A straightforward synthesis of 2-[1-alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4- tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives via domino Michael addition-cyclization reaction

Article abstract of DOI:10.1002/hlca.201100471

A new and efficient synthesis of 2-[1-alkyl-5,6-bis(alkoxycarbonyl)-1,2,3, 4-tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives by a one-pot three-component reaction between primary amine, dialkyl acetylenedicarboxylate, and itaconic anhydride (=3,4-dihydro-3-methylidenefuran-2,5-dione) is reported. The reaction was performed without catalyst and under solvent-free conditions with excellent yields. Notably, the ready availability of the starting materials, and the high level of practicability of the reaction and workup make this approach an attractive complementary method to access to unknown 2-[1-alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives. The structures were corroborated spectroscopically (IR, ¹H- and ¹³C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this type of domino Michael addition-cyclization reaction is proposed (Scheme 2). Copyright

Full text of DOI:10.1002/hlca.201100471

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Helvetica Chimica Acta – Vol. 95 (2012)
A Straightforward Synthesis of 2-[1-Alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-
tetrahydro-2-oxopyridin-3-yl]acetic Acid Derivatives via Domino Michael
AdditionꢀCyclization Reaction
by Abdolali Alizadeh* and Atieh Rezvanian
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: aalizadeh@modares.ac.ir,
abdol_alizad@yahoo.com)
A new and efficient synthesis of 2-[1-alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-
3-yl]acetic acid derivatives by a one-pot three-component reaction between primary amine, dialkyl
acetylenedicarboxylate, and itaconic anhydride (¼ 3,4-dihydro-3-methylidenefuran-2,5-dione) is report-
ed. The reaction was performed without catalyst and under solvent-free conditions with excellent yields.
Notably, the ready availability of the starting materials, and the high level of practicability of the reaction
and workup make this approach an attractive complementary method to access to unknown 2-[1-alkyl-
5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives. The structures were
corroborated spectroscopically (IR, 1H- and 13C-NMR, and EI-MS) and by elemental analyses. A
plausible mechanism for this type of domino Michael additionꢀcyclization reaction is proposed
(Scheme 2).
1. Introduction. – Pyridine synthesis, to which a great deal of work has been devoted
by chemists until recently, has long occupied a significant place in organic synthesis,
resulting in the development of a wide range of synthetic methods1). Nevertheless,
these methods suffer from many limitations such as complicated procedures, harsh
reaction conditions, the requirement for a metal, and substrates that are not readily
available. Consequently, it is desirable to find new, single-step, and efficient methods
for the construction of pyridines. As part of our ongoing research aimed at developing
metal-free, multicomponent, and diversity-oriented domino-based syntheses of bio-
logically relevant heterocycles, here, we report a novel synthesis of 2-[1-alkyl-5,6-
bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives.
2. Results and Discussion. – Recently, we focused our interest on the preparation of
new compound libraries and synthetically nitrogenated analogs of important natural
products in medicinal chemistry by using one-pot synthesis and reactions of enamines
and dienamines [5]. We previously found that the reaction of secondary amines and
electron-deficient acetylenic compounds with Michael acceptors such as arylsulfonyl
1
)
For a recent review of de novo methods for pyridine synthesis, see [1]. For selected recent examples
on the transition metal-catalyzed synthesis of substituted pyridines, see [2]. For selected recent
examples of the synthesis of substituted pyridines via multicomponent reactions, see [3]. For
selected recent examples of the synthesis of substituted pyridines via using ammonium acetate as
the N source, see [4].
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
859
isocyanate successfully led to polysubstituted azetidine-2,4-diones [6] and maleimides
[7] (Scheme 1). Along the same lines, we were interested in the reaction of a primary
amine 1, dialkyl acetylenedicarboxylates 2, and itaconic anhydride (¼ 3,4-dihydro-3-
methylidenefuran-2,5-dione). To the best of our knowledge, there has been no report
on the reaction of enamines (derived from acetylenic compounds) with itaconic
anydride. Under this aspect, we report here a straightforward approach to 2-[1-alkyl-
5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives
via a one-pot process. As compiled in the Table, the one-pot, optimized equimolar
reaction of primary amines 1, dialkyl acetylenedicarboxylates 2, and itaconic anhydride
proceeded smoothly under solvent-free conditions to afford 2-[1-alkyl-5,6-bis(alkoxy-
carbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives 3 after 5 h in
70 – 87% yields (Table).
Scheme 1. Synthesis of Azetidine-2,4-diones and Maleimides via Enamine as the Key Intermediate
Table. Single-Step Synthesis of 2-[1-Alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyridin-3-yl]-
acetic Acid Derivatives
Entry
Products 3
R
R’
Yield [%]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
Pr
Pr
Me
Et
Me
Et
Me
Et
Me
Me
Me
82
76
73
87
72
78
70
81
86
Bu
iBu
iBu
iBu
Bn
4-MeꢀC6H4CH2
4-MeOꢀC6H4CH2
The structures of compounds 3a – 3i were deduced from their elemental analysis,
and IR, high-field 1H- and 13C-NMR, and mass spectra. For example, the mass spectrum
of 3d displayed the Mþ peak at m/z 355, which is in agreement with the proposed

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Helvetica Chimica Acta – Vol. 95 (2012)
structure. The IR spectrum of 3d in KBr showed an absorption band due to the OH
stretching frequency at 3210 cmꢀ1. Further absorption bands at 1727, 1700, and
1
1631 cmꢀ1 are due to the C¼O groups. The H-NMR spectrum of 3d exhibited three
triplets for Me groups (d(H) 0.76 (t, J ¼ 7.3), 1.15 (t, J ¼ 7.1), and 1.24 (t, J ¼ 7.2)), eight
multiplets for seven CH2 and one CH groups, because these H-atoms are diastereotopic
(d(H) 1.37 – 1.45, 2.28 – 2.42, 2.73 – 2.79, 2.84 – 2.89, 3.07 – 3.13, 3.58 – 3.64, 4.04 – 4.10,
1
and 4.18 – 4.28), and one singlet for a OH group (d(H) 9.20). The H-decoupled
13C-NMR spectrum of 3d showed 17 distinct resonances in agreement with the
suggested structure.
Based on these results, a plausible mechanism for the sequential three-component
reaction is proposed (Scheme 2). In the first step, the formation of enamine 4 occurs
through addition of amine 1 to active acetylenic compound 2. Next, Michael addition of
4 to the C¼C bond of itaconic anhydride produces the nonisolable zwitterionic adduct,
intermediate 5, that promptly afforded 2-[1-alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-
tetrahydro-2-oxopyridin-3-yl]acetic acid derivatives 3 by an intramolecular azacycliza-
tion via tautomerization CH/NH or 1,3-H shift and intramolecular nucleophilic attack
of the NꢀH bond of enamine across the C¼O bond (Scheme 2).
Scheme 2. Mechanistic Proposal for the Synthesis of 2-[1-Alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahy-
dro-2-oxopyridin-3-yl]acetic Acid Derivatives 3a – 3i
In summary, we have reported a novel, efficient, and practical one-pot procedure
for the preparation of 2-[1-alkyl-5,6-bis(alkoxycarbonyl)-1,2,3,4-tetrahydro-2-oxopyr-
idin-3-yl]acetic acid derivatives by a unique one-pot three-component reaction of
primary amines, dialkyl acetylenedicarboxylates, and itaconic anhydride. This method
circumvents some of the problems and limitations associated with frequently used
procedures; it is advantageous in terms of simplicity and mildness, and hopefully could
find wide application in the synthesis of complex pyridine-containing compounds.
Notably, this environmentally friendly single-flask approach avoids transition-metal
catalysts and organic solvents, employs readily available materials, and occurs with

Helvetica Chimica Acta – Vol. 95 (2012)
861
complete control of pathway selectivity. Current studies to extend this methodology,
including the use of other nucleophilic partners, are in progress.
Experimental Part
General. The primary amines, dimetyl, and diethyl acetylenedicarboxylate, and itaconic anhydride
were obtained from Merck (Germany) and Fluka (Switzerland), and were used without further
purification. M.p.: Electrothermal 9100 apparatus. IR Spectra: in KBr on a Shimadzu IR-460
spectrometer. 1H- and 13C-NMR spectra: at 500 and 125 MHz, resp., on a BRUKER DRX 500-AVANCE
FT-NMR instrument, in CDCl3 if not otherwise stated. MS: FINNIGAN-MATT 8430 mass spectrometer
operating at an ionization potential of 70 eV. Elemental analyses for C, H and N: Heraeus
CHNꢀOꢀRapid analyzer.
General Procedure (exemplified for 3a). To a magnetically stirred 5-ml flat-bottom flask containing
PrNH2 (0.059 g, 1 mmol) was added dimethyl acetylenedicarboxylate (0.142 g, 1 mmol), and itaconic
anhydride (0.112 g, 1 mmol). The resulting mixture was stirred for 5 h at ambient temp. After completion
of the reaction (the progress of the reaction was followed by TLC (hexane/AcOEt, 7:1)), the crude
product was purified by column chromatography (CC; SiO2 (Merck; 230 – 240 mesh); hexane/AcOEt
7:1).
2-[1,2,3,4-Tetrahydro-5,6-bis(methoxycarbonyl)-2-oxo-1-propylpyridin-3-yl]acetic Acid (3a). Yield:
256 mg (82%). Yellow oil. IR: 3331 (OH), 1730, 1742 (COOMe), 1659 (CO), 1288 (CꢀN), 1124 (CꢀO).
1H-NMR: 0.75 (t, J ¼ 7.4, 3 H); 1.43 – 1.50 (m, 2 H); 2.31 – 2.45 (m, 2 H); 2.76 – 2.82 (m, 2 H); 2.87 – 2.93
(m, 1 H); 3.05 – 3.11 (m, 1 H); 3.56 – 3.62 (m, 1 H); 3.65 (s, 3 H); 3.81 (s, 3 H); 10.13 (br., 1 H).
13C-NMR: 10.4; 20.1; 24.8; 33.7; 35.5; 44.0; 51.6; 52.5; 106.7; 142.7; 163.4; 165.0; 170.2; 176.5. EI-MS
(70 eV): 313 (4, Mþ), 282 (20), 254 (94), 180 (100), 112 (36), 80 (35), 55 (47). Anal. calc. for C14H19NO7
(313.30): C 53.67, H 6.11, N 4.47; found: C 53.68, H 6.09, N 4.45.
2-[1,2,3,4-Tetrahydro-5,6-bis(ethoxycarbonyl)-2-oxo-1-propylpyridin-3-yl]acetic Acid (3b). Yield:
259 mg (76%). Yellow oil. IR: 3210 (OH), 1722, 1703 (COOEt), 1632 (CO), 1280 (CꢀN), 1132 (CꢀO).
1H-NMR: 0.84 (t, J ¼ 7.2, 3 H); 1.27 (t, J ¼ 7.1, 3 H); 1.35 (t, J ¼ 7.1, 3 H); 1.48 – 1.61 (m, 2 H); 2.37 – 2.52
(m, 2 H); 2.82 – 2.89 (m, 2 H); 2.93 – 3.01 (m, 1 H); 3.13 – 3.19 (m, 1 H); 3.63 – 3.71 (m, 1 H); 4.15 – 4.20
(m, 2 H); 4.28 – 4.41 (m, 2 H); 9.50 (br., 1 H). 13C-NMR: 10.8; 13.4; 13.5; 21.8; 25.2; 39.9; 35.6; 46.0; 60.6;
61.5; 107.0; 142.7; 162.9; 164.5; 170.4; 176.3. EI-MS (70 eV): 341 (5, Mþ), 324 (2), 296 (17), 282 (100), 266
(32), 248 (19), 208 (30), 194 (44), 166 (58). Anal. calc. for C16H23NO7 (341.36): C 56.30, H 6.79, N 4.10;
found: C 56.31, H 6.77, N 4.09.
2-[1-Butyl-1,2,3,4-tetrahydro-5,6-bis(methoxycarbonyl)-2-oxopyridin-3-yl]acetic Acid (3c). Yield:
239 mg (73%). Yellow oil. IR: 3280 (OH), 1708, 1722 (COOMe), 1673 (CO), 1258 (CꢀN), 1135 (CꢀO).
1H-NMR: 0.88 (t, J ¼ 7.30, 3 H); 1.29 – 1.49 (m, 4 H); 2.39 – 2.53 (m, 2 H); 2.81 – 3.06 (m, 3 H); 3.16 – 3.24
(m, 1 H); 3.41 – 3.47 (m, 1 H); 3.74 (s, 3 H); 3.90 (s, 3 H); 9.91 (br., 1 H). 13C-NMR: 13.6; 20.0; 25.6; 30.6;
34.3; 36.1; 45.0; 52.2; 53.0; 107.2; 143.3; 163.9; 165.4; 170.7; 176.5. EI-MS (70 eV): 327 (3, Mþ), 296 (9),
268 (47), 220 (25), 180 (54), 85 (30), 59 (100). Anal. calc. for C15H21NO7 (327.33): C 55.04, H 6.47, N 4.28;
found: C 53.68, H 6.09, N 4.45.
2-[1-Butyl-1,2,3,4-tetrahydro-5,6-bis(ethoxycarbonyl)-2-oxopyridin-3-yl]acetic Acid (3d). Yield:
309 mg (87%). Yellow oil. IR: 3210 (OH), 1727, 1720 (COOEt), 1631 (CO), 1265 (CꢀN), 1132
1
(CꢀO). H-NMR: 0.76 (t, J ¼ 7.30, 3 H); 1.15 (t, J ¼ 7.1, 3 H) 1.24 (t, J ¼ 7.1, 3 H); 1.37 – 1.45 (m, 4 H);
2.28 – 2.42 (m, 2 H); 2.73 – 2.79 (m, 2 H); 2.84 – 2.89 (m, 1 H); 3.07 – 3.13 (m, 1 H); 3.58 – 3.64 (m, 1 H);
4.04 – 4.10 (m, 2 H); 4.18 – 4.28 (m, 2 H); 9.20 (br., 1 H). 13C-NMR: 13.4; 13.6; 13.9; 19.7; 25.5; 28.9; 34.1;
36.0; 44.6; 61.0; 62.3; 107.4; 152.9; 163.3; 164.9; 170.7; 176.2. EI-MS (70 eV): 355 (5, Mþ), 296 (100), 194
(41), 166 (42), 83 (42). Anal. calc. for C17H25NO7 (355.38): C 57.45, H 7.09, N 3.94; found: C 57.44, H 7.11,
N 3.92.
2-[1,2,3,4-Tetrahydro-5,6-bis(methoxycarbonyl)-1-(2-methylpropyl)-2-oxopyridin-3-yl]acetic Acid
(3e). Yield: 235 mg (72%). Yellow oil. IR: 3370 (OH), 1732, 1729 (COOMe), 1632 (CO), 1270
(CꢀN), 1136 (CꢀO). 1H-NMR: 0.84 (d, J ¼ 7.1, 6 H); 1.91 – 2.02 (m, 1 H); 2.42 – 2.47 (m, 2 H); 2.81 – 2.99
(m, 3 H); 3.03 – 3.08 (m, 1 H); 3.65 – 3.3.70 (m, 1 H); 3.65 (s, 3 H); 3.81 (s, 3 H); 10.13 (br., 1 H).

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Helvetica Chimica Acta – Vol. 95 (2012)
13C-NMR: 19.25; 19.30; 25.1; 27.7; 34.8; 36.2; 50.7; 51.5; 52.5; 107.7; 142.9; 163.3; 165.0; 170.8; 175.7. EI-
MS (70 eV): 327 (5, Mþ), 296 (19), 268 (87), 252 (30), 224 (18), 180 (100), 152 (16), 84 (17), 55 (35).
Anal. calc. for C15H21NO7 (327.33): C 55.04, H 6.47, N 4.28; found: C 55.02, H 6.48, N 4.25.
2-[1,2,3,4-Tetrahydro-5,6-bis(ethoxycarbonyl)-1-(2-methylpropyl)-2-oxopyridin-3-yl]acetic Acid
(3f). Yield: 277 mg (78%). Yellow oil. IR: 3281 (OH), 1720, 1709 (COOEt), 1632 (CO), 1289
(CꢀN), 1211 (CꢀO). 1H-NMR: 0.83 (t, J ¼ 7.3, 6 H); 1.26 (t, J ¼ 7.0, 3 H) 1.39 (t, J ¼ 7.0, 3 H); 1.92 – 1.97
(m, 1 H); 2.40 – 2.55 (m, 2 H); 2.79 – 2.89 (m, 3 H); 3.63 – 3.69 (m, 1 H); 3.71 – 3.78 (m, 1 H); 4.15 – 4.20
(m, 2 H); 4.29 – 4.39 (m, 2 H); 8.24 (br., 1 H). 13C-NMR: 13.4; 13.6; 19.2; 19.3; 25.1; 27.7; 34.1; 35.9; 50.8;
60.7; 61.9; 107.9; 142.9; 162.8; 164.5; 170.9; 176.2. EI-MS (70 eV): 355 (5, Mþ), 310 (16), 296 (100), 280
(29), 238 (37), 194 (74), 166 (47), 113 (44), 85 (51). Anal. calc. for C17H25NO7 (355.38): C 57.45, H 7.09, N
3.94; found: C 57.47, H 7.10, N 3.95.
2-[1-Benzyl-1,2,3,4-tetrahydro-5,6-bis(methoxycarbonyl)-2-oxopyridin-3-yl]acetic Acid (3g). Yield:
252 mg (70%). Yellow oil. IR: 3290 (OH), 1724, 1703 (COOMe), 1633 (CO), 1271 (CꢀN), 1187 (CꢀO).
1H-NMR: 2.41 – 2.51 (m, 2 H); 2.83 – 2.86 (m, 2 H); 2.97 – 3.08 (m, 1 H); 3.55 (s, 3 H); 3.62 (s, 3 H); 4.52
(d, 2J ¼ 16.0, 1 H); 4.91 (d, 2J ¼ 16.0, 1 H); 7.08 – 7.22 (m, 5 H); 8.50 (br., 1 H). 13C-NMR: 25.4; 34.1; 36.0;
47.2; 52.1; 52.7; 108.4; 127.0; 127.5; 128.4; 136.3; 142.5; 163.7; 165.4; 171.1; 176.0. EI-MS (70 eV): 361 (2,
Mþ), 230 (7), 302 (41), 238 (25), 105 (60), 91 (100), 57 (52). Anal. calc. for C18H19NO7 (361.35): C 59.83,
H 5.30, N 3.88; found: C 59.81, H 5.31, N 3.76.
2-[1,2,3,4-Tetrahydro-5,6-bis(methoxycarbonyl)-1-(4-methylbenzyl)-2-oxopyridin-3-yl]acetic Acid
(3h). Yield: 304 mg (81%). Yellow oil. IR: 3310 (OH), 1721, 1712 (COOMe), 1632 (CO), 1269
1
(CꢀN), 1156 (CꢀO). H-NMR: 2.29 (s, 3 H); 2.44 – 2.55 (m, 2 H); 2.86 – 2.95 (m, 2 H); 3.03 – 3.07 (m,
1 H); 3.67 (s, 3 H); 3.71 (s, 3 H); 4.51 (d, 2J ¼ 15.7, 1 H); 4.93 (d, 2J ¼ 15.7, 1 H); 7.04 – 7.12 (m, 4 H); 8.35
(br., 1 H). 13C-NMR: 21.1; 25.5; 36.1; 37.1; 47.2; 52.1; 52.8; 108.3; 127.1; 129.1; 133.3; 137.2; 142.7; 163.7;
165.4; 171.0; 176.5. EI-MS (70 eV): 375 (1, Mþ), 296 (2), 238 (2), 113 (7), 83 (100). Anal. calc. for
C19H21NO7 (375.37): C 60.79, H 5.64, N 3.73; found: C 60.78, H 5.65, N 3.72.
2-[1,2,3,4-Tetrahydro-1-(4-methoxybenzyl)-5,6-bis(methoxycarbonyl)-2-oxopyridin-3-yl]acetic Acid
(3i). Yield: 336 mg (86%). Yellow oil. IR: 3428 (OH), 1722, 1715 (COOMe), 1634 (CO), 1269
1
(CꢀN), 1168 (CꢀO). H-NMR: 2.41 – 2.51 (m, 2 H); 2.83 – 2.85 (m, 2 H); 2.95 – 3.05 (m, 1 H); 3.57 (s,
3 H); 3.61 (s, 3 H); 3.64 (s, 3 H); 4.47 (d, 2J ¼ 15.5, 1 H); 4.90 (d, 2J ¼ 15.5, 1 H); 7.00 – 7.08 (m, 4 H); 9.34
(br., 1 H). 13C-NMR: 25.5; 34.1; 36.0; 47.1; 52.1; 52.7; 60.4; 108.4; 127.1; 129.1; 137.1; 142.6; 159.1; 163.7;
165.4; 171.0; 176.0. EI-MS (70 eV): 391 (1, Mþ), 344 (9), 316 (51), 296 (43), 238 (52), 194 (30), 105 (100),
69 (62). Anal. calc. for C19H21NO8 (391.37): C 58.31, H, 5.41, N 3.58. found: C 58.33, H 5.38, N 3.57.
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Received November 25, 2011