under reflux for 7 h gave 2-pyridone 4 in 54% yield (Scheme
2, eq 2). 2-Pyridone 4 is formed most probably via the
mechanism shown in Scheme 3. Metalloallenamine 5 is
generated via 1,4-addtion reaction of dimethyl sodiomalonate
Scheme 1
(1) Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: Oxford, U.K., 1991;
Vol. 2, pp 893-951. Arend, M.; Westermann, B.; Risch, N. Angew. Chem.,
Int. Ed. 1998, 37, 1045-1070.
(2) Hayakawa, R.; Shimizu, M. Chem. Lett. 1999, 591. Akiyama, T.;
Takaya, J.; Kagoshima, H. Tetrahedron Lett. 2001, 42, 4025 and references
therein.
(3) Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y. Synlett 1993, 141.
(4) Shimizu, M.; Morita, A.; Kaga. T. Tetrahedron Lett. 1999, 40, 8401.
Shimizu, M.; Ogawa, T.; Nishi. T. Tetrahedron Lett. 2001, 42, 5463.
Shimizu, M.; Nishi, T. Chem. Lett. 2002, 46.
(5) Stadnichuk, M. D.; Khramchikhin, A. V.; Piterskaya, Y. L.; Suvorova,
I. V. Russ. J. Gen. Chem. 1999, 69, 593. Kel’in, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(6) Michael, E. J. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford, U.K., 1991;
Vol. 4, pp 1-67.
During these investigations, we were interested in the
addition to alkynyl imines and have now found a new
approach to 2-pyridone possessing a 5-alkoxycarbonyl group
via nucleophilic addition of malonic esters to alkynyl imines.
10.1021/ol026283c CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/16/2002

Me, R3 ) Ph) in 58% yield accompanied by the decarboxy-
lated 2-pyridone 9 (R1 ) Me, R2 ) Me, R3 ) Ph) in 15%
yield (Table 1, entry 1). Several examples are shown in Table
1.7 When sodium methoxide (NaOMe) was used as a base,
2-pyridone 8 (R1 ) Me, R2 ) Me, R3 ) Ph) and its
decarboxylated derivative 9 (R2 ) Me, R3 ) Ph) were
obtained in 47% and 42% yields, respectively (entry 2).
When 1,4-dioxane as a reaction solvent was used instead of
THF, the yield of 8 increased (entries 3, 5, and 10), and
especially the reaction of 7b with 1a gave 8 as the sole
product in 91% yield (entry 3). Even increasing the steric
bulk of the nucleophile as with dimethyl allylmalonate (7c),
2-pyridones 8 were obtained in moderate yields (entries 6,
7, 12, and 16). However, the reaction of 7c with 1a using
NaOMe in 1,4-dioxane gave 2-pyridone 8 (R1 ) Me, R2 )
(E)-CHdCHCH3, R3 ) Ph) a double bond of which
isomerized internally (entry 7). The reaction of alkynyl imine
1d possessing a TMS group gave the desilylated 2-pyridone
9 (R2 ) Me, R3 ) H) in 82% yield.
Scheme 2
Scheme 3
The alkynyl imine 1e having a double bond still gave good
yields (entries 14-16). We next examined the reaction of
1c with dibenzylmethyl malonate (7d) to clarify the reaction
mechanism. The reaction in THF under reflux for 7 h gave
2-pyridone 8 (R1 ) Bn, R2 ) Me, R3 )TBSO(CH2)3, 21%),
its decarboxylated derivative 9 (R2 ) Me, R3 ) TBSO(CH2)3,
38%), and dibenzyl carbonate (41%) (Scheme 5).
5 to alkynyl imine 1a. The metalloallenamine 5 in turn
isomerizes into metalloenamine 6, and the cyclization gives
2-pyridone 4.
Scheme 5
The reaction of diethylmethyl sodiomalonate possessing
a single acidic proton was next examined to prevent
isomerization of the double bond. We found that the reaction
of diethylmethyl sodiomalonate (7a) with imine 1a in THF
under reflux for 7 h afforded 2-pyridone 8 (R1 ) Et, R2 )
Me, R3 ) Ph) having a 5-ethoxycarbonyl group in 55% yield
along with the recovered 1a in 13% yield (Scheme 4). In
this paper, we describe the novel synthesis of 2-pyridone
possessing a 5-alkoxycarbonyl group via nucleophilic addi-
tion of malonic esters to alkynyl imines.
The amounts of a base and a malonic ester were investi-
gated using the reaction of dimethylmethyl malonate (7b)
with imine 1a. When amounts of both 7b and NaH were
increased, the reaction gave 2-pyridone 8 (R1 ) Me, R2 )
From this result, we propose a plausible reaction mech-
anism as shown in Scheme 6. Metalloallenamine 10 would
be generated via a 1,4-addtion reaction of dialkyl alkyl
sodiomalonate 7 to alkynyl imine 1 and undergoes an
intramolecular cyclization to give cyclobutenone 11 and
sodium alkoxide. The cyclobutenone 11 would be trans-
formed into the metalloenamine 12 via a ring-opening
reaction by a nuecleophilic addition of sodium alkoxide, and
the subsequent cyclization gives 2-pyridone 8 (path a).
Scheme 4
(7) Typical Experimental Procedure. Reaction of Alkynyl Imines with
Malonic Esters. To 60% NaH or sodium methoxide (0.400 mmol) was
added a solution of malonic ester 7 (0.500 mmol) in THF or 1,4-dioxane
(2.0 mL) and a solution of alkynyl imine 1 (0.200 mmol) in THF or 1,4-
dioxane (2.0 mL) at room temperature. The reaction mixture was stirred
under reflux for several hours (see Table 1) and then cooled to room
temperature. Brine (10 mL) was added to quench the reaction. The mixture
was extracted with dichloromethane (15 mL × 3). The combined organic
layers were dried over sodium sulfate. The solvents were evaporated in
vacuo, and then the residue was purified by preparative TLC on silica gel
to give 2-pyridone 8 and 2-pyridone 9, respectively.
2756
Org. Lett., Vol. 4, No. 16, 2002

Table 1. Nucleophilic Addition of Malonic Esters to Iminesa
yield,b %
entry
R1
R2
R3
base
NaH
NaOMe
NaOMe
NaH
NaOEt
NaH
NaOMe
NaH
NaH
NaH
NaH
NaH
solvent
THF
THF
1,4-dioxane
THF
1,4-dioxane
THF
1,4-dioxane
1,4-dioxane
THF
1,4-dioxane
THF
THF
time, h
8
9
1
2
3
4
5
6c
7
8
9
10c
11
12c
13
14
15
16
Me
Me
Me
Et
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7
7
2
7
3
23
2
2
3
2
58
47
91
39
82
59
67d
71
26
57
26
46
15
42
28
Et
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
allyl
allyl
Me
Me
Me
Me
allyl
Me
Me
Me
19
4
11
39
1
53
4
82e
CH3(CH2)3
TBSO(CH2)3
TBSO(CH2)3
TBSO(CH2)3
TBSO(CH2)3
TMS
1-cyclohexeyl
1-cyclohexeyl
1-cyclohexeyl
3
20
0.5
12
4
NaH
NaH
NaOMe
NaH
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
82
72
63
allyl
8
a For reaction conditions, see ref 7. b Isolated yields. c NaH (0.80 mmol, 4.0 equiv) and 7b or 7c (1.0 mmol, 5.0 equiv) were used. d 2-Pyridone 8 possessing
a double bond that isomerized internally was obtained. e Desilylated 2-pyridone 9 was obtained.
The development of the synthetic methods of functionalized
2-pyridones is important as a result of the large number of
biologically active compounds containing a 2-pyridone
structure.8 Numerous methods for the synthesis of 2-pyri-
dones have been reported.9,10 However, the present 2-pyri-
done synthesis is an attractive alternative method because
alkynyl imines and substituted malonic esters are readily
available from alkynals and malonic esters, respectively.11
The synthetic application of 2-pyridones for the synthesis
of bioactive compounds is now in progress.
The metalloallenamine 10 would undergo protonation to
give R,â-unsaturated imine 13. The decarboxylated 2-pyri-
done 9 and dialkyl carbonate 14 would be formed via a
nucleophilic addition of sodium alkoxide to the ester group
of 13 and the subsequent cyclization (path b).
In summary, we have found a novel method for 2-pyridone
synthesis by 1,4-addition of malonic esters to alkynyl imines.
Scheme 6
Acknowledgment. This work was supported by a grant
from the Sumitomo Foundation.
Supporting Information Available: Experimental pro-
cedures and product characterization for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL026283C
(8) For examples, see: Schultz, A. Z. Chem. ReV. 1973, 73, 385. Curran,
D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863. Kozikowski, A. P.;
Campiani, G.; Sun, L.-Q.; Wang, S.; Saxena, A.; Doctor, B. P. J. Am. Chem.
Soc. 1996, 118, 11357. Williams, D. R.; Lowder, P. D.; Gu, Y.-G.
Tetrahedron Lett. 1997, 38, 327.
(9) For reviews, see: Smith, D. M. In ComprehensiVe Organic Chemistry;
Sammes, P. G., Ed.; Pergamon: Oxford, 1979; Vol. 2, p 67. McKillop, A.;
Boulton, A. J. In ComprehensiVe Heterocyclic Chemistry; Boulton, A. J.,
McKillop, Eds.; Pergamon: Oxford, 1979; Vol. 1, p 3. Bailey, T. D.; Goe,
G. L.; Scriven, E. F. V. In Heterocyclic Compounds; Newkome, G. R.,
Ed.; Wiley: New York, 1984; Vol. 14, Part 5, p 1. Jones, G. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, U.K.; Vol. 2A, p 395.
(10) For recent examples of the synthesis of functionalized 2-pyridones,
see: Furukawa, I.; Fujisawa, H.; Kawazome, M.; Nakai, Y.; Ohta, T.
Synthesis 1998, 1715. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.;
Blacque, O. Eur. J. Org. Chem. 1999, 297. Brun, E. M.; Ramo´n, M.; Parra,
M. Synlett 1999, 1088. Bondavalli, F.; Bruno, O.; Lo Presti, E.; Mosti, L.
Synthesis 1999, 1169.
(11) For a recent example of the synthesis of N-aryl-5-alkoxycarbonyl-
2-pyridones, see: Ko, Y. K.; Lee, S. C.; Koo, D. W.; Jung, M.; Kim, D.-
W. Bull. Korean Chem. Soc. 2001, 22, 234 references therein.
Org. Lett., Vol. 4, No. 16, 2002
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