Synthesis of 3-thiocyanato-1H,3H-quinoline-2,4-diones

Article abstract of DOI:10.1002/jhet.5570390632

4-Hydroxy-1H-quinolin-2-ones (1) react with thiocyanogen in acetic acid to the corresponding 3-thiocyanato-1H,3H-quinoline-2,4-diones (2) in good yields. In some cases, 3-bromo-1H,3H-quinoline-2,4-diones (4) were isolated as minor reaction products. Compo

Full text of DOI:10.1002/jhet.5570390632

Nov-Dec 2002
Synthesis of 3-Thiocyanato-1H,3H-quinoline-2,4-diones
1315
Antonín Klásek*, Jirí Polis, and Vladimír Mrkvicˇka
Department of Chemistry and Environmental Technology, Faculty of Technology, Tomas Bata University,
762 72 Zlín, Czech Republic
Janez Kosˇmrlj
Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
Received June 10, 2002
4-Hydroxy-1H-quinolin-2-ones (1) react with thiocyanogen in acetic acid to the corresponding 3-thio-
cyanato-1H,3H-quinoline-2,4-diones (2) in good yields. In some cases, 3-bromo-1H,3H-quinoline-2,4-
diones (4) were isolated as minor reaction products. Compounds 2 are very reactive towards nucleophiles
and easily hydrolyze to the corresponding 4-hydroxy-1H-quinoline-2-ones (1).
J. Heterocyclic Chem., 39, 1315(2002).
Reactions of 3-alkyl/aryl-3-hydroxy-1H,3H-quinoline-
charged" halogen atom exhibit such a strong oxidative
effect that all compounds bearing a free –SH group are
quickly oxidized. Therefore, 3-substituted 1H,3H-quino-
line-2,4-diones bearing sulfur atom at C-3 must be pre-
pared by an alternative pathway, rather than from 3-
halogeno derivatives 3 or 4.
In another possible method accomplish our goal, we
envisioned introduction of a thiocyanato group to the mol-
ecule. Although the a -thiocyanation of b-dicarbonyl com-
pounds is not well established and the products are usually
prone to decomposition, the non-enolizable a -thiocyanato
derivatives have been found to be reasonably stable [7]. In
this paper we describe that 3-alkyl- and 3-aryl-3-thio-
cyanato-1H,3H-quinoline-2,4-diones (2) can be smoothly
prepared by reaction of 3-alkyl- or 3-aryl-4-hydroxy-1H-
quinolin-2-ones (1) with thiocyanogen.
2,4-diones with ethyl (triphenyl-phosphoranylidene)-
acetate proceed with high stereoselectivity to give E-4-
ethoxycarbonylmethylene-3-hydroxy-3,4-dihydro-2-
quinolones [1]. Derivatives of 3aH,5H-furo[2,3-c]quino-
line-2,4-diones were detected and in some cases isolated as
the minor products of Wittig reaction. The independent
synthesis of these butenolides by an intramolecular Wittig
reaction has also been published [2].
The smooth reactivity of 3-hydroxy-1H,3H-quinoline-
2,4-diones in the Wittig reaction, combined with good
yields, but also the fact that many biologically active com-
pounds contain sulfur function [3], stimulated us to con-
tinue our studies on the closely related 3-alkyl- and 3-aryl-
3-sulfanyl-1H,3H-quinoline-2,4(1H,3H)-diones.
However, these compounds have not yet been described in
the literature. Recently, structurally related 3-arylsulfenyl-
4-hydroxy-1H-quinolin-2-ones and 3-diethylaminothio-
carbonylthio-4-hydroxy-1H-quinolin-2-ones were pre-
pared by reaction of 4-hydroxy-1H-quinolin-2-ones with
diaryl disulfides or tetraethylthiuram disulfide, respec-
tively, in dimethylformamide in the presence of potassium
carbonate [4]. We have found that compound 1e reacts,
under analogous reaction conditions, with diacetyl disul-
fide, the reaction of which with b-dicarbonyl compounds
was described [5]. However, instead of the expected
acetylsulfanylation at the 3 position of 1e, acetylation of
hydroxyl group at the 4 position takes place, to give 6e.
Many methods for the introduction of a sulfur function
into the molecule are known [6,7]. We attempted to pre-
pare the desired products from easily accessible [8] 3-
bromo(or chloro)-1H,3H-quinoline-2,4-diones (3 or 4).
However, the reaction of 3b and 3e with sodium hydrogen
sulfide is of redox character and 4-hydroxy-1H-quinolin-
2-ones 1b and 1e were obtained, accompanied with ele-
mental sulfur. The same results were obtained using bromo
derivatives 4b and 4e as substrates.
The reaction scheme is depicted in Scheme 1 and the
key substituents are given in Table 1. Starting 4-hydroxy-
1H-quinolin-2-ones (1) were prepared by condensation of
Scheme 1
Similar results were also obtained using other sulfur
reagents such as sodium thiosulfate, potassium thioacetate,
potassium thiocyanate, and thiourea. It stands to reason
that 3-halogeno derivatives 3 and 4 with "positive

1316
A. Klásek, J. Polis, V. Mrkvicˇka, and J. Kosˇmrlj
Vol. 39
Table 1
Physical and Analytical Data of Compounds 2, 4, and 5
1
2
3
4
5
6
Compound
No.
R
R
R
R
R
R
Method
Yield (%)
Mp (°C)
(Solvent)
Formula
M.W.
Analysis (%)
Calcd./Found
C
H
N
2a
2b
H
n-C H
H
H
H
H
H
H
H
H
61
77
76-9
(hexane)
120-2
C
H
274.34
H N O S
308.36
-
H N O S
322.38
H N O S
N 0 S
61.29
61.47
66.22
65.98
5.14
5.19
3.92
3.93
10.21
9.95
9.08
8.29
4
9
14 14 2 2
H
C H CH
C
6
5
2
2
17 12 2 2
(benzene –
c-C H
)
6
12
2c
2d
H
CH
C H
H
H
H
H
H
H
H
H
0
47
-
-
-
-
6
5
C H CH
105-7
(benzene)
169-71
C
C
67.06
67.12
66.22
66.47
4.38
4.35
3.92
3.83
8.69
8.72
9.08
8.86
3
3
6
5
18 14 2 2
2e
2f
CH
C H
H
H
H
H
H
H
H
H
52
26
6
5
5
17 12 2 2
(benzene –
308.36
H N O S
22 14 2 2
370.42
H N O S
15 16 2 2
c-C H
)
6
12
C H
C H
167-70
(benzene –
c-C H
C
C
71.33
71.48
3.81
3.91
7.56
7.27
6
5
6
)
12
6
2g
2h
2i
H
H
H
H
H
n-C H
H
H
CH
Cl
H
H
H
H
H
72
65
59
85
85
85-9
(hexane)
102-7
(hexane)
68-72
62.48
62.63
54.46
54.82
62.48
62.76
63.55
63.67
68.96
68.69
5.59
5.53
4.24
4.38
5.59
5.48
6.00
6.16
4.93
5.26
9.71
9.76
9.07
8.70
9.71
9.58
9.26
9.12
7.96
7.71
4
9
9
9
9
3
288.37
C H ClN O S
14 13
308.78
C H N O S
15 16
n-C H
4
2 2
n-C H
H
H
CH
H
4
3
2 2
(c-C H
)
288.37
H N O S
302.39
H N O S
°0.2 C H
351.83
6
12
2j
n-C H
CH
CH
H
CH
CH
127-9
(c-C H
C
C
4
3
3
3
16 18 2 2
)
6
12
2k
C H CH
H
H
66-74
(benzene –
c-C H
6
5
2
3
19 16 2 2
6
5
)
12
6
2l
H
C H
CH
H
CH
H
25
200-10
C
C
H N O S
67.06
67.31
4.38
4.28
8.69
8.51
6
5
3
3
3
18 14 2 2
(benzene-
hexane)
104-5
322.38
H N O S
17 20 2 2
2m
2n
CH
H
n-C H
CH
Cl
H
H
CH
H
H
74
26
64.53
64.58
60.59
60.41
6.37
6.52
3.67
3.57
8.85
8.62
7.85
7.79
3
4
9
3
(c-C H
)
316.42
H ClN O S
6
12
C H CH
CH
162-5
\(benzene –
c-C H
C
C
6
5
2
2
3
3
18 13
2 2
356.83
)
12
6
2o
4g
4h
4i
H
H
H
H
C H CH
H
H
H
H
H
CH
Cl
Cl
H
H
H
CH
H
71
175-8
(benzene –
c-C H
H
ClN O S
60.59
60.89
3.67
3.73
7.85
7.71
6
5
18 13
2 2
356.83
BrNO
2
)
12
6
n-C H
A: 11
B: 92
136-8
(hexane-
c-C H
C
H
54.21
53.91
5.20
5.44
4.52
4.44
4
9
9
9
3
14 16
310.19
BrClNO
2
)
12
6
n-C H
H
A: 3
B: 65
146-50
(hexane-
c-C H
C
H
47.23
47.10
3.96
4.03
4.24
4.13
4
13 13
330.60
)
12
6
n-C H
H
CH
A: 3
B: 68
123-6
(hexane-
c-C H
C
H
BrNO
54.21
53.84
5.20
5.55
4.52
4.42
4
3
14 16
2
310.19
6
12)
4j
H
CH
H
n-C H
CH
CH
CH
CH
H
H
-
CH
CH
CH
CH
H
H
H
H
A: 6
C: 12
A: 7
C: 16
B: 65
C: 28
B: 62
C: 31
149-52
(c-C H
74-5
(methanol)
194-7
(benzene)
128-31
C
C
H
BrNO
55.57
55.34
56.82
57.06
44.69
44.97
46.07
45.95
5.60
5.65
5.96
6.26
4.25
4.38
4.59
4.89
4.32
4.36
4.14
4.00
3.47
3.39
3.36
3.19
4
9
9
9
9
3
3
3
3
3
3
3
3
15 18
2
2
)
12
324.21
H BrNO
6
4m
5j
n-C H
3
3
4
16 20
338.24
H Br NO
403.11
H Br NO
n-C H
C
C
4
15 17
2
2
5m
CH
n-C H
-
4
16 19
2
2
(methanol)
417.14
anilines with substituted diethyl malonates, according to
known procedures [9-11]. In our preliminary experiment
we found that the reaction of compound 1e with excess of
thiocyanogen, in situ generated by the addition of bromine
to a solution of 1e and potassium thiocyanate in acetic
acid, results in a mixture of two products. The minor reac-
tion product was isolated and identified as the expected
thiocyanato derivative 2e. The major reaction product was
identified as 3-bromo derivative 4e. This indicates that
both 1e and potassium thiocyanate react with bromine with

Nov-Dec 2002
Synthesis of 3-Thiocyanato-1H,3H-quinoline-2,4-diones
1317
a comparable rate. Therefore, in further experiments, we
first prepared the solution of thiocyanogen (by adding
bromine to the excess of potassium thiocyanate in acetic
acid) to which the solution of starting compound 1 in
acetic acid was added in the next step. Under these condi-
tions the conversion of 1 to 2 proceeded nearly quantita-
tively (according to tlc). However, compounds 2 are sensi-
tive to hydrolysis and workup, such as dilution of the reac-
tion mixture with water, resulted in a rapid conversion of 2
to the starting material 1 and a polymeric yellow sub-
stance. A similar formation of the yellow polymeric mate-
rial during the decomposition of a -thiocyanato-b-
ketoesters has already been described by Prakash et al. [7].
The conversion of 2 to 1 can be explained by nucleophilic
attack of a water molecule at the "positive charged" sulfur
atom of the thiocyanato group (Scheme 2). An analogous
transformation has been described [12] for 3-bromo-
1H,3H-quinoline-2,4-diones (3), which in the presence of
potassium hydroxide in methanol reacted to 4-hydroxy-
(1H)-quinolin-2-ones 1 and hypobromite.
Scheme 2
Table 2
IR and NMR Data of Compounds 2, 4 and 5
1
13
Compound
No.
R
(cm )
H and C NMR (in d -DMSO)
6
-1
d (ppm)
1
2a
2b
2d
2e
3190, 3115, 3069, 3002, 2959, 2934,
2675, 2153, 1702, 1665, 1611, 1594,
1484, 1440, 1439, 1424, 1375, 1323,
1313, 1252, 1237, 1157, 876, 839, 769,
749, 731, 687, 618
3190, 3064, 2997, 2934, 2153, 1702,
1665, 1612, 1594, 1485, 1440, 1430,
1374, 1324, 1256, 1242, 1225, 1159,
1033, 940, 869, 826, 759, 745, 707,
664, 654
H NMR: 0.81 (t, J = 6.5 Hz, 3H, CH ), 1.15-1.33 (m, 4H, H-2 and H-3 of butyl),
3
2.12-2.28 (m, 2H, H-1 of butyl), 7.17 (d, J = 8.3 Hz, 1H, H-8), 7.21 (t, J = 7.9 Hz,
1H, H-6), 7.71 (dt, J = 7.7 and 1.4 Hz, 1H, H-7), 7.86 (dd, J = 7.7 and 1.1 Hz, H-5),
11.49 (s, 1H, NH). C NMR: 13.39, 21.82, 26.65, 35.54, 65.21, 109.76, 116.82,
13
117.79, 123.50, 127.35, 137.26, 141.13, 166.88, 189.46.
1
H NMR: 3.56 (s, 2H, PhCH ), 7.03-7.09 (m, 2H, m-H of Ph), 7.13-7.24 (m, 3H, o- and
2
p-H of Ph), 7.02 (d, J = 8.1 Hz, 1H, H-8), 7.15 (dt, J = 7.5 and 0.8 Hz, 1H, H-6), 7.61
(dt, J = 7.7 and 1.5 Hz, 1H, H-7), 7.78 (dd, J = 7.8 and 1.4 Hz, H-5), 11.50 (s, 1H,
NH). C NMR: 64.77, 109.78, 116.69, 117.84, 123.55, 127.18, 127.60, 128.23, 129.90,
133.16, 137.41, 140.89, 166.45, 189.35.
1
13
3113, 3082, 3062, 3032, 2152, 1689,
1658, 1598, 1493, 1473, 1437, 1361,
1305, 1245, 1141, 1062, 1038, 982,
920, 907, 856, 774, 748, 702, 662
H NMR: 3.36 (s, 3H, N-CH ), 3.52 and 3.57 (two d, 2H, CH ), 6.95-7.05 (m, 2H, m-H
3
2
of Ph), 7.13-7.20 (m, 3H, o- and p-H of phenyl), 7.20-7.32 (m, 2H, H-6 and H-8), 7.72
(dt, J = 7.8 and 1.0 Hz, 1H, H-7), 7.87 (dd, J = 7.7 and 1.0 Hz, H-5). C NMR: 30.28,
43.29, 67.45, 110.45, 116.07, 119.57, 123.71, 127.35, 127.68, 128.06, 129.80, 132.77,
13
137.25, 141.91, 166.18, 189.02.
1
3116, 3086, 3033, 2986, 2940, 2887,
2151, 1710, 1667, 1603, 1494, 1471,
1446, 1418, 1361, 1298, 1240, 1145,
1035, 957, 923, 866, 805, 778, 754,
750, 695, 667
H NMR: 3.49 (s, 3H, CH ), 7.21 (t, J = 7.7 Hz, 1H, H-6), 7.22-7.28 (m, 2H, m-H of
3
Ph), 7.33 (d, J = 8.3 Hz, 1H, H-8), 7.35-7.44 (m, 3H, o- and p-H of Ph), 7.67 (dt,
J = 7.8 and 1.6 Hz, 1H, H-7), 7.86 (dd, J = 7.7 and 1.6 Hz, H-5). C NMR: 30.91,
13
75.84, 111.44, 116.10, 120.67, 123.59, 127.10, 127.41, 129.47, 129.95, 132.89, 136.42,
141.42, 165.88, 187.88.
1
2f
3101, 3067, 3018, 2152, 1713, 1678, 1596,
H NMR: 6.29 (d, J = 8.3 Hz, 1H, H-8), 7.18 (t, J = 7.5 Hz, 1H, H-6), 7.32-7.70 (m,
13
1492, 1463, 1449, 1342, 1300, 1238, 1170, 11H, H-7 and two Ph), 7.92 (d, J = 7.6 Hz, 1H, H-5). C NMR: 76.02, 111.31,
1120, 1069, 1001, 952, 847, 775, 764,
749, 736, 719, 707, 690, 665, 605
3191, 3067, 2956, 2933, 2871, 2153,
1709, 1698, 1666, 1615, 1503, 1426,
1358, 1318, 1233, 1151, 1096, 961,
909, 828, 748, 731, 656
116.78, 120.46, 123.63, 127.22, 127.43, 128.21, 128.62, 129.16, 129.68, 130.08, 130.39,
132.69, 135.91, 137.16, 142.29, 165.93, 187.72.
1
2g
H NMR: 0.81 (t, J = 6.6 Hz, 3H, CH of butyl), 1.11-1.32 (m, 4H, H-2 and H-3 of
3
butyl), 2.13-2.23 (m, 2H, H-1 of butyl), 2.32 (s, 3H, Ar-CH ), 7.07 (d, J = 8.2 Hz, 1H,
3
13
H-8), 7.53 (d, J = 8.2 Hz, 1H, H-7), 7.65 (s, 1H, H-5), 11.42 (s, 1H, NH). C NMR:
13.39, 19.94, 21.82, 26.67, 35.51, 64.90, 109.71, 116.79, 117.58, 126.87, 132.87, 138.17,
138.95, 166.70, 189.48.
1
2h
2i
3117, 3063, 2961, 2932, 2905, 2873, 2152,
H NMR: 0.81 (t, J = 6,9 Hz, 3H, CH of butyl), 1.18-1.33 (m, 4H, H-2 and H-3 of
3
1704, 1667, 1608, 1595, 1497, 1480, 1412, butyl), 2.09-2.25 (m, 2H, H-1 of butyl), 7.19 (d, J = 8.5 Hz, 1H, H-8), 7.72-7.79 (m,
13
1116, 1088, 908, 889, 844, 738, 706,
1360, 1311, 1261, 1205, 663, 600
3252, 2961, 2932, 2663, 2157, 1697,
1672, 1597, 1498, 1465, 1354, 1312,
1262, 1236, 1222, 1143, 1059, 1025,
951, 906, 800, 784, 752, 715, 674
2H, H-5 and H-7), 11.57 (s, 1H, NH). C NMR: 13.39, 21.78, 26.52, 35.54, 65.90,
109.89, 118.91, 119.06, 126.19, 127.31, 136.61, 140.00, 166.91, 188.61.
1
H NMR: 0.81 (t, J = 6.9 Hz, 3H, CH of butyl), 1.19-1.35 (m, 4H, H-2 and H-3 of butyl),
3
2.11-2.25 (m, 2H, H-1 of butyl), 2.35 (s, 3H, Ar-CH ), 7.13 (t, J = 7.6 Hz, 1H, H-6), 7.56 (d,
J = 7.0 Hz, 1H, H-7), 7.70 (d, J = 7.6 Hz, 1H, H-5), 10.59 (s, 1H, NH). C NMR: 13.40,
17.28, 21.74, 26.62, 35.64, 66.28, 109.93, 118.21, 123.21, 125.17, 125.43, 128.22, 138.43,
3
13
139.11, 167.23, 189.68.
1
2j
3036, 3012, 2961, 2929, 2871, 2154,
1703, 1664, 1616, 1578, 1526, 1463,
1428, 1380, 1367, 1291, 1251, 1228,
1216, 1172, 1037, 930, 885, 851, 824,
769, 740, 687, 655
H NMR: 0.81 (t, J = 6.8 Hz, 3H, CH of butyl), 1.18-1.30 (m, 4H, H-2 and H-3 of butyl),
3
2.12-2.20 (m, 2H, H-1 of butyl), 2.31 (s, 3H, Ar-CH ), 2.50 (s, 3H, Ar-CH ), 6.82 (s, 1H,
H-8), 6.87 (s, 1H, H-6), 11.33 (s, 1H, NH). C NMR: 13.41, 21.30, 21.43, 21.77, 26.74,
35.67, 67.54, 110.09, 114.29, 114.95, 127.57, 141.48, 141.76, 146.61, 166.61, 189.69.
3
3
13

1318
A. Klásek, J. Polis, V. Mrkvicˇka, and J. Kosˇmrlj
Vol. 39
Table 2 (continued)
1
13
Compound
No.
R
(cm )
H and C NMR (in d -DMSO)
6
-1
d (ppm)
1
2k
3150, 3068, 3034, 2922, 2844, 2153,
1710, 1701, 1670, 1618, 1578, 1522,
1458, 1437, 1427, 1354, 1320, 1288,
1230, 1032, 915, 909, 852, 754, 704,
681
3216, 3157, 3016, 2921, 2158, 1712,
1703, 1675, 1663, 1616, 1580, 1518,
1461, 1449, 1426, 1358, 1320, 1166,
1036, 851, 813, 750, 694, 553
3032, 2962, 2934, 2875, 2159, 1701,
1665, 1605, 1572, 1491, 1459, 1343,
1320, 1301, 1243, 1167, 1092, 1041,
1023, 921, 845, 809, 785, 749, 735,
688
H NMR: 2.26 (s, 3H, Ar-CH ), 2.46 (s, 3H, Ar-CH ), 3.50 and 3.56 (two d, J = 13.5 Hz,
3 3
2H, CH ), 6.72 (s, 1H, H-8), 6.82 (s, 1H, H-6), 7.02-7.08 (m, 2H, m-H of Ph), 7.17-7.25
(m, 3H, o- and p-H of Ph), 7.36 (s, 1.2 H, benzene), 11.35 (s, 1H, NH). C NMR: 21.27,
21.52, 42.01, 67.79, 110.39, 114.50, 114.89, 127.61, 128.20, 128.22, 129.82, 133.26,
2
13
141.41, 141.66, 146.80, 166.39, 189.43.
1
2l
H NMR: 2.21 (s, 3H, Ar-CH ), 2.50 (s, 3H, Ar-CH ), 6.67 (s, 1H, H-8), 6.77 (s, 1H, H-6),
3 3
7.26-7.32 (m, 2H,m-H of Ph), 7.38-7.48 (m, 3H,o- and p-H of Ph), 11.46 (s, 1H, NH).
13
C NMR: 20.63, 21.16, 76.57, 111.53, 114.74, 115.54, 126.77, 127.15, 129.54, 129.94,
133.25, 140.49, 140.51, 146.02, 165.66, 188.59.
1
2m
H NMR: 0.80 (t, J = 7.0 Hz, 3H, CH of butyl), 1.10-1.38 (m, 4H, H-2 and H-3 of butyl),
3
2.13 (t, J = 7.9 Hz, 2H, H-1 of butyl), 2.39 (s, 3H, Ar-CH ), 2.49 (s, 3H, Ar-CH ), 3.42
(s, 3H, N-CH ), 6.98 (s, 1H, H-6), 7.17 (s, 1H, H-8). C NMR: 13.38, 21.32, 21.52, 21.65,
26.72, 31.04, 36.29, 70.33, 110.53, 114.93, 115.92, 127.85, 141.06, 142.87, 146.29, 166.07,
3
3
13
3
189.77.
1
2n
2o
3233, 3158, 3088, 2156, 1720, 1677,
1597, 1580, 1486, 1460, 1362, 1335,
1255, 1211, 1032, 969, 820, 772, 708,
662
H NMR: 2.27 (s, 3H, Ar-CH ), 3.46 and 3.60 (two d,J = 14.0 Hz), 7.05-7.10 (m, 2H, m-H
3
of Ph), 7.18 (d, J = 8.1 Hz, 1H, H-7), 7.22-7.28 (m, 3H, o- and p-H of Ph), 7.43 (d,J =
8.1 Hz,1H, H-6), 10.61 (s, 1H, NH). C NMR: 17.42, 42.59, 72.42, 111.13, 116.32, 124.82,
13
125.59, 127.78, 128.06, 129.90, 130.46, 132.51, 137.34, 140.28, 166.25, 187.65.
1
3230, 3154, 3067, 3026, 2951, 2924, 2158,
H NMR: 2.31 (s, 3H, Ar-CH ), 3.54 (s, 2H, CH ), 7.02-7.09 (m, 2H, m-H of Ph), 7.16-7.23
3
2
1719, 1674, 1595, 1582, 1491, 1453, 1400, (m, 3H, o- and p-H of Ph), 7.26 (d, J = 8.5 Hz, 1H, H-6), 7.65 (d,J = 8.5 Hz, 1H, H-5),
13
1368, 1340, 1311, 1248, 1216, 1199, 1142, 10.77 (s, 1H, NH). C NMR: 14.07, 42.16, 66.96, 110.31, 117.48, 123.28, 124.09, 125.84,
1081, 1068, 1035, 967, 956, 912, 825, 804, 127.65, 128.07, 129.99, 132.85, 140.27, 141.80, 167.08, 188.86.
1
789, 774, 754, 714, 701, 678, 617
3187, 3064, 2958, 2928, 2871, 1702,
1665, 1615, 1508, 1428, 1417, 1365,
1326, 1236, 1158, 1123, 1099, 1030,
915, 856, 826, 742, 702, 655, 612.
3185, 3122, 3065, 2968, 2927, 2909,
2869, 1708, 1667, 1608, 1593, 1487,
1477, 1427, 1414, 1358, 1316, 1261,
1236, 1217, 1161, 1128, 1097, 964,
916, 843, 730, 652.
H NMR: 0.83 (t, J = 7.2 Hz, 3H, CH of butyl), 0.98-1.22 (m, 2H, H-3 of butyl), 1.22-1.35
3
4g
4h
(m, 2H, H-2 of butyl), 2.31 (s, 3H, Ar-CH ), 2.41 (t, J = 7.9 Hz, 2H, H-1 of butyl), 7.06 (d,
J = 8.2 Hz,1H, H-8), 7.50 (dd,J = 8.2 and 1.4 Hz, 1H, H-7), 7.66 (s, 1H, H-5), 11.20 (s,
1H, NH). C NMR: 13.51, 19.94, 21.92, 27.81, 33.58, 56.46, 116.52, 116.87, 127.23, 132.59,
3
13
137.61, 138.45, 166.73, 187.91.
1
H NMR: 0.75 (t, J = 7.1 Hz, 3H, CH of butyl), 1.11-1.25 (m, 2H, H-3 of butyl), 1.25-1.37
3
(m, 2H, H-2 of butyl), 2.39 and 2.42 (two d, J = 7.0 Hz, 2H, H-1 of butyl), 7.19 (d, J =
8.7 Hz, 1H, H-8), 7.72 (dd, J = 8.7 and 2.5 Hz, 1H, H-7), 7.81 (d, J = 2.5 Hz, 1H, H-5),
11.40 (s, 1H, NH). C NMR: 13.53, 22.38, 27.87, 33.14, 56.56, 118.44, 118.68, 126.48,
13
127.13, 136.20, 139.51, 166.77, 186.83.
1
4i
3108, 3086, 2963, 2929, 2859, 1703,
1667, 1595, 1496, 1466, 1424, 1366,
1311, 1260, 1237, 1175, 1031, 965, 902,
H NMR: 0.85 (t, J = 7.2 Hz, 3H, CH of butyl), 1.07-1.22 (m, 2H, H-3 of butyl), 1.22-1.38 (m,
3
2H, H-2 of butyl), 2.35 (s, 3H, Ar-CH ), 2.43 (t, J = 7.9 Hz, 2H, H-1 of butyl), 7.12 (t, J = 7.6
Hz, 1H, H-6), 7.53 (d, J = 7.3 Hz, 1H, H-7), 7.74 (d,J = 7.6 Hz, 1H, H-5), 10.39 (s, 1H, NH).
3
13
794, 740, 679. C NMR: 13.53, 17.26,
22.35, 27.87, 33.52, 56.01, 117,51, 122.94, 125.09, 125.50, 138.04, 138.64, 167.22, 188.15.
1
4j
3145, 3112, 3070, 3015, 2953, 2930,
2869, 1702, 1667, 1615, 1578, 1524,
1463, 1428, 1403, 1378, 1290, 1223,
H NMR: 0.85 (t, J = 7.2 Hz, 3H, CH of butyl), 1.06-1.18 (m, 2H, H-3 of butyl), 1.22-1.38 (m,
3
2H, H-2 of butyl), 2.30 (s, 3H, Ar-CH ), 2.38 (t, J = 6.7 Hz, 2H, H-1 of butyl), 2.51 (s, 3H,
Ar-CH ), 6.81 (s, 1H, H-8), 6.85 (s, 1H, H-6), 11.13 (s, 1H, NH). C NMR: 13.52, 21.21, 21.61,
3
13
3
1145, 1099, 1028, 926, 883, 857, 735, 671. 22.37, 27.82, 33.61, 57.28, 113,82, 114.71, 127.36, 141.31, 141.83, 145.93, 166.60, 187.92.
1
4m
5j
2973, 2954, 2918, 2872, 1697, 1660,
1609, 1572, 1496, 1458, 1434, 1345,
1328, 1302, 1250, 1181, 1148, 1106,
1073, 1033, 928, 846, 719, 655, 607.
3187, 3119, 3056, 2955, 2871, 1704,
1673, 1603, 1571, 1503, 1454, 1426,
1392, 1269, 1206, 1145, 1101, 992,
927, 871, 845, 739, 678, 650.
2951, 2934, 2869, 1702, 1672, 1587,
1473, 1458, 1411, 1327, 1309, 1278,
1252, 1225, 1159, 1143, 1071, 1022,
929, 845, 722, 670, 622.
H NMR: 0.85 (t, J = 7.3 Hz, 3H, CH of butyl), 1.09-1.22 (m, 2H, H-3 of butyl), 1.22-1.37 (m,
3
2H, H-2 of butyl), 2.34-2.47 (m, 2H, H-1 of butyl), 2.39 (s, 3H, Ar-CH ), 2.52 (s, 3H, Ar-CH ),
3.43 (s, 3H, N-CH ), 6.97 (s, 1H, H-6), 7.15 (s, 1H, H-8). C NMR: 13.54, 21.45, 21.75,
3
3
13
3
22.42, 27.91, 30.77, 34.24, 57.23, 114,66, 115.85, 127.72, 141.59, 142.39, 145.70, 166.00, 187.69.
1
H NMR: 0.86 (t, J = 7.2 Hz, 3H, CH of butyl), 1.12-1.24 (m, 2H, H-3 of butyl), 1.24-1.38 (m,
3
2H, H-2 of butyl), 2.32-2.42 (m, 2H, H-1 of butyl), 2.41 (s, 3H, Ar-CH ), 2.64 (s, 3H,
Ar-CH ), 7.00 (s, 1H, H-8), 11.25 (s, 1H, NH). C NMR: 13.55, 20.92, 22.44, 24.67,
3
13
3
27.89, 33.25, 57.75, 116,37, 122.73, 128.22, 139.75, 140.52, 145.40, 166.24, 187.48.
1
5m
H NMR: 0.87 (t, J = 7.1 Hz, 3H, CH of butyl), 1.16-1.28 (m, 2H, H-3 of butyl), 1.28-1.39
3
(m, 2H, H-2 of butyl), 2.37 (t, J = 7.7 Hz, 2H, H-1 of butyl), 2.51 (s, 3H, Ar-CH ), 2.63
(s, 3H, Ar-CH ), 3.42 (s, 3H, N-CH ), 7.39 (s, 1H, H-8). C NMR: 13.57, 21.07, 22.47,
24.73, 27.96, 30.90, 33.98, 57.93, 116,43, 118.70, 123.49, 139.93, 140.73, 145.16, 165.60,
187.47.
3
13
3
3
The undesired hydrolysis of 2 was successfully elimi-
nated when we diluted the reaction mixture with aqueous
sodium acetate instead of water. Hence the strong hypoth-
iocyanous acid (HOSCN), which probably catalyzes
hydrolytic cleavage of 3-thiocyanato derivatives 2 to 1, is
neutralized. However, even under these reaction condi-
tions, we were not successful in isolating compound 2c,
which was according to tlc monitoring formed, but rapidly
decomposed to the initial compound 1c during the isola-
tion.
In the crystalline form compounds 2 are relatively sta-
ble. In their infrared spectra, a characteristic sharp absorp-

Nov-Dec 2002
Synthesis of 3-Thiocyanato-1H,3H-quinoline-2,4-diones
1319
Perkin-Elmer 2400 CHN Analyser and EA 1108 Elemental
Analyser (Fisons Instrument). The physical and analytical data of
compounds under investigation are given in Table 1, spectral data
are given in Table 2.
tion band of the –SCN group appears in the narrow region
of 2151-2154 cm . In the cases of 8-methyl substituted
-1
derivatives (2i, n, o) this absorption band is shifted to the
-1
region of 2156-2158 cm . Other characteristic bands for 2
-1
Reaction of 4-Hydroxy-1-methyl-3-phenyl-1H-quinolin-2-one
(1e) with Diacetyl Disulfide.
occur at 1689-1720 cm (keto group) and 1664-1677
-1
cm (lactam).
In some cases the crude products of the thiocyanation
reactions contained small amounts of 3-bromo derivatives
4, which we isolated by column chromatography. Their
structures were confirmed by an independent bromination
of 1 with bromine in acetic acid. However, the bromination
of some compounds 1 did not only take place at the 3 posi-
tion but also at the fused benzene ring. For example, the
bromination of 1h resulted in a mixture of 3-bromo and
3,6-dibromo derivatives 4h and 5h even when 0.5 molar
equivalent of bromine was employed in the reaction. By
screening over several different solvents we learned that
both 4h and 5h posses similar chromatographic properties,
not allowing us to isolate the products by column chro-
matography. Thus from the crude reaction product, con-
sisting of 4h, 5h, and unreacted starting material 1h, the 3-
bromo derivative 4h was obtained by repeated crystalliza-
tion. A similar observation was found for the bromination
of 1n.
Besides with water, we found out that thiocyanates 2
also react with nitrogen nucleophiles such as aliphatic
amines and anilines. In all the examined cases of this pre-
liminary research the reactions preceded at the sulfur atom
with migration of -SCN group to the nucleophile, analo-
gously to that reported in the literature [13-19]. In conclu-
sion it seems that the thiocyanato derivatives 2 may not
serve as suitable intermediates for the synthesis of 3-sul-
fanyl-1H,3H-quinoline-2,4-diones. On the other hand,
these can potentially be utilized as thiocyanation agents.
The reactions of 2 with nucleophiles will be the subject of
our forthcoming investigation.
A mixture of 1e (2.51 g, 10 mmoles), diacetyl disulfide (1.50
g, 10 mmoles), and potassium carbonate (2.76 g, 20 mmoles) in
dimethyl formamide (20 ml) was stirred for 6 hrs at room tem-
perature. After addition of cold water (100 ml) the precipitate
was collected by suction filtration. After crystallization from
ethanol, 1.85 g (63%) of 4-acetoxy-1-methyl-3-phenyl-1H-
quinolin-2-one (6e), mp 188-90 °C, was obtained. Isolated com-
pound was identical (ir, mixed mp) with that prepared from 1e by
usual procedure with acetic anhydride in pyridine. For 6e, m.p.
184-7 °C was reported [20].
Anal. Calcd. for C18H15NO3 (293.32): C, 73.71; H, 5.15; N,
4.78. Found: C, 73.58; H, 5.27; N, 4.56.
General Procedure for the Preparation of 3-Alkyl/aryl-3-thio-
cyanato-1H,3H-quinoline-2,4-diones (2).
A solution of appropriate 4-hydroxy-1H-quinolin-2-one 1 [8-
11] (10 mmoles) in acetic acid (50 ml) was added in one portion
to the stirred solution of (SCN)2 prepared by adding bromine
(0.56 ml, 11 mmoles) to the solution of potassium thiocyanate
(2.33 g, 24 mmoles) in acetic acid (50 ml). The stirring was con-
tinued for 2 min and then the reaction mixture was poured into a
well-stirred mixture of sodium acetate (1.98 g, 24 mmoles) in
water (350 ml) and benzene (150 ml). The benzene layer was
separated and the aqueous layer was extracted with benzene
(twice 20 ml). The collected benzene extracts were washed three
times with 50 ml of 5% solution of sodium hydrogen carbonate or
3% solution of potassium carbonate, respectively, dried with
anhydrous sodium sulfate and evaporated to dryness in vacuo.
The residue was crystallized from an appropriate solvent (Table
1). In the cases when 3-bromo-1H,3H-quinoline-2,4-dione 4 was
present (according to tlc), the crude product was purified by col-
umn chromatography on silica gel using solvent system S as elu-
ent. The course of separation and also the purity of isolated sub-
stances were monitored by tlc. Isolated yields of 3-bromo-
1H,3H-quinoline-2,4-diones 4 are given in Table 1 (Method A).
General Procedure for the Preparation of 3-Alkyl/aryl-3-bromo-
1H,3H-quinoline-2,4-diones (4) (Method B).
EXPERIMENTAL
To the stirred solution of initial compound 1 (0.4 mmole) in
acetic acid (3 ml), bromine (0.042 ml, 0.82 mmole) was added.
After 5 min, the red solution was poured into water (25 ml) and
the yellow suspension was extracted twice with benzene (each
portion 20 ml). The collected extracts were dried with sodium
sulfate, evaporated to dryness in vacuo and crystallized to give
compounds 4 (Table 1). In the case of compounds 1j and 1m,
compounds 5j and 5m, respectively, were obtained by this proce-
dure (Table 1).
The melting points were determined on a Kofler block or
Gallenkamp apparatus and are uncorrected. The ir spectra were
recorded on a Perkin-Elmer 421 and 1310 and Mattson 3000
spectrophotometers using samples in potassium bromide disks.
The nmr spectra were recorded on a Bruker DPX-300 spectrome-
ter at 302 K in hexadeuteriodimethyl sulfoxide (unless otherwise
indicated). Chemical shifts are given on the d scale (ppm) and are
referenced to internal TMS. Some 13C chemical shifts are refer-
enced to deuteriochloroform. The column chromatography was
carried out on silica gel 70-230 mesh, 60 Å (Aldrich) using ben-
zene and then successive mixtures of benzene – ethyl acetate (in
rations from 99:1 to 8:2) as eluent (solvent system S). The course
of separation and also the purity of substances were monitored by
tlc (elution systems benzene-ethyl acetate, 4:1 and chloroform-
ethanol, 9:1) on Alugram® SIL G/UV254 foils (Macherey-
Nagel). Elemental analyses (C, H, N) were performed with a
General Procedure for the Bromination of 4-Hydroxy-1H-quino-
lin-2-ones 1j and 1m (Method C).
The procedure was the same as in method A, but only one half
of theoretical quantity of bromine was used. The benzene solu-
tion of crude reaction product was twice washed with potassium
carbonate solution (5%) to eliminate unreacted compound 1. The

1320
A. Klásek, J. Polis, V. Mrkvicˇka, and J. Kosˇmrlj
Vol. 39
solution was dried with sodium sulfate, evaporated to dryness
and repeatedly crystallized to obtain pure 3-bromo-1H-quinoline-
2,4-diones (4j and 4m), and 3,6-dibromo-1H-quinoline-2,4-
diones (5j and 5m), respectively (Table 1).
Republic of Slovenia (Grant No. P0-0503-0103) supported this
study. The authors thank to Mrs. H. Gerzˇová for technical help.
REFERENCES AND NOTES
General Procedure for the Reaction of 3-Benzyl-3-halogeno-
1H,3H-quinoline-2,4-diones (3b and 4b) and 3-Halogeno-1-
methyl-3-phenyl-1H,3H-quinoline-2,4-diones (3e and 4e) with
Sodium Hydrogen Sulfide.
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To the stirring solution of 3-bromo/chloro-1H,3H-quinoline-
2,4-dione 3 or 4 (5 mmoles) in dimethyl formamide (15 ml), 0.55
g (6 mmoles) of NaSH•2H20 was added in small portions during
2 hours. The reaction mixture was poured onto crushed ice (100
ml), precipitated product 1 was collected by filtration with suc-
tion and crystallized from the appropriate solvent. Compounds
1b (benzene, 81% from 3b and 83% from 4b) or 1e, (methanol-
ethyl acetate, 73% from 3e and 74% from 4e), respectively, were
obtained. The identity of isolated compounds was proved by
comparison of their ir spectra with that of authentic specimens
prepared by condensation of diethyl malonates with correspond-
ing anilines [7,12]. The mother liquors after crystallization of 1
were evaporated and extracted three times with methanol (5 ml
each). The insoluble portion was crystallized from benzene-
hexane to give pale yellow crystals, mp 110-2 °C, identified as
elemental sulfur (yields 69% from 3b, 62% from 4b, 57% from
3e, and 58% from 4b).
[3] R. D. Northcross and I. Paterson, Chem. Rev., 95, 2041
(1995); D. J. Faulkner, Nat. Prod. Rep., 12, 223 (1995).
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Tetrahedron, 56, 1551 (2000); [b] S. Kafka, A. Klásek, and J.
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General Procedure for the Reaction of 3-Chloro-1-methyl-3-
phenyl-1H,3H-quinoline-2,4-dione (3e) with Some Sulfur
Reagents.
[11] W. Stadlbauer, O. Schmut, and T. Kappe, Monatsh. Chem.,
111, 1005 (1980).
[12] J. W. Huffman,J. Org. Chem, 26, 1470 (1961).
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Kanaguchi, and S. Akai, Chem. Pharm. Bull, 45, 1887 (1997).
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Chem. Res., 676 (1999).
To the stirring solution of 3-chloro-1-methyl-3-phenyl-1H,3H-
quinoline-2,4-dione (3e) (1.42 g, 5 mmoles) in dimethyl for-
mamide (15 ml), appropriate sulfur reagent (thiourea, sodium
thiosulfate, potassium thioacetate, or potassium thiocyanate,
respectively) (6 mmoles) was added in small portions during 2
hours. The reaction mixture was diluted with water (100 ml), pre-
cipitated compound 1e was collected by filtration with suction
and crystallized from benzene. Yields: (%/sulfur reagent):
85%/thiourea, 56%/sodium thiosulfate, 79%/sodium thioacetate,
or 59%/potassium thiocyanate, respectively. In the case where
potassium thioacetate was used, 30% of the side product 6e was
isolated by repeated crystallization from benzene–cyclohexane.
[18] Y. S. Park and K. Kim, Tetrahedron Letters, 40, 6439
(1999).
[19] A. Khazaei, A. Alizadeh, and R. G. Vaghei, Molecules, 6,
253 (2001).
Acknowledgements.
The Ministry of Education, Youth and Sports of the Czech
Republic and the Ministry of Education, Science and Sport,
[20] Dainippon Pharm. Co., Ltd., Japan Patent 6903356
(1966); Chem. Abstr. 70, 87600n (1969).