Synthesis of 2-oxo-2,3,5,6-tetrahydro-5-thioxoimidazo[1,2-c]quinazolines by one-pot cyclization of α-aminocarboxylic esters with 2-(isothiocyanato)benzonitrile (ITCB)

Article abstract of DOI:10.1016/j.tet.2006.05.075

The cyclization of 2-(isothiocyanato)benzonitrile with α-aminocarboxylic esters and acids afforded a variety of 2-oxo-2,3,5,6-tetrahydro-5-thioxo-imidazo[1,2-c]quinazolines with very good regioselectivity.

Full text of DOI:10.1016/j.tet.2006.05.075

Tetrahedron 62 (2006) 7653–7660
Synthesis of 2-oxo-2,3,5,6-tetrahydro-5-thioxoimidazo[1,2-c]-
quinazolines by one-pot cyclization of a-aminocarboxylic esters
with 2-(isothiocyanato)benzonitrile (ITCB)
Anja Bodtke,a Helmut Reinke,b Dirk Michalikc and Peter Langerb,c,
*
aInstitut fu€r Biochemie, Universita€t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
bInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
cLeibniz-Institut fu€r Katalyse e.V. an der Universita€t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 3 May 2006; revised 25 May 2006; accepted 29 May 2006
Available online 19 June 2006
Abstract—The cyclization of 2-(isothiocyanato)benzonitrile with a-aminocarboxylic esters and acids afforded a variety of 2-oxo-2,3,5,6-
tetrahydro-5-thioxo-imidazo[1,2-c]quinazolines with very good regioselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
cyclization product. The formation of 2-oxo-2,3,5,6-tetra-
hydro-5-thioxoimidazo[1,2-c]quinazoline 3a or its isomer
iso-3a can be discussed. The formation of 3a can be ex-
plained by attack of the amino group onto the isothiocyanate
(intermediate A), attack of the amino group onto the nitrile
(intermediate B), and subsequent attack of the imino group
onto the ester group (Scheme 1). The formation of iso-3a
may proceed by attack of the amino group onto the iso-
thiocyanate, attack of the sulfur atom onto the nitrile (inter-
mediate C), Dimroth rearrangement (intermediate D), and
subsequent attack of the amino group onto the ester. Based
on structural investigations (vide infra), we believe that 3a
is formed in the reaction, although the structure iso-3a cannot
be completely ruled out.
2-(Isothiocyanato)benzonitrile (ITCB) represents a versatile
synthetic building block.1 In recent years, one-pot cycliza-
tions of ITCB with a number of nucleophiles have been
reported. Recently, we and others have reported one-pot
cyclizations of ITCB with hydrazine,2 carboxylic hydra-
zides,3,4 a-aminoketones,5 and carbon nucleophiles.6 In
addition, one-pot cyclizations of ITCB-derived dichloro-
isocyanides have been reported.7,8 Recently, we reported
the synthesis of 2-oxo-2,3,5,6-tetrahydro-5-thioxo-imi-
dazo[1,2-c]quinazolines by one-pot cyclization of ITCB
with a-aminocarboxylic esters.9 Herein, we report full de-
tails of this work and studies related to the preparative scope.
Notably, functionalized quinazolines are of pharmacological
relevance and show antihypertonic, antirheumatic, antiana-
phylactic, antiasthmatic, tranquilizing, neuro-stimulating,
and benzodiazepine binding activity.10 In addition, they
represent useful synthetic building blocks.
The best yields were obtained when a two phase system of
a CH2Cl2 solution of the starting materials and of an aque-
ous solution of Na2CO3 was stirred for 10 min at 20 ꢀC
(formation of A) and subsequently refluxed for 20 min (for-
mation of B). After aqueous work-up, an iPrOH solution of
B was refluxed (formation of 3a). The yield of 3a decreased
when the CH2Cl2 solution was refluxed immediately with-
out stirring at 20 ꢀC. In contrast, intermediate A was iso-
lated when the reaction was carried out at 20 ꢀC without
reflux. The yield of 3a dropped and intermediate B was
isolated when the iPrOH solution was not refluxed for
sufficient time. The reaction could be also carried out as
a one-pot reaction without isolation of B. However, the
yield dropped (36%) compared to the sequential procedure
(58%).
2. Mechanism and optimization
Thereactionofethylglycinate(2a)withITCB(1a) afforded—
based on MS data and elemental analysis—a tricyclic
Keywords: Amino acids; Cyclizations; Domino reactions; Isothiocyanates;
Regioselectivity.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412;
e-mail: peter.langer@uni-rostock.de
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.075

7654
A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
Table 1. Products and yields
O
OEt
NH
R1
R2
% (3)a
N
HN
3
OEt
N
a
b
b
c
d
d
e
f
H
Me
Me
Et
iPr
iPr
iBu
(CH2)2(cHex)
Bn
Ph
CO2Et
CH2CO2Bn
Et
Et
H
Me
Et
H
Me
Et
Me
Et
Et
Bn
58
21
45
20
77
43
86
81
35
62
60
84
O
N
S
N
N
H
S
H
B
A
O
g
h
i
N
N
S
j
N
S
N
H
3a
a
Yields of isolated products.
i, ii, iii
1a
- EtOH
+
S
O
ITCB with diethyl 2-aminomalonate and dibenzyl aspartate
gavethe ester substituted quinazolines 3i and 3j, respectively.
Notably, racemic products were isolated when enantiomeri-
cally pure starting materials were used, due to racemization.
NH
H2N
OEt
N
N
2a
O
iso-3a
The reaction of a-amino-g-butyrolactone with ITCB af-
forded 3-(2-hydroxyethyl)-5-thioxoimidazo[1,2-c]quinazo-
lin-2-one 3k. The formation of 3k can be explained by
attack of the amino group onto the isothiocyanate, subse-
quent cyclization by attack of the amino group onto the nitrile
(intermediate C), and subsequent nucleophilic attack of the
imino group onto the lactone ring and cleavage of the latter
(Scheme 3).
NH
S
S
NH
N
H
O
N
N
H
O
N
OEt
OEt
C
D
N
O
HO
N
Scheme 1. Possible mechanistic pathways of the cyclization of ITCB (1a)
with ethyl glycinate: (i) Na2CO3, H2O, CH2Cl2, 20 ꢀC, 10 min; (ii) reflux,
20 min, isolation of crude intermediate B; (iii) iPrOH, reflux, 10 h.
S
i, ii, iii
N
N
O
N
S
H
H2N
+
O
3k (81%)
3. Scope and limitations
O
O
NH
The reaction of ITCB with ethyl alanate furnished the 2-
oxo-2,3,5,6-tetrahydro-5-thioxoimidazo[1,2-c]quinazoline 3b,
albeit in only 21% yield (Scheme 2, Table 1). The cyclization
of ITCB with the amino acid alanine gave 3b in 45% yield.
The cyclization of ITCB with methyl 2-aminobutyrate af-
forded 3c. The cyclization of ITCB with ethyl valinate and
valine afforded 3d in 77 and 43% yield, respectively. 5-Thi-
oxoimidazo[1,2-c]quinazoline 3e was prepared from methyl
leucinate. The cyclization of ITCB with ethyl 2-amino-4-
cyclohexylbutyrate gave the quinazoline 3f. Heterocycles
3g and 3h were prepared from methyl phenylalanate ester
and ethyl 2-phenylglycinate, respectively. The reaction of
N
N
H
S
C
Scheme 3. Synthesis of 3k: (i) Na2CO3, H2O, CH2Cl2, 20 ꢀC, 10 min; (ii)
reflux, 20 min, isolation of crude C; (iii) iPrOH, reflux, 10 h.
The reaction of ITCB with racemic ethyl 3-aminobutyrate
(4) afforded the racemic pyrimidinone 5, albeit, in only
11% yield (Scheme 4). The final cyclization step (attack of
the imino group onto the ester group) proved to be problem-
atic. The yield could not be improved by extension of the
reaction time or by variation of the concentration.
N
N
O
O
S
N
S
N
1a
N
R1
i, ii, iii
N
N
i, ii, iii
O
N
Me
- R2OH
N
H
S
NH2 O
H2N
+
- EtOH
OR2
N
H
S
+
R1
2a-j
Me
OEt
3a-j
4 (11%)
Scheme 2. Synthesis of 3a–j: (i) Na2CO3, H2O, CH2Cl2, 20 ꢀC, 10 min; (ii)
reflux, 20 min, isolation of crude B; (iii) iPrOH, reflux, 10 h.
Scheme 4. Synthesis of 4, conditions: (i) Na2CO3, H2O, CH2Cl2, 20 ꢀC,
10 min; (ii) reflux, 20 min; (iii) iPrOH, reflux, 10 h.

A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
7655
The reaction of ITCB with methyl 2-amino-2-methylpropio-
nate and methyl 1-aminocyclohexylcarboxylate afforded
2-thioxoimidazolidinones 5a and 5b (Scheme 5, Table 2).
The formation of 5a,b can be explained by attack of the
amino group onto the isothiocyanate and subsequent cycliza-
tion by attack of the ITCB-derived amino group onto the
ester. The change in the mechanism can be explained by (a)
the steric hindrance of the 2-amino-2-methylpropionate and
(b) Thorpe–Ingold effect. Treatment of 5a,b with an aqueous
solution of sodium hydroxide afforded 2-oxoimidazo[1,2-c]-
quinazolines 6a,b by ring cleavage to give a carboxylic acid,
attack of the amino group onto the nitrile, and subsequent
attack of the imino group onto the carboxylic acid.
imidazo[1,2-c]quinazoline 8. The formation of 7 and 8
follows the mechanism as discussed for the formation of
5a,b and 6a,b.
4. Structure elucidation
The structures of products 3a–j were assigned based on the
similarity of their NMR spectroscopic data, on a detailed
structural analysis of 3g and 6a, and on an X-ray crystal struc-
ture analysis of 6a (vide infra). The NMR signals of 3g were
assigned by DEPT and two-dimensional 1H–1H COSY,
1
1H–1H NOESY, and H–13C correlation spectra (HSQC,
HMBC). In the HMBC spectrum cross peaks were found
for C-11 with H-3, H-7, and H-10; as well as NH with CS
and C-10a, which confirm the given structure. The alternative
structure given in Figure 1 can be excluded based on the
HMBC spectrum in which a correlation was found between
the NH proton and the signal for the quaternary aromatic car-
bon atom C-10a at d¼110.7. Furthermore, the NMR data of
3g are in best agreement with those assigned for compound
6a. All derivatives 3a–k exhibit very similar IR absorptions
(C]O), 13C NMR data (C]O and C]S groups and carbon
atoms C-6a, C-8, C-9, C-7, C-10a, and C-3 of the quinazoline
N
N
S
S
N
i, ii
N
H
NH
R1
R2
O
O
H2N
+
OMe
OMe
R1 R2
D
- MeOH
iii
1
O
N
S
moiety), and H NMR data (protons 3-H and NH) (Fig. 1,
Table 3).
R1
N
N
iv, v
R2
S
N
NH
R1
N
H
O
p
R2
S
O
1N
2
m
6a,b
5a,b
NH
10
7
3
i
o
10a
9
8
Scheme 5. Synthesis of 5a,b and 6a,b: (i) Na2CO3, H2O, CH2Cl2, 20 ꢀC,
10 min; (ii) reflux, 20 min, isolation of D; (iii) iPrOH, reflux, 10 h; (iv)
NaOH, H2O (4%), 20 ꢀC, 24 h; (v) H2O, HCl.
4
5
11 N
N
N
6a
N
S
H6
O
Table 2. Products and yields
Figure 1. Atom numbering of 3g for NMR signal assignment.
5,6
R1
R2
% (5)a
% (6)a
The structures of products 6a,b were assigned based on the
similarity of their NMR spectroscopic data, on a detailed
structural analysis of 6a, and on an X-ray crystal structure
analysis of 6a. The NMR signals of 6a were assigned by
DEPT and two-dimensional 1H–1H COSY, 1H–1H NOESY,
and 1H–13C correlation spectra (HSQC, HMBC). In the
HMBC spectrum cross peaks were found for NH with
C]S, C-7, C-10a, and C-6a; C-11 with H-10 and H-7 (4J);
and Me (protons) with C-2 and C-3 (Fig. 2). In the NOESY
spectrum cross peaks were found for the NH proton with
H-7. No other correlations besides this for the aromatic pro-
tons were observed. The structure of 6a was independently
confirmed by X-ray crystal structure analysis (Fig. 3).11
a
b
Me
Me
40
40
80
35
–(CH2)5–
a
Isolated yields.
The reaction of ethyl valinate with 2-isocyanatobenzo-
nitrile—the oxa-analog of ITCB—afforded the imidazo-
lidine-2,5-dione 7 (Scheme 6). Treatment of 7 with an
aqueous solution of NaOH afforded the 2,5-dioxo-
N
N
O
O
i, ii, iii
N
N
NH
O
- EtOH
O
H2N
In conclusion, we have reported the synthesis of 2-oxo-2,3,
5,6-tetrahydro-5-thioxoimidazo[1,2-c]quinazolinesbasedon
the cyclization reactions of 2-(isothiocyanato)benzonitrile
with a-aminocarboxylic esters.
iPr
OEt
+
7 (70%)
iPr
O
iv, v
N
iPr
O
N
5. Experimental
5.1. General
N
H
8 (40%)
Scheme 6. Synthesis of 8: (i) NEt3, CH2Cl2, 20 ꢀC, 10 min; (ii) reflux,
40 min, isolation of intermediate; (iii) iPrOH, NH4OH, reflux, 48 h; (iv)
NaOH, H2O (4%), 20 ꢀC, 24 h; (v) HCl, H2O.
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13
C

7656
A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
Table 3. Characteristic spectroscopic features of 3a–k, 6a, and 8
Nr.
~n(C]O) (cmꢂ1
)
d (ppm)
3-H
d (ppm)
NH
d (ppm)
C-3
d (ppm)
C]O
d (ppm)
C]S
d (ppm)
C-6a
d (ppm)
C-8
d (ppm)
C-9
d (ppm)
C-7
d (ppm)
C-10a
3a
3b
3c
3d
3e
3f
3g
3h
3i
1746, 1627
1743, 1624
1741, 1624
1733, 1627
1746, 1627
1752, 1624
1736, 1624
1743
1752, 1625
1744, 1625
1717, 1624
1729, 1627
4.48
4.57
4.64
4.51
4.62
4.63
4.89
5.64
5.38
4.83
4.64
—
13.85
13.24
13.20
13.25
13.25
13.25
13.30
13.28
13.65
13.26
13.18
13.13
13.79
53.6
59.7
64.4
67.9
62.4
63.8
64.8
67.2
66.2
60.0
61.7
67.4
64.7
184.4
188.4
187.6
186.5
187.9
187.7
187.2
185.1
179.1
186.6
187.8
191.6
187.2
168.3
168.5
168.8
168.5
168.5
168.6
169.1
169.4
169.1
168.8
168.7
169.0
171.9
139.8
139.6
139.7
139.7
139.6
139.6
139.6
139.9
139.9
139.5
139.5
139.8
141.2
137.0
137.0
137.1
137.1
137.0
137.1
137.5
137.3
138.1
137.1
136.9
136.8
136.7
125.6
125.0
125.1
125.2
125.1
125.1
125.5
125.1
125.7
125.2
125.0
125.3
123.3
116.3
115.9
116.0
116.1
115.9
116.0
116.2
116.0
116.4
116.0
115.8
115.9
115.8
111.0
111.2
110.8
110.9
110.9
110.8
110.7
111.0
110.2
111.0
111.0
111.7
109.1
3j
3k
6a
8
1745/1728, 1628
4.39
O
under reflux. After cooling to room temperature, a colorless
precipitate was formed. The latter was filtered off, the or-
ganic and the aqueous layer were separated, and the latter
was extracted with dichloromethane (2ꢁ20 ml). The com-
bined organic layers were dried (Na2SO4), filtered, and the
solvent of the filtrate was removed at reduced pressure.
The residue and the precipitate were suspended in isopropa-
nol (200 ml) and the mixture was refluxed for 12 h. The
product was crystallized after cooling. Concentration of
the mother liquor at reduced pressure gave a further amount
of the product. Yield: 0.80 g (58%), brown roods (acetone),
mp 320–323 ꢀC (decomp.). IR (KBr): ~n¼3105, 3071 (w),
3013, 2993, 2928, 2922, 2847 (m), 1746, 1636, 1627,
1601, 1554, 1529, 1479, 1424, 1342, 1306, 1255, 1226,
1N
2
10
Me
Me
3
N
10a
9
4
5
11
8
6a
N
S
H6
7
Figure 2. Atom numbering of 6a for NMR signal assignment.
1175, 1067 (s), 945 (w), 756, 543 (s) cmꢂ1 1H NMR
.
(DMSO-d6, 300 MHz): d¼4.48 (s, 2H, CH2), 7.41–7.48
(m, 2H, Ar), 7.84–8.07 (m, 2H, Ar), 13.85 (br s, 1H, NH).
13C NMR (DMSO-d6, 75.5 MHz): d¼53.6 (CH2), 111.0
(C), 116.3, 125.6, 127.5, 137.0 (CH), 139.8, 168.1, 168.3
(C), 184.4 (C]O). MS (EI, 70 eV): m/z (%)¼218 (13),
217 (M+, 100), 171 (23), 161 (11), 160 (13), 143 (19), 129
(12), 102 (21). UV–vis (CH3CN): lmax (log 3)¼246 (4.22),
249 (4.22), 267 (4.45), 292 (4.48), 350 (3.68). Anal. Calcd
for C10H7N3OS (217.25): C, 55.29; H, 3.25; N, 19.34; found:
C, 55.35; H, 3.33; N, 19.32.
Figure 3. ORTEP plot of 6a. The thermal ellipsoids of 50% probability are
shown for the non-hydrogen atoms.
5.1.2. 3-Methyl-5-thioxo-5,6-dihydroimidazo[1,2-c]-
quinazolin-2-one (3b). Method A: from alanine (285 mg,
3.2 mmol), 2-(isothiocyanato)benzonitrile (500 mg, 3.2
mmol), TEA (1 ml) in ethanol/water (50 ml/5 ml), and 15 h
reflux. Yield: 330 mg (45%). Method B: from ethyl alaninate
hydrochloride (0.98 g, 6.4 mmol) and 2-(isothiocyanato)-
benzonitrile (1.000 g, 6.4 mmol). Yield: 0.300 g (21%),
yellow prisms (ethanol), mp 314 ꢀC (decomp.). IR (KBr):
~n¼3016, 2982, 2938, 2912 (w), 1743, 1633, 1624 (s), 1600
(m), 1560, 1536, 1533, 1530, 1527, 1478 (s), 1459 (m),
1405, 1351, 1331, 1304 (s), 1284 (m), 1252, 1213, 1161,
NMR, the deuterated solvents indicated were used. The
1H NMR (300.13 MHz) and 13C NMR (75.9 MHz) were
recorded on a Bruker spectrometer ARX 300. In addition
to the routine measurements, spectra of 3g and 6a were
measured on a Bruker Spectrometer AVANCE 500 (1H:
500.13 MHz and 13C: 125.8 MHz). Calibration of spectra
was carried out on the solvent signals (DMSO-d6: d
1H¼2.50, d 13C¼39.7). Mass spectrometric data (MS) were
obtained by electron ionization (70 eV), chemical ionization
(CI, H2O), or electrospray ionization (ESI). For preparative
scale chromatography, silica gel (60–200 mesh) was used.
Melting points are uncorrected.
1
1152 (s) cmꢂ1. H NMR (DMSO-d6, 300 MHz): d¼1.69
(d, J¼7.1 Hz, 3H, CH3), 4.57 (q, J¼7.1 Hz, 1H, 3-H),
7.41–8.09 (m, 4H, Ar), 13.24 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼14.9 (CH3), 59.7 (C-3), 111.2
(C), 115.9, 125.0, 127.4, 137.0 (CH), 139.6, 168.0, 168.5
(C), 188.4 (C]O). MS (EI, 70 eV): m/z (%)¼232 (16), 231
(M+, 100), 216 (17), 198 (39), 171 (22), 161 (20), 160 (18),
143 (24), 102 (18). UV–vis (CH3CN): lmax (log 3)¼251
(4.18), 268 (4.42), 295 (4.49), 352 (3.60). Anal. Calcd for
5.1.1. 5-Thioxo-5,6-dihydroimidazo[1,2-c]quinazolin-2-
one (3a). 2-(Isothiocyanato)benzonitrile (1.00 g, 6.4 mmol)
and ethyl glycinate hydrochloride (1.21 g, 6.4 mmol) were
suspended in dichloromethane (40 ml). A solution of sodium
carbonate (1.83 g in 12 ml water) was added and the mixture
was stirred for 10 min at ambient temperature and for 10 min

A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
7657
C11H9N3OS (231.28): C, 57.13; H, 3.92; N, 18.17; found: C,
57.02; H, 4.12; N, 17.73.
4.62 (dd, J¼8.2, 3.4 Hz, 1H, 3-H), 7.42–7.47 (m, 2H, Ar),
7.84–8.09 (m, 2H, Ar), 13.25 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼21.8, 23.21 (CH3), 23.22 (CH),
36.1 (CH2), 62.4 (C-3), 110.9 (C), 115.9, 125.1, 127.4,
137.0 (CH), 139.6, 168.2, 168.5 (C), 187.9 (C]O). MS
(EI, 70 eV): m/z (%)¼273 (M+, 5), 230 (34), 217 (100),
161 (22), 102 (11), 71 (13). UV–vis (CH3CN): lmax
(log 3)¼247 (4.21), 252 (4.21), 269 (4.44), 296 (4.50), 353
(3.63). Anal. Calcd for C14H15N3OS (273.36): C, 61.51;
H, 5.53; N, 15.37; found: C, 61.47; H, 5.70; N, 15.47.
5.1.3. 3-Ethyl-5-thioxo-5,6-dihydroimidazo[1,2-c]quina-
zolin-2-one (3c). Method B: from methyl 2-aminobutyrate
hydrochloride (0.49 g, 3.2 mmol) and 2-(isothiocyanato)-
benzonitrile (0.500 g, 3.2 mmol). Yield: 0.15 g (20%), color-
less prisms (ethanol), mp 260–264 ꢀC (decomp.). IR (KBr):
~n¼3075, 3017 (w), 2965, 2938, 2918, 2879 (m), 1741,
1624 (s), 1602 (m), 1526, 1477 (s), 1465 (m), 1405 (s), 1351,
1338 (m), 1280 (s), 1257 (m), 1234 (w), 1210 (s), 1154 (m),
1078 (w) cmꢂ1. 1H NMR (DMSO-d6, 300 MHz): d¼0.67 (t,
J¼7.4 Hz, 3H, CH3), 2.11 (m, 1H, CH2), 2.71 (m, 1H, CH2),
4.64 (dd, J¼6.3, 2.7 Hz, 1H, 3-H), 7.43–7.48 (m, 2H, Ar),
7.85–8.09 (m, 2H, Ar), 13.20 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼6.6 (CH3), 21.0 (CH2), 64.4 (C-
3), 110.8 (C), 116.0, 125.1, 127.5, 137.1 (CH), 139.7,
168.5, 168.8 (C), 187.6 (C]O). MS (EI, 70 eV): m/z
(%)¼246 (16), 245 (M+, 100), 230 ([MꢂCH3]+, 50), 217
(71), 216 ([MꢂC2H5]+, 32), 212 (42), 204 (20), 203 (27),
171 (22), 161 (51), 145 (10), 144 (13), 143 (26), 134 (13),
129 (17), 102 (20). UV–vis (CH3CN): lmax (log 3)¼209
(4.38), 252 (4.20), 269 (4.44), 295 (4.51), 352 (3.63). Anal.
Calcd for C12H11N3OS (245.30): C, 58.76; H, 4.52; N,
17.13; found: C, 58.84; H, 4.91; N, 17.07.
5.1.6. 3-(2-Cyclohexylethyl)-5-thioxo-5,6-dihydroimi-
dazo[1,2-c]quinazolin-2-one (3f). Method B: from ethyl
2-amino-4-cyclohexylbutyrate hydrochloride (1.60 g) and
2-(isothiocyanato)benzonitrile (1.000 g, 6.4 mmol). Yield:
1.69 g (81%), colorless prisms (ethanol), mp 278–295 ꢀC
(decomp.). IR (KBr): ~n¼3105, 3016 (w), 2921, 2850, 1752,
1629, 1624 (s), 1602 (m), 1527, 1478 (s), 1449 (m), 1405,
1350 (s), 1336, 1289, 1264 (m), 1215, 1199 (s), 1153,
1072, 756 (m) cmꢂ1 1H NMR (DMSO-d6, 300 MHz):
.
d¼0.78–1.16 (m, 8H, CH2), 1.59–1.63 (m, 5H, 2CH2, CH),
2.11 (m, 1H, CH2 ethyl), 2.65 (m, 1H, CH2 ethyl), 4.63 (dd,
J¼6.5, 2.7 Hz, 1H, 3-H), 7.42–7.48 (m, 2H, Ar), 7.85–8.08
(m, 2H, Ar), 13.25 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼25.1, 25.6, 25.6, 25.9, 29.2, 32.4, 32.6
(CH2), 36.6 (CH), 63.8 (C-3), 110.8 (C), 116.0, 125.1,
127.4, 137.1 (CH), 139.6, 168.5, 168.6 (C), 187.7 (C]O).
MS (EI, 70 eV): m/z (%)¼327 (M+, 25), 295 (21), 294
(100), 232 (12), 230 (44), 219 (13), 218 (24), 217 (96), 204
(21), 203 (21), 198 (12), 178 (13), 161 (26), 55 (17), 41
(20). UV–vis (CH3CN): lmax (log 3)¼247 (4.22), 252
(4.22), 269 (4.44), 295 (4.50), 352 (3.64). Anal. Calcd for
C18H21N3OS (327.45): C, 66.03; H, 6.46; N, 12.83; found:
C, 66.22; H, 6.45; N, 12.45.
5.1.4. 3-Isopropyl-5-thioxo-5,6-dihydroimidazo[1,2-c]-
quinazolin-2-one (3d). Method A: from valine (375 mg,
3.2 mmol), 2-(isothiocyanato)benzonitrile (500 mg, 3.2
mmol), TEA (1 ml) in ethanol/water (50 ml/5 ml), and 16 h
reflux. Yield: 357 mg (43%). Method B: from ethyl valinate
hydrochloride (1.16 g) and 2-(isothiocyanato)benzonitrile
(1.000 g, 6.4 mmol). Yield: 1.28 g (77%), colorless prisms
(isopropanol), mp 278–288 ꢀC (decomp.). IR (KBr):
~n¼3171, 3113, 3079, 3027, 2968 (m), 1733, 1627, 1557,
1529, 1476 (s), 1413 (m), 1348 (s), 1295 (m), 1260, 1207,
1
1149 (s), 1067, 969, 762 (m) cmꢂ1. H NMR (DMSO-d6,
5.1.7. 3-Benzyl-5-thioxo-5,6-dihydroimidazo[1,2-c]-
quinazolin-2-one (3g). Method B: from methyl phenyl
alaninate hydrochloride (1.38 g, 6.4 mmol) and 2-(isothio-
cyanato)benzonitrile (1.000 g, 6.4 mmol). Yield: 0.68 g
(35%), yellow prisms (ethanol), mp 246–252 ꢀC (decomp.).
IR (KBr): ~n¼3185, 3145, 3111, 3095, 3071, 3027, 2934
(w), 1736, 1624, 1550, 1521, 1478, 1404, 1342, 1216
(s), 1153 cmꢂ1. The atom numbering for NMR signal
assignment is given in Figure 1. 1H NMR (DMSO-d6,
300 MHz): d¼0.63 (d, J¼6.8 Hz, 3H, CH3), 1.20 (d,
J¼7.1 Hz, 3H, CH3), 3.34–3.38 (m, 1H, CH(CH3)2), 4.51
(d, J¼3.3 Hz, 1H, 3-H), 7.41–7.48 (m, 2H, Ar), 7.84–8.07
(m, 2H, Ar), 13.25 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼14.9 (CH3), 16.9 (CH3), 25.9 (CH(CH3)2),
67.9 (C-3), 110.9 (C), 116.1, 125.2, 127.6, 137.1 (CH),
139.7, 168.51, 168.52 (C), 186.5 (C]O). MS (EI, 70 eV):
m/z (%)¼260 (18), 259 (M+, 100), 244 (38), 226 (23), 218
(11), 217 (70), 216 (55), 204 (36), 203 (82), 178 (36), 177
(15), 171 (11), 162 (25), 161 (59), 160 (10), 145 (19), 144
(15), 134 (14), 129 (15), 102 (25), 39 (10). UV–vis
(CH3CN): lmax (log 3)¼210 (4.52), 248 (4.20), 253 (4.21),
269 (4.44), 296 (4.51), 352 (3.63). Anal. Calcd for
C13H13N3OS (259.33): C, 60.21; H, 5.05; N, 16.20; found:
C, 60.61; H, 5.48; N, 16.46.
2
3
500 MHz): d¼3.28 (dd, JCH
¼13:6 Hz, J3;CH
¼
;CH
2ðaÞ
2:5 Hz, 1H, CH2(b)), 4.15 (dd, JCH
2ðbÞ
2ðbÞ
2
¼13:6 Hz,
;CH
2ðaÞ
2ðbÞ
3J3;CH ¼6:3 Hz, 1H, CH2(a)), 4.89 (dd, J3;CH ¼ 6:3 Hz,
3
2ðaÞ
2ðaÞ
3J3;CH ¼2:5 Hz, 1H, 3-H), 7.03–7.15 (m, 5H, Ph), 7.34
2ðbÞ
3
3
4
(ddd, J9,10¼8.0 Hz, J8,9¼7.2 Hz, J7,9¼1.0 Hz, 1H, H-9),
3
3
7.41 (br d, J7,8¼8.2 Hz, 1H, H-7), 7.81 (ddd, J7,8¼8.2 Hz,
3J8,9¼7.2 Hz, 4J8,10¼1.5 Hz, 1H, H-8), 7.83 (dd,
3J9,10¼8.0 Hz, J8,10¼1.5 Hz, 1H, H-10), 13.30 (br s, 1H,
4
5.1.5. 3-Isobutyl-5-thioxo-5,6-dihydroimidazo[1,2-c]-
quinazolin-2-one (3e). Method B: from methyl leucinate
hydrochloride (1.16 g, 6.4 mmol) and 2-(isothiocyanato)-
benzonitrile (1 g, 6.4 mmol). Yield: 1.51 g (86%), colorless
prisms (isopropanol), mp 250–264 ꢀC (decomp.). IR (KBr):
~n¼3176, 3108, 3022 (w), 2960 (m), 1746, 1627 (s), 1601
(m), 1550, 1520, 1474 (s), 1402, 1346, 1334, 1221, 1195
NH). 13C NMR (DMSO-d6, 125.8 MHz): d¼33.3 (CH2),
64.8 (C-3), 110.7 (C-10a), 116.2 (C-7), 125.5 (C-9), 127.3
(p-Ph), 127.7 (C-10), 128.4 (m-Ph), 129.3 (o-Ph), 134.5 (i-
Ph), 137.5 (C-8), 139.6 (C-6a), 168.8 (C-11), 169.1 (C]S),
187.2 (C-2). MS (EI, 70 eV): m/z (%)¼308 (21), 307 (M+,
100), 274 (17), 216 (71), 204 (20), 203 (61), 161 (20), 143
(12), 103 (19), 102 (18), 91 (31), 77 (15). UV–vis (CH3CN):
lmax (log 3)¼252 (4.20), 270 (4.42), 296 (4.46), 354 (3.60).
Anal. Calcd for C17H13N3OS (307.36): C, 66.43; H, 4.26; N,
13.67; found: C, 66.19; H, 4.29; N, 13.98.
(m), 1151 (s) cmꢂ1 1H NMR (DMSO-d6, 300 MHz):
.
d¼0.82 (d, J¼6.7 Hz, 3H, CH3), 0.89 (d, J¼6.5 Hz, 3H,
CH3), 1.86 (m, 1H, CH(CH3)2), 2.10–2.26 (m, 2H, CH2),

7658
A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
5.1.8. 3-Phenyl-5-thioxo-5,6-dihydroimidazo[1,2-c]qui-
nazolin-2-one (3h). Method B: from ethyl phenyl glycinate
hydrochloride (1.29 g, 6.4 mmol) and 2-(isothiocyanato)-
benzonitrile (1.000 g, 6.4 mmol). Yield: 1.16 g (62%), color-
less prisms (isopropanol), mp 295 ꢀC (decomp.). IR (KBr):
~n¼3164, 3109, 3073, 3026, 2962, 2956, 2922 (w), 1743,
1677, 1602, 1558, 1526, 1479 (s), 1455 (w), 1403, 1345,
1325 (m), 1296 (s), 1254, 1236 (w), 1210, 1186 (s), 1152
(w), 1744, 1625 (s), 1603 (m), 1558, 1554, 1526 (s), 1479,
1406, 1355 (m), 1333 (s), 1283, 1254 (m), 1220, 1176 (s),
1146 (m), 1073 (w) cmꢂ1. MS (EI, 70 eV): m/z (%)¼365
(M+, 17), 274 (70), 260 (14), 259 (93), 257 (13), 256 (49),
232 (11), 231 (56), 230 (94), 229 (13), 228 (14), 217 (40),
204 (11), 203 (12), 202 (13), 198 (11), 161 (42), 143 (10),
102 (18), 91 (100), 71 (21), 66 (19), 43 (11). UV–vis
(CH3CN): lmax (log 3)¼269 (4.45), 295 (4.48), 354 (4.44).
Anal. Calcd for C19H15N3O3S (365.41): C, 62.45; H, 4.14;
N, 11.50; found: C, 62.38; H, 4.29; N, 11.28.
(s), 1061 (w) cmꢂ1 1H NMR (DMSO-d6, 300 MHz):
.
d¼5.64 (s, 1H, 3-H), 7.23–7.51 (m, 7H, Ar), 7.89–8.17 (m,
2H, Ar), 13.28 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼67.2 (C-3), 111.0 (C), 116.0, 125.1, 126.5,
127.7, 127.8, 128.5 (CH), 133.4 (C), 137.3 (CH), 139.9,
168.2, 169.4 (C), 185.1 (C]O). MS (EI, 70 eV): m/z
(%)¼294 (19), 293 (M+, 100), 261 (13), 260 (63), 171 (15),
143 (21), 129 (10), 104 (12), 102 (15), 91 (11), 77 (13).
UV–vis (CH3CN): lmax (log 3)¼247 (4.28), 269 (4.47), 295
(4.50), 357 (3.66). Anal. Calcd for C16H11N3OS (293.35):
C, 65.51; H, 3.78; N, 14.32; found: C, 65.82; H, 4.11; N,
14.34.
5.1.11. 3-(2-Hydroxyethyl)-5-thioxo-5,6-dihydro-
imidazo[1,2-c]quinazolin-2-one (3k). Method B: from
a-amino-g-butyrolactone hydrobromide (1.16 g, 6.4 mmol)
and 2-(isothiocyanato)benzonitrile (1.000 g, 6.4 mmol).
Yield: 1.69 g (81%), colorless prisms (ethanol), mp 263–
265 ꢀC (decomp.). IR (KBr): ~n¼3410, 3254, 3018 (w),
2962, 2940, 2918, 2860 (m), 1717, 1624 (s), 1602 (m),
1533 (s), 1480, 1426, 1405 (m), 1329 (s), 1286, 1238,
1
1221, 1201, 1156, 1084, 752 (m) cmꢂ1. H NMR (DMSO-
d6, 300 MHz): d¼2.27–2.38 (m, 1H, CH2), 2.70–2.81 (m,
1H, CH2), 3.36–3.44 (m, 1H, CH2), 4.47–4.50 (m, 1H,
CH2), 4.64 (dd, J¼7.1, 2.6 Hz, 1H, 3-H), 7.41–7.47 (m,
2H, Ar–H), 7.83–8.08 (m, 2H, Ar–H), 13.18 (br s, 1H,
NH). 13C NMR (DMSO-d6, 75.5 MHz): d¼30.6, 56.0
(CH2), 61.7 (C-3), 111.0 (C), 115.8, 125.0, 127.5, 136.9
(CH), 139.5, 168.4, 168.7 (C), 187.8 (C]O). MS (EI,
70 eV): m/z (%)¼261 ([M]+, 1), 243 ([MꢂH2O]+, 4), 230
([MꢂCH2OH]+, 6), 217 ([MꢂC2H3OH]+, 25), 143 (2), 129
(3). UV–vis (CH3CN): lmax (log 3)¼207 (4.33), 231 (4.07),
248 (4.18), 251 (4.18), 269 (4.37), 295 (4.40), 349 (3.64).
Anal. Calcd for C12H11N3O2S (261.30): C, 55.16; H, 4.24;
N, 16.08; found: C, 55.35; H, 4.48; N, 15.79.
5.1.9. Ethyl 2-oxo-5-thioxo-2,3,5,6-tetrahydroimi-
dazo[1,2-c]quinazolin-3-carboxylate (3i). Method B:
from diethyl 2-aminomalonate hydrochloride (1.35 g,
6.4 mmol) and 2-(isothiocyanato)benzonitrile (1.000 g,
6.4 mmol). Yield: 1.11 g (60%), colorless prisms (isopropa-
nol), mp 229–239 ꢀC (decomp.). IR (KBr): ~n¼3185 (m),
3121, 3081, 3022, 2982, 2959, 2934 (w), 1752, 1724, 1625
(s), 1598 (m), 1549, 1518 (s), 1479, 1409, 1345 (m), 1301
(s), 1241 (m), 1202, 1143 (s), 1078, 1023, 762, 565
(m) cmꢂ1
.
1H NMR (DMSO-d6, 300 MHz): d¼1.22 (t,
J¼7.2 Hz, 3H, CH3), 4.23 (q, J¼7.2 Hz, 2H, CH2), 5.38 (s,
1H, 3-H), 7.48–7.53 (m, 2H, Ar), 7.93–8.12 (m, 2H, Ar),
13.65 (br s, 1H, NH). 13C NMR (DMSO-d6, 75.5 MHz):
d¼13.8 (CH3), 62.1 (CH2), 66.2 (C-3), 110.2 (C), 116.4,
125.7, 127.8, 138.1 (CH), 139.9, 162.4, 167.7 (C), 169.1,
179.1 (C]O). MS (EI, 70 eV): m/z (%)¼290 (17), 289
(M+, 100), 243 ([MꢂC2H6O]+, 31), 217 (41), 216
([MꢂCOOC2H5]+, 93), 215 (39), 171 (14), 160 (28), 143
(15), 134 (13), 129 (18), 103 (13), 102 (57), 90 (16), 76
(31), 65 (11), 64 (12). UV–vis (CH3CN): lmax (log 3)¼209
(4.29), 247 (4.18), 269 (4.50), 294 (4.46), 358 (3.62). Anal.
Calcd for C13H11N3O3S (289.31): C, 53.97; H, 3.83; N,
14.52; found: C, 54.02; H, 4.26; N, 14.64.
5.1.12. 4-Methyl-6-thioxo-3,4,5,6-tetrahydropyrimi-
dino[2,3-c]quinazolin-2-one (4). Method B: from ethyl
3-aminobutyrate hydrochloride (0.84 g, 6.4 mmol) and
2-(isothiocyanato)benzonitrile (1.000 g, 6.4 mmol). Yield:
0.18 g (11%), colorless prisms (ethanol), mp 290–307 ꢀC
(decomp.). IR (KBr): ~n¼3243, 3209, 3129, 3073, 3033,
2978, 2962 (w), 1687, 1621, 1606, 1549, 1528, 1510, 1486
(s), 1447 (m), 1403 (s), 1311, 1278 (m), 1261, 1175, 1155
1
(s), 1125, 1095 (m), 1081 (w), 1005 (m) cmꢂ1. H NMR
(DMSO-d6, 300 MHz): d¼1.26 (d, J¼6.6 Hz, 3H, CH3),
2.45 (dd, J¼15.0, 1.6 Hz, 1H, CH2), 2.93 (dd, J¼15.0,
6.6 Hz, 1H, CH2), 5.78 (dq, J¼6.6, 1.6 Hz, 1H, CHCH3),
7.34–7.40 (m, 2H, Ar), 7.74–7.79 (m, 1H, Ar), 8.17–8.20
(m, 1H, Ar), 13.25 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼15.8 (CH3), 35.8 (CH2), 51.5 (CHCH3),
115.5, 124.9 (CH), 127.0 (C), 127.2, 135.7 (CH), 138.6,
153.2, 172.2 (C), 175.8 (C]O). MS (EI, 70 eV): m/z
(%)¼246 (12), 245 ([M]+, 87), 230 ([MꢂCH3]+, 7), 212
(21), 204 (30), 203 (100), 161 (30), 145 (26), 144 (14), 143
(12). UV–vis (CH3CN): lmax (log 3)¼209 (4.44), 231
(3.82), 252 (4.14), 271 (4.35), 298 (4.54), 349 (3.74). Anal.
Calcd for C12H11N3OS (245.30): C, 58.76; H, 4.52; N,
17.13; found: C, 58.82; H, 4.88; N, 17.53.
5.1.10. Benzyl (2-oxo-5-thioxo-2,3,5,6-tetrahydroimi-
dazo[1,2-c]quinazolin-3-yl)acetate (3j). Method A: from
dibenzyl aspartate (714 mg, 3.2 mmol), 2-(isothiocyanato)-
benzonitrile (500 mg, 3.2 mmol), TEA (1 ml) in ethanol/
water (50 ml/5 ml), and 15 h reflux. Yield: 350 mg (30%).
Method B: from dibenzyl aspartate toluenesulfonate
(3.10 g, 6.4 mmol) and 2-(isothiocyanato)benzonitrile
(1.000 g, 6.4 mmol). Yield: 1.97 g (84%), colorless platelets
(ethanol), mp 233–234 ꢀC (decomp.). 1H NMR (DMSO-d6,
300 MHz): d¼3.35–3.52 (m, 1H, CH2COO), 3.90 (m,
J¼17.3, 5.9 Hz, 1H, CH2COO), 4.83 (m, J¼5.9, 3.3 Hz,
1H, 3-H), 4.95–5.07 (q(AB), J¼12.4 Hz, 2H, OCH2), 7.22–
7.25 (m, 5H, phenyl), 7.43–7.48 (m, 2H, CH), 7.85–8.05
(m, 2H, CH), 13.26 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼32.9 (CH2), 60.0 (C-3), 65.9 (OCH2), 111.0
(C), 116.0, 125.2, 127.5, 127.7, 127.9, 128.2 (Ar–H), 135.4
(C), 137.1 (Ar–H), 139.5, 168.6, 168.8 (C), 169.0, 186.6
(C]O). IR (KBr): ~n¼3175, 3116, 3082, 3031, 2979, 2953
5.1.13. 2-(4,4-Dimethyl-5-oxo-2-thioxoimidazolidin-
1-yl)-benzonitrile (5a). Method B: from methyl 2-amino-
isobutyrate hydrochloride (0.49 g, 3.2 mmol) and 2-(isothio-
cyanato)benzonitrile (0.50 g, 3.2 mmol). Yield: 0.31 g
(39%), colorless prisms (ethanol), mp 260–264 ꢀC

A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
7659
(decomp.). IR (KBr): ~n¼3304 (s), 3114 (w), 2237 (m), 1764
temperature, diluted with water, and acidified with concd hy-
drochloric acid. The solid precipitate was collected and
dried. Yield: 0.40 g (40%), colorless prisms (ethanol), mp
363–370 ꢀC (decomp.). IR (KBr): ~n¼3244, 3230 (m),
2930, 2863 (w), 1724, 1626, 1544, 1517 (s), 1482, 1454,
1391, 1354, 1323 (m), 1276, 1207, 1167, 1141, 1082
(s), 1600 (w), 1517, 1460 (s), 1402 (m), 1278, 1183 (s),
1
1131, 766 (m), 634 (w), 599 (m) cmꢂ1. H NMR (DMSO-
d6, 300 MHz): d¼1.46 (s, 3H, CH3), 1.49 (s, 3H, CH3),
7.65–8.06 (m, 4H, Ar), 10.91 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼22.9 (CH3), 24.1 (CH3), 61.4
(C(CH3)2), 112.4 (CN), 115.4 (C), 130.2, 131.2, 133.1,
134.1 (CH), 135.7, 176.4 (C), 179.2 (C]O). MS (EI,
70 eV): m/z (%)¼246 (12), 245 (M+, 100), 161 (48), 160
(80), 143 (8), 129 (11), 115 (10), 102 (24), 100 (16). Anal.
Calcd for C12H11N3OS (245.30): C, 58.76; H, 4.52; N,
17.13; found: C, 58.71; H, 4.62; N, 17.18.
1
(m) cmꢂ1. H NMR (DMSO-d6, 300 MHz): d¼1.24–1.29
(m, 1H, CH2), 1.54–1.71 (m, 5H, CH2), 2.07–2.11 (m, 2H,
CH2), 3.52–3.60 (m, 2H, CH2), 7.37–7.42 (m, 2H, Ar),
7.80–7.84 (m, 1H, Ar), 8.06–8.09 (m, 1H, Ar), 13.06 (br s,
1H, NH). 13C NMR (DMSO-d6, 75.5 MHz): d¼19.5
(2CH2), 23.8 (CH2), 25.7 (2CH2), 68.8 (C-3), 111.5, 115.7
(C), 125.0, 127.6, 130.5, 136.9 (CH), 167.5 (C]N), 168.7
(C), 190.3 (C]O). MS (EI, 70 eV): m/z (%)¼285 ([M]+,
4), 198 (13), 118 (100), 91 (38). UV–vis (CH3CN): lmax
(log 3)¼211 (4.36), 254 (4.14), 270 (4.34), 301 (4.47), 354
(3.57). C15H15N3OS (285.37).
5.1.14. 3,3-Dimethyl-5-thioxo-5,6-dihydroimidazo[1,2-c]-
quinazolin-2-one (6a). Compound 5a (100 mg, 0.4 mmol)
was dissolved in a mixture of an aqueous solution of sodium
hydroxide (2%, 30 ml) and isopropanol (2 ml). The mixture
was stirred for 12 h at room temperature, diluted with water,
and acidified with concd hydrochloric acid. The solid
precipitate was collected and dried. Yield: 65 mg (65%),
colorless prisms (ethanol), mp 320–327 ꢀC (decomp.). IR
(KBr): ~n¼3437 (w), 3246 (s), 3124, 2978 (w), 1729, 1627,
1601, 1543, 1510 (s), 1474, 1392, 1374, 1348 (m), 1303
(s), 1273, 1245 (m), 1210 (s), 1157 (m), 1135 (s), 1100
(m) cmꢂ1. The atom numbering for NMR signal assignment
is given in Figure 2. 1H NMR (DMSO-d6, 500 MHz): d¼1.74
5.1.17. 2-(4-Isopropyl-2,5-dioxoimidazolidin-1-yl)benzo-
nitrile (7). 2-(Isocyanato)benzonitrile (1.44 g, 10.0 mmol)
and ethyl valinate hydrochloride (1.81 g 10.0 mmol) were
suspended in 40 ml of dry dichloromethane. A dichloro-
methane solution (20 ml) of TEA (1.01 g, 10.0 mmol) was
dropwise added with stirring. The mixture was stirred for
10 min at 20 ꢀC and for 1 h under reflux. The solvent was
removed in vacuo and the residue was washed with water
(100 ml) and dried by exposure to air. Yield of noncyclized
intermediate: 2.07 g (79%), colorless solid. IR (KBr):
~n¼3329 (m), 2969, 2876 (w), 2219 (w, CN), 1739 (s), 1708
(m), 1655 (s), 1608, 1582 (m), 1555 (s), 1474, 1451, 1301,
3
3
4
(s, 6H, 2Me), 7.42 (dt, J9,10¼8.0 Hz, J8,9¼7.2 Hz, J7,9
¼
3
1.0 Hz, 1H, H-9), 7.43 (d, J7,8¼8.2 Hz, 1H, H-7), 7.84
3
3
4
(ddd, J7,8¼8.2 Hz, J8,9¼7.2 Hz, J8,10¼1.5 Hz, 1H, H-8),
3
4
8.11 (dd, J9,10¼8.0 Hz, J8,10¼1.5 Hz, 1H, H-10), 13.13
(br s, 1H, NH). 13C NMR (DMSO-d6, 125.8 MHz): d¼21.1
(2Me), 67.4 (C-3), 111.7 (C-10a), 115.9 (C-7), 125.3 (C-9),
128.0 (C-10), 137.3 (C-8), 139.8 (C-6a), 168.1 (C-11), 169.0
(C]S), 191.6 (C-2). MS (EI, 70 eV): m/z (%)¼246 (12), 245
(M+, 100), 230 ([MꢂCH3]+, 32), 213 (13), 212 (84), 204 (14),
171 (39), 161 (31), 160 (11), 143 (32), 102 (21). UV–vis
(CH3CN): lmax (log 3)¼209 (4.44), 252 (4.18), 269 (4.40),
299 (4.51), 354 (3.60). C12H11N3OS (245.30).
1238, 1208, 1157 (m) cmꢂ1
.
1H NMR (DMSO-d6,
300 MHz): d¼0.91 (d, J¼7.2 Hz, 3H, CH3), 0.93 (d,
J¼7.1 Hz, 3H, CH3), 1.22 (t, J¼7.1 Hz, 3H, CH3 ester),
2.07–2.13 (m, 1H, CH), 4.11–4.20 (m, 3H, CH2 ester, CH),
7.09–7.14 (m, 1H, Ar), 7.44 (d, J¼8.3 Hz, 1H, NH), 7.56–
7.71 (m, 2H, Ar), 8.09–8.11 (m, 1H, Ar), 8.72 (s, 1H, NH).
An isopropanol solution (100 ml) of the open-chained prod-
uct (1.200 g, 4.6 mmol) and TEA (3 ml) was refluxed for
24 h. The solvent was removed in vacuo. A few drops of
methanol were added to the residue to give product 7 as a pre-
cipitate, which was filtered off. Yield: 0.78 g (70%), colorless
prisms (isopropanol), mp 129.0–133.0 ꢀC (decomp.). IR
(KBr): ~n¼3243, 3129, 2968 (m), 2233 (w, CN), 1778 (m),
1727 (s), 1497, 1459 (m), 1415 (s), 1350, 1297, 1237, 1177
5.1.15. 3-(2-Cyanophenyl)-2-thioxo-1,3-diazaspiro[4,5]-
decan-4-one (5b). Method A: from 1-aminocyclohexanoic
acid (460 mg, 3.2 mmol), 2-(isothiocyanato)benzonitrile
(500 mg, 3.2 mmol), TEA (320 mg) in ethanol/water
(50 ml/5 ml), and 16 h reflux. Yield: 0.32 g (35%), colorless
prisms (isopropanol), mp 302–312 ꢀC (decomp.). IR (KBr):
~n¼3293, 3179, 2941, 2859, 2234 (w), 1767, 1513 (s), 1457,
(m) cmꢂ1
.
1H NMR (DMSO-d6, 300 MHz): d¼0.95 (d,
J¼6.8 Hz, 3H, CH3), 1.09 (d, J¼7.0 Hz, 3H, CH3), 2.11–
2.19 (m, 1H, CH), 4.25 (m, 1H, CH), 7.55–7.69 (m, 2H,
Ar), 7.84–7.89 (m, 1H, Ar), 8.00–8.03 (m, 1H, Ar), 8.74
(br s, 1H, NH). 13C NMR (DMSO-d6, 75.5 MHz): d¼15.9
(CH3), 18.4 (CH3), 29.8, 61.9 (CH), 111.4 (CN), 115.8 (C),
129.5, 129.8, 133.4, 134.1 (CH), 134.3 (C), 154.8, 172.1
(C, C¼O). MS (EI, 70 eV): m/z (%)¼243 ([M]+, 9), 202
(11), 201 (100), 145 (32), 144 (17). UV–vis (CH3CN): lmax
(log 3)¼242 (4.62), 249 (4.60), 273 (4.30), 312 (4.11), 324
(4.19). Anal. Calcd for C13H13N3O2 (243.26): C, 64.19; H,
5.39; N, 17.27; found: C, 64.58; H, 5.48; N, 17.14.
1401, 1262 (m), 1225 (s), 1074 (m) cmꢂ1 1H NMR
.
(DMSO-d6, 300 MHz): d¼1.38–1.83 (m, 10H, 5CH2),
7.64–7.72 (m, 2H, Ar), 7.86–8.05 (m, 2H, Ar), 11.21 (br s,
1H, NH). 13C NMR (DMSO-d6, 75.5 MHz): d¼20.4
(2CH2), 24.2 (CH2), 32.0 (CH2), 33.3 (CH2), 64.6 (C-3),
112.5 (CN), 115.6 (C), 130.3, 131.4, 133.3, 134.2 (CH),
135.8, 175.9 (C), 179.7 (C]O). MS (EI, 70 eV): m/z
(%)¼286 (17), 285 ([M]+, 100), 256 (16), 230 (53), 229
(13), 161 (52), 160 (18), 143 (12), 129 (16), 102 (22), 97
(18), 96 (11). Anal. Calcd for C15H15N3OS (285.37): C,
63.13; H, 5.30; N, 14.73; found: C, 62.80; H, 5.72; N, 14.35.
5.1.18. 3-Isopropyl-2,5-dioxo-5,6-dihydroimidazo[1,2-
c]quinazoline (8). Compound 7 (0.500 g, 2.0 mmol) was
dissolved in a mixture of an aqueous solution of sodium hy-
droxide (4%, 100 ml) and isopropanol (5 ml). The mixture
was stirred over night at room temperature, diluted with
water, and acidified with concd hydrochloric acid. The solid
5.1.16. Spirocyclohexan-1,30-2-oxo-2-thioxo-4,5-di-
hydroimidazo[1,2-c]quinazoline (6b). Compound 5b
(100 mg, 0.35 mmol) was dissolved in a mixture of an aque-
ous solution of sodium hydroxide (2%, 50 ml) and of isopro-
panol (5 ml). The solution was stirred for 12 h at room

7660
A. Bodtke et al. / Tetrahedron 62 (2006) 7653–7660
3. (a) Francis, J. E.; Cash, W. D.; Barbaz, W. D.; Bernard, P. S.;
Lovell, R. A.; Mazzenga, G. C.; Friedmann, R. C.; Hyun,
J. L.; Braunwalder, A. F.; Loo, P. S.; Bennett, D. A. J. Med.
Chem. 1991, 34, 281; (b) Francis, J. E.; Cash, W. D.;
Psychoyos, S.; Ghai, G.; Wenk, P.; Friedmann, R. C.; Atkins,
C.; Warren, V.; Furness, P.; Hyun, J. L.; Stone, G. A.; Desai,
M.; Williams, M. J. Med. Chem. 1988, 31, 1014.
4. Blank, J.; Kandt, M.; Pfeiffer, W.-D.; Hetzheim, A.; Langer, P.
Eur. J. Org. Chem. 2003, 182.
5. Langer, P.; Bodtke, A. Tetrahedron Lett. 2003, 5965.
6. Albrecht, U.; Langer, P. Synlett 2004, 1963.
precipitate was collected and dried. Yield: 0.34 g (68%),
colorless prisms (isopropanol), mp 258–265 ꢀC (decomp.).
IR (KBr): ~n¼3211, 3154 (w), 3101, 3085, 3058, 3019,
2966, 2907, 2882 (m), 1745, 1728, 1705, 1628, 1601,
1562, 1519, 1487, 1449 (s), 1353 (m), 1317 (s), 1258 (w),
1189, 1147 (m) cmꢂ1 1H NMR (DMSO-d6, 300 MHz):
.
d¼0.74 (d, J¼6.9 Hz, 3H, CH3), 1.15 (d, J¼7.1 Hz, 3H,
CH3), 2.74–2.80 (m, 1H, CH), 4.39 (d, J¼3.3 Hz, 1H,
3-H), 7.26–7.35 (m, 2H, Ar), 7.76–7.82 (m, 1H, Ar),
8.01–8.04 (m, 1H, Ar), 11.79 (s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼16.0 (CH3), 17.0 (CH3), 27.4
(CH(CH3)2), 64.7 (CH, C-3), 109.1 (C), 115.8, 123.3,
127.7, 136.7 (CH), 141.2, 145.6 (C), 171.9, 187.2 (C]O).
MS (EI, 70 eV): m/z (%)¼243 (M+, 0.4), 228 (12), 201
(75), 188 (14), 145 (15). UV–vis (CH3CN): lmax (log 3)¼
231 (4.70), 252 (3.93), 262 (3.98), 277 (3.99), 290 (3.85),
335 (3.69). Anal. Calcd for C13H13N3O2 (243.26): C,
64.15; H, 5.35; N, 17.28; found: C, 64.29; H, 5.37; N, 17.46.
7. Bodtke, A.; Langer, P. Tetrahedron Lett. 2004, 45, 8741.
8. Pfeiffer, W. D.; Pazdera, P.; Hetzheim, A.; Muecke, J.
Pharmazie 1995, 50, 21.
9. Langer, P.; Bodtke, A. Synlett 2003, 1743.
10. (a) Cianci, C.; Chung, T. D. Y.; Menwell, N.; Putz, H.; Hagen,
M.; Colonno, R. J.; Krystal, M. Antiviral Chem. Chemother.
1996, 7, 353; (b) Gineinah, M. M.; Ismaiel, A. M.; El-
Kerdawy, M. M. J. Heterocycl. Chem. 1990, 27, 723; (c) Liu,
K. C.; Hu, M. K. Arch. Pharm. (Weinheim, Ger.) 1986, 319,
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Knocke, D. DD 253,623, 1988; Chem. Abstr. 1988, 109,
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Acknowledgements
Financial support by the state of Mecklenburg-Vorpommern
(scholarship for A.B.) and by the Deutsche Forschungs-
gemeinschaft is gratefully acknowledged.
2,146,076, 1972;
Chem. Abstr. 1972, 77, 48501; (f)
Kathawala, F.; Hardtmann, G. E. Ger. Offen. 2,261,095, 1971;
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References and notes
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11. Crystallographic data (excluding structure factors) for the
structure in this paper (6a) have been deposited in the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-603359. Copies of these data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.uk/conts/
retrieving.html.
€
2. Pfeiffer, W.-D.; Hetzheim, A.; Pazdera, P.; Bodtke, A.; Mucke,
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