Reaction of 1-substituted 3-aminoquinolinediones with isocyanic and isothiocyanic acid

Article abstract of DOI:10.1016/j.tet.2011.02.002

1-Substituted-3-aminoquinoline-2,4(1H,3H)-diones react with potassium cyanate or potassium thiocyanate in boiling acetic acid to give ureido- or thioureidooxindoles, spiro-oxindoles and dihydroimidazoquinolones. However, if the starting compounds are subs

Full text of DOI:10.1016/j.tet.2011.02.002

Tetrahedron 67 (2011) 2407e2413
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Reaction of 1-substituted 3-aminoquinolinediones with isocyanic and
isothiocyanic acid
a
a
b
,
c
a,
*
ꢀ
ꢀ
ꢀ
ꢁ
Vladimír Mrkvicka , Ondrej Rudolf , Antonín Lycka , Antonín Klasek
a Department of Chemistry, Faculty of Technology, Tomas Bata University,762 72 Zlín, Czech Republic
b Research Institute for Organic Syntheses (VUOS), Rybitví 296, 533 54 Pardubice 20, Czech Republic
c
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
University of Hradec Kralove, Faculty of Education, Rokitanskeho 62, CZ 500 03 Hradec Kralove 3, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Substituted-3-aminoquinoline-2,4(1H,3H)-diones react with potassium cyanate or potassium thiocy-
anate in boiling acetic acid to give ureido- or thioureidooxindoles, spiro-oxindoles and dihy-
droimidazoquinolones. However, if the starting compounds are substituted with a benzyl group at
position 3, a C-debenzylation proceeds to give imidazoquinolones. According to a proposed reaction
mechanism, a molecular rearrangement of the primarily formed mono-substituted urea or thiourea takes
place. All compounds were characterized by 1H, 13C and IR spectroscopy and MS data.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 September 2010
Received in revised form 12 January 2011
Accepted 1 February 2011
Available online 23 February 2011
Keywords:
a
eAminoketones
CeDebenzylation
Rearrangement
Thioxo group
Thiourea derivatives
R1
S
1. Introduction
R2
X
O
N
HN
NHR2
R1
O
R2
N
Recently, we published the reaction of 1-unsubstituted
3-amino-1H,3H-quinoline-2,4-diones 1 with isothiocyanic acid
(prepared in situ from potassium thiocyanate) in boiling acetic
acid.1 During a rearrangement of the addition products, novel 2,3-
dihydro-3-thioxoimidazo[1,5-c]quinazolin-5(6H)-ones 2 arose in
high yields. However, if the starting compounds were substituted
with a benzyl group at position 3, a C-debenzylation proceeded to
give 2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4(5H)-ones
3. When using thiourea as a source of thiocyanic acid, the yields of
compounds 2 and 3 were substantially lower. The reaction of 1 with
urea2 or potassium cyanate1 in boiling acetic acid resulted in no
observed C-debenzylation; instead, only 2,6-dihydro-imidazo[1,5-
c]quinazoline-3,5-diones 4 were obtained (Scheme 1).
These interesting results gave us the incentive to perform analo-
gous reactions with 1-substituted 3-amino-1H,3H-quinoline-2,4-
diones 5. We had studied the reaction of these compounds with urea
in acetic acid earlier3 and, depending on the type of substitution at
position 3 and on the nitrogen atom of the 3-amino group, four novel
types of heterocycliccompounds(6e9)could beobtained(Scheme2).
All of these compounds arose due to rearrangement of the in-
termediate 3-ureido-1H,3H-quinoline-2,4-diones or 9b-hydroxy-
N
or
N
H
N
O
N
H
O
1
H
2; X = S
4; X = O
3; if R1 = CH2Ph
Scheme 1.
3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones, which
are obtained by the reaction of 5 with nitrourea and subsequently
converted to 6e9 by boiling in acetic acid.4
In this work, we would like to describe the reaction of
1-substituted 3-amino-1H,3H-quinoline-2,4-diones 5 with potas-
sium cyanate or potassium thiocyanate in boiling acetic acid. In the
reaction of 5 with potassium cyanate, we expect the formation of
the same products (6e9) as those produced in the reaction with
urea.3 The production of novel sulfur analogues of compounds 6e9
are expected when using potassium thiocyanate. Finally, the for-
mation of 1-substituted analogues of compounds 3 is expected
when the starting compound bears a benzyl group at position 3.
2. Results and discussion
Reactions of 3-aminoquinolinediones 5 with the appropriate
reagent (Scheme 2) were performed by boiling the reaction
* Corresponding author. Fax: þ420 57 72 10 722; e-mail address: klasek@ft.utb.cz
ꢁ
(A. Klasek).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.002

ꢀ
V. Mrkvicka et al. / Tetrahedron 67 (2011) 2407e2413
2408
X
X
1
X
X
4´
2
R3
2´
1
Methods:
2´
COR2
O
1´
1´
N
5
2
N
4
7
4
NHR3
HN
5
8
3
H
H
A) KSCN, AcOH
B) KOCN, AcOH
C) urea, AcOH
N
NH
9
6
3
4
3
H
3a
4´
N
R3
9a
5a
R3
3a
NH
Pr
N
3a
3´a
2
R3
R2
O
or
2
1´´
R2
O
or
O
or
O
O
2´
1
N
N
1´
N
7a
7; X = O
6; X = O
10; X = S
N
N
4
7´a
7a
R1
R1
11; X = S
5
7´
7
R1
9; X = O
13; X = S
R1
R1
8; X = O
O
1
R3
X
2
12; X = S
1
N
2
HN
4
4´
HN
H
9
9a
N
3a
Key of substituents:
a
b
c
d
e
f
g
h
3´a
R3
5
1´´
Ph
R1 Me Me Me Ph Me Ph Me Ph
or
or
O
2´
R2 Bu
R3
Ph Bu Bu Ph Ph Bn Bn
Bu Bu Bu Bu Bu Bu
1´
N
5a
N
O
7´a
4
15; X = O
16; X = S
6
7´
R1
R1
H
H
14
Scheme 2.
components in acetic acid. Starting aminoketones 5 were prepared
from the corresponding 3-chloro derivatives in accordance with the
procedure described earlier.5 Potassium thiocyanate (method A) or
potassium cyanate (method B) were used as reagents. In two cases
(compounds 5g,h), urea was also used. In preliminary experiments,
reaction of thiourea with compounds 11 and 5 did not give good
results; accordingly, we did not use this reagent further in our
work. The trituration of the crude reaction product with sodium
hydroxide solution, described in our previous paper1 to remove
traces of cyanuric or 1,3,5-trithiocyanuric acid, was omitted due to
the high solubility of some reaction products in an alkaline
medium.
We have found that the reaction of 5aef with potassium cyanate
(method B) proceed in the same manner as those with urea.3
Compounds 6a,b,e,f, 7c,d, 8e,f and 9e were isolated (Table 1) in
yields comparable to those obtained from the reaction of 5aef with
urea.3 In addition, a new compound (Z)-7a was isolated. In the
presence of potassium thiocyanate (method A), the reaction of
compounds 5aef proceed as expected affording the novel com-
pounds 10b,f, 11a,c,d, 12e and 13f, sulfur analogues of compounds
6, 7, 8 and 9; all of these compounds were obtained in good yields
except for 10f and 12e, both having a phenyl group as substituent
R2. The NMR spectra of these new compounds are very similar to
those of compounds 6e9 (Tables 2e4), with the only significant
difference between them being the shift of the C]S group signals
to 179e196 ppm compared to the C]O group signals.3
Compounds 5g,h, bearing the benzyl group at position 3, react
with potassium cyanate (method B) differently to give only small
amounts of the expected compounds 14g,h. In the NMR spectra of
the observed products (Table 4), no signals corresponding to
a benzyl group are seen. Mass spectra of these products also in-
dicate that no benzyl group is present, leading us to identify these
products as structures 15g,h. The loss of the C-benzyl group is
surprising, as we do not observe this phenomenon in the potassium
cyanate reaction method with the analogous compounds unsub-
stituted at position 1.1 This observation indicates that not only the
very strong isothiocyanic acid (pKa ꢀ1.3),6,7 arising by isomeriza-
tion of weak thiocyanic acid (pKa 5.4),6 but also mesoscale isocyanic
acid (pKa 3.9), arising from isomerization of weak thiocyanic acid
(pKa 5.4),6 can eliminate the benzyl group from compounds 5g,h.
Thus, not only the acidity of the reaction medium, but also the type
of substituent at position 1 of the starting compounds 5 influence
the course of the reaction. In the reaction of 5g,h with isothiocyanic
acid (method A), C-debenzylated compounds 16g,h were obtained
in moderate yields as the only reaction products. This result is in
agreement with our expectation based on the results of the same
reaction using 1-unsubstituted analogues.1 However, these re-
actions afforded approximately half the expected yields for 16g,h
compared to reactions of 1-unsubstituted analogues1 indicating
that other transformations are able to produce side products, which
seemingly have not been isolated. The NMR spectra comparison of
compounds 15 and 16 (Table 4) shows a significant difference only
in the chemical shifts of the C]S and C]O groups. The same dif-
ference is seen in the comparison of NMR spectra for 11 and 14
(Table 3). However, these compounds can differ in their configu-
ration at the butylidene or benzylidene double bonds. The stereo-
chemistry of the individual compounds 7,11 and 14 was established
by 2D-NOESY experiments.
In our opinion, the formation of an E- or Z-isomer is dependent
on the steric conditions of intermediate D (Scheme 3). If D contains
a butyl group, a strong steric interaction exists between the N(3)-
butyl and C(4)-butyl or -benzyl groups, resulting unambiguously in
the formation of the isomers (E)-7c,d, (E)-11c,d and (E)-14g,h. If
there is a hydrogen atom at N(3), such a steric interaction does not
exist, and elimination of the proton occurs preferentially to give the
(Z)-7a and (Z)-11a isomers. We have observed similar behaviour in
analogous compounds isolated from the reaction of 3-butylquino-
linediones with isothiocyanates.8 In the case of compound 11a,
a mixture of both stereoisomers was isolated, but with a signifi-
cantly greater quantity of the Z-isomer (Table 3). Our proposal for
the reaction mechanism of the conversion of compounds 5 to the
products 6e16 (Scheme 3) is different from that described earlier.3
In our original proposal we thought to describe the mechanism of
the transformation of compounds 5 during their reaction with urea
by means of two different paths, depending on whether starting
compound 5 bore a primary or secondary amino group. However,
afterwards we prepared4 addition products of 5 with nitrourea,
whose structures corresponded to intermediates A and B in
Table 1
Reaction of 3-aminoquinolinediones 5 with potassium thiocyanate (method A),
potassium cyanate (method B) and urea (method C)
Entry
5
Substituents
Method Time
Product
(min) (yield, %)
R1
R2
R3
H
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Me
Bu
A
B
A
B
A
B
A
B
A
B
A
B
A
B
C
A
B
C
30
60
35
50
30
50
50
60
45
40
40
45
30
60
60
50
60
60
(E/Z)-11a (30)
6a (43)a, (Z)-7a (11)
10b (74)
Me
Me
Ph
Ph
Bu
Bu
Ph
Ph
Bn
H
6b (39)b
Bu
Bu
Bu
Bu
Bu
(E)-11c (68)
(E)-7c (70)a
(E)-11d (79)
(E)-7d (72)a
9
Me
Ph
12e (7)
10
11
12
13
14
15
16
17
18
8e (47)a, 6e (5)a, 9e (4)a
10f (13), 13f (8), NPI (6)c
8f (36)a, 6f (2)a
16g (33)
g
Me
15g (43), (E)-14g (13)
15g (38), (E)-14g (14)
16h (27)
15h (42), (E)-14h (16)
15h (42), (E)-14h (12)
h
Ph
Bn
Bu
a
Identical in all respects to the authentic compound.3
b
Mp 178e179 ꢁC (benzene/hexane), identical in all respects to the authentic
compound, for which incorrect mp 83e86 ꢁC was formerly published.3
c
N-Phenylisatin.

ꢀ
V. Mrkvicka et al. / Tetrahedron 67 (2011) 2407e2413
2409
Table 2
1H and 13C chemical shifts (
d, ppm) of compounds 5, 10 and 13 in DMSO-d6
Position
5g
5h
10b
10f
13f
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
2
3
3a
4
4a
5
6
7
d
171.8
74.4
d
d
172.0
74.4
d
d
172.3
56.6
125.6
123.5
d
d
173.4
d
174.1
58.8
127.1
129.7
d
d
d
6.09
d
5.72
d
58.4
5.70
d
b
d
d
a
b
d
195.2
121.0
126.7
122.9
136.4
d
d
195.5
120.7
126.9
123.2
136.2
d
7.35
d
7.36
d
d
d
d
a
d
b
7.82
7.18
7.62
d
7.91
7.16
7.43
d
7.05
7.35
7.03
d
122.1
128.8
108.6
144.3
d
7.11
7.11
7.32
d
123.0
127.7
121.8
142.5
d
a
a
b
b
7a
8
8a
d
d
d
142.5
d
7.12
d
115.5
142.5
29.6
d
6.14
d
116.4
143.4
137.4
129.2
128.8
130.5
130.3
128.9
46.7
d
d
d
d
d
d
d
10(R1)
20(R1)
3.33
d
d
3.20
d
26.5
d
d
a
135.7
d
144.6
116.7
b
7.30
7.05
7.64
7.59
7.57
3.27
3.21
d
6.93
30(R1)
d
d
d
d
7.25
129.2
a
b
40(R1)
10(R2)
d
d
d
d
d
6.86
d
119.9
d
a
b
3.09
47.0
132.2
d
132.1
20(R2)
30(R2)
40(R2)
50(R2)
10(R3)
20(R3)
30(R3)
40(R3)
10(NH)
20(C]S)
40(C]O)
d
133.7
129.8
127.6
127.0
44.1
32.2
19.8
13.9
d
133.8
130.2
128.0
127.2
44.1
32.2
19.8
13.9
d
8.01
7.59
7.71
d
128.7
128.5
133.1
d
d
d
a
b
b
b
6.89
7.10
7.10
2.27
1.38
1.31
0.86
2.50
d
7.04
7.19
7.19
2.42
1.39
1.30
0.87
2.60
d
a
d
d
a
d
d
d
d
d
d
11.67
d
d
3.75
1.62
1.33
0.94
10.75
d
40.3
29.4
19.5
13.7
d
3.73
1.57
1.29
0.90
10.72c
d
40.2
29.4
19.5
13.7
d
d
d
d
d
d
11.32
d
d
d
d
181.3
167.9
183.7
170.1
182.9
d
d
d
d
d
d
d
d
a
dH¼7.18e7.64.
b
dC¼126.2e130.3.
c
dH¼7.51 (NHC6H5).
Table 3
1H and 13C chemical shifts (
d, ppm) of compounds 7, 11 and 14 in DMSO-d6
Position
(Z)-7a
(Z)-11aa
(E)-11aa
(E)-11c
(E)-11d
(E)-14g
(E)-14h
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
1 (NH)
2
4
7.54
d
d
9.22
d
d
9.15
d
d
9.45
d
d
9.60
d
d
7.94
d
d
8.12
d
d
159.8
138.2
65.9
174.7
130.2
124.1
123.2
129.8
109.0
143.9
26.5
d
181.6
139.9
69.7
173.4
128.4
124.3
123.4
130.3
109.3
143.8
22.3
d
179.6
139.6
68.6
172.4
128.1
124.5
123.5
130.4
109.3
143.4
22.4
d
179.8
139.0
66.7
172.3
128.2
124.3
123.6
130.5
109.3
143.5
26.6
d
179.6
139.1
66.9
157.7
140.1
63.6
173.3
129.2
123.7
122.9
129.8
108.8
143.4
26.1
d
157.5
139.5
63.7
d
d
d
d
d
d
d
5
d
d
d
d
d
d
d
20
d
d
d
d
d
171.9
128.0
124.9
124.2
130.5
109.7
143.3
133.8
126.3
130.1
128.7
103.1
27.5
d
d
172.5
129.1
124.5
123.7
130.0
109.4
143.3
133.7
126.1
129.5
128.2
100.2
134.6
3a0
40
d
d
d
d
d
d
d
7.27
7.14
7.41
7.10
d
7.25
7.17
7.43
7.12
d
7.31
7.17
7.46
7.12
d
7.21
7.17
7.47
7.17
d
7.32
7.23
7.41
6.85
d
7.19
7.02
7.23
6.64
d
7.36
7.15
7.27
6.51
d
50
60
7
7a0
10(R1)
20(R1)
30(R1)
40(R1)
100
3.17
d
3.18
d
3.22
d
3.24
d
d
2.80
d
d
7.43
7.68
7.58
4.93b
1.64
1.41
1.15
1.06
0.60
d
3.93b
3.81b
1.49
1.40
0.99
7.05
7.57
7.47
5.94b
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
b
3.61
1.90
96.2
27.5
3.81
2.03b
99.2
27.4
4.77
101.5
27.1
4.84b
1.42
1.27
1.07
0.98
0.55
d
102.7
27.2
5.82b
d
99.4
134.3
b
200
1.24
1.16
1.00
0.90
0.52
d
300
1.19
22.4
1.22
22.3
22.4
22.4
22.5
6.52
129.2
6.64
129.0
400
0.77
d
9.34b
13.3
d
0.78
d
10.77b
13.3
d
13.5
d
13.4
d
13.5
d
6.98
6.98
3.64b
3.56b
1.67b
1.45
1.01
127.2
125.9
39.3
7.01
7.01
3.67b
3.59b
1.69b
1.47
1.02
127.6
126.1
39.3
500
10(R3)
d
d
10.71
d
3.90 b
3.78 b
1.59
1.40
0.98
42.2
42.3
b
20(R3)
30(R3)
40(R3)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
27.9
19.4
14.0
27.9
19.4
13.9
28.1
19.3
13.9
28.1
19.5
13.9
a
Measured as a 2.6:1 mixture of (Z)- and (E)-isomers.
Through-space interaction observed in NOESY allowing geometrical isomer determination and, for (Z)-7a, also the assignment of NH protons.
b

ꢀ
V. Mrkvicka et al. / Tetrahedron 67 (2011) 2407e2413
2410
Table 4
1H and 13C chemical shifts (
d, ppm) of compounds 12, 15 and 16 in DMSO-d6
Position
12e
15g
15h
16g
16h
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
1 (NH)
2
3a
4
5a
6
7
8
9
d
d
12.01
d
d
12.17
d
d
13.78
d
d
13.39
d
d
d
194.3
83.6
165.1
141.3
116.9
135.5
124.2
126.2
116.9
182.8
30.3
d
153.7
113.1
152.8
136.5
115.6
128.5
122.2
121.5
110.9
128.1
28.8
d
153.8
113.1
152.9
137.6
116.4
128.3
122.5
121.5
110.8
129.0
137.8
129.6
130.0
128.9
d
166.8
110.1
152.4
137.0
115.9
122.6
122.3
129.5
117.4
131.8
29.1
d
167.0
110.1
152.5
138.4
117.5
122.8
122.2
129.0
117.5
132.5
137.4
129.5
130.1
129.3
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
7.43
7.69
7.31
7.96
d
7.59
7.56
7.34
7.89
d
6.60
7.34
7.32
7.98
d
7.62
7.62
7.38
8.12
d
6.59
7.43
7.34
8.20
d
9a
9b
d
d
d
d
d
10(R1)
20(R1)
30(R1)
40(R1)
10(R2)
20(R2)
30(R2)
40(R2)
10(R3)
3.48
d
3.69
d
d
3.70
d
d
7.38
7.67
7.60
d
7.39
7.67
7.62
d
d
d
d
d
d
d
d
d
d
d
d
d
d
131.9
126.1
130.1
130.4
45.9
d
d
d
d
7.06
7.51
7.51
3.83
3.53
1.76
1.29
1.20
0.82
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
4.05
40.9
4.03
41.0
4.48
44.4
4.45
44.5
20(R3)
28.1
1.68
31.9
1.68
31.9
1.75
30.9
1.70
30.8
30(R3)
40(R3)
19.8
13.6
1.32
0.93
19.4
13.7
1.32
0.92
19.4
13.7
1.28
0.98
19.4
13.8
1.35
0.92
19.4
13.7
H+
N
X
3
X
X
1
HN
C(X)NH2
NR3
O
HN
HO
NR3
R2
O
9
b
NR3
R3
N
3a
b
a
R2
O
5 + HNCX
CH2Ph
O
a
4
+
- PhCH2
- H2O
N
N
N
O
5
N
6
R1
R1
A
R1
R1
B
C
8; X = O
12; X = S
if R2 = CH2Ph
15; X = O
16; X = S
X
X
X
a
NR3
NR3
H
NR3
NHC(X)NHR3
NHC(X)N(R3)COR2
O
O
H
HN
HN
HN
R2
R2 H2O
+
O
H2O
Y
O
O
O
N
- H+
N
N
N
N
R1
R1
R1
9; X = O
13; X = S
R1
D
R1
E
7; X = O, Y = Pr
6; X = O
10; X = S
if R3 = H or R2 = Ph
if R2 = Bu, CH2Ph
11; X = S, Y = Pr
14; X = O, Y = Ph
Scheme 3.
Scheme 3. Both identically substituted compounds A, B and also 8
(prepared by dehydration of B) were rearranged in boiling acetic
acid under formation of the same reaction product. Compounds of
type 8 derived from primary amines 5 (R3¼H) could not be
obtained by dehydrating compounds B (R3¼H). Hence, it was
considered that the rearrangement occurs with these compounds
already in the stage of aminocarbinol B.
The alternative path b, which is dominant in the reactions of
5g,h with isothiocyanic acid (method A), leads to debenzylated
compounds 15g,h and 16g,h. It is still unclear why compounds 5g,h
are debenzylated also by the weak isocyanic acid, considering such
reactions were not observed when using analogous 1-unsub-
stituted compounds 1.1
Therefore, we suppose that compounds 5 react with isocyanic or
isothiocyanic acid to give intermediate A that cyclizes to form in-
termediate B and subsequently dehydrates to give intermediate C.
This intermediate is one of the final products in cases where R2¼Ph
(compounds 8 and 12). The crucial step in the mechanism is the acid-
catalyzed migration of the amide group in B or C tothe C(9b), to form
intermediate D (path a). If a hydrogen atom is present on the first
carbon atom of the substituent R2 (R2¼Bu or CH2Ph), it is eliminated
to form compounds 7,11 and 13. If R2 is a phenyl group, the addition
of water to intermediate D leads to the formation of intermediate E,
inwhich the imidazolidine ringopens to afford compounds 6 and 10,
and their hydrolytic products 9 and 13. It is interesting to note that
compounds 6 and 10 arise via intermediate E even in cases where
R3¼H. We never observed the elimination of the hydrogen from the
N(3) atom of intermediate D to give a C]N bond.
3. Conclusions
In conclusion, we would like to emphasize that the described
reaction of 3-aminoquinolinediones 5 with isocyanic or iso-
thiocyanic acid allows the preparation of 3-ureido- or thiour-
eidooxindoles and different types of spiro-oxindole derivatives in
good yields. While many biologically active compounds contain
sulfur atoms,9,10 compounds 10e13 could also be interesting
structures for further studies.
The C-debenzylation of starting compounds 5 bearing a benzyl
group at position 3 not only has theoretical significance but also
enables the targeted preparation of compounds 15 and 16 by
a simple procedure. To our surprise, only one compound 15, de-
scribed as the eOH tautomer (5-butyl-2-hydroxy-1-methyl-1,5-
dihydro-imidazo[4,5-c]quinolin-4-one), and only one compound

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V. Mrkvicka et al. / Tetrahedron 67 (2011) 2407e2413
2411
16, described as the eSH tautomer (5-butyl-2-mercapto-1-methyl-
1,5-dihydro-imidazo[4,5-c]quinolin-4-one), were found in the lit-
erature.11 Both of these compounds, which induce contraction in
tracheal strips of passively sensitized guinea pigs, were prepared by
five different multi-step reactions starting from 3-nitro-quinolin-2-
ones bearing the hydroxy, chloro, or methylamino substituents in
position 4 and also from N-butylisatoic anhydride.
%): 398 (Mþ, 2), 307 (100), 252 (13), 223 (13),196 (8),195 (7),167 (8),
91 (25), 77 (9), 65 (5). For NMR spectra see Table 2. Anal. Calcd
(found) for C26H26N2O2: C 78.36 (78.55); H 6.58 (6.65); N 7.03 (7.12).
4.3. General procedure for the preparation of compounds
6e15
A mixture of the appropriate 3-aminoquinolinedione (5aeh)
(2.5 mmol) and the appropriate reagent (see below) in acetic acid
(3 mL) was heated to reflux for the time given in Table 1. The course
of the reaction was monitored by TLC. After cooling, the reaction
mixture was poured onto ice (50 g). The precipitated product was
filtered off with suction, washed with water, dried and crystallized
from an appropriate solvent or column chromatographed.
Reagents: method A: potassium thiocyanate (583 mg, 6 mmol);
method B: potassium cyanate (487 mg, 6 mmol); method C: urea,
see Ref. 3.
4. Experimental
4.1. General
Melting points were determined on a Kofler block or Gallen-
camp apparatus. IR (KBr) spectra were recorded on a Mattson 3000
spectrophotometer. NMR spectra were recorded on a Bruker
Avance spectrometer (500.13 MHz for 1H, 125.76 MHz for 13C and
50.68 MHz for 15N) in DMSO-d6. 1H and 13C chemical shifts are
given on the
d scale (ppm) and are referenced to internal TMS. All
2D experiments (gradient-selected (gs)-COSY, NOESY, gs-HMQC,
gs-HMBC) were performed using manufacturer’s software. Proton
spectra were assigned using gs-COSY. Protonated carbons were
assigned by gs-HMQC. Quaternary carbons were assigned by gs-
HMBC. The positive-ion EI mass spectra were measured on a Shi-
madzu QP-2010 instrument within the mass range m/z¼50e600
using direct inlet probe (DI). Samples were dissolved in dichloro-
4.3.1. (Z)-4-Butylidene-10-methyl-10H-spiro[imidazolidine-5,30-in-
dole]-2,20-indole (7a). Compound was prepared besides 6a from 5a
in 11% yield (method B). Colourless crystals, mp 236e238 ꢁC (ethyl
acetate/hexane); IR: 3254, 3104, 2950, 2929, 2869, 1724, 1713, 1694,
1617, 1496, 1472, 1450, 1391, 1370, 1355, 1314, 1239, 1192, 1161, 1130,
1106,1060,1022,973,896,848, 801, 757, 728, 697, 679, 539cmꢀ1. EIMS
(m/z, %): 271 (Mþ, 86), 242 (82), 228 (39), 214 (14), 200 (100),188 (82),
171 (16),160 (45),146 (31),132 (50),117 (14),104 (24), 84 (17), 77 (23),
54 (22), 41 (12). For NMR spectra see Table 3. Anal. Calcd (found) for
C15H17N3O2: C 66.40 (66.24); H 6.32 (6.32); N 15.49 (15.54).
methane (30 mg/mL) and 10 mL of the solution was evaporated in DI
cuvette at 50 ꢁC. The ion source temperature was 200 ꢁC; the en-
ergy of electrons was 70 eV. Only signals exceeding relative abun-
dance of 9% are listed. Column chromatography was carried out on
Silica gel (Merck, grade 60, 70e230 mesh) using chloroform and
then successive mixtures of chloroform/ethanol (in rations from
99:1 to 8:2) or benzene and then successive mixtures of benzene/
ethyl acetate (in rations from 99:1 to 8:2). Reactions as well as the
course of separation and also the purity of substances were mon-
itored by TLC in elution systems benzene/ethyl acetate (4:1),
chloroform/ethanol (9:1 and/or 19:1) and chloroform/ethyl acetate
(7:3) on AlugramÒ SIL G/UV254 foils (MachereyeNagel). Elemental
analyses (C, H and N) were performed with a EA 1108 Elemental
Analyzer (Fisons Instrument).
4.3.2. 3-(30-Benzoylthioureido)-1-methyl-2-oxo-2,3-di-hydro-1H-in-
dole (10b). Compound was prepared from 5b in 74% yield (method
A). Yellowish crystals, mp 219e220 ꢁC (benzene); IR: 3245, 3060,
3033, 2934, 2900, 1709, 1684, 1613, 1532, 1494, 1469, 1449, 1423,
1375, 1353, 1311, 1259, 1197, 1169, 1125, 1087, 1074, 1054, 1019, 981,
940, 932, 913, 879, 821, 786, 753, 697, 664, 643, 594, 539 cmꢀ1. EIMS
(m/z, %): 325 (17), 204 (18), 188 (6), 161 (15), 146 (13), 118 (16), 105
(100), 91 (10), 77 (54), 51 (16). For NMR spectra see Table 2. Anal.
Calcd (found) for C17H15N3O2S: C 62.75 (62.66); H 4.65 (4.63); N
12.91 (12.93); S 9.85 (9.79).
4.2. Preparation of 3-aminoquinoline-2,4(1H,3H)-diones (5)
4.3.3. 3-(30-Benzoyl-30-butyl-thioureido)-1-phenyl-2-oxo-2,3-dihy-
dro-1H-indole (10f). Compound was prepared from 5f besides 13f
and N-phenylisatin in 13% yield (method A). Colourless crystals, mp
173e176 ꢁC (benzene/hexane); IR: 3187, 3061, 3050, 2957, 2930,
2870, 1749, 1629, 1592, 1576, 1506, 1492, 1447, 1436, 1405, 1353,
1313, 1288, 1232, 1223, 1181, 1161, 1123, 1079, 1027, 966, 949, 924,
855, 822, 792, 759, 729, 697, 659, 625, 550, 518 cmꢀ1. EIMS (m/z, %):
443 (Mþ, 14), 279 (22), 180 (8), 105 (100), 77 (38). For NMR spectra
see Table 2. Anal. Calcd (found) for C26H25N3O2S: C 70.40 (70.36); H
5.68 (5.69); N 9.47 (9.61); S 7.23 (7.14).
Starting 1-substituted 3-amino-1H,3H-quinoline-2,4-diones
5aeh were prepared from corresponding 3-chloro derivatives
according to the general procedure described in literature.5 Two
new derivatives (5g,h) were prepared.
4.2.1. 3-Benzyl-3-butylamino-1-methyl-1H,3H-quinoline-2,4-dione
(5g). Compound was prepared from 3-benzyl-3-chloro-1-methyl-
1H,3H-quinoline-2,4-dione and butyl-amine in 53% yield. Colour-
less crystals, mp 70e71 ꢁC (cyclohexane); IR: 3312, 3032, 2961,
2928, 2861, 2824, 1691, 1652, 1599, 1492, 1472, 1435, 1412, 1362,
1302, 1282, 1245, 1207, 1179, 1149, 1121, 1079, 1051, 1033, 939, 917,
845, 769, 750, 735, 701, 661, 633, 587, 526 cmꢀ1. EIMS (m/z, %): 336
(Mþ, 2), 246 (16), 245 (100), 203 (7), 191 (12), 190 (15), 189 (7), 161
(15), 146 (7), 118 (6), 104 (5), 91 (26), 77 (8), 65 (6). For NMR spectra
see Table 2. Anal. Calcd (found) for C21H24N2O2: C 74.97 (75.09); H
7.19 (7.23); N 8.33 (8.14).
4.3.4. (E/Z)-4-Butylidene-10-methyl-2-thioxo-10H-spiro[imidazoli-
dine-5,30-indole]-20-one (11a). Compound was prepared from 5a in
30% yield (method A). Colourless crystals, mp 182e187 ꢁC (ethyl
acetate/hexane); IR: 3241, 3156, 2957, 2928, 2867, 1731, 1709, 1612,
1518, 1470, 1416, 1366, 1349, 1302, 1205, 1158, 1125, 1102, 1006, 952,
753, 695, 593, 539 cmꢀ1. EIMS (m/z, %): 288 (19), 287 (Mþ, 100), 258
(39), 244 (22), 216 (55), 200 (53), 184 (13), 172 (11), 146 (12), 143
(10), 118 (12), 117 (14), 116 (11), 115 (10), 102 (10), 77 (12), 41 (11).
For NMR spectra of both stereoisomers see Table 3. Anal. Calcd
(found) for C15H17N3OS: C 62.69 (62.62); H 5.96 (6.04); N 14.62
(14.51); S 11.16 (10.85).
4.2.2. 3-Benzyl-3-butylamino-1-phenyl-1H,3H-quinoline-2,4-dione
(5h). Compound was prepared from 3-benzyl-3-chloro-1-phenyl-
1H,3H-quinoline-2,4-dione and butyl-amine in 61% yield. Colourless
crystals, mp 137e139 ꢁC (benzene/hexane); IR: 3310, 3061, 3032,
2948, 2926, 2869, 2823, 1696, 1660, 1598, 1494, 1466, 1454, 1438,
1347, 1303, 1268, 1241, 1205, 1183, 1162, 1112, 1089, 1073, 1026, 942,
917, 843, 780, 767, 735, 701, 664, 651, 557, 542, 525 cmꢀ1. EIMS (m/z,
4.3.5. (E)-3-Butyl-4-butylidene-10-methyl-2-thioxo-10H-spiro[imida-
zolidine-5,30-indole]-20-one (11c). Compound was prepared from 5c
in 68% yield (method A). Colourless crystals, mp 152e154 ꢁC

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V. Mrkvicka et al. / Tetrahedron 67 (2011) 2407e2413
2412
(benzene/hexane); IR: 3405, 3314, 3058, 2955, 2930, 2868, 1735,
1723, 1677, 1609, 1492, 1468, 1438, 1418, 1368, 1343, 1303, 1291,
1251, 1194, 1156, 1129, 1109, 1279, 1021, 985, 942, 878, 853, 760, 693,
668, 565, 539 cmꢀ1. EIMS (m/z, %): 343 (Mþ, 100), 314 (52), 310 (36),
298 (14), 286 (51), 282 (35), 272 (23), 258 (55), 256 (20), 244 (11),
226 (14), 216 (28), 213 (24), 204 (20), 200 (29), 184 (25), 143 (14),
140 (11), 130 (11), 115 (15), 77 (10), 55 (17), 41 (40). For NMR spectra
see Table 3. Anal. Calcd (found) for C19H25N3OS: C 66.44 (66.40); H
7.34 (7.35); N 12.23 (12.22); S 9.34 (9.13).
besides 15h from 5h in respective yields 16% (method B) and 12%
(method C). Colourless crystals, mp 161e165 ꢁC (benzene/hexane);
IR: 3199, 3080, 2951, 2931, 2870, 1740, 1717, 1663, 1615, 1596, 1501,
1480,1465,1445,1432,1370,1327,1295,1281,1251,1233,1210,1177,
1134, 1114, 1089, 1039, 1026, 986, 940, 924, 897, 816, 786, 750, 702,
676, 628, 583, 551 cmꢀ1. EIMS (m/z, %): 424 (30), 423 (Mþ, 100), 395
(10), 381 (12), 319 (19), 318 (80), 290 (30), 277 (13), 263 (11), 262
(56), 251 (13), 250 (75), 194 (26), 117 (34), 91 (31), 90 (10), 77 (23),
66 (10), 41 (16). For NMR spectra see Table 3. Anal. Calcd (found) for
C27H25N3O2: C 76.57 (76.59); H 5.95 (5.95); N 9.92 (9.78).
4.3.6. (E)-3-Butyl-4-butylidene-10-phenyl-2-thioxo-10H-spiro[imida-
zolidine-5,30-indole]-20-one (11d). Compound was prepared from 5d
in 79% yield (method A). Colourless crystals, mp 147e150 ꢁC (ben-
zene/hexane); IR: 3406, 3056, 3013, 2957, 2930, 2869, 1720, 1669,
1615,1596,1500,1464, 1417,1355, 1327, 1297, 1287,1260, 1227, 1213,
1199,1175,1150,1114,1092,1049,1028,1003, 978, 938, 820, 774, 751,
702, 666, 618, 559, 510 cmꢀ1. EIMS (m/z, %): 406 (29), 405 (Mþ, 100),
378 (26), 377 (98), 376 (48), 373 (33), 372 (56), 360 (12), 350 (11), 349
(30), 348 (57), 345 (17), 344 (67), 335 (24), 334 (42), 321 (10), 320
(23), 318 (18), 316 (11), 289 (15), 288 (13), 279 (14), 278 (73), 276 (12),
275 (35), 274 (15), 266 (17), 262 (17), 261 (15), 247 (14), 246 (30), 219
(10), 218 (10), 217 (13), 205 (11), 204 (15),180 (15),140 (14),128 (10),
115 (12), 77(34), 55 (18), 54(17), 51 (12), 41 (44). For NMR spectrasee
Table 3. Anal. Calcd (found) for C24H27N3OS: C 71.08 (71.00); H 6.71
(6.73); N 10.36 (10.43); S 7.91 (7.78).
4.3.11. 3-Butyl-5-methyl-1H-imidazo[4,5-c]quinoline-2,4(3H,5H)-di-
one (15g). Compound was prepared from 5g besides (E)-14g in
respective yields 43% (method B) and 38% (method C). Colourless
crystals, mp 289e290 ꢁC (chloroform/ethyl acetate); IR: 2954,
2870, 2824, 2748, 1685, 1657, 1638, 1593, 1571, 1528, 1466, 1376,
1354, 1323, 1294, 1245, 1227, 1168, 1117, 1086, 1044, 968, 940, 903,
881, 857, 826, 746, 726, 710, 665, 650, 551, 539 cmꢀ1. EIMS (m/z, %):
272 (10), 271 (Mþ, 55), 254 (11), 229 (12), 228 (26), 216 (16), 215
(100), 200 (15). For NMR spectra see Table 4. Anal. Calcd (found) for
C15H17N3O2: C 66.40 (66.50); H 6.32 (6.30); N 15.49 (15.70).
4.3.12. 3-Butyl-5-phenyl-1H-imidazo[4,5-c]quinoline-2,4(3H,5H)-di-
one (15h). Compound was prepared from 5h besides (E)-14h in
42% yield (method B, method C). Colourless crystals, mp
329e333 ꢁC (acetic acid); IR: 3102, 3036, 2955, 2874, 2809, 2727,
1706, 1663, 1636, 1594, 1567, 1520, 1491, 1468, 1453, 1416, 1373,
1324, 1280, 1246, 1226, 1171, 1153, 1118, 1096, 1070, 1050, 1012, 934,
892, 824, 794, 750, 729, 702, 654, 601, 503 cmꢀ1. EIMS (m/z, %): 334
(15), 333 (Mþ, 63), 316 (16), 304 (11), 291 (18), 290 (20), 278 (21),
277 (100), 276 (53), 262 (15), 77 (24). For NMR spectra see Table 4.
Anal. Calcd (found) for C20H19N3O2: C 72.05 (71.91); H 5.74 (5.75); N
12.60 (12.43).
4.3.7. 3-Butyl-5-methyl-3a-phenyl-2-thioxo-3,3a-dihydro-5H-imi-
dazo[4,5-c]quinoline-2-one (12e). Compound was prepared from 5e
in 7% yield (method A). Yellow crystals, mp 175e180 ꢁC (benzene/
hexane); IR: 2957, 2936, 2894, 2873, 2855, 1689, 1609, 1589, 1469,
1448, 1399, 1356, 1324, 1283, 1270, 1253, 1219, 1165, 1126, 1064, 1043,
1013, 993, 969, 860, 776, 751, 726, 697, 659, 619, 612, 571, 529 cmꢀ1
.
EIMS (m/z, %): 363(Mþ, 29), 331 (25), 330(100), 320(10), 307 (31), 293
(12), 292 (24), 248 (10), 204 (19),118 (12),104 (48),103 (10), 77 (16), 41
(13). For NMR spectra see Table 4. Anal. Calcd (found) for C21H21N3OS:
C 69.39 (69.49); H 5.82 (5.85); N 11.56 (11.49); S 8.82 (8.65).
4.3.13. 3-Butyl-2,3-dihydro-5-methyl-2-thioxo-1H-imid-azo[4,5-c]
quinolin-4(5H)-one (16g). Compound was prepared from 5g in 33%
yield (method A). Colourless crystals, mp 299e303 ꢁC (benzene);
IR: 3029, 2954, 2927, 1670, 1638, 1588, 1571, 1525, 1481, 1458, 1433,
1392, 1324, 1295, 1245, 1215, 1164, 1115, 1084, 1043, 970, 844, 775,
745, 732, 679, 624, 593, 583, 521 cmꢀ1. EIMS (m/z, %): 287 (Mþ, 60),
255 (16), 254 (84), 244 (11), 243 (10), 232 (29), 231 (100), 203 (11),
202 (36), 117 (12), 116 (13). For NMR spectra see Table 4. Anal. Calcd
(found) for C15H17N3OS: C 62.69 (62.51); H 5.96 (5.99); N 14.62
(14.51); S 11.16 (10.85).
4.3.8. 1-Butyl-3-(2-oxo-1-phenylindolin-3-yl)thiourea
(13f). Compound was prepared besides 10f and N-phenylisatin
from 5f in 8% yield (method A). Colourless crystals, mp 111e114 ꢁC
(cyclohexane), get blue on air and light; IR: 3330, 3166, 3048, 2959,
2932, 2871, 1745, 1598, 1580, 1510, 1499, 1455, 1438, 1413, 1352,
1283, 1260, 1229, 1190, 1174, 1129, 1110, 1081, 1033, 923, 878, 826,
797, 748, 693, 649, 637, 618, 577, 540 cmꢀ1. EIMS (m/z, %): 340 (23),
339 (Mþ, 100), 337 (12), 266 (31), 250 (10), 237 (13), 224 (29), 223
(12), 209 (13), 208 (33),195 (29),181 (16), 180 (92),179 (19), 77 (18),
74 (16), 72 (16), 66 (7), 51 (7), 41 (11). For NMR spectra see Table 2.
Anal. Calcd (found) for C19H21N3OS: C 67.23 (67.37); H 6.24 (6.33); N
12.38 (12.43); S 9.45 (9.39).
4.3.14. 3-Butyl-2,3-dihydro-5-phenyl-2-thioxo-1H-imid-azo[4,5-c]
quinolin-4(5H)-one (16h). Compound was prepared from 5h in 27%
yield (method A). Colourless crystals, mp 349e350 ꢁC (acetic acid);
IR: 3154, 3120, 3069, 3055, 2958, 2932, 2871, 2733,1672,1634,1591,
1565, 1518, 1478, 1459, 1393, 1362, 1338, 1323, 1294, 1278, 1258,
1235, 1214, 1160, 1119, 1096, 1071, 1046, 1029, 1004, 943, 852, 836,
755, 733, 699, 681, 662, 605, 561, 513 cmꢀ1. EIMS (m/z, %): 350(17),
349 (Mþ, 71), 317 (34), 316 (100), 307 (11), 306 (10), 294 (37), 293
(97), 292 (68), 277 (11), 275 (10), 274 (10), 261 (12), 260 (20), 205
(14), 77 (32), 51 (14), 41 (14). For NMR spectra see Table 4. Anal.
Calcd (found) for C20H19N3OS: C 68.74 (68.92); H 5.48 (5.45); N
12.02 (12.21); S 9.18 (9.12).
4.3.9. (E)-4-Benzylidene-3-butyl-10-methyl-10H-spiro-[imidazoli-
dine-5,30-indole]-2,20-indole (14g). Compound was prepared from
5g besides 15g in respective yields 13% (method B) or 14% (method
C). Colourless crystals, mp 198e200 ꢁC (benzene/hexane); IR: 3216,
3085, 3012, 2960, 2932, 2873, 1734, 1719, 1666, 1613, 1494, 1470,
1456,1426,1371,1342,1305,1261,1229,1175,1155,1127,1088,1066,
1011, 945, 923, 898, 863, 824, 786, 751, 700, 674, 666, 620, 539 cmꢀ1
.
EIMS (m/z, %): 362 (25), 361 (Mþ, 100), 319 (15), 276 (10), 270 (15),
256 (39), 247 (14), 228 (51), 215 (13), 200 (41), 189 (13), 188 (99),
160 (34), 132 (42), 131 (25), 118 (14), 117 (50), 116 (16), 104 (14), 91
(62), 90 (17), 89 (14), 77 (15), 41 (30). For NMR spectra see Table 3.
Anal. Calcd (found) for C22H23N3O2: C 73.11 (72.92); H 6.41 (6.41); N
11.63 (11.58).
Acknowledgements
This study was supported by the Ministry of Education, Youth
and Sports of the CzechRepublic (Grant No. MSM 7088352101) and
the Czech Science Foundation (Grant No. 203/07/0320). The au-
thors thank Dr. R. Vícha for mass spectra measurement and Mrs. H.
4.3.10. (E)-3-Butyl-4-benzylidene-10-phenyl-10H-spiro-[imidazoli-
dine-5,30-indole]-2,20-dione (14h). Compound was prepared
Gerzova for technical help (both Faculty of Technology, Tomas Bata
University in Zlín).
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2413
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5. Kafka, S.; Klasek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002, 57, 1659.
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Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.002.
7. Chiang, Y.; Kresge, A. J. Can. J. Chem. 2000, 78, 1627.
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8. Klasek, A.; Mrkvicka, V.; Lycka, A.; Miksík, I.; Ruzicka, A. Tetrahedron 2009, 65,
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References and notes
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