FeCl3-promoted [3+3] cycloaddition: Efficient preparation of 1,2-dihydro-2-oxo-3-pyridinecarboxylate and 1,2-dihydro-2-oxo-3- pyridinecarboxamide derivatives

Article abstract of DOI:10.1002/jhet.5570450651

(Chemical Equation Presented) A facile approach was developed on assembly of the 2-pyridone nucleus by ferric chloride promoted [3+3] cycloaddition in propionic acid. The tandem process involves cyclization of Michael adduct followed by aromatization. Thus, different substituted 1,2-dihydro-2-oxo-3- pyridinecarboxylate and 1,2-dihydro-2-oxo-3-pyridinecarboxamide derivatives were prepared in good yields from various enones with malonamic ester and malonamide, respectively.

Full text of DOI:10.1002/jhet.5570450651

Nov-Dec 2008
1875
FeCl3-Promoted [3+3] Cycloaddition: Efficient Preparation of 1,2-
Dihydro-2-oxo-3-pyridinecarboxylate and 1,2-Dihydro-2-oxo-3-
pyridinecarboxamide Derivatives
Shuheng Li, Shaozhong Wang*
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China
E-mail: wangsz@nju.edu.cn
Received January 28, 2008
O
O
EWG
Ar1
EWG
Ar1
NH2
Ar2
FeCl3 (2eq)
NH
Ar2
O
Propionic acid, reflux
EWG = CO2Et, CONH2
A facile approach was developed on assembly of the 2-pyridone nucleus by ferric chloride promoted
[3+3] cycloaddition in propionic acid. The tandem process involves cyclization of Michael adduct
followed by aromatization. Thus, different substituted 1,2-dihydro-2-oxo-3-pyridinecarboxylate and 1,2-
dihydro-2-oxo-3-pyridinecarboxamide derivatives were prepared in good yields from various enones with
malonamic ester and malonamide, respectively
J. Heterocyclic Chem., 45, 1875 (2008).
INTRODUCTION
out the preparation of 1,2-dihydro-2-oxo-3-pyridine-
carboxylate and 1,2-dihydro-2-oxo-3-pyridinecarbox-
amide derivatives from enones with malonamic ester and
malonamide, respectively.
Considerable attention was given to the assembly of 2-
pyridone rings due to a number of natural and synthetic
compounds containing the 2-pyridone moiety which
possess potent pharmacological and agrochemical
activities [1]. Generally, two main synthetic approaches to
elaborate 2-pyridone rings, one is by conversion from
other heterocycles, the other is by condensation from
acyclic compounds. Among them, [3+3] annulation is one
of the most efficient strategies to rapidly construct 2-
pyridone scaffolds and the key of [3+3] annulation is the
aromatization of the possible intermediate dihydro-
pyridone. Recently, Ciufolini developed a one-step
procedure to prepare substituted 3-cyano-2-pyridones
from various enones and cyanoacetamide in DMSO using
t-BuOK as a base under an oxygen atmosphere. The
proposed mechanism involves a single electron transfer
(SET) process, which enables the aromatization of the
ring [2-4]. Later, Katritzky reported a benzotriazole-
assisted preparation of 3-unsubstituted 2-pyridones which
concerns cyclization of Michael adduct and subsequent
aromatization by dehydration and loss of benzotriazole
[5-6]. Although these base-promoted [3+3] annulation
approaches have been applied successfully in total
synthesis and solid-phase synthesis, limitations still exist.
As mentioned by Ciufolini, upon base-promoted reaction
with enones, malonamide produced only Michael adducts
without any 2-pyridones, while malonamic ester afforded
hydrolyzed product 2-oxo-3-pyridinecarboxylic acids. In
order to overcome the limitations and enlarge the scope of
[3+3] annulation to attain 2-pyridones, we herein
provided an efficient approach promoted by FeCl3 to carry
RESULTS AND DISCUSSION
Scheme 1
O
EtO2C
Ph
O
NH
Ph
NH2COCH2CO2Et
Conditions
Ph
Ph
1a
2a
Table 1
Preparation of 2a under conditions.a
Entry
Catalyst
1eq FeCl3
2eq FeCl3
2eq FeCl3·6H2O
2eq Fe2(SO4)3·9H2O
2eq Fe(NO3)3·9H2O
2eq FeCl3
Ratiob
1:1
Yield (%)c
1
2
3
4
5
6
30
60
48
35
20
65
1:1
1:1
1:1
1:1
1:1.2
b
aThe reaction time is 1h. Ratio is 1a: ethyl 3-amino-3-oxo-propionate.
cYield of purified product after flash chromatography.
Initial studies were carried out using 1,3-diphenyl-2-
propen-1-one (1a) and ethyl 3-amino-3-oxo-propionate as
a model system (Scheme 1, Table 1). When 1a and ethyl
3-amino-3-oxo-propionate were treated with 1.0 eq FeCl3
in propionic acid at reflux temperature, after an hour the
anticipated ethyl 1,2-dihydro-2-oxo-3-pyridinecarboxylate
was obtained in 30% yield (entry 1). However, when 2eq
of FeCl3 was employed, the yield increased to 60% (entry

1876
S. Li and S. Wang
Vol 45
2). Control experiment without any FeCl3 showed no
product detected as well as intermediate dihydropyridone.
In addition, other iron salts such as FeCl3ꢀ6H2O,
Fe2(SO4)3ꢀ9H2O and Fe(NO3)3ꢀ9H2O were tested but gave
inferior results (entry 3-5). The presence of crystallization
water may inhibit keto-amide cyclization process and
different counter-anions of iron salts also affect the
reaction. Optimization of the ratio of 1a and ethyl 3-
amino-3-oxo-propionate resulted in slight improvement of
the yield (entry 6).
oxo-3-pyridinecarboxylates. In addition, attempt to
prepare 1,2-dihydro-2-oxo-3-pyridinecarbonitrile from
1,3-diphenyl-2-propen-1-one and cyanoacetamide proved
to be unsuccessful, which led to the formation of 1,2-
dihydro-2-oxo-3-pyridinecarboxamide.
A proposed mechanism for the formation of ethyl 1,2-
dihydro-2-oxo-3-pyridinecarboxylates and 1,2-dihydro-2-
oxo-3-pyridinecarboxamides by FeCl3-promoted [3+3]
cycloaddition between enones with malonamic ester and
malonamide consists of Michael addition and cyclization
of amide-ketone followed by aromatization of 3,4-
dihydro-2-pyridone (Scheme 3). This cycloaddition with
excellent regioselectivity and functional group tolerance
is different from those base-promoted [3+3] annulation
and the proposed intermediate 3,4-dihydro-2-pyridone
was aromatized without employing extra oxidants or
leaving groups.
Scheme 2
O
EWG
Ar1
EWGCH2CONH2, FeCl3 (2eq)
propionic acid, reflux 1 h
O
NH
Ar2
Ar1
Ar2
1b-l
2b-l
In summary, a novel approach was developed for the
preparation of 1,2-dihydro-2-oxo-3-pyridinecarboxylates
and 1,2-dihydro-2-oxo-3-pyridinecarboxamides, which
can be further modified as lead compounds such as
cytokine inhibitors [7] and anaplastic lymphoma kinase
inhibitors [8]. The [3+3] cycloaddition promoted by FeCl3
in acid media involves cyclization of Michael adduct
amide-ketone and subsequent aromatization, which is
supplementary to the existing approaches for the assembly
of 2-pyridone derivatives. Besides, the novel [3+3]
cycloaddition also shows another application of FeCl3 in
organic synthesis [9-11]. Further explorations of this
procedure are in progress
Table 2
FeCl3-promoted Preparation of 2b-l.
Entry
Ar1
Ar2
EWG
Yield(%)a
2b
2c
2d
2e
2f
2g
2h
2i
4-CH3OC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
C6H5
C6H5
CO2Et
71
75
65
60
70
70
65
60
68
75
70
C6H5
CO2Et
C6H5
CO2Et
C6H5
CO2Et
CO2Et
2,5-Cl2C6H3
C6H5
C6H5
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
C6H5
C6H5
4-PhC6H4
4-ClC6H4
C6H5
2j
2k
2l
4-CH3C6H4
4-ClC6H4
3,4-Cl2C6H3
C6H5
4-CH3C6H4
aYield of isolated products after flash chromatography.
EXPERIMENTAL
All melting points were determined on a Yanaco apparatus
and are uncorrected. IR spectra were recorded on a Shimider
IDP440 spectrometer as KBr pellets. 1H NMR spectra were
recorded on a Bruker DPX-300 spectrometer. MS spectra were
taken on a VG-ZAB-HS mass spectrometer at 70 eV. Elemental
analyses were performed on a Perkin-Elmer 240C instrument.
General procedure for the preparation of ethyl 1,2-
dihydro-2-oxo-3-pyridinecarboxylates 2a-f and 1,2-dihydro-
2-oxo-3-pyridinecarboxamides 2g-l. Enones 2a-l (2.5 mmol),
ethyl 3-amino-3-oxo-propionate (3.0 mmol) or malonamide (3.0
mmol) and FeCl3 (5.0 mmol) were dissolved in propionic acid
(5.0 mL) and the formed solution was refluxed for 1 h. After
cooling, the mixture was poured into 1.0 N HCl (30 mL), then
extracted by CHCl3 (3 ꢀ 30 mL). The combined organic layer
was washed successively with aq NaHCO3 (30 mL) and H2O (30
According to the optimized condition, various substrates
were tested to screen the scope of this reaction. As shown
in Table 2, enones with electron-withdrawing and
electron-donating substituents underwent [3+3] cyclo-
addition smoothly and converted into the corresponding
ethyl 1,2-dihydro-2-oxo-3-pyridine-carboxylates (2b-f) in
the yield ranging from 65% to 75%. Among them, enone
containing o-chloro substituent displays lower reactivity
than corresponding p-substituted enone. On the other
hand,
different
substituted
1,2-dihydro-2-oxo-3-
pyridinecarboxamides (2g-l) were obtained conveniently
in 60-70% yield from various enones and malonamide
according to the procedure similar to ethyl 1,2-dihydro-2-
Scheme 3
O
O
O
CONH2
O
Fe3+
EWG
Ar1
EWG
Ar1
Ar1
Ar2
EWG
Ar1
NH
Ar2
NH
Ar2
Ar2
O
EWG
EWG = CO2Et, CONH2
H2N

Nov-Dec 2008
FeCl3-Promoted [3+3] Cycloaddition
1877
mL). The organic layer was dried (MgSO4) and the solvent was
removed by distillation. The crude products obtained were
purified by flash column chromatography to give 1,2-dihydro-2-
oxo-3-pyridinecarboxylates 2a-f and 1,2-dihydro-2-oxo-3-
pyridinecarboxamides 2g-l.
CDCl3): ꢀ 13.7, 61.3, 110.7, 122.0, 127.5, 128.5, 129.1, 130.8,
130.9, 131.4, 133.0, 133.8, 137.5, 144.3, 152.2, 162.3, 166.0;
ms: m/z 391 (M+4, 9), 389 (M+2, 60), 387 (M+, 100), 315 (94).
Anal. Calcd. for C20H15Cl2NO3: C, 61.87; H, 3.89; N, 3.61.
Found: C, 61.88; H, 4.01; N, 3.78.
Ethyl 1,2-dihydro-4,6-diphenyl-2-oxo-3-pyridine-carboxyl-
ate (2a). This compound was obtained as white solids (HOAc-
1,2-Dihydro-4,6-diphenyl-2-oxo-3-pyridinecarboxamide (2g).
This compound was obtained as white solids (HOAc-EtOH), mp
1
EtOH), mp 202-204°; ir: 1724, 1629 cm-1; H nmr (CDCl3): ꢀ
1
228-230°; ir: 1662, 1629 cm-1; H nmr (DMSO-d6) ꢀ 6.63 (s,
1.06 (t, 3H, J = 7.1 Hz), 4.17 (q, 2H, J = 7.1 Hz), 6.65 (s, 1H),
7.44-7.52 (m, 8H), 7.87-7.91 (m, 2H), 13.13 (s, 1H); 13C NMR
(75 MHz, CDCl3): ꢀ 14.2, 61.6, 107.2, 121.6, 127.5, 127.9,
128.9, 129.5, 130.9, 133.2, 138.6, 148.4, 153.6, 163.1, 166.9;
ms: m/z 320 (M+1, 20), 319 (M+, 88), 245 (100). Anal. Calcd.
for C20H17NO3: C, 75.22; H, 5.37; N, 4.39. Found: C, 75.42; H,
5.27; N, 4.34.
1H), 7.29 (s, 1H), 7.42-7.50 (m, 6H), 7.57-7.60 (m, 2H), 7.73 (s,
1H), 7.83-7.86 (m, 2H), 12.04 (s, 1H); ms: m/z 290 (M+, 1), 289
(M-1, 8), 272 (100). Anal. Calcd. for C18H14N2O2: C, 74.47; H,
4.86; N, 9.65. Found: C, 74.49; H, 4.83; N, 9.68.
6-[1,1'-Biphenyl]-4-yl-1,2-dihydro-2-oxo-4-phenyl-3-pyri-
dinecarboxamide (2h). This compound was obtained as white
solids (HOAc-EtOH), mp 266-270°; ir: 1669, 1624 cm-1; 1H nmr
(DMSO-d6) ꢀ 6.72 (s, 1H), 7.32 (s, 1H), 7.38-7.52 (m, 7H),
7.59-7.63 (m, 2H), 7.73-7.81 (m, 4H), 7.96 (d, 2H, J = 8.4 Hz),
12.06 (s, 1H); ms: m/z 366 (M+, 6), 365 (M-1, 45), 348 (100).
Anal. Calcd. for C24H18N2O2: C, 78.67; H, 4.95; N, 7.65. Found:
C, 78.61; H, 4.97; N, 7.61.
Ethyl 1,2-dihydro-4-(4-methoxyphenyl)-2-oxo-6-phenyl-3-
pyridinecarboxylate (2b). This compound was obtained as
white solids (HOAc-EtOH), mp 218-220°; ir: 1724, 1618 cm-1;
1H nmr (CDCl3): ꢀ 1.13 (t, 3H, J = 7.1 Hz), 3.87 (s, 3H), 4.21 (q,
2H, J = 7.1 Hz), 6.62 (s, 1H), 6.94-6.99 (m, 2H), 7.43-7.52 (m,
5H), 7.84-7.87 (m, 2H), 12.75 (s, 1H); 13C NMR (75 MHz,
CDCl3): ꢀ 13.8, 55.2, 61.1, 106.8, 113.9, 120.8, 127.0, 128.9,
130.3, 132.9, 147.5, 152.5, 160.3, 162.6, 166.6; ms: m/z 351
(M+2, 4), 349 (M+, 100), 275 (75). Anal. Calcd. for C21H19NO4:
C, 72.19; H, 5.48; N, 4.01. Found: C, 72.13; H, 5.65; N, 4.00.
Ethyl 4-(4-chlorophenyl)-1,2-dihydro-2-oxo-6-phenyl-3-
pyridinecarboxylate (2c). This compound was obtained as
white solids (HOAc-EtOH), mp 238-240°; ir: 1728, 1626 cm-1;
1H nmr (CDCl3): ꢀ 1.10 (t, 3H, J = 7.1 Hz), 4.19 (q, 2H, J = 7.1
Hz), 6.60 (s, 1H), 7.43 (s, 4H), 7.48-7.52 (m, 3H), 7.84-7.87 (m,
2H), 12.76 (s, 1H); 13C NMR (75 MHz, CDCl3): ꢀ 14.2, 61.8,
107.1, 121.3, 127.5, 129.2, 129.3, 129.5, 131.3, 133.1, 135.7,
136.9, 148.8, 152.4, 162.9, 166.6; ms: m/z 355 (M+2, 32), 353
(M+, 100), 279 (76). Anal. Calcd. for C20H16ClNO3: C, 67.90; H,
4.56; N, 3.96. Found: C, 67.87; H, 4.53; N, 4.10.
Ethyl 4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-phenyl-3-
pyridinecarboxylate (2d). This compound was obtained as
white solids (HOAc-EtOH), mp 165-167°; ir: 1734, 1623 cm-1;
1H nmr (CDCl3): ꢀ 1.11 (t, 3H, J = 7.1 Hz), 4.20 (q, 2H, J = 7.1
Hz), 6.60 (s, 1H), 7.36-7.44 (m, 3H), 7.49-7.53 (m, 4H), 7.85-
7.89 (m, 2H), 13.26 (s, 1H); 13C NMR (75 MHz, CDCl3): ꢀ 13.8,
61.3, 106.3, 121.1, 125.7, 127.1, 127.6, 129.0, 129.8, 130.6,
132.5, 134.4, 139.7, 148.4, 151.5, 162.6, 166.0; ms: m/z 355
(M+2, 33), 353 (M+, 100), 279 (75). Anal. Calcd. for
C20H16ClNO3: C, 67.90; H, 4.56; N, 3.96. Found: C, 67.73; H,
4.60; N, 4.28.
Ethyl 4-(2-chlorophenyl)-1,2-dihydro-2-oxo-6-phenyl-3-
pyridinecarboxylate (2e). This compound was obtained as
white solids (HOAc-EtOH), mp 198-200°; ir: 1728, 1627 cm-1;
1H nmr (CDCl3): ꢀ 0.94 (t, 3H, J = 7.1 Hz), 4.08 (q, 2H, J = 7.1
Hz), 6.67 (s, 1H), 7.31-7.39 (m, 3H), 7.46-7.53 (m, 4H), 7.92-
7.94 (m, 2H), 12.76 (s, 1H); 13C NMR (75 MHz, CDCl3): ꢀ 13.5,
61.0, 108.6, 126.5, 127.2, 128.9, 129.3, 129.4, 129.6, 130.5,
131.8, 133.3, 137.6, 150.1, 151.9, 163.1, 166.0; ms: m/z 355
(M+2, 2), 353 (M+, 6), 290 (100). Anal. Calcd. for C20H16ClNO3:
C, 67.90; H, 4.56; N, 3.96. Found: C, 67.80; H, 4.62; N, 3.98.
Ethyl 6-(2,5-dichlorophenyl)-1,2-dihydro-2-oxo-4-phenyl-
3-pyridinecarboxylate (2f). This compound was obtained as
white solids (HOAc-EtOH), mp 218-220°; ir: 1730, 1624 cm-1;
1H nmr (CDCl3): ꢀ 1.05 (t, 3H, J = 7.1 Hz), 4.15 (q, 2H, J = 7.1
Hz), 6.55 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), 7.37-7.48 (m, 6H),
7.56 (d, 1H, J = 2.3 Hz), 12.67 (s, 1H); 13C NMR (75 MHz,
6-(4-Chlorophenyl)-1,2-dihydro-2-oxo-4-phenyl-3-pyridin-
ecarboxamide (2i). This compound was obtained as white
solids (HOAc-EtOH), mp 239-240°; ir: 1669, 1620 cm-1; 1H nmr
(DMSO-d6) ꢀ 6.74 (s, 1H), 7.32 (s, 1H), 7.38-7.49 (m, 3H),
7.53-7.61 (m, 4H), 7.73 (s, 1H), 7.90 (d, 2H, J = 8.4 Hz), 11.99
(s, 1H); ms: m/z 326 (M+2, 0.3), 324 (M+, 1), 323 (M-1, 14),
308 (36), 306 (100). Anal. Calcd. for C18H13ClN2O2: C, 66.57; H,
4.03; N, 8.63. Found: C, 66.51; H, 4.11; N, 8.67.
1,2-Dihydro-4-(4-methylphenyl)-2-oxo-6-phenyl-3-pyridin-
ecarboxamide (2j). This compound was obtained as white
solids (HOAc-EtOH), mp 246-248°; ir: 1648, 1627 cm-1; 1H nmr
(DMSO-d6) ꢀ 2.34 (s, 3H), 6.60 (s, 1H), 7.22-7.24 (m, 3H),
7.47-7.50 (m, 5H), 7.69 (s, 1H), 7.82-7.84 (m, 2H), 11.99 (s,
1H); ms: m/z 304 (M+, 2), 303 (M-1, 9), 286(100). Anal. Calcd.
for C19H16N2O2: C, 74.99; H, 5.30; N, 9.20. Found: C, 74.98; H,
5.26; N, 9.12.
4-(4-Chlorophenyl)-1,2-dihydro-2-oxo-6-phenyl-3-pyridin-
ecarboxamide (2k). This compound was obtained as white
solids (HOAc-EtOH), mp 238-240°; ir: 1665, 1640 cm-1; 1H nmr
(DMSO-d6) ꢀ 6.63 (s, 1H), 7.34 (s, 1H), 7.49-7.59 (m, 7H) 7.83-
7.85 (m, 3H), 12.10 (s, 1H); ms: m/z 326 (M+2, 0.6), 324 (M+,
3), 323 (M-1, 13), 308 (22), 306 (100). Anal. Calcd. for
C18H13ClN2O2: C, 66.57; H, 4.03; N, 8.63. Found: C, 66.71; H,
4.02; N, 8.74.
4-(3,4-Dichlorophenyl)-1,2-dihydro-6-(4-methylphenyl)-2-
oxo-3-pyridinecarboxamide (2l). This compound was obtained
as white solids (HOAc-EtOH), mp 250-252°; ir: 1665, 1630
1
cm-1; H nmr (DMSO-d6) ꢀ 2.35 (s, 3H) 6.63 (s, 1H), 7.30 (d,
2H, J = 8.4 Hz) 7.39 (s, 1H), 7.48-7.51 (m, 1H), 7.68-7.78 (m,
4H), 7.92 (s, 1H), 12.12 (s, 1H); ms: m/z 375 (M+3, 0.4), 374
(M+2, 0.9), 373 (M+1, 9), 372 (M+, 3), 371 (M-1, 26), 356 (26),
354 (100). Anal. Calcd. for C19H14Cl2N2O2: C, 61.14; H, 3.78; N,
7.51. Found: C, 61.11; H, 3.74; N, 7.41.
Acknowledgement. We thank Nanjing University and 973
Program ( 2007CB936400) for financial support.
REFERENCES
[1] Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9,
1757.

1878
S. Li and S. Wang
Vol 45
[2] Jain, R.; Roschangar, F.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 3307.
[3] Carles, L.; Narkunan, K.; Penlou, S.; Rousset, L.; Bouchu,
[7] Liverton, N. J.; Claremon, D. A.; Butcher, J. W.; Theberge,
C. R. WO 0100208, 2001; Chem. Abstr. 2001, 134, 86270h.
[8] Li, R.; Xue, L.; Zhu, T.; Jiang, Q.; Yan, Z.; McGee, D.;
Wang, J.; Gantla, V. R.; Pickens, J. C.; Mcgrath, D.; Chucholowski, A.;
Morris, S. W.; Webb, T. R. J. Med. Chem. 2006, 49, 1006.
[9] Christoffers, J. Synlett 2001, 723.
D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304.
[4] Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2007, 72, 8489.
[5] Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A. E.;
Henderson, S. A.; Chen, J. J. Org. Chem. 1997, 62, 6210.
[6] Katritzky, A. R.; Chassaing, C.; Barrow, S. J.; Zhang, Z.;
Vvedensky, V.; Forrood, B. J. Comb. Chem. 2002, 4, 249.
[10] Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
104, 6217.
[11] Furstner, A.; Martin, R. Chem. Lett. 2005, 34, 624.