A novel, two-step synthesis of 4-pyridone-3-carboxamides from 2-cyano-4-pyrones

Article abstract of DOI:10.1016/j.tetlet.2013.03.132

Reactions of 2-cyano-6-(trifluoromethyl)-4-pyrone, 2-cyano-4-pyrone, and 2-cyano-6-methyl-4-pyrone with aliphatic and aromatic amines in ethanol at -20 C for 2-21 days gave 5-amino-3-oxopent-4-enamides in 28-78% yields, which were cyclized with DMF-DMA in toluene under ambient conditions to afford 4-pyridone-3-carboxamides in 31-70% yields.

Full text of DOI:10.1016/j.tetlet.2013.03.132

Accepted Manuscript
A novel, two-step synthesis of 4-pyridone-3-carboxamides from 2-cyano-4-py‐
rones
Dmitrii L. Obydennov, Ekaterina S. Sidorova, Boris I. Usachev, Vyacheslav Ya.
Sosnovskikh
PII:
S0040-4039(13)00579-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.132
TETL 42772
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 February 2013
11 March 2013
28 March 2013
Please cite this article as: Obydennov, D.L., Sidorova, E.S., Usachev, B.I., Sosnovskikh, V.Y., A novel, two-step
synthesis of 4-pyridone-3-carboxamides from 2-cyano-4-pyrones, Tetrahedron Letters (2013), doi:http://dx.doi.org/
10.1016/j.tetlet.2013.03.132
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Graphical abstract
________________________________________________________________________________
A novel, two-step synthesis of 4-pyridone-3-carboxamides from 2-cyano-4-pyrones
Dmitrii L. Obydennov, Ekaterina S. Sidorova, Boris I. Usachev, Vyacheslav Ya. Sosnovskikh
O
O
O
MeO OMe
NMe2
R1
R
CONHR1
2 R1NH2
NH
O
O
NHR1
R
N
R1
R
CN
R = CF3, H, Me; R1 = Alk, Ar
________________________________________________________________________________________________________________________
 Corresponding author. Fax: +7 343 261 59 78;
e-mail: dobydennov@mail.ru

A novel, two-step synthesis of 4-pyridone-3-carboxamides from 2-cyano-4-
pyrones
Dmitrii L. Obydennov, Ekaterina S. Sidorova, Boris I. Usachev,
Vyacheslav Ya. Sosnovskikh
Department of Chemistry, Ural Federal University, prosp. Lenina 51, 620000 Ekaterinburg, Russia
A B S T R A C T
Reactions of 2-cyano-6-(trifluoromethyl)-4-pyrone, 2-cyano-4-pyrone, and 2-cyano-6-methyl-4-
pyrone with aliphatic and aromatic amines in ethanol at –20 °C for 2–21 days gave 5-amino-3-
oxopent-4-enamides in 28–78% yields, which were cyclized with DMF-DMA in toluene under
ambient conditions to afford 4-pyridone-3-carboxamides in 31–70% yields.
Keywords: 2-Cyano-4-pyrones; 5-Amino-3-oxopent-4-enamides; 4-Pyridone-3-carboxamides;
DMF-DMA; Cyclization
4-Pyridone-3-carboxamides belong to an important class of nitrogen-containing heterocyclic
compounds with a broad spectrum of biological activities. Many of their derivatives are selective
CB2 cannabinoid receptor ligands,1 and possess herbicidal2 and anti-inflammatory3 activity. These
heterocyclic amides also exhibit properties of plant growth regulators4 and are the key frameworks
of some natural products (for example, aspernigrine A and pestalamides B and C5) (Figure 1).
Reported synthetic methods for the preparation of 4-pyridone-3-carboxamides are based on the
reactions of 4-pyrone-3-carboxylic acid derivatives with amines (transformation of the 4-pyrone
ring into a 4-pyridone ring),1,4 the treatment of α-acylated enaminoamides with N,N-dimethylamide
dimethyl acetals,4b,c the reaction of 3-aminoacrylic acid derivatives with 2,2,6-trimethyl-1,3-dioxin-
 Corresponding author. Tel.: +7-343-261-7411; fax: +7-343-261-7411; e-mail: dobydennov@mail.ru
2

4-one4 or diketene,3 the transformation of 4-hydroxy-6-methyl-2-pyrone (triacetic acid lactone) into
4-pyridone-3-carboxylic acid derivatives,1 as well as the self-condensation of N-aryl
acetoacetamides mediated by sodium persulfate5b or p-toluenesulfonic acid in refluxing benzene
with azeotropic removal of water.3 In this Letter, we report a novel synthesis of 4-pyridone-3-
carboxamides from 5-amino-3-oxopent-4-enamides, which in turn were prepared from the
corresponding 2-cyano-4-pyrones.
O
O
O
O
NH2
NH2
N
H
N
OH
aspernigrin A
pestalamide C
O
O
O
Me
N
CO2H
H
N
H
pestalamide B
Figure 1. Examples of natural compounds containing a 4-pyridone-3-carboxamide framework.
We previously found6 that dehydration of 4-oxo-6-(trifluoromethyl)-4H-pyran-2-carboxamide
(1a)7 with trifluoroacetic anhydride in the presence of pyridine at 0 C led to the formation of 2-
cyano-6-(trifluoromethyl)-4-pyrone (2a) in 61% yield. We now report the synthesis of 2-cyano-4-
pyrone (2b) and 2-cyano-6-methyl-4-pyrone (2c) from the corresponding 4-pyrone-2-carboxamides
1b,c under the same conditions, in 48%8 and 55% yields, respectively (it proved important to carry
out the reaction at –10 C). Surprisingly, as in the case of 1a and 2a, the isolation and
characterization of which had not been reported prior to our work,6,7 none of these simple 2-cyano-
and 2-carbamoyl-4-pyrones had been recorded in the literature (Scheme 1).
Pyrone 2a, due to activation of the conjugated system by two electron-withdrawing groups (CF3
and CN), is a highly electrophilic substrate, which is able to react with different nucleophiles with
or without affecting the pyrone ring.6 We found that 2a reacted easily with both aliphatic and
aromatic amines in ethanol at –20 C over two days to produce CF3-containing 5-amino-3-oxopent-
3

4-enamides 4a–f in yields of 28–78%. The first step of the reaction leading to 4 presumably
involves attack of the NH2 group at C-6 of 2a with concomitant opening of the pyrone ring to give
intermediate A, which is a reactive acyl cyanide. Subsequent substitution of the cyano group
adjacent to the carbonyl group occurs by the action of a second amine molecule and leads to the
carbamoylated aminoenones 4. This reaction reveals the high reactivity of the pyrone ring of 2a in
contrast to the pyrone ring of 2-cyano-4-pyrone (2b), which reacted with benzylamine and p-
anisidine at –20 C over eight days to give aminoenones 4g,h in good yields (49–62%). The less
reactive 2-cyano-6-methyl-4-pyrone (2c) reacted under the same conditions only with benzylamine,
over three weeks, to produce compound 4i in 50% yield, which has been previously obtained from
triacetic acid lactone (3c) and benzylamine9 (Scheme 1, Table 1). Thus, 2-cyano-4-pyrones 2 can be
considered as synthetic equivalents of 4-hydroxy-2-pyrones 3, of which 4-hydroxy-6-
(trifluoromethyl)-2-pyrone (3a) and 4-hydroxy-6-methyl-2-pyrone (3c) are known compounds.10
O
O
(CF3CO)2O, py
-H2O
6
2
O
R
O
R
O
CN
1a-c
NH2
2a-c
R1NH2
OH
R1HN
O
O
CN
R
R
O
O
A
3a-c
R1NH2
-HCN
3c 2 R1NH2
2a-c
-H2O
R1
NH
O
O
R
NHR1
4
R = CF3 (a), H (b), Me (c)
Scheme 1. Synthesis of 5-amino-3-oxopent-4-enamides 4.
5-Amino-3-oxo-4-enamides 4 belong to a poorly explored class of polyfunctional compounds,
the chemical properties of which have still not been investigated (besides acid hydrolysis to 4-
hydroxy-2-pyridones6,9). In connection with this, we examined the reactivity of carbamoylated
4

aminoenones 4 to construct biologically interesting CF3-containing 4-pyridone-3-carboxamides as
well as non-fluorinated pyridones. We reasoned that reaction of DMF-DMA with an appropriately
substituted amide 4 would provide the desired 4-pyridones. During the optimization studies, it was
found that treatment of compounds 4a–i with DMF-DMA in toluene under ambient conditions for
24 hours gave 4-pyridone-3-carboxamides 5a–i in 31–70% yields.11,12 The mechanism of the
reaction involves α-enamination of 4 with DMF-DMA to give intermediate B, which then
undergoes cyclization to afford 4-pyridone-3-carboxamides 5. Indeed, in the case of N,N'-dibutyl
substituted amide 4f, intermediate acyclic product 6 was isolated as a single isomer in 65% yield.
The latter was converted into the corresponding 4-pyridone 5f by treatment with methanesulfonic
acid in toluene at room temperature over 0.5 hours (Scheme 2, Table 1).
Scheme 2. Synthesis of 4-pyridone-3-carboxamides 5.
Table 1. Yields and melting points of amides 4 and pyridones 5.
R
R1
Amide
4a
Yield (%)
Mp (°C)
104–105
108–109
119–120
131–132
187–188
65–66
Pyridone
5a
Yield (%)
Mp (°C)
175–176
161–162
212–213
182–183
241–242
liq.
CF3
CF3
CF3
CF3
CF3
CF3
H
Me
37
78
59
58
28
76
62
49
50
64
60
62
68
31
56a
54
70
58
Ph
4b
4c
5b
2-MeOC6H4
4-MeOC6H4
4-BrC6H4
n-Bu
5c
4d
4e
5d
5e
4f
5f
PhCH2
4-MeOC6H4
PhCH2
113–114
152–153
107–108b
129–130
201–202
163–164
4g
5g
H
4h
5h
Me
4i
5i
a From 6. b Mp 106–108 C (ref. 13).
5

Although the chemistry of 4-pyridones has been well documented,1–5 compounds 5 are hitherto
unreported. This new cyclization process allows the preparation of a variety of 4-pyridone-3-
carboxamides 5 with substituents on the amide and ring nitrogen atoms, and proves that the
methylene component of the β-ketoamide moiety is more reactive to DMF-DMA than the
methylene component of the aminoenone moiety.
The structures of all the compounds were established from their elemental analyses and spectral
(1H, 13C NMR, and IR) data. In the 1H NMR spectra of pyridones 5, protons H-2 and H-5 appeared
as singlets at δ 8.37–8.67 and δ 5.63–7.26, respectively (doublets for 5g,h, 3J = 7.4 Hz, 4J = 2.2 Hz).
Another characteristic feature was the appearance of the NH signal in the range of δ 9.8–12.5,
indicating that there is intramolecular hydrogen bonding in 5.3 In the 13C NMR spectrum of 5d,
three characteristic quartets due to the CF3 (δ 119.3, 1JC,F = 275.0 Hz), C-5 (δ 119.9, 3JC,F = 4.2 Hz)
2
and C-6 (δ 138.2, JC,F = 33.5 Hz) carbons were observed, additionally confirming the 4-pyridone
structure.
In summary, we have developed a simple two-step synthesis of potentially biologically active 4-
pyridone-3-carboxamides, including CF3-containing derivatives, which involves the preparation of
5-amino-3-oxopent-4-enamides via the reaction of 2-cyano-4-pyrones with amines, and their
subsequent cyclization under the action of DMF-DMA.
Acknowledgment
This work was supported by Ural Federal University (Program of Support of Young Scientists).
References and notes
1. (a) El Bakali, J.; Muccioli, G. G.; Renault, N.; Pradal, D.; Body-Malapel, M.; Djouina, M.;
Hamtiaux, L.; Andrzejak, V.; Desreumaux, P.; Chavatte, P.; Lambert, D. M.; Millet, R. J. Med.
Chem. 2010, 53, 7918–7931; (b) El Bakali, J.; Gilleron, P.; Body-Malapel, M.; Mansouri, R.;
Muccioli, G. G.; Djouina, M.; Barczyk, A.; Klupsch, F.; Andrzejak, V.; Lipka, E.; Furman, C.;
Lambert, D. M.; Chavatte, P.; Desreumaux, P.; Millet, R. J. Med. Chem. 2012, 55, 8948−8952.
2. Goto, Y.; Yagihara, H.; Masamoto, K.; Morishima, Y.; Sagawa, Y.; Osabe, H. US Patent
4936121, 1990; Chem. Abstr. 1989, 111, 134013.
6

3. Pierce, J. B.; Ariyan, Z. S.; Ovenden, G. S. J. Med. Chem. 1982, 25, 131–136.
4. (a) Ueda, Y.; Hirako, Y.; Masamoto, K.; Goto, Y.; Yagihara, H.; Morishima, Y.; Osabe, H. US
Patent 4744819, 1988; Chem. Abstr. 1986, 105, 172307; (b) Goto, Y.; Masamoto, K.; Yagihara,
H.; Morishima, Y.; Osabe, H. US Patent 4844732, 1989; Chem. Abstr. 1987, 107, 58876; (c)
Goto, Y.; Masamoto, K.; Yagihara, H.; Morishima, Y.; Osabe, H. US Patent 4946497, 1990;
Chem. Abstr. 1987, 107, 154249.
5. (a) Isaka, M.; Palasarn, S.; Chinthanom, P.; Thongtan, J.; Sappan, M.; Somrithipol, S.
Tetrahedron Lett. 2012, 53, 4848–4851; (b) Zhang, Z.; Fang, S.; Liu, Q.; Zhang, G. J. Org.
Chem. 2012, 77, 7665–7670.
6. Usachev, B. I.; Obydennov, D. L.; Röschenthaler, G.-V.; Sosnovskikh, V. Y. J. Fluorine Chem.
2012, 137, 22–26.
7. Usachev, B. I.; Bizenkov, I. A.; Sosnovskikh, V. Y. Russ. Chem. Bull. 2007, 56, 558–559.
8. 2-Cyano-4-pyrone (2b). Yield 50 mg (48%), yellowish crystals, mp 89–90 C (toluene). IR
1
(ATR) 1705, 1621, 1599, 1502, 1483, 1474 cm–1; H NMR (400 MHz, DMSO-d6) δ 6.53 (1H,
dd, J = 6.0, 2.6 Hz, H-5), 7.32 (1H, d, J = 2.6 Hz, H-3), 8.26 (1H, d, J = 6.0 Hz, H-6). Anal.
Calcd for C6H3NO2: C, 59.51; H, 2.50; N, 11.57. Found: C, 59.41; H, 2.37; N, 11.11.
9. Castillo, S.; Bouissou, T.; Favrot, J.; Brazier, J. F.; Fayet, J. P. Spectrochim. Acta 1993, 49A,
1591–1604.
10. (a) German, L. S.; Sterlin, S. R.; Cherstkov, V. F. Russ. Chem. Bull. 1982, 31, 1476–1477; (b)
Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.;
Academic Press: New York, 1992; Vol. 53, pp 1–84.
11. General procedure for the preparation of pyridones 5. Amide 4 (0.14 mmol) was added to a
solution of DMF-DMA (27 mg, 0.28 mmol) in toluene (2 mL). The reaction mixture was stirred
in toluene under ambient conditions for 24 h, then the solvent was removed and the residue
recrystallized from an appropriate solvent.
12. N,1-Bis(4-methoxyphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyridine-3-carboxamide (5d).
This compound was obtained from 4d as a colorless solid, yield 35 mg (68%), mp 182–183 C
(EtOH). IR (ATR) 3080, 3000, 1679, 1611, 1578, 1508 cm–1; 1H NMR (400 MHz, DMSO-d6) δ
3.74 (3H, s, MeO), 3.85 (3H, s, MeO), 6.94 (2H, d, J = 9.0 Hz, Ar), 7.12 (2H, d, J = 9.0 Hz, Ar),
7.20 (1H, s, H-5), 7.61 (2H, d, J = 9.0 Hz, Ar), 7.64 (2H, d, J = 9.0 Hz, Ar), 8.37 (1H, s, H-2),
19
13
12.00 (1H, s, NH); F NMR (376.5 MHz, DMSO-d6, C6F6) δ 101.9 (s, CF3); C NMR (100
1
MHz, DMSO-d6) δ 55.2, 55.6, 114.2, 114.4, 118.9, 119.3 (CF3, q, JC,F = 275.0 Hz), 119.9 (q,
2
3JC,F = 4.2 Hz), 121.2, 128.8, 131.1, 132.7, 138.2 (q, JC,F = 33.5 Hz), 149.2, 155.8, 160.2,
160.4, 176.3. Anal. Calcd for C21H17F3N2O4: C, 60.29; H, 4.10; N, 6.70. Found: C, 60.40; H,
4.28; N, 6.82. N,1-Bis(4-methoxyphenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (5h). This
7

compound was obtained from 4h as a colorless solid, yield 29 mg (70%), mp 201–202 C
(PhMe). 1H NMR (400 MHz, DMSO-d6) δ 3.75 (3H, s, MeO), 3.84 (3H, s, MeO), 6.65 (1H, d, J
= 7.4 Hz, H-5), 6.88 (2H, d, J = 8.9 Hz, Ar), 7.14 (2H, d, J = 8.9 Hz, Ar), 7.62 (4H, m, Ar), 8.17
(1H, dd, J = 8.9, 2.4 Hz, H-6), 8.62 (1H, d, J = 2.4 Hz, H-2), 12.50 (1H, s, NH); 13C NMR (100
MHz, DMSO-d6) δ 55.2, 55.6, 114.2, 115.0, 118.5, 119.9, 121.1, 124.8, 131.6, 135.9, 141.3,
143.9, 155.5, 159.4, 161.3, 176.7. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00.
Found: C, 68.70; H, 5.20; N, 8.02.
13. Patel, B. H.; Mason, A. M.; Barrett, A. G. M. Org. Lett. 2011, 13, 5156–5159.
8