Reaction of 1-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones with urea. Synthetic route to novel 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones, 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′- diones, and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones

Article abstract of DOI:10.1016/S0040-4020(03)00785-3

1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with urea in boiling acetic acid to give products depending on the type of substitution in position 3 and at the nitrogen atom of the 3-amino group. Starting compounds bearing a primary amino group in position 3 give 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones. Starting compounds bearing a secondary amino group in position 3 react according to the character of the other substituent in position 3. If there is a hydrogen atom α to the carbon atom C(3), 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′- diones arise. If a hydrogen atom is not present in this position, the reaction leads to 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. Reaction mechanisms for these transformations are proposed. All compounds were characterized by their ¹H, ¹³C, IR and atmospheric pressure chemical ionization mass spectra and some of them also by ¹⁵N NMR data.

Full text of DOI:10.1016/S0040-4020(03)00785-3

Tetrahedron 59 (2003) 5279–5288
Reaction of 1-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones
with urea. Synthetic route to novel
3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones,
4-alkylidene-10H-spiro[imidazolidine-5,30-indole]-2,20-diones,
and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones
a
Antonın Klasek, Kamil Koristek, Antonın Lycka and Michal Holcapek
a
b
c
,
*
´
´
ˇ
´
ˇ
ˇ
a
´
Department of Chemistry and Environmental Technology, Faculty of Technology, Tomas Bata University, 762 72 Zlın, Czech Republic
´
b
Research Institute for Organic Syntheses, 532 18 Pardubice-Rybitvı, Czech Republic
cDepartment of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, 53210 Pardubice, Czech Republic
Received 18 February 2003; revised 22 April 2003; accepted 15 May 2003
Abstract—1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with urea in boiling acetic acid to give products depending
on the type of substitution in position 3 and at the nitrogen atom of the 3-amino group. Starting compounds bearing a primary amino group in
position 3 give 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones. Starting compounds bearing a secondary amino group in position 3 react
according to the charac0ter of the other substituent in position 3. If there is a hydrogen atom a to the carbon atom C(3), 4-alkylidene-10H-
spiro[imidazolidine-5,3 -indole]-2,20-diones arise. If a hydrogen atom is not present in this position, the reaction leads to 3,3a-dihydro-5H-
imidazo[4,5-c]quinoline-2,4-diones. Reaction mechanisms for these transformations are proposed. All compounds were characterized by
1
their H, 13C, IR and atmospheric pressure chemical ionization mass spectra and some of them also by 15N NMR data. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
only where the starting compound 1 contains a secondary
lactam group in the quinoline nucleus. Therefore, we
decided to study the reaction of urea with compounds
analogous to 1, but containing a tertiary lactam group in the
quinoline ring. In our present study, we demonstrate that
1-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones 5 react
with urea in boiling acetic acid in a different manner to
unsubstituted compounds 1. Depending on the character of
substitution in starting compounds 5, either a molecular
rearrangement of the quinolone system to indolinone system
comes about with formation of hitherto undescribed 3-(3-
acylureido)-2,3-dihydro-1H-indol-2-ones 60or 4-alkylidene-
10H-spiro[imidazolidine-5,30-indole]-2,2 -diones 7, or
Recently, an unprecedented reaction of 3-amino-1H,3H-
quinoline-2,4-diones 1 with urea in boiling acetic acid
has been described.1 The expected 3,3a-dihydro-5H-
imidazo[4,5-c]-quinoline-2,4-diones 2 do not arise but a
molecular rearrangement takes place, producing
novel 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones
3 (Scheme 1). Their formation was proposed to take
place via intermediate A containing an isocyanate
group.
An isocyanate mechanism may, of course, be applicable
Scheme 1.
Keywords: molecular rearrangement; urea derivatives; a-aminoketones; reaction mechanism; NMR; MS.
*
Corresponding author. Tel.: þ420-576-031-413; fax: þ420-577-210-722; e-mail: klasek@ft.utb.cz
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00785-3

´
A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5280
Scheme 2.
expected 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-
diones 8 arise.
substitution at the nitrogen atom in the same position in
starting compounds 5. Therefore, the following survey of
results and discussion is divided into three parts according
to this criterion.
2. Results and discussion
The first group is formed by starting compounds bearing a
primary amino group in position 3 (5a, 5b). From the results
of elemental analyses, it followed that products of their
reaction with urea have one molecule of water more than
expected. In the 1H NMR spectra of the products, two
doublets for protons corresponding to the CH–NH grouping
appear at 5.21 and 9.06 ppm or 5.31 and 9.35 ppm,
respectively. The signal of CH carbon atom in this grouping,
according to results of 2D experiments, appears in 13C NMR
spectrum at approx. 52 ppm. This implies the atom in
question is C(3) of 3-acylamino-2,3-dihydro-1H-indol-2-
one because the signal of atom C(3) in quinolone derivatives
5 ranges from 67–77 ppm2 and the signal of C(3) in
3-acyloxy-2,3-dihydro-1H-indol-2-ones lies in the region
69–71 ppm.3 Besides the signal of the mentioned NH group
at 9.06 or 9.35 ppm, signals of another NH group appear in
Reactions were performed in the same manner as in our
previous paper,1 i.e. by boiling amines 5 with urea in a
solution of acetic acid. The starting amines 5 were obtained
from the corresponding chloro derivatives 4 in accordance
with procedures described in Ref. 2 (Scheme 2). NMR
spectral characteristics of starting compounds are presented
in Table 1.
Products, which markedly differ from each other in spectral
characteristics (IR, MS, NMR), were obtained in good to
very good yields from the reaction of amines 5 with urea.
Even the results of elemental analyses of some reaction
products were not in accord with the assumed structures. We
soon recognized that product structure depended both on the
character of substituent in position 3 as well as on the
Table 1. 1H and 13C NMR shifts (d, ppm) of compounds 4a and 5a,c,d,g (in DMSO-d6)
Position
4a
5a
5c
5d
5g
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
2
3
4
4a
5
6
7
8
8a
–
–
–
–
7.97
7.33
7.84
7.49
–
166.39
67.98
188.00
118.91
128.02
123.71
137.17
116.32
142.17
30.46
–
36.19
26.64
22.25
13.64
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.86
7.27
7.76
7.41
–
3.43
2.20
1.52, 1.57a
1.02, 1.17a
1.06
0.72
–
–
–
–
–
–
–
–
–
172.94
68.93
195.62
120.06
126.98
123.00
136.04
115.66
142.69
29.84
–
42.01
25.16
22.02
13.77
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.89
7.25
7.76
7.40
–
3.45
Not found
1.71, 1.77a
1.06, 1.16
1.13
0.74
2.28, 2.31a
1.35
1.28
0.84
–
–
–
–
–
–
–
172.50
73.58
195.23
120.62
126.97
123.00
136.37
115.75
142.66
29.67
44.08
39.73
25.11
22.18
13.70
44.08
32.26
19.83
13.70
–
–
–
–
–
7.95
7.24
7.57
6.38
–
172.65
74.07
195.25
120.29
127.21
123.28
136.09
116.59
143.60
–
–
–
–
–
7.86
7.18
7.52
6.39
–
–
Not found
–
–
–
171.48
77.54
192.90
120.59
127.64
123.48
136.03
116.74
143.17
–
CH3 (1)
NH (NH2)
10(3)
3.41
–
–
1.91
1.91b
1.23b
1.23
0.82
2.44b
1.41b
1.34
0.87
–
7.37
7.66b
7.58
–
–
–
–
–
–
–
–
2.30
1.31
1.27
0.85
–
–
–
–
–
–
–
–
–
–
–
–
39.89
25.33
22.30
13.90
44.13
32.36
19.93
13.90
137.54
129.24
130.35
128.98
–
200(3)
3 (3)
40(3)
–
–
10(3–N)
20(3-N)
30(3-N)
40(3-N)
ipso-Ph (1)
o-Ph (1)
m-Ph (1)
p-Ph (1)
ipso-Ph (3)
o-Ph (3)
m-Ph (3)
p-Ph (3)
2.46, 2.60a
1.47
1.35
0.89
–
44.48
32.36
20.00
13.99
137.60
130.39
130.60b
128.79
137.60
126.89
129.09
129.19
–
–
–
–
–
–
–
7.44b
7.69b
7.60
–
7.51
7.43
7.37
–
–
–
–
–
–
–
–
a
Prochiral methylene group.
Broad signal.
b

´
A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5281
Scheme 3.
the 1H NMR spectra of products from reaction of 5a and 5b
with urea at 10.44 or 10.88 ppm, and three signals of
carbonyl groups are present in their 13C NMR spectra at
152.95, 173.84 and 175.08 ppm, or at 153.25, 168.37 and
173.96 ppm, respectively. The signal at highest field must
belong to the NH–CO–NH fragment, the other two are then
signals for carbon atoms of amide and lactam groups. The
identification of the fragments mentioned above and results
of 1D and 2D NMR experiments led us to formulate
structures 6a and 6b (Scheme 3) for products of the reaction
of 5a and 5b with urea. Even though more than one hundred
derivatives of 3-aminoindolin-2-one have been described in
the literature, only six of these have an acylated amino
group and none have an acylated carbamoyl group.
All signals in H and 13C NMR spectra of compounds 6a
and 6b were assigned to the corresponding atoms (Table 2)
on the basis of COSY, HMBC and HMQC experiments, and
their positions are in accord with the proposed structure.
Assigning the signals to the corresponding atoms is
supported in particular by proved interactions C(2)O with
N–CH3, C(3)H and N(10)H; C(20)O with C(3)H and N(10)H;
C(40)O with N(30)H and pertinent protons of the R group in
HMBC spectra. In addition to the peaks of protonated
molecules, the MS and MS/MS spectra of 6a and 6b show
characteristic ammonium ions [C6H4N(CH3)COCHNH3]þ
(m/z 163) formed by the cleavage of the bond between N-10
and C-20 followed by the loss of ammonia (m/z 146).
Both spectra also yield other structurally important ions,
1
1
Table 2. H and 13C NMR shifts (d, ppm) of compounds 6a,b, 10e,g, and 11e (in DMSO-d6)
Position
6a
6b
10ea
10ga
11e
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
2
3
3a
4
5
6
7
7a
–
5.21
–
173.84
52.41
127.13
122.13
122.13
128.64
108.44
143.99
26.27
–
–
5.31
–
173.96
52.67
128.26
123.48
122.24
128.20
108.54
144.13
26.37
–
153.25
–
168.37
–
–
–
–
5.25
–
173.92
53.43
126.32
124.20
122.82
129.20
108.30
143.90
26.54
–
–
5.39
–
7.46
7.12
7.26
6.82
–
–
9.90
–
–
–
3.69
1.50
1.10
0.72
–
7.41
7.46
7.49
–
173.36
53.70
126.02
124.45
123.29
129.08
109.55
144.09
–
–
5.00
–
175.18
52.80
128.67
123.31
122.03
128.30
108.25
143.85
26.15
–
157.53
–
–
40.18
32.13
19.68
13.85
–
7.26
7.06
7.36
7.00
–
3.16
9.06
–
7.33
7.08
7.36
7.05
–
3.18
9.35
–
10.88
–
–
–
–
–
–
8.01
7.57
7.68
–
–
–
–
7.38
7.06
7.31
6.84
–
3.27
9.79
–
7.22
7.06
7.32
7.00
–
3.14
6.68
–
N–CH3
100
–
2
152.95
–
154.78
–
154.78
–
30
10.44
–
–
–
6.18
–
40
1-Bu
175.08
35.42
26.57
21.71
13.77
–
–
–
–
–
175.08
47.07
31.55
19.66
13.39
136.09
126.02
128.61
130.36
–
175.11
47.07
31.56
19.66
13.39
136.10
126.02
128.62
130.40
134.43
126.69
129.62
128.16
2.36
1.56
1.32
0.91
–
–
–
–
–
3.67
1.48
1.09
0.71
–
7.40
7.43
7.46
–
3.00
1.39
1.30
0.91
–
–
–
–
–
2-Bu
3-Bu
4-Bu
–
ipso-Ph (40)
o-Ph (40)
m-Ph (40)
p-Ph (40)
ipso-Ph (1)
o-Ph (1)
m-Ph (1)
p-Ph (1)
132.62
128.76
128.33
133.02
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.48
7.53
7.39
–
–
–
a
In deuteriochloroform.

´
A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5282
Table 3. 1H and 13C NMR shifts (d, ppm) of compounds 7c and 7d (in
DMSO-d6)
to shift to the oxygen atom in position 4, is present in the
molecule of 3-hydroxy-1H,3H-quinoline-2,4-diones and,
therefore, these smoothly rearrange.3,4 However, the
hydrogen atom of the amino group in compounds 5 becomes
acidic only after substitution of the ureido group for an
amino group. The suggested reaction mechanism
(Scheme 3) presumes in the first stage a reaction of 5 with
isocyanic acid (arising by thermal breakdown of urea)
producing intermediate B containing a sufficiently acidic
hydrogen atom. This intermediate rearranges similarly to
3-hydroxy-1H,3H-quinoline-2,4-diones3,4 and intermediate
C is produced through a 1,2-shift of the carboxamide group.
An analogous intermediate, bearing an acyl group in
position 3, arises as a by-product of the rearrangement of
3-hydroxy-1H,3H-quinoline-2,4-diones.3 Further trans-
formation of intermediate C produces epoxide D, which
opens giving rise to intermediate E. It is only at this stage
that a further course of rearrangement appears, differen-
tiated from rearrangements of 3-hydroxy-1H,3H-quinoline-
2,4-diones. Intramolecular substitution of the amino group
for the iminoester group in position 3 gives rise to
intermediate F, which is tautomeric with product 6.
However, even direct formation of epoxide D from
intermediate B cannot be ruled out.
Position
7c
7d
dH
dC
dH
dC
2
4
–
–
–
–
–
7.24
7.16
7.45
7.14
–
7.79
3.39, 3.47
1.54
1.35
0.97
4.51
1.23, 1.35
0.95, 1.05
0.54
3.22
–
157.76
137.49
63.31
173.57
129.23
124.13
124.40
130.12
109.08
143.65
–
38.93
28.43
19.36
13.84
98.54
28.06
22.66
13.45
26.43
–
–
–
–
–
–
7.36
7.24
7.41
6.86
–
7.97
3.46, 3.5?
1.57
1.38
0.97
4.61
1.48, 1.62
1.02, 1.29
0.59
–
157.72
137.55
63.54
173.16
128.58
124.83
124.11
130.22
109.54
143.35
–
39.06
28.10
19.41
13.88
99.04
27.12
22.83
13.57
–
5
20
3a0
40
50
60
70
7a0
NH
1 (3)
2 (3)
3 (3)
4 (3)
1 (4)
2 (4)
3 (4)
4 (4)
CH3 (10)
ipso-Ph0 (10)
o-Ph (1 )
m-Ph (10)
p-Ph (10)
–
133.98
126.28
130.07
128.42
–
–
–
–
–
–
7.44
7.68
7.56
The second group of starting compounds 5 consists of
compounds bearing a mono-substituted amino group in
position 3 (5c–g). These compounds react with urea in a
different manner depending on whether the substituent
bound in position 3 is aliphatic or aromatic. Compounds 5c
and 5d bear a butyl group in position 3 as well as on the
nitrogen atom of the amino group. Products of their reaction
with urea again possess a basic 2,3-dihydro-1H-indol-2-one
structure as with 6a and 6b, which was deduced from a
signal present at approx. 63 ppm in their 13C NMR spectra
(Table 3). This signal corresponds to carbon atom C(3) and
is shifted to a lower field compared to signals of carbon
atoms C(3) in compounds 6a and 6b. Both products of the
reaction 5c and 5d with urea show the presence of an
[C6H4N(CH3)COCH(NCO)]þ, [C6H5CONH3]þ, and
[C6H5CO]þ for 6b and [C6H4N(CH3)COCH(NHCONH3)]þ
for 6a.
Recently, base catalysed or thermally induced rearrange-
ment of 3-alkyl/aryl-3-hydroxy-1H,3H-quinoline-2,4-
diones to 3-acyloxy-1,3-dihydro-2H-indol-2-ones have
been described.3,4 In the case of 3-amino derivatives 5,
their rearrangement to compounds 6 could be its nitro-
geneous analogy and the reaction mechanism should be
similar. Using TLC monitoring, we proved that amines 5a
and 5b themselves do not change even at temperatures high
above their melting points, and that only at temperatures
above 2608C does their undefined breakdown to a complex
mixture of compounds occur. It is hence obvious, for
facilitating rearrangement, that the presence of an acidic
hydrogen atom on a heteroatom in position 3 is important.
The acidic hydrogen atom of the hydroxyl group, being able
1
N-butyl group in H and 13C NMR spectra. However, the
second butyl group, initially bound to carbon C(3) in
compounds 5c and 5d, transformed after the reaction in both
cases into a butylidene group. Protons of the two methylenes
of this group and the N–CH2 group are diastereotopic. From
1
the proton-detected H–15N HMBC experiment it follows
Scheme 4.

´
A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5283
that one of the three nitrogen atoms present in the molecule
is of NH type and its proton interacts with the other nitrogen
atom by means of 3J (15N, 1H), which supports the presence
of an NH(CO)N arrangement in the molecule. The third
nitrogen atom shows—with the product of the reaction of 5d
with urea—correlation with ortho protons of the phenyl
group and also with a proton whose chemical shift has a
value of 6.86 ppm. All these results led to formulating
structures 7c and 7d (Scheme 4) for products of the reaction
compounds 5c,d to isocyanic acid, forming through break-
down of urea, with production of intermediate G. In the case
of intermediate G, however, a hydrogen atom at the 3-amino
group is not available as it was with intermediate B in the
case of rearranging compounds 5a,b (Scheme 3). For this
reason a 1,4-hydrogen shift cannot occur and intermediate
H must directly arise, analogous to intermediate D in
Scheme 3. When starting compounds for this intermediate
were 5a,b, the C–C bond of the epoxide ring would open,
conditioned by the 1,5-hydrogen shift in intermediate D.
However, in the case of rearranging compounds 5c,d
(Scheme 4) this position in intermediate H is occupied by
a butyl group. For this reason, an opening of the epoxide
ring comes about in the C–O bond by a nucleophilic attack
of the carbamoyl group with the formation of aminal
intermediate I. If a hydrogen atom is present a to the
hydroxyl group of I, a molecule of water eliminates and
compounds 7c,d arise (Scheme 4). When proposing the
transformation of compounds 5a,b (Scheme 3), we took into
account two paths for producing intermediate D. In the light
of the results provided by compounds 5c,d transforming into
7c,d (Scheme 4) we regard the path leading directly through
intermediate D as being the more probable.
1
of 5c and 5d with urea. All signals in H and 13C NMR
spectra of compounds 7c and 7d were assigned to the
corresponding atoms on the basis of COSY, HMBC and
HMQC experiments (Table 3) and their positions are in
accord with the proposed structure. Assignment of the
signals to the corresponding atoms is especially supported
by proving an interaction of C(2)O0 with N(1)H and protons
of a-methylene group at N(3); C(2 )O with vCH proton of
butylidene group (7c,d) and N–CH3 (7c). E-Stereo-
chemistry at the double bond of compounds 7c and 7d
follows from a NOE experiment proving a spatial
interaction of the proton of the C(4)vCH group with
protons of the first two methylenes of the N-butyl group.
The APCI mass spectra of compounds 7c and 7d exhibit
predominant [MþH]þ ions with very low fragmentation.
The appearance of both spectra is identical but shifted in m/z
values according to the difference between methyl and
phenyl substituent. The characteristic cleavage for these
compounds containing an imidazole moiety is the neutral
loss of the whole aliphatic chain from the position N(3)
yielding the corresponding ammonium fragment ions
followed by the loss of HNCO or NH3.
Compounds 5e–g bear a phenyl group in position 3. If their
rearrangement took place during the reaction with urea, we
should expect a similar reaction course up to the
intermediate stage, which would be similar to intermediate
I in Scheme 4. In such an intermediate, however, a hydrogen
atom in a to the hydroxyl group would not be available and
elimination of water would have to occur only during a
subsequent molecular rearrangement. Surprisingly, we
isolated products 8e–g (Scheme 5) from the reaction of
compounds 5e–g with urea. More than one hundred
imidazo[4,5-c]quinolin-2-ones are known and a number of
these display biological activity, but none are substituted in
position 3a. Three signals of carbonyl groups appear in the
13C NMR spectra of products of the reactions of 5e,f,g with
urea; two of these are at approx. 166 ppm and the third at
approx. 183 ppm (Table 4). This last signal should not
To the best of our knowledge, spiro-compounds of type 7
have not been described in the literature so far and only their
analogues having an oxygen atom in position 4 instead of an
alkylidene group are known. A proposed reaction mechan-
ism for compounds 5c,d transforming into 7c,d is given in
Scheme 4. In this case, it must be also assumed that the
primary reaction is the addition of the amino groups of
Scheme 5.

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5284
Table 4. 1H and 13C NMR shifts (d, ppm) of compounds 8e,f,g and 9e (in DMSO-d6)
Position
8e
8f
8g
9e
a
a
dC
a
a
dC
a
dH
a
dC
dH
dH
dC
dH
dC
dH
2
3a
4
5a
6
7
8
9
9a
–
–
–
–
7.39
7.66
7.28
7.90
–
–
–
3.47
–
3.12, 3.40
1.27, 1.53
1.18
0.79
–
7.07
7.43
7.43
–
–
–
–
7.03
7.46
7.12
7.89
–
166.23
77.43
166.62
141.07
116.71
135.38
124.09
126.48
117.31
183.83
–
166.55
78.05
166.90
140.90
115.47
134.74
123.97
126.85
117.76
183.38
–
–
–
–
–
7.35
7.64
7.28
7.90
–
–
–
3.44
–
3.29
c
164.59
77.54
166.72
141.03
116.70
135.25
124.10
126.40
117.46
183.12
–
–
–
–
–
6.37
7.29
7.15
8.01
–
166.48
78.49
–
–
–
–
7.06
7.36
7.01
7.12
–
4.77
5.22
3.52
–
3.48, 3.20
1.79, 1.37
1.15
161.51
70.28
169.19
138.72
114.91
130.17
123.39
130.23
119.04
61.95
–
167.22
142.02
117.42
134.43
124.22
126.85
117.38
183.26
–
9b
–
–
–
–
N–H
N–CH3
N–Ph
1 (3)
2 (3)
3 (3)
4 (3)
ipso-Ph (3a)
o-Ph (3a)
m-Ph (3a)
p-Ph (3a)
3.44
–
3.40, 3.15
1.62, 1.36
1.17
0.77
–
7.01
30.20
–
29.95
–
30.22
–
54.24
–
–
29.81
–
b
b
42.19
30.04
19.74
13.72
133.15
126.14
129.96
130.07
42.76
30.19
20.12
13.56
134.75
126.13
129.74
129.74
3.42, 3.18
1.68, 1.41
1.20
0.79
–
7.01
42.78
30.19
20.21
13.61
136.76
126.47
129.72
130.04
43.95
31.45
20.26
13.30
135.53
127.33
128.77
128.99
c
c
c
c
c
0.79
–
7.32
7.34
7.32
–
132.97
126.46
129.79
130.16
7.12
7.43
7.43
7.27
7.24
7.27
7.24
a
In deuteriochloroform.
N-Phenyl group is not symmetrical at the NMR timescale, all hydrogen and carbon atoms are non-equivalent and considerably broadened (ipso-C: –/132.98;
b
c
other detectable signals: 7.59, 7.52, 7.31, 7.18/130.76, 130.22).
All hydrogen and carbon atoms of cyclohexyl group are non-equivalent. 1H NMR: 3.29, 2.15, 2.03, 1.98, 1.82, 1.51 (2H), 1.24, 1.06, 0.82, and 0.52 ppm. 13
C
NMR: 54.24 (CH), 29.64, 28.12, 25.92, 25.53, and 25.06 (all CH2). From HMQC spectra the following correlations for methylene groups were found: 2.15
and 2.03/29.64, 1.98 and 0.52/28.12, 1.82 and 1.24/25.92, 1.51 and 0.82/25.53, 1.51 and 1.06/25.06.
belong to the keto group because the signal of the CvO
group in 5 has a value of approx. 196 ppm.2 Nevertheless, it
could relate to the CvN–C(O)–N fragment even though, in
our opinion, it lies at a field value too low and does not
correspond to the respective value in simulated 13C NMR
spectra of compounds 8. Several imidazolin-2-ones contain-
ing the CvN–C(O)–N grouping are known, for instance
D3-adamantano[2,1-d]imidazolin-2-one,5 4,5,5-triphenyl-
1,5-dihydroimidazol-2-one,6 4,5-diphenyl-5-methyl-1,5-
dihydroimidazol-2-one,7 and 3-acetyl-4,5-dimethyl-2-oxo-
3,4-dihydro-2H-imidazole-4-carboxylic acid dimethyl
ester.8 We did not, however, succeed in finding any 13C
NMR data for these or similar compounds in the literature.
In the NMR spectra of compound 8e (Table 4), the N-methyl
group was correlated with the CvO group at 166.62 ppm
and the N-methylene group was correlated with the CvO
group at 166.23 ppm. Protons of the first two methylenes of
the butyl group are prochiral and, in HMBC, correlations of
this sp3 carbon atom (77.43 ppm) with the ortho protons
of the phenyl group and protons of the N–CH2 group are
clear. Also in HMBC, correlation of the signal at
183.83 ppm with the peri-proton H(9) (7.90 ppm, 3J) is
quite clear as well as a weak interaction with proton H(6)
(4J). From these it follows that the carbon resonating at
183.83 ppm is bound directly to an aromatic nucleus. When
measuring the proton-detected correlation 1H–15N in
DMSO-d6, merely two chemical shifts obtained by
correlation through 3J were found. When measuring a
more concentrated solution in deuteriochloroform, a
correlation additionally found was that of the nitrogen
atom of the CvN group with the proton H(9) (7.89 ppm,
4J), a weak interaction with the proton H(6) (7.03 ppm, 5J),
and no correlation was found (by means of 4J) with protons
of the N-methyl group which should be detectable in the
case of condensation with lactam carbonyl. The 15N
chemical shifts (measured in deuteriochloroform and
referred to external nitromethane) are 272.7 (vN–),
2253.7 (N–CH3), and 2259.5 (N–C4H9) ppm. All these
data support the structure 8e.
In order to obtain further evidence for the correctness of the
structure as presented, compound 8e was reduced with zinc
in acetic acid (Scheme 5). The structure of the reduction
product 9e followed unambiguously from interpretation of
its NMR spectra (Table 4). The mutual NOE enhancement
between protons H-9b and H-9 due to their space proximity
in compound 9e independently proves the site of conden-
sation of compound 5a with urea. The site in which
reduction of 8e occurred is also confirmed by the 15N NMR
spectrum of 9e. Existence of the NH group (created in the
reduction) was proved by means of 1J (15N,H) (88.3 Hz) and
the 15N chemical shift of the CvN group (272.7 ppm in 8e)
changed to a value 2290.7 ppm for the CH–NH group in
9e. Chemical shifts of the remaining nitrogen atoms are
2275.0 ppm (N–C4H9) and 2251.1 ppm (N–CH3) (in
deuteriochloroform). The molecular mass of 9e was
confirmed on the basis of [MþH]þ ion as the only peak in
the MS spectrum. The fragmentation paths observed in MS/
MS measurements follow the same rules as described for
other compounds and hence they enable confirmation of the
structure.
More complex NMR spectra than those of compound 8e are
exhibited by cyclohexyl derivative 8f (Table 4), in which all
hydrogen and carbon atoms of the cyclohexyl group are
non-equivalent due to its restricted rotation. In the case of
diphenyl derivative 8g all hydrogen and carbon atoms of the
N-phenyl group are non-equivalent, which is caused by the

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5285
fact that the group is not symmetrical on the NMR timescale
(Table 4). The protonated molecules are the only peaks
observed in APCI mass spectra of compounds 8e and 8g. In
the case of compound 8f, the base peak of [MþH]þ ion is
accompanied by a less intensive peak corresponding to the
neutral loss of cyclohexene from the protonated molecule
which is also the only peak in MS/MS spectrum of m/z 374.
The neutral losses of H2O, HNCO, CO, and butene are
observed in MS/MS spectra of 8e and 8g and additionally
the loss of C6H4 for 8g. The fragmentation behaviour is in
accordance with the suggested structures.
substituent R3 may rearrange, though to a limited extent.
The mechanism of this rearrangement is not quite clear yet
but we presume that aminal intermediate J (Scheme 5)
might originate to a limited degree through a succession of
reactions similar to rearrangement of compounds 5c,d. A
molecule of water cannot split off from intermediate J
owing to the phenyl group present in position 4. Therefore,
an opening of the imidazole ring thus occurs, maybe with a
1,5-hydrogen shift, to give compounds 10.
From the text above it is apparent that a reaction—very
simple at first glance—of a-aminoketones with urea can
proceed in a very complex manner and offer great surprises.
However, it should be realized that the system in question is
really quite complex, and apart from urea in excess contains
isocyanic acid, ammonia, perhaps also biuret and cyanuric
acid. The described reaction of 3-amino-1H,3H-quinoline-
2,4-diones (5) with urea is not merely interesting from a
theoretical point of view but, owing to the simple reaction
protocol, presents an easy pathway to preparing novel
heterocyclic systems that might be interesting structures for
studying biological activity.
Employing column chromatography of mother liquors after
crystallization of the main product (8e) of the reaction of 5e
with urea, we succeeded in isolating three further minor
compounds (Scheme 5). The first of them is urea derivative
11e, as determined from the NMR (Table 2) and mass
spectra. Compound 11e dissociates so easily that the
[MþH]þ ion has only 2% relative abundance in the APCI
mass spectrum measured under standard conditions. The
special soft setting of tuning parameters (i.e. ‘compound
stability’ parameter reduced to 20%) increases the relative
abundance of [MþH]þ ion to 100%, which confirms the
expected molecular weight. The structures of fragment ions
with m/z 146 and 163 are the same as for compounds 6a and
6b. The characteristic cleavage of the whole aliphatic chain
(m/z 146) leading to the base peak in the MS/MS spectrum
of compound 11e distinguishes between two potential
structures with a five-membered indole ring and a six-
membered quinoline ring. The latter possibility is reason-
ably excluded, because the main loss of CH3CH2CH2CH2-
NHCONH2 from [MþH]þ ion is a logical fragmentation
path for the indole-containing structure but highly
improbable for the quinoline-containing alternative.
3. Experimental
Melting points were determined on a Kofler block or
Gallencamp 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, 50.68 MHz for 15N) in DMSO-
d6 or CDCl3. 1H and 13C chemical shifts are given on the d
scale (ppm) and are referenced to internal TMS. 15N
chemical shifts were referred to external neat nitromethane
in co-axial capillary (d¼0.0). All 2D experiments (gradient-
selected (gs)-COSY, NOESY, proton-detected gs-HMQC,
gs-HMBC) were performed using manufacturer’s software.
Proton spectra were assigned using gs-COSY. Benzene ring
protons were assigned according to their characteristic
multiplet pattern. Protonated carbons were assigned by gs-
HMQC. Quaternary carbons were assigned by gs-HMBC.
The positive-ion APCI mass spectra were measured on an
ion trap analyser Esquire 3000 (Bruker Daltonics, Bremen,
Germany) within the mass range m/z¼50–500. Samples
were dissolved in acetonitrile and analysed by direct
infusion at the flow rate of 50 ml/min. The ion source
temperature was 350EC, the APCI probe temperature was
350EC, the flow rate and the pressure of nitrogen were
4 l/min and 45 psi, respectively. For MS/MS measurements,
the isolation width of precursor ions was 4 m/z and the
collision amplitude was in the range 0.7–0.8 V. The tuning
parameter ‘compound stability’ was reduced to 20% for the
measurement of compound 9e. Column chromatography
was carried out on Silica gel (Merck, grade 60, 70–230
mesh) using chloroform and then successive mixtures of
chloroform–ethanol (in ratios from 99:1 to 8:2, solvent
system S1) or benzene and then successive mixtures of
benzene–ethyl acetate (in ratios from 99:1 to 8:2, solvent
system S2). Reactions as well as the course of separation
and also the purity of substances were monitored by TLC
(elution systems benzene–ethyl acetate, 4:1, and chloro-
form–ethanol, 9:1 and/or 19:1) on Alugramw SIL G/UV254
foils (Macherey-Nagel). Elemental analyses (C, H, N) were
The second isolated minor product of the reaction of 5e with
urea is the benzoyl derivative of 11e. Its structure (10e),
analogous to that of compounds 6a and 6b, results from
interpreting NMR spectra (Table 2). Compound 11e almost
certainly originates through hydrolysis of 10e during
processing of the reaction mixture. Benzoic acid, arising
simultaneously during hydrolysis of 10e, was isolated as the
third minor product.
From the reaction of the 1,3-diphenyl derivative 5g with
urea, which proceeds with relatively low yield as compared
to similar reactions of other compounds 5, we managed to
isolate (using column chromatography), besides the main
product 8g, minor product 10g. Its structure was resolved by
interpreting NMR spectra (Table 2) and it is in good
agreement with those of compounds 6a,b, 10e and 11e. The
MS and MS/MS spectra of compounds 10e and 10g are
nearly identical differing only in the relative abundances of
particular ions but with the mass shift of 62 mass units
similarly to the pair of compounds 7c and 7d. The base peaks
in MS spectra are [MþH]þ ions used for the molecular weight
determination and [MþH–CH3CH2CH2CH2NCO]þ ions are
the base peaks in MS/MS spectra. All identified fragment ions
can be correlated with the structures.
From the structure of the side-products 10e, 10g, and 11e it
follows that even starting compounds 5 that do not have
available a hydrogen atom capable of elimination in

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A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5286
performed with a EA 1108 Elemental Analyzer (Fisons
Instrument).
dione (5) (5 mmol) and urea (1.8 g, 30 mmol) in acetic
acid (10 ml) was refluxed for 30–50 min and the course of
the reaction was monitored by TLC. After cooling, the
reaction mixture was diluted with water (150 ml). The
precipitated product (6a,b, 7c,d, 8f) was filtered off with
suction and recrystallized from the appropriate solvent.
3.1. General procedure for the preparation of 3-chloro-
1H,3H-quinoline-2,4-diones (4a–g)
Compounds 4a–g were prepared by reaction of appropriate
4-hydroxy-1H-quinolone-2-one with sulfuryl chloride
according to procedure described in Ref. 2.
The reaction (30 min) of 5e (4.84 g, 15 mmol) with urea
(5.36 g, 90 mmol) in acetic acid (12 ml) afforded a crude
reaction product (3.98 g, portion A), which was, according
to TLC, a mixture of several compounds. The filtrate after
separation of portion A was extracted with benzene
(3£15 ml). The combined extracts were dried over sodium
sulfate and evaporated in vacuo (0.62 g, portion B). The
main reaction product (8e) (2.35 g, 45%) was obtained by
crystallization of crude reaction product (portion A) with
benzene. The mother liquors after crystallization of 8e were
column chromatographed on silica gel using solvent system
S2. After evaporation of combined fractions and crystal-
lization, three substances were isolated in the following
elution order: 10e (70 mg, 1.3%), 8e (180 mg, 3.5%), and
11e (69 mg, 1.8%). Portion B was column chromatographed
on silica gel using solvent system S1. After evaporation of
combined fractions and crystallization, two substances were
isolated in the following elution order: 8e (12 mg, 0.2%) and
11e (48 mg, 1.0%). The non-crystallized portions after
chromatography were collected and, after evaporation to
dryness, extracted with 5% solution sodium hydrogen
carbonate (5£3 ml). The combined extracts were filtered
and the filtrate was acidified with conc. hydrochloric acid.
Separated crystals were filtered off and identified (mp, IR)
as benzoic acid (16 mg, 0.8%).
3.1.1. 3-Butyl-3-chloro-1-methyl-1H,3H-quinoline-2,4-
dione (4a). Yield 58% (after column chromatography,
solvent system S2). Yellow oil, IR: 2958, 2933, 2871, 1707,
1675, 1602, 1472, 1359, 1302, 1108, 1089, 764, 751, 672,
643, 529 cm21. Anal. calcd (found) for C14H16ClNO2: C
63.28 (63.07); H 6.07 (6.15); N 5.27 (5.01).
3.2. General procedure for the preparation of 3-amino-
1H,3H-quinoline-2,4-diones (5a–g)
Compounds 5a–g were prepared by the reaction of
appropriate 3-chloro-1H,3H-quinoline-2,4-dione with an
amine (Method A) or a mixture of ammonium chloride
and potassium carbonate (Method B), respectively, in
dimethylformamide according to the general procedures
described in Ref. 2.
3.2.1. 3-Amino-3-butyl-1-methyl-1H,3H-quinoline-2,4-
dione (5a). Yield 58% (method B, 160 h). Colorless plates,
mp 85–868C (benzene–hexane), IR: 3389, 3316, 3112,
2953, 2936, 2904, 1706, 1665, 1605, 1475, 1358, 1301,
1221, 1193, 1108, 972, 844, 778, 755, 666, 617, 533 cm21
.
Anal. calcd (found) for C14H18N2O2: C 68.27 (68.38); H
7.37 (7.59); N 11.37 (11.18).
The reaction (25 min) of 5g (1.43 g, 3.7 mmol) with urea
(1.34 g, 22.3 mmol) in acetic acid (4 ml) afforded a crude
reaction product (1.07 g), which was column chromato-
graphed on silica gel using solvent system S2. After
evaporation of combined fractions and crystallization, two
substances were isolated in the following elution order: 10g
(17 mg, 1.1%) and 8g (235 mg, 15.6%).
3.2.2. 3-Butyl-3-butylamino-1-methyl-1H,3H-quinoline-
2,4-dione (5c). Yield 70% (method A, 3 h, chromatography
with solvent system S2). Yellow oil, IR: 3332, 3083, 2957,
2930, 2871, 1703, 1665, 1602, 1471, 1356, 1302, 1167,
1109, 1046, 996, 952, 863, 758, 664, 530 cm21. Anal. calcd
(found) for C18H26N2O2: C 71.49 (71.33); H 8.67 (8.69); N
9.26 (9.08).
3.3.1. 1-Methyl-3-(3-pentanoylureido)-2-oxo-2,3-di-
hydro-1H-indole (6a). Yield 83% (45 min). Colorless
plates, mp 190–1968C (ethanol), IR: 3320, 3231, 3096,
2976, 2958, 2930, 1722, 1704, 1686, 1614, 1537, 1511,
1494, 1378, 1354, 1324, 1266, 1235, 1188, 1121, 1091,
1046, 863, 763, 697, 672, 638, 588, 555 cm21. Anal. calcd
(found) for C15H19N3O3: C 62.27 (62.06); H 6.62 (6.60); N
14.52 (14.37). APCI-MS: m/z 290 [MþH]þ (80%), 272
[MþH–H2O]þ, 206 [C6H4N(CH3)COCH(NHCONH3)]þ,
188 [C6H4N(CH3)COCH(NCO)]þ, 163 [C6H4N(CH3)-
COCH(NH3)]þ, 161 [C6H4N(CH3)COCH(NH)]þ, 146 [C6-
H4N(CH3)COCH)]þ (100%). APCI-MS/MS of precursor
ion m/z 290: 206 [C6H4N(CH3)COCH(NHCONH3)]þ,
(100%), 188 [C6H4N(CH3)COCH(NCO)]þ, 163 [C6H4-
N(CH3)COCH(NH3)]þ, 146 [C6H4N(CH3)COCH]þ.
3.2.3. 3-Butyl-3-butylamino-1-phenyl-1H,3H-quinoline-
2,4-dione (5d). Yield 68% (method A, 23 h). Colorless
prisms, mp 64–678C (hexane), IR: 3438, 3343, 2957, 2928,
2870, 2857, 1708, 1674, 1602, 1461, 1342, 1297, 1243,
1178, 1160, 1121, 1071, 929, 760, 705, 649, 585, 518 cm21
.
Anal. calcd (found) for C23H28N2O2: C 75.79 (75.49); H
7.74 (7.73); N 7.69 (7.47).
3.2.4. 3-Butylamino-1,3-diphenyl-1H,3H-quinoline-2,4-
dione (5g). Yield 70% (method A, 1 h). Colorless needles,
mp 110–1128C (hexane), IR: 3416, 3380, 3329, 3064, 2959,
2922, 2851, 1706, 1673, 1600, 1492, 1459, 1338, 1302,
1247, 1149, 1109, 1034, 978, 912, 876, 834, 766, 718, 695,
655, 605 cm21. Anal. calcd (found) for C25H24N2O2: C
78.10 (77.89); H 6.29 (6.19); N 7.29 (7.07).
3.3.2. 3-(3-Benzoylureido)-1-methyl-2-oxo-2,3-dihydro-
1H-indole (6b). Yield 32% (30 min). Colorless plates, mp
213–2148C (ethanol), IR: 3295br, 3059, 2935br, 1726,
1698, 1671, 1614, 1531, 1495, 1470, 1374, 1318, 1273,
1227, 1117, 1087, 1018, 901, 852, 751, 709br, 634, 594,
558, 541 cm21. Anal. calcd (found) for C17H15N3O3: C
3.3. General procedure for the reaction of 3-amino-
1H,3H-quinoline-2,4-diones (5a–g) with urea
A mixture of appropriate 3-amino-1H,3H-quinoline-2,4

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A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5287
66.01 (66.10); H 4.89 (4.82); N 13.58 (13.43). APCI-MS:
m/z 310 [MþH]þ (100%), 292 [MþH–H2O]þ, 267
[MþH–NHCO]þ, 188 [C6H4N(CH3)COCH(NCO)]þ, 163
3.3.7. 3-Butyl-3a,5-diphenyl-3,3a-dihydro-5H-imi-
dazo[4,5-c]quinoline-2,4-dione (8g). Yield 16% (25 min).
Colorless plates, mp 83–868C (benzene–hexane), IR: 2960,
2938, 2871, 1728, 1706, 1613, 1491, 1464, 1447, 1352,
1308, 1277, 1246, 1133, 1072, 772, 755, 737, 699, 686,
611 cm21. Anal. calcd (found) for C26H23N3O2: C 76.26
(76.32); H 5.66 (5.80); N 10.26 (10.15). APCI-MS: m/z 410
[MþH]þ (100%). APCI-MS/MS of precursor ion m/z 410:
m/z 392 [MþH–H2O]þ, 354 [MþH–CH3CH2CHvCH2]þ
(100%), 311 [MþH–CH3CH2CHvCH2–HNCO]þ, 279
[MþH–CH3CH2CHvCH2–C6H4]þ, 251 [MþH–CH3-
[C6H4N(CH3)COCH(NH3)]þ,
161
[C6H4N(CH3)-
COCH(NH)]þ,
146
[C6H4N(CH3)COCH)]þ,
122
[C6H5CONH3]þ, 105 [C6H5CO]þ. APCI-MS/MS of
precursor ion m/z 310: m/z 267 [MþH–NHCO]þ, 188
[C6H4N(CH3)COCH(NCO)]þ,
163
[C6H4N(CH3)-
COCH(NH3)]þ, 146 [C6H4N(CH3)COCH)]þ (100%), 122
[C6H5CONH3]þ, 105 [C6H5CO]þ.
3.3.3. (E)-3-Butyl-4-butylidene-10-methyl-10H-spiro[imi-
dazolidine-5,30-indole]-2,20-dione (7c). Yield 92%
(30 min). Colorless needles, mp 196–2008C (ethanol), IR:
3214, 3090, 2959, 2932, 2867, 1729, 1712, 1675, 1611,
1493, 1453, 1428, 1372, 1341, 1259, 1234, 1192, 1126,
CH2CHvCH2–C6H4–CO]þ,
208 [MþH–CH3CH2-
CHvCH2–C6H4–HNCO–CO]þ, 160.
3.3.8. 3-Butyl-5-methyl-3a-phenyl-3,3a,5,9b-tetrahydro-
1H-imidazo[4,5-c]quinoline-2,4-dione (9e). Powdered
zinc (327 mg, 5 mmol) was added in small portions to the
stirred solution of 8e (347 mg, 1 mmol) in acetic acid
(10 ml) during 10 min at 1008C. The mixture was for stirred
additional 30 min, cooled, evaporated in vacuo to one half
of its volume and diluted with water (20 ml). The yellow
precipitate was filtered with suction and column chromato-
graphed using solvent system S2. Collected fractions were
crystallized. Yield 129 mg (37%). Colorless prisms, mp
246–2488C (benzene), IR: 3216br, 2956, 2930, 2874, 1706,
1672, 1640, 1606, 1475, 1398, 1367, 1278, 1140, 1106, 752,
703, 636 cm21. Anal. calcd (found) for C21H23N3O2: C
72.18 (72.29); H 6.63 (6.80); N 12.03 (12.15). APCI-MS:
m/z 350 [MþH]þ (100%). APCI-MS/MS of precursor ion
m/z 350: m/z 333 [MþH–NH3]þ, 322 [MþH–CO]þ, 307
[MþH–HNCO]þ, 294 [MþH–CH3CH2CHvCH2]þ, 277
[MþH–CH3CH2CHvCH2-NH3]þ, 251 [MþH–CH3CH2-
CHvCH2–HNCO]þ, 160 [C6H4N(CH3)COCHCH2]þ
(100%), 146 [C6H4NHCOCHCH2]þ, 104 [C6H5CH2CH]þ.
1087, 1020, 934, 879, 764, 737, 695, 676, 612, 538 cm21
.
Anal. calcd (found) for C19H25N3O2: C 69.70 (69.51); H
7.70 (7.51); N 12.83 (12.66). APCI-MS: m/z 328 [MþH]þ
(100%), 272 [MþH–CH3CH2CHvCH2]þ. APCI-MS/MS
of precursor ion m/z 328: m/z 285 [MþH–NHCO]þ, 272
[MþH–CH3CH2CHvCH2]þ, 255 [MþH–CH3CH2-
CHvCH2–NH3]þ, 229 [MþH–CH3CH2CHvCH2–
NHCO]þ (100%), 148.
3.3.4. (E)-3-Butyl-4-butylidene-10-phenyl-10H-spiro[imi-
dazolidine-5,30-indole]-2,20-dione (7d). Yield 69%
(50 min). Yellowish needles, mp 124–1288C (benzene–
hexane), IR: 3219, 2957, 2931, 2870, 1742, 1674, 1612,
1594, 1499, 1451, 1423, 1365, 1175, 1130, 940, 750,
704, 623 cm21. Anal. calcd (found) for C24H27N3O2:
C 74.01 (73.73); H 6.99 (6.95); N 10.79 (10.47). APCI-
MS: m/z 390 [MþH]þ (100%), 334 [MþH–CH3CH2-
CHvCH2]þ, 291 [MþH–CH3CH2CHvCH2-NHCO]þ.
APCI-MS/MS of precursor ion m/z 390: m/z 373 [MþH–
NH3]þ, 347 [MþH–NHCO]þ, 334 [MþH–CH3CH2-
CHvCH2]þ, 317 [MþH–CH3CH2CHvCH2-NH3]þ,
291 [MþH–CH3CH2CHvCH2-NHCO]þ (100%), 250,
210.
3.3.9. 3-(3-Benzoyl-3-butylureido)-1-methyl-2-oxo-2,3-
dihydro-1H-indole (10e). Side product of the reaction of
5e with urea, yield 1.3%. Colorless prisms, mp 156–1588C
(benzene–hexane), IR: 3295, 3053, 2959, 2927, 2871, 1718,
1684, 1657, 1612, 1503, 1468, 1376, 1355, 1294, 1222,
1084, 1018, 757, 724, 697, 671, 657 cm21. Anal. calcd
(found) for C21H23N3O3: C 69.02 (69.23); H 6.34 (6.45); N
11.50 (11.37). APCI-MS and APCI-MS/MS of precursor
ion: m/z 366 are the same: m/z 366 [MþH]þ (100% for MS
spectrum), 348 [MþH–H2O]þ, 267 [MþH–CH3CH2CH2-
CH2NCO]þ (100% for MS/MS spectrum), 244 [MþH–
C6H5CONH3]þ, 178 [C6H5CONH2(CH2CH2CH2CH3)]þ,
161 [C6H4N(CH3)COCH(NH)]þ, 146 [C6H4N(CH3)-
COCH]þ, 105 [C6H5CO]þ.
3.3.5. 3-Butyl-5-methyl-3a-phenyl-3,3a-dihydro-5H-imi-
dazo[4,5-c]quinoline-2,4-dione (8e). Yield 49% (40 min).
Yellowish plates, mp 198–2008C (benzene–hexane), IR:
2957, 2938, 2893, 2873, 1736, 1690, 1611, 1468, 1359,
1286, 1154, 1070, 1042, 974, 772, 755, 699, 608 cm21
.
Anal. calcd (found) for C21H21N3O2: C 72.60 (72.46); H
6.09 (6.07); N 12.10 (11.97). APCI-MS: m/z 348 [MþH]þ
(100%). APCI-MS/MS of precursor ion m/z 348: m/z 330
[MþH–H2O]þ, 305 [MþH–NHCO]þ, 292 [MþH–CH3-
CH2CHvCH2]þ (100%), 264 [MþH–CH3CH2CHvCH2–
CO]þ, 249 [MþH–CH3CH2CHvCH2–NHCO]þ, 221,
217, 160, 146, 104.
3.3.10. 3-(3-Benzoyl-3-butylureido)-1-phenyl-2-oxo-2,3-
dihydro-1H-indole (10g). Side product of the reaction of
5 g with urea, yield 1.1%. Colorless plates, mp 183–1888C
(benzene–hexane), IR: 3251, 3050, 2959, 2930, 2873, 1732,
1676, 1642, 1613, 1530, 1500, 1467, 1451, 1375, 1321,
1301, 1225, 1176, 1107, 757, 724, 704, 648 cm21. Anal.
calcd (found) for C26H25N3O3: C 73.05 (73.16); H 5.89
(5.97); N 9.83 (9.72). Both APCI-MS and APCI-MS/MS of
precursor ion m/z 428: m/z 428 [MþH]þ (100% for MS
spectrum), 410 [MþH–H2O]þ, 385 [MþH–HNCO]þ (only
in MS spectrum), 329 [MþH–CH3CH2CH2CH2NCO]þ
(100% for MS/MS spectrum), 306 [MþH–C6H5CONH3]þ,
288 [MþH–C6H5CO–NH3-H2O]þ (only in MS spectrum),
3.3.6. 3-Cyclohexyl-5-methyl-3a-phenyl-3,3a-dihydro-
5H-imidazo[4,5-c]quinoline-2,4-dione (8f). Yield 89%
(40 min). Colorless plates, mp 291–2948C (ethanol), IR:
2957, 2932, 2918, 2853, 1734, 1692, 1621, 1605, 1469,
1449, 1359, 1312, 1285, 1206, 1156, 1126, 1073, 984, 942,
892, 773, 750, 702, 651, 609, 529 cm21. Anal. calcd (found)
for C23H23N3O2: C 73.97 (73.89); H 6.21 (6.19); N 11.25
(11.07). APCI-MS: m/z 374 [MþH]þ (100%), 292 [MþH–
C6H10]þ. APCI-MS/MS of precursor ion m/z 374: m/z 292
[MþH–C6H10]þ (100%).

´
A. Klasek et al. / Tetrahedron 59 (2003) 5279–5288
5288
250 [MþH–C6H5CO–CH3CH2CH2CH2NH2]þ, 223 [C6-
H4N(C6H5)COCH(NH)]þ, 208 [C6H4N(C6H5)COCH]þ,
178 [C6H5CONH2(CH2CH2CH2CH3)]þ.
the Czech Republic. A. L. thanks the Grant Agency of the
Czech Republic for financial support (Grant No.
ˇ
´
203/03/0356). The authors thank Mrs H. Gerzova (Faculty
of Technology, Tomas Bata University in Zlın) for technical
´
3.3.11. 3-(3-Butylureido)-1-methyl-2-oxo-2,3-dihydro-
1H-indole (11e). Side product of the reaction of 5e with
urea, yield 2.8%. Colorless plates, mp 192–1958C
(benzene), IR: 3323, 3058, 2957, 2931, 2861, 1712, 1629,
1579, 1495, 1469, 1375, 1348, 1307, 1262, 1125, 1091, 749,
652 cm21. Anal. calcd (found) for C14H19N3O2: C 64.35
(64.06); H 7.33 (7.30); N 16.08 (15.85). APCI-MS: m/z 262
[MþH]þ (100%), 188 [C6H4N(CH3)COCH(NCO)]þ,
163 [C6H4N(CH3)COCH(NH3)]þ, 161 [C6H4N(CH3)-
COCH(NH)]þ, 146 [C6H4N(CH3)COCH]þ. APCI-MS/MS
of precursor ion m/z 262: m/z 188 [C6H4N(CH3)-
COCH(NCO)]þ, 163 [C6H4N(CH3)COCH(NH3)]þ, (100%),
146 [C6H4N(CH3)COCH]þ, 74 [CH3CH2CH2CH2NH3]þ.
help.
References
´ ˇ ˇ ˇ
1. Klasek, A.; Koristek, K.; Lycka, A.; Holcapek, M. Tetrahedron
2003, 59, 1283–1288.
´
2. Kafka, S.; Klasek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002,
ˇ
57, 1659–1682.
´ ˇ
3. Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Tetrahedron
ˇ
2000, 56, 1551–1560.
´ ˇ
4. Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Heterocycles
ˇ
1998, 48, 2309–2326.
5. Sasaki, T.; Eguchi, S.; Okano, T. Synthesis 1980, 6, 472–475.
6. Zaher, H. A.; Ibrahim, Y. A.; Sherif, O.; Mohammady, R.
Indian J. Chem. 1983, 22B, 559–561.
Acknowledgements
This study was supported by the Ministry of Education
Youth and Sports of the Czech Republic (Grant No. MSM
265200015). M. H. acknowledges the support of grant
project No. 203/02/0023 sponsored by the Grant Agency of
7. Schwellkopf, U.; Lau, H.-H.; Scheunemann, K.-H.; Blume, E.;
Matawinata, K. Liebigs Ann. Chem. 1980, 600–610.
8. Boehme, H.; Schneider, H. Chem. Ber. 1958, 91, 988–996.