Full text of DOI:10.1002/jhet.5570390102

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones and
Diaminomethylene Meldrum's Acids Derivatives
as Potential Potassium Channel Openers
Bénédicte Erb, Benoît Rigo*
15
Laboratoire d'Ingénierie Moléculaire, Ecole des Hautes Etudes Industrielles, 13, rue de Toul, 59046 Lille, Cedex
Bernard Pirotte
Laboratoire de Chimie Pharmaceutique, 1, Avenue de l'Hôpital, Centre Hospitalier Universitaire,
B-4000 Liège, Belgique
Daniel Couturier
Laboratoire d'Ingénierie Moléculaire, Université des Sciences et Technologies de Lille,
59655 Villeneuve d'Ascq, France
Received March 5, 2001
Starting from 5-bismethylthiomethylene Meldrum's acid, the synthesis of 5-diaminomethylene Meldrum's
acids and 2-aminoquinolone derivatives, structurally related to potassium channels openers pinacidil and
diazoxide, is described.
J. Heterocyclic Chem., 39, 15 (2002).
Potassium channels represent a very diversified group of
ring (pyridine or halobenzene), the presence of a lipophilic
substituent (in the 3-position of the thiadiazine heterocycles
3 and 4, in the 2-position of the quinazoline heterocycle 5 or
in the N-position of the N-alkyl-N'-aryl-N''-cyanoguanidine
1) and the presence of an electronegative site (iminonitrile,
amide or sulfonamide group). Therefore, we decided to
apply the bioisosteric exchange of the sulfonamide or amide
moiety by the chemically related oxo group as well as the
exchange of a N-cyano group by a Meldrum's moiety
ionic channels [1]. Many hypotensive or myorelaxant
agents such as aprikalim, cromakalim, minoxidil sulfate,
pinacidil (1) or diazoxide (2) have the properties to open
the subtype of potassium channels called ATP-sensitive
potassium channels or K
channels [2]. Using the
ATP
bioisosterism concept [3], the structural elements of com-
pounds 1 and 2 were mixed. Products 3 and 4 resulting
from this concept were found to be powerful inhibitors of
insulin secretion [4]. Some compounds 3, being more
potent on the pancreatic than on the vascular smooth mus-
cle tissue, are tissue selective K
channel openers [4]. In
ATP
a first publication [5] we applied the bioisosteric exchange
of the sulfamide moiety by the chemically related amide
group, and some products 5 possess interesting biological
properties (Scheme 1).
In the chemical structure of compounds 1-5 (Scheme 1),
like in that of other potassium channel openers, it is possible
to observe the presence of an electron deficient aromatic

16
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39
(Scheme 2). We use also a nitro or halobenzene (X = F, Cl,
Br) as an electron deficient aromatic ring, with the aim at
obtaining a compound with a better activity and/or a better
tissue selectivity.
this treatment of diaminomethylene Meldrum's derivatives
7b, 8e, 8f, 10e and 10f only yield quinoline-2,4-diones 12',
13', 14' (Scheme 4). Another way leading to 2-amino-
quinolones 11-14 was to react 2-methylthio-4-quinolones
22, 23 with amines (Table 3, method I). The latter com-
pounds 22, 23 were obtained in good yields by heating
Meldrum's derivatives 17, 19 in polyphosphoric acid
(Scheme 4).
In this paper, we describe the synthesis of diaminometh-
ylene Meldrum's acids 6-10 considered as pinacidil
analogs and the synthesis of 2-amino-4-quinolones 11-14
considered as analogs of compounds 2-5 (Scheme 2).
Antimicrobial properties of 4-oxoquinoline-3-car-
boxylic acids are well known [6a] and those of 3-amino-4-
quinolones have been studied [6b]. However, only few
publications deal with diaminomethylene derivatives of
Meldrum's acid and with 2-amino-4-quinolones. A general
method for the synthesis of diaminomethylene derivatives
of Meldrum's acid (15) consists in starting from compound
16 [7a,b] whose reaction with two different amines can be
conducted sequentially [8]. By using this method, products
6-10 were easily obtained; interestingly, it was not neces-
sary to use a catalyst such as mercuric chloride [8,9,10] to
perform the condensation between compounds 17-21 and
aromatic or aliphatic amines (Scheme 3).
It is to be noticed that cyclization of the Meldrum's deriv-
ative 8d mainly yields the quinolone 11k (Scheme 5). The
polyphosphoric acid cyclizations were usually performed at
130-140 °C by using only 4 grams of dehydrating agent for
about 10 mmoles of compound 6-10. When these ratios of
reagents were used with the dianilino Meldrum's deriva-
tive 6d, product 11d was obtained as the major compound.
However, by using a higher amount of polyphosphoric
acid (10 grams for 10 mmoles of 6d), a 45/55 mixture of
Heating compounds 6-10 in polyphosphoric acid is a
first way to synthesize 2-amino-4-quinolones 11-14, but
variable yields (see Table 3, method H) were obtained, and

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones
17
compounds 11d and 24 was obtained (Scheme 6). This result
seems to indicate that, at the low temperature utilized for these
reactions in polyphosphoric acid, other intermediates than imi-
doylketenes (25) or methyleneketenes (26) [11] could explain
the ring closure reactions (Scheme 6). In analog cyclizations
giving 22 or 22', performed in diphenyl ether, compound 17'
was thought to gives intermediates 25' at 150 °C [9], and com-
pound 17 was thought to yield 25'' at 220 °C [13].
polybromination of Meldrum's derivative 17 occurred. A
selective bromination of aryl amines can be realized by
using N-bromosuccinimide [14-16]; by using this reagent,
polybromination of 17 was still observed at room tempera-
ture, but by working at -40 °C, only compound 18 was
obtained (Scheme 8). On the other hand, quinolone 22
reacted with one equivalent of bromine to give 86 % of
pure product 27. A second equivalent of bromine can then
oxidize the thioether group [17], giving sulfoxide 28
(Scheme 8). In the quinazolinone series, bromine oxidation
of compound 29 yielded the hydrolyzed product 30, with-
out isolation of sulfoxide 31 [5] (Scheme 8).
The reaction of carbon disulfide with Meldrum's acid 15
yields compound 16. As an alternate way to this synthesis
we have checked the reaction of heterocycle 15 with other
reagents: condensation of Meldrum's acid with dicyclo-
Some reactions performed in the hydrazine/hydrazide
series are described in Scheme 7. These products were
synthesized in order to extend the structure of the com-
pounds submitted to biological investigation. It is to be
noticed that good yields without side reaction were
obtained during the condensation of aryl hydrazides with
Meldrum's acid 17.
We have submitted compounds 17 and 22 to the action of
bromine in water or in acetic acid in order to test their reac-
tivity. In these conditions, whatever the temperature, a
hexylcarbodiimide has been described [18] and its reaction
with iminoethers is well documented. Starting from urea
32, we synthesized the corresponding carbodiimide 33 fol-
lowing the method of Apple [19], and isourea 34 was
obtained [20,21] by using triethyloxonium fluoroborate
[22,23]. Whatever the conditions, a reaction between com-
pounds 33 or 34 and Meldrum's acid was never observed. It
is also known that Meldrum's acid reacts with isocyanates
[24] or acylisothiocyanates [25], and that malonic deriva-
tives, instead of Meldrum's acid, react with isothiocyanates

18
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones
19
[26,27]. Condensation of Meldrum's acid with phenyl or
chlorophenyl isothiocyanates was then performed giving
compounds 17 and 19 in medium yield (Scheme 9).
A very important feature of the potassium channel open-
ers 2, 3 and 4 shown in Scheme 1, is the presence of the
NH group in the 4 position of the thiadiazine ring. Thus,
the ultra-violet spectrum of the butylamino compound 11a
was compared to the spectrum of its N-methyl analog 35.
The strong analogy between the two spectra (Figure1)
seems to indicate that, in methanol solution, quinolone 11a
mainly exists as a 1H-quinoline-4-one tautomer 11a rather
than as the 4-quinolinol tautomer 11a' (see Figure 1) [28].
Compound 35 was prepared in the way described in
Scheme 10.

20
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39
Figure 1. Ultra-violet Spectra of Butylamino Quinoles 11a and 35.
Table 1 (continued)
C
Table 1
Elemental Analyses of Synthesized Compounds, % Calcd./Found
N°
Formula
H
N
7d
C
C
C
C
C
C
C
C
C
C
C
H
BrN O
2 4
54.69
4.11
4.23
4.44
4.43
4.99
4.99
6.00
6.09
6.62
6.51
5.84
5.97
4.60
4.65
4.95
4.91
5.47
5.51
6.29
6.63
6.91
6.94
6.71
6.54
6.50
6.80
5.54
5.51
7.94
8.05
7.36
7.25
11.06
11.11
7.51
7.49
7.24
7.38
6.08
5.88
8.33
8.39
7.69
7.93
N°
6a
6c
6d
6e
6f
Formula
C
H
N
19 17
54.91
55.70
55.06
54.66
54.41
57.87
58.05
59.92
59.80
56.92
56.34
61.21
61.79
62.10
62.00
59.94
60.06
60.70
60.64
62.62
62.61
7e
7f
H
BrN O [a]
C
C
C
C
C
C
C
C
C
C
H
N O
64.13
64.01
62.59
62.51
67.45
67.72
68.17
68.46
64.78
65.22
58.59
58.72
57.77
57.86
51.40
50.72
53.66
53.85
50.95
51.04
6.97
7.02
6.71
6.95
5.36
5.35
5.72
5.82
6.15
6.17
5.34
5.43
4.36
4.44
5.33
5.31
5.92
5.78
5.23
5.30
8.80
8.78
12.17
12.36
8.28
8.07
7.95
7.85
6.57
6.55
8.91
8.88
10.10
10.13
7.05
7.04
6.59
6.55
9.90
9.71
20 19
2
4
6
17 22
2
4
4
4
4
H
BrN O
H
N O
23 25
2
18 23
3
8a
8b
8c
8d
8e
8f
H
ClN O
H
N O
17 21
2
4
4
19 18
2
H
ClN O
H
N O
19 25
2
20 20
2
H
ClN O [a]
3 4
H
N O [a]
18 22
23 26
2
6
8
H
ClN O [a]
6g
6h
7a
7b
7c
H
N O
19 17
2
4
4
6
23 25
3
H
ClN O
H
ClN O
3 5
20 19
2
20 18
H
ClN O
H
BrN O [a]
23 25
2
17 21
2
4
4
4
9a
9b
H
FN O
H
BrN O
17 21
2
4
4
19 25
2
H
FN O
H
BrN O
19 25
2
18 22
3

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones
21
Table 1 (continued)
Table 1 (continued)
N°
Formula
C
H
N
N°
Formula
C
H
N
9c
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
H
FN O [a]
59.50
59.01
64.04
64.31
64.86
65.04
62.15
62.01
56.19
56.30
58.30
58.17
55.38
55.54
59.53
59.79
60.45
60.20
58.59
58.35
69.11
68.99
76.25
75.81
76.78
76.82
70.35
69.52
58.91
59.12
53.46
53.60
6.10
6.13
4.81
4.91
5.17
5.20
5.67
5.76
5.83
5.92
6.44
6.50
5.68
5.67
4.47
4.41
4.82
4.80
5.34
5.30
7.04
7.17
5.12
5.91
5.64
5.79
6.21
7.20
5.46
5.72
5.98
5.71
11.56
11.33
7.86
7.89
7.56
7.56
6.30
6.40
11.56
11.50
10.74
10.68
14.35
14.44
10.96
10.84
10.57
10.42
8.91
11j
C
C
C
C
C
C
C
C
C
C
C
C
C
C
H
N O
66.96
66.68
66.55
66.87
49.86
50.43
52.19
52.28
56.59
56.08
58.10
58.57
60.54
60.79
55.91
55.92
58.33
57.96
70.84
71.22
44.46
44.06
41.97
41.59
64.50
64.60
73.01
72.67
6.09
6.43
4.10
3.83
5.47
5.33
5.01
5.34
4.75
5.21
6.38
6.34
5.81
5.62
6.14
6.17
5.59
5.21
4.09
4.07
2.98
3.01
2.82
3.30
5.03
4.94
7.88
7.99
19.52
19.52
10.35
10.55
8.94
18 22
3
4
4
4
6
12 13
3
9d
H
FN O
11k
12a
12c
12f
13a
13c
14a
14c
24
H
ClN O
19 17
2
15 11
2
9e
H
FN O
H
BrN O, H O [a]
20 19
2
13 15
2
2
9.05
9f
H
FN O
H
BrN O
13.04
12.84
6.95
23 25
2
14 16
3
10a
10b
10c
10d
10e
10f
11c
11d
11e
11f
11g
11i
H
N O
H
BrN O [a]
2 3
17 21
3
6
6
6
6
6
8
19 19
6.82
H
N O
H
ClN O, H O [a]
10.42
10.52
15.13
14.77
15.04
14.64
19.43
19.18
10.33
10.27
5.18
5.06
4.89
4.76
10.74
10.69
12.16
12.55
19 25
3
13 15
2
2
H
N O
H
ClN O
18 22
4
14 16
3
H
N O
H
N O , H O
19 17
3
13 15
3
3
3
2
H
N O
H
N O
20 19
3
14 16
4
H
N O
H
N O , 0.5 H O
2 2 2
23 25
3
16 10
8.73
H
N O
17.27
17.26
11.86
11.52
11.19
11.10
8.64
27
H BrNOS
14 17
3
10
10
8
H
N O [a]
28
H BrNO S [a]
15 12
2
8
2
H
N O
32
H
ClN O
16 14
2
14 13
2
H
N O [a]
35
H
N O
19 20
2 3
14 18
2
8.47
H
N O , H O
10.85
11.00
20.78
20.55
19 19
3
5
2
[a] Due to purification difficulties caused by a lack of solubility, we were
not able to obtain a good elemental analysis for this compound; the nmr
spectra are however consistent with the structure proposed.
C H N O, 1.5H O
9
9
3
2
Table 2
Yields and Physical Properties of Meldrum’s Derivatives
1
2
-1
N°
X
R R N
Method
Temperature
(time, hours)
Yields
%
MP °C
IR (KBr) ν cm
6a
6c
6d
6e
6f
H
H
n-BuNH
A
C
D
D
D
E
60 (4)
60 (5)
60 (7)
60 (5)
60 (5)
78 (10)
78 (10)
60 (12)
60 (12)
60 (8)
60 (16)
60 (8)
93
94
82
67
92
72
77
91
84
98
80
100
161
(ether)
195
(acetone)
155
(methyl alcohol)
121-123
(methyl alcohol)
105
(methyl alcohol)
208
(methyl alcohol)
(210)
(methyl alcohol)
88-90
(ethyl alcohol)
120-121
(ethyl alcohol)
195-197
(acetone)
143-145
3100, 1650, 1590, 1500, 1470
3100, 1705, 1650, 1605, 1510, 1495
3120, 1635, 1580, 1505, 1450
1-methyl
piperazinyl
PhNH
H
H
PhCH NH
3650, 3080, 1670, 1635, 1590, 1500,
1450
3400, 1655, 1635, 1595, 1590, 1540,
1515, 1450
3500, 3250, 1695, 1680, 1645, 1620,
1590, 1530, 1495, 1450
3450, 3250, 1690, 1640, 1595, 1550,
1520, 1485
2
H
3,4-(MeO) Ph-
2
CH CH NH
2
2
6g
6h
7a
7b
7c
7d
7e
H
3,4,5-(MeO) Ph-
CONHNH
p-ClPh-
CONHNH
n-BuNH
3
H
E
Br
Br
Br
Br
Br
A
B
C
D
D
3270, 1675, 1635, 1580, 1545, 1490
t-BuCHMeNH
3300, 1650, 1620, 1575, 1530, 1490,
1455
1700, 1645, 1630, 1600, 1565, 1485,
1440
1-methyl
piperazinyl
PhNH
1650, 1600, 1575, 1520, 1490, 1450
(ethyl alcohol)
175-177
(ethyl alcohol)
PhCH NH
3280, 1660, 1630, 1590, 1570, 1520,
1485, 1450
2

22
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39
Table 2 (continued)
1
2
-1
N°
X
R R N
Method
Temperature Yields
(time, hours)
MP °C
IR (KBr) ν cm
%
7f
Br
Cl
Cl
Cl
Cl
Cl
Cl
F
3,4-(MeO) Ph-
D
A
B
C
D
D
D
A
B
C
D
D
D
A
B
C
D
D
D
60 (12)
92
72
114-117
(ethyl alcohol)
99
(ether)
116
(ether)
193
(ether)
151
(methyl alcohol)
152-156
(methyl alcohol)
100-103
(methyl alcohol)
83-85
(ether)
127-128
(ethyl alcohol)
190-192
(acetone)
135-136
(ethyl alcohol)
148-149
(ethyl alcohol)
103-104
(ethyl alcohol)
116
(ethyl alcohol)
146-147
(ethyl alcohol)
>200
(methyl alcohol)
152
(ethyl alcohol)
150
(ethyl alcohol)
131-132
(ethyl alcohol)
118 (ether)
(119-121 [7a,b])
148 (methyl alcohol)
(153 [8])
128-130(methyl alcohol) 3300, 1720, 1650, 1590, 1550, 1495
(143 [8])
137 (methyl alcohol)
(143 [8])
3250, 1650, 1630, 1575, 1540, 1520,
1490, 1470
3095, 1675, 1645, 1600, 1590
2
CH CH NH
2
2
8a
8b
8c
n-BuNH
60 (5)
60 (12)
60 (5)
60 (7)
60 (6)
60 (6)
60 (12)
60 (8)
60 (48)
60 (48)
60 (8)
60 (8)
60 (8)
60 (8)
60 (8)
60 (8)
60 (8)
60 (8)
t-BuCHMeNH
53
3280, 1665, 1650, 1595, 1575, 1535,
1495, 1460
3550, 2950, 1690, 1645, 1610, 1570,
1495
3500, 3100, 1670, 1620, 1590, 1490,
1450
1670, 1630, 1590, 1575, 1490, 1450
1-methyl
piperazinyl
PhNH
82
8d
8e
65
PhCH NH
87
2
8f
3,4-(MeO) Ph-
75
3500, 3150, 1665, 1635, 1595, 1585,
1495
3275, 1660, 1630, 1600, 1540, 1510,
1465
3300, 1670, 1640, 1600, 1550, 1510,
1470
3480, 1700, 1630, 1610, 1575, 1510,
1460
3280, 1670, 1640, 1600, 1590, 1525,
1505, 1450
3280, 1655, 1635, 1605, 1585, 1535,
1510, 1450
3300, 1675, 1645, 1605, 1590, 1555,
1510, 1465
3280, 1675, 1640, 1605, 1595, 1540,
1515, 1470
2
CH CH NH
2
2
9a
9b
9c
n-BuNH
81
F
t-BuCHMeNH
72
F
1-methyl
piperazinyl
PhNH
87
9d
9e
F
68
F
PhCH NH
100
96
2
9f
F
3,4-(MeO) Ph-
2
CH CH NH
2
2
10a
10b
10c
10d
10e
10f
16
17
18
19
20
21
NO
NO
NO
NO
NO
NO
n-BuNH
87
2
2
2
2
2
2
t-BuCHMeNH
80
3280, 1655, 1645, 1605, 1595, 1540,
1515, 1460
1700, 1640, 1615, 1595, 1575, 1520,
1490, 1440
1-methyl
piperazinyl
PhNH
61
88
1670, 1635, 1605, 1590, 1520, 1450
PhCH NH
100
100
33
3300, 1655, 1635, 1605, 1595, 1520,
1495, 1455, 1445
3250, 1655, 1635, 1605, 1595, 1515,
1455
2
3,4-(MeO) Ph-
2
CH CH NH
2
2
3010, 1730, 1680, 1280
H
Br
Cl
F
G
G
55
85
88
3200, 3010, 1710, 1670, 1280, 1210
60 (1)
60 (1)
F
G
G
54
85
93
3500, 3100, 1715, 1660
60 (1.5)
60 (0.5)
F
148-152
(methyl alcohol)
128-129
3200, 3160, 1715, 1660, 1600, 1550,
1505, 1435
1710, 1660, 1610, 1580, 1545, 1510
NO
G
60 (12)
70
2
(methyl alcohol)
The structures of the new products were established by
elemental analysis and spectral data. Due to purification
difficulties caused by a lack of solubility, we were not able
to obtain a good elemental analysis for some compounds;
the nmr spectra were however consistent with the struc-
tures proposed. Preliminary biological results indicate that
some of the synthesized compounds act on pancreatic as
well as on the vascular smooth muscle tissue and appear to
adopt, at least in part, the pharmacological profile of potas-
sium channel openers (data not shown). However, the
exact mechanism of action remains to be elucidated.
EXPERIMENTAL
Melting points were measured on an 'Electrothermal' apparatus
and are uncorrected. The ir spectra were recorded on a 'Perkin-

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones
23
Table 3
Yields and Physical Properties of 1,4-Dihydro-4-quinolones
1
2
-1
N°
X
R R N
Method Yields % MP °C
IR (KBr) ν cm
11a
11c
11d
11e
11f
11g
11i
11j
11k
12a
12c
12f
13a
13c
14a
14b
14c
22
H
H
H
H
H
H
H
H
H
Br
Br
Br
Cl
Cl
NO
NO
NO
H
Cl
H
H
H
H
n-BuNH
1-methylpiperazinyl
PhNH
H
I
H
I
80
55
51
62
80
76
65
100
25
60
40
50
63
20
20
9
221 (189 [29])
273
> 310
248
236
274
224
254
3270, 3100, 1670, 1660, 1615, 1515, 1460
3450, 1635, 1595, 1540, 1500
3080, 1655, 1600, 1500, 1450
3250, 3200, 1650, 1600, 1500, 1460
3275, 3100, 1670, 1640, 1610, 1510, 1455
3150, 1675, 1640, 1620, 1590, 1520, 1495, 1470
3240, 1660, 1625, 1610, 1500, 1460
3100, 1625, 1595, 1580, 1565, 1495, 1475, 1460
3250, 3200, 1640, 1605, 1500, 1460
3250, 1660, 1620, 1530, 1470
PhCH NH
2
3,4-(MeO) PhCH CH NH
3,4,5-(MeO) PhCONHNH
H
2
2
2
3
H NNH
I
2
Me C=NNH
2
4-ClPh
n-BuNH
1-methylpiperazinyl
3,4-(MeO) PhCH CH NH
n-BuNH
1-methylpiperazinyl
n-BuNH
t-BuCHMeNH
1-methylpiperazinyl
H
H
H
H
H
H
H
H
H
J
> 320
280-284
308-310
230-235
250-255
280-285
> 310
> 310
> 310
225 (222 [8], 225 [10])
259-260 (257 [8])
>300
3225, 1620, 1580, 1540, 1480
3320, 1665, 1620, 1610, 1540, 1480
3300, 3180, 1660, 1590, 1520, 1460
3250, 3200, 1640, 1590, 1550, 1470
3275, 1650, 1620, 1540, 1460
3300, 1660, 1620, 1550, 1460
3275, 1640, 1620, 1560, 1480
3280, 1640, 1580, 1500, 1460
3280, 1640, 1575, 1530, 1490, 1465
3060, 1640, 1620, 1580
3250, 1620, 1600, 1575, 1540, 1490
3230, 1640, 1620, 1575, 1540, 1490
3280, 1650, 1620, 1580, 1560
2
2
2
2
2
2
16
78
80
51
86
95
23
24
27
28
J
H
249
247
35
n-BuNH (N -Me)
step 1:20 155
step 2:60
1
step 3:50
Table
4
NMR Spectra of Meldrum’s Derivatives
1
13
N°
H NMR δ ppm (deuteriochloroform)
C NMR δ ppm (deuteriochloroform)
6a
0.81 (t, J = 6.5 Hz, 3H), 1.11-1.36 (m, 2H), 1.36-1.57 (m, 2H), 1.73
(s, 6H, H ), 2.77 (q, J = 6.5 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H, H ),
13.5, 19.7, 26.3 (C ), 31.4, 45.5, 74.7 (C ), 102.6 (C ), 124.8 (C ),
6,7 5 2 11
126.6 (C ), 129.5 (C ), 138.2 (C ), 161.8 (C ), 167.0 (C )
7,8
11
13
12
10
9
4,6
7.23-7.31 (m, 1H, H ), 7.33-7.46 (m, 2H, H ), 10.09 (bs, 1H, NH),
13
12
11.44 (bs, 1H, NH)
1.72 (s, 6H, H ), 2.27 (s, 3H), 2.42 (t, J = 4.9 Hz, 4H), 3.32 (t, J =
6c
26.5 (C ), 45.9, 50.4, 53.2, 76.2 (C ), 102.4 (C ), 124.2 (C ), 126.8
7,8 5 2 11
7,8
4.9 Hz), 7.10 (d, J = 7.3 Hz, 2H, H ), 7.20-7.30 (m, 1H, H ), 7.33-
(C ), 129.8 (C ), 139.2 (C ), 163.8 (C ), 165.0 (C )
11
13
13 12 10 9 4,6
7.44 (m, 2H, H ), 9.52 (bs, 1H, NH)
12
6d
6e
1.78 (s, 6H, H ), 6.80-7.06 (ArH), 11.87 (bs, 2H, NH)
26.4 (C ), 75.2 (C ), 103.1 (C ), 124.0 (C ), 125.9 (C ), 128.7
7,8 5 2 11 13
7,8
(C ), 136.4 (C ), 159.0 (C ), 167.1 (C )
12
10
9
4,6
1.71, 1.73 (2s, 6H, H ), 4.01 (d, J = 5.5 Hz, 1H, NCH ), 4.56 (d, J =
26.2 and 26.3 (C ), 48.4 and 49.3 (N-CH ), 74.5 and 75.0 (C ),
7,8
2
7,8 2 5
6.2 Hz, 1H, N-CH ), 6.98-7.08 (m, 1H), 7.11-7.45 (m, 9H, H , H
,
102.4 and 102.8 (C ), 125.1 (C ), 126.5 and 127.2 (ArH), 126.9
2 11
2
11
12
ArH), 10.52 (bs, 1H, NH-CH ), 11.56 (bs, 1H, NH-Ar)
(C ), 128.1 and 128.2 (ArH), 128.9 and 129.2 (ArH), 129.5 (C ),
2
1
3
1
2
136.3 (C ), 137.2 and 137.8 (Ar), 161.9 and 164.3 (C ), 166.9 (C )
4,6
10
9
6f
1.61 (s, 1H, NH-Ar), 1.71 (s, 6H, H ), 2.69 (t, J = 6.6 Hz, 2H, 3.05
26.3 (C ), 35.5, 47.4, 56.0, 74.8 (C ), 102.7 (C ), 111.4, 112.0,
7,8
6,7 5 2
(q, J = 6.1 Hz, 2H), 3.84 (s, 6H), 6.55 (bs, 1H), 6.60 (d, J = 8 Hz, 1H),
120.9, 124.8 (C ), 126.7 (C ), 129.6 (C ), 130.1, 138.3 (C ),
11 13 12 10
6.77 (d, J = 8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H, H ), 7.21-7.32 (m, 1H, 148.1, 149.1, 162.0 (C ), 166.9 (C )
11
9
4,6
H
), 7.34-7.46 (m, 2H, H ), 10.18 (bs, 1H, NH-CH )
13
12 2
6g
6h
7a
7b
1.74 (s, 6H, H ), 3.74 (s, 6H), 3.84 (s, 3H), 6.35 (s, 2H), 7.18-7.42
26.3 (C ), 56.3, 60.9, 74.2 (C ), 103.5 (C ), 104.2, 124.7 (C ),
7,8 5 2 11
7,8
(m, 5H, H , H , H ), 3.27/7.73/11.37/11.77 (bs, 3H, NH)
125.9 (C ), 127.3, 129.7 (C ), 137.6 (C ), 141.6, 153.1, 163
11
12
13
13 12 10
(C ), 165.2, 166.7 (C
)
9
4,6
1.73 (s, 6H, H ), 7.03 (d, J = 8.3 Hz, 2H), 7.17-7.31 (m, 5H, H , H
, 26.3 (C ), 74.1 (C ), 103.5 (C ), 124.8 (C ), 127.5 (C ), 128.5
7,8
11
12
7,8 5 2 11 13
H
), 7.35 (d, J = 8.3 Hz, 2H), 3.26/7.71/11.42/11.79 (bs, 3H, NH)
(C ), 128.9, 129.0, 129.9, 137.4 (C ), 139.1, 163.0 (C ), 164.4,
13
12
10
9
166.7 (C
)
4,6
0.84 (t, J = 7.3 Hz, 3H), 1.17-1.39 (m, 2H), 1.39-1.60 (m, 2H), 1.72 (s, 13.5, 19.7, 26.2 (C ), 31.4, 45.8, 74.8 (C ), 102.7 (C ), 119.7 (C13),
6,7
5
2
6H, H ), 2.73-2.85 (m, 2H), 7.06 (dt, J = 8.7, 2.5 Hz, 2H, H ), 7.51
126.1 (C ), 132.6 (C ), 137.4 (C ), 162.0 (C ), 166.9 (C )
7,8
11
11 12 10 9 4,6
(dt, J = 8.7, 2.5 Hz, 2H, H ), 10.11 (bs, 1H, NH), 11.40 (bs, 1H, NH)
12
0.83 (s, 9H), 0.92 (d, J = 6.6 Hz, 3H), 1.73 (s, 6H, H ), 2.92-3.11 (m, 14.6, 25.9, 26.2 (C ), 35.8, 58.6, 74.8 (C ), 102.7 (C ), 120.3 (C ),
7,8
7,8
5
2
13
1H), 7.10 (dt, J = 8.7, 2.5 Hz, 2H, H ), 7.54 (dt, J = 8.7, 2.5 Hz, 2H,
126.3 (C ), 132.8 (C ), 137.9 (C ), 162.2 (C ), 167 (C
)
11
11
12
10
9
4,6
H
), 10.13 (d, J = 9.7 Hz, 1H NH-CH, 2.75/11.41 (2 bs, 1H, NH-Ar)
12

24
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39
Table 4 (continued)
1
13
N°
7c
7d
7e
H NMR δ ppm (deuteriochloroform)
C NMR δ ppm (deuteriochloroform)
1.63 (s, 6H, H ), 2.39 (bs, 3H), 2.56 (bs, 4H), 3.45 (bs, 4H), 6.96 (d,
J = 8.4 Hz, 2H, H ), 7.42 (d, J = 8.4 Hz, 2H, H ), 9.71 (bs, 1H, NH)
1.78 (s, 6H, H ), 2.70 (bs, 1H, NH), 6.78 (dt, J = 8.7, 2.5 Hz, 2H, H ), 26.4 (C ), 75.3 (C ), 103.2 (C ), 119.1 (C ), 124.0, 125.4 (C ),
6.82-6.91 (m, 2H), 6.92-7.08 (m, 3H), 7.12 (dt, J = 8.7, 2.5 Hz, 2H, H ) 126.9, 128.9, 131.7 (C ), 135.5, 136.1 (C ), 159.1 (C ), 166.9 (C
26.6 (C ), 45.4 (bs), 49.8 (bs), 53.3 (bs), 74.9 (C ), 102.6 (C ), 119.6
(C ), 125.2 (C ), 132.6 (C ), 138.3 (C ), 163.0 (C ), 164.5 (C
7,8
7,8
5
2
)
11
12
13
11
12
10
9
4,6
7,8
11
7,8
5
2
13
11
)
12
12
10
9
4,6
1.73 (s, 6H, H ), 2.86 (bs, 1H, NH), 4.04 (d, J = 5.7 Hz, 2H), 6.98-
26.3 (C ), 49.5, 75.1 (C ), 102.9 (C ), 120.1 (C ), 126.4 (C ),
7,8
7,8 5 2 13 11
7.10 (m, 4H, H , ArH), 7.23-7.35 (m, 3H, ArH), 7.49 (d, J = 8.6 Hz,
127.1, 128.2, 129.0, 132.6 (C ), 135.9, 136.9 (C ), 162.1 (C ),
12 10 9
11
2H, H ), 10.56 (bs, 1H, NH)
166.9 (C )
12
4
7f
1.70 (s, 6H, H ), 2.72 (t, J = 6.8 Hz, 2H), 3.06 (q, J = 6.3 Hz, 2H),
26.2 (C ), 35.4, 47.7, 55.9, 74.9 (C ), 102.7 (C ), 111.4, 111.9,
7,8 5 2
7,8
3.85 (s, 6H), 6.58 (d, J = 2 Hz, 1H), 6.63 (dd, J = 8,2 Hz, 1H), 6.79
119.7, 120.8 (C ), 126.0 (C ), 129.9, 132.6 (C ), 137.3 (C ),
13 11 12 10
(d, J = 8 Hz, 1H), 7.03 (dt, J = 8.7, 2.5 Hz, 2H, H ), 7.52 (dt, J =
148.1, 149.1, 162.0 (C ), 166.7 (C )
9 4,6
11
8.7, 2.5 Hz, 2H, H ), 2.70/10.18/11.38 (3 bs, 2H, NH)
12
8a
8b
0.83 (t, J = 7.1 Hz, 3H), 1.17-1.39 (m, 2H), 1.39-1.58 (m, 2H), 1.72
13.5, 19.7, 26.2 (C ), 31.4, 45.7, 74.7 (C ), 102.8 (C ), 125.8 (C ),
6,7 5 2 11
(s, 6H, H ), 2.72-2.85 (m, 2H), 7.12 (dt, J = 8.7, 2.5 Hz, H ), 7.37
129.6 (C ), 132.0 (C ), 136.8 (C ), 162.0 (C ), 166.9 (C )
7,8
11
12 13 10 9 4,6
(dt, J = 8.7, 2.5 Hz, 2H, H ), 10.40 (bs, 1H, NH), 11.43 (bs, 1H, NH)
12
0.83 (s, 9H), 0.91 (d, J = 6.6 Hz, 3H), 1.73 (s, 6H, H ), 2.92-3.10 (m, 14.6, 25.9, 26.2 (C ), 35.8, 58.6, 74.8 (C ), 102.7 (C ), 126.1 (C ),
7,8
7,8
5
2
11
1H), 7.15 (dt, J = 8.6, 2.4 Hz, 2H, H ), 7.38 (dt, J = 8.6, 2.4 Hz, 2H,
129.9 (C ), 132.6 (C ), 137.4 (C ), 162.3 (C ), 167.0 (C )
11
12 13 10 9 4,6
H
), 10.14 (d, J = 10.1 Hz, 1H, NH-CH), 3.15/11.42 (2 bs, 1H, NH-Ar)
12
8c
1.72 (s, 6H, H ), 2.71 (s, 3H), 3.15 (bs, 4H), 3.49 (bs, 4H), 6.98 (d, J
26.5 (C ), 43.6, 47.4, 52, 75.7 (C ), 103(C ), 124.3 (C ), 130.3
7,9 5 2 11
7,8
= 8.5 Hz, 2H, H ), 7.36 (d, J = 8.5 Hz, 2H, H ), 10.19 (bs, 1H, NH)
(C ), 132.8 (C ), 136.5 (C ), 163.4 (C ), 166.7 (C )
11
12
12 13 10 9 4,6
8d
1.78 (s, 6H, H ), 3.05 (bs, 1H, NH), 6.74-6.91 (m, 2H), 6.80 (dt, J =
26.4 (C ), 75.3 (C ), 103.2 (C ), 124.0, 125.1 (C ), 126.3, 128.7,
7,8 5 2 11
7,8
8.7, 2.4 Hz, 2H, H ), 6.91-7.11 (m, 3H), 6,97 (dt, J = 8.7, 2.4 Hz, 2H, 128.9 (C ), 131.4 (C ), 135.0, 136.1 (C ), 159.1 (C ), 167.0 (C
)
11
12
13
10
9
4,6
H
), 11.84 (bs, 1H, NH)
12
8e
8f
1.73 (s, 6H, H ), 2.98 (bs, 1H, NHAr), 4.03 (d, J = 5.7 Hz, 2H), 6.99- 26.3 (C ), 49.4, 75.1 (C ), 102.9 (C ), 126.1 (C ), 127.1, 128.2,
7,8 7,8 5 2 11
7.07 (m, 2H), 7.09 (dt, J = 8.9, 2.6 Hz, 2H, H ), 7.22-7.31 (m, 3H),
129.0, 129.6 (C ), 132.4 (C ), 135.9 (C ), 136.4 (C ), 162.1 (C ),
12 13 17 10 9
11
7.33 (dt, J = 8.9, 2.6 Hz, 2H, H ), 10.57 (bt, J = 5.7 Hz, 1H, NH-CH ) 166.9 (C )
12
2
4,6
1.70 (s, 6H, H ), 2.72 (t, J = 6.7 Hz, 2H), 3.05 (q, J = 6.2 Hz, 2H),
26.2 (C ), 35.4, 47.7, 55.9, 74.9 (C ), 102.8 (C ), 111.4, 111.9,
7,8 5 2
7,8
3.85 (s, 6H), 6.58 (d, J = 1.9 Hz, 1H), 6.63 (dd, J = 8.1, 1.9 Hz, 1H),
120.8, 125.8 (C ), 129.7 (C ), 129.9, 132.1 (C ), 136.8 (C ),
11 12 13 10
6.79 (d, J = 8.1, 1H), 7.09 (dt, J = 8.8, 2.5 Hz, 2H, H ), 7.37 (dt, J = 8.8, 148.1, 149.1, 162.1 (C ), 166.8 (C )
11
9
4,6
2.5 Hz, 2H, H ), 10.20 (bs, 1H, NH-CH ), 11.42 (bs, 1H, NH-Ar)
12
2
9a
9b
9c
9d
9e
9f
0.83 (t, J = 7.2 Hz, 3H), 1.14-1.37 (m, 2H), 1.37-1.58 (m, 2H), 1.73
13.5, 19.7, 26.2 (C ), 31.4, 45.5, 74.6 (C ), 102.7 (C ), 116.4 (d, J =
7,8 5 2
(s, 6H, H ), 2.69-2.82 (m, 2H), 7.03-7.23 (m, 4H, H
), 10.12
23 Hz, C ), 126.7 (d, J = 8 Hz, C ), 134.2 (d, J = 3 Hz, C ), 161.0
7,8
11,12
12 11 10
(bs, 1H, NH), 11.43 (bs, 1H, NH)
(d, J = 246 Hz, C ), 162.0 (C ), 167.0 (C )
13 9 4,6
0.82 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H), 1.72 (s, 6H, H ) , 2.88-3.05
14.7, 25.9, 26.2 (C ), 35.6, 58.3, 74.6 (C ), 102.6 (C ), 116.6 (d, J =
7,8
7,8 5 2
(m, 1H), 7.05-7.26 (m, 4H, H , H ), 10.14 (d, J = 10.1 Hz, 1H,
24 Hz, C ), 126.9 (d, J = 9 Hz, C ), 134.7 (d, J = 3 Hz, C ), 161.3
12 11 10
11
12
NH-CH), 2.90/11.42 (2 bs, 1H, NH-Ar)
1.58 (s, 6H, H ), 2.39 (bs, 3H), 2.57 (bs, 4H), 3.48 (bs, 4H), 6.93-
(d, J = 248 Hz, C ), 162.3 (C ), 167.0 (C )
13 9 4,6
26.5 (C ), 45.4 (bs), 49.3 (bs), 53.3 (bs), 74.5 (C ), 102.5 (C ), 116.3
7,8
7,8
5
2
7.13 (m, 4H, H , H ), 9.72 (bs, 1H, NH)
(d, J = 24 Hz, C ), 125.8 (d, J = 10 Hz, C ), 135.1 (C ), 160.9 (d,
11
12
12 11 10
J = 248 Hz, C ), 163.5 (C ), 164.4 (C )
4,6
13
9
1.79 (s, 6H, H ), 2.76 (bs, 1H, NH), 6.70 (dt, J = 8.6, 2.7 Hz, 2H,
26.4 (C ), 75.2 (C ), 103.1 (C ), 115.5 (d, J = 24 Hz, C ), 124.3,
7,8
7,8 5 2 12
H
), 6.78-6.91 (m, 4H, H , ArH), 6.91-7.10 (m, 3H)
125.9 (d, J = 9 Hz, C ), 126.3, 128.8, 132.5 (d, J = 3 Hz, C ),
11 10
12
11
136.2, 159.4 (C ), 160.4 (d, J = 247 Hz, C ), 167.0 (C )
9
13
4,6
1.73 (s, 6H, H ), 4.01 (d, J = 5.6 Hz, 2H), 6.97-7.18 (m, 6H, H
,
26.2 (C ), 49.2, 74.9 (C ), 102.8 (C ), 116.4 (d, J = 23 Hz, C ),
7,8
11
7,8 5 2 12
H
, ArH), 7.22-7.34 (m, 3H, ArH), 10.56 (bt, J = 5.6 Hz, 1H,
127.0 (d, J = 8 Hz, C ), 127.1, 128.1, 129.0, 133.7 (d, J = 3 Hz, C ),
11 10
12
NH- CH ), 11.53 (bs, NH-Ar)
136.1, 161.2 (d, J = 248 Hz, C ), 162.2 (C ), 166.9 (C )
2
13 9 4,6
1.70 (s, 6H, H ), 2.70 (t, J = 6.7 Hz, 2H), 3.02 (q, J = 6.3 Hz, 2H),
26.2 (C ), 35.5, 47.4, 55.9, 74.7 (C ), 102.7 (C ), 111.4, 112.0,
7,8 5 2
7,8
3.85 (s, 6H), 6.56 (d, J = 2 Hz, 1H), 6.61 (dd, J = 8.1, 2 Hz, 1H),
116.5, (d, J = 23 Hz, C ), 120.8, 126.7 (d, J = 9 Hz, C11), 130.0,
12
6.78 (d, J = 8.1 Hz, 1H), 7.04-7.22 (m, 4H, H , H ),
134.2 (d, J = 3 Hz, C ), 148.1, 149.1, 161.0 (d, J = 247 Hz, C ),
11
12
10
13
2.68/10.16/11.40 (bs, 2H, NH)
10a 0.86 (t, J = 7.2 Hz, 3H), 1.21-1.43 (m, 2H), 1.47-1.66 (m, 2H), 1.74
(s, 6H, H ), 2.82-2.94 (m, 2H), 7.26 (d, J = 8.9 Hz, 2H, H ), 8.29
162.2 (C ), 166.9 (C )
9 4,6
13.5, 19.7, 26.3 (C ), 31.5, 46.6, 75.7 (C ), 103.2 (C ), 123.0 (C ),
7,8
5
2
11
125.3 (C ) , 144.3 (C ), 144.9 (C ), 162.2 (C ), 166.8 (C )
7,8
11
12
10
13
9
4,6
(dt, J = 8.9, 2.5 Hz, H ), 10.34 (bs, 1H, NH), 11.66 (bs, 1H, NH)
12
10b 0.87 (s, 9H), 1.02 (d, J = 6.6 Hz, 3H), 1.74 (s, 6H, H ), 2.93-3.13
14.3, 26.0, 26.3 (C ), 36.3, 59.8, 75.7 (C ), 103.1 (C ), 123.3 (C ),
7,8 5 2 11
7,8
(m, 1H), 7.33 (dt, J = 9, 2.5 Hz, 2H, H ), 8.30 (dt, J = 9.0, 2.5 Hz,
125.1 (C ), 145.0 (C ), 145.3 (C ), 162.6 (C ), 166.9 (C )
11
12 10 13 9 4,6
2H, H ), 10.30 (d, J = 10.2 Hz, 1H, NH-CH), 2.88/11.63 (2 bs,
12
1H, NH Ar)
10c 1.70 (s, 6H, H ), 2.62 (s, 3H), 3.02 (bs, 4H), 3.59 (bs, 4H), 7.18
26.8 (C ), 43.8, 47.2, 52.4, 75.5 (C ), 103.2 (C ), 122.4 (C ),
7,8
7,8
5
2
11
(d, J = 8.7 Hz, 2H, H ), 8.23 (d, J = 8.7 Hz, 2H, H
)
125.4 (C ), 144.5 (C ), 145.3 (C ), 163.3 (C ), 164.2 (C )
11
12
12 10 13 9 4,6
10d 1.79 (s, 6H, H ), 6.89-7.14 (m, 7H, H , ArH), 7.90 (dt, J = 9.1, 2.5
26.5 (C ), 76.1 (C ), 103.6 (C ), 123.3, 123.6 (C ), 124.3 (C ),
7,8 5 2 11 12
7,8
11
Hz, 2H, H ), 2.75/12.05/12.14 (3 bs, 2H, NH)
126.8, 129.4, 136.2, 142.3 (C ), 144.6 (C ), 159.2 (C ), 167 (C
)
12
10
13
2
4,6
10e 1.74 (s, 6H, H ), 4.11 (d, J = 5.6 Hz, 2H), 7.02-7.11 (m, 2H), 7.27
26.3 (C ), 50.2, 75.9 (C ), 103.3 (C ), 123.4 (C ), 125.3 (C ),
7,8
7,8 5 2 11 12
(dt, J = 9.1, 2.5 Hz, 2H, H ), 7.26-7.34 (m, 3H), 8.27 (dt, J = 9.1,
127.2, 128.5, 129.1, 135.4, 144.0 (C ), 145.1 (C ), 162.3 (C ),
10 13 9
11
2.5 Hz, 2H, H ), 2.69/10.74/11.74 (3 bs, 2H, NH)
166.7 (C )
12
4,6

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones
25
Table 4 (continued)
1
13
N°
H NMR δ ppm (deuteriochloroform)
C NMR δ ppm (deuteriochloroform)
10f 1.71 (s, 6H, H ), 2.79 (t, J = 6.5 Hz, 2H), 3.12 (q, J = 5.8 Hz, 2H),
26.3 (C ), 35.6 (C ), 48.7, 55.9, 75.7 (C ), 103.3 (C ), 111.6,
7,8 17 5 2
7,8
3.86 (s, 6H), 6.63-6.71 (m, 2H), 6.81 (s, 6H), 6.63-6.71 (m, 2H),
112.1, 120.9, 122.9 (C ), 125.4 (C ), 129.5, 144.2 (C ), 144.9
11 12 10
6.81 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 9 Hz, 2H, H ), 8.28 (d, J =
(C ), 148.3, 149.2, 162.3 (C ), 166.8 (C )
13 9 4,6
11
9 Hz, 2H, H ), 2.81/10.37/11.60 (bs, 2H, NH)
12
16
17
1.75 (s, 6H, H ), 2.66 (s, 6H)
21.5, 26.9 (C ), 103.2 (C ), 103.4 (C ), 160.2 (C ), 192.9 (C )
7,8 5 2 4,6 9
7,8
1.77 (s, 6H, H ), 1.80 (s, 1H, NH), 2.28 (s, 3H), 7.28-7.52 (m, 5H,
19.0, 26.5 (C ), 86.5 (C ), 103.3 (C ), 125.5 (C11), 128.2 (C ),
7,8
7,8 5 2 13
H
, H , H
)
129.7 (C ), 137.5 (C ), 164.2 (C ), 178.3 (C )
12 10 9 4,6
11
12
13
18
19
20
1.77 (s, 6H, H ), 1.78/3.25 (bs, 1H, NH), 2.33 (s, 3H), 7.21 (d, J =
19.1, 26.4 (C ), 86.8 (C ), 103.4 (C ), 121.9 (C ), 127.1 (C ),
7,8
7,8
5
2
13
11
8.4 Hz, 2H, H ), 7.59 (d, J = 8.4 Hz, H
)
133.8 (C ), 136.4 (C ), 164.1 (C ), 175.1 (C
)
11
12
12
10
9
4,6
1.61 (s, 1H, NH), 1.77 (s, 6H, H ), 2.32 (s, 3H), 7.27 (dt, J = 8.7,
7,8
2.4 Hz, H ), 7.43 (dt, J = 8.7, 2.4 Hz, 2H, H
)
11
12
1.77 (s, 6H, H ), 1.78/3.25 (bs, 1H, NH), 2.33 (s, 3H), 7.17-
18.9, 25.4 (C ), 86.3 (C ), 103.3 (C ), 116.6 (d, J = 23 Hz, C ),
7,8 5 2 12
7,8
7.27 (m, 2H, H ), 7.49-7.63 (m, 2H, H
)
127.5 (d, J = 9 Hz, C ), 133.3 (d, J = 3 Hz, C ) , 161.9 (d, J = 248
11
12
11 10
Hz, C ), 164.1 (C ), 175.7 (C )
4,6
13
9
21
36
1.78/3.48 (bs, 1H, NH), 1.79 (s, 6H, H ), 2.34 (s, 3H), 7.54 (d, J =
7,8
8.9 Hz, 2H, H ), 8.34 (d, J = 8.9 Hz, 2H, H
)
11
12
1.73 (bs, 6H), 2.55 (s, 3H), 3.65 (s, 3H), 7.36 (dd, J = 7.9 Hz, 2H),
7.41-7.52 (m, 3H)
Table 5
NMR Spectra of 1,4-Dihydro-4-quinolones
1
13
N°
Solvant
H NMR δ ppm
C NMR δ ppm
11a
deuteriochloroform 0.95 (t, J = 7.3 Hz, 3H), 1.32-1.55 (m, 2H), 1.55-1.78 (m,
13.3, 19.9, 30.4, 42.5, 91.1 (C ), 116.3 (C ), 117 (C ),
3
4a
8
and 5%
2H), 3.30 (t, J = 7.2 Hz, 2H), 6.28 (s, 1H, H ), 7.42 (d, J
3
trifluoroacetic acid
= 8.1 Hz, 1H, H ), 7.44 (t, J = 7.8 Hz, 1H, H ), 7.71 (t, J = 7.8
124.2 (C ), 125.8 (C ), 134.2 (C ), 137.1 (C ), 154.5
5 6 7 8a
8
6
Hz, 1H, H ), 8.05 (d, J = 8.1 Hz, 1H, H ), 9.89 (bs, 1H, NH)
(C ), 165.9 (C )
7
5
2 4
11c
methanol-d
2.36 (s, 3H), 2.61 (bt, J = 5.1 Hz, 4H), 2.71 (bs, 1H, NH), 3.53
(bt, J = 5.1 Hz, 4H), 5.82 (s, 1H, H ), 7.28 (dt, J = 6.9, 2 Hz,
46.1, 47.7, 55.4, 93.4 (C ), 118.4 (C ), 123.8 (C ), 124.3
3 8 4a
4
(C ), 125.7 (C ), 133 (C ), 140.7 (C ), 157 (C ),
3
6
5
7
8a
2
1H, H ), 7.49-7.64 (m, 2H, H , H ), 8.09 (d, J = 8.2 Hz, 1H, H )
179.7 (C )
6
7
8
5
4
11d deuteriochloroform 6.60 (s, 1H, H ), 7.31-7.45 (m, 3H, C , ArH), 7.45-7.64 (m,
92.4 (C ), 117 (C ), 117.3 (C ), 124.5 (C ), 125.8 (Ar),
3 4a 8 5
3
8
and 5%
4H, H , ArH), 7.76 (t, J = 7.9 Hz, 1H, H ), 8.17 (d, J = 8.2 Hz,
126.4 (C ), 129.6 (Ar), 131.3 (Ar), 133.6 (Ar), 134.4
6
7
6
trifluoroacetic acid
1H, H ), 8.80 (bs, 1H, NH), 8.97 (bs, 1H, NH), 8.97 (bs, 1H, NH) (C ), 136.6 (C ), 153.7 (C ), 167 (C )
5
7
8
a
2
4
11e
11f
deuteriochloroform 4.55 (s, 2H), 6.33 (s, 1H, H ), 7.25-7.48 (m, 6H, H , ArH),
46.6, 91.2 (C ), 116.3 (C ), 117.1 (C ), 124.2 (C ),
3 4a 8 5
3
8
and 5%
7.43 (t, J = 7.9 Hz, 1H, H ), 7.70 (dt, J = 7.9, 1.2 Hz, 1H,
125.9 (C ), 127.3 (Ar), 129.2 (Ar), 129.8 (Ar), 134.3
6
6
trifluoroacetic acid
H ), 8.06 (d, J = 8.2 Hz, 1H, H ), 10.22 (bs, 1H, NH)
(C ), 134.4 (Ar), 137.1 (C ), 154.7 (C ), 166.4 (C )
7 8a 2 4
7
5
deuteriochloroform 2.94 (t, J = 6.3 Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 3.82 (s,
34.9, 44.6, 56.3, 56.9, 90.3 (C ), 113 (Ar), 113.8 (Ar),
3
and 5%
3H), 3.87 (s, 3H), 6.17 (bs, 1H, H ), 6.84 (s, 3H, ArH), 7.25
116.2 (C ), 116.9 (C ), 122.7 (Ar), 124.2 (C ),
4a 8 5
3
trifluoroacetic acid
(d, J = 8.2 Hz, 1H, H ), 7.43 (t, J = 7.8 Hz, 1H, H ), 7.69 (t,
125.9 (C ), 131.4 (Ar), 134.3 (C ), 137 (C ), 148
8
6
6 7 8a
J = 7.8 Hz, 1H, H ), 8.06 (d, J = 8.2 Hz, 1H, H )
(Ar), 148.6 (Ar), 154.7 (C ), 166.2 (C )
2 4
7
5
11g
deuteriochloroform 3.92 (s, 6H), 3.99 (s, 3H), 6.73 (s, 1H, H ), 7.26 (s, 2H, Ar),
56.4, 61.6, 90.1 (C ), 105.9 (Ar), 117 (C ), 117.9
3
3 8
and 5%
7.46 (t, J = 7.6 Hz, 1H, H ), 7.54 (d, J = 8.7 Hz, 1H, H ),
(C ),124.1 (C ), 124.9 (Ar), 126.8 (C ), 134.8 (C ),
4a 5 6 7
6
8
trifluoroacetic acid
7.74 (t, J = 7.6 Hz, 1H, H ), 7.97 (d, J = 8 Hz, 1H, H ), 9.19
136.7 (C ), 142 (Ar), 153.3 (Ar), 155.3 (C ), 167.6
7
5
8
a
2
(bs, 1H, NH)
5.69 (s, 1H, H ), 7.23 (t, J = 7.6 Hz, 1H, H ), 7.53 (td, J =
(C ), 170.6 (N-CO)
4
11i
11j
dimethyl
sulfoxide-d
87.7 (C ), 117.6 (C ), 120.7 (C ), 122.8 (C ), 123.8
3
7
3 8 4a 6
7.6, 1.5 Hz, 1H, H ), 7.79 (d, J = 7.1 Hz, 1H, H ), 7.98 (dd,
(C ), 131.2 (C ), 138 (C ), 156.4 (C ), 169.9 (C )
5 7 8a 2 4
6
6
8
J = 8.1, 1.5 Hz, 1H, H ), 8.86 (bs, 1H, NH)
5
deuteriochloroform 2 (s, 3H), 2.09 (s, 3H), 6.06 (s, 1H, H ), 7.27 (t, J = 7.4 Hz,
(dimethyl sulfoxide-d ) 17.7, 24.9, 88.9 (C ), 118
6 3
3
1H, H ), 7.57 (t, J = 7.4 Hz, 1H, H ), 7.81 (d, J = 8.1 Hz,
(C ),122.1 (C ), 122.5 (C ), 124.1 (C ), 131 (C ),
6
7
8 4a 6 5 7
1H, H ), 8.02 (d, J = 7.9 Hz, 1H, H ), 10.28 (bs, 1H, NH)
138.6 (C ), 151.7 (C CMe ), 172.6 (C )
8a 2, 2 4
8
5
11k dimethyl
6.23 (s, 1H, H ), 7.21 (td, J = 7.1, 1.8 Hz, 1H, H ), 7.32 (d,
3
7
sulfoxide-d
J = 8.3 Hz, 2H, ArH), 7.45-7.61 (m, 2H, H , H ), 7.75 (d, J =
6 8
6
8.3 Hz, 2H, ArH), 7.96 (d, J = 7.9 Hz, 1H, H )
5
12a deuteriochloroform 0.95 (t, J = 7.1 Hz, 3H), 1.30-1.53 (m, 2H), 1.58-1.78 (m,
and 5%
2H), 3.34 (t, J = 7.2 Hz, 2H), 6.33 (s, 1H, H ), 7.34 (d, J =
3
trifluoroacetic acid
8.8 Hz, 1H, H ), 7.77 (dd, J = 8.8, 1.8 Hz, 1H, H ), 8.17 (d,
8 7
J = 1.8 Hz, H )
5
12c
deuteriochloroform 3.09 (bs, 3H), 3.22-3.54 (m, 2H), 3.71-4.04 (m, 4H), 4.19-
and 5%
4.54 (m, 2H), 6.66 (s, 1H, H ), 7.57 (d, J = 8.9 Hz, 1H, H ),
3
8
trifluoroacetic acid
7.93 (dd, J = 8.9, 2 Hz, 1H, H ), 8.36 (d, J = 2 Hz, 1H, H )
7 5

26
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39
Table 5 (continued)
1
13
N°
Solvant
H NMR δ ppm
C NMR δ ppm
12f
deuteriochloroform 2.95 (t, J = 6.6 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 3.85 (s,
and 5%
3H), 3.89 (s, 3H), 6.16 (s, 1H, H ), 6.89 (m, 3H, Ar), 7.20
3
trifluoroacetic acid
(d, J = 8.8 Hz, 1H, H ), 7.79 (dd, J = 8.8, 2.1 Hz, 1H, H ),
8
7
8.21 (d, J = 2.1 Hz, 1H, H )
5
13a dimethyl
0.89 (t, J = 7.3 Hz, 3H), 1.25-1.43 (m, 2H), 1.43-1.64 (m,
2H), 3.10-3.26 (m, 2H), 5.55 (bs, 1H, H ), 6.99 (bs, 1H,
sulfoxide-d
6
3
NH), 7.47 (bs, 2H, H , H ), 7.84 (bs, 1H, H )
7
8
6
13c
dimethyl
2.35 (s, 3H), 2.59 (m, 4H), 3.55 (m, 4H), 6.05 (bs, 1H, H ),
3
sulfoxide-d
7.45 (dd, J = 8.8, 2.3 Hz, 1H, H ), 7.53 (d, J = 8.8 Hz, 1H,
7
6
H ), 7.87 (d, J = 2.3 Hz, 1H, H )
8
5
14a deuteriochloroform 0.97 (t, J = 7.1 Hz, 3H), 1.32-1.52 (m, 2H), 1.58-1.82 (m,
and 5%
2H), 3.30-3.51 (m, 2H), 6.47 (bs, 1H, H ), 7.68 (d, J = 9.1
3
trifluoroacetic acid
Hz, 1H, H ), 8.51 (dd, J = 9.1, 2.4 Hz, 1H, H ), 8.93 (d, J
8 7
= 2.4 Hz, 1H, H )
5
14b deuteriochloroform 1.0 (s, 9H), 1.30 (d, J = 6.5 Hz, 3H), 3.44-3.67 (m, 1H),
and 5%
6.55 (bs, 1H, H ), 6.98 (bd, J = 10 Hz, 1H, NH), 7.65 (d, J =
3
trifluoroacetic acid
9.3 Hz, 1H, H ), 8.52 (dd, J = 9.3, 2.4 Hz, 1H, H ), 8.98 (d,
8 7
J = 2.4 Hz, 1H, H )
5
14c
22
23
24
27
28
35
dimethyl
sulfoxide-d
2.41 (s, 3H), 2.52-2.82 (m, 4H), 3.53-3.93 (m, 4H), 6.16 (s,
1H, H ), 7.59 (d, J = 8.8 Hz, 1H, H ), 7.97 (bs, 1H, NH),
6
3
8
8.24 (d, J = 8.8 Hz, 1H, H ), 8.76 (bs, 1H, H )
7
5
deuteriochloroform 2.70 (s, 3H), 6.97 (s, 1H, H ), 7.62 (t, J = 7.7 Hz, 1H, H ),
and 5%
trifluoroacetic acid
deuteriochloroform 2.71 (s, 3H), 6.95 (s, 1H, H ), 7.69 (d, J = 9 Hz, 1H, H ),
and 5%
trifluoroacetic acid
deuteriochloroform 7.65 (t, J = 8.2 Hz, 2H, H ), 7.79 (d, J = 8.2 Hz, 2H, H ),
and 5%
trifluoroacetic acid
dimethyl
sulfoxide-d
(dimethyl sulfoxide-d ) 13.8, 104.8 (C ), 117.4 (C ),
6 3 8
3
6
7.73 (d, J = 8.3 Hz, 1H, H ), 7.88 (t, J = 7.7 Hz, 1H, H ),
123(C , C ), 124.9 (C ), 131.6 (C ), 140.7 (C ),
8
7
4a 6 5 7 8a
8.21 (d, J = 8.3 Hz, 1H, H ), 11.98 (bs, 1H, NH)
152.9 (C ), 175.5 (C )
2 4
5
3
8
7.80 (dd, J = 9, 2.3 Hz, 1H, H ), 8.08 (d, J = 2.3 Hz, 1H, H )
7
5
6
8
8.01 (t, J = 7.8 Hz, 2H, H ), 8.47 (d, J =7.8 Hz, 2H, H ),
7
5
9.2 (bs, 2 H, NH)
2.76 (s, 3H), 7.41 (t, J = 7.6 Hz, 1H, H ), 7.70 (td, J = 7.6,
6
1.5 Hz, 1H, H ), 7.83 (d, J = 8.4 Hz, 1H, H ), 8.11 (d, J =
6
7
8
8.2 Hz, 1H, H )
5
dimethyl
sulfoxide-d
3.05 (s, 3H), 7.48 (t, J = 7.6 Hz, 1H, H ), 7.77 (td, J = 7.6
39.6, 100.5 (C ),119.8 (C ), 124 (C ), 125 (C ), 125.3
3 8 4a 6
6
Hz, 1H, H ), 8.16 (dd, J = 8.2, 1.6 Hz, 1H, H ), 8.20 (d, J =
(C ), 132.5 (C ), 139.5 (C ), 152.8 (C8a), 170.8 (C )
6
7
8
5 7 2 4
7.8 Hz, 1H, H )
5
deuteriochloroform 0.91 (t, J = 7.4 Hz, 3H), 1.23-1.50 (m, 2H), 1.58-1.81 (m, 2H),
3.20-3.36 (m, 2H), 3.76 (s, 3H), 6.27 (s, 1H, H ), 6.91 (bs, 1H,
(deuteriochloroform and 5% trifluoroacetic acid) 13.3,
19.9, 30.7, 33 (NCH ), 44.2, 90.4 (C ), 115.6 (C ),
3
3
4
4a
NH), 7.24 (d, J = 8.7 Hz, 1H, H ), 7.33 (t, J = 8.7 Hz, 1H, H ),
117.5 (C ), 125.3 (C ),125.8 (C ), 134.8 (C ), 139.6
8
6
8 5 6 8
7.56 (t, J = 7.8 Hz, 1H, H ), 8.10 (d, J = 7.8 Hz, 1H, H )
(C ), 155.4 (C ), 165.6 (C )
8a 2 4
7
5
Elmer' 700 spectrometer and the nmr spectra on a Varian 'Gemini
2000' at 200 MHz for H and 50 MHz for C, using tetramethylsi-
lane as an internal reference. Elemental analyses were performed by
from the hot solution, washed with ethanol, then recrystallized
from ethanol. Data are reported in Tables 1, 2 and 4.
1
13
5-[(4-Bromophenylamino)(3,3-dimethyl-2-butylamino)methyl-
ene]-2,2-dimethyl-4,6-dioxo-1,3-dioxane (7b) (Method B).
t
he «Service Central de Microanalyses» (CNRS, Vernaison, France).
5-[(Anilino)(4-methylpiperazino)methylene]-2,2-dimethyl-4,6-
dioxo-1,3-dioxane (6c) (Method C).
A stirred mixture of 3,3-dimethyl-2-butylamine (4.25 g, 42
mmol) and of compound 18 (Method G) (11.2 g, 30 mmol) in
chloroform (20 ml) was refluxed for 12 hours. Volatile com-
pounds were removed under vacuum, then the residue was recrys-
tallized from ethanol. Data are reported in Tables 1, 2 and 4.
A stirred mixture of N-methylpiperazine (3.8 ml, 3.4 g, 34
mmol) and of compound 17 (Method F or G) (5 g, 17 mmol) in
chloroform (20 ml) was refluxed for 5 hours. The solvent was
evaporated, then the residue was stirred in ether (50 ml). The
solid was washed with ether, then recrystallized from acetone.
Data are reported in Tables 1, 2 and 4.
5-[(Anilino)(4-chlorophenylamino)methylene]-2,2-dimethyl-
4,6-dioxo-1,3-dioxane (8d) (Method D).
A stirred mixture of aniline (5 ml, 5.1 g, 55 mmol) and com-
pound 19 (Method F or G) (9.8 g, 30 mmol) in chloroform (20
ml) was refluxed for 7 hours. The solvent was evaporated, then
the residue was stirred in ether (50 ml). The solid was washed
with ether, then recrystallized from methanol. Data are reported
in Tables 1, 2 and 4.
5-[(Anilino)(4-chlorobenzoylhydrazino)methylene]-2,2-dimethyl-
4,6-dioxo-1,3-dioxane (6h) (Method E).
A stirred mixture of 4-chlorobenzhydrazide (7.7 g, 45 mmol)
and of compound 17 (Method F or G) (8.8 g, 30 mmol) in ethanol
(25 ml) was refluxed for 10 hours. The precipitate was filtered

Jan-Feb 2002
Synthesis of 2-Amino-1,4-dihydro-4-quinolinones
27
5-[(Butylamino)(4-nitrophenylamino)methylene]-2,2-dimethyl-
4,6-dioxo-1,3-dioxane (10a) (Method A).
then 4-chlorophenyl isothiocyanate (8.5 g, 50 ml) was added. After
stirring for 12 hours, methyl iodide (3.2 ml, 7.1 g, 50 mmol) was
added. After stirring for 4 hours, the mixture was poured into water
(0 °C, 800 ml) and the solution was neutralized with 2 N hydrochlo-
ric acid. The solid obtained was washed with water then recrystal-
lized from methanol. Data are reported in Tables 2 and 4.
A stirred mixture of butylamine (4.7 ml, 3.5 g, 48 mmol) and
of compound 21 (Method G) (8.1 g, 24 mmol) in chloroform (40
ml) was refluxed for 8 hours. Volatile compounds were removed
under vacuum, then the residue was recrystallized from ethanol.
Data are reported in Tables 1, 2 and 4.
5-[(4-Fluorophenylamino)(methylthio)methylene]-2,2-dimethyl-
4,6-dioxo-1,3-dioxane (20) (Method G).
1,4-Dihydro-2-(4-methylpiperazino)-4-quinolinone (11c)
(Method I).
A stirred mixture of 4-fluoroaniline (23 ml, 27 g, 242 mmol)
and of compound 16 [7a,b] (59.6 g, 240 mmol) in chloroform
(240 ml) was refluxed for 0.5 hour. The solvent was evaporated
then ether (150 ml) was added. The mixture was stirred for 1 hour
and the solid was recrystallized from methanol. Data are reported
in Tables 2 and 4.
A stirred mixture of N-methylpiperazine (33 ml, 29.8 g, 298
mmol) and of compound 22 (Method J) (5.8 g, 30 mmol) was
refluxed for 24 hours. After cooling, acetone (60 ml) was added.
The solid obtained was purified by washing with water, then with
acetone. Data are reported in Tables 1, 3 and 5.
6-Chloro-1,4-dihydro-2-methylthio-4-quinolinone (23) (Method J).
2-Phenylamino-1,4-dihydro-4-quinolinone (11d).
Polyphosphoric acid (6 g) was stirred at 130 °C, then com-
pound 19 (Method F or G) (5 g, 15 mmol) was added. When the
carbon dioxide evolution was complete, the mixture was allowed
to cool to 100 °C. The solid obtained after neutralization with 2 N
sodium hydroxide was washed with water and purified by reflux-
ing in acetone. The product was not analyzed, but directly used
for the next syntheses. Data are reported in Tables 3 and 5.
Polyphosphoric acid (6 g) was stirred at 140 °C and compound
6d (Method D) (2.1 g, 6 mmol) was added. When the carbon
dioxide evolution was complete (30 minutes), the mixture was
allowed to cool at 100 °C and neutralized with 2 N sodium
hydroxide. The solid obtained was washed with dilute hydrochlo-
ric acid then with water. The yellow powder was stirred in ace-
tone then in ethanol. The insoluble quinolone 24 was collected by
filtration and obtained in 51% yield. The organic phases were
evaporated, giving 43% of compound 11d. Data are reported in
Tables 1, 3 and 5.
3-Bromo-1,4-dihydro-2-methylthio-4-quinolinone (27).
Bromine (2.6 ml, 8 g, 50 mmol) was added dropwise to a
stirred solution of compound 22 (Method J) (9.6 g, 50 mmol) in
acetic acid (200 ml). The mixture was stirred for 1 hour. The solid
obtained was purified by washing with water. Data are reported
in Tables 1, 3 and 5.
2-Benzylamino-1,4-dihydro-4-quinolinone (11e).
A stirred mixture of benzylamine (11.5 ml, 11.3 g, 105 mmol)
and of compound 22 (Method J) (10 g, 52 mmol) was refluxed
for 3 hours. After cooling, ethanol (25 ml) was added. The solid
obtained was purified by washing with ether. Data are reported in
Tables 1, 3 and 5.
3-Bromo-1,4-dihydro-2-methylsulfinyl-4-quinolinone (28).
Bromine (0.5 ml, 1.6 g, 10 mmol) was added dropwise to a
suspension of compound 27 (2.7 g, 10 mmol) in water (20 ml).
The mixture was stirred for 1 hour. The solid obtained was
washed with water. Data are reported in Tables 1, 3 and 5.
1,4-Dihydro-2-hydrazino-4-quinolinone (11i).
A stirred mixture of hydrazine hydrate (200 ml, 206 g, 4.1
mol) and compound 22 (Method J) (50 g, 262 mmol) was
refluxed for 24 hours. After cooling, the solution was dropped in
icy cooled water (800 ml). The solid obtained was purified by
washing with water.
1-Benzyl-3-(4-chlorophenyl)urea (32).
A solution of 4-chlorophenylisocyanate (10 g, 65 mmol) in
dichloromethane (60 ml) was added dropwise to a solution of
benzylamine (7.1 ml, 7 g, 65 mmol) in dichloromethane (20 ml).
The mixture was stirred for 1 hour. The solid obtained was
washed with dichloromethane, giving 97 % of pure product 32;
1,4-Dihydro-2-(2-propylidenehydrazino)-4-quinolinone (11j).
A mixture of compound 11i (1.75 g, 10 mmol) and acetone (30
ml) was stirred at 20 °C for 1 hour. The solid obtained was puri-
fied by washing with ether. Data are reported in Tables 1, 3 and 5.
1
mp 201 °C, H nmr (deuteriochloroform): δ 4.47 (s, 2H), 7.10-
7.60 (m, 9H) ppm. Elemental analyses are reported in Table 1.
1-Benzyl-3-(4-chlorophenyl)carbodiimide (33).
6-Bromo-1,4-dihydro-2-(3,4-dimethoxyphenethylamino)-4-
quinolinone (12f) (Method H).
A mixture of urea 32 (16.3 g, 63 mmol), triphenylphosphine
(24.3 g, 93 mmol), triethylamine (11.3 ml, 8.2 g, 81 mmol) and
carbon tetrachloride (11.1 ml, 17.7 g, 115 mmol) in
dichloromethane (100 ml) was refluxed for 4 hours (nitrogen). A
part of solvents was evaporated then ether (50 ml) was added.
The solid (triethylamine hydrochloride and triphenylphosphine
oxide) was filtered and volatile compounds were evaporated.
Ether (20 ml) and heptane (20 ml) were added and the solution
was cooled (-40 °C) for 3 days ; the solid was filtered and volatile
compounds were evaporated. These operations were repeated 3
times. Compound 33 was obtained as an oil (76 %) that was used
Compound 7f (Method D) (6 g, 12 mmol) was added to hot
(130 °C), stirred, polyphosphoric acid (5 g). When the carbon
dioxide evolution was complete, the mixture was allowed to cool
to 100 °C and neutralized with 2 N sodium hydroxide. The solid
obtained was washed with water and purified by stirring first in
acetone then in ethanol. Data are reported in Tables 1, 3 and 5.
5-[(4-Chlorophenylamino)(methylthio)methylene]-2,2-dimethyl-
4,6-dioxo-1,3-dioxane (19) (Method F).
Meldrum's acid (7.2 g, 50 mmol) was added to a suspension of
lithium hydride (0.795 g, 100 mmol) in dimethyl sulfoxide (100 ml).
The mixture was stirred 1 hour at room temperature under nitrogen
1
directly in the next syntheses, H nmr (deuteriochloroform): δ
4.44 (s, 2H), 6.70-7.50 (m, 9H) ppm.

28
B. Erb, B. Rigo, B. Pirotte, and D. Couturier
Vol. 39
P. De Tullio, M. Hermann, A. Herchuelz, J. Delarge and P. Lebrun,
Biochem. Pharmacol., 47, 1381 (1994); P. De Tullio, B. Pirotte, P.
Lebrun, J. Fontaine, L. Dupont, M.-H. Antoine, M.-H. Ouedraogo, C.
Maggetto, B. Masereel, S. Khelili, O. Diouf, T. Podona, and J.
Delarge, J. Med. Chem., 39, 937 (1996).
[5] B. Erb, R. Akue, B. Rigo, B. Pirotte and D. Couturier, J.
Heterocyclic Chem., 37, 253 (2000)
[6a] D. C. Hooper and J. S. Wolfson, Quinolone Antimicrobial
Agents, American Society for Microbiology, Washington, D.C.,
1993; [b] R. Krishnan, S. A. Lang and M. M. Siegel, J. Heterocyclic
Chem., 23, 1801 (1986).
[7a] X. Huang and B.-C. Chen, Synthesis, 967 (1986); [b] A.
Ben Cheikh, J. Chuche, N. Manisse, J. C. Pommelet, K.-P. Netsch, P.
Lorencak and C. Wentrup, J. Org. Chem., 56, 970 (1991).
[8] F.-C. Ye, B.-C. Chen and X. Huang, Synthesis, 317 (1989).
[9] B. E. Fulloon and C. Wentrup, J. Org. Chem., 61, 1363
(1996).
[10] C. Wentrup, V. V. R. Rao, W. Franck, B. E. Fulloon, D. W.
J. Moloney and T. Mosandl, J. Org. Chem., 64, 3608 (1999).
[11] For the generation of imidoylketenes and methyl-
eneketenes from pyrolysis of Meldrum's derivatives, see
[7b,9,10,12,13].
[12] T. Mosandl, C. O. Kappe, R. Flammang and C. Wentrup,
J. Chem. Soc., Chem. Commun., 1571 (1992).
[13] C. O. Kappe, G. Kollenz, R. Leung-Toung and C.
Wentrup, J. Chem. Soc., Chem. Commun., 487 (1992).
[14] R. H. Mitchell, Y. H. Lai and R. V. Williams, J. Org.
Chem., 44, 4733 (1979).
1-Benzyl-3-(4-chlorophenyl)-O-ethylisourea (34).
Epichlorohydrin (5.1 ml, 6.1 g, 66 mmol) was added dropwise
to a refluxing solution of boron trifluoride etherate (10.4 ml, 12
g, 85 mmol) in ether (25 ml) (nitrogen). The mixture was
refluxed for 2 hours. The precipitate obtained was washed with
ether (nitrogen), then urea 32 (14.8 g, 56.8 mmol) was intro-
duced. The mixture was stirred at 80 °C for 6 hours. After cool-
ing, ether (100 ml) was added. Triethylamine (10 ml, 7.3 g, 72
mmol) was added to the cooled (ice) mixture. The solid obtained
was filtered and the solution was washed 3 times with water. The
organic phases were dried (sodium sulfate) then evaporated giv-
ing 58 % of compound 34 (oil) which was used directly in the
1
next syntheses. H nmr (deuteriochloroform): δ 1.30 (t, J = 7.4
Hz, 3H), 4.26 (bs, 2H), 4.27 (q, J = 7.4 Hz, 2H), 6.80 (d, J = 8.9
Hz, 2H), 7.13-7.36 (m, 7H) ppm.
2-Butylamino-1,4-dihydro-1-methyl-4-quinolinone (35).
A stirred mixture of N-methylaniline (1.6 g, 15 mmol) and
compound 16 [7a,b] (3.7 g, 15 mmol) in triethylamine (1.5 g, 15
mmol) and chloroform (10 ml) was refluxed for 48 hours. The
solvent was evaporated, water (50 ml) was added and the suspen-
sion was stirred for 1 hour. The solid obtained was washed with
1
water, then dried, giving product 36 (20 %). H nmr (deuteri-
ochloroform): δ 1.73 (bs, 6H), 2.55 (s, 3H), 3.65 (s, 3H), 7.36
(dd, J = 7.9 Hz, 2H), 7.41-7.49 (m, 3H) ppm.
This compound was added to butylamine (2 ml, 1.5 g, 20
mmol) and the mixture was refluxed for 24 hours. Volatile com-
pounds were evaporated and the residue was washed with water,
giving product 37 (60 %). This compound was added to hot (130
°C) stirred polyphosphoric acid (0.7 g). When the carbon dioxide
evolution was complete, the mixture was allowed to cool at 100
°C, then neutralized with 2 N sodium hydroxide. The solid
obtained was washed with water, giving product 35 (50 %). Data
are reported in Tables 1, 3 and 5.
[15] E. J. Glamkowski and Y . Chiang, J. Heterocyclic Chem.,
24, 733 (1987).
[16] M. C. Carreno, J. L. Garcia Ruano, G. Sanz, M. A. Toledo
and A. Urbano, J. Org. Chem., 60, 5328 (1995).
[17] Oxidation of thioethers by molecular bromine in
dichloromethane in the presence of silica, without any base, was
recently described: M. H. Ali and G. J. Bohnert, Synthesis, 1238
(1998).
[18] A. Stephen, Monatsh. Chem., 97, 695 (1966).
[19] R. Apple, Angew. Chem., 24, 863 (1975).
[20] E. Profft and F. J. Becker, J. Prakt. Chem., 30, 18 (1965).
[21] S. Petersen and E. Tietze, Ann., 623, 166 (1969).
[22] H. Meerwein, G. Hinz, P. Hofmann, E. Kroning and E.
Pfeil, J . Prakt. Chem., 147, 257 (1937).
[23] H. Meerwein, Org. Synth., Coll. Vol. V, 1081 (1973).
[24] H. K. Lee, J. P. Lee, G. H. Lee and C. S. Pak, Synlett, 129
(1996).
REFERENCES AND NOTES
*
Email: rigo@hei.fr
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