Synthesis of an 4-oxo-1,4-dihydropyridinomethylidene substituted 2-indolinone

Article abstract of DOI:10.1002/jhet.5570440124

(Chemical Equation Presented) The (Z)-3-substituted 2-indolinone 6 was prepared using the aldehydes 4 and 8 unknown up to now and 2-indolinone.

Full text of DOI:10.1002/jhet.5570440124

Jan-Feb 2007
155
Synthesis of an 4-Oxo-1,4-dihydropyridinomethylidene Substituted
2-Indolinone
Astrid Lumetzberger and Werner Löwe*
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany
Manuela Weber and Peter Luger
Institut für Kristallographie, Freie Universität Berlin, Takustr. 6, 14195 Berlin, Germany
Received April 28, 2006
O
O
H
N
H
H
O
O
N
N
v
vi
viii
H
H
.
O
.
O
H2 O
H2 O
H
N
O
O
O
O
5
6
4
8
The (Z)-3-substituted 2-indolinone 6 was prepared using the aldehydes 4 and 8 unknown up to now and
2-indolinone.
J. Heterocyclic Chem., 44, 155 (2007).
Scheme 1
The 3-substituted 2-indolinones have been designed as
a novel class of tyrosine kinase inhibitors, which exhibit
selectivity toward different receptor tyrosine kinases
(RTKs) [1]. Investigations led to SU 5416, which is a
potent and selective inhibitor of the vascular endothelial
growth factor receptor (VEGF, Flk-1/KDR) that inhibits
tyrosine kinase catalysis, tumor vascularization and
growth of multiple tumor types [2]. In order to get a
similar compound to SU 5416, which contains the 2-
indolinone pharmacophore, compound 6 was prepared
(Figure 1).
O
O
O
O
O
O
O
O
HO
OH
C2H5O
OH
C2H5O
i
ii
O
O
O
1
2
iii
OH
O
H
HO
O
O
O
H
HO
iv
H2O
O
O
O
3
4a
4
v
H
H
vii
N
N
H
O
O
N
O
H
H
N
H
N
N
HO
O
path 1
path 2
O
6
SU5416
O
O
7
5
Figure 1
vi
iv
H
N
OH
O
The 3-substituted 2-indolinone
6
was prepared
H
N
H
N
H
HO
O
viii
following path 1 in Scheme 1. The synthesis is starting
with chelidonic acid, which is partially esterified by 5%
alcoholic hydrogen chloride to give the monoethyl
chelidonate 1 [3]. After decarboxylation of 1 the resulting
ethyl comanate 2 [3] was reduced by sodium borohydride
H
H
N
H2O
O
O
8a
8
O
6
i, 5% ethanolic hydrochloric acid; ii, 230°C; iii, sodium borohydride,
methanol, -20°C; iv, methanol/acetone/dichloromethane (1:1:1),
activated manganese (IV) dioxide, 50°C; v, pyridine, 2-indolinone, ꢀT;
vi, ammonium acetate, glacial acetic acid, ꢀT; vii, ammonium
carbonate (10%), ammonia (25%), ꢀT; viii, piperidine, 2-indolinone.
to give the 2-hydroxymethyl-4-pyrone
3 [4]. The
following oxidation in the presence of manganese (IV)
dioxide led to the desired aldehyde-hydrate 4, which exists
in equilibrium with the geminale diol-structure (6:4).

156
A. Lumetzberger, W. Löwe, M. Weber and P.Luger
Vol 44
Compound 5, which interestingly is the E-isomer
0.02 mm could be obtained. In no case could one single
crystalline needle be isolated.
(Scheme 1), is formed from the aldehyde 4 and 2-
indolinone by Knoevenagel-condensation. With respect to
the pharmacological results the Z-isomer is desired [1].
The last stage therefore is to realize ring-transformation
connected with E-Z-isomerization (5 ꢀ 6). This is
possible using ammonium acetate in glacial acetic acid. A
lot of resonance structures exist for compound 6, from
which, for example, structure 6b permits rotation between
the pyridone-subunit and the 2-indolinone structure. The
formation of the Z-isomer is preferred, due to the
intramolecular hydrogen-bond interaction between the N-
1' of the pyridone ring and the C-2 carbonyl oxygen atom
of the 2-indolinone ring (Scheme 2).
The conception of the synthesis also allows to prepare
the 3-substituted 2-indolinone 6 following path 2 in
Scheme 1. A ring-transformation of the 2-hydroxy-
methyl-4-pyrone
3 in the presence of ammonium
carbonate in ammonia is required to get the hydroxy-
methylpyridone 7. Oxidation using manganese (IV)
dioxide led to the desired aldehyde-hydrate 8 that also
exists in equilibrium with the geminale diol-structure
(2:8). The desired Z-isomer, compound 6, is formed under
the conditions of a Knoevenagel-reaction (Scheme 1).
Scheme II
Figure 2. Structure of compound 5, generated with ORTEP [5].
H
H
H
N
N
N
The geometry of compound 6 was demonstrated using
NOESY-1D analysis. After having been irradiated with
the frequency of the vinyl proton, the signal intensity of
H-4 and H-3' increased. Irradiation with the frequency of
H-4 led to an increase in the signal intensity of the vinyl
proton and H-5. The only conceivable explanation
therefore is the Z-isomer of compound 6 (Figure 3).
O
O
O
vi
H
N
H
N
+
O
O
O
O
-
5
6
6a
H
N
H
H
N
N
H
1
N
1
O
O
+
5
O
O
4
H
H
2
2
H
N
N
3
3
4
H
H
N
N
H
H
H
H
1'
NOE
1'
2'
3'
NOE
2'
NOE
O
O
NOE
-
3'
H
O
O
6b
6
6
6
vi, ammonium acetate, glacial acetic acid, ꢀT
Figure 3
The 3-substituted 2-indolinones may exist as either the
Z- or E-isomer depending on the characteristics of the
substituents at the C-3 position of the 3-substituted 2-
indolinone. In compound 5 the orientation, due to the
double bond, is E, which was determined by X-ray
technique. Figure 2 shows the results of X-ray analysis
together with the numbering scheme.
An X-ray analysis of compound 6 could not be
executed, due to the poor crystal quality. Only extreme
thin needle shaped crystals with diameters of less than
EXPERIMENTAL
Melting points (mp) were determined on
apparatus and are uncorrected. The infrared (ir) spectra were
recorded on a Perkin-Elmer 297 spectrometer. The nuclear
magnetic resonance (1H NMR) spectra were recorded at 400
MHz on a Bruker AC 300 spectrometer. The chemical shift
values are expressed in ꢁ values (parts per million) relative to
a
Lindström

Jan-Feb 2007
Synthesis of an 4-Oxo-1,4-dihydropyridinomethylidene Substituted 2-Indolinone
157
Table 1
Table 2 (continued)
C(4)-C(5)-H(5)
C(5)-C(6).-N(7)
C(5)-C(6)-C(1)
N(7)-C(6)-C(1)
C(8)-N(7)-C(6)
C(8)-N(7)-H(7)
C(6)-N(7)-H(7)
O(8)-C(8)-N(7)
O(8)-C(8)-C(9)
N(7)-C(8)-C(9)
C(10)-C(9)-C(1)
C(10)-C(9)-C(8)
C(1)-C(9)-C(8)
Atomic Coordinates (x 104) and Equivalent Isotropic Displacement
Parameters (Å2 x 103) for Compound 5. U (eq) is defined as
one third of the trace of the orthogonalized Uij tensor.
121.7(11)
127.31(14)
122.60(15)
110.09(14)
111.35(13)
124.1(12)
124.4(12)
126.16(13)
127.42(14)
106.42(14)
138.28(13)
116.27(14)
105.42(12)
131.82(15)
116.6(9)
X
Y
Z
U (eq)
51(1)
60(1)
68(1)
70(1)
65(1)
54(1)
61(1)
55(1)
70(1)
50(1)
53(1)
52(1)
53(1)
53(1)
69(1)
64(1)
74(1)
69(1)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
N(7)
C(8)
3877(1)
4256(1)
4639(1)
4646(1)
4273(1)
3901(1)
3498(1)
3191(1)
2802(1)
3432(1)
3213(1)
3340(1)
3203(1)
3355(1)
3273(1)
3615(1)
3723(1)
3607(1)
3514(2)
4934(3)
6673(3)
7036(3)
5661(3)
3921(2)
2341(2)
881(2)
808(1)
1432(1)
1402(1)
752(1)
123(1)
160(1)
-405(1)
-179(1)
-554(1)
632(1)
983(1)
1744(1)
2056(1)
2824(1)
3140(1)
3181(1)
2828(1)
2121(1)
O(8)
C(9)
-651(2)
1559(2)
271(3)
C(9)-C(10)-C(11)
C(9)-C(10)-H(10)
C(11)-C(10)-H(10)
C(12)-C(11)-O(16)
C(12)-C(11)-C(10)
O(16)-C(11)-C(10)
C(11)-C(12)-C(13)
C(11)-C(12)-H(12)
C(13)-C(12)-H(12)
O(13)-C(13)-C(14)
O(13)-C(13)-C(12)
C(14)-C(13)-C(12)
C(15)-C(14)-C(13)
C(15)-C(14)-H(14)
C(13)-C(14)-H(14)
C(14)-C(15)-O(16)
C(14)-C(15)-H(15)
O(16)-C(15)-H(15)
C(11)-O(16)-C(15)
C(10)
C(11)
C(12)
C(13)
O(13)
C(14)
C(15)
O(16)
382(2)
111.5(9)
-1246(2)
-1107(2)
-2628(2)
939(3)
2482(3)
2267(2)
121.66(13)
122.94(15)
115.40(13)
121.71(14)
118.1(10)
120.2(10)
123.57(13)
122.60(14)
113.83(13)
120.83(14)
117.7(12)
121.4(12)
123.74(16)
127.0(13)
109.2(13)
118.0 (13)
Table 2
Bond Length [Å] and Angles [°] for Compound 5.
C(1)-C(2)
C(1)-C(6)
C(1)-C(9)
C(2)-C(3)
C(2)-H(2)
C(3)-C(4)
C(3)-H(3)
C(4)-C(5)
1.389(2)
1.4101(19)
1.456(2)
1.380(2)
0.967(17)
1.387(3)
1.006(19)
1.377(3)
1.002(19)
1.373(2)
Table 3
C(4)-H(4)
C(5)-C(6)
C(5)-H(5)
Hydrogen Coordinates (x 104) and Isotropic Displacement Parameters
(Å2 x 103) for Compound 5.
0.96(2)
C(6)-N(7)
N(7)-C(8)
N(7)-H(7)
C(8)-O(8)
C(8)-C(9)
C(9)-C(10)
1.391(2)
1.356(2)
0.88(2)
1.210(2)
X
Y
Z
U(eq)
70(5)
81(6)
78(5)
79(5)
81(6)
54(4)
63(5)
82(6)
95(6)
H(2)
H(3)
H(4)
H(5)
4245(9)
4911(11)
4907(11)
4268(11)
3421(11)
2931(9)
3004(10)
3697(11)
3903(13)
4650(30)
7720(30)
8320(30)
5900(30)
2340(30)
-1010(20)
-2550(30)
1240(30)
3900(30)
1879(10)
1850(11)
720(11)
-335(12)
-867(13)
699(9)
1756(10)
3661(12)
3023(13)
1.5231(19)
1.341(2)
1.4558(18)
0.972(16)
1.337(2)
1.3557(19)
1.448(2)
0.969(16)
1.2343(18)
1.432(2)
H(7)
C(10)-C(11)
C(10)-H(10)
C(11)-C(12)
C(11)-O(16)
C(12)-C(13)
C(12)-H(12)
C(13)-O(13)
C(13)-C(14)
C(14)-C(15)
C(14)-H(14)
C(15)-O(16)
C(15)-H(15)
C(2)-C(1)-C(6)
C(2)-C(1)-C(9)
C(6)-C(1)-C(9)
C(3)-C(2)-C(1)
C(3)-C(2)-H(2)
C(1)-C(2)-H(2)
C(2)-C(3)-C(4)
C(2)-C(3)-H(3)
C(4)-C(3)-H(3)
C(5)-C(4)-C(3)
C(5)-C(4)-H(4)
C(3)-C(4)-H(4)
C(6)-C(5)-C(4)
C(6)-C(5)-H(5)
H(10)
1H(12)
H(14)
H(15)
tetramethyl silane as the internal standard. The coupling
constants (J) are quoted in Hz. The 13C nmr spectra were
recorded on a DPX 400 BRUKER. The mass spectra (electron
impact) were obtained on a CH-7A-Varian MAT (70 eV).
Elemental analyses were performed on
Elementae-Vario EL. Silica gel 60 (Merck, 230-400 mesh) and
silica gel plates (Merck, 60 F254 were used for flash
chromatography and tlc. The petroleum ether, used for
recrystallization, had a bp of 40-70°C. Dichloromethane was
distilled from phosphorous pentoxide. Anhydrous methanol and
ethanol were obtained after reflux over small amounts of
magnesium and distillation. All other reagents were obtained
from commercial suppliers and used without further purification.
6-(Ethoxycarbonyl)-4-oxo-4H-pyran-2-carboxylic acid (1).
Chelidonic acid (120 g, 6.45 moles) was refluxed with 600 mL
ethanolic hydrochloric acid (5%) for 3 hours. After cooling to -
10°C the reaction mixture was stirred for one hour. The solid
1.318(2)
0.94(2)
1.3623(19)
0.96(2)
a Perkin-Elmer
117.80(15)
135.49(13)
106.71(13)
119.83(15)
122.2(10)
117.9(10)
120.90(18)
120.3(11)
118.8(11)
120.68(18)
118.1(11)
121.2(11)
118.19(15)
120.1(11)
)

158
A. Lumetzberger, W. Löwe, M. Weber and P.Luger
Vol 44
Table 5
Crystal data and Structure Refinement for Compound 5.
Table 4
Torsion Angles [°] for Compound 5.
Formula
Formula weight
Temperature
Wavelength
Crystal system/Space group
Unit cell dimensions
C14H9N03
239.22
293 K
C(6)-C(1)-C(2)-C(3)
0.0(2)
179.42(16)
0.5(3)
-0.3(3)
-0.4(3)
-179.44(16)
1.0(2)
-0.8(2)
179.65(13)
179.57(13)
0.03(16)
-178.84(15)
0.76(18)
178.85(15)
-1.17(17)
-2.1(3)
177.34(18)
179.88(17)
-0.70(15)
2.6(2)
-177.40(13)
-178.88(15)
1.14(15)
1.5(3)
179.36(15)
-167.36(16)
12.9(2)
C(9)-C(1)-C(2)-C(3)
C(1)-C(2)-C(3)-C(4)
C(2)-C(3)-C(4)-C(5)
C(3)-C(4)-C(5)-C(6)
C(4)-C(5)-C(6)-N(7)
C(4)-C(5)-C(6)-C(1)
C(2)-C(1)-C(6)-C(5)
C(9)-C(1)-C(6)-C(5)
C(2)-C(1)-C(6)-N(7)
C(9)-C(1)-C(6)-N(7)
C(5)-C(6)-N(7)-C(8)
C(1)-C(6)-N(7)-C(8)
C(6)-N(7)-C(8)-O(8)
C(6)-N(7)-C(8)-C(9)
C(2)-C(1)-C(9)-C(10)
C(6)-C(1)-C(9)-C(10)
C(2)-C(1)-C(9)-C(8)
C(6)-C(1)-C(9)-C(8)
O(8)-C(8)-C(9)-C(10)
N(7)-C(8)-C(9)-C(10)
O(8)-C(8)-C(9)-C(1)
N(7)-C(8)-C(9)-C(1)
C(1)-C(9)-C(10)-C(11)
C(8)-C(9)-C(10)-C(11)
C(9)-C(10)-C(11)-C(12)
C(9)-C(10)-C(11)-O(16)
O(16)-C(11)-C(12)-C(13)
C(10)-C(11)-C(12)-C(13)
C(11)-C(12)-C(13)-O(13)
C(11)-C(12)-C(13)-C(14)
O(13)-C(13)-C(14)-C(15)
C(12)-C(13)-C(14)-C(15)
C(13)-C(14)-C(15)-C(16)
C(12)-C(11)-O(16)-C(15)
C(10)-C(11)-O(16)-C(15)
C(14)-C(15)-O(16)-C(11)
1.54180 A
monoclinic/C2/c
a = 20.780(9) Å
ꢁ = 90.00(3) deg.
b = 6.323(3) Å
ꢂ = 125.87(3) deg.
c = 20.931(6) Å
ꢃ = 90.00(4) deg.
2228.6(16) Å3
8, 1.426 Mg/m3
0.843 mm-1
Volume
Z, calculated density
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
992
0.44 x 0.26 x 0.08 mm
4.76 to 65.02 deg.
-24<=g<=24/0<=k<=7/-
24<=1<=24
3817/1911 [R(int) = 0.0250]
100.0 %
Full-matrix least-squares on F2
1911/0/200
Reflections collected/unique
Completeness to 2theta = 65.02
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I<2sigma(I)]
R indices (all data)
Extinction coefficient
1.044<41
R1 = 0.0313, wR2 = 0.0852
R1 = 0.0460, wR2 = 0.0921
0.00128 (14)
0.130 and -0.143 e..A-3
Largest diff. peak and hole
-1.9(2)
178.34(14)
-175.92(15)
3.4(2)
177.20(18)
-2.1(3)
-0.7(3)
-1.1(2)
178.72(12)
2.4(3)
This aqueous solution was neutralized with sulfuric acid (10%)
and concentrated. The reaction mixture was refluxed in 100 mL
ethyl acetate/ethanol (9:1) for ten minutes, dried over sodium
sulphate and concentrated. The brown oil obtained was purified
by flash chromatography (silica gel, ethyl acetate/ethanol (9:1))
and recrystallized with ethanol and petroleum ether to give white
crystals: Yield 5.6 g (50%), mp 66°C, ir (potassium bromide):
3389, 3214 (OH), 2911, 2853 (CH), 1661 (C=O) cm-1; H-nmr
1
(dimethyl sulfoxide-d6): ꢀ 8.11 (d, 1H, J= 5.4 Hz, H6), 6.23 (m,
2H, H3 and H5), 5.66 (t, 1H, J= 6.0 Hz, OH), 4.29 ppm (d, 2H,
J= 6.0 Hz, CH2), ms: (m/z) 126 (M+., 90%). Anal. Calcd for
C6H6O3 (126.1): C, 57.14 H, 4.80. Found: C, 57.11 H, 4.86.
material was collected by filtration and washed with ether (3 x 150
mL) to yield product 1 as pale brown crystals: Yield 101.2 g (74%),
mp 218-220°C, ir (potassium bromide): 3072 (CH olef.), 2986 (CH
1
aliph.), 1758, 1650 (C=O), 1173 (C-O) cm-1; H-nmr (dimethyl
4-Oxo-4H-pyran-2-carbaldehyde hydrate (4) and 2-
Dihydroxymethyl-4H-pyran-4-one (4a). To a solution of
150 mg (1.2 mmoles) of compound 3 in 20 mL methanol/
acetone/ dichloromethane (1:1:1) was added 200 mg
manganese (IV) dioxide and the reaction mixture was stirred
at 60°C for four hours. Every hour another 200 mg of
manganese (IV) dioxide was added after which the suspension
was filtered and the solvents were removed by evaporation.
The precipitated solid was purified by flash chromatography
(silica gel, ethyl acetate/ ethanol, 8:2) and recrystallized with
ethyl acetate and n-hexane to give pale yellow crystals: Yield
1.02 g (38%, 4, 4a), ir (potassium bromide): 3245 (OH), 3075
(CH), 1659, 1647 (C=O) cm-1; 1H-nmr (dimethyl sulfoxide-d6)
of 4: ꢀ 9.64 (s, 1H, CHO), 8.29 (d, 1H, J= 5.8 Hz, H6), 7.06
(d, 1H, J= 2.6 Hz, H3), 6.48 (dd, 1H, J= 2.6 Hz, J= 5.8 Hz,
H5) ppm; 1H-nmr (dimethyl sulfoxide-d6) of 4a: ꢀ 8.14 (d,
1H, J= 5.8 Hz, H6), 6.84 (d, 2H, J= 5.5 Hz, 2 OH), 6.32 (d,
1H, J= 2.5 Hz, H3), 6.25 (dd, 1H, J= 2.5 Hz, J= 5.8 Hz, H5),
5.47 ppm (1H, m, HO-CH-OH); ms: (m/z) 124 (M+., 71%).
Anal. Calcd for C6H4O3•H2O: (142.1): C, 53.51 H, 3.88.
Found: C, 53.20 H, 3.78.
sulfoxide-d6): ꢀ 7.01 (m, 2H, H3 and H5), 4.37 (m, 2H, O-CH2-
CH3), 1.32 ppm (m, 3H, O-CH2-CH3); ms: (m/z) 212 (M+., 60%).
Ethyl 4-oxo-4H-2-pyran-carboxylate (2). Compound 1 (56
g, 0.6 moles) was heated to 230°C in portions of approximately
4 x 14 g in a flask with air condenser. A pale yellow liquid was
produced, already partially crystallized in the air condenser.
Flash chromatography (ethyl acetate/ethanol (9:1)) of the crude
reaction compound yielded the pure white compound 2: Yield
11 g (25%), mp 96-98°C, ir (potassium bromide): 3056 (CH),
2991 (CH), 1729, 1621 (C=O) cm-1; 1H-nmr (dimethyl
sulfoxide-d6): ꢀ 8.21 (d, 1H, J= 5.9, H6), 6.90 (d, 1H, J= 2.6 Hz,
H3), 6.48 (dd, 1H, J= 2.6 Hz, J= 5.9 Hz, H5), 4.35 (q, 2H, J=
7.2 Hz, O-CH2-CH3), 1.31 ppm (t, 3H, J= 7.2 Hz, O-CH2-CH3);
ms: (m/z) 168 (M+. , 100%).
2-(Hydroxymethyl)-4H-pyran-4-one (3). A solution of 11 g
(88.7 mmoles) of compound 2 in 114 mL dry methanol was
cooled to -20°C at which time 3.6 g (95.2 mmoles) sodium
borohydride was added and the reaction mixture was stirred at -
20°C for one hour. 50 mL of the solvent were evaporated and
the remaining suspension was poured onto 100 mL ice water.

Jan-Feb 2007
Synthesis of an 4-Oxo-1,4-dihydropyridinomethylidene Substituted 2-Indolinone
159
(E)-3-((4-Oxo-4H-pyran-2-yl)methylene)indolin-2-one (5).
A mixture of 240 mg (1.7 mmoles) of compounds 4, 4a and 250
mg (1.9 mmoles) indolin-2-one were dissolved in 15 mL
pyridine and refluxed for 30 minutes. The reaction mixture was
poured onto ice and treated with 15 mL concentrated
hydrochloric acid (pH 2-3). The aqueous layer was extracted
with ethyl acetate (3 x 50 mL). Then the organic layer was dried
with sodium sulfate and concentrated. The crude compound was
recrystallized from ethanol to yield orange crystals: Yield 200
mg (45%), mp 254°C, ir (potassium bromide): 3081 (CH), 1717
and the pH was adjusted to 6 with sulfuric acid (10%). The
solution was stirred with a mixture of ethyl acetate and ethanol
(9:1) to eliminate the organic impurities. The aqueous layer was
concentrated and the residue was refluxed with ethanol (50 mL)
for ten minutes. The organic layers were combined and dried
with sodium sulfate and concentrated. The resulting light brown
oily product was recrystallized from ethanol to give a white
compound: Yield 1.3 g (66%), mp 197°C, ir (potassium
bromide): 3426 (OH), 3080, 2926 (CH), 1512 cm-1; 1H-nmr
(dimethyl sulfoxide-d6): ꢀ 11.08 (br, 1H, NH), 7.69 (m, 1H, H6),
6.26 (m, 1H, H5), 6.15 (s, 1H, H3), 5.50 (m, 1H, OH), 4.36 ppm
(m, 2H, CH2), ms: (m/z) 125 (M+. , 49%). Anal. Calcd for
C6H7NO2 (125.1): C, 57.59 H, 5.64 N, 11.20. Found: C, 57.68 H,
5.78 N, 11.26.
1
(CO-NH), 1649, 1630 (C=O) cm-1; H-nmr (dimethyl sulfoxide-
d6): ꢀ 10.76 (s, 1H, NH), 8.47 (d, 1H, J= 5.8 Hz, H6'), 8.07 (d,
1H, J= 7.8 Hz, H4), 7.35 (t, 1H, J= 7.8 Hz, H6), 7.17 (s, 1H,
CH), 7.02 (t, 1H, J= 7.8 Hz, H5), 6.92 (d, 1H, J= 2.5 Hz, H3'),
6.90 (d, 1H, J= 7.8 Hz, H7), 6.43 ppm (dd, 1H, J= 2.5 Hz, J=
5.8 Hz, H5'), 13C-nmr (dimethyl sulfoxide-d6): ꢀ 177.8, 167.9,
160.1, 155.9 (C6') 144.5, 131.9 (C6), 131.6, 127.1 (C4), 123.9
(CH=), 121.9 (C5), 120.9 (C3'), 119.8, 116.8 (C5'), 110.2 (C7);
ms: (m/z) 239 (M+., 100%). Anal. Calcd for C14H9NO3 (239.2):
C, 70.29 H, 3.79 N, 5.86. Found: C, 69.99 H, 3.71 N, 5.73.
(Z)-3-((4-Oxo-1,4-dihydropyridine-2-yl)methylene)indolin-
2-one (6). Method A: A solution of 80 mg (0.3 mmoles) of
compound 5 and 20 mg ammonium acetate in 30 mL glacial acetic
acid was refluxed for three hours. The reaction mixture was
poured onto 200 mL ice/water and neutralized with saturated
sodium carbonate solution. The aqueous layer was concentrated
and resolved in a mixture of ethyl acetate/ethanol (8:2). The
precipitated salts were removed and the organic layer was purified
by flash chromatography (silica gel, ethyl acetate/ethanol (8:2))
and recrystallized from ethanol to yield red crystals.
4-Oxo-1,4-dihydro-pyridine-2-carbaldehyde hydrate (8)
and 2-(Dihydroxymethyl)-1,4-dihydropyridine-4-one (8a). To
a solution of 1.3 g (10.4 mmoles) of compound 7 in 20 mL
methanol/ acetone/dichloromethane (1:1:1) was added 1.5 g
manganese (IV) dioxide and the reaction mixture was stirred at
60°C for four hours. Every hour were added another 1.5 g of
manganese (IV) dioxide, after which the suspension was filtered
and the solvents were removed by evaporation. The precipitated
solid was purified by flash chromatography (silica gel, ethyl
acetate) and recrystallized with ethyl acetate and ethanol to give
pale yellow crystals: Yield (8, 8a) 87.3 mg (71%), mp 148-
153°C, ir (potassium bromide): 3431 (OH, NH), 1632 (C=O)
1
cm-1; H-nmr (dimethyl sulfoxide-d6) of 8: ꢀ 10.65 (s, 1H, NH),
9.94 (s, 1H, CHO), 8.15 (m, 1H, H6), 6.92 (s, 1H, H3), 6.66
ppm (m, 1H, H5); 1H-nmr (dimethyl sulfoxide-d6) of 8a: ꢀ 11.16
(s, 1H, NH), 7.47 (m, 1H, H6), 6.79 (d, 2H, J= 6.4 Hz, 2 OH),
6.11 (m, 1H, H3), 5.98 (m, 1H, H5), 5.57 ppm (t, 1H, J= 6.4 Hz,
HO-CH-OH); ms: (m/z) 123 (M+., 26%). Anal. Calcd for
C6H5NO2 • H2O (141.1): C, 52.56 H, 4.82 N, 10.22. Found: C,
52.69 H, 4.79 N, 10.05.
Method B: The reaction mixture of 37 mg (0.3 mmoles) of
compounds 8/8a, 40 mg (0.3 mmoles) of 2-indolinone and 2
drops of piperidine in 5 mL ethanol was refluxed for two hours
and concentrated. The reaction product was purified by flash
chromatography (silica gel, ethyl acetate/ ethanol, 8:2) and
recrystallized from ethanol to yield red crystals: mp 256°C, ir
(potassium bromide): 3059, 2920 (CH), 1681 (CO-NH), 1603
REFERENCES AND NOTES
1
(C=O) cm-1; H-nmr (dimethyl sulfoxide-d6): ꢀ 13.65 (m, 1H,
[1] L. Sun, N. Tran, F. Tang, H. App, P. Hirth, G. McMahon
and C. Tang, J. Med. Chem., 41, 2588 (1998).
NH1'), 11.37 (s, 1H, NH1), 7.91 (m, 1H, H6'), 7.77 (d, 1H, J=
7.2 Hz, H4), 7.66 (s, 1H, CH=), 7.32 (t, 1H, J= 6.9 Hz, H6),
7.09 (t, 1H, J= 7.2 Hz, H5), 6.93 (d, 1H, J= 6.9 Hz, H7), 6.58
(s, 1H, H3'), 6.15 ppm (d, 1H, J= 5.9 Hz, H5'); ms: (m/z) 238
(M+., 83%). Anal. Calcd for C14H10N2O2•H2O (256.3): C, 65.62
H, 4.72 N, 10.93. Found: C, 65.68 H, 4.74 N, 10.92.
[2] A. T. T Fong, L. K. Shwawver, L. Sun, C. Tang, H. App, T.
J. Powell, Y. H. Kim, R. Schreck, X. Y. Wang, W. Risau, A. Ullrich, K.
P. Hirth and G. McMahon, Cancer Res., 59, 99 (1999).
[3] J. Attenburrow, J. Elks, D. F. Elliot, B. A. Hems, J. O. Harris
and C. I. Brodrick, J. Chem. Soc., 2, 571 (1945).
[4] W. Löwe, S. A. Brätter, M. Weber, P. Luger and J. Buddrus, J.
Heterocyclic Chem., 38, 365 (2001).
[5] C. K. Johnson, OrtepII, Report Ornl-5138, Oak Ridge
National Laboratory, Tennessee, USA (1976).
2-(Hydroxymethyl)-1,4-dihydropyridine-4-one (7).
A
solution of 2 g (15.8 mmoles) of compound 3 and 30 mL of
ammonium carbonate (10%) and ammonia (25%) (1:1) was
refluxed for one hour. The reaction mixture was poured onto ice