Molecular rearrangement of 1-substituted 3-aminoquinoline-2,4-diones in their reaction with urea and nitrourea synthesis and transformations of reaction intermediates

Article abstract of DOI:10.1002/jhet.5570430517

1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones (6) react with nitrourea to give 3-ureido-1H,3H-quinoline-2,4-diones (10), 9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones (11), and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones (12). Compounds 11 were dehydrated to 12 by the action of phosphorus pentoxide. All three types of compounds rearrange in boiling acetic acid to give three different types of products of molecular rearrangement. A proposed reaction mechanism is discussed.

Full text of DOI:10.1002/jhet.5570430517

Sep-Oct 2006
1251
Molecular Rearrangement of 1-Substituted 3-Aminoquinoline-2,4-
diones in Their Reaction with Urea and Nitrourea
Synthesis and Transformations of Reaction Intermediates
Antonín Kláseka,*, Antonín Lyꢀka,b Michal Holꢀapek,c Michal Kováꢁa, and Ignác Hozaa
aDepartment of Food Engineering and Chemistry, Faculty of Technology, Tomas Bata University, 762 72 Zlín,
Czech Republic, E-mail: klasek@ft.utb.cz
bResearch Institute for Organic Syntheses (VUOS), Rybitví 296, 532 18 Pardubice 20, Czech Republic
cDepartment of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, 53210
Pardubice, Czech Republic
Received December 2, 2005
O
N
R2
O
N
R2
CONH2
O
O
N
HN
NHR3
HO
R3
N
R3
R3
R2
R2
nitrourea
and/or
and
N
R1
O
6
N
R1
O
N
R1
O
12
N
R1
O
11
10
R1 = Alkyl, phenyl
R2 = Butyl, phenyl
R3 = H, Alkyl
AcOH, reflux
R3
O
O
O
R3
R3
N
N
HN
N
N
HN
HN
COR2
H
O
C3H7
O
or
O
and/or
15
if R2 = Ph or R3 = H
N
R1
N
14
13
R1
R1
if R2 = Bu and R3 =
/ H
1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones (6) react with nitrourea to give 3-ureido-
1H,3H-quinoline-2,4-diones (10), 9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones
(11), and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones (12). Compounds 11 were dehydrated to 12 by
the action of phosphorus pentoxide. All three types of compounds rearrange in boiling acetic acid to give three
different types of products of molecular rearrangement. A proposed reaction mechanism is discussed.
J. Heterocyclic Chem., 43, 1251 (2006).
Recently, molecular rearrangement of 1-unsubstituted
3-amino-1H,3H-quinoline-2,4-diones (1) in a reaction
with urea in boiling acetic acid, producing 2,6-dihydro-
readily than urea, we attempted to obtain assumed
reaction intermediates by adapting reaction conditions.
The reaction of compounds 1 with nitrourea in dioxane or
Scheme 1
O
N
R1
H
HO
CONH2
O
O
H
N
R2
N
N
R2
R2
H2NCONHNO2
R1
O
R1
or
dioxane
N
H
N
O
N
O
H
H
3
1
boiling AcOH
4
H2NCONH2
P2O5/CHCl3
boiling AcOH
boiling AcOH
R2
N
R1
O
N
R2
N
R1
O
boiling AcOH
R1 = alkyl, Ph; R2 = H, alkyl
N
N
O
N
O
5
H
H
2
imidazo[1,5-c]quinazoline-3,5-diones (2) (Scheme 1), has
been described [1]. Nitrourea reacts with compounds 1 in
acetic acid in the same manner as urea. However, as
nitrourea is converted to isocyanic acid much more
aqueous dioxane produced new 3-ureido-1H,3H-
quinoline-2,4-diones (3) or 9b-hydroxy-3,3a,5,9b-tetra-
hydro-1H-imidazo[4,5-c]quinol-ine-2,4-diones (4) [2].
Dehydration of compounds 4 yields highly unstable

1252
A. Klásek, A. Lyꢀka, M. Holꢀapek, M. Kováꢁ, and I. Hoza
Vol 43
position 3. A further objective was to find if the reaction
products of compounds 6 with nitrourea would transform
to compounds 7 and 8 by boiling in acetic acid and may
thus be regarded as intermediates of molecular
rearrangement.
3a-alkyl/aryl-3,3a-dihydro-5H-imidazo[4,5-c]quinoline-
2,4-diones (5) (Scheme 1). Compounds 3, 4 and 5
rearrange to imidazoquinazoline derivatives 2 by boiling
in acetic acid [2] and, therefore, they are anticipated
intermediates of the molecular rearrangement of
compounds 1 in their reaction with urea. Compounds
analogous to 3 and 4 were also obtained from 1 by a
reaction with isocyanates [3].
On the contrary, compounds 6 substituted in position
1 with an alkyl or aryl group react with urea in boiling
acetic acid differently to give three different types of
compounds [4]. Depending on the character of
substitution in starting compounds 6, either a molecular
rearrangement of the quinolone system to indolinone
system occurs with formation of 3-(3-acylureido)-2,3-
dihydro-1H-indol-2-ones (7) or 4-alkylidene-1´H-
spiro[imidazolidine-5,3´-indole]-2,2´-diones (8), or
expected 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-
diones (9) arise (Scheme 2). As opposed to analogous
compounds 5, compounds 9 are relatively stable.
Results and Discussion.
Starting aminoketones 6 were prepared according to
the general protocol described in the literature [5].
Reactions of compounds 6 with nitrourea (Scheme 3)
were performed analogously to the described reactions
[2] of compounds 1, that is by boiling in dioxane.
Results are presented in Table I.
Already first results of nmr spectra measurements
indicated the reaction of compounds
6
with
nitrourea proceeds similarly to that of compounds 1
[2] and three different types of products arise
(Scheme 3). Ureido derivatives 10 are formed only
when a primary amino group (10a,b) is present in
position 3 of starting ꢀ-aminoketones. The high
Scheme 2
R2
R3
O
O
NH
O
H
N
O
O
N
H
HN
NHR3
R3
NH
N
H2NCONH2
C3H7
R2
O
O
O
Ph
N
R1
boiling AcOH
or
N
R1
or
N
R1
N
R1
O
8
7
9
6; R1 = alkyl, Ph
if R3 = H if R2 = butyl, R3 = alkyl if R2 = Ph, R3 = alkyl
Owing to the fact that compounds 1 produced new
heterocyclic systems 3 and 4 with high yields by reacting
with nitrourea in dioxane or with isocyanates, we also
decided to study an analogous reaction of 1-substituted ꢀ-
aminoketones 6. Our first aim was to find whether
compounds to be formed would be corresponding 3-ureido
derivatives or their cyclic carbinolamide forms, and also to
verify what influence is exerted on the course of reaction
by substituents in positions 1,3, and at the amino group in
yield of 10b is surprising because an acyclic isomer
was formed by reacting analogous compounds 1
with nitrourea merely in case a butyl group was
present in position 3 of the starting primary amine
[2]. Cyclic amidocarbinols 11a,b arose together
with ureido derivatives 10a,b, even though
compound 11a appeared only in negligible quantity.
The formation of a mixture of cyclic and acyclic
isomers during hydration of 3-(thiocyanatoacetyl)-
Table 1
Reaction of N-Substituted ꢀ-Aminoketones 6a-g with Nitrourea.
Entry
Starting compound 6
Reaction
Isolated compounds (yield %)
time (hrs)
R1
Me
Me
Me
Me
Me
Ph
R2
Bu
Ph
Bu
Ph
Ph
Bu
Ph
Ph
R3
H
H
Bu
Bu
c-Hex
Bu
Bu
Bu
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
2
5
2.5
8
14
3
3
10a (55), 11a (1.5)
10b (58), 11b (14)
6c (43), 11c (25), 12c (3)
11d (70), 12d (12)
6e (15), 11e (33), 12e (17)
6f (17), 11f (24), 12f (22)
6g (48), 11g (27)
6g
6g
Ph
Ph
15
6g (6), 11g (18), 12g (22)

Sep-Oct 2006
Molecular Rearrangement of 1-Substituted 3-Aminoquinoline-2,4-diones
1253
Scheme 3
O
2´
O
2
3´
1
N
1
HN
9b
CONH2
O
3
N
R2
3
5
1´
9
6
HO
9a
R3
9
9a
5a
R3
N
R2
9b
3a
4
R3
N
R2
H2NCONHNO2
boiling dioxane
3
3a
4
N
R1
and
6
and/or
1
N
R1
N
R1
O
O
O
11
5a
5
CHCl3
P2O5
8
6
12
10
For key of substituents see Table 1.
(H2O), 28 (CO), 43 (NHCO), 56 (butene), 58 (butane), 60
(urea), 73 (butylamine), 99 (butylisocyanate), etc.
azetidin-2-ones was described by Sápi et al. [6]. On the
other hand, formation of cyclic isomers of 3-alkyl/aryl-
1H,3H-quinoline-2,4-diones substituted with a carbamoy-
lthio group in position 3 was not observed [7]. Reactions of
secondary ꢀ-aminoketones 6c-g with nitrourea proceeded
independently of the character of substituents R1, R2 and R3,
merely with formation of cyclic isomers 11c-g.
Table 2
1H and 13C Chemical Shifts (ꢁ, ppm)
of Compounds 10a,b, and 15e in DMSO-d6
Position
10a
10b
15e
Only several examples of the conversion of ꢀ-
aminoketones to 3-unsubstituted 4-hydroxy-tetrahydro-
imidazol-2-ones are described in literature. The oldest
papers on this problem deal with compounds of 3-amino-
bornan-2-one series [8,9]. With the exception of our
previous paper [2], only two papers have been recently
published describing this conversion in 4-amino-3-oxo-
tetrahydrothiophene series [10,11]. Acid catalyzed ring
opening of 4-hydroxy-tetrahydroimidazol-2-ones under
formation of 2-ureidoketones was described in only one
case [8].
The structure of isolated products unambiguously
followed from results of 13C nmr spectra. Compounds 10
exhibit in the 13C nmr spectrum a characteristic signal of
keto group C-4 in the 191-194 ppm range (Table 2), while
this signal is missing in the 13C nmr spectra of compounds
11 and, instead, a signal of sp3 hybridized carbon atom C-
9b appears in the 82-90 ppm range (Tables 3 and 4).
Based on 2D experiments, all signals were assigned to
their respective atoms (Tables 2 - 4).
ꢁꢂ
ꢁꢂ
ꢃ
ꢁꢂ
ꢁC
ꢁC
ꢁC
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
7.92
7.26
7.77
ꢃ
7.42
172.1
67.2
ꢃ
193.6
120.3
127.3
122.7
136.1
ꢃ
115.7
142.8
ꢃ
157.9
ꢃ
ꢃ
170.9
71.1
ꢃ
191.2
120.0
127.0
123.0
136.2
ꢃ
115.9
142.4
ꢃ
158.2
ꢃ
175.1
52.7
128.7
2
3
3a
4
4a
5
6
7
7a
8
8a
ꢃ
ꢃ
ꢃ
ꢃ
7.85
7.22
7.75
ꢃ
5.00
ꢃ
7.22 123.3
ꢃ
7.04 122.0
7.31 128.3
6.99 108.2
ꢃ
ꢃ
ꢃ
6.10
ꢃ
6.56
ꢃ
3.14
3.37
[c]
[c]
[c]
ꢃ
143.8
ꢃ
7.44
ꢃ
7.08
ꢃ
ꢃ
ꢃ
1´ (NH)
2´ [a]
3´ (NH)
3´ (NH2)
1´ (R1)
1´ (R2) [b]
2´ (R2) [b]
3´ (R2) [b]
4´ (R2) [b]
7.42
ꢃ
ꢃ
156.8
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
5.72
3.44
1.71
1.17
1.17
0.79
5.84
3.55
ꢃ
7.34
7.41
7.41
30.2
134.7
126.8
129.1
129.2
26.1
48.2
33.3
25.3
24.6
29.9
36.7
24.7
22.2
13.7
[a] Position 2 in the case of 15e; [b] At R3 in the case of 15e; [c] Cyclohexane
methylene protons (10H) occur in region of 1.15-1.92 ppm (ꢁ).
The fragmentation behaviour of compounds 10-12 and
15 in APCI mass spectra follows the similar rules as
described in our previous works [1-4]. There is no
difference between mass spectra of compounds from 10
and 11 series (e.g., 10a and 11a, 10b and 11b), which
suggests that compounds 10 are converted to 11 during
the ionization process and then the fragmentation
behaviour is identical. The presence of hydroxyl group at
9b position causes an extensive fragmentation and low
relative abundance of quasimolecular ions unlike
compounds 12 without hydroxyl group, where the
[M+H]+ ions are the base peaks and the fragmentation in
the first-order spectra is negligible. The molecular
weights are determined in all cases on the basis of
[M+H]+ ions in positive-ion and [M-H]- ions in negative-
ion mode of the first-order APCI mass spectra. The
typical neutral losses are the following: 17 (NH3), 18
Apart from compounds 10 and/or 11, also unreacted
starting ꢀ-aminoketones 6 and dehydration products 12
(Table 1) were isolated from raw products of the reaction
of 6 with nitrourea. Prolonged reaction time admittedly
brings about a subsequently reduced content of unreacted
starting compound 6 in the reaction mixture, but, at the
same time, the proportion of dehydration product 12 is
increased (see entries 7 and 8 in Table 1). A partial
transformation of 11g to 12g was already observed during
long-term heating of its benzene solution. Thermal
instability of compounds 11 is also indicated by double
melting point determined in the case of 11d and 11e.
Compounds 12d,e,g were already isolated earlier [4] as
products of the reaction of corresponding amines 6d,e,g
with urea in acetic acid. Structure of new compounds
12c,f was established from analogy of their nmr spectra to
nmr spectra of previously described compounds 12d,e,g

1254
A. Klásek, A. Lyꢀka, M. Holꢀapek, M. Kováꢁ, and I. Hoza
Vol 43
Table 3
1H and 13C Chemical Shifts (ꢀ, ppm) of Compounds 11a-e in DMSO-d6
Position
11a
11b
11c
11d
11e
ꢀꢁ
ꢀꢁ
ꢀꢁ
ꢀꢁ
ꢀꢁ
7.27
ꢂ
ꢀC
ꢂ
ꢀC
ꢂ
ꢀC
ꢂ
ꢀC
ꢂ
ꢀC
ꢂ
1
2
7.29 [a]
7.56 [a]
7.29
ꢂ
7.57
ꢂ
ꢂ
ꢂ
160.2
160.4
158.9
160.6
159.2
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
7.15
7.41
7.18
7.78
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
7.30
7.45
7.13
7.61
ꢂ
ꢂ
3.51
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
7.28
7.44
7.11
7.60
ꢂ
ꢂ
3.51
ꢂ
3
3a
4
5a
6
7
8
9
9a
7.16 [a]
7.72 [a]
ꢂ
ꢂ
ꢂ
7.19
7.42
7.15
7.72
ꢂ
ꢂ
ꢂ
ꢂ
7.34
7.51
7.19
7.70
ꢂ
ꢂ
3.46
ꢂ
7.21
66.9
171.3
136.9
114.6
129.7
122.7
126.7
125.1
83.6
70.5
170.6
137.1
115.1
130.0
123.3
127.2
124.5
84.5
69.1
170.7
136.5
114.5
129.6
123.0
126.1
125.7
82.6
75.4
170.0
136.9
115.0
130.0
123.1
127.4
124.0
89.5
76.4
169.8
136.9
114.8
129.9
123.0
127.3
124.1
83.9
ꢂ
ꢂ
9b
1´ (R1)
1´ (R2)
2´ (R2)
3.37
1.74
1.01
0.97
1.14
0.75
ꢂ
29.9
31.9
25.0
30.0
135.6
126.5
3.40
1.92
1.00
0.76
1.17
0.72
3.53
3.35
1.61
1.50
1.33
0.95
6.57
29.4
31.3
24.5
29.8
133.5
128.0
29.9
134.0
127.9
ꢂ
7.24
ꢂ
7.24
3´ (R2)
4´ (R2)
1´ (R3)
22.6
13.7
ꢂ
7.28
7.28
ꢂ
127.9
127.8
ꢂ
22.6
13.9
40.4
7.34
7.34
3.28
3.02
2.03
1.65
1.23
0.89
6.55
128.4
128.3
44.1
7.33
7.33
2.94
128.7
128.2
55.2
2´ (R3)
32.7
31.0
[b]
[b]
ꢂ
ꢂ
ꢂ
ꢂ
3´ (R3)
4´ (R3)
OH
19.9
13.9
ꢂ
20.3
13.9
ꢂ
[b]
[b]
6.45
[b]
[b]
ꢂ
ꢂ
ꢂ
6.56
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
6.37
ꢂ
ꢂ
ꢂ
[a] The assignment may be opposite; [b] N-Cyclohexyl group is not „symmetrical“ on the NMR time scale, all hydrogen and carbon atoms are
non-equivalent and considerably broadened (ꢀH = 2.32 – 1.01, ꢀC = 32.0, 28.9, 26.7, 26.4, 25.7).
(Table 4). Results of attempts at preparing compounds 12
by dehydrating compounds 10 and 11 with phosphorus
pentoxide in chloroform are presented in Table 5.
Consistently with dehydration results of compounds 3 and
4, when we did not succeed in obtaining anticipated
products 5a,b [2], we were also unsuccessful in obtaining
dehydrated products 12a,b from analogous compounds
10a,b and 11b. Complex mixtures of compounds arose
and these could not be chromatographically separated.
Dehydration of compounds substituted at the nitrogen
atom in position 3 (11c-g) proceeded without problems
and corresponding compounds 12c-g were obtained in
high yields (Table 5). Stability of 1-substituted
imidazoquinolinediones 12 is substantially higher than
that of analogous compounds 5. Comparing results of
Entries 5 and 6 (Table 5) is worth attention; prolonged
reaction time when dehydrating 11c effects a subsequent
molecular rearrangement of primarily formed product 12c
to spiro-compound 14c. When dehydrating other
compounds 11 no formation of rearranged products was
observed.
acetic acid [4], analogous compounds 11 and 12 also yield
derivatives of indol-2-one by boiling in acetic acid
(Scheme 4). Secondary ꢀ-aminoketones 6, bearing a
phenyl group in position 3, produced imidazoquinoline-
diones 9 by a reaction with urea in acetic acid, and indole
derivatives 7 were isolated in merely insignificant
quantity as products of molecular rearrangement [4].
From Table 6 it is obvious that also in the reaction of
compounds 11d,e,g and 12d,e,g (Table 6, Entries 6-9 and
12-13) in boiling acetic acid the yield of rearranged
products 13 and/or 15 was relatively low while a
considerable quantity of 12, largely stable under given
reaction conditions, was recovered. In the reactions of 11e
and 12e (Table 6, Entries 8-9), the primary product of the
rearrangement is certainly compound 13e. However,
under given reaction conditions, it is hydrolyzed to 15e
and benzoic acid. At the same time, hydrolysis of ureido
group under formation of N-cyclohexyl benzamide takes
place.
Compounds 12d,g, 13a,b,d and 14c,f were tested for
their enzyme inhibition activity against cyclin-dependent
kinase (CDK) and their toxicity against cell lines K-562
(chronic myeloid leukemia) and MCF7 (breast
carcinoma). No compound exhibits any significant
activity against CDK and only one compound (14f)
As assumed, products of molecular rearrangement arise
by boiling compounds 10, 11 and 12 in acetic acid
(Scheme 4, Table 6). In accord with results of molecular
rearrangement of compounds 6 when reacted with urea in

Sep-Oct 2006
Molecular Rearrangement of 1-Substituted 3-Aminoquinoline-2,4-diones
1255
Table 4
1H and 13C Chemical shifts (ꢀ, ppm) of Compounds 11f-g and 12c,f in DMSO-d6
Position
11f
11g
12c
12f
ꢀꢁ
ꢀꢁ
ꢀꢁ
ꢂ
ꢂ
ꢂ
ꢂ
ꢀꢁ
ꢂ
ꢂ
ꢂ
ꢂ
ꢀC
ꢂ
159.0
69.5
ꢀC
ꢂ
160.6
75.8
ꢀC
ꢂ
ꢀC
ꢂ
166.3
75.3
168.4
142.6
117.2
135.1
124.0
126.3
116.0
1
2
3a
4
5a
6
7
8
9
9a
9b
1´ (R1)
2´ (R1)
3´ (R1)
4´ (R1)
1´ (R2)
7.45
ꢂ
ꢂ
ꢂ
ꢂ
6.17
7.22
7.15
7.83
ꢂ
7.75
ꢂ
ꢂ
ꢂ
ꢂ
6.37
7.26
7.12
7.70
ꢂ
166.1
75.0
168.2
141.5
116.6
135.5
124.0
126.1
116.3
184.6
29.8
ꢂ
171.0
137.5
115.5
129.3
123.2
126.6
125.3
83.1
137.9
129.0
130.3
128.7
31.4
170.2
137.8
116.2
129.7
123.3
127.8
123.9
84.3
137.9
129.0
130.3
128.8
133.3
ꢂ
ꢂ
7.48
7.79
7.37
7.91
ꢂ
ꢂ
3.37
ꢂ
6.45
7.60
7.34
7.98
ꢂ
ꢂ
ꢂ
[a]
ꢂ
ꢂ
ꢂ
ꢂ
184.4
137.0
[a]
[a]
[a]
7.20
7.63
7.55
2.03
2.01
1.20
7.40
7.68
7.59
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
35.3
[a]
[a]
2.22
1.81
0.84
0.70
1.14
0.74
3.51
3.37
1.81
2.39
2.16
0.87
0.80
1.22
0.80
3.51
3.34
1.79
35.2
2´ (R2)
24.7
7.51
128.2
24.3
24.4
3´ (R2)
4´ (R2)
1´ (R3)
1.26
0.80
3.47
3.35
1.63
1.52
1.34
1.30
0.86
6.71
22.7
13.7
40.6
7.45
7.38
3.26
3.01
2.00
1.65
1.27
1.21
0.86
6.71
128.4
128.5
44.1
21.2
13.7
41.4
21.3
13.7
41.4
2´ (R3)
3´ (R3)
32.6
19.9
30.9
20.2
30.6
20.0
30.6
19.9
1.40
1.38
4´ (R3)
OH
13.9
ꢂ
13.8
ꢂ
0.98
ꢂ
13.7
ꢂ
0.95
ꢂ
13.7
ꢂ
[a] N-Phenyl group is not „symmetrical“ on the NMR time scale, all hydrogen and carbon atoms are non-equivalent and considerably broadened.
Scheme 4
R3
3
4
O
O
O
R3
R3
1´
3´
1´
HN
3´
N
N
1
HN
HN
N
4
7
4
4´
5
COR2
H
10a,b
11b-g
12c-g
3
3
AcOH
reflux
O
C3H7
O
O
and/or
and/or
2´
N
N
R1
N
7
R1
7´
R1
15d,e
14c,f
13a,b,d,g
For key of substituents see Table 1.
exhibits high toxicity against K-562 and MCF7 (GI50 = 22
and 25 μmoles, respectively). Analogous compound 14c,
substituted with methyl group at N-1, exhibits essentially
lower toxicity against K-562 and MCF7 (GI50 > 100 and >
167 μmoles, respectively).
In our earlier work [4] we sought to describe the
mechanism of molecular rearrangements of compounds
6 during their reaction with urea by means of two
different paths, depending on whether starting ꢀ-
aminoketone 6 bore a primary or secondary amino
compounds 11 and/or 12 because couples of identically
substituted 11 or 12 yield the same reaction product.
Compounds of type 12 derived from primary amino
derivatives 6 could not be obtained by dehydrating
compounds 11a,b (Table 5). Thence it may be
considered that rearrangement in acetic acid occurs
with these compounds already in the stage of
amidocarbinol 11. The significant role of compound 11
in rearrangement mechanism is also indicated by the
fact that greater yields of rearranged product were
obtained when 11 was the starting compound (compare
Entries 4, 5 and 10, 11 in Table 6). A proposed reaction
mechanism is presented in Scheme 5.
group. From results presented in Table
unambiguously follows that the anticipated
intermediates of molecular rearrangement are
6
it

1256
A. Klásek, A. Lyꢀka, M. Holꢀapek, M. Kováꢁ, and I. Hoza
Vol 43
Table 6
Table 5
Rearrangement of Compounds 10, 11, and 12
Dehydration of 10 and 11 with Phosphorus Pentoxide
in Boiling Acetic Acid
Entry
Starting
compound
10a
Reaction time
Yield of 12
Entry
Starting
compound
10a
Reaction
time (hrs)
Isolated compounds
(yield %)
13a (41)
13b (69)
13b (61)
(min)
60
300
45
45
20
30
30
20
20
15
30
(%)
[a]
[a]
[a]
[a]
58
17 [b]
69
76
85
72
68
75
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
3.5
2
1.5
1
1
2
10a
10b
11b
11c
11c
11d
11d
11e
10b
11b
11c
12c
11d
12d
14c (64)
14c (43)
12d (25), 15d (9)
12d (69), 13d (7),
15d (6)
15e (39), [a]
12e (11), 15e (37),
[b]
14f (82)
14f (75)
11g (10), 12g (19),
13g (31)
5
8
9
11e
12e
1.5
2
10
11
12
11f
11g
11g
30
10
11
12
11f
12f
11g
1
2.5
1.5
[a] Inseparable mixture of several compounds arises; [b] Compound 14c
(15%) was also obtained.
13
12g
1.5
12g (25), 13g (28)
Compound 10 is in equilibrium with compound 11. We
have already described similar equilibrium between
acyclic ureido derivatives and cyclic amidocarbinols
[2,3]. Dehydration of 11 gives imidazoquinolinedione 12
but, this change can be reversible. The key intermediate is
carbocation A, which arises by nucleophilic 1,2-shift of
secondary amide group in 11 or 12. Intermediate A can be
stabilized in two ways. The first is elimination of proton
from the butyl group (R3) with formation of products
14c,f that can take place only in those cases when
substituent R2 is an alkyl and R3 is not hydrogen.
[a] Benzoic acid (40%) and N-cyclohexylbenzamide (6%) were also
isolated; [b] Benzoic acid (51%) and N-cyclohexylbenzamide (4%)
were also isolated.
benzoylureido derivatives 13d,e, originated benzoic acid
was isolated (Table 6, Entries 8 and 9). In our previous
work [4], reactions of 3-phenyl-substituted aminoketones
6 with urea produced compounds 13 and 15 in merely
trace quantities as side-products, the principal products
being compounds 12. When we now proceeded from
compounds 11d,e,g and 12d,e,g, corresponding products
Scheme 5
O
N
R2
O
H
R3
N H
CONH2
N
O
N
HO
R3
R3
N
R2
N
R2
O
R3
HN
- H2O
O
O
N
O
+ H2O
N
N
O
N
R1
R1
R1
R1
12
15d,e
10
11
H+
+ H+
+ H2O
H2O
- R2COOH
- H2O
R3
N
COR2
R3
N
R3
O
O
R3
O
R2
N
N
O
NH
+
HN
R2
HN
HN
O
- H+
H
H2O
- H+
C3H7
O
14c,f
O
O
O
N
N
N
N
R1
A
B
R1
R1
R1
13a,b,d,e,g
if R3 = H or R2 = Ph
if R2 = Bu and R3 = H
/
For key of substituents see Table 1
The second way of transforming intermediate A (in
case R2 is phenyl or R3 is hydrogen) is formation of C=N
or C=N+ double bond. After addition of water, unstable
carbinolamide B arises, in which a splitting of the labile
C-C bond between carbinolamide and lactame groupings
proceeds to give acylureido derivatives 13a,b,d,e,g.
Ureido derivatives 15d,e are formed through hydrolysis of
13 and 15 were obtained in greater quantities but reaction
yield was nevertheless low (Table 6, Entries 6-9 and 12-
13). That indicates the presence of phenyl group in
position 3a is a stabilizing factor for compounds 11 and
12 derived from secondary amines.
For generalization of molecular rearrangement of 3-
ureidoquinolinediones and 9b-hydroxy-3,3a,5,9b-tetrahydro-

Sep-Oct 2006
Molecular Rearrangement of 1-Substituted 3-Aminoquinoline-2,4-diones
1257
reaction products of 6a and 6b). The crude products of the
reactions of 6c, 6d, and 6e were repeatedly crystallized from
appropriate solvents; the mother liquors after crystallization
were collected with the benzene extract of the aqueous fraction
and column chromatographed on silica gel using solvent system
S1 or S2. In cases when evaporated reaction mixture was oily
(crude products of the reaction of 6f and 6g), it was mixed with
water (50 ml) and three times extracted with benzene. The
benzene extract was evaporated to dryness and column
chromatographed on silica gel using solvent system S1 or S2.
1H-imidazo[4,5-c]quinoline-2,4-diones it will be
necessary to study also rearrangements of compounds 10
and 11 analogues bearing an alkyl or aryl group in
position 3´. At the present time, we are starting work on
this problem.
The conversion of compounds 10 and 11 to spiro
compounds 14 or 3-ureidoindoles 13 and 15, respectively,
is not merely interesting from a theoretical point of view
but, owing to the simple reaction protocol and relatively
good yields, presents an easy pathway to preparing
unsymmetrical 1,3-disubstituted ureas based on indol-2-
one structure.
3-Butyl-1-methyl-3-ureido-1H,3H-quinoline-2,4-dione (10a).
This compound was obtained in 55% yield by repeated
fractional crystallization (ethyl acetate) of its mixture with 11a.
Colorless crystals, mp 110-119°C (ethyl acetate); ir: ꢁ 3452,
3356, 3260, 2956, 2932, 2871, 1660, 1601, 1538, 1474, 1365,
1302, 1226, 1195, 1116, 863, 758, 665, 620, 550, 534 cm-1.
Positive-ion APCI-ms: m/z 290 [M+H]+, 272 [M+H-H2O]+, 255
[M+H-H2O-NH3]+, 247 [M+H-NHCO]+, 229 [M+H-NHCO-
H2O]+ (100%), 216 [M+H-H2O-butene]+, 201 [M+H-NHCO-
H2O-CO]+. Positive-ion APCI-ms/ms of m/z 272: m/z 255
[M+H-H2O-NH3]+ (100%), 242 [M+H-H2CO]+, 229 [M+H-
NHCO-H2O]+, 216 [M+H-H2O-butene]+. Negative-ion APCI-
ms: m/z 288 [M-H]-, 270 [M-H-H2O]-, 245 [M-H-NHCO]-, 230
[M-H-NHCONH]-(100%), 214 [M-H-H2O-butene]-, 187 [M-H-
NHCO-butane]-. Negative-ion APCI-ms/ms of m/z 270: m/z 227
[M-H2O-NHCO]-, 213 [M-H-H2O-butyl]-., 187 [M-H-NHCO-
butane]- (100%).
EXPERIMENTAL
The 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
1
for 13C, 50.68 MHz for 15N) in DMSO-d6 or CDCl3. H and 13C
chemical shifts are given on the ꢀ 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
and negative-ion APCI mass spectra were measured on an ion trap
analyzer Esquire 3000 (Bruker Daltonics, Bremen, Germany)
within the mass range m/z = 50 - 1000. Samples were dissolved in
acetonitrile and analyzed by direct infusion at the flow rate of 50
μL/min. The ion source temperature was 350°C, the APCI probe
temperature was 350°C, 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 0.8 V. The tuning parameter target mass was set at
400 m/z. Column chromatography was carried out on Silica gel
(Merck, grade 60, 70-230 mesh) using benzene and then
successive mixtures of benzene-ethyl acetate (in rations from 99:1
to 8:2, solvent system S1) or using chloroform and then successive
mixtures of chloroform-ethanol (in rations from 99:1 to 8:2,
solvent system S2). Reactions as well as the course of separation
and also the purity of compounds were monitored by tlc (elution
systems benzene-ethyl acetate, 4:1 (S3), chloroform-ethanol, 9:1
(S4) and/or 19:1 (S5), and chloroform-isopropyl alcohol, 9:1 (S6)
on Alugram® SIL G/UV254 foils (Macherey-Nagel). Elemental
analyses (C, H, N) were performed with an EA 1108 Elemental
Analyzer (Fisons Instrument).
Anal. Calcd. for C15H19N3O3: C, 62.27; H, 6.62; N, 14.52.
Found: C, 62.35; H, 6.72; N, 14.37.
1-Methyl-3-phenyl-3-ureido-1H,3H-quinoline-2,4-dione (10b).
This compound was obtained in 58% yield by repeated
crystallization (isopropyl alcohol) of its mixture with 11b.
Colorless crystals, mp 246-252°C; ir: ꢁ 3431, 3411, 3313, 3260,
1682, 1661, 1599, 1495, 1476, 1364, 1301, 1194, 1181, 1131,
1037, 781, 764, 693, 631, 574, 545, 527 cm-1. Positive-ion
APCI-ms: m/z 310 [M+H]+, 292 [M+H-H2O]+, 267 [M+H-
NHCO]+, 249 [M+H-H2O-NHCO]+ (100%), 221 [M+H-H2O-
NHCO-CO]+, 189 [M+H-H2O-NHCO-NH2CONH2]+, 161
[C6H4NHCOCH2CO]+, 146 [C6H4(CO)NCO]+. Positive-ion
APCI-ms/ms of m/z 292: m/z 264 [M+H-H2O-CO]+, 249 [M+H-
H2O-NHCO]+, 221 [M+H-H2O-NHCO-CO]+, 189 [M+H-H2O-
NHCO-NH2CONH2]+, 161 [C6H4NHCOCH2CO]+, 146
[C6H4(CO)NCO]+ (100%). Negative-ion APCI-ms: m/z 308 [M-
H]-, 290 [M-H-H2O]-, 264 [M-H-NH2CO]-., 250 [M-H-
NHCONH2]- (100%), 208 [M-H-NHCONH-CH2CO]-, 187 [M-
H-H2O-NHCO-NH2CONH2]-. Negative-ion APCI-ms/ms of m/z
290: m/z 275 [M-H-H2O-CH3]-, 247 [M-H-H2O-NHCO]-, 187
[M-H-H2O-NHCO-NH2CONH2]- (100%).
Anal. Calcd. for C17H15N3O3: C, 66.01; H, 4.89; N, 13.58.
Found: C, 65.85; H, 4.97; N, 13.42.
3-Amino-1H,3H-quinoline-2,4-diones (6a-g) were prepared
according to the general procedure described in literature [5].
General Procedure for the Reaction of 1-Substituted 3-Amino-
1H,3H-quinoline-2,4-diones (6a-g) with Nitrourea.
3a-Butyl-9b-hydroxy-5-methyl-3,3a,5,9b-tetrahydro-1H-imidazo-
[4,5-c]quinoline-2,4-dione (11a).
This compound was obtained in 1.5% yield by repeated
fractional crystallization (ethyl acetate) of its mixture with 10a.
Colorless crystals, mp 186-196°C; ir: ꢁ 3312, 3251, 2956, 2930,
2872, 1717, 1636, 1604, 1478, 1392, 1297, 1234, 1119, 1077,
985, 947, 758, 733, 701, 634, 604, 541, 515 cm-1. All ms and
ms/ms spectra are identical as for 10a.
Nitrourea (1.05 g, 10 mmoles) was added to a stirred solution
of 6 (5 mmoles) in dioxane (10 ml). The solution was stirred at
80°C for the time given in Table 1. The solution was cooled and
evaporated to dryness. Water (50 ml) was added; the insoluble
portion was collected by filtration with suction and repeatedly
crystallized from appropriate solvent (in the case of the crude

1258
A. Klásek, A. Lyꢀka, M. Holꢀapek, M. Kováꢁ, and I. Hoza
Vol 43
Anal. Calcd. for C15H19N3O3: C, 62.27; H, 6.62; N, 14.52.
Found: C, 62.35; H, 6.72; N, 14.37.
NHCO-cyclohexene-NH3-CO]+, 146 [C6H4(CO)NCO]+.
Positive-ion APCI-ms/ms of m/z 392: m/z 349 [M+H-NHCO]+
(100%), 267 [M+H-NHCO-cyclohexene]+, 250 [M+H-NHCO-
cyclohexene-NH3]+, 222 [M+H-NHCO-cyclohexene-NH3-CO]+.
Negative-ion APCI-ms: m/z 390 [M-H]-, 346 [M-H-NH2CO]-.,
296 [M-H-H2O-C6H4]- (100%), 214 [M-H-H2O-C6H4-
cyclohexene]-. Negative-ion APCI-ms/ms of m/z 390: m/z 346
[M-H-NH2CO]-. (100%).
9b-Hydroxy-5-methyl-3a-phenyl-3,3a,5,9b-tetrahydro-1H-imi-
dazo[4,5-c]quinoline-2,4-dione (11b).
This compound was obtained in 14% yield by repeated
crystallization (isopropyl alcohol) of its mixture with 10b.
Colorless crystals, mp 228-236°C; ir: ꢀ 3430, 3400, 3196, 3101,
2843, 1725, 1656, 1601, 1472, 1421, 1377, 1301, 1272, 1173,
1150, 1132, 1081, 1049, 1032, 855, 782, 763, 722, 698, 655, 551
cm-1. All ms and ms/ms spectra are identical as for 10b.
Anal. Calcd. for C17H15N3O3: C, 66.01; H, 4.89; N, 13.58.
Found: C, 65.85; H, 4.97; N, 13.42.
Anal. Calcd. for C23H25N3O3: C, 70.57; H, 6.44; N, 10.73.
Found: C, 70.48; H, 6.61; N, 10.59.
3,3a-Dibutyl-9b-hydroxy-5-phenyl-3,3a,5,9b-tetrahydro-1H-
imidazo[4,5-c]quinoline-2,4-dione (11f).
This compound was obtained in 24% yield as colorless
crystals, mp 124-132°C (benzene–hexane); ir: ꢀ 3365, 3238,
2959, 2870, 1710, 1692, 1604, 1593, 1498, 1466, 1418, 1365,
1343, 1309, 1257, 1124, 1071, 1049, 1002, 955, 755, 701, 629,
569, 515 cm-1. Positive-ion APCI-ms: m/z 408 [M+H]+, 390
[M+H-H2O]+ (100%), 365 [M+H-NHCO]+, 334 [M+H-H2O-
butene]+, 308 [M+H-NHCO-butyl]+.. Positive-ion APCI-ms/ms
of m/z 408: m/z 365 [M+H-NHCO]+ (100%). Negative-ion
APCI-ms: m/z 406 [M-H]- (100%), 388 [M-H-H2O]-, 360 [M-H-
H2O-CO]-, 332 [M-H-H2O-butene]-, 289 [M-H-H2O-butene-
NHCO]-. Negative-ion APCI-ms/ms of m/z 406: m/z 363 [M-H-
NHCO]- (100%), 319 [M-H-NHCO-NH2CO]-..
3,3a-Dibutyl-9b-hydroxy-5-methyl-3,3a,5,9b-tetrahydro-1H-
imidazo[4,5-c]quinoline-2,4-dione (11c).
This compound was obtained in 25% yield as colorless
crystals, mp 117-122°C (benzene–hexane); ir: ꢀ 3310, 2958,
2934, 2971, 1689, 1676, 1606, 1475, 1419, 1368, 1303, 1114,
1070, 1048, 995, 755, 653, 608, 543, 514 cm-1. APCI-ms: m/z
346 [M+H]+, 328 [M+H-H2O]+ (100%), 303 [M+H-NHCO]+,
272 [M+H-H2O-butene]+, 255 [M+H-H2O-butylamine]+, 229
[M+H-H2O-butene-NHCO]+,
216
[M+H-H2O-2*butene]+.
Positive-ion APCI-ms/ms of m/z 346: m/z 303 [M+H-NHCO]+
(100%). Negative-ion APCI-ms: m/z 344 [M-H]-, 326 [M-H-
H2O]- (100%), 298 [M-H-H2O-CO]-., 270 [M-H-H2O-butene]-,
227 [M-H-H2O-butene-NHCO]-, 212 [M-H-H2O-butene-NHCO-
CH3]-., 187. Negative-ion APCI-ms/ms of m/z 344: m/z 326 [M-
H-H2O]-, 300 [M-H-NH2CO]- (100%), 244 [M-H-NH2CO-
butene]-., 227 [M-H-H2O-butene-NHCO]-, 212 [M-H-H2O-
butene-NHCO-CH3]-..
Anal. Calcd. for C24H29N3O3: C, 70.74; H, 7.17; N, 10.31.
Found: C, 70.53; H, 7.32; N, 10.16.
3-Butyl-3a,5-diphenyl-9b-hydroxy-3,3a,5,9b-tetrahydro-1H-
imidazo[4,5-c]quinoline-2,4-dione (11g).
This compound was obtained in respective yields of 27%
(Table 1, Entry 7) and 18% (Table 1, Entry 8) as colorless
crystals, mp 157-161°C (benzene–cyclohexane); ir: ꢀ 3420,
3248, 2954, 2928, 2869, 1704, 1686, 1605, 1593, 1498, 1464,
1410, 1374, 1347, 1263, 1229, 1137, 1067, 1071, 979, 943, 872,
808, 756, 701, 636, 608, 520 cm-1. Positive-ion APCI-ms: m/z
428 [M+H]+, 410 [M+H-H2O]+ (100%), 385 [M+H-NHCO]+.
Positive-ion APCI-ms/ms of m/z 428: m/z [M+H-NHCO]+
(100%). Negative-ion APCI-ms: m/z 426 [M-H]-, 383 [M-H-
NHCO]-, 332 [M-H-H2O-C6H4]- (100%). Negative-ion APCI-
ms/ms of m/z 426: m/z 383 [M-H-NHCO]- (100%).
Anal. Calcd. for C19H27N3O3: C, 66.06; H, 7.88; N, 12.16.
Found: C, 66.21; H, 7.61; N, 12.03.
3-Butyl-9b-hydroxy-5-methyl-3a-phenyl-3,3a,5,9b-tetrahydro-
1H-imidazo[4,5-c]quinoline-2,4-dione (11d).
This compound was obtained in 70% yield as colorless
crystals, mp 140-158°C and then 208-211°C (methanol); ir: ꢀ
3288, 3071, 3034, 2954, 2861, 1699, 1665, 1604, 1476, 1411,
1370, 1299, 1219, 1151, 1136, 1113, 1085, 1052, 1010, 866,
828, 757, 965, 633, 517 cm-1. Positive-ion APCI-ms: m/z 366
[M+H]+, 348 [M+H-H2O]+ (100%), 323 [M+H-NHCO]+, 292
[M+H-H2O-butene]+, 250 [M+H-NHCO-butylamine]+, 222
[M+H-NHCO-butylamine-CO]+. Positive-ion APCI-ms/ms of
m/z 366: m/z 323 [M+H-NHCO]+ (100%). Negative-ion APCI-
ms: m/z 364 [M-H]-, 320 [M-H-NHCO]-., 270 [M-H-H2O-C6H4]-
(100%). Negative-ion APCI-ms/ms of m/z 364: m/z 320 [M-H-
NHCO]-. (100%).
Anal. Calcd. for C26H25N3O3: C, 73.05; H, 5.89; N, 9.83.
Found: C, 72.89; H, 6.03; N, 9.77.
3,3a-Dibutyl-5-methyl-3,3a-dihydro-5H-imidazo[4,5-c]quino-
line-2,4-dione (12c).
This compound was obtained in 3% yield as colorless
crystals, mp 100-102°C (benzene–hexane); ir: ꢀ 2950, 2930,
2876, 2858, 1734, 1690, 1610, 1471, 1347, 1292, 1258, 1164,
1127, 1096, 1047, 1002, 982, 961, 773, 684, 574, 535, 505 cm-1.
Positive-ion APCI-ms: m/z 328 [M+H]+ (100%), 272 [M+H-
butene]+, 255 [M+H-butylamine]+, 229 [M+H-butylisocyanate]+.
Positive-ion APCI-ms/ms of m/z 328: m/z 272 [M+H-butene]+,
255 [M+H-butylamine]+, 229 [M+H-butylisocyanate]+ (100%).
Negative-ion APCI-ms: m/z 326 [M-H]-, 298 [M-H-CO]-, 270
[M-H-butene]- (100%), 227 [M-H-butene-NHCO]-, 213 [M-H-
butene-butane]-, 187. Negative-ion APCI-ms/ms of m/z 326: m/z
298 [M-H-CO]-, 227 [M-H-butene-NHCO]- (100%), 213 [M-H-
butene-butane]-, 187.
Anal. Calcd. for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50.
Found: C, 68.85; H, 6.52; N, 11.37.
3-Cyclohexyl-9b-hydroxy-5-methyl-3a-phenyl-3,3a,5,9b-tetra-
hydro-1H-imidazo[4,5-c]quinoline-2,4-dione (11e).
This compound was obtained in 33% yield as colorless
crystals, mp 255-260°C and then 285-290°C (methanol); ir: ꢀ
3548, 3223, 3079, 2932, 2918, 2849, 1697, 1674, 1604, 1501,
1468, 1410, 1362, 1311, 1267, 1225, 1150, 1074, 1052, 1012,
786, 758, 697, 654, 634, 537 cm-1. Positive-ion APCI-ms: m/z
392 [M+H]+, 374 [M+H-H2O]+ (100%), 349 [M+H-NHCO]+,
292 [M+H-H2O-cyclohexene]-, 267 [M+H-NHCO-cyclo-
hexene]+, 250 [M+H-NHCO-cyclohexene-NH3]+, 221 [M+H-
Anal. Calcd. for C19H25N3O2: C, 69.70; H, 7.70; N, 12.83.
Found: C, 69.57; H, 7.87; N, 12.59.

Sep-Oct 2006
Molecular Rearrangement of 1-Substituted 3-Aminoquinoline-2,4-diones
1259
3-Butyl-5-methyl-3a-phenyl-3,3a-dihydro-5H-imidazo[4,5-c]-
quinoline-2,4-dione (12d).
residue was crystallized from appropriate solvent. In some cases,
the mother liquors were chromatographed on silica gel using
solvent system S1 or S2. Results are listed in Table 6.
This compound was obtained in 12% yield as yellowish
crystals, mp 198-199°C (benzene–hexane); lit [4], mp 198-
200°C (benzene–hexane). The ir spectrum of 12d was identical
with that of authentic sample [4].
1-Methyl-3-(3-pentanoylureido)-2-oxo-2,3-dihydro-1H-indole
(13a).
This compound was obtained from 10a in 41% yield as
colorless crystals, mp 193-197°C (methanol); lit [4], mp 190-
196°C (ethanol). The ir spectrum of 13a was identical with that
of authentic sample [4].
3-Cyclohexyl-5-methyl-3a-phenyl-3,3a-dihydro-5H-imidazo-
[4,5-c]quinoline-2,4-dione (12e).
This compound was obtained in 17% yield as colorless
crystals, mp 290-292°C (methanol); lit [4], mp 291-294°C
(ethanol). The ir spectrum of 12e was identical with that of
authentic sample [4].
3-(3-Benzoylureido)-1-methyl-2-oxo-2,3-dihydro-1H-indole
(13b).
This compound was obtained in respective yields of 69%
(from 10b) and 61% (from 11b) as colorless crystals, mp 211-
213°C (methanol); lit [4], mp 213-214°C (ethanol). The ir
spectrum of 13b was identical with that of authentic sample [4].
3,3a-Dibutyl-5-phenyl-3,3a-dihydro-5H-imidazo[4,5-c]quino-
line-2,4-dione (12f).
This compound was obtained in 22% yield as yellowish
crystals, mp 151-154°C (hexane); ir: ꢀ 3053, 2956, 2928, 2871,
1737, 1704, 1617, 1605, 1492, 1465, 1345, 1292, 1279, 1249,
1162, 1113, 1093, 1006, 765, 757, 701, 651, 601, 577, 514 cm-1.
Positive-ion APCI-ms: m/z 390 [M+H]+ (100%), 334 [M+H-
butene]+, 291 [M+H-butylisocyanate]+. Positive-ion APCI-
ms/ms of m/z 390: m/z 373 [M+H-NH3]+, 347 [M+H-NHCO]+,
334 [M+H-butene]+, 317 [M+H-butene-NH3]+, 291 [M+H-
butylisocyanate]+ (100%). Negative-ion APCI-ms: m/z 388 [M-
H]-, 360 [M-H-CO]-, 332 [M-H-butene]- (100%), 289 [M-H-
butene-NHCO]-. Negative-ion APCI-ms/ms of m/z 388: m/z 360
[M-H-CO]- (100%), 289 [M-H-butene-NHCO]-.
3-(3-Benzoyl-3-butylureido)-1-methyl-2-oxo-2,3-dihydro-1H-
indole (13d).
This compound was obtained in 7% yield from 12d as
colorless crystals, mp 155-158°C (ethanol); lit [4], mp 156-
158°C (benzene-hexane). The ir spectrum of 13d was identical
with that of authentic sample [4].
3-(3-Benzoyl-3-butylureido)-1-phenyl-2-oxo-2,3-dihydro-1H-
indole (13g).
This compound was obtained in respective yields of 31%
(from 11g) and 28% (from 12g) as colorless crystals, mp 193-
198°C (methanol); lit [4], mp 183-188°C (benzene-hexane). The
ir spectrum of 13g was identical with that of authentic sample
[4].
Anal. Calcd. for C24H27N3O2: C, 74.01; H, 6.99; N, 10.79.
Found: C, 74.16; H, 7.08; N, 10.57.
3-Butyl-3a,5-diphenyl-3,3a-dihydro-5H-imidazo[4,5-c]quino-
line-2,4-dione (12g).
(E)-3-Butyl-4-butylidene-1´-methyl-1´H-spiro[imidazolidine-
5,3´-indole]-2,2´-dione (14c).
This compound was obtained as yellowish crystals, mp 177-
179°C (benzene–hexane); lit [4], mp 83-86°C (benzene –
hexane). Now we found that published [4] mp belong to an
adduct of 12g with benzene and mp of sample dried at 105°C for
2 h is 177-179°C; ir: ꢀ 2964, 2953, 2923, 2870, 1735, 1701,
1614, 1602, 1594, 1492, 1464, 1448, 1352, 1309, 1278, 1247,
1135, 1070, 776, 765, 751, 697, 652, 603, 511 cm-1.
This compound was obtained in respective yields of 64%
(from 11c) and 43% (from 12c) as colorless crystals, mp 197-
201°C (ethanol); lit [4], mp 196-200°C (ethanol). The ir
spectrum of 14c was identical with that of authentic sample [4].
(E)-3-Butyl-4-butylidene-1´-phenyl-1´H-spiro[imidazolidine-
5,3´-indole]-2,2´-dione (14f).
General Procedure for the Reaction of 10 and 11 with
Phosphorus Pentoxide.
This compound was obtained in respective yields of 82%
(from 11f) and 75% (from 12f) as colorless crystals, mp 125-
129°C (benzene-hexane); lit [4], mp 124-128°C (benzene-
hexane). The ir spectrum of 14f was identical with that of
authentic sample [4].
Phosphorus pentoxide (0.1064 g, 0.75 mmol) was added in
one portion to the vigorously stirred and cooled (0°C) solution
of compound 11 or 12 (0.5 mmol) in chloroform (15 ml). The
mixture was stirred at rt under absorption tube filled with
anhydrous calcium chloride for the time given in Table 4. After
this time, the reaction mixture was poured into the column of
silica gel (10 g). The column was washed with chloroform,
eluent was evaporated to dryness in vacuo and crystallized from
appropriate solvent. Yields are given in Table 5, isolated
compounds 12 were identical with those characterized in the
foregoing general procedure chapter.
3-(3-Butylureido)-1-methyl-2-oxo-2,3-dihydro-1H-indole (15d).
This compound was obtained in respective yields of 9% (from
11d) and 6% (from 12d) as colorless crystals, mp 190-193°C
(ethanol); lit [4], mp 192-195°C (benzene). The ir spectrum of
15d was identical with that of authentic sample [4].
3-(3-Cyclohexylureido)-1-methyl-2-oxo-2,3-dihydro-1H-indole
(15e).
General Procedure for Rearrangement of 10, 11 and 12 in Acetic
Acid.
This compound was obtained in respective yields of 39%
(from 11e) and 37% (from 12e) as colorless crystals, mp 218-
223°C (methanol); ir: ꢀ 3348, 3286, 3099, 3059, 3001, 2920,
2850, 1711, 1628, 1566, 1518, 1495, 1468, 1420, 1375, 1349,
1314, 1248, 1226, 1155, 1126, 1090, 1017, 891, 748, 685, 575,
A solution of starting compound 10, 11, or 12 (0.5 mmol) in
acetic acid (5 ml) was refluxed for the time given in Table 6.
After cooling, the solution was evaporated to dryness and the

1260
A. Klásek, A. Lyꢀka, M. Holꢀapek, M. Kováꢁ, and I. Hoza
Vol 43
540, 483 cm-1. Positive-ion APCI-ms: m/z 288 [M+H]+, 188
[M+H-cyclohexyl-NH3]+., 161 [M+H-cyclohexane-NHCO]+,
146 [C6H4(CO)NCO]+ (100%). Positive-ion APCI-ms/ms of m/z
288: m/z 188 [M+H-cyclohexyl-NH3]+., 161 [M+H-cyclohexane-
NHCO]+ (100%), 146 [C6H4(CO)NCO]+, 100 [cyclohexylNH3]+.
Negative-ion APCI-ms: m/z 286 [M-H]- (100%), 187 [M-H-
cyclohexylNH]-., 160 [M-H-cyclohexyl-NHCO]-.. Negative-ion
APCI-ms/ms of m/z 286: m/z 187 [M-H-cyclohexylNH]-.
(100%), 160 [M-H-cyclohexyl-NHCO]-..
REFERENCES AND NOTES
[1] A. Klásek, K. Koꢁistek, A. Lyꢀka, and M. Holꢀapek,
Tetrahedron, 59, 1283 (2003).
[2] A. Klásek, A. Lyꢀka, M. Holꢀapek, and I. Hoza,
Tetrahedron, 60, 9953 (2004).
[3] A. Klásek, A. Lyꢀka, M. Holꢀapek, and I. Hoza, J.
Heterocyclic Chem., 43, 203 (2006).
[4] A. Klásek, K. Koꢁistek, A. Lyꢀka, and M., Holꢀapek,
Tetrahedron, 59, 5279 (2003).
Anal. Calcd. for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62.
Found: C, 66.67; H, 7.52; N, 14.49.
[5] S. Kafka, A. Klásek, J. Polis, and J. Koꢃmrlj, Heterocycles,
57, 1659 (2002).
[6] A. Sápi, J. Fetter, K. Lempert, and M. Kajtár-Peredy,
Tetrahedron, 53, 12729 (1997).
Acknowledgements.
[7] A. Klásek, V. Mrkviꢀka, A., Pevec, and J. Koꢃmrlj, J. Org.
Chem., 69, 5646 (2004).
[8] M. O. Forster and H. E. Fierz, J. Chem. Soc., Trans., 87, 110
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4954 (1981).
This study was supported by the Ministry of Education, Youth
and Sports of the Czech Republic (Grant No. MSM
7088352101). M.H. acknowledges the support of grant project
No. 203/05/2106 sponsored by the Czech Science Foundation.
The authors thank Prof. M. Strnad (Laboratory of plant-growth
regulators, Faculty of Science, Palackꢂ University in Olomouc)
for biological testing of some compounds and Mrs. H. Ger ová
(Faculty of Technology, Tomas Bata University in Zlín) for
technical help.
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Chem., 67, 5527 (2002).