Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones into N-(α-ketoacyl)anthranilic acids Dedicated to Professor Slovenko Polanc on his 65th birthday

Article abstract of DOI:10.1016/j.tet.2013.10.092

N-(α-Ketoacyl)anthranilic acids were prepared by oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones by using paraperiodic acid (H₅IO₆) or sodium periodate (NaIO₄). The optimisation of the reaction conditions is

Full text of DOI:10.1016/j.tet.2013.10.092

Tetrahedron 69 (2013) 10826e10835
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones
into N-(a-ketoacyl)anthranilic acids
,
a
b
Stanislav Kafka a , Karel Proisl , Vera Kasparkova , Damijana Urankar ,
ꢁ a
*
ꢀ
*
ꢀ ꢁ
a
b,
ꢀ
Roman Kimmel , Janez Kosmrlj
a Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlin, 762 72 Zlin, Czech Republic
b Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2013
Received in revised form 14 October 2013
Accepted 28 October 2013
Available online 1 November 2013
N-(
a-Ketoacyl)anthranilic acids were prepared by oxidative ring opening of 3-hydroxyquinoline-
2,4(1H,3H)-diones by using paraperiodic acid (H5IO6) or sodium periodate (NaIO4). The optimisation of
the reaction conditions is described as well as the utilisation of N-(a-ketoacyl)anthranilic acids in the
preparation of anthranilic acid hydrochlorides.
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Professor Slovenko Polanc on
his 65th birthday
Keywords:
N-(a-Ketoacyl)anthranilic acid
Quinolinones
Quinolinediones
Paraperiodic acid
Periodate
O
1. Introduction
COOH
O O
O
CH3
N-(a-Ketoacyl)anthranilic acids, exemplified by N-pyruvoylan-
N
C C CH3
N
H
thranilic acid A in Fig. 1, can serve as valuable precursors for the
construction of heterocycles, such as 4H-benzo[d][1,3]oxazin-4-
ones (B)1 and 1H-benzo[e][1,4]oxazepin-2,5-diones (C and D).2 In
O
A
B
coordination chemistry, N-(a-ketoacyl)anthranilic acid derivatives
O
O
can serve as multidentate ligands for transition metal ions.3
N-Pyruvoylanthranilic acid (A) has been proposed to be an in-
termediate in the biosynthesis of anthranilic acid.4
O
O
OH
CH3
N
H
N
O
O
H
Despite potential biological and synthetic relevance the synthesis
of N-(
Although several methods exist for the preparation of
mides,5 to our knowledge, the synthetic procedures to the title
a
-ketoacyl)anthranilic acids has remained largely unexplored.
C
D
a-ketoa-
Fig. 1. The structure of N-pyruvoylanthranilic acid A and its heterocyclic products
BeD.
compounds are largely limited to amidation of a-ketoacyl chlorides
with anthranilic acid.2,6e9 An exception is the work of Podesva and
co-workers8 who reported in 1968 that oxidative ring opening
of 3-hydroxyquinoline-2,4(1H,3H)-diones with paraperiodic acid
this reaction was only demonstrated on two substrates and was not
investigated further. Induced by our research interest in the chem-
istry of 3-hydroxyquinoline-2,4(1H,3H)-diones12e24 and due to
(H5IO6)10,11 leads to N-(
a-ketoacyl)anthranilic acids. Unfortunately,
a need for preparing N-(a-ketoacyl)anthranilic acids we were
prompted to explore the scope of the title reaction. Herein we report
the optimisation of the reaction conditions and comparison be-
tween paraperiodic acid and sodium periodate (NaIO4) to finally
afford the target compounds in good to excellent yields.
* Corresponding authors. Fax: þ420 57 72 10 172 (S.K.); fax: þ386 1 241 9220
(J.K.); e-mail addresses: kafka@ft.utb.cz (S. Kafka), janez.kosmrlj@fkkt.uni-lj.si
ꢀ
(J. Kosmrlj).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.092

S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
10827
2. Results and discussion
derivative. Unfortunately, as it is evident by comparing entries 1, 5,
7, 10, 17, 22, 26 and 27 (Table 2) the generalization of this reaction
protocol to other analogues 2 turned out to be rather limited re-
quiring prolonged reaction times of as much of several days and
affording products 3 in moderate yields. These unacceptably slow
conversions of compounds 2 could be attributed to their sparing
solubility in water-rich reaction media. Attempts to accelerate the
reactions by heating were counterproductive, resulting in complex
mixtures of products and consequently low yield of 3 (compare
entries 27 with 28). Also unsatisfactory were the results of oxida-
tions conducted in other solvents, such as acetic acid and N,N-
dimethylformamide (compare entry 17 with 19 and 20, and entry
26 with 31).
The starting compounds for this study were prepared by known
thermal condensation of the appropriate anilines with substituted
malonates to give 4-hydroxyquinolin-2(1H)-ones 1.12,25,26 In few
cases very small amounts of propanediamide side products 10 were
formed, which were easily removed from the reaction mixtures by
filtration. Subsequent oxidation of 4-hydroxyquinolin-2(1H)-ones 1
into 3-hydroxyquinoline-2,4(1H,3H)-diones 2 was accomplished
with peroxyacetic acid in aqueous alkali following the literature re-
ported methods.12,16,27 Employing several anilines and 2-substituted
diethyl malonates afforded sixteen 3-hydroxyquinoline-2,4(1H,3H)-
diones 2. The key of substituents is given in Scheme 1 and Table 1.
reaction
mixtures
O
R2
O
R3
R3
EtO
EtO
R3 OH
R3
O
N
, Δ
OH
R2
R4
R5
R4
R5
R4
R5
R2
O
R4
R5
CH3CO3H
aq. NaOH
O
+
R1
− 2 EtOH
N
2 R2
O
N
H
N
R6 R1
1
R6
R6 R1
R6 R1
2
1'
Scheme 1. The preparation of 3-hydroxyquinoline-2,4(1H,3H)-diones 2. For key of substituents, see Table 1.
Table 2
Table 1
Key of substituents R1eR6
Screening for the optimal reaction conditions for the oxidation of 3-
hydroxyquinoline-2,4(1H,3H)-diones 2 with paraperiodic acid (H5IO6) into N-(
ketoacyl)anthranilic acids 3 shown in Scheme 2
a
-
a
2
R1
R2
R3
R4
R5
R6
Entry
2
Equiv of Solvent
H5IO6 (mL/mmol of 2)
Temperature Reaction 3, yieldb
a
b
c
H
H
H
Me
Et
Et
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
OMe
H
H
Me
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
OMe
H
Me
Me
H
time
1
2
3
4
5
6
7
8
2b 1.0
2b 3.0
2b 4.0
2b 7.9
2c 1.3
2c 8.0
2d 1.3
2d 6.0
2d 8.0
2e 1.3
2e 6.0
2e 8.0
30% EtOH (11)
60% EtOH (4.8) rt
EtOH (7.7)
EtOH (32.5)
EtOH (15)
EtOH (15)
rt
24 hc
9 h
24 h
24 h
5 days
21 h
7 days
30 h
7 h
3 days
24 h
22 h
3b, 92,d 47
3b, 88
3b, 84
3b, 85
3c, 63
d
e
f
H
H
H
Et
Et
Et
rt
rt
rt
rt
g
h
i
j
k
l
m
n
o
p
H
H
H
H
H
H
H
Me
Me
Me
Et
Et
3c, 73
60% EtOH (8.6) rt
3d, 89,d 59
3d, 81,e 70
3d, 51
Bu
Bu
Bu
Bu
Ph
Et
H
H
H
H
Me
OMe
H
H
H
Me
OMe
EtOH (10)
EtOH (10)
EtOH (5.9)
EtOH (5.0)
EtOH (5.5)
EtOH (5.4)
EtOH (6.5)
EtOH (4.9)
EtOH (2.5)
EtOH (15)
EtOH (40)
AcOH (20)
DMF (3.3)
EtOH (15)
EtOH (13)
EtOH (8.3)
EtOH (4.4)
EtOH (4.8)
EtOH (11)
EtOH (16)
EtOH (5.3)
EtOH (25)
EtOH (12.5)
DMF (3.3)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
reflux
rt
rt
9
e(CH)4e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3e, 88
H
H
H
H
H
H
H
H
3e, 81
3e, 79,d 63
3f, 88
Bu
Ph
H
H
2f
2h 6.5
2j 4.0
4.0
27 h
24 h
11
23 h
3h, 71
3j, 73
2k 3.0
2m 1.5
2m 8.0
2m 1.1
2m 1.1
2n 6.0
2o 1.5
2o 2.0
2o 4.1
2o 8.0
2p 1.1
2p 1.3
2p 1.3
2p 8.0
2p 8.0
2p 2.0
3k, 97,e 87
3m, 46
9 daysc
5.5 h
5 days
4 days
2 h
Having in hand the library of 3-hydroxyquinoline-2,4(1H,3H)-
diones 2aep we focused our attention on the oxidative ring
opening as shown in Scheme 2. Initially, the transformation was
attempted with 3-ethyl-3-hydroxyquinoline-2,4(1H,3H)-dione
(2b). By employing an equimolar amount of paraperiodic acid
(H5IO6) in wet ethanol at room temperature, the reaction was
conducted for 24 h with 2-[(2-oxobutanoyl)amino]benzoic acid
(3b) isolated in good yield (Table 2, Entry 1). These reaction con-
ditions as well as the outcome were comparable to those reported
by Podesva and co-workers8 for H5IO6 oxidation of 6-chloro-3-
hydroxy-3-phenylquinoline-2,4(1H,3H)-dione and its N-methyl
3m, 95,e 84
3m, 59
3m, 38
3n, 62
5 daysc
6 h
3o, 50f
3o, 64
3o, 63
3o, 65
3p, 59
4.5 h
4.5 h
3 days
2 days
5.5 h
5 h
3p, 58
3p, 25f
3p, 92
6 h
3 days
3p, 75,e 63
3p, 39f
rt
a
Reaction conditions: 1 mmol of 2 in solvent, equiv of H5IO6 (aqueous solution,
O
1.25 mL of water/mmol of H5IO6), temperature.
OH
R2
COOH
b
Refers to percent yield of pure product obtained after purification by re-
H5IO6
R1
N
crystallization, unless otherwise noted.
c
The reaction was stopped despite the fact that some starting material remained
H2O / EtOH
(R3−R6)
N
O
R2
(R3−R6)
unconsumed (TLC).
R1
O
d
Crude product, isolated by filtration from the reaction mixture, contaminated by
O
2
small amounts of impurities by TLC.
3
e
Crude product, isolated by filtration from the reaction mixture, pure according
Scheme 2. Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones 2 with
paraperiodic acid (H5IO6) into N-( -ketoacyl)anthranilic acids 3.
to TLC and IR analysis.
f
a
Isolated by column chromatography.

10828
S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
Finally, we found out that using paraperiodic acid in 3e8 M
1He13C HSQC, 1He13C HMBC and 1He15N HMBC. Characteristic in 13
C
excess to 3-hydroxyquinoline-2,4(1H,3H)-diones 2 significantly
reduced the reaction times giving products 3 in good to excellent
yields (entries 2e4, 6, 8, 9, 11e16, 18, 21, 24, 25, 29, 30). It is also
evident from Table 2 that for the optimal performance the amount
of paraperiodic acid should not be exceeded as this can cause
a serious loss of products 3, presumably by overoxidation (compare
entries 8 with 9 and 11 with 12, for example). Thus, fine tuning of
the reaction conditions for optimal results is suggested for each
specific substrate 2.
Periodic acid is known to equilibrate in solution with different
species including periodate.10 Since considerably different re-
activity towards organic compounds have been reported for these
two species we were prompted to test the oxidation of
3-hydroxyquinoline-2,4(1H,3H)-diones 2 also with sodium peri-
odate (NaIO4) (Scheme 3). As demonstrated in Table 3, this oxi-
dizing agent proved to be equally or in some instances slightly less
NMR spectra of N-(
a
-ketoacyl)anthranilic acids 3aem (R1¼H,
R2¼alkyl) are resonances for the carboxyl, amide (NCO) and
a-
ketoacyl (NC(O)CO) carbon atoms, resonating at 166e169 ppm,
158e161 ppm and 196e201 ppm, respectively. The presence of
a methyl group at the amide nitrogen atom (3n, o) results in
downfield shift of amide (NCO) and
resonances to 166 ppm and 200e201 ppm, respectively. The phenyl
group in compounds 3m, p shows a considerable effect to -ketoacyl
a-ketoacyl (NC(O)CO) carbon
a
(NC(O)CO) carbon atom, shifting its resonance upfield to
187e192 ppm (Fig. 2). In a few instances (2j and 3a, h, i, j), 15N NMR
chemical shifts were extracted from 2D 1He15N HMBC spectra. In
comparison to 2j (dN¼129 ppm), the nitrogen atom in 3j is shielded
and resonates at 118 ppm. Single crystal analysis confirmed the
structures of compounds 1e,38 1p28 and 2e,29 as reported previously.
reactive than H5IO6 providing the same products, N-(
a-ketoacyl)
anthranilic acids 3, in up to 91% yield.
O
OH
R2
COOH
R1
N
NaIO4
(R3−R6)
N
O
R2
H2O / EtOH
(R3−R6)
R1
O
O
2
Fig. 2. Selected 13C and 15N chemical shifts for compounds 3.
3
Scheme 3. Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones 2 with
sodium periodate (NaIO4) into N-(a-ketoacyl)anthranilic acids 3.
An easy access to N-(a-ketoacyl)anthranilic acids 3 renders
these compounds as attractive precursors for the preparation of
various benzo-fused heterocyclic compounds. Additionally,
through a simple hydrolytic workup compounds 3 can be con-
verted into the corresponding anthranilic acid derivatives. In this
context it is noteworthy that the chemistry reported herein pro-
vides a facile entry to highly functionalized anthranilic acids that
are inaccessible through other routes. To demonstrate this, se-
Table 3
Oxidation of 3-hydroxyquinoline-2,4(1H,3H)-diones
(NaIO4) into N-( -ketoacyl)anthranilic acids 3 shown in Scheme 3
2 with sodium periodate
a
a
Entry
2
Equiv
of NaIO4
Solvent
(mL/mmol of 2)
Reaction
3, yieldb
time
1
2
3
4
5
6
7
8
2a
3.0
8.0
8.0
8.0
8.0
8.0
3.1
3.7
3.1
8.0
8.0
8.0
EtOH (4.0)
EtOH (7.5)
EtOH (25)
EtOH (27)
EtOH (3.8)
EtOH (2.5)
EtOH (3.3)
EtOH (1.0)
EtOH (6.9)
EtOH (41)
EtOH (25)
EtOH (25)
2 days
24 h
3a, 90
2b
2c
2d
2e
2g
2i
2i
2l
2m
2o
2p
3b, 79,c 44
3c, 67
lected N-(a-ketoacyl)anthranilic acids 3bee, n were hydrolysed
3 daysd
3 daysd
10 h
with hot aqueous HCl, affording anthranilic acid hydrochlorides
4bee, n in good to excellent yields as shown in Scheme 4 and
Table 4.
3d, 26
3e, 70
20 h
22 h
8 h
28 h
24 h
4 h
21 h
3g, 44
3i, 95,e 83
3i, 86,e 71
3l, 65
9
10
11
12
3m, 91e
3o, 60
3p, 56,e 49
a
Reaction conditions: 1 mmol of 2 in solvent, equiv of NaIO4 (aqueous solution,
1.25 mL/mmol of NaIO4), room temperature.
b
Refers to percent yield of pure product obtained after purification by re-
Scheme 4. Hydrolysis of N-(
drochlorides 4.
a-ketoacyl)anthranilic acids 3 into anthranilic acid hy-
crystallization, unless otherwise noted.
c
Crude product, isolated by filtration from the reaction mixture, contaminated by
small amounts of impurities by TLC.
d
The reaction was stopped after 3 days despite the fact that some starting ma-
terial remained unconsumed (TLC).
Table 4
e
Crude product, isolated by filtration from the reaction mixture, pure according
Hydrolysis of 3 into anthranilic acid hydrochlorides 4
to TLC and IR analysis.
Entry
3
Reaction time (h)
4, yield (%)
1
2
3
4
5
3b
3c
3d
3e
3n
4
6
7
1
2
4b, 85
4c, 91
4d, 64
4e, 68
4n, 73
The fact that sodium periodate (NaIO4) and paraperiodic acid
equilibrate in solution and comparable results from Tables 2 and 3
suggests that the same species is operating in the oxidative ring
opening of 3-hydroxyquinoline-2,4(1H,3H)-diones 2.
All compounds under this investigation were fully characterized
by standard analytical and spectroscopic techniques. Some com-
pounds were previously described in the literature with limited or
no NMR spectroscopic data, which we decided to provide herein. For
compounds 2h, j and 3a, h, i, j, l, p proton and carbon peak assign-
ments were made on the basis of 2D NMR spectra: 1He1H COSY,
3. Conclusions
We report an easy approach to N-(
by paraperiodic acid or sodium periodate mediated ring opening of
a
-ketoacyl)anthranilic acids

S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
10829
3-hydroxyquinoline-2,4(1H,3H)-diones. The scope of the reaction
was investigated and under optimized reaction conditions N-(
ketoacyl)anthranilic acids were obtained in good to excellent iso-
lated yield. These compounds can serve as valuable precursors for
the preparation of highly functionalized anthranilic acid derivatives
that are inaccessible through other routes.
mp31 265e268 ꢀC (butanol). 1H NMR (500 MHz, DMSO-d6)
d
2.02 (s,
a
-
3H), 7.15 (ddd,1H, J¼7.7, 7.7, 1.0 Hz), 7.27 (d, 1H, J¼7.7 Hz), 7.44 (ddd,
1H, J¼7.7, 7.7, 1.0 Hz), 7.89 (dd, 1H, J¼8.1, 1.0 Hz), 10.13 (br s, 1H),
11.36 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
d
9.4, 106.8, 114.8,
2600e3400
115.4, 121.0, 122.4, 129.6, 137.2, 157.1, 163.8; IR (cmꢂ1):
n
br, 1643 s, 1607 s, 1501 m, 1478 m, 1401 s, 1342 m, 1284 m, 1274 s,
1225 m, 1160 m, 752 m. HRMS (ESIþ): m/z calcd for C10H10NO2þ
[MþH]þ 176.0706, found 176.0707.
4. Experimental section
4.1. General
4.2.2. 3-Ethyl-4-hydroxyquinolin-2(1H)-one (1b).32e34 Colourless
solid, yield 13.1
g
(69%), mp 265e267 ꢀC (ethanol), mp33
The column chromatography was carried out on Fluka Silica gel
60 (particle size 0.063e0.2 mm, activity acc. Brockmann and
Schodder 2e3). Melting points were determined on the microscope
hot stage, Kofler, PolyTherm, manufacturer Helmut Hund GmbH,
Wetzlar. TLC was carried out on pre-coated TLC sheets ALUGRAMÒ
SIL G/UV254 for TLC, MACHEREY-NAGEL. NMR spectra were recor-
ded on a Bruker Avance DPX 300 spectrometer operating at
300 MHz (1H) and 75 MHz (13C), and Bruker Avance III 500 MHz
NMR instrument operating at 500 MHz (1H), 126 MHz (13C) and
51 MHz (15N). Proton spectra were referenced to TMS as internal
standard. Carbon chemical shifts were determined relative to the
13C signal of DMSO-d6 (39.5 ppm). 15N chemical shifts were
extracted from 1He15N HMBC spectra determined with respect to
external nitromethane and are corrected to external ammonia by
260e261 ꢀC (ethanol). 1H NMR (500 MHz, DMSO-d6)
d 1.03 (t, 3H,
J¼7.4 Hz), 2.59 (q, 2H, J¼7.4 Hz), 7.14 (ddd, 1H, J¼7.6, 7.6, 1.0 Hz),
7.26 (d, 1H, J¼7.6 Hz), 7.44 (ddd, 1H, J¼7.6, 7.6, 1.0 Hz), 7.88 (dd, 1H,
J¼7.6, 1.0 Hz), 10.06 (br s, 1H), 11.31 (br s, 1H). 13C NMR (126 MHz,
DMSO-d6)
d 13.2, 16.4, 113.0, 114.8, 115.4, 120.9, 122.5, 129.6, 137.3,
156.6, 163.4; IR (cmꢂ1):
n
2600e3400 br, 1638 s, 1605 s, 1590 s, 1553
m, 1500 m, 1428 m, 1401 m, 1269 m, 1207 s, 1151 m, 754 m. IR:34
1641 cmꢂ1. HRMS (ESIþ): m/z calcd for C11H12NOþ2 [MþH]þ
190.0863, found 190.0866.
4.2.3. 3-Ethyl-4-hydroxy-6-methoxyquinolin-2(1H)-one
(1c).32,35 Yellowish solid, yield 14.0 g (64%), mp 220e224 ꢀC (eth-
anol), mp35 172 ꢀC. 1H NMR (300 MHz, DMSO-d6)
d 1.04 (t, 3H,
J¼7.3 Hz), 2.60 (q, 2H, J¼7.3 Hz), 3.80 (s, 3H), 7.10 (dd, 1H, J¼8.9,
addition of 380.5 ppm. Chemical shifts are given on the
d scale
2.5 Hz), 7.22 (d, 1H, J¼8.9 Hz), 7.39 (d, 1H, J¼2.5 Hz), 9.98 (br s, 1H),
(parts per million). Coupling constants (J) are given in Hertz. Mul-
tiplicities are indicated as follows: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), or br (broadened). Infrared spectra were
recorded on Mattson 3000 FTIR Spectrometer or Thermo Scientific
Nicolet iS10 FT-IR Spectrometer using samples in potassium bro-
mide disks and only the strongest/structurally most important
peaks are listed; absorption bands intensities are indicated as fol-
lows: s (strong), m (medium), w (weak) or b (broad). MS (EI)
spectra were recorded on a Shimadzu QP-2010 instrument at 70 eV.
HRMS spectra were recorded with Agilent 6224 Accurate Mass TOF
LC/MS system. Elemental analyses (C, H, N) were performed with
FlashEA1112 Automatic Elemental Analyzer (Thermo Fisher Scien-
tific Inc.).
11.20 (br s, 1H); 13C NMR (75 MHz, DMSO-d6)
d 13.2, 16.4, 55.4,
104.3, 113.5,115.8, 116.2,118.6,131.8, 153.8,156.2,162.9; IR (cmꢂ1):
n
2700e3500b, 1648 s, 1623 s, 1556 m, 1511 s, 1466 m, 1446 m, 1422
m, 1380 m, 1330 m, 1288 m, 1271 m, 1243 m, 1222 s, 1179 m, 1147 m,
1118 m; MS (EI) m/z (%): 220 ([Mþ1]þ, 13), 219 ([M]þ, 95), 218 (35),
204 (100), 106 (23), 55 (26); Anal. Calcd for C12H13NO3 (219.24): C,
65.74; H, 5.98; N, 6.39%. Found: C, 65.50; H, 5.93; N, 6.41%.
4.2.4. 3-Ethyl-4-hydroxy-7-methoxyquinolin-2(1H)-one
(1d).32,36 White solid, yield 14.9 g (68%), mp 262e266 ꢀC (ethanol),
mp36 260e261 ꢀC (methanol). 1H NMR (300 MHz, DMSO-d6)
d 1.03
(t, 3H, J¼7.4 Hz), 2.56 (q, 2H, J¼7.4 Hz), 3.80 (s, 3H), 6.77 (d, 1H,
J¼8.5 Hz), 6.79 (s, 1H), 7.80 (d, 1H, J¼8.5 Hz), 9.92 (br s, 1H), 11.15 (br
s, 1H); 13C NMR (75 MHz, DMSO-d6)
d 13.3, 16.2, 55.2, 97.7, 109.4,
4.2. General procedure for the preparation of 4-
109.5, 110.5, 124.0, 139.0, 156.9, 160.5, 163.8; IR (cmꢂ1):
n
hydroxyquinolin-2(1H)-ones (1)
2700e3300, 2971 m, 1624 s, 1595 s, 1556 s, 1437 s, 1425 s, 1272s,
1222 s, 1153 m, 1112 m, 1031 m, 882, 856 m, 833 m; MS (EI) m/z
(%):220 ([Mþ1]þ, 7), 219 ([M]þ, 50), 204 (100), 191 (22); Anal. Calcd
for C12H13NO3 (219.24): C, 65.74; H, 5.98; N, 6.39%. Found: C, 65.69;
H, 6.22; N, 6.22%.
A mixture of the appropriate aniline (100 mmol) and substituted
diethyl malonate (102 mmol) was heated in a flask equipped with
distillation head on a metal bath at 220e230 ꢀC for 1 h and then at
260e270 ꢀC until the distillation of ethanol stopped (3e6 h). With
the exception of preparation of 1f, l, m, the hot liquid reaction
mixture was carefully poured into stirred toluene (50 mL), cooled
down to room temperature and the precipitate was collected by
filtration. In the case of 1f, l, m, the hot reaction mixture solidified
and it was cooled down to room temperature. The above precipitate
or solidified material was mixed with aqueous sodium hydroxide
solution (0.5 M, 250 mL) and toluene (50 mL). The substance that
remained undissolved (in the preparation of 1c and 1m) was re-
moved by filtration, purified by recrystallization and identified as
propanediamide derivatives (1c0 and 1m0, respectively). The layers
of the filtrate were separated and the aqueous layer was washed
with toluene (2ꢁ40 mL). The water layer was treated with de-
colorizing charcoal, filtered and then acidified with 10% HCl to
Congo red. The precipitated hydroxyquinolone 1 was collected by
filtration, washed with water, and if necessary, purified by
recrystallization.
4.2.5. 3-Ethyl-4-hydroxy-8-methoxyquinolin-2(1H)-one
(1e).32,34,37 White solid, yield 13.6 g (62%), mp 225e227 ꢀC (etha-
nol), mp34 226e227 ꢀC, mp37 225e226 ꢀC. 1H NMR (300 MHz,
DMSO-d6)
7.08e7.13 (m, 2H), 7.48 (dd, 1H, J¼4.6, 4.6 Hz), 10.04 (br s, 1H), 10.11
(br s, 1H); 13C NMR (75 MHz, DMSO-d6)
13.1, 16.4, 56.0, 110.3,
113.4, 114.3, 115.9, 120.8, 127.3, 145.4, 156.7, 162.7; IR (cmꢂ1):
d
1.02 (t, 3H, J¼7.3 Hz), 2.58 (q, 2H, J¼7.3 Hz), 3.89 (s, 3H),
d
n
2700e3400 br, 1635 s, 1604 s, 1571 s, 1492 m, 1393 m, 1333 m, 1302
m, 1267 m, 1254 m, 1223 m, 1155 m, 1089 s, 771 m,724 m; IR:34
1640 cmꢂ1. MS (EI) m/z (%): 220 ([Mþ1]þ, 5), 219 ([M]þ, 34), 218
(23), 204 (31), 149 (28), 71 (27), 69 (28), 57 (100), 55 (35), 43 (30),
41 (34). X-ray structure is reported.38
4.2.6. 3-Ethyl-4-hydroxy-6-methylquinolin-2(1H)-one (1f). White
solid, yield 12.0 g (59%), mp 261e264 ꢀC. 1H NMR (500 MHz, DMSO-
d6)
1H, J¼8.2 Hz), 7.26 (dd,1H, J¼8.2, 1.6 Hz), 7.68 (s, 1H), 9.96 (br s, 1H),
11.22 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
13.2, 16.3, 20.6,
112.9, 114.6, 115.2, 122.0, 129.6, 130.7, 135.2, 156.3, 163.2; IR (cmꢂ1):
d
1.02 (t, J¼7.4 Hz, 3H), 2.35 (s, 3H), 2.58 (q, 2H, J¼7.4 Hz), 7.16 (d,
4.2.1. 4-Hydroxy-3-methylquinolin-2(1H)-one
powder, yield 13.5 g (77%), mp 274e275 ꢀC (ethanol), mp30 268 ꢀC,
(1a).30,31 White
d

10830
S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
n
3131 m, 2976 m, 1640 s, 1622 s, 1558 s, 1513 m, 1433 m, 1416 m,
one exception; the temperature of the metal bath was kept at
180 ꢀC throughout the condensation. White crystals, yield 24.9 g
(93%), mp 309e313 ꢀC (ethanol). 1H NMR (500 MHz, DMSO-d6)
1332 m, 1233 m, 1207 m, 1149 m, 1116 m, 855 w, 814 w; HRMS
(ESIþ): m/z calcd for
C
12H14NOþ2 ([MþH]þ): 204.1019, found
204.1022. Anal. Calcd for C12H13NO2 (203.24): C, 70.92; H, 6.45; N,
6.89%. Found: C, 70.75; H, 6.43; N, 6.79%.
d
0.93 (t, 3H, J¼7.2 Hz), 1.35e1.44 (m, 2H), 1.46e1.53 (m, 2H),
2.65e2.70 (m, 2H), 7.58e7.67 (m, 3H), 7.96 (d, 1H, J¼7.4 Hz), 7.99 (d,
1H, J¼8.9 Hz), 8.90 (d, 1H, J¼8.0 Hz), 10.19 (br s, 1H), 11.82 (br s, 1H);
4.2.7. 3-Ethyl-4-hydroxy-8-methylquinolin-2(1H)-one
(1g).39 Yellow solid, yield 12.2 g (60%), mp 228e229 ꢀC (acetic
acid), mp39 217.5e220 ꢀC (acetic acid). 1H NMR (500 MHz, DMSO-
13C NMR (126 MHz, DMSO-d6)
d 14.1, 22.3, 22.9, 30.4, 111.2, 111.8,
120.0, 121.3, 121.4, 122.3, 126.2, 127.4, 128.3, 133.5, 134.0, 157.9,
164.0; IR (cmꢂ1):
n 1763 s, 1618 m, 1601 m, 1196 s, 1067 m, 779 m;
d6)
d
1.04 (t, 3H, J¼7.4 Hz), 2.41 (s, 3H), 2.61 (q, 2H, J¼7.4 Hz), 7.06
MS (EI) m/z (%): 268 ([Mþ1]þ, 5), 267 (Mþ, 24), 238 (17), 226 (16),
225 (100), 224 (33), 115 (16), 55 (18); HRMS (ESIꢂ): m/z calcd for
(dd, 1H, J¼7.7, 7.7 Hz), 7.30 (d, 1H, J¼7.7 Hz), 7.77 (d, 1H, J¼7.7 Hz),
10.04 (br s, 1H), 10.47 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
C
C
17H16NOe2 [MꢂH]e 266.1187, found 266.1187. Anal. Calcd for
d
13.2, 16.4, 17.4, 112.7, 115.5, 120.5, 120.6, 122.9, 130.9, 135.7, 157.0,
17H17NO2 (267.32): C, 76.38; H, 6.41; N, 5.24%. Found: C, 76.29; H,
163.7; IR (cmꢂ1):
n
3395 m, 2966 m, 2934 m, 1636 s, 1601 s, 1565 s,
6.49; N, 5.07%.
1488 m, 1396 m, 1334 m, 1292 m, 1238 s, 1210 s, 1151 s, 766 m;
HRMS (ESIþ): m/z calcd for C12H14NOþ2 [MþH]þ 204.1019, found
204.1024.
4.2.13. 4-Hydroxy-3-phenylquinolin-2(1H)-one
(1m).32,40 White
solid, yield 20.9 g (88%), mp 334e338 ꢀC (acetic acid), mp40
325e327 ꢀC (DMF). 1H NMR (500 MHz, DMSO-d6)
d 7.16e7.21 (m,
4.2.8. 5-Chloro-3-ethyl-4-hydroxy-8-methylquinolin-2(1H)-one
1H), 7.28e7.33 (m, 2H), 7.37e7.43 (m, 4H), 7.49e7.53 (m, 1H), 7.96
(1h). White solid, yield 11.6 g (49%), mp 235e238 ꢀC (ethanol). 1H
(dd, 1H, J¼8.1, 1.0 Hz), 10.10 (br s, 1H), 11.49 (br s, 1H); 13C NMR
NMR (DMSO-d6, 500 MHz)
(q, 2H, J¼7.3 Hz), 7.10 (d, 1H, J¼8.0 Hz), 7.23 (d, 1H, J¼8.0 Hz), 9.98
(br s,1H),10.41 (br s,1H); 13C NMR (DMSO-d6,126 MHz)
12.8,16.2,
17.4, 112.4, 114.3, 122.5, 124.2, 127.0, 130.7, 137.8, 157.2, 162.4; IR
(cmꢂ1):
3471 m, 3166 w, 2959 w, 2870 w, 1647 s, 1459 w, 1338 w,
d
1.02 (t, 3H, J¼7.3 Hz), 2.38 (s, 3H), 2.60
(126 MHz, DMSO-d6) d 112.6, 114.9, 115.4, 121.1, 123.1, 126.9, 127.7,
130.6, 131.2, 133.4, 138.0, 157.3, 162.7; IR (cmꢂ1):
n 2700e3330 br,
d
1645 s, 1610 s, 1588 s, 1499 m, 1408 m, 1365 m, 1289 m, 1244 m,
1226 m, 757 m, 696 m, 557 m; HRMS (ESIþ): m/z calcd for
n
C
15H12NOþ2 [MþH]þ 238.0863, found 238.0866.
1324 w, 1210 w, 1147 m, 822 w, 628 w; HRMS (ESIþ): m/z calcd for
C
C
12H13ClNOþ2 [MþH]þ 238.0629, found 238.0630. Anal. Calcd for
4.2.14. 3-Ethyl-4-hydroxy-1-methylquinolin-2(1H)-one
12H12ClNO2 (237.68): C, 60.64; H, 5.09; N, 5.89%. Found: C, 60.53;
(1n).41 White solid, yield 18.1 g (89%), mp 188e191 ꢀC, mp41
H, 5.05; N, 5.92%.
184e185 ꢀC (ethanol). 1H NMR (500 MHz, DMSO-d6)
d 1.03 (t, 3H,
J¼7.4 Hz), 2.63 (q, 2H, J¼7.4 Hz), 3.59 (s, 3H), 7.22e7.27 (m, 1H), 7.46
4.2.9. 3-Butyl-4-hydroxyquinolin-2(1H)-one (1i).20 White solid
(microscopic crystals), yield 14.1 g (65%), mp 195e201, 54%, mp
201e204 ꢀC (ethanol), mp20 199e200 ꢀC (ethanol). For 1H and 13C
(br d, 1H, J¼8.3 Hz), 7.55e7.60 (m, 1H), 7.99 (dd, 1H, J¼8.0, 1.4 Hz),
10.09 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
d 13.2, 17.2, 29.1,
112.6,114.2,116.3, 121.2, 123.0,130.1,138.2,155.4,162.6; IR (cmꢂ1):
n
NMR spectra see Ref. 20. IR (cmꢂ1):
n
2700e3400 br, 2954 m,1639 s,
2700e3400 br, 2964 w, 1641 s, 1607 s, 1584 s, 1571 s, 1392 m, 1219 s,
1205 s,1165 s,1126 m, 750 s; HRMS (ESIþ): m/z calcd for C12H14NO2þ
[MþH]þ 204.1019, found 204.1020.
1604 s, 1590 s, 1557 m, 1503 m, 1480 m, 1469 m, 1426 m, 1404 m,
1273 m, 1197 s, 1154 s, 761 s; Anal. Calcd for C13H15NO2 (217.26): C,
71.87; H, 6.96; N, 6.45%. Found: C, 71.67; H, 6.04; N, 6.39%.
4.2.15. 3-Butyl-4-hydroxy-1-methylquinolin-2(1H)-one
ꢀ
4.2.10. 3-Butyl-4-hydroxy-6,8-dimethylquinolin-2(1H)-one
(1o). Colourless crystals, yield 16.4 g (71%), mp 145e149 C (eth-
(1j). Colourless shiny crystals, yield 14.7 g (60%), mp 225e228 ꢀC
anol), mp42 141 ꢀC. For NMR data, see Ref. 20. IR (cmꢂ1):
n
(ethanol). 1H NMR (500 MHz, DMSO-d6)
1.30e1.45 (m, 4H), 2.31 (s, 3H), 2.37 (s, 3H), 2.56e2.60 (m, 2H), 7.12
d
0.90 (t, 3H, J¼7.3 Hz),
2800e3400 br, 2954 w, 1632 m, 1604 s, 1582 s, 1466 w, 1342 w, 1192
s, 1165 m, 1157 m, 1083 w, 747 m, 471 w.
(s, 1H), 7.56 (s, 1H), 9.88 (br s, 1H), 10.40 (br s, 1H). 13C NMR
(126 MHz, DMSO-d6)
d
14.1, 17.2, 20.6, 22.3, 22.8, 30.5, 111.4, 115.4,
3382 s,
4.2.16. 4-Hydroxy-1-methyl-3-phenylquinolin-2(1H)-one
120.0, 122.8, 129.4, 132.2, 133.7, 157.1, 163.7; IR (cmꢂ1):
n
(1p).43 White solid, yield 23.4 g (93%), mp 227e230 ꢀC, mp43
2931 m, 2849 m, 1645 s, 1618 s, 1381 m, 1329 m, 1257 m, 1238 s,
1168 s, 1134 s, 1103 m, 1069 m, 871 m, 493 m; HRMS (ESIe): m/z
calcd for C15H18NOe2 [MꢂH]e 244.1343, found 244.1338; calcd for
226 ꢀC (ethanol). 1H NMR (500 MHz, DMSO-d6)
d 3.61 (s, 3H),
7.27e7.31 (m, 1H), 7.30e7.37 (m, 3H), 7.39e7.43 (m, 2H), 7.52 (br d,
1H, J¼8.3 Hz), 7.63e7.67 (m, 1H), 8.05 (dd, 1H, J¼8.0, 1.4 Hz), 10.07
C
15H19NO2 (245.32): C, 73.44; H, 7.81; N, 5.71%. Found: C, 73.51; H,
(br s, 1H). 13C NMR (126 MHz, DMSO-d6)
d 29.5, 112.3, 114.4, 116.3,
6.52; N, 5.11%.
121.4, 123.6, 127.0, 127.8, 131.0, 131.2, 133.7, 139.0, 156.2, 162.0; IR
(cmꢂ1):
n
2750e3250 br, 3060 w, 2953 w, 1629 s, 1612 s, 1594 s,
4.2.11. 3-Butyl-4-hydroxy-6,8-dimethoxyquinolin-2(1H)-one
1581 s, 1572 s, 1328 m, 1251 m, 755 m, 693 m, 511 w; MS (EI) m/z
(%): 252 ([Mþ1]þ, 16), 251 ([M]þ, 96), 250 (100), 134 (45), 125 (11),
116 (12), 91 (10), 77 (27). HRMS (ESIþ): m/z calcd for C16H14NO2þ
[MþH]þ 252.1019, found 252.1022. X-ray structure is reported.28
(1k). Colourless crystals, yield 15.3 g (55%), mp 240e244 ꢀC (eth-
anol). 1H NMR (500 MHz, DMSO-d6)
d
0.90 (t, 3H, J¼7.3 Hz),
1.29e1.46 (m, 4H), 2.54e2.59 (m, 2H), 3.80 (s, 3H), 3.87 (s, 3H), 6.74
(d, 1H, J¼2.4 Hz), 6.98 (d, 1H, J¼2.4 Hz), 9.96 (br s, 1H), 10.12 (br s,
1H); 13C NMR (126 MHz, DMSO-d6)
d
14.1, 22.3, 23.0, 30.4, 55.4, 56.1,
4.2.17. 2-Ethyl-N,N0-bis(4-methoxyphenyl)propanediamide
95.2, 100.8, 112.8, 115.7, 122.2, 146.6, 154.0, 156.7, 162.5; IR (cmꢂ1):
n
(1c0). White solid, yield 1.37 g (4%), mp 237e241 ꢀC (etha-
3374 s, 2954 m, 2929 m, 1661 m, 1613 s, 1583 m, 1504 s, 1327 m,
1257 s, 1228 m, 1206 s, 1162 s, 1093 s, 1056 m; HRMS (ESIþ): m/z
calcd for C15H20NOþ4 [MþH]þ 278.1387, found 278.1386. Anal. Calcd
for C15H19NO4 (277.32): C, 64.97; H, 6.91; N, 5.05%. Found: C, 65.02;
H, 6.94; N, 5.04%.
nolebenzene). 1H NMR (500 MHz, DMSO-d6)
d 0.92 (t, 3H,
J¼7.4 Hz) 1.91 (dq, 2H, J¼7.4, 7.4 Hz), 3.33 (t, 1H, J¼7.4 Hz), 3.72 (s,
6H), 6.86e6.91 (m, 4H), 7.50e7.54 (m, 4H), 9.80 (br s, 2H); 13C
NMR (126 MHz, DMSO-d6)
d
12.0, 23.1, 55.2, 56.2, 113.8, 120.9,
3279 m, 2968 w, 2836 w, 1673 s,
132.0, 155.3, 167.5; IR (cmꢂ1):
n
1601 m, 1539 m, 1512 s, 1412 m, 1249 m, 1236 m, 1166 m, 1029 m,
824 m; MS (EI) m/z (%): 343 ([Mþ1]þ, 10), 342 (Mþ, 47), 193 (38),
178 (63), 149 (20), 124 (13), 123 (100), 122 (42), 108 (40), 55 (10);
4.2.12. 3-Butyl-4-hydroxybenzo[h]quinolin-2(1H)-one (1l). General
procedure was followed for the preparation of this compound with

S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
10831
HRMS (ESIþ): m/z calcd for C19H23N2Oþ4 [MþH]þ 343.1652, found
C
12H13NO4$1/3 H2O (241.24): C, 59.76; H, 5.71; N, 5.81%. Found: C,
59.82; H, 5.78; N, 5.52%.
343.1650.
4.2.18. N,N0,2-Triphenylpropanediamide (1m0).44 White solid, yield
1.65 g (5%), mp 198e202 ꢀC (ethanol), mp44 201e202 ꢀC (ethanol).
4.3.4. 3-Ethyl-3-hydroxy-7-methoxyquinoline-2,4(1H,3H)-dione
(2d). White solid, yield 83%, mp 162e164 ꢀC (benzene). 1H NMR
1H NMR (500 MHz, DMSO-d6)
d
4.88 (s, 1H), 7.04e7.08 (m, 2H),
7.28e7.34 (m, 5H), 7.36e7.40 (m, 2H), 7.44e7.48 (m, 2H), 7.59e7.63
(m, 4H),10.25 (br s, 2H); 13C NMR (126 MHz, DMSO-d6)
59.9,119.3,
123.6,127.4,128.2,128.8,129.0,135.5,138.9,166.6; IR (cmꢂ1):
3313
(300 MHz, DMSO-d6)
d
0.78 (t, 3H, J¼7.4 Hz), 1.63e1.84 (m, 2H),
3.83 (s, 3H), 5.57 (s, 1H), 6.58 (d, 1H, J¼2.3 Hz), 6.70 (dd, 1H, J¼8.7,
d
2.3 Hz), 7.70 (d, 1H, J¼8.7 Hz), 10.67 (br s, 1H); 13C NMR (75 MHz,
n
DMSO-d6) d 7.4, 33.2, 55.7, 81.2, 100.0, 109.7, 112.6, 129.0, 143.6,
m, 1672 s, 1647 m, 1618 m, 1605 s, 1551 s, 1497 s, 1443 s, 1334 m, 763
m, 749 m, 718 m, 697 m; HRMS (ESIþ): m/z calcd for C21H19N2O2þ
[MþH]þ 331.1441, found 331.1441.
165.1,173.1,194.2; IR (cmꢂ1):
n 3258 s, 3067 m,1713 s, 1668 s,1612 s,
1589 s, 1482 m, 1461 m, 1409 m, 1349 m, 1274 s, 1207 s, 1173 s, 1119
s, 1108 m; Anal. Calcd for C12H13NO4$1/6C6H6: C, 62.90; H, 5.68; N,
5.64%. Found: C, 63.01; H, 5.73; N, 5.60%. The presence and quantity
of residual benzene in the sample is confirmed by 1H and 13C NMR
4.3. General procedure for the preparation of 3-
hydroxyquinoline-2,4(1H,3H)-diones (2)
resonances at d 7.37 ppm and 128.3 ppm, respectively.
To a solution of the appropriate 4-hydroxyquinolin-2(1H)-one
(1, 20 mmol) in aqueous sodium hydroxide solution (0.5 M, 20 mL),
peroxyacetic acid (32e36 wt. % in dilute acetic acid, 20 mL,
100 mmol) was added dropwise under stirring during 30 min. The
precipitate was collected by filtration and washed with small por-
tions of 5% aqueous potassium carbonate solution until the filter
cake is free of potentially unreacted starting material 1 (until the
filtrate is not clear solution upon acidification with conc. hydro-
chloric acid). Then the solid was washed with water (3ꢁ30 mL), air
dried and recrystallized from the appropriate solvent. Analytical
and spectral data of 3-hydroxyquinoline-2,4(1H,3H)-diones 2 are
given below.
4.3.5. 3-Ethyl-3-hydroxy-8-methoxyquinoline-2,4(1H,3H)-dione
(2e).29 Yellow crystals, yield 83%, mp 70e72 ꢀC (benzene). 1H NMR
(300 MHz, DMSO-d6)
d
0.78 (t, 3H, J¼7.4 Hz),1.61e1.86 (m, 2H), 3.87
(s, 3H), 5.63 (s,1H), 7.09 (dd,1H, J¼7.9, 7.9 Hz), 7.29 (d,1H, J¼7.9 Hz),
7.31 (d, 1H, J¼7.9 Hz), 9.85 (br s, 1H); 13C NMR (75 MHz, DMSO-d6)
d
7.3, 32.9, 56.2, 82.2, 117.1, 117.7, 119.5, 122.6, 131.0, 146.3, 172.4,
196.0; IR (cmꢂ1):
n 3579 m, 3486 m, 1710 s, 1667 s, 1615 m, 1591 m,
1508 m, 1384 m, 1266 s, 1203 m, 1187 m, 1018 m, 1004 m. Anal.
Calcd for C12H13NO4$H2O: C, 56.91; H, 5.97; N, 5.53%. Found: C,
56.90; H, 5.88; N, 5.57%. The presence of H2O in a 1:1 ratio relative
to 2e was confirmed by single crystal structure analysis.29
4.3.6. 3-Ethyl-3-hydroxy-6-methylquinoline-2,4(1H,3H)-dione
4.3.1. 3-Hydroxy-3-methylquinoline-2,4(1H,3H)-dione
(2f). White solid, yield 91%, mp 198e205 ꢀC. 1H NMR (500 MHz,
(2a).45 White solid, yield 2.94 g (77%), mp 212e216 ꢀC (ethanol),
DMSO-d6)
d
0.78 (t, 3H, J¼7.4 Hz), 1.65e1.81 (m, 1H), 2.25 (s, 3H),
mp45 201 ꢀC (ethanolewater). 1H NMR (500 MHz, DMSO-d6)
d
1.40
5.62 (s, 1H), 6.98 (d, 1H, J¼8.2 Hz), 7.41 (dd, 1H, J¼8.2, 1.7 Hz), 7.52
(s, 3H), 5.81 (s, 1H), 7.09 (d, 1H, J¼8.0 Hz), 7.10e7.14 (m, 1H), 7.60
(d, 1H, J¼1.7 Hz), 10.67 (br s, 1H). 13C NMR (126 MHz, DMSO-d6)
(ddd, 1H, J¼7.7, 7.7, 1.5 Hz), 7.75 (dd, 1H, J¼7.7, 1.3 Hz), 10.76 (br s,
d
7.3, 20.0, 32.9, 81.9, 116.1, 118.9, 126.3, 131.7, 136.7, 139.1, 172.7,
1H); 13C NMR (126 MHz, DMSO-d6)
d
26.2, 78.0, 116.2, 118.4, 122.5,
196.1; IR (cmꢂ1):
n 3588 w, 3449 w, 3191 w, 2914 w, 1712 s, 1670 s,
127.0, 136.0, 141.5, 173.3, 196.2; IR (cmꢂ1):
n
1709 s, 1671 s, 1614 s,
1618 m, 1504 m, 1421 w, 1200 w, 1159 w, 849 w, 540 w; HRMS
1598 m, 1487 m, 1455 m, 1441 m, 1405 m, 1243 m, 1190 m, 753 m;
HRMS (ESIþ): m/z calcd for C10H10NOþ3 [MþH]þ 192.0655, found
192.0658.
(ESIꢂ): m/z calcd for
C
12H12NOe3 ([MꢂH]e) 218.0823, found
218.0827.
4.3.7. 3-Ethyl-3-hydroxy-8-methylquinoline-2,4(1H,3H)-dione
4.3.2. 3-Ethyl-3-hydroxyquinoline-2,4(1H,3H)-dione (2b).27 White
solid, yield 3.73 g (91%), mp 174e176 ꢀC (benzeneeethanol), mp27
(2g). Yellow solid, yield 66%, mp 164 ꢀC. 1H NMR (500 MHz, DMSO-
d6)
d
0.78 (t, 3H, J¼7.2 Hz), 1.64e1.81 (m, 1H), 2.31 (s, 3H), 5.66 (br s,
170e172 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d
0.78 (t, 3H,
1H), 7.04 (dd, 1H, J¼7.6, 7.6 Hz), 7.45 (d, 1H, J¼7.6 Hz), 7.58 (d, 1H,
J¼7.4 Hz), 1.66e1.82 (m, 2H), 5.65 (s, 1H), 7.07 (d, 1H, J¼8.0 Hz),
J¼7.6 Hz), 9.94 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
d 7.3, 17.2,
7.09e7.13 (m, 1H), 7.59 (ddd, 1H, J¼7.7, 7.7, 1.5 Hz), 7.72 (dd, 1H,
32.8, 82.0, 119.5, 122.3, 124.4, 124.6, 137.0, 139.3, 173.1, 196.2; IR
J¼7.7, 1.4 Hz), 10.76 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
d
7.4,
(cmꢂ1):
n 3585 m, 3472 m, 3294 m, 1706 s, 1668 s, 1598 m, 1469 m,
32.8, 82.0, 116.2, 119.1, 122.5, 126.7, 135.9, 141.4, 172.9, 196.0; IR
1374 m, 1194 m; HRMS (ESIþ): m/z calcd for C12H14NOþ3 [MþH]þ
(cmꢂ1):
n
3457 m, 1709 s, 1667 s, 1617 m, 1487 m, 1365 m, 1185 m,
220.0968, found 220.0974.
774 m, 753 m; MS (EI) m/z (%): 97(22), 83(25), 74(26), 72(73),
71(22), 69(32), 59(100), 55(48); HRMS (ESIþ): m/z calcd for
4.3.8. 5-Chloro-3-ethyl-3-hydroxy-8-methylquinoline-2,4(1H,3H)-
C
C
11H12NOþ3 [MþH]þ 206.0812, found 206.0816. Anal. Calcd for
dione (2h). Colourless solid, yield 4.16 g (82%), mp 158e166 ꢀC
11H11NO3 (205.21): C, 64.23; H, 5.40; N, 6.83%. Found: C, 64.08; H,
5.37; N, 6.65%.
(cyclohexane). 1H NMR (500 MHz, DMSO-d6)
d
0.80 (t, 3H, J¼7.2 Hz,
CH3CH2), 1.76 (q, 2H, J¼7.2 Hz, CH2), 2.28 (s, 3H, CH3eC8), 5.76 (br s,
1H, OH), 7.11 (d,1H, J¼8.1 Hz, H6), 7.38 (d,1H, J¼8.1 Hz, H7), 9.99 (br
s, 1H, NH); 13C NMR (126 MHz, DMSO-d6) 7.8 (CH3CH2), 17.3
(CH3eC8), 32.2 (CH2), 83.2 (C3), 117.8 (C4a), 124.2 (C8), 124.7 (C6),
129.5 (C5), 136.2 (C7), 140.3 (C8a), 172.0 (C2), 194.9 (C4); IR (cmꢂ1):
4.3.3. 3-Ethyl-3-hydroxy-6-methoxyquinoline-2,4(1H,3H)-dione
(2c).35 Yellow solid, yield 4.29 (89%), mp 186e193 ꢀC (ethanol),
mp35 198 ꢀC (watereDMF). 1H NMR (500 MHz, DMSO-d6)
d 0.78 (t,
3H, J¼7.5 Hz), 1.65e1.82 (m, 2H), 3.78 (s, 3H), 5.62 (br s, 1H), 7.02 (d,
n 3438 m, 3294 m, 1717 s, 1682 s, 1587 s, 1499 m, 1458 m, 1389 m,
1H, J¼8.8 Hz), 7.18 (d, 1H, J¼3.0 Hz), 7.22 (dd, 1H, J¼8.8 Hz, 3.0 Hz),
1375 m, 1272 m, 1250 m, 1187 s, 1064 m, 1053 m, 813 m; HRMS
10.58 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
d
7.4, 32.9, 55.5, 81.8,
3414
(ESIþ): m/z calcd for
C
12H13ClNOþ3 [MþH]þ 254.0578, found
108.4, 117.8, 119.6, 123.8, 135.4, 154.6, 172.5, 196.1; IR (cmꢂ1):
n
254.0578.
m, 3200e2800 br, 3072 m, 1709 s, 1669 s, 1625 m, 1502 s, 1431 m,
1282 s, 1212 m, 1182 m, 1160 m, 848 m; MS (EI) m/z (%): 236
([Mþ1]þ, 9), 235 (Mþ, 63), 220 (20), 123 (20), 122 (47), 109 (29), 106
(28), 79 (26), 57 (21), 52 (26); HRMS (ESIþ): m/z calcd for
4.3.9. 3-Butyl-3-hydroxyquinoline-2,4(1H,3H)-dione
3.73 g (80%), mp24 146e149 ꢀC (benzene). 1H NMR (500 MHz,
DMSO-d6)
0.77 (t, 3H, J¼7.0 Hz), 1.12e1.28 (m, 4H), 1.62e1.78 (m,
4H), 5.67 (br s, 1H), 7.08 (d, 1H, J¼8.0 Hz), 7.09e7.13 (m, 1H), 7.59
(2i). Yield24
d
C
12H14NOþ4 [MþH]þ 236.0917, found 236.0916; Anal. Calcd for

10832
S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
(ddd, 1H, J¼7.6, 7.6, 1.8 Hz), 7.72 (dd, 1H, J¼7.6, 1.8 Hz), 10.79 (br s,
1H); 13C NMR (126 MHz, DMSO-d6)
13.8, 22.0, 24.7, 39.3, 81.7,
116.2, 119.0, 122.5, 126.7, 135.9, 141.4, 172.9, 196.1; IR (cmꢂ1):
3476
(m, 1H), 7.80 (dd, 1H, J¼7.7, 1.6 Hz); 13C NMR (126 MHz, DMSO-d6)
d
d 7.5, 29.8, 33.2, 82.4, 115.6, 120.4, 123.0, 126.8, 136.0, 142.6, 172.4,
n
195.3; IR (cmꢂ1):
n 3379 m, 2990 w, 2940 w, 1711 s, 1680 s, 1605 s,
m, 3192 w, 2950 m, 2866 m, 1705 s, 1666 s, 1617 m, 1595 m, 1486 m,
1382 m, 1091 m, 755 m; HRMS (ESIþ): m/z calcd for C13H16NO3þ
[MþH]þ 234.1125, found 234.1126.
1473 s, 1359 m, 1102 m, 707 w, 755 w, 666 w, 530 w; HRMS (ESIþ):
m/z calcd for C12H14NOþ3 [MþH]þ 220.0968, found 220.0969.
4.3.15. 3-Butyl-3-hydroxy-1-methylquinoline-2,4(1H,3H)-dione
(2o).24 White solid, yield 4.20 g (85%), mp 104e108 ꢀC (cyclohex-
ane), mp24 104e108 ꢀC (cyclohexane). 1H NMR (500 MHz, DMSO-
4.3.10. 3-Butyl-3-hydroxy-6,8-dimethylquinoline-2,4(1H,3H)-dione
(2j). Colourless microcrystals, yield 4.93 g (87%), mp 175e184 ꢀC
(cyclohexane). 1H NMR (500 MHz, DMSO-d6)
CH3CH2), 1.10e1.29 (m, 4H, CH2CH2CH3), 1.61e1.75 (m, 2H,
CH2eC3), 2.25 (s, 3H, CH3eC6), 2.27 (s, 3H, CH3eC8), 5.63 (s, 1H,
OH), 7.27 (s, 1H, H7), 7.38 (s, 1H, H5), 9.86 (br s, 1H, NH); 13C NMR
d
0.76 (t, 3H, J¼7.5 Hz,
d6)
d
0.74 (t, 3H, J¼7.0 Hz), 1.08e1.28 (m, 4H), 1.61e1.75 (m, 2H),
3.37 (s, 3H), 5.73 (br s, 1H), 7.22 (dd, 1H, J¼7.4, 7.4 Hz), 7.35 (d, 1H,
J¼8.4 Hz), 7.72 (ddd, 1H, J¼8.2, 8.2, 1.7 Hz), 7.80 (dd, 1H, J¼7.7,
1.6 Hz); 13C NMR (126 MHz, DMSO-d6)
d 13.7, 21.9, 24.8, 29.8, 39.6,
(126 MHz, DMSO-d6)
d
13.7 (CH3CH2), 17.1 (CH3eC8), 19.8
82.1, 115.6, 120.4, 123.0, 126.9, 136.0, 142.5, 172.4, 195.4; IR (cmꢂ1):
n
(CH3eC6), 21.9 (CH2CH3), 24.6 (CH2CH2eC3), 39.3 (CH2eC3), 81.7
3471 m, 2944 m, 1702 s, 1661 s, 1603 s, 1475 s, 1346 m, 1324 m, 1296
m, 1189 m, 1106 m, 1081 s, 1028 m, 1020 m, 769 m.
(C3), 119.3, 124.1 (C5), 124.5, 131.4, 137.0, 137.9 (C7), 173.1 (C2), 196.3
(C4); 15N NMR (DMSO-d6, 51 MHz): 129; IR (cmꢂ1):
n 3455 m, 3231
m, 2954 m, 2932 m, 1704 s, 1662 s, 1615 m, 1491 s, 1378 s, 1283 m,
1236 m, 1220 m, 1158 m, 1068 m, 791 w; HRMS (ESIþ): m/z Calcd
for C15H20NOþ3 [MþH]þ 262.1438, found 262.1437; Anal. Calcd for
4.3.16. 3-Hydroxy-1-methyl-3-phenylquinoline-2,4(1H,3H)-dione
(2p).24,27 White solid, yield 4.81 g (90%), mp 159e162 ꢀC (ethanol),
mp27 160e162 ꢀC (ethanolewater). For yield,24 mp24 and IR spec-
C
17H17NO3 (283.32): C, 72.07; H, 6.05; N, 4.94%. Found: C, 72.16; H,
trum27 see literature. 1H NMR (500 MHz, DMSO-d6)
d 3.49 (s, 3H),
6.13; N, 5.11%.
6.49 (br s, 1H), 7.18 (dd, 1H, J¼7.3, 7.3 Hz), 7.25e7.31 (m, 5H), 7.40 (d,
1H, J¼7.3 Hz), 7.68e7.50 (m, 2H); 13C NMR (126 MHz, DMSO-d6)
4.3.11. 3-Butyl-3-hydroxy-6,8-dimethoxyquinoline-2,4(1H,3H)-dione
d 30.0, 83.0, 116.0, 120.5, 123.3, 125.6, 127.3, 128.7, 136.3, 138.5,
(2k). Pale yellow crystals, yield 3.34 g (57%), mp 119e121 ꢀC (cy-
142.4, 171.0, 193.4 (one signal not observed); IR (cmꢂ1):
n 3615 w,
clohexane). 1H NMR (500 MHz, DMSO-d6)
d
0.77 (t, 3H, J¼7.0 Hz),
3422 w, 1709 s, 1668 s, 1602 m, 1474 s, 1359 s, 1297 m, 1099 m, 1015
m, 759 m, 744 m, 700 m; MS (EI) m/z (%): 268 ([Mþ1]þ, 5), 267
([M]þ, 26), 162 (65), 146 (11), 105 (100), 91 (12), 77 (43), 51 (12).
Anal. Calcd for C16H13NO3 (267.28): C, 71.90; H, 4.90; N, 5.24%.
Found: C, 71.71; H, 4.86; N, 5.00%.
1.11e1.28 (m, 4H), 1.60e1.75 (m, 2H), 3.78 (s, 3H), 3.85 (s, 3H), 5.64
(br s, 1H), 6.77 (d, 1H, J¼2.6 Hz), 6.89 (d, 1H, J¼2.6 Hz), 9.76 (br s,
1H); 13C NMR (126 MHz, DMSO-d6) 13.8, 22.0, 24.7, 55.5, 56.3, 82.0,
98.8, 106.3, 119.4, 125.5, 147.6, 155.0, 172.3, 196.1 (one resonance not
observed); IR (cmꢂ1):
n 3486 m, 3213 m, 2960 m, 2934 m, 1709 s,
1668 s, 1618 m, 1505 s, 1455 m, 1370 m, 1205 m, 1155 m, 841 w;
HRMS (ESIþ): m/z calcd for C15H20NOþ5 [MþH]þ 294.1336, found
278.1338.
4.4. Oxidation of 3-hydroxyquinoline-2,4(1H,3H)-diones 2
with paraperiodic acid into N-(a-ketoacyl)anthranilic acids 3
An aqueous solution of H5IO6 (1.25 mL of water per 1 mmol of
H5IO6, Table 2) was added to the stirred solution of 3-
hydroxyquinoline-2,4(1H,3H)-dione 2 (1 mmol) in Solvent (Table
2) at room temperature. The reaction mixture was stirred at the
temperature and for the time indicated in Table 2. Then it was left
overnight at 5e10 ꢀC. The resulting precipitate was collected by
filtration and repeatedly washed with small portions of water (to-
tally 15e50 mL) to afford the first crop of product 3. The filtrate was
evaporated to dryness suspended in water and filtered. The filtrate
was washed with water as described above to give the second crop
of the product. Re-crystallisation of the combined crops from the
solvent indicated below gave pure 3.
4.3.12. 3-Butyl-3-hydroxybenzo[h]quinoline-2,4(1H,3H)-dione
(2l). Pale yellow solid, yield 4.59 (81%), mp 117e121 ꢀC (benzene).
1H NMR (500 MHz, DMSO-d6)
d
0.76 (t, 3H, J¼7.2 Hz), 1.11e1.36 (m,
4H), 1.71e1.86 (m, 2H), 5.79 (s, 1H), 7.62e7.68 (m, 2H), 7.71e7.79
(m, 2H), 7.99 (d,1H, J¼8.3 Hz), 8.65 (d,1H, J¼8.3 Hz),11.00 (br s,1H);
13C NMR (126 MHz, DMSO-d6)
d 13.8, 22.0, 24.8, 81.9, 114.4, 121.6,
121.9, 122.7, 123.6, 126.8, 128.6, 129.6, 136.8, 139.7, 174.5, 196.2 (one
signal not observed); IR (cmꢂ1): 3489 w, 3294 w, 2955 w, 2928 w,
1705 s, 1666 s, 1626 m, 1578 m, 1389 m, 820 w, 797 w, 765 w; MS
(EI) m/z (%): 284 ([Mþ1]þ, 8), 283 (Mþ, 41), 240 (38), 199 (100), 198
(50), 170 (13), 142 (14), 140 (17), 115 (45), 114 (16), 57 (22), 41 (19).
HRMS (ESIþ): m/z calcd for C17H18NOþ3 [MþH]þ 284.1281, found
284.1279. Anal. Calcd for C17H17NO3 (283.32): C, 72.07; H, 6.05; N,
4.94%. Found: C, 71.96; H, 6.06; N, 4.81%.
4.5. Oxidation of 3-hydroxyquinoline-2,4(1H,3H)-diones 2
with sodium periodate into N-(a-ketoacyl)anthranilic acids 3
4.3.13. 3-Hydroxy-3-phenylquinoline-2,4(1H,3H)-dione
(2m).46,24 White solid, yield 3.80 g (75%), mp 245e250 ꢀC (etha-
nol), mp46 224e226 ꢀC (ethanol). 1H NMR (500 MHz, DMSO-d6)
An aqueous solution of NaIO4 (1.25 mL of water per 1 mmol of
NaIO4, Table 3) was added to the stirred solution of 3-
hydroxyquinoline-2,4(1H,3H)-dione 2 (1 mmol) in ethanol (Table
3) at room temperature within 5 min. The stirring was continued
for the time indicated in Table 3. The reaction mixture was left at
5e10 ꢀC overnight. The precipitate was collected by filtration and
washed repeatedly with small portions of water (totally
100e200 mL) to give the first crop of product 3. The above water
filtrates were combined, solvents were evaporated in vacuo and the
residue was suspended in water (40 mL). The precipitate was col-
lected by filtration and washed with water (3ꢁ5 mL) to give the
second crop of product 3. Re-crystallisation of the combined crops
from the solvent indicated below gave pure 3.
d
6.41 (br s,1H), 7.08e7.15 (m, 2H), 7.27e7.35 (m, 3H), 7.36e7.39 (m,
2H), 7.61 (ddd, 1H, J¼7.8, 7.8, 1.3 Hz), 7.68 (dd, 1H, J¼7.8, 1.3 Hz),
11.11 (br s, 1H); 13C NMR (126 MHz, DMSO-d6)
82.5, 116.4, 119.0,
122.9, 125.4, 127.2, 128.6, 128.7, 136.4, 138.4, 141.4, 171.6, 194.2; IR
(cmꢂ1):
3441 s, 3250 m, 1732 s, 1708 s, 1675 s, 1613 m, 1482 m,
d
n
1368 m, 1169 m, 760 m, 739 m, 696 m; HRMS (ESIþ): m/z calcd for
C
15H12NOþ3 [MþH]þ 254.0812, found 254.0813.
4.3.14. 3-Ethyl-3-hydroxy-1-methylquinoline-2,4(1H,3H)-dione
(2n).45 White solid, yield 3.16 g (72%), mp 121e126 ꢀC (ethyl ace-
tate), mp45 146 ꢀC (xyleneecyclohexane). 1H NMR (500 MHz,
DMSO-d6)
d
0.75 (t, 3H, J¼7.4 Hz), 1.64e1.80 (m, 2H), 3.38 (s, 3H),
4.5.1. 2-[(2-Oxopropanoyl)amino]benzoic acid (3a). For UV, IR and
1H NMR (60 MHz) data, see Ref. 2 White solid, mp 207e210 ꢀC
5.73 (br s, 1H), 7.20e7.24 (m, 1H), 7.36 (d, 1H, J¼8.4 Hz), 7.69e7.74

S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
10833
(ethyl acetate), mp2 194e196 ꢀC (benzene). 1H NMR (500 MHz,
DMSO-d6)
2.45 (s, 3H, CH3), 7.24 (dd, 1H, J¼7.5, 7.5 Hz, H5), 7.67
J¼7.5, 2.0 Hz), 7.86 (d, 1H, J¼2.0 Hz), 8.57 (d, 1H, J¼7.5 Hz), 12.23 (br
s,1H), 13.76 (br s, 1H); 13C NMR (126 MHz, DMSO-d6): 7.1, 20.3, 29.4,
d
(ddd, 1H, J¼7.5, 7.5, 1.0 Hz, H4), 8.05 (dd, 1H, J¼7.5, 1.0 Hz, H6), 8.67
116.9, 119.5, 131.6, 132.9, 134.8, 137.1, 158.5, 169.2, 198.7; IR (cmꢂ1):
n
(d, 1H, J¼7.5 Hz, H3), 12.31 (br s, 1H, NH), 13.81 (br s, 1H, COOH); 13
C
3480 w, 3275 m, 1693 s, 1673 s, 1595 m, 1524 s, 1419 m, 1292 m,
1270 s, 1223 s, 916 m, 893 m, 794 m, 754 m, 665 m; HRMS (ESIþ):
m/z calcd for C12H14NOþ4 [MþH]þ 236.0917, found 236.0914.
NMR (126 MHz, DMSO-d6)
d 24.1 (CH3), 117.1 (C1), 119.4 (C3), 123.7
(C5), 131.5 (C6), 134.3 (C4), 139.5 (C2), 158.8 (NCO), 169.2 (COOH),
196.2 (COCH3); 15N NMR (51 MHz, DMSO-d6) 118; IR (cmꢂ1):
d
n
3260 m,1725 s, 1700 s, 1673 s, 1585 m,1520 s, 1451 m,1419 s, 1281 s,
1253 s, 1138 s, 760 s; MS (EI) m/z (%): 208 ([Mþ1]þ, 1), 207 (Mþ, 8),
164 (31), 146 (100), 119 (18), 90 (33), 65 (10), 43 (38). HRMS (ESIþ):
m/z calcd for C10H10NOþ4 [MþH]þ 208.0604, found 208.0610.
4.5.7. 3-Methyl-2-[(2-oxobutanoyl)amino]benzoic
Yellowish solid, mp 130e136 ꢀC (benzene). 1H NMR (500 MHz,
DMSO-d6)
acid
(3g).
d
1.03 (t, 3H, J¼7.2 Hz), 2.20 (s, 3H), 2.90 (q, 2H, J¼7.2 Hz),
7.29 (dd, 1H, J¼7.7, 7.7 Hz), 7.48 (d, 1H, J¼7.7 Hz), 7.69 (d, 1H,
J¼7.7 Hz), 10.29 (br s, 1H), 12.97 (br s, 1H); 13C NMR (126 MHz,
4.5.2. 2-[(2-Oxobutanoyl)amino]benzoic acid (3b). Off-white crys-
tals, mp 179e182 ꢀC (benzene); colourless needles, mp 194e196 ꢀC
(ethyl acetate); Rf¼0.13 (5% ethanol in chloroform); 1H NMR
DMSO-d6) d 7.0, 18.2, 30.1, 126.2, 127.8, 127.9, 134.0, 134.5, 135.7,
159.4, 167.5, 199.0; IR (cmꢂ1):
n 2600e3400 br, 3343 w, 2985 w,
1724 s, 1697 s, 1678 s, 1597 m, 1515 s, 1468 m, 1431 m, 1405 m, 1291
s, 1193 m, 1113 m, 756 s; HRMS (ESIþ): m/z calcd for C12H14NO4þ
[MþH]þ 236.0917; found 236.0922.
(300 MHz, DMSO-d6)
d
1.04 (t, 3H, J¼7.0 Hz), 2.96 (q, 2H, J¼7.0 Hz),
7.24 (dd, 1H, J¼7.6, 7.6 Hz), 7.67 (dd, 1H, J¼7.6, 7.6 Hz), 8.05 (d, 1H,
J¼7.6 Hz), 8.67 (d, 1H, J¼7.6 Hz), 12.31 (br s, 1H), 13.77 (br s, 1H); 13
C
NMR (75 MHz, DMSO-d6)
d
7.0, 29.3, 117.0, 119.5, 123.6, 131.4, 134.2,
4.5.8. 6-Chloro-3-methyl-2-[(2-oxobutanoyl)amino]benzoic
(3h). Colourless crystals, mp 189e191 ꢀC (benzene). 1H NMR
(500 MHz, DMSO-d6)
1.02 (t, 3H, J¼7.2 Hz, CH3CH2), 2.12 (s, 3H,
acid
139.4, 158.6, 169.1, 198.6; IR (cmꢂ1):
n 2700e3300 br, 3266 w, 2983
w,1721 m,1693 s,1672 s,1602 m,1584 m,1519 s,1416 m,1277 s, 761
m, 662 w; MS (EI) m/z (%):222 ([Mþ1]þ, 1), 221 (Mþ, 8), 164 (35),
146 (100), 119 (16), 90 (19), 57 (30). Anal. Calcd for C11H11NO4
(221.21): C, 59.73; H, 5.01; N, 6.33%. Found: 59.72; H 5.03; N, 6.30%.
d
CH3eC3), 2.87 (q, 2H, J¼7.2 Hz, CH2), 7.37 (d, J¼8.3 Hz, 1H, H4), 7.41
(d, 1H, J¼8.3 Hz, H5), 10.22 (br s, 1H, NH), 13.01 (br s, 1H, COOH); 13
C
NMR (126 MHz, DMSO-d6) d 7.0 (CH3CH2), 17.2 (CH3eC3), 30.4 (CH2),
126.6 (C6), 128.1 (C5), 131.8 (C4), 133.2 (C2), 133.4 (C1), 135.6 (C3),
4.5.3. 5-Methoxy-2-[(2-oxobutanoyl)amino]benzoic
acid
160.4 (NHCO), 165.9 (COOH), 199.0 (COCH2); 15N NMR (51 MHz,
(3c). Colourless shiny crystals, mp 205e207ꢀ C (ethyl acetate);
Rf¼0.11 (5% ethanol in chloroform); 1H NMR (300 MHz, DMSO-d6)
DMSO-d6) d n 2700e3500 br, 3219 w, 2983 w, 2936 w,
118; IR (cmꢂ1):
1716 s,1668 s,1530 m,1210 s,1171 s,1107 m, 694 m; HRMS (ESIe): m/
d
1.03 (t, 3H, J¼7.1 Hz), 2.94 (q, 2H, J¼7.1 Hz), 3.80 (s, 3H), 7.27 (dd,
z calcd for C12H11ClNOe4 [MꢂH]e 268.0382, found 268.0393.
1H, J¼9.2, 3.1 Hz), 7.52 (d, 1H, J¼3.1 Hz), 8.60 (d, 1H, J¼9.2 Hz),12.05
(br s, 1H), 13.87 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
7.0, 29.4,
55.4, 115.4, 118.4, 120.1, 121.1, 132.7, 154.8, 158.2, 168.7, 198.9; IR
(cmꢂ1):
2500e3300 br, 3270 w, 2978 w, 1722 m, 1697 s, 1689 s,
d
4.5.9. 2-[(2-Oxohexanoyl)amino]benzoic acid (3i). Colourless shiny
crystals, mp 147e151 ꢀC (ethyl acetate); 1H NMR (500 MHz, DMSO-
n
d6)
d
0.90 (t, 3H, J¼2.4 Hz, CH3), 1.29e1.37 (m, 2H, CH2CH3),
1673 s, 1525 s, 1439 s, 1299 s, 1287 s, 1251 s, 1216 s, 1045 m, 829 m;
MS (EI) m/z (%): 251 (Mþ, 4), 207 (15), 194 (17), 176 (51), 167 (46),
150 (28), 149 (70), 122(47), 107(15), 52(16), 45(24), 44(90); Anal.
Calcd for C12H13NO5 (251.24): C, 57.37; H, 5.22; N, 5.58%. Found: C,
57.53; H, 5.42; N, 5.58%.
1.50e1.57 (m, 2H, CH2CH2CH3), 2.93 (t, 2H, J¼7.3 Hz, COCH2), 7.24
(ddd, 1H, J¼7.7, 7.7, 1.0 Hz, H5), 7.67 (ddd, 1H, J¼7.7, 7.7, 1.6 Hz, H4),
8.05 (dd, 1H, J¼7.7, 1.6 Hz, H6), 8.67 (dd, 1H, J¼7.7, 1.0 Hz, H3), 12.33
(br s,1H, NH), 13.81 (br s,1H, COOH); 13C NMR (126 MHz, DMSO-d6)
d
13.8 (CH3), 21.6 (CH2CH3), 24.8 (CH2CH2CH3), 35.4 (CH2CO), 117.0
(C1), 119.5 (C3), 123.6 (C5), 131.5 (C6), 134.3 (C4), 139.4 (C2), 158.6
4.5.4. 4-Methoxy-2-[(2-oxobutanoyl)amino]benzoic acid (3d). Off-
white crystals, mp 201e203 ꢀC (benzeneeethyl acetate), Rf¼0.08 (5%
(NCO), 169.1 (COOH), 198.1 (COCH2); 15N NMR (51 MHz, DMSO-d6)
d
119; IR (cmꢂ1):
n 2300e3300 br, 3252 w, 2957 w, 2871 w, 1723 m,
ethanol in chloroform). 1H NMR (300 MHz, DMSO-d6)
d
1.03 (t, 3H,
1695 s, 1668 s, 1603 m, 1586 s, 1521 s, 1412 m, 1283 s, 1265 s, 762 s,
662 m; MS (EI): m/z, (%) 249 (Mþ, 6), 164 (43), 146 (100), 90 (19), 57
(32); HRMS (ESIþ): m/z Calcd for C13H16NOþ4 [MþH]þ 250.1074;
found 250.1075. Anal. Calcd for C13H15NO4 (249.26): C, 62.64; H,
6.07; N, 5.62%. Found: C, 62.93; H 6.14; N, 5.70%.
J¼7.1 Hz), 2.94 (q, 2H, J¼7.1 Hz), 3.23 (s, 3H), 6.80 (dd, 1H, J¼8.9,
2.5 Hz), 7.99 (d, 1H, J¼8.9 Hz), 8.30 (d, 1H, J¼2.5 Hz), 12.46 (br s, 1H),
13.40 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
d 7.0, 29.3, 55.5,
104.6, 109.3, 109.4, 133.3,141.4, 158.8, 163.5, 168.9,198.4; IR (cmꢂ1):
n
2800e3400 br, 3180 w, 2972 w, 1698 s, 1688 s, 1661 s, 1608 s, 1583 s,
1530s, 1248 s, 1211 s, 1140 m, 1027 m, 830 m, 624 w; MS (EI) m/z (%):
252 ([Mþ1]þ, 2), 251 (Mþ, 6), 176 (55), 97 (43), 85 (49), 83 (45), 71
(79), 69 (43), 57 (100), 43 (77). Anal. Calcd for C12H13NO5 (251.24): C,
57.37; H, 5.22; N, 5.58%. Found: C, 57.28; H 5.43; N, 5.41%.
4.5.10. 3,5-Dimethyl-2-[(2-oxohexanoyl)amino]benzoic acid (3j).
Colourless crystals, mp 109e110 ꢀC (cyclohexane). 1H NMR
(500 MHz, DMSO-d6)
d
0.89 (t, 3H, J¼7.4 Hz, CH3CH2), 1.28e1.36 (m,
2H, CH2CH3), 1.50e1.57 (m, 2H, CH2CH2CH3), 2.15 (s, 3H, CH3eC3),
2.31 (s, 3H, CH3eC5), 2.86 (q, 2H, J¼7.3 Hz, COCH2), 7.29 (d, 1H,
J¼1.3 Hz, H4), 7.50 (d, 1H, J¼1.3 Hz, H6), 10.17 (br s, 1H, NH), 12.89
4.5.5. 3-Methoxy-2-[(2-oxobutanoyl)amino]benzoic acid (3e). Off-
white crystals, mp 142e146 ꢀC (benzeneecyclohexane), Rf¼0.13
(br s, 1H, COOH); 13C NMR (126 MHz, DMSO-d6)
d 13.7 (CH2CH3),
(5% ethanol in chloroform). 1H NMR (300 MHz, DMSO-d6)
d
1.03 (t,
18.0 (CH3eC3), 20.2 (CH3eC5), 21.5 (CH2CH3), 24.8 (CH2CH2CH3),
36.2 (COCH2), 127.6 (C1), 128.3 (C6), 132.0 (C2), 134.5 (C4), 135.5
(C3), 135.6 (C1), 159.6 (NHCO), 167.6 (COOH), 198.8 (COCH2); 15N
3H, J¼7.2 Hz), 2.87 (q, 2H, J¼7.2 Hz), 3.81 (s, 3H), 7.27e7.41 (m, 3H),
9.83 (br s, 1H), 12.89 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
7.1,
30.2, 56.1, 115.3, 121.5, 124.3, 127.0, 128.8, 154.1, 159.5, 167.3, 199.2;
IR (cmꢂ1):
2800e3400 br, 3330 m, 2974 w, 2943 w, 1716 s, 1679 s,
d
NMR (51 MHz, DMSO-d6) d n 3332 w, 2500e3300 br,
118; IR (cmꢂ1):
n
2963 w, 2930 w, 1726 m, 1690 s, 1671 s, 1511 s, 1431 m, 1313 m, 1242
m, 1150 w, 727 w; HRMS (ESIe): m/z Calcd for C15H18NOe4 [MꢂH]e
276.1241, found 276.1248.
1537 m, 1479 m, 1287 m, 1203 m, 1054 m, 760 w, 760 w, 720 w, 647
w; Anal. Calcd for C12H13NO5$0.25H2O (255.74): C, 56.36; H, 5.32;
N, 5.48%. Found: C, 56.31; H 5.25; N, 5.48%.
4.5.11. 3,5-Dimethoxy-2-[(2-oxohexanoyl)amino]benzoic acid (3k).
Pale yellow microcrystals, mp 101e105 ꢀC (cyclohexane). 1H NMR
4.5.6. 5-Methyl-2-(2-oxobutanamido)benzoic acid (3f). Colourless
shiny crystals, mp 199e205 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d
1.03
(500 MHz, DMSO-d6)
d
0.89 (t, 3H, J¼7.4 Hz), 1.28e1.35 (m, 2H),
(t, 3H, J¼7.2 Hz), 2.32 (s, 3H), 2.95 (q, 2H, J¼7.2 Hz), 7.47 (dd, 1H,
1.50e1.55 (m, 2H), 2.83 (t, 2H, J¼7.2 Hz), 3.78 (s, 3H), 3.81 (s, 3H),

10834
S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
6.84 (d, 1H, J¼2.7 Hz), 6.89 (d, J¼2.7 Hz), 9.66 (br s, 1H), 12.93 (br s,
1H); 13C NMR (126 MHz, DMSO-d6)
13.8, 21.7, 25.0, 36.4, 55.6,
56.2, 102.5, 105.4, 117.5, 129.9, 155.5, 158.2, 159.9, 167.1, 199.2; IR
(cmꢂ1):
3384 m, 2500e3200 br, 2964 w, 2875 w, 1698 s, 1601 m,
1510 s, 1465 m, 1355 m, 1299 m, 1211 s, 1154 s, 1070 m, 1048 m;
HRMS (ESIþ): m/z calcd for C15H20NOþ6 [MþH]þ 310.1285, found
310.1284; Anal. Calcd for C15H19NO6 (309.31): C, 58.25; H, 6.19; N,
4.53%. Found: C, 58.07; H, 6.20; N, 5.02%.
Rf¼0.21 (5% ethanol in chloroform), 0.05 (20% ethyl acetate in
benzene); 1H NMR (500 MHz, CD3CN)
3.37 (s, 3H, CH3), 7.34 (dd,
d
d
1H, J¼7.8,1.2 Hz, H3), 7.39 (ddd, J¼7.8, 7.8,1.2 Hz, H5), 7.44e7.50 (m,
3H, H4, H30, H50), 7.61e7.65 (m, 1H, H40), 7.79e7.82 (m, 2H, H20,
H60), 7.89 (dd, 1H, J¼7.8, 1.2 Hz, H6), resonances for exchangeable
n
protons in the baseline; 13C NMR (126 MHz, CD3CN)
d 36.9 (CH3),
129.9 (C30, C50), 130.1 (C5), 130.2 (C1), 130.4 (C20, C60), 132.0 (C3),
132.9 (C6), 134.1 (C10), 134.6 (C4), 135.6 (C40), 141.9 (C2), 166.2
(COOH), 166.8 (NCO), 192.0 (COPh); IR (cmꢂ1):
n 2500e3300 br,
4.5.12. 1-[(2-Oxohexanoyl)amino]naphthalene-2-carboxylic
(3l). White powder, mp 98e105 ꢀC (cyclohexane). 1H NMR
(500 MHz, DMSO-d6)
2H, CH2CH3), 1.56e1.62 (m, 2H, CH2CH2CH3), 2.92 (t, 3H, J¼7.3 Hz,
COCH2), 7.60 (ddd, 1H, J¼7.6, 7.6, 1.0 Hz, H7), 7.66 (ddd, 1H, J¼7.6,
7.6, 1.0 Hz, H6), 7.91 (d, 1H, J¼8.6 Hz, H3), 7.96 (d, 1H, J¼8.6 Hz, H4),
8.00 (br d, 1H, J¼7.6 Hz, H8), 8.01 (d, 1H, J¼8.1 Hz, H5), 10.76 (br s,
1H, NH), 13.17 (br s, 1H, COOH); 13C NMR (126 MHz, DMSO-d6)
acid
1719 s, 1680 s, 1616 s, 1593 s, 1576 m, 1249 s, 1236 s, 1220 s, 1081 s,
779 s, 715 s, 668 m; MS (EI) m/z (%): 105 (69), 77 (58), 57 (26), 45
(28), 44 (100), 43 (92), 42 (27), 41 (36); HRMS (ESIþ): m/z calcd for
d
0.92 (t, 3H, J¼7.4 Hz, CH3CH2), 1.32e1.40 (m,
C
C
16H14NOþ4 [MþH]þ 284.0917, found 284.0918; Anal. Calcd for
16H13NO4 (283.28): C, 67.84; H, 4.63; N, 4.94%. Found: C, 67.81; H
4.60; N, 4.90%.
4.6. Hydrolysis of N-(
a
-ketoacyl)anthranilic acids 3
d
13.8 (CH2CH3), 21.7 (CH2CH3), 25.0 (CH2CH2CH3), 36.3 (COCH2),
124.9 (C2), 125.4 (C2), 126.0 (C3), 126.7 (C7), 126.8 (C4), 127.8 (C5),
128.1 (C6), 129.3 (C8a), 134.1 (C1), 135.0 (C4a), 160.8 (NCO), 167.6
To a stirred suspension of N-(a-ketoacyl)anthranilic acids 3
(3 mmol) in water (10 mL) aqueous hydrochloric acid (37%, 15 mL)
was added portion-wise at room temperature. The reaction mix-
ture was refluxed, until the starting compound 3 was present
according to TLC analysis (1e7 h). The reaction mixture was cooled
down to room temperature and the precipitate (if formed) was
removed by filtration. The filtrate was evaporated to dryness using
rotary evaporator and the residue was recrystallized to give
anthranilic acid hydrochloride (4$HCl).
(COOH), 198.6 (COCH2); IR (cmꢂ1):
n 2800e3300 br, 3294 w, 2961
w, 2877 w, 1694 s, 1675 s, 1571 m, 1501, 1409 m, 1284 m, 1258 m,
764 m; MS (EI, 70 eV) m/z (%): 300 ([Mþ1]þ, 2), 299 (Mþ, 11), 214
(50), 197 (14), 196 (100), 187 (27), 169 (44), 141 (19), 140 (49), 115
(33), 114 (16), 85 (17), 57 (58), 43 (11), 41 (50). HRMS (ESIþ): m/z
calcd for C17H18NOþ4 [MþH]þ 300.1230, found 300.1229. Anal. Calcd
for C17H17NO4 (173.60): C, 68.21; H, 5.72; N, 4.68%. Found: C, 68.45;
H 5.91; N, 5.71%.
4.6.1. 2-Aminobenzoic acid hydrochloride (4b$HCl). N-(a-Ketoacyl)
4.5.13. 2-{[Oxo(phenyl)acetyl]amino}benzoic acid (3m).9 For IR and
1H NMR (60 MHz) data, see Ref. 9 Colourless crystals, mp
199e200 ꢀC (ethanol), mp9 200 ꢀC, Rf¼0.18 (5% EtOH in CHCl3). 1H
anthranilic acids 3b; Reaction time: 4 h. White crystalline solid,
yield 443 mg (85%), mp 167e172 ꢀC (ethanoleethyl acetate), mp47
193e194 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d
6.93 (dd, 1H, J¼7.6,
NMR (300 MHz, DMSO-d6)
d
7.29 (dd, 1H, J¼7.5, 7.5 Hz), 7.60 (dd,
7.6 Hz), 7.13 (d, 1H, J¼7.6 Hz), 7.43 (dd, 1H, J¼7.6, 7.6, 1.5 Hz), 7.8 (br
2H, J¼7.5, 7.5 Hz), 7.68e7.78 (m, 2H), 8.08 (d, 1H, J¼7.5 Hz), 8.24 (d,
2H, J¼7.5 Hz), 8.67 (d, 1H, J¼7.5 Hz), 12.43 (br s, 1H), 13.80 (br s, 1H);
s, 4H), 7.84 (dd, 1H, J¼7.6, 1.5 Hz); 13C NMR (126 MHz, DMSO-d6)
d
115.5, 119.9, 120.2, 131.3, 133.9, 144.1, 168.4; IR (cmꢂ1):
n
13C NMR (75.5 MHz, DMSO-d6)
d
117.7, 120.1, 124.0, 128.6, 130.8,
2400e3300 br, 2980 w, 2681 w, 2569 w, 1693 s, 1561 m, 1494 m,
1460 m, 1393 m, 1219 s, 1100 m, 758 m, 752 m, 650 m; HRMS
(ESIþ): m/z calcd for C7H8NO2þ [MþH]þ 138.0550, found 138.0548.
131.4, 133.0, 134.1, 134.4, 139.3, 160.2, 169.1, 187.4; IR (cmꢂ1):
n
2600e3300 br, 3236 w, 3070 w,1696 s,1682 s,1672 s,1585 s,1524 s,
1409 m, 1265 s, 758 m, 689 w, 660 w.
4.6.2. 2-Amino-5-methoxybenzoic acid hydrochloride (4c$HCl). N-
4.5.14. 2-[Methyl(2-oxobutanoyl)amino]benzoic
(3n). Colourless crystals, mp 113e115 ꢀC (ethanol). 1H NMR
(500 MHz, DMSO-d6)
acid
(a-Ketoacyl)anthranilic acids 3c; Reaction time: 6 h. Yellowish
solid, yield 556 mg (91%), mp 211e214 ꢀC (ethanoleethyl acetate),
d
0.75 (t, 3H, J¼7.3 Hz), 2.50e2.71 (m, 2H),
mp48 213e214 ꢀC (ethanolediethyl ether); 1H NMR (500 MHz,
3.17 (s, 3H), 7.44e7.50 (m, 2H), 7.64 (ddd, 1H, J¼7.7, 7.7, 1.6 Hz), 7.90
DMSO-d6)
d
3.80 (s, 3H), 7.25 (dd, 1H, J¼8.8, 3.0 Hz), 7.45 (d, 1H,
(dd, 1H, J¼7.7, 1.6 Hz), 13.29 (br s, 1H). 13C NMR (126 MHz, DMSO-
J¼3.0 Hz), 7.50 (d, 1H, J¼8.8 Hz), 9.8 (br s, 4H); 13C NMR (126 MHz,
d6):
d
6.8, 31.9, 36.6, 128.4, 128.5, 130.0, 131.3, 133.4, 141.5, 165.6,
DMSO-d6)
d 55.7, 115.5, 119.9, 122.8, 124.9, 128.8, 156.8, 166.8; IR
166.4, 200.6; IR (cmꢂ1):
n
2800e3200, 2985 w, 1732 m, 1709 s, 1632
(cmꢂ1):
n 2500e3300 br, 2845 w, 2617 w, 1698 s, 1614 s, 1509 s,
s, 1598 m, 1237 s, 861 w, 644 w; MS (EI) m/z (%): 179 (11), 178 (100),
134 (61),105 (35),104 (20), 77 (32), 57 (43); HRMS (ESIþ): m/z calcd
for C12H14NOþ4 [MþH]þ 236.0917, found 236.0912.
1404 m, 1273 s, 1234 s, 1025 m, 845 m, 741 m; HRMS (ESIþ): m/z
calcd for C8H10NOþ3 [MþH]þ 168.0655, found 168.0652.
4.6.3. 2-Amino-4-methoxybenzoic acid hydrochloride (4d$HCl). N-
4.5.15. 2-[Methyl(2-oxohexanoyl)amino]benzoic
acid
(a-Ketoacyl)anthranilic acids 3d; Reaction time: 7 h. Colourless
(3o). Colourless crystals, mp 101e105 ꢀC (benzene), Rf¼0.18 (5%
crystals, yield 391 mg (64%), mp 176e179 ꢀC (ethanolediethyl
ether), mp48 178e180 ꢀC; 1H NMR (300 MHz, DMSO-d6) 3.72 (s,
3H), 6.11 (dd, 1H, J¼8.9, 2.5 Hz), 6.25 (d, 1H, J¼2.5 Hz), 7.61 (d, 1H,
ethanol in chloroform). 1H NMR (300 MHz, DMSO-d6)
d 0.74 (t, 3H,
J¼7.2 Hz), 0.98e1.11 (m, 2H, CH2CH3), 1.19e1.31 (m, 2H,
CH2CH2CH2), 2.43e2.70 (m, 2H, COCH2), 3.17 (s, 3H), 7.42e7.52 (m,
2H), 7.64 (ddd, 1H, J¼7.7, 7.7, 1.3 Hz), 7.91 (dd, 1H, J¼7.7, 1.3 Hz),
J¼8.9 Hz), resonances for exchangeable protons in the baseline; 13
C
NMR (75.5 MHz, DMSO-d6) d 54.9, 98.6, 103.16, 103.21, 132.9, 153.5,
13.25 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
d
13.5, 21.2, 24.3,
163.6, 169.2; IR (cmꢂ1):
n 2600e3300 br, 2577 w, 1687 s, 1631 m,
36.5, 38.1, 128.5, 128.6, 130.2, 131.3, 133.3, 141.3, 165.7, 166.3, 200.1;
1596 m; 1403 m, 1338 m, 1246 s, 1113 m, 1021 m; HRMS (ESIþ): m/z
calcd for C8H10NOþ3 [MþH]þ 168.0655, found 168.0653. Anal. Calcd
for C8H10ClNO3 (203.62): C, 47.19; H, 4.95; N, 6.88. Found: C, 47.38;
H 5.10; N, 6.82.
IR (cmꢂ1):
n
2600e3300 br, 2959 w, 2623 w, 1714 s, 1620 s, 1595 m,
1396 m, 1247 m, 1140 w, 1083 w, 1067 w, 784 w, 710 w; Anal. Calcd
for C14H17NO4 (263.29): C, 63.87; H, 6.51; N, 5.32%. Found: C, 63.70;
H 6.47; N, 5.26%.
4.6.4. 2-Amino-3-methoxybenzoic acid hydrochloride (4e$HCl). N-
4.5.16. 2-(N-Methyl-2-oxo-2-phenylacetamido)benzoic acid (3p).
Colourless crystals, mp 145e146 ꢀC (benzene-cyklohexane),
(
a
-Ketoacyl)anthranilic acids 3e; Reaction time: 1 h. White solid,
yield 415 mg (68%) (crude, analytically pure product), mp

S. Kafka et al. / Tetrahedron 69 (2013) 10826e10835
10835
178e188 ꢀC, mp49 205e206 ꢀC (hydrochloric acid); 1H NMR
(500 MHz, DMSO-d6)
10. Fatiadi, A. J. Synthesis 1974, 229e272.
11. Ermolinsky, B. S.; Mikhailov, S. N. Russ. J. Bioorg. Chem. 2000, 26, 429e504.
d
3.82 (s, 3H), 6.61 (dd, 1H, J¼8.0, 8.0 Hz), 7.02
ꢁ
12. Klasek, A.; Kafka, S.; Kappe, T. Collect. Czech. Chem. Commun. 1995, 60,
(dd, 1H, J¼8.0, 1.0 Hz), 7.36 (dd, 1H, J¼8.0, 1.0 Hz), resonances for
2137e2146.
exchangeable protons in the baseline; 13C NMR (126 MHz, DMSO-
ꢁ
13. Klasek, A.; Kafka, S. J. Heterocycl. Chem. 1998, 35, 307e311.
ꢁ
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
d n
55.8, 111.1, 113.7, 115.4, 122.5, 139.6, 147.3, 169.4; IR (cmꢂ1):
14. Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Heterocycles 1998, 48, 2309e2326.
d6)
15. Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Tetrahedron 2000, 56, 1551e1560.
3485 m, 3418 m, 2500e3400 br, 3064 w, 2616 w, 1699 s, 1651 s,
1589 m, 1478 s, 1362 s, 1286 s, 1213 s, 1049 s, 755 m; HRMS (ESIþ):
m/z calcd for C8H10NOþ3 [MþH]þ 168.0655, found 168.0653. Anal.
Calcd for C8H10ClNO3 (203.62): C, 47.19; H, 4.95; N, 6.88%. Found: C,
47.32; H 5.11; N, 6.85%.
ꢁ
ꢀ
16. Kafka, S.; Klasek, A.; Kosmrlj, J. J. Org. Chem. 2001, 66, 6394e6399.
ꢁ
ꢀ
ꢀ
17. Klasek, A.; Polis, J.; Mrkvicka, V.; Kosmrlj, J. J. Heterocycl. Chem. 2002, 39,
1315e1320.
ꢁ
ꢀ
18. Kafka, S.; Klasek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002, 57, 1659e1682.
ꢁ
ꢀ
ꢀ
19. Klasek, A.; Koristek, K.; Kafka, S.; Kosmrlj, J. Heterocycles 2003, 60, 1811e1820.
ꢁ
ꢀ
ꢀ
20. Klasek, A.; Mrkvicka, V.; Pevec, A.; Kosmrlj, J. J. Org. Chem. 2004, 69, 5646e5651.
ꢀ
21. Kosmrlj, J.; Kafka, S.; Leban, I.; Grad, M. Magn. Reson. Chem. 2007, 45, 700e704.
ꢀ
ꢁ
ꢀ
22. Pomeisl, K.; Kvícala, J.; Paleta, O.; Klasek, A.; Kafka, S.; Kubelka, V.; Havlícek, J.;
Cejka, J. Tetrahedron 2007, 63, 10549e10561.
23. Kafka, S.; Klasek, A.; Polis, J.; Rosenbreierova, V.; Palík, C.; Mrkvicka, V.; Kosmrlj,
4.6.5. 2-(Methylamino)benzoic acid hydrochloride (4n$HCl). N-(a-
ꢀ
Ketoacyl)anthranilic acids 3n; Reaction time: 2 h. Colourless nee-
ꢁ
ꢁ
ꢀ
ꢀ
dles, yield 411 mg (73%), mp 136e140 ꢀC (ethanolebenzene), mp50
J. Tetrahedron 2008, 64, 4387e4402.
ꢁꢀ
ꢁ
24. Kafka, S.; Kovar, M.; Klasek, A.; Kappe, T. J. Heterocycl. Chem. 1996, 33,
1977e1982.
141 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 2.85 (s, 3H), 6.65 (dd, 1H,
J¼7.7, 7.7 Hz), 6.78 (d, 1H, J¼7.7 Hz), 7.42 (ddd, 1H, J¼7.7, 7.7, 1.6 Hz),
€
25. Baumgarten, P.; Kargel, W. Ber. Dtsch. Chem. Ges. 1927, 60, 832e842.
26. Bowman, R. E.; Campbell, A.; Tanner, E. M. J. Chem. Soc. 1959, 444e447.
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7.81 (dd, 1H, J¼7.7, 1.6 Hz), resonances for exchangeable protons in
the baseline; 13C NMR (126 MHz, DMSO-d6)
d
29.8, 111.0, 111.8,
115.2, 131.6, 134.5, 150.6, 169.7; IR (cmꢂ1):
n 3386 m, 2898 m, 2730
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m, 2650 m, 1694 m, 1662 s, 1304 s, 1271 s, 1122 m, 772 m, 750 s, 699
m; HRMS (ESIe): m/z Calcd for C8H8NOe2 [MꢂH]e 150.0561, found
150.0558. Anal. Calcd for C8H10ClNO2 (187.62): C, 51.21; H, 5.37; N,
7.47%. Found: C, 51.32; H 5.24; N, 7.71%.
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Acknowledgements
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This study was supported by the internal grant of the TBU in Zlin
(No. IGA/FT/2013/003) funded from the resources of specific uni-
versity research and the Ministry of Higher Education, Science and
Technology of the Republic of Slovenia and the Slovenian Research
Agency (Grant P1-0230-0103). This work was also partly supported
through the infrastructure of the EN-FIST Centre of Excellence,
Ljubljana.
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