An efficient organocatalytic method for tandem synthesis of functionalized 2-pyridones

Article abstract of DOI:10.1016/j.tetlet.2011.10.029

Highly functionalized 2-pyridones are obtained via a tandem reaction between primary amines and acetylenic esters in the presence of N-methylimidazole as an organocatalyst.

Full text of DOI:10.1016/j.tetlet.2011.10.029

Tetrahedron Letters 52 (2011) 6649–6651
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient organocatalytic method for tandem synthesis of functionalized
2-pyridones
⇑
Issa Yavari , Mohammad J. Bayat
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly functionalized 2-pyridones are obtained via a tandem reaction between primary amines and
acetylenic esters in the presence of N-methylimidazole as an organocatalyst.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 April 2011
Revised 26 September 2011
Accepted 7 October 2011
Available online 14 October 2011
Keywords:
Primary amine
Acetylenic ester
2-Pyridone
MCRs
Tandem reaction
The last decade has witnessed significant advances in the use of
small organic molecules to catalyze chemical transformations,1–3
and organocatalytic methods have emerged as a powerful ap-
proach for the preparation of important building blocks or com-
pounds.4–7 In this Letter, we report a novel three-component
reaction for the synthesis of highly functionalized 2-pyridones
using N-methylimidazole as an organocatalyst.
and K2CO3 were unsuccessful (Table 1, entries 6–8). Thus,
N-methylimidazole was used as the catalyst for further studies.
A variety of different reaction conditions were employed in an
attempt to optimize the yields and improve the purity of the prod-
ucts. First, the reaction was carried out using various amounts of
the catalyst; 5 mol % of N-methylimidazole in MeCN was found
The 2-pyridone moiety is found in a large number of pharma-
ceuticals, agrochemicals, and functional materials.8,9 It is also a
versatile synthon that can act as a common intermediate for the
preparation of a wide variety of alkaloids.9–11 Thus, the develop-
ment of efficient synthetic methods for heterocycles of this type
has become important in synthetic and medicinal chemistry. Re-
cent interest in the 2-pyridone ring system has led to several
new procedures for its preparation.11–21
In our initial investigations on the preparation of 2-pyridones,
we examined the reaction between benzylamine (2a, 1 mmol),
and dimethyl acetylenedicarboxylate (DMAD, 2 mmol) in the
presence of N-methylimidazole (0.5 mmol). The reaction pro-
ceeded smoothly to give trimethyl 1-benzyl-6-oxo-1,6-dihydro-
2,3,4-pyridinetricarboxylate (4a) in 80% yield (Table 1, entry 2).
1,4-Diazabicyclo[2.2.2]octane (DABCO), pyridine, and isoquinoline
were found to be less effective catalysts than N-methylimidazole
under identical reaction conditions (Table 1, entries 3–5). Other
catalysts, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), PPh3,
Table 1
Reaction of benzylamine (2a) with DMAD in the presence of various organocatalysts
in MeCNa
CO2Me
CO2Me
+
CO2Me
CO2Me
catalyst (50 mol%)
MeCN, r.t., 1.5 h
Bn-NH2
+
N
CO2Me
O
CO2Me
CO2Me
DMAD
Bn
4a
2a
DMAD
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
None
N-Methylimidazole
DABCO
Pyridine
Isoquinoline
DBU
—
80
71
57
32
—
PPh3
K2CO3
—
—
a
Reaction conditions: 2a (1 mmol), DMAD (2 mmol), catalyst (0.5 mmol), MeCN
(5 mL).
⇑
Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
b
Yield of isolated pure product after column chromatography.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.029

6650
I. Yavari, M. J. Bayat / Tetrahedron Letters 52 (2011) 6649–6651
Table 2
Synthesis of compounds 4a–j under the optimized reaction conditionsa
CO2R3
CO2R1
CO2R1
CO2R3
N-methylimidazole (5 mol%)
+
R2NH2
+
MeCN, r.t., 1.5 h
O
N
CO2R1
CO2R1
CO2R3
3a,b
R2
4a-j
1a,b
2a-f
Acetylenic ester R1
Amine R2
Acetylenic ester R3
Product
Yieldb (%)
1a
1a
1a
1a
1a
1a
1b
1b
1a
1b
Me
Me
Me
Me
Me
Me
Et
Et
Me
Et
2a
2b
2c
2d
2e
2f
2a
2b
2a
2a
Bn
3a
3a
3a
3a
3a
3a
3b
3b
3b
3a
Me
Me
Me
Me
Me
Me
Et
Et
Et
Me
4a
4b
4c
4d
4e
4f
4g
4h
4i
80
78
87
78
85
75
68
72
74
77
4-MeC6H4CH2
4-MeOC6H4CH
2-CIC6H4CH2
4-MeOC6H4
n-Bu
Bn
4-MeOC6H4CH
Bn
Bn
4j
a
Reaction conditions: primary alkylamine 2 (1 mmol), acetylenic ester 1 and 3 (1 mmol), N-methylimidazole (5 mol %), MeCN (5 mL).
Yield of isolated pure compound after column chromatography.
b
to give the best result. Subsequently, the solvent effects were
examined, and the best results were obtained in MeCN.
The generality of this transformation was demonstrated by
applying various primary amines and acetylenic esters under opti-
mized conditions and the results are shown in Table 2.22
The reaction of primary amines 2 and acetylenic esters 1a,b in
the presence of N-methylimidazole proceeded smoothly in MeCN
at rt to afford trialkyl 1-[alkyl(aryl)amino]-6-oxo-1,6-dihydro-
2,3,4-pyridinetricarboxylates 4a–h in good yields (Table 2). A wide
range of structurally varied primary amines were employed in this
reaction. Addition of an equimolar amount of 2 and the first acety-
lenic ester 1 to a 1:1 mixture of N-methylimidazole and the second
acetylenic ester 3 in MeCN, produced 2,3-dialkyl 4-alkyl 1-1-(alky-
l(aryl)amino)-6-oxo-1,6-dihydro-2,3,4-pyridinetricarboxylates
4i,j.23
The structures of compounds 4a–j were deduced from their IR,
1H NMR and 13C NMR spectra. The mass spectra of these
compounds displayed molecular ion peaks at the appropriate m/z
values. The 1H and 13C NMR spectroscopic data, as well as IR spec-
tra, were in agreement with the proposed structures. For example,
the 1H NMR spectrum of 4a in CDCl3 exhibited five sharp singlets
readily recognized as arising from methoxy (d = 3.69, 3.78 and
3.89), methylene (d = 5.29), and vinyl (d = 6.85) protons along with
characteristic resonances for the phenyl group. The 1H-decoupled
13C NMR spectrum of 4a exhibited 16 signals in agreement with
the proposed structure. The 1H NMR and 13C NMR spectra of prod-
ucts 4b–j were similar to those for 4a, except for the patterns rep-
resented by the alkyl and aryl groups.
Presumably, the zwitterionic intermediate 6, formed from
N-methylimidazole (R3N) and acetylenic ester 3, is protonated by
3
4
R3N
CO2R3
1 + 2
CO2R3
R3N
O
CO2R1
CO2R3
R3N
CO2R1
N
CO2R1
CO2R1
6
R2
R2HN
11
5
CO2R3
CO2R1
CO2R1
R3O2C
R3O2C
CO2R1
R3N
+
R3O2C
NR3
N
R2
N
CO2R1
8
R2
7
CO2R3
CO2R1
10
R3N
R3O2C
N
CO2R1
R2
9
Scheme 1. A plausible mechanism for the formation of compounds 4.

I. Yavari, M. J. Bayat / Tetrahedron Letters 52 (2011) 6649–6651
6651
NH2
CO2Me
CO2Me
CO2Me
CO2Et
N
N-methylimidazole (5 mol%)
+
+
MeCN, r.t.
CO2Me
CO2Et
1a
2a
12
13
Scheme 2. Synthesis of compound 13.
20. Kondo, T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T. Tetrahedron Lett. 2006, 47,
7107.
21. Yavari, I.; Bayat, M. J. Synlett 2010, 2293.
22. General procedure for the preparation of compounds 4a–h: To a stirred solution
of amine 2 (2 mmol) and acetylenic ester 1 (4 mmol) in MeCN (5 mL), was
added N-methylimidazole (0.1 mmol) at rt. After completion of the reaction
[1.5 h; TLC (AcOEt/hexane 1:4) monitoring], the solvent was evaporated and
the residue was purified by column chromatography [silica gel (230–400
mesh; Merck), AcOEt/hexane 1:3].
the enamino ester 5, generated in situ from primary amine 2 and
acetylenic ester 1, to produce intermediates 7 and 8 (Scheme 1).
Nucleophilic attack of the conjugate base 7 on intermediate 8 leads
to adduct 9, which undergoes two proton shifts to afford new
zwitterionic intermediate 10. Finally, intramolecular cyclization
affords 11, which is converted into
N-methylimidazole.
4 by elimination of
Trimethyl 1-benzyl-6-oxo-1,6-dihydro-2,3,4-pyridinetricarboxylate(4a). White
To extend the scope of this reaction, ethyl propiolate (12) was
used instead of 3. Surprisingly, the expected tandem reaction
was not observed, and instead, dimethyl 2-{N-[(E)-2-(ethoxycar-
bonyl)vinyl]-N-benzylamino}maleate (13) was obtained in 65%
yield (Scheme 2).
Formation of 13 is probably the result of the lower electrophi-
licity of 12 compared to 3. The expected reaction did not proceed
in the presence of pyridine or N-methylimidazole as catalyst. The
reverse reaction was unsuccessful.
powder; mp: 99–101 °C; yield: 0.57 g (80%). IR (KBr) (m
max/cmÀ1): 2942,
1718, 1443, 1267. 1H NMR (500.1 MHz, CDCl3): d = 3.69 (3H, s, MeO), 3.78 (3H,
s, MeO), 3.89 (3H, s, MeO), 5.29 (2H, s, CH2N), 6.85 (1H, s, CH), 7.18 (2H, d,
3J = 6.9 Hz, CH), 7.28–7.32 (3H, m, CH). 13C NMR (125.7 MHz, CDCl3): d = 49.0
(CH2N), 52.8 (MeO), 53.1 (MeO), 53.3 (MeO), 108.1 (C), 121.2 (CH), 127.6 (2
CH), 128.7 (CH), 128.6 (2 CH), 134.9 (C), 142.3 (C), 144.4 (C), 160.6 (C@O), 162.0
(C@O), 163.8 (C@O), 165.5 (C@O). MS: m/z (%) = 360 (M++1, 4), 359 (M+, 17),
344 (4), 328 (11), 300 (65), 272 (18), 91 (25), 77 (13), 59 (5). Anal. Calcd for
C
18H17NO7 (359.33): C, 60.17; H, 4.77; N, 3.90. Found: C, 60.39; H, 4.82; N, 3.81.
Triethyl 1-benzyl-6-oxo-1,6-dihydro-2,3,4-pyridinetricarboxylate (4g). Yellow oil;
yield: 0.55 g (68%). IR (KBr) (
max/cmÀ1): 2945, 1725, 1435, 1251. 1H NMR
m
(500.1 MHz, CDCl3): d = 1.07 (3H, t,3J = 7.2 Hz, Me), 1.28 (3H, t,3J = 7.1 Hz, Me),
1.38 (3H, t, 3J = 7.2 Hz, Me), 4.15 (2H, q, 3J = 7.2 Hz, CH2O), 4.23 (2H, q,
3J = 7.1 Hz, CH2O), 4.35 (2H, q, 3J = 7.2 Hz, CH2O), 5.31 (2H, s, CH2N), 6.84 (1H, s,
CH), 7.18 (2H, d, 3J = 7.1 Hz, CH), 7.25-7.35 (3H, m, CH). 13C NMR (125.7 MHz,
CDCl3): d = 14.1 (Me), 14.8 (Me), 14.9 (Me), 51.0 (CH2N), 63.0 (CH2O), 63.2
(CH2O), 63.9 (CH2O), 109.2 (C), 128.3 (2 CH), 128.8 (CH), 129.5 (2 CH), 135.9
(C), 139.9 (C), 143.7 (C), 145.6 (C), 161.7 (C@O), 162.6 (C@O), 164.4 (C@O),
166.1 (C@O). MS: m/z (%) = 402 (M++1, 5), 401 (M+, 21), 372 (5), 356 (25), 328
(73), 300 (27), 91 (35), 77 (29), 73 (15). Anal. Calcd for C21H23NO7 (401.41): C,
62.84; H, 5.78; N, 3.49. Found: C, 63.20; H, 5.70; N, 3.55.
In summary, we have developed a simple, one-pot synthesis of
highly functionalized 2-pyridones from reactions of primary
amines with acetylenic esters in the presence N-methylimidazole
at rt. Short reaction times, readily available starting materials,
and catalysts are the main advantages of this methodology.
Supplementary data
23. General procedure for the preparation of compounds 4i,j: To a stirred solution of
amine 2a (2 mmol) and the first acetylenic ester 1 (2 mmol) in MeCN (5 mL),
was added N-methylimidazole (0.1 mmol) and the second acetylenic ester 3
(2 mmol) at rt. After completion of the reaction [1.5 h; TLC (AcOEt/hexane 1:4)
monitoring], the solvent was evaporated and the residue was purified by
column chromatography [silica gel (230–400 mesh; Merck), AcOEt/hexane
1:3].
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.029.
References and notes
4-Ethyl 2,3-dimethyl 1-benzyl-6-oxo-1,6-dihydro-2,3,4-pyridinetricarboxylate
(4i). White powder; mp: 84–86 °C; yield: 0.55 g (74%). IR (KBr) (m
max/cmÀ1):
1. MacMillan, D. W. C. Nature 2008, 455, 304.
2. Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2999.
2958, 1736, 1677, 1445, 1276. 1H NMR (500.1 MHz, CDCl3): d = 1.35 (3H,
t,3J = 7.1 Hz, Me), 3.69 (3H, s, MeO), 3.77 (3H, s, MeO), 4.35 (2H, q, 3J = 7.1 Hz,
CH2O), 5.30 (2H, s, CH2N), 6.85 (1H, s, CH), 7.19 (2H, d, 3J = 7.1 Hz, CH), 7.26-
7.32 (3H, m, CH). 13C NMR (125.7 MHz, CDCl3): d = 14.0 (Me), 49.0 (CH2N), 52.7
(MeO), 53.3 (MeO), 62.4 (CH2O), 108.3 (C), 121.2 (CH), 127.5 (2CH), 128.0 (CH),
128.6 (2CH), 140.0 (C), 142.5 (C), 144.3 (C), 160.7 (C@O), 162.1 (C@O), 163.9
(C@O), 165.0 (C@O). MS: m/z (%) = 374 (M++1, 11), 373 (M+, 53), 358 (4), 342
(26), 328 (7), 314 (61), 286 (16), 91 (32), 77 (27), 59 (8). Anal. Calcd for
3. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
4. Wang, Y.; Jiang, H.; Liu, H.; Liu, P. Tetrahedron Lett. 2005, 46, 3935.
5. Syu, S.; Wang, D.; Chen, P.; Hung, Y.; Jhang, Y. Tetrahedron Lett. 2010, 51, 5943.
6. Kand, K.; Saranya, N.; Kalaivani, A.; Perumal, P. T. Synlett 2010, 2751.
7. Waldmann, H.; Khedkar, V.; Duckert, H.; Schurmann, M. Angew. Chem., Int. Ed.
2008, 47, 6869.
8. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
9. Rigby, J. H. Synlett 2000, 1.
10. Lazaar, J.; Hoarau, C.; Mongin, F.; Trécourt, F.; Godard, A.; Quéguiner, G.;
Marsais, F. Tetrahedron Lett. 2005, 46, 3811.
C
19H19NO7 (373.36): C, 61.12; H, 5.13; N, 3.75. Found: C, 60.79; H, 5.20; N, 3.83.
Dimethyl 2-{benzyl[(E)-3-ethoxy-3-oxo-1-propenyl]amino}-2-butenedioate (13).
White powder; mp: 96–98 °C; yield: 0.45 g (65%). IR (KBr) (
max/cmÀ1): 2955,
m
1712, 1463, 1255. 1H NMR (500.1 MHz, CDCl3): d = 1.24 (3H, t, 3J = 7.0 Hz, Me),
3.66 (3H, s, MeO), 4.00 (3H, s, MeO), 4.14 (2H, q, 3J = 7.0 Hz, OCH2), 4.66 (2H, s,
CH2N), 5.17 (1H, d, 3J = 13.4 Hz, CH), 5.23 (1H, s, CH), 7.15 (2H, d, 3J = 7.6 Hz,
CH), 7.29 (2H, t, 3J = 7.1 Hz, CH), 7.36 (1H, t, 3J = 7.4 Hz, CH), 7.61 (1H, d,
3J = 13.4 Hz, CH). 13C NMR (125.7 MHz, CDCl3): d = 14.2 (Me), 51.2 (CH2N), 51.9
(MeO), 53.5 (MeO), 60.1 (OCH2), 96.9 (CH), 99.1 (CH), 125.7 (2 CH), 127.9 (CH),
129.1 (2 CH), 133.0 (C), 163.3 (CH), 150.1 (C), 164.4 (C@O), 166.3 (C@O), 167.0
(C@O). MS: m/z (%) = 347 (M+, 3), 332 (8), 288 (11), 91 (25), 77 (13), 59 (5).
Anal. Calcd for C18H21NO6 (347.36): C, 62.24; H, 6.09; N, 4.03. Found: C, 61.93;
H, 6.14; N, 4.11.
11. Pemberton, N.; Jakobsson, L.; Almqvist, F. Org. Lett. 2006, 8, 935.
12. Yermolayev, S. A.; Gorobets, N. Y.; Desenko, S. M. J. Comb. Chem. 2009, 11, 44.
13. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285.
14. Donohoe, T. J.; Bower, J. F.; Basutto, J. A.; Fishlock, L. P.; Procopiou, P. A.; Callens,
C. K. A. Tetrahedron 2009, 65, 8969.
15. Serry, A. M.; Luik, S.; Laufer, S.; Abadi, A. H. J. Comb. Chem. 2010, 12, 559.
16. Singh, P.; Sharma, P.; Bisetty, K.; Mahajan, M. P. Tetrahedron 2009, 65, 8478.
17. Yavari, I.; Souri, S. Synlett 2007, 2969.
18. Zhang, Y.; Loertscher, B. M.; Castle, S. L. Tetrahedron 2009, 65, 6584.
19. Gorobets, Y. N.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60, 8633.