Reaction of 1-substituted 3-aminoquinoline-2,4-diones with isothiocyanates. An easy pathway to generate novel 2-thioxo-1′H-spiro[imidazoline-5,3′-indole]-2,2′-diones

Article abstract of DOI:10.1016/j.tet.2009.04.009

3-Butyl-3-amino-1H,3H-quinoline-2,4-diones react with isothiocyanates to give novel 3a-butyl-9b-hydroxy-2-thioxo-1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-2-ones in high yields. These compounds rearrange in boiling acetic acid or concd hydrochloric a

Full text of DOI:10.1016/j.tet.2009.04.009

Tetrahedron 65 (2009) 4908–4916
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reaction of 1-substituted 3-aminoquinoline-2,4-diones with isothiocyanates.
An easy pathway to generate novel 2-thioxo-10H-spiro[imidazoline-5,30-
indole]-2,20-diones
a,
a
b,
c
d
,
c
e
*
ꢀ
ˇ
´
´
´
ˇ
´
ˇ
ˇ´
ˇ
˚
Antonın Klasek , Vladimır Mrkvicka , Antonın Lycka , Ivan Miksık , Ales Ruzicka
a Department of Chemistry, Faculty of Technology, Tomas Bata University, 762 72 Zl´ın, Czech Republic
b Research Institute for Organic Syntheses (VUOS), Rybitv´ı 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
d Institute of Physiology of the Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic
e Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, 53210 Pardubice, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Butyl-3-amino-1H,3H-quinoline-2,4-diones react with isothiocyanates to give novel 3a-butyl-9b-hy-
droxy-2-thioxo-1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-2-ones in high yields. These compounds
rearrange in boiling acetic acid or concd hydrochloric acid to give (E)- and/or (Z)-4-butylidene-2-thioxo-
10H-spiro[imidazoline-5,30-indole]-2,20-diones. All compounds were characterized by their 1H, 13C, IR and
MS spectra, and some of them also by 15N NMR. The structure of one compound was investigated by
single-crystal X-ray diffraction.
Received 15 January 2009
Received in revised form 16 March 2009
Accepted 2 April 2009
Available online 9 April 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
a
-Aminoketones
Enamides
Rearrangement
Thiourea derivatives
Spiro-heterocycles
1. Introduction
quite exceptional structural diversity. This gave us incentive to
perform an analogous reaction of 3-aminoquinoline-2,4-diones
In our laboratory, attention has been given to study the re-
activity of 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones. We
have recently investigated the reaction of these compounds with
isocyanates to yield 30-substituted 3-ureidoquinoline-2,4-diones
and/or their cyclic isomers.1,2 These compounds rearrange in boil-
ing acetic acid to form new heterocyclic systems. In cases where the
starting compounds are not substituted at position 1, their rear-
rangement in acetic acid produced mixtures of 3-ureidoindoles and
1,3-disubstituted ureas, whereas rearrangement in concd hydro-
chloric acid yielded derivatives of imidazolinone.1,3,4 However, if
position 1 in the starting compound bears an alkyl or aryl group,
three different derivatives of spiro-imidazolidinyl-oxindoles arise.2
An illustrative survey of these reactions was given in our latest
paper.2
with isothiocyanates, and to examine how the products of this re-
action behave in an acidic environment. We anticipated the rise of
new compounds containing a sulfur atom, which may be in-
teresting, since many biologically active compounds belong to this
group.5,6 Molecular rearrangements of the adducts of 3-amino-
quinolinediones with isocyanates1–4 gave results that were largely
dependent on the character of the substituents at positions 1 and 3
of the starting compound. Thus, according to this criterion, we now
divided the starting 3-aminoquinolinediones into three different
groups. The first group contained compounds substituted at posi-
tion 1 with an alkyl or aryl group and at position 3 with an alkyl
group. The second group contained compounds having the same
type of substitution at position 1, but bearing a phenyl group at
position 3. The third group comprised compounds without any
substituent at position 1.
Molecular rearrangement of the addition products of 3-amino-
quinoline-2,4-diones with isocyanates yields products displaying
We would like to demonstrate in this work that the reaction of
1-substituted 3-butyl-3-aminoquinolinediones
1
with iso-
thiocyanates providesdcontrary to their reactions with iso-
cyanatesda single product 3, which rearranges in an acid
environment to give 4-butylidene-2-thioxo derivatives of spiro-
imidazolidinyl-oxindoles 4.
* Corresponding author. Tel.: þ420 576 031 413; fax: þ420 577 210 722.
´
E-mail address: klasek@ft.utb.cz (A. Klasek).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.009

´
A. Klasek et al. / Tetrahedron 65 (2009) 4908–4916
4909
2. Results and discussion
we subjected the raw product of the reaction of 1c with phenyl-
isothiocyanate to heating in DMSO, and obtained nearly pure 3d,
despite the weak signals of compound 2d (approx. 5%) always
present in the NMR spectrum. Signals of trace quantities of com-
pounds 2 were noticed in the NMR spectra of almost all of the
compounds 3, even though these were pure according to TLC. Such
results indicate the possibility of a chemical equilibrium between
compounds 2 and their cyclic isomers 3 in DMSO, albeit one that is
strongly shifted in favour of compounds 3. The reaction of 1 with
isothiocyanates did not produce, in any case, a tautomeric compound
bearing SH group that could theoretically arise from compounds
having R2¼H, i.e., 3a–d. Signals of the thioxo group of compounds 3
lie in a narrow region of 181.3–182.4 ppm, which is typical of the
C]S group, and excludes the presence of the C–SH group.
Reactions of 3-aminoquinoline-2,4-diones
1
with iso-
thiocyanates were performed by boiling the reaction components
in chloroform (Scheme 1, Table 1). Methylisothiocyanate and phe-
nylisothiocyanate were chosen as model isothiocyanates. All
starting compounds had a butyl group at position 3, which fulfils
the conditions for compounds 1 of the first group (see above). The
substituent selected for position 1 was methyl or phenyl, and
a primary amino or butylamino group was chosen as the second
substituent at position 3. Starting aminoketones 1 were obtained
from the corresponding 3-chloro derivatives in accordance with
procedures described in Ref. 7. One novel amine, 1c, was prepared
and its NMR spectra are given in Table 2.
The molecular rearrangement of compound 3 was carried out in
accordance with our latest work2 by boiling in acetic acid or concd
hydrochloric acid. The results are presented in Table 3. A compar-
ison of the yields of the rearrangement of 3 into 4 shows only
a slight influence of the reaction medium on the reaction course,
which is a different result from that observed for the rearrange-
ment of the 2-oxaanalogues of 3.2,4 A suggested reaction mecha-
nism for the rearrangement (Scheme 1) supposes that compounds
3, by protonation and loss of water, produce intermediate A that is
S
R3
S
C-NHR3
N1
O
O
N3
NHR2
HO
9b
N
R2
R3NCS
CHCl3
R2
3a
4
Bu
O
Bu
O
3 (57-94%)
H+, - H2O
S
Bu
O
N
R1
N
R1
N
6
1
2
R1
Key of substituents:
R3
a
b
c
d
e
f
g
h
N
R1
R2
R3
Me Me Ph Ph Me Me
Ph Ph
Bu Bu
Me Ph
transformed into intermediate
B through migration of the
N
R2
Bu
N(R1)(C]O) group from the 3a to the 9b position. Further trans-
formations of intermediate B depend on the character of the sub-
stituents at positions 3 and 4.2,4
H
H
H
H
Bu Bu
Me Ph Me Ph
Me Ph
N
O
A
R1
3 R2
S
S
H
2
A butyl group is present at position 4 in all of the compounds
studied. If a butyl group is bonded to the nitrogen atom in position
3, intermediate B stabilizes by splitting-off of a proton, thus giving
spiro-compounds 4. Interestingly, the formation of stable enamides
4 takes place even in cases where R2¼H. The formation of tauto-
meric imines was not observed. We observed that coupling con-
stants 1J (15N, 1H) for the nitrogen atom at position 3 of 99.4ꢀ0.4 Hz,
which unambiguously indicated the presence of an NH group.
A comparison of the NMR spectral characteristics of compounds
4 (Table 4) showed that these compounds differ by configuration at
the double bond of the butylidene group. Key compounds for de-
termination of the configuration turned out to be two isomeric
products isolated from the rearrangement of compound 3c. These
two isomers displayed very similar MS spectra. In their NMR
spectra, the same number of signals was present; however, they
differed in chemical shifts. Conclusive results were obtained from
2D-NOESY measurements. A through-space interaction of the
N(3)–H proton and the ]CH proton of the butylidene group was
observed (Fig. 1) in the 2D-NOESY spectrum of the major product of
the rearrangement of 3c (Table 3). Hence, this compound is the E-
isomer, and the minor product of the rearrangement of 3c (Table 3)
is the Z-isomer (Fig. 2). The greatest differences between the NMR
spectra of the (E)-3c and (Z)-4c isomers were found in the chemical
shifts of the protons of the butylidene group and the carbon atoms
of the C]S group, which was used in to assign the corresponding
configuration of the other compounds 4 (Table 4).
The formation of an E- or Z-isomer is influenced by the steric
conditions in intermediate B (Scheme 1). Intermediates Be–h dis-
play strong steric interactions between the N(3)-butyl and C(4)-
butyl groups, which unambiguously preferences the formation of
the (E)-4e–h isomers. In the case of compounds 4a,b (R2¼H), such
an interaction is absent, and elimination of a proton from in-
termediate B occurs preferentially to give formation of the Z-iso-
mer. However, with compounds 4c,d, which, in contrast to 4a,b
bear a phenyl group at position 10, both isomers arise. This may be
due to steric interaction between the 4-butyl group and the bulky
phenyl substituent at C-10.
3
2
S
N
R2
N 4
N 4
R3
1
R3
1
3N´a
N
C3H7
N
4´
R3
4´
3´a
5
5
5´
6´
5´
6´
Bu
O
C3H7
O
2´
1´
R1
O
2´
1´
and/or
7´aN
7´aN
7´
7´
N
R1
R1
B
(Z)-4a-d (5-49%)
(E)-4c-h (15-98%)
Scheme 1.
Table 1
Preparation of compounds 3 by the reaction of 3-aminoquinoline-2,4(1H,3H)-diones
(1) with isothiocyanates
Entry
Educt
Substituentsa
Time (h)
Product (yield, %)
R1
R2
R3
1
2
3
4
5
6
7
8
1a
1a
1c
1c
1e
1e
1g
1g
Me
Me
Ph
H
H
H
H
Bu
Bu
Bu
Bu
Me
Ph
Me
Ph
Me
Ph
Me
Ph
3
1
2
3a (94)
3b (89)
3c (57)
3d (81)b
3e (58)
3f (68)
3g (92)
3h (86)
Ph
1
Me
Me
Ph
3.5
4.5
6.5
13
Ph
R3 from isothiocyanate.
A mixture of 2d and 3d, subsequently converted in 65% yield to almost pure 3d
a
b
by heating in DMSO.
The reaction of aminoketones 1 with isothiocyanates should
produce 3-thioureido-1H,3H-quinoline-2,4-diones 2 and/or 9b-
hydroxy-2-thioxo-1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-
4-ones 3 (Scheme 1). However, compounds 3 arose (Table 1) in
a total majority in good to very good yields in this case, contrary to
the reaction of 1 with isocyanates.2 The NMR spectra of 3 are pre-
sented in Table 2.
Only in one casedfrom starting compound 1c and phenyl-
isothiocyanate (Table 1, entry 4)dwas a mixture of compounds
obtained that could not be separated chromatographically. Never-
theless, when the NMR spectra of those reaction products were ac-
quired in DMSO-d6, it was found that the second component in the
mixture, probably compound 2d, diminished with time, and within 2
days, almost fully transformed into cyclic isomer 3d. For that reason,
In the case of E-4f, the structure was confirmed by single-
crystal X-ray diffraction (Fig. 3). Single crystals of E-4f suitable for

Table 2
1H and 13C chemical shifts (
d
, ppm) of compounds 1e and 3a–h in DMSO-d6
Position
1c
3a
3b
3c
3d
3e
3f
3g
3h
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
2
3
3a
4
4a
5
5a
6
7
8
8a
9
d
d
d
d
d
173.1
69.4
d
d
d
d
d
d
d
d
182.1
d
d
d
d
d
d
d
d
181.8
d
d
d
d
d
d
d
d
182.4
d
d
d
d
d
d
d
d
182.1
d
d
181.9
d
d
d
d
d
d
d
d
181.3
d
d
d
d
d
d
d
d
182.2
d
d
d
d
d
d
d
d
181.6
d
d
d
68.3
169.0
d
69.3
169.0
d
68.7
169.3
d
69.8
169.2
d
71.2
168.5
d
71.1
168.4
d
71.6
168.8
d
72.7
168.7
d
195.5
119.8
127.1
d
d
d
7.91
d
d
d
d
d
d
d
d
d
d
a
137.0
115.1
130.7
123.2
d
136.9
114.7
130.5
122.8
d
138.1
116.1
130.4
123.4
d
138.0
115.8
130.8
122.8
d
dd
136.7
115.0
130.7
123.3
d
136.9
114.5
130.4
122.7
d
137.8
116.1
130.4
123.4
d
7.23
7.54
6.39
123.1
135.5
116.4
143.6
d
7.25
7.52
7.28
7.23
7.38
6.88
6.26
7.33
7.27
6.21
7.32
6.85
7.23
7.51
7.29
7.18
7.35
6.88
6.20
7.26
7.21
6.12
7.08
6.81
115.6
130.5
122.9
d
b
d
d
d
d
d
d
d
d
d
d
d
d
d
7.84
d
127.5
121.8
88.7
d
7.07
d
127.6
121.8
90.4
d
7.90
d
128.0
121.5
89.1
d
7.16
d
127.7
121.4
90.8
d
7.86
d
127.4
122.0
87.9
d
7.16
d
127.4
122.1
89.0
d
7.86
d
128.8
122.0
88.2
d
7.22
d
9a
9b
OH
10Bu)
d
121.7
89.4
d
d
d
d
d
d
d
d
d
d
d
7.04
7.55
7.15
7.71
7.02
7.39
7.07
7.51
1.84
41.7
1.90
1.85
0.95
31.0
1.93
1.90
0.98
31.1
1.98
1.95
1.28
1.16
1.14
0.82
30.9
2.07
2.04
1.32
1.23
1.32
0.84
30.9
2.07
2.01
0.99
0.97
1.16
31.0
2.18
2.11
1.01
0.81
1.25
0.72
3.40
30.7
2.12
2.08
1.14
30.5
2.21
2.17
1.16
30.7
1.81
1.35
1.21
1.23
0.84
20(Bu)
25.3
24.7
24.6
24.8
24.8
24.5
24.5
24.7
24.6
30 (Bu)
40 (Bu)
10 (R1)
20 (R1)
22.1
13.9
1.14
0.73
3.36
22.4
13.6
29.9
d
1.18
0.75
3.40
22.5
13.6
29.7
d
22.5
13.7
137.6
129.0
22.6
13.7
137.7
129.1
22.5
13.6
29.5
d
22.5
13.6
29.6
d
1.23
0.75
22.6
13.8
137.3
130.2
1.26
0.77
22.6
0.71
3.32
13.8
a
d
137.7
129.4
129.1
130.3
130.2
128.9
d
d
d
d
d
7.40
7.33
7.65
d
d
7.21
7.21
d
d
7.14
7.20
130.4
30(R1)
d
d
d
d
7.63
130.3
7.67
130.2
d
d
d
d
d
d
7.57
128.9
7.62
b
40(R1)
7.56
2.22
d
d
d
d
d
d
7.57
9.50
128.8
d
7.57
9.83
128.8
d
d
d
7.50
3.90
3.77
1.82
1.48
1.29
0.91
2.80
127.8
44.9
7.53
3.94
3.84
1.91
1.57
1.34
0.93
b
10 (R2)
9.41
9.73
3.94
44.8
4.03
44.8
45.1
3.88
1.87
1.51
1.37
0.97
2.73
3.99
1.97
1.61
1.38
1.01
20 (R2)
d
d
d
d
d
d
d
d
d
d
31.6
31.6
31.6
31.6
20.0
30 (R2)
40 (R2)
10 (R3)
20 (R3)
30 (R3)
40(R3)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
20.0
14.0
28.5
d
20.0
14.0
136.6
130.6
128.0
127.4
19.9
13.8
28.6
d
d
d
13.8
a
2.70
27.5
d
136.3
130.8
127.9
127.6
2.83
27.7
d
136.5
130.4
128.1
127.9
d
d
c
c
c
c
c
c
b
d
d
d
7.24
7.24
7.24
d
d
d
7.18
7.24
7.24
d
d
d
d
d
d
d
d
d
d
128.2
b
d
d
d
d
a
137.6, or 137.4, or 137.0.
130.2, or 129.0, or 127.8, or 127.7.
7.15–7.30 (broadened signals).
b
c

´
A. Klasek et al. / Tetrahedron 65 (2009) 4908–4916
4911
5,30-indole]-2,20-diones 4 have not been previously described in the
literature. The only compounds hitherto known are their 2-oxoa-
nalogues, whose preparation was described in our previous work.2
The presented results expand the array of compounds containing
the spiro-oxindole structural motif, which appears in several indole
alkaloids,10 and in other compounds exhibiting various biological
activities.11,12 They also increase the variety of methods for pre-
paring spiro-oxindoles.11 At the same time, our results expand the
number of compounds containing the 4,4-spiro-2-thioxo-
imidazolidine structural fragment. Only a few of such compounds
have been previously described in literature, and they contain
Table 3
Molecular rearrangement of compounds 3 in boiling acetic acid (method A) and
concd hydrochloric acid (method B)a
Entry
Educt
Method
Time (h)
Products (yield, %)
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
3
1
2
1.5
2.5
2.5
4
2
3
3
3
1
3
2
3
2
(Z)-4a (49)
(Z)-4a (36)
(Z)-4b (28), 3b (13)b
(Z)-4b (35)
(E)-4c (61), (Z)-4c (6)
(E)-4c (61)
(E)-4d (15), (Z)-4d (5), 3d (19)b
(E)-4d (45), (Z)-4d (11), 3d (17)b
(E)-4e (62)
9
a
cyclohexylidene,13,14 cyklopentylidene,14 or dihydroacridinyl
10
11
12
13
14
15
16
(E)-4e (72)
(E)-4f (98)
(E)-4f (98)
(E)-4g (76)
(E)-4g (64)
(E)-4h (83)
(E)-4h (86)
group15 as the second component of the spiro-structure. Since
a number of simple N-substituted 2-thioxoimidazolines exhibit, for
example, inflammatory activity,16 gentamycin nephrotoxicity,17
3f
3g
3g
3h
3h
dopamine b-hydroxylase inhibitory activity and anti-aggregating
activity against collagen,18 it may be assumed that 4,4-spiro-2-thi-
oxoimidazolidines can also display significant biological activity.
a
For key of substituents see Table 1.
Regenerated starting compound.
b
4. Experimental
analysis were prepared from a benzene–hexane mixture. Com-
pound E-4f crystallizes in the triclinic space group P-1. The view
of the molecular structure of E-4f (Figs. 3 and 4) shows an almost
planar arrangement of the five-membered core (spiro) ring with
interplanar angles of 88.2(2)ꢁ, which is comparable to the values
of 88.3(2)ꢁ observed for 1-butyl-10-methyl-4-phenyl-10H-spiro-
[imidazoline-5,30-indole]-2,20-dione and 89.3(2)ꢁ and 85.9(1)ꢁ for
4.1. General considerations
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
500 spectrometer (500.13 MHz for 1H, 125.76 MHz for 13C,
50.68 MHz for 15N) in DMSO-d6. 1H and 13C chemical shifts are given
(4R
*
,5S
)-3-butyl-4-hydroxy-1,4,10-triphenyl-10H-spiro[imidazo-
*
on the
chemical shifts were referred to external neat nitromethane in
co-axial capillary (
¼0.0). All 2D experiments (gradient-selected
d
scale (ppm) and are referenced to internal TMS. 15N
lidine-5,30-indole]-2,20-dione.2 The C3–C18 distance (1.321(4) Å) in
compound E-4f revealed a shortening that was typical of the
presence of a double bond compared to the standard single bond
C(sp2)–C(sp2) distance of 1.31 Å.8 Also, the C10–O1 (1.207(3) Å)
distance and the geometry of the respective groups were sug-
gestive of the presence of a double bond. The identity of the
S]C(–N)2 moiety in E-4f was compared with 2648 analogous
compounds in the Cambridge Structural Database, and was in very
good agreement with respect to both the interatomic distances
and the bond angles, thus proving such an arrangement.9 Non-
classical H-bonding interactions are taking place in the E-4f
structure through O1–H22a–C22 (2.533(4) Å) and O1–H21c–C21
(2.717(3) Å) connecting the C]O group of one molecule to the first
CH2 group of the butyl moiety and the CH3 end group of the
–C]CH–C3H7 moiety (Fig. 4).
d
(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- and negative-ion
APCI mass spectra were measured on an ion trap analyser Agilent
LC-MSD Trap XCT-Ultra (Agilent, Palo Alto, CA, USA) within the mass
range m/z¼50–500. Samples were dissolved in acetonitrile and
analyzed after direct injection (2 mL) at the flow rate of 400 mL/min
acetonitrile. 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 m/z 4 and the collision
amplitude was 0.8 V. 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 (S3), chloroform–ethanol, 9:1 (S4) and/or 19:1
(S5), and chloroform–ethyl acetate, 7:3 (S6)) on AlugramÒ SIL G/
UV254 foils (Macherey-Nagel). Elemental analyses (C, H, N) were
performed with an EA 1108 Elemental Analyzer (Fisons Instrument).
X-ray analysis. The X-ray data for colourless crystals of (E)-4f
(crystallized from a mixture of benzene and hexane) were obtained
at 150(1) K using Oxford Cryostream low-temperature device on
The APCI mass spectra of all of the compounds yielded peaks of
the [MþH]þ ions in the positive-ion mode and the [MꢂH]ꢂ ions in
the negative-ion mode. In general, these ions were base peaks, or at
least very intense peaks in the spectra. These mass spectra provide
complementary ions in both polarity modes, which are useful for the
determination and identification of the alkyl/aryl substitution, such
as the neutral loss of butene for butyl substitution and similar frag-
mentation for other substituents (methyl, phenyl). Another typical
neutral loss is NCS (or appropriate alkyl/aryl–NCS). A typical neutral
loss for compounds containing a tertiary hydroxyl group is the loss of
water. However, the above fragmentations were as useful for iden-
tification as water loss was is our previously published results.1–4
3. Conclusions
a
Nonius KappaCCD diffractometer with Mo
Ka
radiation
(
l
¼0.71073 Å), a graphite monochromator, and the
4
and scan
c
In conclusion, we would like to emphasize that the described
method allows the preparation, in good to very good yields, of new
spiro-oxindoles 4, starting from aminoquinolinediones 1. The mo-
lecular rearrangement of adduct 3 not only has theoretical signifi-
cance, but enables through a simple procedure, the targeted
preparation of new spiro-oxindoles suitable for biological testing
and further synthetic utilization. 2-Thioxo-10H-spiro[imidazoline-
mode. Data reductions were performed with DENZO-SMN.19 The
absorption was corrected by integration methods.20 Structures
were solved by direct methods (Sir92)21 and refined by full matrix
least-square based on F2 (SHELXL97).22 Hydrogen atoms were
mostly localized on a difference Fourier map, however, to ensure
uniformity of treatment of crystal, all hydrogens were recalculated
into idealized positions (riding model) and assigned temperature

Table 4
1H and 13C chemical shifts ( , ppm) of 4-butylidene-3-butyl-2-thioxo-10H-spiro[imidazoline-5,30-indole]-2,20-diones (4) in DMSO-d6
d
Position
(Z)-4a
(Z)-4b
(Z)-4c
(E)-4c
(Z)-4d
(E)-4d
(E)-4e
(E)-4f
(E)-4g
(E)-4h
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
1
d
d
d
d
d
ꢂ265.8a
181.4
d
ꢂ264.9a
179.4
ꢂ253.4a,c
136.9
72.4
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
2 (C]S)
3
4
d
181.2
d
d
181.5
d
d
d
d
181.4
d
d
179.5
d
179.8
d
179.9
d
d
179.8
d
d
179.8
d
d
d
d
ꢂ243.9a,b
d
d
d
d
d
d
137.1
73.9
d
d
137.3
75.5
d
d
137.2
d
d
137.2
75.6
d
d
137.0
74.3
d
137.2
71.0
d
137.4
72.6
d
137.3
71.1
d
d
137.1
72.6
d
5
d
d
d
73.7
d
d
d
d
d
d
d
10
d
d
d
ꢂ233.5a
d
ꢂ230.0a
d
d
d
d
d
d
20
d
171.9
127.6
124.5
123.8
130.9
109.8
144.2
99.9
26.7
d
172.4
127.1
125.3
123.6
130.7
109.4
143.7
100.1
27.3
d
171.6
d
171.7
d
171.9
126.9
126.0
124.4
131.0
109.7
143.6
100.9
27.4
d
170.9
125.6
126.1
124.5
131.2
109.7
143.1
102.6
27.8
d
171.0
125.2
124.5
124.0
131.2
109.8
143.9
102.8
27.4
d
171.6
125.8
125.2
123.8
131.0
109.5
143.5
103.3
27.4
d
170.6
125.0
125.2
124.8
131.4
110.2
143.5
103.2
27.8
d
170.9
125.7
125.8
124.5
131.2
109.8
143.2
103.8
27.9
3a0
d
d
d
126.4
125.1
124.5
131.1
d
124.9
125.4
124.7
131.3
d
d
d
d
d
d
40
7.28
7.18
7.50
7.20
d
7.53
7.15
7.37
7.00
d
7.37
7.26
7.45
6.88
d
7.42
7.28
7.45
6.91
d
7.59
7.16
7.25
6.65
d
7.65
7.18
7.31
6.58
d
7.21
7.21
7.53
7.26
d
7.47
7.18
7.40
7.01
d
7.32
7.29
7.48
6.93
d
7.58
7.26
7.37
6.64
d
50
60
70
110.1
110.2
7a0
143.9
100.3
27.4
143.4
102.3
27.9
10(C-4)
20(C-4)
3.89
2.05
2.02
1.24
1.20
0.79
3.22
d
3.93
2.11
2.08
1.26
1.23
0.82
3.09
d
4.15
2.10
2.07
1.28
1.24
0.82
d
4.91
1.59
1.43
1.12
0.99
0.58
d
4.21
2.17
2.13
1.34
1.30
0.87
d
4.99
1.56
1.38
1.09
0.98
0.55
d
4.92
1.44
1.27
1.08
0.98
0.55
3.29
d
5.04
1.47
1.30
1.12
1.02
0.57
3.09
d
5.02
1.70
1.50
1.18
1.05
0.61
d
5.16
1.69
1.53
1.22
1.10
0.63
d
30(C-4)
22.3
22.3
22.3
22.4
22.3
22.4
22.2
22.2
22.3
22.3
40(C-4)
10(R1)
20(R1)
30(R1)
40(R1)
10(R2)
13.3
27.1
d
13.5
27.2
d
13.3
133.6
126.8
129.9
128.8
d
13.6
133.4
126.4
130.2
129.0
d
13.3
133.4
126.5
130.0
128.8
d
13.6
133.2
126.0
130.2
128.9
d
13.4
26.7
d
13.4
26.5
d
13.5
133.4
126.4
130.1
129.0
43.4
13.6
133.2
126.0
130.2
128.9
43.5
7.54
7.65
7.57
11.03
7.50
7.69
7.58
11.02
7.17
7.55
7.47
11.42
7.03
7.57
7.48
11.35
7.52
7.69
7.59
3.99
3.90
1.64
1.48
0.98
2.85
d
7.06
7.61
7.53
4.10
4.00
1.72
1.43
1.02
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
10.95
d
11.31
d
3.96
3.85
1.60
1.39
0.97
2.70
d
43.3
4.06
3.95
1.69
1.48
1.01
d
43.4
20(R2)
30(R2)
40(R2)
10(R3)
20(R3)
30(R3)
40(R3)
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
27.8
19.4
14.0
29.5
d
27.8
19.5
14.0
136.2
129.6
128.8
128.4
27.8
19.4
14.0
29.6
d
27.9
19.5
14.0
136.4
129.7
128.9
128.6
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
2.70
d
29.5
d
d
136.8
129.3
128.7
128.1
2.86
d
29.6
d
2.77
d
28.8
d
d
136.7
129.3
128.9
128.4
d
136.2
129.6
128.9
128.5
7.08
7.28
7.25
7.09
7.28
7.26
6.98
7.28
7.26
6.94
7.28
7.28
6.99
7.33
7.33
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
a
d (
15N).
b
c
1J (15N, 1H)¼99.8 Hz.
1J (15N, 1H)¼99.0 Hz.

´
A. Klasek et al. / Tetrahedron 65 (2009) 4908–4916
4913
Figure 1. The 1H NMR spectrum (bottom trace) and a trace from gradient-selected 2D
NOESY spectrum (upper trace) showing through-space interaction of N(3)–H proton (
d
(1H)¼11.02) and ]CH proton of butylidene group (
d
(1H)¼4.91) in compound (E)-4c.
Positive signal at 3.49 ppm is due to an exchange of N(3)–H protons and protons of
water present in the solvent.
Figure 3. Molecular structure of compound (E)-4f with atom numbering scheme.
ORTEP 50% probability level, arbitrary spheres for hydrogen atoms.
factors Hiso(H)¼1.2 Ueq(pivot atom) or of 1.5 Ueq for the methyl
moiety with C–H¼0.96, 0.97 and 0.93 Å for methyl, methylene and
hydrogen atoms in aromatic ring or a double bond, respectively.
Crystallographic data for (E)-4f: C25H29N3OS, M¼419.57, triclinic, P-1,
4.2.1. 3-Amino-3-butyl-1-phenyl-1H,3H-quinoline-2,4-dione (1c)
Compound was prepared from 3-butyl-3-chloro-1-phenyl-
1H,3H-quinoline-2,4-dione, ammonium chloride and potassium
carbonate in 47% yield. Colourless crystals, mp 119–120 ꢁC (ben-
zene–hexane); IR: 3385, 3320, 2951, 2922, 2870, 1714, 1677, 1599,
1491, 1465, 1345, 1299, 1229, 1218, 1155, 1102, 1072, 1025, 957, 852,
a¼9.1510(4) Å, b¼10.6580(4) Å, c¼13.3390(8) Å,
a
¼112.814(4)ꢁ,
¼
b
100.639(5)ꢁ,
m
g
¼98.897(4)ꢁ, Z¼2, V¼1141.23(9) Å3, Dc¼1.221 g cmꢂ3
,
¼0.163 mmꢂ1, Tmin¼0.949, Tmax¼0.981; 21,250 reflections mea-
sured (qmax¼27.5ꢁ), 5175 independent (Rint¼0.0450), 3716 with
I>2
s
(I), 271 parameters, S¼1.127, R1 (obsd data)¼0.0600, wR2
768, 758, 707, 645, 526, 509 cmꢂ1
. Anal. Calcd (found) for
(all data)¼0.1391; max, min residual electron density¼0.315,
C19H20N2O2: C 74.00 (74.22); H 6.54 (6.39); N 9.08 (9.15). For 1H and
13C NMR see Table 2. Positive-ion APCI-MS: m/z 309 [MþH]þ
(100%). Positive-ion APCI-MS/MS of m/z 309: 292 [MþHꢂNH3]þ
(100%). Negative-ion APCI-MS: m/z 307 [MꢂH]ꢂ (31%), 292
[MꢂCH3]ꢂ (100%). Negative-ion APCI-MS/MS of m/z 307: 249
[MꢂHꢂCH3ꢂC3H7]ꢂ (100%), 188 [MꢂHꢂC6H5NCO]ꢂ.
ꢂ0.275 e Åꢂ3
.
Crystallographic data for structural analysis have been de-
posited with the Cambridge Crystallographic Data Centre, CCDC No.
702717. Copies of this information may be obtained free of charge
from The Director, CCDC, 12 Union Road, Cambridge CB2 1EY, UK
(fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk orwebsite:
http://www.ccdc.cam.ac.uk).
4.3. General method for the preparation of 9b-hydroxy-2-
thioxo-1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-2-
ones (3) from 3-aminoquinolinediones 1
4.2. Preparation of 3-amino-1H,3H-quinoline-2,4-diones (1)
Starting 3-substituted 3-amino-1H,3H-quinoline-2,4-diones (1)
were prepared from corresponding 3-chloro derivatives according
to the protocol described in literature.10 One new amine was
prepared.
Phenylisothiocyanate (0.144 mL, 1.2 mmol) or methyl-
isothiocyanate (88 mg, 1.2 mmol) was added to the cooled (0 ꢁC)
and stirred solution of 1 (1 mmol) in chloroform (5 mL). After
stirring at rt for 3 h, the solution was heated to reflux for the time
given in Table 1. The course of the reaction was monitored by TLC.
After cooling and evaporating in vacuo to dryness, the residue was
crystallized from appropriate solvent. In the case of the reaction of
1a with phenyl isothiocyanate, the residue was column
chromatographed.
4.3.1. 3a-Butyl-1,5-dimethyl-9b-hydroxy-2-thioxo-1,2,3,3a,5,9b-
hexahydro-imidazo[4,5-c]quinolin-4-one (3a)
Colourless crystals, yield 94%, mp 176–180 ꢁC (benzene–hexane);
IR: 3368, 3247, 2959, 2931, 2859, 1646, 1603, 1473, 1443, 1398, 1372,
1315,1280,1212,1160,1138,1115,1077,1048, 997, 969, 942, 911, 850,
759, 698, 679, 616, 576, 526 cmꢂ1. For 1H and 13C NMR see Table 2.
Positive-ion APCI-MS: m/z 320 [MþH]þ (100%), 302 [MþHꢂH2O]þ,
247 [MþHꢂCH3NCS]þ. Positive-ion APCI-MS/MS of m/z 320: 247
[MþHꢂCH3NCS]þ (100%), 230 [MþHꢂCH3NHCSNH2]þ. Negative-
ion APCI-MS: m/z 318 [MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of
m/z 318: 261 [MꢂHꢂC4H9]ꢂ, 245 [MꢂHꢂCH3NCS]ꢂ,185
[MꢂHꢂC4H8ꢂNHCSꢂH2O]ꢂ (100%). Anal. Calcd (found) for
C16H21N3O2S: C 60.16 (60.23); H 6.63 (6.72); N 13.16 (13.31).
Figure 2. The 1H NMR spectrum (bottom trace) and a trace from gradient-selected 2D
NOESY spectrum (upper trace) showing through-space interaction of N(3)–H proton (
d
(1H)¼11.03) and ]CHCH2 protons of butylidene group (
pound (Z)-4c.
d
(1H)¼2.07–2.10) in com-

´
4914
A. Klasek et al. / Tetrahedron 65 (2009) 4908–4916
Figure 4. View of non-classical H-bonding in (E)-4f.
4.3.2. 3a-Butyl-9b-hydroxy-5-methyl-1-phenyl-2-thioxo-
1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-4-one (3b)
2957, 2928, 280, 1665, 1601, 1530, 1495, 1463, 1406, 1350, 1312,
1300, 1251, 1162, 1128, 1094, 1067, 1023, 1004, 981, 938, 909, 834,
755, 705, 661, 624, 597, 584, 571, 539, 520 cmꢂ1. For 1H and 13C NMR
see Table 2. Positive-ion APCI-MS: m/z 444 [MþH]þ (41%), 309
[MþHꢂC6H5NCS]þ (100%). Positive-ion APCI-MS/MS of m/z 444:
309 [MþHꢂC6H5NCS]þ (100%), 292 [MþHꢂC6H5NHCSNH2]þ, 208.
Negative-ion APCI-MS: m/z 442 [MꢂH]ꢂ (100%). Negative-ion APCI-
MS/MS of m/z 442: 382, 323 [MꢂHꢂC6H5NCO]ꢂ (100%). Anal. Calcd
(found) for C26H25N3O2S: C 70.40 (70.21); H 5.68 (5.73); N 9.47
(9.54).
Colourless crystals, yield 81%, mp 170–176 ꢁC (benzene–hex-
ane); IR: 3618, 3246, 2961, 2931, 2860, 1648, 1606, 1474, 1405, 1373,
1341, 1304, 1268, 1226, 1179, 1120, 1099, 1072, 1053, 995, 940, 863,
757, 703, 652, 578, 546 cmꢂ1. For 1H and 13C NMR see Table 2.
Positive-ion APCI-MS: m/z 382 [MþH]þ (100%), 348, 247
[MþHꢂC6H5NCS]þ. Positive-ion APCI-MS/MS of m/z 382: 247
[MþHꢂC6H5NCS]þ (100%), 230 [MþHꢂC6H5NHCSNH2]þ. Negative-
ion APCI-MS: m/z 380 [MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of
m/z 318: 261 [MꢂHꢂC6H5NCO]ꢂ (100%). Anal. Calcd (found) for
C21H23N3O2S: C 66.12 (66.32); H 6.08 (6.21); N 11.01 (11.21).
4.3.5. 3,3a-Dibutyl-1,5-dimethyl-9b-hydroxy-2-thioxo-
1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-4-one (3e)
4.3.3. 3a-Butyl-9b-hydroxy-1-methyl-5-phenyl-2-thioxo-
1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-4-one (3c)
Colourless crystals, yield 67%, mp 190–191 ꢁC (benzene); IR:
3310, 3208, 2961, 2939, 2873, 1678, 1604, 1490, 1464, 1455, 1399,
1353, 1336, 1299, 1176, 1127, 1119, 1106, 1057, 984, 938, 766, 705,
628, 579, 552, 508 cmꢂ1. For 1H and 13C NMR see Table 2. Positive-
ion APCI-MS: 382 [MþH]þ (100%), 364 [MþHꢂH2O]þ, 350
[MþHꢂS]þ (100%). Positive-ion APCI-MS/MS of m/z 382: 309
[MþHꢂCH3NCS]þ (100%). Negative-ion APCI-MS: m/z 380 [MꢂH]ꢂ
(100%), 362 [MꢂH2O]ꢂ. Negative-ion APCI-MS/MS of m/z 380: 323
[MꢂHꢂC4H9]ꢂ, 185 [MꢂHꢂC6H5NCOꢂC4H9ꢂH2O]ꢂ (100%). Anal.
Calcd (found) for C21H23N3O2S: C 66.12 (66.27); H 6.08 (6.27); N
11.01 (11.24).
Colourless crystals, yield 58%, mp 178–182 ꢁC (benzene); IR:
3355, 2957, 2931, 2862, 1651, 1606, 1503, 1476, 1423, 1412, 1371,
1286, 1223, 1189, 1172, 1123, 1088, 1052, 1039, 1023, 977, 944, 866,
844, 772, 733, 692, 648, 582, 535 cmꢂ1. For 1H and 13C NMR see
Table 2. Positive-ion APCI-MS: m/z 376 [MþH]þ (77%), 358
[MþHꢂH2O]þ (100%). Positive-ion APCI-MS/MS of m/z 376: 303
[MþHꢂCH3NCS]þ (100%). Positive-ion APCI-MS/MS of m/z 358: 302
[MþHꢂC4H8ꢂH2O]þ (100%), 268 [MþHꢂC4H9ꢂH2OCH3]þ, 246
[MþHꢂ2ꢃC4H8ꢂH2O]þ. Negative-ion APCI-MS: m/z 374 [MꢂH]ꢂ
(47%), 356 [MꢂHꢂH2O]ꢂ (100%). Negative-ion APCI-MS/MS of m/z
374: 330 [MꢂHꢂC3H8]ꢂ, 241 [MꢂHꢂC4H9NCS]ꢂ (100%). Negative-
ion APCI-MS/MS of m/z 356: 341 [MꢂHꢂCH3]ꢂ (100%), 270
[MꢂHꢂ2ꢃC3H7]ꢂ. Anal. Calcd (found) for C20H29N3O2S: C 63.97
(63.81); H 7.78 (7.58); N 11.19 (11.26).
4.3.4. 3a-Butyl-1,5-diphenyl-9b-hydroxy-2-thioxo-1,2,3,3a,5,9b-
hexahydro-imidazo[4,5-c]quinolin-4-one (3d)
4.3.6. 3,3a-Dibutyl-9b-hydroxy-5-methyl-1-phenyl-2-thioxo-
1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-4-one (3f)
Colourless crystals, yield 81%, mp 191–197 ꢁC (benzene–hex-
ane); IR: 3352, 2958, 2928, 2870, 2858,1695,1654,1599,1529,1493,
1463, 1353, 1324, 1298, 1258, 1238, 1162, 1113, 1068, 1026, 971, 903,
Colourless crystals, yield 68%, mp 188–190 ꢁC (benzene); IR:
3436, 2957, 2931, 2870, 1661, 1605, 1499, 1474, 1403, 1378, 1286,
1229, 1125, 1052, 1023, 915, 834, 760, 729, 709, 693, 650, 617, 585,
550 cmꢂ1. For 1H- and 13C NMR see Table 2. Positive-ion APCI-MS:
m/z 438 [MþH]þ (65%), 420 [MþHꢂH2O]þ (100%), 404, 303
[MþHꢂC6H5NCS]þ (100%). Positive-ion APCI-MS/MS of m/z 438:
303 [MþHꢂC6H5NCS]þ (100%). Negative-ion APCI-MS: m/z 436
[MꢂH]ꢂ (100%), 356 [MꢂHꢂOH]ꢂ. Negative-ion APCI-MS/MS of
m/z 436: 392 [MꢂHꢂC3H8]ꢂ, 317 [MꢂHꢂC6H5NCO]ꢂ, 303
759, 724, 704, 661, 648, 597, 520, 509 cmꢂ1. According to 1H and 13
C
NMR, this product is a mixture of 2d and 3d. The mixture was
heated to 60 ꢁC in a 5% solution of DMSO for 5 h, the solution was
evaporated in vacuo to dryness and the residue was crystallized
from benzene–hexane mixture. Compound 3d, containing ca. 5% of
2d in an equilibrium (see text), was obtained in 65% yield. Col-
ourless crystals, mp 191–199 ꢁC (benzene–hexane); IR: 3424, 3352,

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A. Klasek et al. / Tetrahedron 65 (2009) 4908–4916
4915
[MꢂHꢂC4H9NCSꢂH2O]ꢂ, 244 [MꢂHꢂC4H9NCSꢂC6H5]ꢂ (100%).
4.4.2. (Z)-4-Butylidenene-10-methyl-1-phenyl-2-thioxo-10H-
Anal. Calcd (found) for C25H31N3O2S: C 68.62 (68.57); H 7.14 (7.29);
N 9.60 (9.72).
spiro[imidazoline-5,30-indole]-2,20-dione ((Z)-4b)
Yellowish crystals, yield 28% (method A), or 35% (method B), mp
268–273 ꢁC (acetic acid); IR: 3449, 3187, 3139, 2954, 2928, 2869,
1733, 1702, 1613, 1493, 1471, 1399, 1368, 1343, 1256, 1181, 1155, 1131,
1105, 1081, 1042, 1025, 851, 749, 696, 661, 646, 625, 564 cmꢂ1. For
1H and 13C NMR see Table 4. Positive-ion APCI-MS: m/z 364 [MþH]þ
(100%). Positive-ion APCI-MS/MS of m/z 364: 321 [MþHꢂC3H7]þ,
308 [MþHꢂC4H8]þ, 306 [MþHꢂNCS]þ, 271, 249 [MþHꢂ
C4H9NCS]þ, 229 [MþHꢂC6H5NCS]þ (100%). Negative-ion APCI-MS:
m/z 362 [MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of m/z 362: 319
[MꢂHꢂC3H7]ꢂ (100%), 227 [MꢂHꢂC6H5NCS]ꢂ. Anal. Calcd (found)
for C21H21N3OS: C 69.39 (69.27); H 5.82 (5.99); N 11.56 (11.71).
4.3.7. 3,3a-Dibutyl-9b-hydroxy-1-methyl-5-phenyl-2-thioxo-
1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-4-one (3g)
Colourless crystals, yield 92%, mp 172–175 ꢁC (benzene–hexane);
IR: 3415, 3290, 2957, 2931, 2868, 1684, 1659, 1604, 1594, 1555, 1497,
1464, 1412, 1367, 1331, 1287, 1232, 1182, 1125, 1084, 1070, 1050, 1022,
973, 943, 834, 757, 730, 702, 650, 581, 529, 510 cmꢂ1. For 1H and 13
C
NMR see Table 2. Positive-ion APCI-MS: m/z 438 [MþH]þ (28%), 420
[MþHꢂH2O]þ (100%), 406, 365 [MþHꢂCH3NCS]þ. Positive-ion APCI-
MS/MS of m/z 438: 365 [MþHꢂCH3NCS]þ (100%). Positive-ion APCI-
MS/MS
of
m/z
420:
364
[MþHꢂH2OꢂC4H8]þ,
330
[MþHꢂH2OꢂC4H9ꢂCH3]þ, 308 [MþHꢂH2Oꢂ2ꢃC4H8]þ. Negative-
ion APCI-MS: m/z 436 [MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of
m/z 436: 241 [MꢂHꢂC6H5NHCOꢂC4H9ꢂH2O]ꢂ (100%). Anal. Calcd
(found) for C25H31N3O2S: C 68.62 (68.51); H 7.14 (7.29); N 9.60 (9.48).
4.4.3. (E)-4-Butylidene-1-methyl-10-phenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((E)-4c)
Yellow crystals, yield 61% by both methods, mp 202–207 ꢁC
(benzene–hexane); IR: 3275, 2954, 2924, 2865, 1719, 1684, 1610,
1592, 1497, 1467, 1454, 1436, 1395, 1370, 1325, 1295, 1284, 1265,
1208, 1173, 1103, 1046, 968, 887, 784, 756, 703, 682, 669, 644, 608,
519 cmꢂ1. For 1H and 13C NMR see Table 4. Positive-ion APCI-MS:
m/z 364 [MþH]þ (100%), 332 [MþHꢂS]þ. Positive-ion APCI-MS/MS
of m/z 364: 308 [MþHꢂC4H8]þ (100%), 291 [MþHꢂCH3NCS]þ.
Negative-ion APCI-MS: m/z 362 [MꢂH]ꢂ (100%). Negative-ion APCI-
MS/MS of m/z 362: 334 [MꢂHꢂCO]ꢂ (100%). Anal. Calcd (found) for
C21H21N3OS: C 69.39 (69.59); H 5.82 (5.63); N 11.56 (11.42).
4.3.8. 3,3a-Dibutyl-1,5-diphenyl-9b-hydroxy-2-thioxo-
1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-4-one (3h)
Colourless crystals, yield 86%, mp 206–212 ꢁC (benzene–hex-
ane); IR: 3255, 2955, 2932, 2869, 1685, 1603, 1591, 1498, 1463, 1416,
1378, 1332,1307, 1288, 1273, 1257, 1229, 1185, 1144, 1129, 1114, 1078,
1021, 957, 911, 839, 798, 758, 746, 726, 707, 662, 645, 619, 594, 582,
533 cmꢂ1. For 1H and 13C NMR see Table 2. Positive-ion APCI-MS: m/z
500 [MþH]þ (51%), 482 [MþHꢂH2O]þ, 468 [MþHꢂS]þ, 450, 365
[MþHꢂC6H5NCS]þ (100%). Positive-ion APCI-MS/MS of m/z 500:
365 [MþHꢂC6H5NCS]þ (100%). Negative-ion APCI-MS: m/z 498
[MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of m/z 498: 454
[MꢂHꢂC3H8]ꢂ (100%). Anal. Calcd (found) for C30H33N3O2S: C 72.11
(72.30); H 6.66 (6.81); N 8.41 (8.58).
4.4.4. (Z)-4-Butylidene-1-methyl-10-phenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((Z)-4c)
Yellowish crystals, yield 6% (method A), mp 150–160 ꢁC (ben-
zene–hexane); IR: 3325, 2958, 2928, 2893, 2964, 1714, 1687, 1609,
1593, 1484, 1467, 1425, 1371, 1353, 1330, 1294, 1252, 1176, 1103,
1070, 1038, 985, 935, 869, 756, 702, 588, 480, 469 cmꢂ1. For 1H and
13C NMR see Table 4. Positive-ion APCI-MS: m/z 364 [MþH]þ
(100%), 332 [MþHꢂS]þ. Positive-ion APCI-MS/MS of m/z 364: 321
[MþHꢂC3H7]þ, 308 [MþHꢂC4H8]þ (100%), 291 [MþHꢂCH3NCS]þ.
Negative-ion APCI-MS: m/z 362 [MꢂH]ꢂ (100%). Negative-ion APCI-
MS/MS of m/z 362: 334 [MꢂHꢂOHꢂC2H4]ꢂ (100%). Anal. Calcd
(found) for C21H21N3OS: C 69.39 (69.31); H 5.82 (5.97); N 11.56
(11.43).
4.4. General methods for the molecular rearrangement of
compounds 3
Method A. The solution of starting compound 3 (1 mmol) in
acetic acid (8 mL) was heated to reflux for the time given in Table 3.
The course of the reaction was monitored using TLC. After cooling,
the reaction mixture was evaporated to dryness in vacuo and the
residue was crystallized from appropriate solvent or separated by
column chromatography on silica gel.
Method B. The solution of starting compound 3 (1 mmol) in
concd hydrochloric acid (5 mL) was heated to reflux for the time
given in Table 4. In same cases, a small quantity of acetic acid was
added to dissolute the starting compound. The course of the re-
action was monitored using TLC. After cooling, the precipitated
product was filtrated off with suction and recrystallized from ap-
propriate solvent. In cases when the reaction mixture was ho-
mogenous, the reaction mixture was evaporated to dryness in
vacuo and the residue was crystallized from appropriate solvent or
separated by column chromatography on silica gel.
4.4.5. (E)-4-Butylidene-1,10-diphenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((E)-4d)
Yellowish crystals, yield 15% (method A) or 45% (method B), mp
228–231 ꢁC (benzene–hexane); IR: 3453, 3189, 3144, 2956, 2926,
2867, 1733, 1699, 1612, 1596, 1498, 1474, 1357, 1368, 1324, 1248,
1210, 1175, 1109, 1071, 1026, 987, 936, 822, 798, 753, 693, 663, 620,
547 cmꢂ1. For 1H and 13C NMR see Table 4. Positive-ion APCI-MS:
m/z 426 [MþH]þ (100%). Positive-ion APCI-MS/MS of m/z 426: 383
[MþHꢂC3H7]þ, 370 [MþHꢂC4H8]þ, 333, 311 [MþHꢂC4H8NHCS]þ,
291 [MþHꢂC6H5NCS]þ (100%), 274 [MþHꢂC6H5NHCSNH2]þ, 210.
Negative-ion APCI-MS: m/z 424 [MꢂH]ꢂ (100%). Negative-ion APCI-
MS/MS of m/z 424: 396 [MꢂHꢂCO]ꢂ (100%), 381 [MꢂHꢂC3H7]ꢂ.
Anal. Calcd (found) for C26H23N3OS: C 73.38 (73.51); H 5.45 (5.57);
N 9.87 (9.75).
4.4.1. (Z)-4-Butylidene-1,10-dimethyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((Z)-4a)
Yellow crystals, yield 49% (method A) or 36% (method B), mp
152–160 ꢁC (benzene–hexane); IR: 3326, 2957, 2932, 2871, 1714,
1698, 1611, 1490, 1469, 1451, 1426, 1391, 1369, 1347, 1269, 1180, 1154,
1131, 1093, 1008, 973, 761, 696, 641, 611 cmꢂ1. For 1H and 13C NMR
see Table 4. Positive-ion APCI-MS: m/z 302 [MþH]þ (100%). Posi-
tive-ion APCI-MS/MS of m/z 302: 246 [MþHꢂC4H8]þ (100%), 229
[MþHꢂCH3NCS]þ. Negative-ion APCI-MS: m/z 300 [MꢂH]ꢂ (100%).
Negative-ion APCI-MS/MS of m/z 338: 285 [MꢂHꢂCH3]ꢂ, 272
[MꢂHꢂCO]ꢂ, 257 [MꢂHꢂC3H7]ꢂ, 227 [MꢂHꢂCH3NCS]ꢂ (100%).
Anal. Calcd (found) for C16H19N3OS: C 63.76 (63.59); H 6.35 (6.48);
N 13.94 (13.81).
4.4.6. (Z)-4-Butylidene-1,10-diphenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((Z)-4d)
Colourless crystals, yield 5% (method A) or 11% (method B), mp
212–216 ꢁC (benzene–hexane); IR: 3446, 3193, 3110, 2955, 2930,
2868,1735,1689,1611,1595,1499,1466,1402,1368,1358,1324,1295,
1236, 1181, 1110, 1070, 1025, 937, 809, 754, 697, 660, 591, 542 cmꢂ1
.
Positive-ion APCI-MS: m/z 426 [MþH]þ (100%). Positive-ion APCI-
MS/MS of m/z 426: 383 [MþHꢂC3H7]þ, 370 [MþHꢂC4H8]þ, 333, 311
[MþHꢂC4H8NHCS]þ, 291 [MþHꢂC6H5NCS]þ (100%), 274 [MþHꢂ
C6H5NHCSNH2]þ, 210. Negative-ion APCI-MS: m/z 424 [MꢂH]ꢂ

´
A. Klasek et al. / Tetrahedron 65 (2009) 4908–4916
4916
(100%). Negative-ion APCI-MS/MS of m/z 424: 396 [MꢂHꢂCO]ꢂ
(100%), 381 [MꢂHꢂC3H7]ꢂ. Anal. Calcd (found) for C26H23N3OS: C
73.38 (73.29); H 5.45 (5.53); N 9.87 (9.78).
1677,1613,1594,1497,1465,1417,1362,1321,1294,1260,1238,1224,
1209, 1190, 1175, 1157, 1146, 1125, 1110, 1070, 1025, 990, 953, 937,
868, 815, 753, 732, 717, 698, 662, 619, 571, 531, 513 cmꢂ1. For 1H and
13C NMR see Table 4. Positive-ion APCI-MS: m/z 482 [MþH]þ (69%),
450 [MþHꢂS]þ (100%). Positive-ion APCI-MS/MS of m/z 482: 426
[MþHꢂC4H8]þ (100%), 392 [MþHꢂC4H9ꢂSH]þ, 370 [MþHꢂ
2ꢃC4H8]þ, 311 [MþHꢂC4H9NCSꢂC4H8]þ. Negative-ion APCI-MS:
m/z 480 [MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of m/z 480:
450, 424 [MꢂHꢂC4H8]ꢂ, 394 [MꢂHꢂ2ꢃC3H7]ꢂ (100%), 365
[MꢂHꢂC4H9NCS]ꢂ, 322 [MꢂHꢂC4H9NCSꢂC3H7]ꢂ, 272. Anal. Calcd
(found) for C30H31N3OS: C 74.81 (74.67); H 6.49 (6.57); N 8.72
(8.91).
4.4.7. (E)-3-Butyl-4-butylidene-1,10-dimethyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((E)-4e)
Colourless crystals, yield 62% (method A) or 72% (method B), mp
83–87 ꢁC (hexane); IR: 2955, 2929, 2868, 1732, 1677, 1608, 1468,
1410, 1383, 1355, 1304, 1191, 1131, 1093, 1000, 949, 891, 758, 751,
692, 668, 630 cmꢂ1. For 1H and 13C NMR see Table 4. Positive-ion
APCI-MS: m/z 358 [MþH]þ (100%). Positive-ion APCI-MS/MS of m/z
358: 302 [MþHꢂC4H8]þ (100%), 268 [MþHꢂC4H9ꢂH2OꢂCH3]þ,
246 [MþHꢂ2ꢃC4H8]þ. Negative-ion APCI-MS: m/z 356 [MꢂH]ꢂ
(100%). Negative-ion APCI-MS/MS of m/z 356: 341 [MꢂHꢂCH3]ꢂ
(100%), 326 [MꢂHꢂ2ꢃCH3]ꢂ, 312 [MꢂHꢂC3H8]ꢂ, 300 [MꢂHꢂ
C4H8]ꢂ, 284, 270 [MꢂHꢂ2ꢃC3H7]ꢂ. Anal. Calcd (found) for
C20H27N3OS: C 67.19 (67.24); H 7.61 (7.81); N 11.75 (11.58).
Acknowledgements
This study was supported by the Ministry of Education, Youth
and Sports of the Czech Republic (Grant No. MSM 7088352101) and
The Czech Science Foundation (Grant No. 203/07/0320). The au-
4.4.8. (E)-3-Butyl-4-butylidene-10-methyl-1-phenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((E)-4f)
ꢀ
´
thors thank Mrs. H. Gerzova (Faculty of Technology, Tomas Bata
Colourless crystals, yield 98% by both methods, mp 163–166 ꢁC
(benzene–hexane); IR: 3436, 3061, 2957, 2931, 2869, 1724, 1672,
1609, 1496, 1470, 1451, 1416, 1383, 1361, 1296, 1258, 1191, 1127, 1108,
1085, 1023, 981, 861, 790, 763, 751, 696, 683, 661, 588, 537 cmꢂ1. For
1H and 13C NMR see Table 4. Positive-ion APCI-MS: m/z 420 [MþH]þ
(100%). Positive-ion APCI-MS/MS of m/z 420: 364 [MþHꢂC4H8]þ
(100%), 330 [MþHꢂC4H9ꢂH2OꢂCH3]þ (100%), 308 [MþHꢂ
2*C4H8]þ, 249 [MþHꢂC4H9NCSꢂC4H8]þ. Negative-ion APCI-MS:
m/z 418 [MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of m/z 418: 388,
362 [MꢂHꢂC4H8]ꢂ, 332 [MꢂHꢂ2*C3H7]ꢂ (100%), 303
[MꢂHꢂC4H9NCS]ꢂ, 260 [MꢂHꢂC4H9NCSꢂC3H7]ꢂ. Anal. Calcd
(found) for C25H29N3OS: C 71.56 (71.49); H 6.97 (7.03); N 10.01
(9.92).
´
University in Zlın) for technical help.
References and notes
ˇ
ˇ
1. Kla´sek, A.; Lycka, A.; Holcapek, M.; Hoza, I. J. Heterocycl. Chem. 2006, 43, 203–
211.
´
ꢀ
ˇ
ˇ
ˇ´
˚
2. Klasek, A.; Lycka, A.; Miksık, I.; Ruzicka, A. Helv. Chim. Acta 2009, 92, 689–708.
3. Kla´sek, A.; Lycka, A.; Holcapek, M.; Hoza, I. Helv. Chim. Acta 2008, 91, 354–370.
4. Klasek, A.; Lycka, A.; Holcapek, M. Tetrahedron 2007, 63, 7059–7069.
5. Northcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041–2114.
6. Faulkner, D. J. Nat. Prod. Rep. 1995, 12, 223–269.
ˇ
ˇ
´
ˇ
ˇ
ˇ
7. Kafka, S.; Kla´sek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002, 57, 1659–1682.
8. (a) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R.
J. Chem. Soc., Perkin Trans. 2 1987, S1–S19; (b) Orpen, A. G.; Brammer, L.; Allen, F.
H.; Kennard, O.; Watson, D. G.; Taylor, R. J. Chem. Soc., Dalton Trans. 1989, S1–
S83; (c) Ibers, J. A.; Hamilton, W. C. In International Tables for Crystallography C;
Wilson, A. J. C., Ed.; Kluwer Acad.: Boston, 1992; pp 707–791.
9. Allen, F. H.; Kennard, O. Chem. Des. Autom. News 1993, 8, 31–37.
10. Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843–868 and references cited
therein.
11. Savitha, G.; Niveditha, S. K.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett.
2007, 48, 2943–2947.
12. Teng, D.; Zhang, H.; Mendonca, A. Molecules 2006, 11, 700–706.
13. Doyle, F. P.; Holland, D. O.; Nayler, J. H. C. J. Chem. Soc. 1955, 2265–2272.
14. Collington, E. W.; Middlemiss, D.; Panchal, T. A.; Wilson, D. R. Tetrahedron Lett.
1981, 22, 3675–3678.
15. Klika, K. D.; Imrich, J.; Vilkova, M.; Bernat, J.; Pihlaja, K. J. Heterocycl. Chem.
2006, 43, 739–743.
16. Fatimi, J.; Lagorce, J. F.; Duroux, J. L.; Chabernaud, M. L.; Buxeroud, J.; Raby, C.
Chem. Pharm. Bull. 1994, 42, 698–701.
17. Ali, B. H.; Bashir, A. A.; Tanira, M. O. M. Hum. Exp. Toxicol. 1995, 14, 13–17.
18. Kruse, L. I.; Kaiser, C.; DeWolf, W. E.; Frazee, J. S.; Garvey, E.; Hilbert, E. L.;
Faulkner, W. A.; Flaim, K. E.; Sawyer, J. L.; Berkowitz, B. A. J. Med. Chem. 1986, 29,
2465–2472.
19. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307–326.
20. Coppens, P. In Crystallographic Computing; Ahmed, F. R., Hall, S. R., Huber, C. P.,
Eds.; Munksgaar: Copenhagen, 1970; pp 255–270.
4.4.9. (E)-3-Butyl-4-butylidene-1-methyl-10-phenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((E)-4g)
Colourless crystals, yield 76% (method A) or 64% (method B), mp
80–85 ꢁC (hexane); IR: 3444, 2961, 2930, 2870, 1731, 1677, 1613,
1594, 1497, 1463, 1413, 1362, 1322, 1294, 1241, 1208,1174,1146, 1102,
1072,1023, 982, 936, 893, 845, 803, 764, 745, 702, 675, 623, 576, 527,
484 cmꢂ1. For 1H and 13C NMR see Table 4. Positive-ion APCI-MS:
m/z 420 [MþH]þ (100%), 404, 388, 362. Positive-ion APCI-MS/MS of
m/z 420: 364 [MþHꢂC4H8]þ (100%), 330 [MþHꢂC4H9ꢂH2OꢂCH3]þ,
308 [MþHꢂ2ꢃC4H8]þ. Negative-ion APCI-MS: m/z 434 (5%), 418
[MꢂH]ꢂ (100%). Negative-ion APCI-MS/MS of m/z 418: 403
[MꢂHꢂCH3]ꢂ (100%), 388, 383 [MꢂHꢂH2S]ꢂ, 362 [MꢂHꢂC4H8]ꢂ,
332 [MꢂHꢂ2ꢃC3H7]ꢂ, 314, 272. Anal. Calcd (found) for C25H29N3OS:
C 71.56 (71.43); H 6.97 (7.03); N 10.01 (9.89).
4.4.10. (E)-3-Butyl-4-butylidene-1,10-diphenyl-2-thioxo-10H-
spiro[imidazoline-5,30-indole]-2,20-dione ((E)-4h)
Colourless crystals, yield 83% (method A) or 86% (method B), mp
139–143 ꢁC (benzene–hexane); IR: 3447, 2953, 2927, 2867, 1734,
21. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Crystallogr.
1993, 26, 343–350.
22. Sheldrick, G. M. SHELXL-97, Program for Refinement of Crystal Structures; Uni-
versity of Go¨ttingen: Germany, 1997.