Reaction of isatin-1-acetamides with alkoxides: Synthesis of novel 1,4-dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides

Article abstract of DOI:10.1055/s-2007-965949

The study of the reactivity of a series of isatin-1-acetamides with hot alkoxides is described. These reactions lead to 1,4-dihydro-3-hydroxy-4-oxo-2- quinolinecarboxamides as main products, and 3-hydroxy-2-oxindoles as well as other minor products. Exper

Full text of DOI:10.1055/s-2007-965949

PAPER
829
Reaction of Isatin-1-acetamides with Alkoxides: Synthesis of Novel
1,4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides
S
ynthesis of 1,4-Dihyd
a
ro-3-hydro
r
xy-4-oxo
í
-2-quin
a
olinecarboxamid
M
es ercedes Blanco, Mónica Dal Maso, María Sol Shmidt, Isabel Amalia Perillo*
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Junín 956, 1113 Buenos Aires, Argentina
Fax +54(11)49648250; E-mail: iperillo@ffyb.uba.ar
Received 8 August 2006; revised 15 December 2006
(2,3-dihydro-2,3-dioxo-1H-indole) derivatives. Thus, by
analogy with the proposed mechanism for the Gabriel–
Colman reaction,1b,3 alkoxide-promoted rearrangement of
isatin-1-acetic acid derivatives 1 should lead, through an
Abstract: The study of the reactivity of a series of isatin-1-acet-
amides with hot alkoxides is described. These reactions lead to 1,4-
dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides as main prod-
ucts, and 3-hydroxy-2-oxindoles as well as other minor products.
Experimental results indicate that the starting compounds undergo isatinic ester intermediate, to 1,4-dihydro-3-hydroxy-4-
transformation through two principal routes: ring expansion of isa-
oxo-2-quinolinecarboxylic acid derivatives 2, a family of
scarcely explored 4-quinolinones4 (Scheme 1). Although
tin leading to quinoline carboxamides, probably as the result of a
ring-opening and ring-closure rearrangement, and reduction of the
extensive reviews have been published in 1975, 1994 and
keto carbonyl group due to the reductive ability of alkoxides.
2001,5 in which many examples of reactions with nucleo-
philes leading to isatin rearrangement are shown, there are
no previous reports of successful reactions with alkoxides.
Key words: 4-quinolinones, isatin, alkylation, rearrangement, re-
duction
The only accounts found in the literature date from the
first half of the past century. Thus, in 1934 Ainley and
Alkoxide-promoted rearrangement of phthalimidoacetic
Robinson concluded that isatin ring expansion failed
acid derivatives (A, Ar = C6H4, C6H3R) leading to 4-hy-
droxyisoquinolinones (B, Ar = C6H4, C6H3R) (Gabriel–
Colman rearrangement) (Equation 1) is well known.1
Ring expansion of pentagonal cyclic imides has also been
employed to prepare hydroxynaphthyridinones (B,
Ar = C5H3N) from 2,3- and 3,4-pyridinedicarboximides
(A, Ar = C5H3N).2 However, until now, only a few at-
tempts to perform alkoxide-induced rearrangement of
aromatic pentagonal cyclic amides have been reported.
when the reaction of ethyl isatinacetate (1; X = OC2H5)
with sodium methoxide did not produce a compound giv-
ing colored reaction with ferric chloride.6 At the same
time, while studying the same reaction, Putokhin obtained
isatin-1-acetic acid (1, X = OH) and the hydroxy acid 2
(X = OH) that were characterized as its silver salt and
O,O-diethyl derivative.7
We present in this work the study of the reactions of isa-
tin-1-acetamide (1, X = NRR¢) with alkoxides. Starting
compounds 1a–f were obtained by N-alkylation of isatin
with the corresponding chloroacetamides (Scheme 2). Re-
action of amides 1 with hot alkoxides under different con-
ditions led in all cases to two main compounds. The major
products were the expected 1,4-dihydro-3-hydroxy-4-
oxo-2-quinolinecarboxamides 28 (Table 1). These com-
pounds are a new family of compounds structurally relat-
ed to other heterocyclic carboxamides (1,2-dihydro-4-
hydroxy-2-oxo-3-quinolinecarboxamides) having impor-
tant biological activity.9
OH
O
N-CH2-COX
COX
RO–
ROH
Ar
Ar
N
H
O
O
A
B
X = OR, NRR', Ar
Equation 1 Alkoxide-induced rearrangement of imidoacetic acid
derivatives
Following the ongoing research on potentially bioactive The minor products were 3-hydroxy-2-oxindoles 3 (2,3-
compounds, we were interested in the behavior of isatin dihydro-3-hydroxy-2-oxo-1H-indole-1-acetamides) ob-
O
O
O
OH
RO–/ROH
RO–/ROH
CO2R
COX
O
N
N
H
COX
N
H
CH2
COX
1
2
Scheme 1
SYNTHESIS 2007, No. 6, pp 0829–0834
x
x
.
x
x
.2
0
0
7
Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965949; Art ID: M05006SS
© Georg Thieme Verlag Stuttgart · New York

830
M. M. Blanco et al.
PAPER
O
O
O
OH
RO–/ROH
ClCH2COX
O
O
∆
K2CO3, DMF
N
N
H
COX
N
CH2
COX
H
1
2
Scheme 2
Other isolated by-products from the reaction of com-
pounds 1 with sodium methoxide are the corresponding
isatinic acid 4, the o-aminobenzoic acids 5, and the fluo-
rescent hydroxy acid 2 (X = OH). Experimental results
shown above indicate that reaction follows two pathways
(Scheme 3). On the one hand the 1 → 2 isomerization
would result from a ring-opening/ring-closing rearrange-
ment, taking place by initial alkoxide attack with forma-
tion of an isatinic ester intermediate I followed by
Dieckmann cyclization as shown in Scheme 1. On the oth-
er hand, formation of compounds 3 can be explained by
the carbonyl reductive ability of alkoxides derived from
metals with low ionization potentials (Meerwein–
Ponndorf–Verley type reductions)10 and which probably
proceeds through radical intermediates (SET mecha-
nism).11
Table 1 Compounds 1 and 2 Prepared
Compounds 1, 2
X
Yield (%)
1
2
a
b
c
d
e
f
NH2
68
81
78
76
69
83
73
75
72
69
64
60
NHCH(CH3)2
NHC6H11
NHC6H5
N(C2H5)2
N(CH3)C6H5
tained from reduction of the ketone carbonyl of the start-
ing compound (Scheme 3). These compounds display a
remarkable reducing character related to their a-hydroxy
ketone structure. They undergo spontaneous oxidation in
solution and when adsorbed on chromatographic sup-
ports.
Acids 4 and 5 might have originated by the direct hydrol-
ysis of isatin moiety in the presence of small amounts of
water in the reaction medium, or may result from a side re-
action of ester intermediate I with alkoxides, most proba-
bly through an SN2 mechanism, common for this type of
intermediates.1b,3
The ratio between yields of products 2 and 3 varied ac-
cording to the nature and number of equivalents of alkox-
ides used. Thus, the best yields of quinolinones 2 (60–
75%) were obtained with eight equivalents of sodium
methoxide in methanol, whereas with sodium ethoxide or
isopropoxide the ratio decreases.
In conclusion, a two-step synthetic approach to the novel
potentially bioactive 3-hydroxy-4-oxo-1,4-dihydro-2-
quinolinecarboxamides from isatin is described. Although
yields are in some cases diminished due to the reductive
ability of alkoxides, the low number of steps and the start-
ing material availability give added value to this method.
CO2H
CO-CO2H
– CO
NH-CH2-COX
5b,d
(8–10%)
NH-CH2-COX
4e
(5%)
?
O
N
OH–
?
CO-CO2R
OH
RO–
O
RO–
NH-CH2-COX
COX
O
I
H
2a–f
(60–75%)
N
OH
CH2
H
COX
1a–f
O
N
CH2 COX
3a–f
(12–20%)
Scheme 3 X in compounds 3,4 and 5 corresponds to those indicated for compounds 1 and 2
Synthesis 2007, No. 6, 829–834 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides
831
Melting points were taken on a Büchi capillary apparatus and are
uncorrected. The 1H and 13C NMR spectra were recorded on a Bruk-
er MSL 300 MHz spectrometer at 25 °C. DMSO-d6 was used as sol-
vent, and standard concentration of the samples was 20 mg/mL.
Chemical shifts are reported in ppm (d) relative to TMS as an inter-
nal standard. D2O was employed to confirm exchangeable protons
(ex.). Splitting multiplicities are reported as singlet (s), broad signal
(br s), doublet (d), double doublet (dd), triplet (t), double triplet (dt),
quartet (q), and multiplet (m). Two-dimensional spectra (HMQC
and HMBC) were recorded in a Bruker Avance DRX 300 MHz
spectrometer. Electron impact MS were recorded with a GC-MS
Shimadzu QP-1000 spectrometer operating at 70 eV. The IR spectra
were recorded on a PerkinElmer Spectrum One FT-IR spectrome-
ter. TLC analyses were carried out on silica gel 60 F254 using
CHCl3–MeOH (9:1) as solvent. Preparative thin layer separations
(PLC) were carried out by centrifugally accelerated, radial chroma-
tography using Chromatotron model 7924T. The rotors were coated
with Silica Gel 60 PF254 and the layer thickness was 2 mm. CHCl3
and increasing percentages of MeOH were used as eluent. Reagents,
solvents and starting materials were purchased from standard sourc-
es and purified according to literature procedures.
1H NMR (300 MHz, DMSO-d6): d = 8.04 (d, J = 6.9 Hz, 1 H, ex.,
NH), 7.63 (t, J = 7.6 Hz, 1 H, H-6), 7.57 (d, J = 7.6 Hz, 1 H, H-4),
7.13 (t, J = 7.6 Hz, 1 H, H-5), 6.96 (d, J = 7.6 Hz, 1 H, H-7), 4.27
(s, 2 H, CH2), 3.53 (m, 1 H, NHCH), 1.69–1.50 (m, 5 H, C6H11),
1.24–1.02 (m, 5 H, C6H11).
13C NMR (75.5 MHz, DMSO-d6): d = 183.1, 164.7, 158.3, 150.7,
138.1, 124.3, 123.3, 117.6, 110.7, 47.9, 42.7, 32.3, 25.1, 24.5.
MS: m/z (%) = 286 (21, M+·), 161 (100).
Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C,
67.29; H, 6.37; N, 9.81.
2,3-Dihydro-2,3-dioxo-N-phenyl-1H-indole-1-acetamide (1d)
Yield: 76%; mp 213–215 °C (i-PrOH).
IR (KBr): 3302, 2930, 2854, 1743, 1655, 1612, 1546, 1346 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.24 (br s, 1 H, ex., NH), 7.67
(t, J = 7.4 Hz, 1 H, H-6), 7.63 (d, J = 7.4 Hz, 1 H, H-4), 7.48 (d,
J = 7.8 Hz, 2 H, H-2¢, H-6¢), 7.32 (t, J = 7.8 Hz, 2 H, H-3¢, H-5¢),
7.13 (t, J = 7.4 Hz, 1 H, H-5), 7.09 (t, J = 7.8 Hz, 1 H, H-4¢), 7.02
(d, J = 7.4 Hz, 1 H, H-7), 4.56 (s, 2 H, CH2).
13C NMR (75.5 MHz, DMSO-d6): d = 183.6, 164.8, 158.4, 150.8,
2,3-Dihydro-2,3-dioxo-1H-indole-1-acetamides (Isatin-1-acet-
amides) 1a–f; General Procedure
142.3, 138.3, 128.8, 124.5, 123.8, 123.5, 119.5, 117.5, 111.0, 43.1.
MS: m/z (%) = 280 (35, M+·), 132 (100).
A mixture of isatin (1 g, 0.007 mol), K2CO3 (1.10 g, 0.008 mol), the
corresponding halogen derivative (0.008 mol) and DMF (5 mL) was
heated for 2–3 h in an oil bath (80–90 °C) and the reaction was mon-
itored by TLC. After completion of the reaction, the mixture was
poured into ice-water and the resulting solid filtered, washed with
H2O and recrystallized.
Anal. Calcd for C16H12N2O3: C, 68.57; H, 4.32; N, 9.99. Found: C,
68.73; H, 4.28; N, 10.04.
N,N-Diethyl-2,3-dihydro-2,3-dioxo-1H-indole-1-acetamide (1e)
Yield: 69%; mp 175–176 °C (i-PrOH).
IR (KBr): 2976, 1738, 1651, 1614, 1471, 760 cm–1.
2,3-Dihydro-2,3-dioxo-1H-indole-1-acetamide (1a)
1H NMR (300 MHz, DMSO-d6): d = 7.57 (d, J = 7.7 Hz, 1 H, H-4),
7.53 (t, J = 7.7 Hz, 1 H, H-6), 7.11 (t, J = 7.7 Hz, 1 H, H-5), 6.90
(d, J = 7.7 Hz, 1 H, H-7), 4.52 (s, 2 H, CH2CO), 3.44–3.35 (m, 4 H,
CH2CH3), 1.29 (t, J = 7.1 Hz, 3 H, CH3), 1.12 (t, J = 7.4 Hz, 3 H,
CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 183.3, 164.3, 158.4, 151.4,
138.5, 124.5, 123.4, 117.7, 111.3, 41.9, 41.0, 14.1, 12.9.
Yield: 68%; mp 246–248 °C (MeOH) (Lit.12 mp ca. 260 °C).
IR (KBr): 3680, 3660, 2981, 2938, 1736, 1656, 1346, 1055, 761
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.74 (br s, 1 H, ex., NH2), 7.64
(t, J = 7.5 Hz, 1 H, H-6), 7.58 (d, J = 7.5 Hz, 1 H, H-4), 7.31 (br s,
1 H, ex., NH2), 7.13 (t, J = 7.5 Hz, 1 H, H-5), 7.01 (d, J = 7.5 Hz, 1
H, H-7), 4.25 (s, 2 H, CH2).
13C NMR (75.5 MHz, DMSO-d6): d = 183.1, 168.9, 158.4, 150.6,
138.1, 124.4, 123.5, 117.7, 110.7, 42.5.
MS: m/z (%) = 204 (31, M+·), 132 (100).
MS: m/z (%) = 260 (20, M+·), 72 (100).
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.69; H, 6.17; N, 10.81.
Anal. Calcd for C10H8N2O3: C, 58.82; H, 3.95; N, 13.72. Found: C,
58.97; H, 3.98; N, 13.67.
2,3-Dihydro-N-methyl-2,3-dioxo-N-phenyl-1H-indole-1-acet-
amide (1f)
Yield: 83%; mp 188–189 °C (i-PrOH).
IR (KBr): 2938, 1734, 1613, 1595, 1494, 1346, 759 cm–1.
2,3-Dihydro-N-isopropyl-2,3-dioxo-1H-indole-1-acetamide (1b)
Yield: 81%; mp 193–195 °C (i-PrOH).
IR (KBr): 3265, 2974, 1740, 1649, 1609, 1378, 748 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.05 (d, J = 6.8 Hz, 1 H, ex.,
NH), 7.64 (t, J = 7.7 Hz, 1 H, H-6), 7.57 (d, J = 7.7 Hz, 1 H, H-4),
7.13 (t, J = 7.7 Hz, 1 H, H-5), 6.97 (d, J = 7.7 Hz, 1 H, H-7), 4.26
(s, 2 H, CH2), 3.86 (m, 1 H, CH), 1.02 (d, J = 6.8 Hz, 6 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 183.1, 164.8, 158.3, 150.7,
138.1, 124.3, 123.3, 117.6, 110.7, 42.7, 40.8, 22.2.
MS: m/z (%) = 246 (40, M+·), 132 (100).
1H NMR (300 MHz, DMSO-d6): d = 7.65 (t, J = 7.6 Hz, 1 H, H-6),
7.62 (d, J = 7.6 Hz, 1 H, H-4), 7.56–7.43 (m, 4 H, H-2¢, H-3¢, H-5¢,
H-6¢), 7.12 (t, J = 7.6 Hz, 1 H, H-5), 7.08 (d, J = 7.6 Hz, 1 H, H-7),
7.05 (t, J = 7.9 Hz, 1 H, H-4¢), 4.20 (s, 2 H, CH2), 3.18 (s, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 183.0, 165.0, 158.1, 151.1,
142.1, 138.4, 130.1, 128.4, 127.4, 124.4, 123.5, 117.2, 111.4, 41.9,
37.2.
MS: m/z (%) = 294 (51, M+·), 134 (100).
Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.52; H, 4.82; N 9.47.
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.55; H, 5.70; N, 11.33.
Reaction of Compounds 1 with Sodium Alkoxides; General
Procedure
To a solution of NaOMe, prepared from Na (0.71 g, 0.031 mol) in
anhyd MeOH (7.6 mL), heated in an oil bath (100–120 °C), was
added the respective isatin-1-acetamide 1a–f (3.8 mmol) all at once
as the powder. After 2 h, the mixture was cooled, poured onto ice
N-Cyclohexyl-2,3-dihydro-2,3-dioxo-1H-indole-1-acetamide
(1c)
Yield: 78%; mp 223–225 °C (i-PrOH).
IR (KBr): 3318, 1741, 1683, 1613, 1553, 1742, 751 cm–1.
Synthesis 2007, No. 6, 829–834 © Thieme Stuttgart · New York

832
M. M. Blanco et al.
PAPER
and extracted with CH2Cl2 (10 mL) and EtOAc (10 mL). The aque-
ous layer was acidified to pH 2 with concd HCl and the precipitate
was collected by filtration. The crude products obtained from 1a–f
show two main spots by TLC. Separation of the two compounds
was achieved by centrifugal PLC. The first band that eluted gave the
3-hydroxy-2-oxindoles 3a–f (12–20%). The slower moving band
afforded the quinolinone derivatives 2a–f (60–75%). The structure
of compounds 3 was confirmed by comparison with authentic sam-
ples obtained by reduction of compounds 1 with NaBH4 following
a literature procedure.13 These compounds gave positive reactions
with Tollens reagent.
Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C,
67.00; H, 6.36; N, 9.81.
1,4-Dihydro-3-hydroxy-4-oxo-N-phenyl-2-quinolinecarbox-
amide (2d)
Yield: 69%; mp 230–233 °C (i-PrOH).
IR (KBr): 3440, 3260, 2989, 1658, 1645, 1579, 1505, 1450, 1234,
760 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 14.10 (br s, 1 H, ex., NH),
12.46 (br s, 1 H, ex., NH), 8.30 (d, J = 7.6 Hz, 1 H, H-5), 7.81 (d,
J = 7.7 Hz, 2 H, H-2¢, H-6¢), 7.59 (d, J = 7.6 Hz, 1 H, H-8), 7.43 (t,
J = 7.7 Hz, 2 H, H-3¢, H-5¢), 7.20–7.00 (m, 3 H, H-7, H-6, H-4¢).
13C NMR (75.5 MHz, DMSO-d6): d = 169.8, 158.0, 138.8, 135.2,
134.7, 129.0, 127.6, 124.1, 123.8, 123.3, 121.8, 119.5, 112.7, 107.1.
MS: m/z (%) = 280 (86, M+·), 93 (100).
When compounds 1 were reacted with 2–5 equivalents of NaOMe
yields of the products 2 were the lowest. When NaOEt in EtOH or
sodium isopropoxide in isopropanol were used, yield 2/yield 3 ratio
was decreased. Compounds 4, 5 and the acid 2 (X = OH), were iso-
lated as by-products from the reaction of compounds 1 with NaOMe
following the general procedure described above.
Anal. Calcd for C16H12N2O3: C, 68.57; H, 4.32; N, 9.99. Found: C,
68.44; H, 4.36; N, 10.01.
1,4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamide (2a)
Yield: 73%; mp 222–225 °C (i-PrOH).
IR (KBr): 3350, 1657, 1527, 1494, 1457, 1397, 1233, 751 cm–1.
N,N-Diethyl-1,4-dihydro-3-hydroxy-4-oxo-2-quinolinecarbox-
amide (2e)
1H NMR (300 MHz, DMSO-d6): d = 12.25 (br s, 1 H, ex., NH),
11.81 (br s, 2 H, ex., NH2), 8.50 (d, J = 7.7 Hz, 1 H, H-5), 7.63 (br
s, 1 H, ex., OH), 7.49 (d, J = 7.7 Hz, 1 H, H-8), 7.19 (t, J = 7.7 Hz,
1 H, H-7), 7.08 (t, J = 7.7 Hz, 1 H, H-6).
13C NMR (75.5 MHz, DMSO-d6): d = 171.7, 162.5, 134.4, 132.6,
128.7, 124.0, 123.1, 120.3, 112.7, 112.0.
Yield: 64%; mp 233–235 °C (i-PrOH).
IR (KBr): 3360, 2980, 1651, 1642, 1570, 1522, 1458, 749 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.28 (br s, 1 H, ex., NH), 8.29
(s, 1 H, ex., OH), 8.00 (d, J = 7.0 Hz, 1 H, H-5), 7.40 (d, J = 7.0 Hz,
1 H, H-8), 7.20 (t, J = 7.0 Hz, 1 H, H-7), 7.16 (t, J = 7.0 Hz, 1 H,
H-6), 3.45 (q, J = 6.8 Hz, 2 H, CH2), 3.12 (q, J = 6.8 Hz, 2 H, CH2),
1.14 (t, J = 6.8 Hz, 3 H, CH3), 0.97 (t, J = 6.8 Hz, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 165.1, 162.8, 138.8, 135.2,
125.6, 122.8, 121.5, 121.1, 112.1, 103.8, 42.4, 38.3, 13.8, 12.2.
MS: m/z (%) = 260 (14, M+·), 73 (100).
MS: m/z (%) = 204 (2, M+·), 143 (100).
Anal. Calcd for C10H8N2O3: C, 58.82; H, 3.95; N, 13.72. Found: C,
58.94; H, 3.98; N, 13.67.
1,4-Dihydro-3-hydroxy-N-isopropyl-4-oxo-2-quinolinecarbox-
amide (2b)
Yield: 75%; mp 225–227 °C (i-PrOH).
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.45; H, 6.17; N, 10.80.
IR (KBr): 3427, 3263, 3038, 2970, 1657, 1644, 1576, 1506, 1448,
1439, 1218, 748 cm–1.
1,4-Dihydro-3-hydroxy-N-methyl-4-oxo-N-phenyl-2-quinoline-
carboxamide (2f)
1H NMR (300 MHz, DMSO-d6): d = 12.49 (br s, 1 H, ex., NH),
10.87 (d, J = 6.6 Hz, 1 H, ex., CHNH), 8.16 (d, J = 7.6 Hz, 1 H, H-
5), 7.59 (d, J = 7.6 Hz, 1 H, H-8), 7.30 (t, J = 7.6 Hz, 1 H, H-7),
7.23 (t, J = 7.6 Hz, 1 H, H-6), 4.13 (m, 1 H, CH), 1.26 (d, J = 6.8
Hz, 6 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 168.6, 158.6, 136.2, 134.4,
127.1, 124.2, 122.9, 122.2, 112.9, 105.3, 41.3, 22.3.
Yield: 60%; mp 168–170 °C (i-PrOH).
IR (KBr): 3340, 3290, 2989, 1656, 1646, 1582, 1505, 1447, 1236,
759 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.60 (br s, 1 H, ex., NH), 7.55
(d, J = 7.4 Hz, 1 H, H-5), 7.50 (d, J = 7.8 Hz, 2 H, H-2¢,H-6¢), 7.46–
7.35 (m, 3 H, H-3¢, H-4¢, H-5¢), 7.28 (d, J = 7.4 Hz, 1 H, H-8), 7.17
(t, J = 7.4 Hz, 1 H, H-7), 6.96 (t, J = 7.4 Hz, 1 H, H-6), 5.25 (br s,
1 H, ex., OH), 3.50 (s, 3 H, CH3).
MS: m/z = 246 (100%, M+·).
13C NMR (75.5 MHz, DMSO-d6): d = 167.9, 157.6, 142.1, 137.2,
135.1, 129.9, 128.6, 126.7, 126.0, 125.6, 122.3, 121.3, 120.7, 111.8,
36.7.
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.55; H, 5.76; N, 11.43.
MS: m/z (%) = 294 (2, M+·), 107 (100).
N-Cyclohexyl-1,4-dihydro-3-hydroxy-4-oxo-2-quinolinecar-
boxamide (2c)
Yield: 72%; mp 245–246 °C (i-PrOH).
Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.49; H, 4.83; N, 9.47.
IR (KBr): 3430, 3256, 2979, 1656, 1646, 1575, 1510, 1450, 751
cm–1.
1,4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxylic Acid (2,
X = OH)
1H NMR (300 MHz, DMSO-d6): d = 12.48 (br s, 1 H, ex., NH),
10.95 (d, J = 7.0 Hz, 1 H, ex., CHNH), 8.13 (d, J = 7.5 Hz, 1 H, H-
5), 7.58 (d, J = 7.5 Hz, 1 H, H-8), 7.30 (t, J = 7.5 Hz, 1 H, H-7),
7.22 (t, J = 7.5 Hz, 1 H, H-6), 3.93 (m, 1 H, CH), 1.91–1.38 (m, 10
H, C6H11).
13C NMR (75.5 MHz, DMSO-d6): d = 168.6, 158.3, 136.2, 134.3,
127.0, 124.0, 122.8, 122.1, 112.9, 105.2, 47.4, 31.8, 25.2, 23.6.
This compound was isolated from the reaction of 1e with NaOMe
(6%); mp 260–262 °C (acetone) (Lit.4b mp 261–262 °C).
IR (KBr): 3434, 2079, 1645, 1032, 1014 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 14.60 (br s, 3 H, ex., OH and
NH), 8.15–8.08 (m, 2 H, H-5, H-8), 7.70 (t, J = 7.6 Hz, 1 H, H-6 or
H-7), 7.43 (t, 1 H, J = 7.6 Hz, H-6 or H-7).
13C NMR (75.5 MHz, DMSO-d6): d = 164.8, 164.4, 143.5, 135.8,
131.6, 126.1, 124.5, 123.3, 121.2, 119.8.
MS: m/z (%) = 286 (99, M+·), 98 (100).
Synthesis 2007, No. 6, 829–834 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides
833
MS: m/z (%) = 205 (53, M+·), 103 (100).
Anal. Calcd for C16H14N2O3: C, 68.08; H, 5.00; N, 9.92. Found: C,
68.20; H, 5.03; N, 9.87.
2,3-Dihydro-3-hydroxy-2-oxo-1H-indole-1-acetamide (3a)
Yield: 12%; mp 198–200 °C (MeOH).
IR (KBr): 3575, 3561, 2966, 1682, 1665, 1615, 1469 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.55 (br s, 2 H, ex., NH2), 7.31
(d, J = 7.6 Hz, 1 H, H-4), 7.23 (t, J = 7.6 Hz, 1 H, H-6), 7.03 (t,
J = 7.6 Hz, 1 H, H-5), 6.81 (d, J = 7.6 Hz, 1 H, H-7), 6.26 (br s, 1
H, ex., OH), 4.95 (s, 1 H, H-3), 4.26 (d, 1 H, J = 16.6 Hz, CH2), 4.11
(d, 1 H, J = 16.6 Hz, CH2).
13C NMR (75.5 MHz, DMSO-d6): d = 176.1, 168.5, 143.1, 129.0,
128.4, 124.5, 122.3, 108.6, 68.7, 42.0.
N,N-Diethyl-2,3-dihydro-3-hydroxy-2-oxo-1H-indole-1-acet-
amide (3e)
Yield: 20%; mp 128–130 °C (i-PrOH).
IR (KBr): 3364, 2975, 1717, 1642, 1616, 1468, 773 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.40 (d, J = 7.4 Hz, 1 H, H-
4), 7.23 (t, J = 7.4 Hz, 1 H, H-6), 7.03 (t, J = 7.4 Hz, 1 H, H-5), 6.73
(d, J = 7.4 Hz, 1 H, H-7), 5.05 (s, 1 H, H-3), 4.75 (br s, 1 H, ex.,
OH), 4.53 (d, J = 16.1 Hz, 1 H, COCH2), 4.40 (d, J = 16.1 Hz, 1 H,
COCH2), 3.43–3.33 (m, 4 H, CH2CH3), 1.27 (t, J = 7.3 Hz, 3 H,
CH3), 1.10 (t, J = 7.3 Hz, 3 H, CH3).
MS: m/z (%) = 206 (35, M+·), 134 (100).
13C NMR (75.5 MHz, DMSO-d6): d = 176.8, 165.3, 143.1, 129.4,
127.4, 125.0, 123.1, 109.3, 69.7, 41.7, 41.6, 40.8, 14.3, 12.9.
MS: m/z (%) = 262 (32, M+·), 100 (100).
Anal. Calcd for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59. Found: C,
58.15; H, 4.91; N, 13.65.
2,3-Dihydro-3-hydroxy-N-isopropyl-2-oxo-1H-indole-1-acet-
amide (3b)
Anal. Calcd for C14H18N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C,
63.99; H, 6.91; N, 10.70.
Yield: 18%; mp 192–193 °C (i-PrOH).
2,3-Dihydro-3-hydroxy-N-methyl-2-oxo-N-phenyl-1H-indole-
1-acetamide (3f)
Yield: 19%; pasty solid.
IR (KBr): 3660, 2980, 1733, 1650, 1469, 770 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.02 (d, J = 7.8 Hz, 1 H, ex.,
NH), 7.33 (d, J = 7.7 Hz, 1 H, H-4), 7.25 (t, J = 7.7 Hz, 1 H, H-6),
7.02 (t, J = 7.7 Hz, 1 H, H-5), 6.78 (d, J = 7.7 Hz, 1 H, H-7), 6.32
(br s, 1 H, ex., OH), 4.94 (s, 1 H, H-3), 4.26 (d, J = 16.4 Hz, 1 H,
CH2), 4.10 (d, J = 16.4 Hz, 1 H, CH2), 3.84 (m, 1 H, CH), 1.07–1.01
(m, 6 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 176.4, 165.2, 143.1, 129.2,
127.9, 124.8, 122.7, 108.9, 69.0, 42.9, 42.1, 22.0.
MS: m/z (%) = 248 (26, M+·), 43 (100).
1H NMR (300 MHz, DMSO-d6): d = 7.60–7.45 (m, 5 H, C6H5), 7.31
(d, J = 7.3 Hz, 1 H, H-4), 7.25 (t, J = 7.3 Hz, 1 H, H-6), 7.01 (t,
J = 7.3 Hz, 1 H, H-5), 6.84 (d, J = 7.3 Hz, 1 H, H-7), 6.29 (br s, 1
H, ex., OH), 5.15 (s, 1 H, H-3), 4.19 (d, J = 16.6 Hz, 1 H, CH2), 4.08
(d, J = 16.6 Hz, 1 H, CH2), 3.19 (s, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 176.6, 166.0, 142.9, 142.2,
130.3, 129.6, 128.7, 127.1, 126.9, 125.1, 123.2, 108.4, 69.7, 42.0,
37.8.
MS: m/z (%) = 296 (23, M+·), 134 (100).
Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C,
62.80; H, 6.53; N, 11.24.
Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C,
68.78; H, 5.46; N, 9.40.
N-Cyclohexyl-2,3-dihydro-3-hydroxy-2-oxo-1H-indole-1-acet-
amide (3c)
Yield: 20%; mp 187–190 °C (i-PrOH).
IR (KBr): 3660, 3650, 2977, 1736, 1650, 1219, 712 cm–1.
2-(N,N-Diethylcarbamoylmethylamino)phenylglyoxylic Acid
(4e)
This compound was obtained from 1e in 5% yield when the reaction
1H NMR (300 MHz, DMSO-d6): d = 8.03 (d, J = 7.9 Hz, 1 H, ex.,
NH), 7.32 (d, J = 7.3 Hz, 1 H, H-4), 7.25 (t, J = 7.3 Hz, 1 H, H-6),
7.02 (t, J = 7.3 Hz, 1 H, H-5), 6.78 (d, J = 7.3 Hz, 1 H, H-7), 6.30
(br s, 1 H, ex., OH), 4.94 (s, 1 H, H-3), 4.28 (d, J = 16.3 Hz, 1 H,
CH2), 4.12 (d, J = 16.3 Hz, 1 H, CH2), 3.50 (m, 1 H, NHCH), 1.73–
1.51 (m, 5 H, C6H11), 1.26–1.04 (m, 5 H, C6H11).
13C NMR (75.5 MHz, DMSO-d6): d = 176.0, 165.2, 143.2, 128.5,
128.3, 124.4, 122.1, 108.6, 68.7, 47.7, 42.2, 32.3, 25.1, 24.4.
MS: m/z (%) = 288 (28, M+·), 145 (100).
mixture was quenched with AcOH; mp 110 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 13.05 (br s, 1 H, ex., OH), 8.36
(br s, 1 H, ex., NH), 7.76 (d, J = 7.6 Hz, 1 H, H-6), 7.33 (t, J = 7.6
Hz, 1 H, H-4), 6.64 (t, J = 7.6 Hz, 1 H, H-5), 6.51 (d, J = 7.6 Hz, 1
H, H-3), 4.00 (s, 2 H, NCH2), 3.40–3.31 (m, 4 H, CH2CH3), 1.32 (t,
J = 7.2 Hz, 3 H, CH3), 1.20 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 188.3, 164.3, 158.4, 151.4,
138.5, 124.5, 123.4, 117.3, 111.3, 41.2, 40.8, 40.2, 14.1, 12.9.
MS: m/z (%) = 278 (1, M+·), 132 (100).
Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C,
66.50; H, 6.96; N, 9.68.
Anal. Calcd for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07. Found: C,
60.36; H, 6.55; N, 10.02.
2,3-Dihydro-3-hydroxy-2-oxo-N-phenyl-1H-indole-1-acet-
amide (3d)
Yield: 15%; mp 178–180 °C (i-PrOH).
IR (KBr): 3666, 3652, 2990, 1730, 1646, 1463, 750 cm–1.
2-(N-Isopropylcarbamoylmethylamino)benzoic Acid (5b)
This compound was obtained from 1b in 10% yield; mp 198 °C
(dec.) (EtOH).
IR (KBr): 3305, 2973, 1649, 1570, 1547, 1616, 1219, 773 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.29 (br s, 1 H, ex., NH), 7.56
(d, J = 7.7 Hz, 2 H, H-2¢, H-6¢), 7.36–7.21 (m, 4 H, H-4, H-6, H-3¢,
H-5¢), 7.07–7.01 (m, 2 H, H-5, H-4¢), 6.93 (d, J = 7.6 Hz, 1 H, H-
7), 6.37 (br s, 1 H, ex., OH), 4.99 (s, 1 H, H-3), 4.53 (d, J = 16.9 Hz,
1 H, CH2), 4.43 (d, J = 16.9 Hz, 1 H, CH2).
13C NMR (75.5 MHz, DMSO-d6): d = 176.3, 165.3, 143.2, 138.7,
129.0, 128.9, 128.3, 124.6, 123.6, 122.3, 119.2, 108.8, 68.7, 42.7.
1H NMR (300 MHz, DMSO-d6): d = 12.62 (br s, 1 H, ex., OH), 8.14
(br s, 1 H, ex., NH), 7.94 (d, J = 6.46 Hz, 1 H, ex., CONH), 7.78 (d,
J = 7.6 Hz, 1 H, H-6), 7.35 (t, J = 7.6 Hz, 1 H, H-4), 6.57 (t, J = 7.6
Hz, 1 H, H-5), 6.48 (d, J = 7.6 Hz, 1 H, H-3), 3.86 (m, 1 H, CH),
3.74 (s, 2 H, CH2), 1.04 (d, J = 6.2 Hz, 6 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 169.7, 167.8, 150.1, 134.5,
131.7, 114.6, 111.3, 110.6, 45.7, 41.3, 40.2, 22.4.
MS: m/z (%) = 282 (25, M+·), 134 (100).
MS: m/z (%) = 236 (9, M+·), 43 (100).
Synthesis 2007, No. 6, 829–834 © Thieme Stuttgart · New York

834
M. M. Blanco et al.
PAPER
Anal. Calcd for C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C,
61.14; H, 6.80; N, 11.82.
(4) To the best of our knowledge, the parent acid and its ester,
obtained with low yields from the preformed 4-quinolinone
nucleus were the only compounds previously described in
the literature: (a) Behrman, E. J.; Kiser, R. L.; Garas, W. F.;
Behrman, E. C.; Pitt, B. M. J. Chem. Res., Synop. 1995, 164.
(b) Coppini, D. Gazz. Chim. Ital. 1950, 80, 36. The acid,
named as 3,4-dihydroxyquinoline-2-carboxylic was isolated
from a MeOH extract of A. aerofoba: (c) Fattorusso, E.;
Forenza, S.; Minale, L.; Sodano, G. Gazz. Chim. Ital. 1971,
101, 104.
(5) (a) Sumpter, W. C. Chem. Rev. 1944, 34, 393. (b) Popp, F.
D. Adv. Heterocycl. Chem. 1975, 18, 1. (c) da Silva, J. F.
M.; Garden, S. J.; da C. Pinto, A. J. Braz. Chem. Soc. 2001,
12, 273.
(6) Ainley, A. D.; Robinson, R. J. Chem. Soc. 1934, 1508.
(7) Putokhin, N. I. Zh. Obshch. Khim. 1935, 5, 1176; Chem.
Abstr. 1935, 30, 1055.
(8) Structure of compounds 2 was determined by HMQC and
HMBC spectra. Predominance of lactam (4-oxo) over lactim
forms (4-hydroxy) is common for 4-quinolinones with a
varied substitution pattern: (a) Mphahlele, M. J.; El-Nahas,
A. M. J. Mol. Struct. 2004, 688, 129; and references cited
therein. (b) de la Cruz, A.; Elguero, J.; Goya, P.; Martínez,
A.; Pfeiderer, W. Tetrahedron 1992, 48, 6135. On the other
hand, stabilization of C-3 enol hydroxyl is possible through
intramolecular hydrogen bonds.
(9) Amides derived from 1,2-dihydro-4-hydroxy-2-oxo-3-
quinolinecarboxylic acid present an important immuno-
modulator and anti-angiogenic activity, among others:
(a) Jönsson, S.; Andersson, G.; Fex, T.; Fristedt, T.;
Hedlund, G.; Jansson, K.; Abramo, L.; Fritzson, I.; Pekarski,
O.; Runström, A.; Sandin, H.; Thuvesson, I.; Björk, A. J.
Med. Chem. 2004, 47, 2075. (b) Shi, J.; Xiao, Z.; Ihnat, M.
A.; Kamat, C.; Pandit, B.; Hu, Z.; Li, P.-K. Bioorg. Med.
Chem. Lett. 2003, 13, 1187. (c) Tsuji, K.; Spears, G. W.;
Nakamura, K.; Tojo, T.; Seki, N.; Sugiyama, A.; Matsuo, M.
Bioorg. Med. Chem. Lett. 2002, 12, 85.
(10) (a) Screttas, C. G.; Cazianis, T. Tetrahedron 1978, 34, 933;
and references cited therein. (b) Kleinfelter, D. C. J. Org.
Chem. 1967, 32, 840; and references cited therein.
(11) Ashby, E. C.; Argyropoulos, J. N. Tetrahedron Lett. 1986,
27, 465; and references cited therein.
(12) Langenbeck, W. Ber. Dtsch. Chem. Ges. 1928, 61B, 942.
(13) Kapadia, J. G.; Shukla, Y. N.; Basak, S. P.; Sokoloski, E. A.;
Fales, H. M. Tetrahedron 1980, 36, 2441.
2-(N-Phenylcarbamoylmethylamino)benzoic Acid (5d)
This compound was obtained from 1d in 8% yield; mp 228–230 °C
(dec.) (EtOH).
1H NMR (300 MHz, DMSO-d6): d = 13.70 (br s, 1 H, ex., OH),
10.14 (br s, 1 H, ex., CONH), 8.25 (br s, 1 H, ex., NH), 7.81 (d,
J = 7.9 Hz, 1 H, H-6), 7.59 (d, J = 7.3 Hz, 2 H, H-2¢, H-6¢), 7.37 (t,
J = 7.9 Hz, 1 H, H-4), 7.31 (t, J = 7.3 Hz, 2 H, H-3¢, H-5¢), 7.04 (t,
J = 7.3 Hz, 1 H, H-4¢), 6.61 (t, J = 7.9 Hz, 1 H, H-5), 6.50 (d,
J = 7.9 Hz, 1 H, H-3), 4.05 (s, 2 H, CH2).
13C NMR (75.5 MHz, DMSO-d6): d = 169.6, 168.0, 150.1, 138.0,
133.4, 131.7, 131.1, 128.8, 123.3, 119.2, 114.7, 111.4, 46.3.
MS: m/z (%) = 270 (11, M+·), 132 (100).
Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36, Found: C,
66.54; H, 5.25; N, 10.31.
Acknowledgment
This work was financially supported by the Universidad de Buenos
Aires.
References
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cited therein.
(2) (a) Blanco, M. M.; Lorenzo, M. G.; Perillo, I. A.; Schapira,
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1358.
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Synthesis 2007, No. 6, 829–834 © Thieme Stuttgart · New York