Reaction of 3-aminoquinoline-2,4-diones with isothiocyanic acid - An easy pathway to thioxo derivatives of imidazo[1,5-c]quinazolin-5-ones and imidazo[4,5-c]quinolin-4-ones

Article abstract of DOI:10.1016/j.tet.2010.08.056

3-Amino-1H,3H-quinoline-2,4-diones react with thiourea or potassium thiocyanate in boiling acetic acid to give novel 2,3-dihydro-3-thioxoimidazo[1, 5-c]quinazolin-5(6H)-ones in high yields. However, if the starting compounds are substituted with a benzyl group at position 3, a C-debenzylation proceeds to give 2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4(5H)-ones. According to a proposed reaction mechanism, a molecular rearrangement of the primarily formed mono-substituted thiourea takes place. All compounds were characterized by ¹H, ¹³C and ¹⁵N NMR and IR spectroscopy as well as by mass spectrometry.

Full text of DOI:10.1016/j.tet.2010.08.056

Tetrahedron 66 (2010) 8441e8445
Contents lists available at ScienceDirect
Tetrahedron
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Reaction of 3-aminoquinoline-2,4-diones with isothiocyanic aciddan easy
pathway to thioxo derivatives of imidazo[1,5-c]quinazolin-5-ones and imidazo-
[4,5-c]quinolin-4-ones
a
b
a
a,
*
ꢀ
ꢀ
ꢀ
Vladimír Mrkvicka , Antonín Lycka , Ondrej Rudolf , Antonín Klásek
a Department of Chemistry, Faculty of Technology, Tomas Bata University,762 72 Zlín, Czech Republic
b Research Institute for Organic Syntheses (VUOS), Rybitví 296, 533 54 Pardubice 20, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2010
Received in revised form 3 August 2010
Accepted 23 August 2010
Available online 27 August 2010
3-Amino-1H,3H-quinoline-2,4-diones react with thiourea or potassium thiocyanate in boiling acetic acid
to give novel 2,3-dihydro-3-thioxoimidazo[1,5-c]quinazolin-5(6H)-ones in high yields. However, if the
starting compounds are substituted with a benzyl group at position 3, a C-debenzylation proceeds to give
2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4(5H)-ones. According to a proposed reaction mecha-
nism, a molecular rearrangement of the primarily formed mono-substituted thiourea takes place. All
compounds were characterized by 1H, 13C and 15N NMR and IR spectroscopy as well as by mass
spectrometry.
Keywords:
a
-Aminoketones
Ó 2010 Elsevier Ltd. All rights reserved.
C-Debenzylation
Rearrangement
Thioxo group
Thiourea derivatives
1. Introduction
We have described the reaction of 3-amino-1H,3H-quinoline-
2,4-diones 1 with urea in boiling acetic acid, which produces novel
In our laboratory, much attention has been paid to the reactivity
of 3-alkyl/aryl-3-amino-quinolinediones 1. The addition products
of these compounds with isocyanic acid (from the decomposition of
urea or nitrourea) or isocyanates rearrange in an acidic medium to
give imidazoquinazolines, oxindoles, indolylureas, bis[2-(imida-
zolyl)phenyl]ureas, imidazol-ones, or spiro-linked imidazolidine-
oxindoles, depending on the character of the substituents. An
illustrative survey of these transformations is given in our last
paper on this topic.1
2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones 2 (Scheme 1,
method A).4 In anticipation of the possibility that 3-aminoquino-
linediones 1 could have reacted analogously with isothiocyanic
acid, we carried out experiments leading to this objective. We
demonstrate in this work that the reaction of 3-aminoquino-
linediones 1 with potassium thiocyanate in boiling acetic acid
yields two structurally diverse products 3 and 4, whereas the re-
action of 1 with urea or potassium cyanate produces only single
product 2.
The exceptional structural diversity of the reaction products of
the molecular rearrangement mentioned above gave us incentive to
perform an analogous reaction of 3-aminoquinolinediones 1 with
isothiocyanates. We have found that the addition products of 1 with
isothiocyanates also rearrange in an acidic medium, resulting in
(E)- and/or (Z)-4-butylidene-2-thioxo-10H-spiro[imidazoline-5,30-
indole]-2,20-diones,2 4-(2-aminophenyl)-1H-imid-azole-2(3H)-thi-
ones,3 and 1,3-bis(2-(2,3-dihydro-2-thioxo-1H-imidazol-5-yl)phe-
nyl)ureas.3 Owing to the simple reaction protocols, these
transformations open an easy pathway to the preparation of new
types of heterocyclic compounds.
S
R
R
1
HN
1
Methods: a) urea, AcOH
b) thiourea, AcOH
c) KSCN, AcOH
N
O
3
N
3a
3
10
9
NHR
X
R
N
4
R
O
d) KOCN, AcOH
or
5
4
N
H
N
H
O
N
H
O
6
5
7
1
6
2a-i:
3a,c-f,i: X = S
X = O
4b,g,h
Key of substituents:
a
b
c
d
e
f
g
h
i
R
R
Bu CH2Ph Ph Ph Bu Bu CH2Ph CH2Ph Ph
Bu Bu CH2Ph Bu CH2Ph CH2Ph
H
H
H
Scheme 1.
2. Results and discussion
Reactions of aminoketones 1 with compounds providing iso-
cyanic or isothiocyanic acid (potassium cyanate, urea, thiourea,
* Corresponding author. Fax: þ420 57 72 10 722; e-mail address: klasek@ft.utb.cz
(A. Klásek).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.056

ꢀ
V. Mrkvicka et al. / Tetrahedron 66 (2010) 8441e8445
8442
potassium thiocyanate) were performed by boiling the reaction
components in acetic acid (Table 1). The starting aminoketones 1
were obtained from the corresponding 3-chloro derivatives in ac-
cordance with procedures described earlier.5
Mass spectra of compounds in the second group exhibit a mo-
lecular peak, that is, m/z 90 less than expected. In addition, signals
corresponding to the C-benzyl group were not found in 1H and 13
C
NMR spectra of the reaction products from 1b,g,h, which shows
that a C-debenzylation must occur during the reaction. We postu-
lated that the reaction products were 2,3-dihydro-2-thioxo-1H-
imidazo[4,5-c]quinolin-4(5H)-ones 4b,g,h. These structures were
confirmed by certain assignment of all resonances using 2D NMR
spectra (Table 3). In the NOESY spectrum, the H-1 protons have
a cross-peak with the H-9 protons and the CONH protons have
a cross-peak with the H-6 protons, which evidences their spatial
vicinity. The determination of 1J (15N,1H) for all NH protons (Table 3)
excludes the possibility of the presence of SeH tautomers.
Table 1
Reactions of 3-aminoquinolinediones 1 with urea (method A)a, thiourea (method B),
KSCN (method C) and KOCN (method D)
Ewntry
Starting compound
Method
Time
Products (yield, %)
(min)
1
a
R1
R2
1
2
3
4
Bu
H
A
B
C
D
90
30
5
2a (73)
3a (5), Ac-1a (18)b
3a (93)
60
2a (62)
For comparison, we also carried out the reaction of compounds 1
with potassium cyanate in boiling acetic acid (Table 1, method D).
From these experiments, only compounds 2 were obtained in yields
somewhat lower than those obtained by method A.4 A C-debenzy-
lation was not observed in any case. This result pointed to the
decisive conclusion that potassium thiocyanate is required for the
debenzylation process. From potassium thiocyanate, only weak
thiocyanic acid H-SCN (pKa 5.4)7 can be liberated with acetic acid
(pKa 4.75). However, this weak acid isomerizes promptly tothe more
stable isothiocyanic acid H-NCS, which is very strong acid (pKa
ꢀ1.3).7,8 The formation of this acid causes the strong acidification of
the reaction mixture, which leads to C-debenzylation. We have
observed asimilarreaction(C-debutylation) in thecase of3-butyl-3-
thiocyanato-quinoline-2,4-diones during their reaction with con-
centrated sulfuric acid in the presence of phosphorus pentoxide.9
Isocyanic acid (pKa 3.9), arising from potassium cyanate and acetic
acid through the weak isomeric cyanic acid (pKa 6.4), is a mesoscale
acid and does not induce a debenzylation of compounds 1.
5
6
7
8
b
c
d
e
f
Bz
Ph
Ph
Bu
Bu
Bz
Bz
Ph
H
A
B
C
D
20
30
5
2b (71)
1b (22)b
4b (70)
2b (64)
30
9
H
A
B
C
D
5
30
9
2c (90)
3c (16)
3c (82)
2c (58)
10
11
12
50
13
14
15
16
Bu
Bu
Bz
Bu
Bz
Bz
A
B
C
D
30
30
30
25
2d (76)
3d (2), 1d (12)c
3d (70)
2d (80)
17
18
19
20
A
B
C
D
30
25
30
40
2e (95)
3e (3), 1e (45)c
3e (79)
2e (78)
21
22
23
24
A
B
C
D
30
65
30
60
2f (93)
3f (4), 1f (24)c
3f (53)
The proposed reaction mechanism (Scheme 2) supposes the
addition of a-aminoketone 1 to isocyanic or isothiocyanic acid. This
2f (74)
25
26
27
28
g
h
i
A
B
C
D
120
20
5
2g (87)
4g (4), 1g (57)c
4g (66)
would create the intermediate A, which cyclizes to intermediate B
and subsequently converts into intermediate D. In a medium-
acidity environment, both of these intermediates convert to the
isocyanate intermediate C, which provides product 2 (X¼O) or 3
(X¼S). The rearrangement of intermediate B to isocyanate in-
termediate C was observed in the reaction of compounds 1 with
isocyanates.10 On the other hand, in a strong-acidic medium,
protonation of intermediate D proceeds and the protonated
intermediate D stabilizes by ejecting the benzylic cation. We pre-
sumed that this cation reacts with high nucleophilic thiocyanate
anion. Indeed, the presence of benzyl thiocyanate as the main
component of the benzene extract of the aqueous portion after
reaction of 1g with potassium thiocyanate was evidenced by TLC
analysis in three different solvent systems. This extract contains
also a small quantity of benzyl alcohol; however, the presence of
benzyl acetate was not observed.
120
2g (74)
29
30
31
32
A
B
C
D
120
30
10
2h (66)
1h (21)a
4h (71)
2h (64)
130
33
34
35
36
A
B
C
D
d
d
3i (33), 1i (3)c
3i (78)
120
30
120
2i (67)
a
Data from Ref. 4.
b
N(3)-Acetylated compound 1a, identical in all respects to the authentic
compound.6
c
Recovered starting material.
We have found that the reactions of 1 with thiourea (method B)
are relatively unsuccessful and in many cases only the starting
compound was recovered (Table 1).
3. Conclusions
In contrast to urea, thiourea decomposes to isothiocyanic acid in
only small amounts under the given reaction conditions. Therefore,
we focused our attention on the reaction of 1 with potassium
thiocyanate (method C). This reaction affords two different sets of
products (Table 1). The first group of the products has 1H and 13C
NMR spectra that are very similar to those of compounds 2.4 The
only exception is the presence of NMR signals in the
In conclusion, we would like to emphasize that the described
reaction of 3-aminoquinolinediones 1 with isothiocyanic acid
generated from potassium thiocyanate allows the preparation, in
very good yields, of 2,3-dihydro-3-thioxoimidazo[1,5-c]quinazolin-
5(6H)-ones (3) and 2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]qui-
nolin-4(5H)-ones (4). Compounds 3 have not been previously de-
scribed in the literature. Since many biologically active compounds
contain a sulfur atom,11,12 compounds 3 could also be interesting
structures for study.
The C-debenzylation of starting compounds 1 bearing a benzyl
group at position 3 not only has theoretical significance, but en-
ables the targeted preparation of compounds 4 through a simple
procedure. To our surprise, only one compound of this type, de-
scribed as tautomeric 5-butyl-2-mercapto-1-methyl-1H-imidazo
d
160.1e161.6 ppm region (Table 2). It is evident that these signals
can be attributed to C]S carbon atoms at the position 3; therefore,
compounds of the first group are 2,3-dihydro-3-thioxoimidazo[1,5-
c]quinazolin-5(6H)-ones 3a,cef,i. In cases 3a and 3c, the NH proton
signals appear at
d 12.87 and 10.98 or 13.22 and 11.11 ppm. The
occurrence of 1J (15N,1H) for all of these protons (Table 2) excludes
the possibility of SeH tautomers.

ꢀ
V. Mrkvicka et al. / Tetrahedron 66 (2010) 8441e8445
8443
Table 2
1H and 13C chemical shifts of compounds 2i and 3a,cef,i in DMSO-d6
Position
2i
3a
3c
3d
3e
3f
3i
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
dH
dC
1
3
5
6
6a
7
8
9
d
117.8
148.3
145.0
d
d
123.9
160.7
145.1
d
d
122.6
161.6
145.1
d
d
123.8
160.2
144.8
d
d
125.0
160.1
144.8
d
d
125.2
161.4
144.8
d
d
123.9
161.4
144.8
d
d
d
d
d
d
d
d
d
d
10.98a
d
d
11.11b
d
d
d
d
d
10.81
d
11.17
d
11.06
d
11.13
d
11.23
d
134.5
115.3
128.3
122.6
121.2
112.9
113.5
128.1
131.0
129.4
130.1
43.9
134.3
115.1
128.0
123.2
121.8
113.4
119.8
24.2
30.0
21.7
13.8
d
134.6
115.3
128.8
122.6
120.9
112.7
120.3
128.2
129.2
129.9
129.9
d
134.4
115.2
128.9
122.7
121.4
112.2
120.3
128.0
131.2
129.8
130.6
43.7
134.2
115.1
128.3
123.3
122.0
112.7
119.3
23.7
30.1
21.9
13.7
43.2
29.5
19.6
13.7
d
134.3
115.2
128.5
123.3
122.1
112.6
119.7
24.1
29.4
21.8
13.6
46.2
134.5
115.3
129.0
122.7
121.5
112.2
120.8
127.7
131.0
129.5
130.5
46.9
7.04
7.18
6.79
6.73
d
7.09
7.29
7.15
7.63
d
7.10
7.27
6.90
7.19
d
7.10
7.25
6.84
6.67
d
7.11
7.32
7.19
7.66
d
7.13
7.32
7.18
7.61
d
7.12
7.26
6.83
6.68
d
10
10a
10b
10(R1)
20(R1)
30(R1)
40(R1)
10(R2)
20(R2)
30(R2)
40(R2)
50(R2)
d
d
d
d
d
d
d
d
2.83
1.62
1.40
0.94
12.87c
d
d
d
2.99
1.60
1.53
0.99
4.18
1.69
1.43
0.99
d
2.84
1.20
1.34
0.81
5.65
d
d
7.40
7.55
7.58
4.72
d
7.60
7.60
7.60
13.22d
d
7.63
7.70
7.70
3.91
1.52
1.14
0.72
d
7.36
7.54
7.61
5.29
d
137.0
126.7
128.5
127.3
d
d
28.9
19.3
13.5
d
136.4
126.7
128.7
127.5
136.0
126.7
128.3
127.2
6.99
7.27
7.27
d
d
d
d
7.28
7.39
7.32
6.98
7.24
7.24
d
d
d
d
d
d
d
d
a
1J (15N, 1H)¼97.4 Hz.
1J (15N, 1H)¼91.5 Hz.
1J (15N, 1H)¼92.1 Hz.
1J (15N, 1H)¼97.6 Hz.
b
c
d
Table 3
1H, 13C and 15N chemical shifts of compounds 4b,g,h in DMSO-d6
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
Position
4b
4g
4h
are given on the
15N 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.
dH
dC
dH
dC
dH
dC
b,c
1 (NH)
2
13.57a
d
13.30e
d
ꢀ219.4b
167.1
ꢀ221.9b
119.3
152.4
ꢀ233.9b
136.4
116.2
128.9
122.3
121.7
109.7
133.4
ꢀ221.9b
d
13.81
d
13.96d
d
d
d
166.2
ꢀ214.1b
118.0
152.9
ꢀ232.6b
136.3
116.1
129.2
122.4
121.7
109.5
132.8
44.4
167.5
d
3 (NR2)
3a
d
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-ion EI mass
spectra were measured on a Shimadzu QP-2010 instrument within
the mass range m/z¼50e600 using direct inlet probe (DI). Samples
d
d
117.9
152.8
d
4
d
11.90f
d
d
11.93g
d
d
5 (NH)
5a
6
7
8
9
9a
9b
11.95
d
136.4
116.2
129.3
122.5
121.8
109.5
133.1
47.3
137.3
127.7
128.3
127.3
7.46
7.52
7.30
8.05
d
7.47
7.53
7.31
8.09
d
7.47
7.54
7.29
8.11
d
were dissolved in dichloromethane (30 mg/mL) and 10 mL of the
solution was evaporated in DI cuvette at 50 ꢁC. The ion source
temperature was 200 ꢁC; the energy of the electrons was 70 eV.
Only signals exceeding relative abundance of 5% are listed. Column
chromatography was carried out on Silica gel (Merck, grade 60,
70e230 mesh) using chloroform and then successive mixtures of
chloroform/ethanol (in rations from 99:1 to 8:2) or benzene and
then successive mixtures of benzene/ethyl acetate (in rations from
99:1 to 8:2). Reactions as well as the course of separation and also
the purity of substances were monitored by TLC in elution systems
benzene/ethyl acetate (4:1), chloroform/ethanol (9:1 and/or 19:1)
and chloroform/ethyl acetate (7:3) on AlugramÒ SIL G/UV254 foils
(MachereyeNagel). Elemental analyses (C, H, N) were performed
with a EA 1108 Elemental Analyzer (Fisons Instrument) at our
Institute.
d
13.30g
d
d
d
10(R2)
20(R2)
30(R2)
40(R2)
50(R2
4.50
1.79
1.38
0.96
d
5.76
d
30.9
19.4
13.8
d
d
d
7.43
7.32
7.26
d
d
d
d
1J (15N, 1H)¼98.1 Hz.
a
b
c
d
e
f
d (
15N).
Not found.
Broadened signal.
1J (15N, 1H)¼99.4 Hz.
1J (15N, 1H)¼89.7 Hz.
1J (15N, 1H)¼90.0 Hz.
g
[4,5-c]quinolin-4(5H)-one, was found in the literature. This com-
pound, which induces contraction in tracheal strips of passively
sensitized guinea pigs, was prepared by five different multi-step
reactions starting from 3-nitroquinolin-2-ones bearing a hydroxy,
chloro, or methylamino substituent in position 4.13
4.2. Starting 3-amino-1H,3H-quinoline-2,4-diones (1)
Compounds (1) were prepared from corresponding 3-chloro
derivatives according to the protocol described in literature.6
4. Experimental
4.1. General
4.3. General procedure for the preparation of compounds 2, 3
and 4
A mixture of appropriate 3-amino-1H,3H-quinoline-2,4-dione
(1aei) (1 mmol) and appropriate reagent (see below) in acetic
acid (3 mL) was heated to reflux for the time given in Table 1. The
Melting points were determined on a Kofler block or Gallen-
camp apparatus. IR (KBr) spectra were recorded on a Mattson 3000

ꢀ
8444
V. Mrkvicka et al. / Tetrahedron 66 (2010) 8441e8445
X
X
X
H2N
O
HN
HN
N
HO
NR2
N
R1
R2
N
R1
R2
HNCX
AcOH
R1
O
1
N
H
O
N
H
O
C
A
B
X = O,S
H+
X
R2
S
N
R1
N
HN
N
3
N
R1
R2
R2
X
+
- PhCH2
N
N
O
N
H
O
N
H
O
2,3
H
D
4
if R1 = CH2Ph and X = S
if R1 = Bu, Ph
Scheme 2.
course of reaction was monitored by TLC. After cooling, the re-
action mixture was poured onto ice (50 g). The precipitated
product was filtered off and triturated with a solution of sodium
hydroxide (1 M, 50 mL) to remove cyanuric acid or 1,3,5-tri-
thiocyanuric acid. The insoluble portion was filtered off with
suction and recrystallized from an appropriate solvent. Using
method B, the aqueous portion after filtration of the precipitated
product was basified with ammonia and extracted three times
with chloroform. The collected extracts were evaporated and the
residue was crystallized from appropriate solvent or column
chromatographed.
356e362 ꢁC (acetic acid). IR: 3077, 2986, 2919, 1731, 1633, 1615,
1591, 1506,1488, 1445, 1388, 1345, 1256, 1224,1159, 1131,1101,1067,
781, 754, 699, 669, 569 cmꢀ1. EIMS: m/z (%): 293 (Mþ, 100), 260
(10), 234 (17), 206 (8), 190 (8), 117 (9), 104 (16), 89 (6), 77 (9), 51 (5).
Anal. Calcd (found) for C16H11N3OS: C 65.51 (65.30); H 3.78 (3.76);
N 14.32 (14.44); S 10.93 (11.00).
4.3.4. 2-Butyl-2,3-dihydro-1-phenyl-3-thioxoimidazo[1,5-c]quinazo-
lin-5(6H)-one (3d). Yield 7 mg (2%, method B) or 245 mg (70%,
method C). Colourless needles, mp 265e267 ꢁC (acetic acid). IR:
3226, 3163, 3098, 2955, 2932, 2871, 1727, 1654, 1615, 1592, 1484,
1394, 1375, 1330, 1292, 1266, 1229, 1183, 1134, 1076, 1061, 1025,
1000, 921, 864, 829, 790, 757, 742, 711, 696, 671, 588 cmꢀ1. EIMS m/z
(%) 349 (Mþ, 37), 316 (100), 293 (45), 260 (6), 233 (13), 206 (8), 190
(8), 149 (7), 135 (7), 111 (11), 104 (19), 97 (19), 85 (21), 71 (29), 57
(55). Anal. Calcd (found) for C20H19N3OS: C 68.74 (68.55); H 5.48
(5.46); N 12.02 (11.98); S 9.18 (8.97).
Method A: Urea was used as reagent; see Ref. 4.
Method B. Thiourea (457 mg, 6 mmol) was used as reagent.
Method C. Potassium thiocyanate (583 mg, 6 mmol) was used as
reagent.
Method D. Potassium cyanate (487 mg, 6 mmol) was used as
reagent.
In the case of 1g, the aqueous portion after filtration of 4g was
extracted with benzene. The extract was dried with anhydrous
potassium carbonate and analyzed by TLC using benzyl acetate,
benzyl thiocyanate and benzyl alcohol as reference compounds.
4.3.5. 1,2-Dibutyl-2,3-dihydro-3-thioxoimidazo[1,5-c]quinazolin-5
(6H)-one (3e). Yield 10 mg (3%, method C) or 260 mg (79%, method
D). Colourless prisms, mp 273e274 ꢁC (acetic acid). IR: 3239, 3190,
3130, 2956, 2930, 2871, 1727, 1629, 1612, 1590, 1490, 1467, 1377,
1342, 1291, 1261, 1231, 1154, 1134, 1080, 1052, 1016, 937, 909, 822,
741, 696, 682, 660, 574, 556, 537 cmꢀ1. EIMS: m/z (%): 329 (Mþ, 44),
296 (100), 272 (12), 254 (7), 245 (8), 231 (31), 172 (15), 130 (10), 69
(6), 55 (16). Anal. Calcd (found) for C18H23N3OS: C 65.62 (65.56); H
7.04 (7.03); N 12.75 (12.81); S 9.73 (9.68).
4.3.1. 2-Benzyl-1-phenyl-2,6-dihydroimidazo[1,5-c]quin-azoline-3,5-
dione (2i). Yield 246 mg (67%, method D). Colourless prisms, mp
290e296 ꢁC (acetic acid). IR: 3295, 3250, 3065, 2931, 2865, 1763,
1751, 1679, 1635, 1614, 1589, 1495, 1483, 1445, 1376, 1365, 1347,
1326, 1315, 1266, 1174, 1071, 1030, 1011, 970, 924, 915, 884, 790, 755,
740, 697, 669, 654, 599, 583, 521 cmꢀ1. For 1H and 13C NMR see
Table 2. EIMS m/z (%): 368 (21), 367 (Mþ, 81), 277 (19), 276 (99), 248
(10), 235 (13), 234 (71), 206 (22), 205 (10), 161 (6), 149 (7), 133 (6),
132 (8), 118 (6), 117 (6), 106 (6), 105 (43), 104 (16), 92 (11), 91 (100),
90 (13), 77 (34), 76 (6), 72 (8), 71 (6), 65 (26), 57 (10), 55 (7), 51 (13),
41 (7). Anal. Calcd (found) for C23H17N3O2: C 75.19 (75.15); H 4.66
(4.67); N 11.44 (11.35).
4.3.6. 2-Benzyl-1-butyl-2,3-dihydro-3-thioxoimidazo[1,5-c]quinazo-
lin-5(6H)-one (3f). Yield 15 mg (4%, method B) or 193 mg (53%,
method C). Colourless needles, mp 253e254 ꢁC (acetic acid). IR:
3190, 2955, 2928, 2870, 1729, 1612, 1590, 1492, 1455, 1397, 1375,
1324, 1291, 1245, 1216, 1153, 1126, 1089, 1054, 1023, 967, 911, 841,
822, 754, 741, 710, 695, 585, 569, 550, 535 cmꢀ1. EIMS: m/z (%): 363
(Mþ, 65), 330 (77), 321 (15), 288 (6), 272 (19), 230 (28), 218 (9), 172
(10), 130 (7), 97 (7), 91 (100), 85 (10), 71 (12), 65 (16), 57 (20). Anal.
Calcd (found) for C21H21N3OS: C 69.39 (69.52); H 5.82 (5.86); N
11.56 (11.58); S 8.82 (8.72).
4.3.2. 1-Butyl-2,3-dihydro-3-thioxoimidazo[1,5-c]quin-azolin-5(6H)-
one (3a). Yield 14 mg (5%, method B) or 254 mg (93%, method C).
Colourless needles, mp 305e313 ꢁC dec (AcOH). IR: 3080, 2947,
2925, 2865, 2748, 1721, 1636, 1615, 1589, 1498, 1448, 1386, 1360,
1285, 1253, 1226, 1127, 1075, 826, 779, 753, 741, 527, 485 cmꢀ1
.
4.3.7. 2-Benzyl-2,3-dihydro-1-phenyl-3-thioxoimidazo [1,5-c]quina-
zolin-5(6H)-one (3i). Yield 127 mg (33%, method B) or 299 mg
(78%, method C). Colourless plates, mp 282e284 ꢁC (acetic acid).
IR: 3230, 3166, 3102, 3064, 3003, 2946, 1727, 1645, 1590, 1484,
1443, 1425, 1382, 1324, 1253, 1233, 1077, 836, 789, 758, 743, 712,
700, 670, 568 cmꢀ1. EIMS: m/z (%) 383 (Mþ, 64), 350 (99), 234
(91), 206 (15), 149 (6), 135 (12), 111 (11), 104 (13), 97 (16), 91
(100), 85 (19), 71 (26), 65 (20), 57 (50). Anal. Calcd (found) for
EIMS: m/z (%): 273 (Mþ, 59), 230 (100), 201(9), 187 (5), 172 (50), 144
(10), 130 (27), 116 (15), 102 (20), 90 (9), 77 (8), 63 (6), 52 (8). Anal.
Calcd (found) for C14H15N3OS: C 61.51 (61.55); H 5.53 (5.50); N
15.37 (15.31); S 11.73 (11.71).
4.3.3. 2,3-Dihydro-1-phenyl-3-thioxoimidazo[1,5-c]quin-azolin-5
(6H)-one (3c). Yield 241 mg (82%, method C). Yellowish plates, mp

ꢀ
V. Mrkvicka et al. / Tetrahedron 66 (2010) 8441e8445
8445
C23H17N3OS: C 72.04 (72.11); H 4.47 (4.51); N 10.96 (10.94); S
8.36 (8.16).
Anal. Calcd (found) for C17H13N3OS: C 66.43 (66.37); H 4.26 (4.27);
N 13.67 (13.46); S 10.43 (10.15).
4.3.8. 2,3-Dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4(5H)-one
(4b). Yield 152 mg (70%, method C). Colourless needles,
mp>350 ꢁC dec (acetic acid). IR: 3071, 3009, 2928, 2844,1709, 1655,
1619, 1573, 1500, 1481, 1450, 1426, 1384, 1340, 1257, 1200, 1164,
1154, 964, 941, 885, 769, 688, 624, 602, 516, 470 cmꢀ1. EIMS m/z (%):
217 (Mþ, 100), 207 (9), 185 (18), 157 (7), 118 (5), 103 (23), 91 (5), 76
(14), 65 (7), 51 (9). Anal. Calcd (found) for C10H7N3OS: C 55.29
(55.39); H 3.25 (3.41); N 19.34 (19.37); S 14.76 (14.64).
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-
thors thank Dr. R.Vícha for mass spectra measurement and Mrs. H.
ꢀ
Gerzová for technical help (both Faculty of Technology, Tomas Bata
University in Zlín).
4.3.9.
1-Butyl-2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4
References and notes
(5H)-one (4g). Yield 11 mg (4%, method B) or 180 mg (66%, method
C). Colourless needles, mp>350 ꢁC (acetic acid). IR: 3101, 2993,
2870, 1661, 1615, 1571, 1520, 1500, 1466, 1442, 1370, 1347, 1289,
1256, 1243, 1208, 1151, 1101, 1035, 939, 853, 799, 746, 699, 679, 603,
536 cmꢀ1. EIMS: m/z (%): 273 (Mþ, 47), 240 (62), 231 (8), 217 (100),
129 (12), 103 (11). Anal. Calcd (found) for C14H15N3OS: C 61.51
(61.58); H 5.53 (5.53); N 15.37 (15.57); S 11.73 (11.59).
ꢀ
ꢀ
ꢁꢀ ꢀ
1. Klásek, A.; Lycka, A.; Miksík, I.; Ruzicka, A. Helv. Chim. Acta 2009, 92, 689 and
references cited therein.
2. Klásek,A.;Mrkvicka, V.;Lycka, A.;Miksík,I.;Ruzicka, A. Tetrahedron2009, 65, 4908.
3. Prucková, Z.; Klásek, A.; Lycka, A.; Miksík, I.; Ruzicka, A. Tetrahedron 2009, 65,
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ꢀ
ꢀ
ꢁꢀ ꢀ
ꢀ
ꢀ
ꢁꢀ ꢀ
9103.
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ꢀ
4. Klásek, A.; Koristek, K.; Lycka, A.; Holcapek, M. Tetrahedron 2003, 59, 1283.
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5. Kafka, S.; Klásek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002, 57, 1659.
6. Kafka, S.; Klásek, A.; Polis, J.; Rosenbreierová, V.; Palík, C.; Mrkvicka, V.; Kosmrlj,
J. Tetrahedron 2008, 64, 4387.
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7. Gaitan, E. Environmental Goitrogenesis; CRC: Boca Raton, Florida, USA, 1989; p
16.
8. Chiang, Y.; Kresge, A. J. Can. J. Chem. 2000, 78, 1627.
4.3.10. 3-Benzyl-2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4
(5H)-one (4h). Yield 218 mg (71%, method C). Colourless prisms,
mp>350 ꢁC (acetic acid). IR: 3420, 3103, 3046, 2991, 2890, 2836,
1659,1614,1571,1518,1496,1477,1456,1434,1377,1346,1322,1254,
1201, 1145, 1102, 1077, 1033, 993, 935, 868, 794, 751, 705, 674, 604,
585, 528 cmꢀ1. EIMS: m/z (%) 307 (Mþ, 365), 274 (24), 137 (5), 129
(7), 97 (11), 92 (9), 91 (100), 83 (13), 71(13), 69 (15), 59 (22), 55 (33).
ꢀ
ꢀ
9. Klásek, A.; Mrkvicka, V.; Pevec, A.; Kosmrlj, J. J. Org. Chem. 2004, 69, 5646.
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10. Klásek, A.; Lycka, A.; Holcapek, M.; Hoza, I. Helv. Chim. Acta 2008, 91, 354.
11. Northcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
12. Faulkner, D. J. Nat. Prod. Rep. 1995, 12, 223.
13. Suzuki, F.; Kuroda, T.; Nakasato, Y.; Manabe, H.; Ohmori, K.; Kitamura, S.;
Ichikawa, S.; Ohno, T. J. Med. Chem. 1992, 35, 4045.