Synthesis of 5-thioxo-6H-imidazo[1,2-c]quinazolines and related compounds based on cyclocondensations of 2-isothiocyanatobenzonitrile (ITCB) with α-aminoketones

Article abstract of DOI:10.1016/j.tet.2007.08.090

Pharmacologically relevant 5-thioxo-6H-imidazo[1,2-c]quinazolines and 5-oxo-6H-imidazo[1,2-c]quinazolines were prepared by sequential reactions of α-aminoketones with 2-isothiocyanatobenzonitrile (ITCB) and 2-isocyanatobenzonitrile (ICB), respectively. Th

Full text of DOI:10.1016/j.tet.2007.08.090

Tetrahedron 63 (2007) 11287–11298
Synthesis of 5-thioxo-6H-imidazo[1,2-c]quinazolines and
related compounds based on cyclocondensations of
2-isothiocyanatobenzonitrile (ITCB) with a-aminoketones
a
Anja Bodtke, Wolf-Diethard Pfeiffer, Helmar Gorls, Horst Dollinger and Peter Langer
a
b
c
d,e,
*
€
aInstitut fu€r Biochemie, Universita€t Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
bInstitut fu€r Anorganische und Analytische Chemie, Universita€t Jena, August-Bebel-Strasse 2, 07740 Jena, Germany
cBoehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach/Riss, Germany
dInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
eLeibniz-Institut fu€r Katalyse e.V. an der Universita€t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Received 8 July 2007; revised 7 August 2007; accepted 28 August 2007
Available online 1 September 2007
Abstract—Pharmacologically relevant 5-thioxo-6H-imidazo[1,2-c]quinazolines and 5-oxo-6H-imidazo[1,2-c]quinazolines were prepared
by sequential reactions of a-aminoketones with 2-isothiocyanatobenzonitrile (ITCB) and 2-isocyanatobenzonitrile (ICB), respectively.
The functionalization of the thioxo moiety allowed the synthesis of 5-amino-6H-imidazo[1,2-c]quinazolines and of 1,2,4-triazolo[4,3-a]-
imidazo[1,2-c]quinazolines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
manganese(III)acetate mediated oxidative dimerization18
of ITCB and radical-type cyclizations.1 The cyclization of
ITCB with amines20 and hydrazine21 was reported to give
4-imino-1,2,3,4-tetrahydroquinazoline-2-thiones. We reported
the synthesis of 4-alkylidene-3,4-dihydroquinazoline-
2(1H)thiones by cyclization of ITCB with arylaceto-
nitriles.22 In addition, convenient syntheses of tricylic
1,2,3,4-tetrahydroquinazoline derivatives based on one-pot
domino cyclizations of ITCB with carboxylic hydrazides23
and a-aminoesters were developed.24
Isocyanates and isothiocyanates represent versatile ‘relais
species’ in one-pot reactions. Carbanionic one-pot cycliza-
tions of isocyanates and isothiocyanates with a nucleophile
and an electrophile generally proceed as follows: the attack
of the nucleophile onto the carbon atom of the cumulene
gives rise to the formation of an ambident allyl-type anion.
Subsequently, the nitrogen or the sulfur atom of the inter-
mediate anion undergoes a nucleophilic attack onto the elec-
trophile. A number of synthetically useful examples of this
process have been reported in recent years.1–9 2-Isothiocya-
natobenzonitrile (ITCB) and isocyanatobenzonitrile (ICB)
represent versatile difunctional building blocks containing
a nitrile and an isothiocyanate or an isocyanate function,
respectively. 2-Isocyanatobenzonitrile can be prepared by
reaction of 2-aminobenzonitrile with phosgene10 or diphos-
gene11 or by reaction of the oxime of isatine with thionyl
chloride.12 2-Isothiocyanatobenzonitrile is available by
reaction of 2-aminobenzonitrile with thiophosgene13 and
also by other methods.14–16 The reaction of ITCB with
butan-1-ol,17 anilines18 and acetamidines19 was reported to
give open-chained products. Zanardi et al. reported the
Recently, we reported the synthesis of 5-thioxo-6H-imid-
azo[1,2-c]quinazolines by one-pot cyclization of ITCB
with a-aminoketones.25 Herein, we report full details of
these studies. With regard to our preliminary communica-
tion,25 we extended the preparative scope and also studied
the functionalization of the products based on reactions of
the thioxo group. For example, tetracyclic 1,2,4-tri-
azolo[4,3-a]-imidazo[1,2-c]quinazolines were prepared
for the first time. The transformations reported herein
provide a convenient access to a variety of 5-thioxo-6H-
imidazo[1,2-c]quinazolines. It is noteworthy that related
1,2,4-triazolo[1,5-c]quinazolines possess interesting bio-
logical activity (antihypertonic, antirheumatic, antiana-
phylactic, antiasthmatic, tranquilizing, neuro-stimulating
and benzodiazepine binding activity).10,11,26–28 Benzimid-
azo[2,1-b]quinazoline-12(5H)-ones are potent immuno-
suppressors.29
Keywords: Cyclizations; N-Heterocycles; Isocyanates; Isothiocyanates;
Sequential reactions.
* Corresponding author. Fax: +49 381 4986412; e-mail: peter.langer@
uni-rostock.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.090

11288
A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
2. Results and discussion
O
Ph
NH
N
HN
Ph
2.1. Mechanism and optimization
N
O
N
S
N
H
S
During the optimization of the cyclization of a-aminoaceto-
phenone hydrochloride (2a) with ITCB (1) the choice of the
base proved to be an important parameter. The use of NEt3 or
piperidine (in CH2Cl2 or EtOH) resulted in the formation of
complex mixtures. In contrast, employment of a two-phase
system (Na2CO3/H2O/CH2Cl2, 10 min, 20 ꢀC) resulted in
the clean formation of the open-chained condensation prod-
uct A (90% yield). However, extension of the reaction time
did not result in cyclization. In contrast, reflux of A for
10 min cleanly afforded quinazoline B (88%). The second
cyclization could again not be realized by extension of the
reaction time. A change of the solvent was mandatory: reflux
of an EtOH solution of B for 8 h resulted in formation of
5-thioxo-6H-imidazo[1,2-c]quinazoline 3a in 85% yield.
Based on the optimization outlined above, we developed
a sequential reaction of 1 with 2a, which afforded 3a in
73% yield. It is noteworthy that the crude quinazoline B
had to be isolated during this process. A one-pot procedure
(with addition of EtOH during the reaction but without
isolation of B) was successfully applied to the synthesis of
product 3d (vide infra, Table 1). However, the yield
decreased (31%) compared to the overall yield of the corre-
sponding two-step procedure (80%).
H
B
A
path A
N
Ph
N
N
S
N
S
N
H
3a (73%)
1
i, ii, iii
+
S
O
NH
H2N
Ph
N
N
2a
Ph
iso-3a
path B
NH
S
S
NH
N
H
N
N
H
N
The formation of 3a can be explained by attack of the amino
group onto the isothiocyanate (intermediate A), attack of the
amino group onto the nitrile (intermediate B) and subse-
quent attack of the imino nitrogen onto the carbonyl group
(Scheme 1). The formation of iso-3a is theoretically possi-
ble. Its formation may proceed by attack of the amino group
onto the isothiocyanate, attack of the sulfur atom onto the ni-
trile (intermediate C), Dimroth rearrangement (intermediate
D) and subsequent attack of the amino group onto the ke-
tone. Products 3a and iso-3a can theoretically undergo
a Dimroth rearrangement to give products Dimroth-3a and
Dimroth-iso-3a (Fig. 1). However, based on extensive struc-
tural investigations (vide infra), we believe that product 3a is
selectively formed in the reaction.
O
O
Ph
Ph
C
D
Scheme 1. Possible mechanistic pathways of the cyclization of ITCB (1)
with phenacyl bromide: (i) Na2CO3, H2O, CH2Cl2, 20 ꢀC, 10 min; (ii)
reflux, 20 min, isolation of crude intermediate B; (iii) i-PrOH, reflux, 10 h.
S
N
NH
Ph
N
N
N
N
H
S
Ph
Dimroth-3a
Dimroth-iso-3a
2.2. Preparative scope
Figure 1. Structures of Dimroth-3a and Dimroth-iso-3a.
The reaction of 1 with a variety of functionalized a-amino-
acetophenones afforded the methyl-, methoxy-, bromo-,
chloro-, fluoro- and nitro-substituted imidazo[1,2-c]quin-
azolines 3b–3g (Scheme 2, Table 1). Quinazoline 3h was
CN
S
R1
S
N
N
R2
Table 1. Products and yields of 3a–k
1
i, ii, iii
N
_
a
%
O
R1
R2
H2O
2
3
N
H2N
H
3a-k
R1
+
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
Ph
H
H
H
H
H
H
H
H
H
H
Ph
73
96
67
80
91
78
34
76
37
53
79
R2
2a-k
4-MeC6H4
4-(MeO)C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-(NO2)C6H4
2-Naphthyl
Me
NH R2
R1
N
O
N
H
S
E
j
k
j
k
t-Bu
Ph
Scheme 2. Synthesis of 6H-imidazo[1,2-c]quinazolines 3a–3k: (i) Na2CO3,
H2O, CH2Cl2, 20 ꢀC, 10 min; (ii) reflux, 10 min, isolation of E and direct
use for the next step; (iii) EtOH, reflux, 8–24 h.
a
Isolated yields.

A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
11289
prepared from 2-(a-aminoacetyl)naphthalene. The cycliza-
tion of 1 with a-aminoacetone and 1-amino-3,3-dimethylbu-
tan-2-one afforded quinazolines 3i and 3j, respectively.
Imidazo[1,2-c]quinazoline 3k was prepared from a-amino-
a-phenylacetophenone. All cyclizations proceeded with
very good chemo- and regioselectivity and afforded the
corresponding products in good to very good yields (except
for 3g and 3i). The low yield of 3g can be explained by
the low nucleophilicity of the nitro-substituted a-amino-
acetophenone 2g. The low yield of 3i can be explained
by the high reactivity of aminoacetone (2i) which readily
undergoes a dimerization under the reaction conditions
employed.
The reaction of a-aminoacetophenone with isocyanato-
benzonitrile (ICB, 4)—the oxygen analogue of 1—was
previously studied by Zinner and Thom.30 The application
of the reaction conditions developed for the cyclization of
aminoketones with ITCB (1) gave unsatisfactory results
for 4, due to hydrolysis of the isocyanate moiety. The best
results were obtained when the reaction was carried out as
follows: a CH2Cl2 solution of a-aminoacetophenone (2a),
4 and NEt3 was stirred for 10 min at 20 ꢀC and subsequently
refluxed for 40 min to give 5a in 90% isolated yield (Scheme
3). Reflux of an i-PrOH solution of 5a, in the presence of
NH4OH, afforded the 5-oxo-6H-imidazo[1,2-c]quinazoline
6a in 74% yield. The protocol was successfully applied to
the cyclization of 4 with other a-aminoketones. These trans-
formations afforded the imidazo[1,2-c]quinazolines 6a–6d
in good yields and with very good chemo- and regioselec-
tivity (Table 2).
Figure 2. ORTEP plot of 3b.
CN
O
R1
CN
O
N
4
O
i, ii
O
N
H
N
H
H2N
R1
+
5a-d
R1
iii
N
N
N
O
H
6a-d
Scheme 3. Synthesis of 6H-imidazo[1,2-c]quinazolines 6a–6d: conditions:
(i) NEt3, CH2Cl2, 20 ꢀC, 10 min; (ii) reflux, 40 min, isolation of A; (iii)
i-PrOH, NH4OH, reflux, 8–32 h.
Figure 3. ORTEP plot of 3i.
NOESY studies support the structure of 5-thioxo-6H-imid-
azo[1,2-c]quinazolines 3 based on interactions between
the NH group and the neighbouring arene proton of the
quinazoline moiety. The structures of 3b and 3i were inde-
pendently confirmed by X-ray crystal structure analyses
(Figs. 2 and 3).31
2.3. Reactions of 6H-imidazo[1,2-c]quinazolines
5-Thioxoquinazolines 3a–3k represent versatile synthetic
building blocks for further functionalizations. The NaOH
or NaOMe mediated reaction of 3a, 3d, 3e and 3k with
methyl iodide, allyl bromide and benzyl bromide resulted
in S-alkylation and formation of imidazo[1,2-c]quinazolines
7a–7k in good yields (Scheme 4, Table 3).
Table 2. Products and yields of 5a–d and 6a–d
5,6
R1
% (5)a
% (6)a
Detailed 2D NMR studies were carried out on 7k and 7f. For
the CH2 and the CH3 groups located next to the sulfur atom
a characteristic highfield shift was observed. The structure of
7k was independently confirmed by X-ray crystal structure
analysis (Fig. 4).31
a
b
c
C6H5
90
88
78
75
74
78
75
61
4-MeC6H4
4-BrC6H4
4-ClC6H4
d
a
Isolated yields.

11290
A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
R1
R1
R1
R1
S
N
N
N
N
i
i
method
N
N
N
N
HNR2
2
N
SR2
N
NR2
N
SMe
2
N
H
3a,d,e,k
7a,g,j
8a-j
7a-k
Scheme 5. Synthesis of 6H-imidazo[1,2-c]quinazolines 8a–8j: conditions:
(i) neat, reflux, 16 h.
Scheme 4. Synthesis of 6H-imidazo[1,2-c]quinazolines 7a–7k: (i): method
A: NaOH, R3X, 60 ꢀC; method B: NaOH, 20 ꢀC, R3X; method C: MeOH,
NaOMe, R3X, 2 h reflux (R3X¼MeI, H2C]CHCH2Br, BnBr).
Table 4. Synthesis of 8a–8j
a
%
R1
R2
Table 3. Synthesis of 7a–7k
8
7
R1
R2
% (Method)a
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
–(CH2)5–
89
85
83
79
95
81
85
93
86
84
–(CH2)2O(CH2)2–
–(CH2)4–
–(CH2)5–
–(CH2)2O(CH2)2–
–(CH2)4–
–(CH2)5–
–(CH2)2O(CH2)2–
–(CH2)4–
–(CH2)2NMe(CH2)2–
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
Ph
Me
Allyl
Bn
(CH2)2C6H5
Bn
Me
Allyl
Bn
Me
Allyl
Bn
75 (A), 79 (B)
76 (B), 80 (C)
71 (C)
82 (C)
75 (C)
74 (A), 77 (C)
76 (B), 81 (C)
72 (C)
77 (C)
84 (B), 88 (C)
76 (C)
4-MeC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
j
a
j
k
Yields of isolated products.
a
Yields of isolated products.
5-Thioxo-6H-imidazo[1,2-c]quinazoline 3d could be trans-
formed, by oxidation of 7g, into 5-oxo-6H-imidazo[1,2-
c]quinazoline 6c (Scheme 6). The spectroscopic data of
compound 6c, prepared from 3d, were identical with those
of the material obtained from 4 (vide supra). This experi-
ment further supports the structure assigned for compounds
3, 6 and 7.
Br
Br
N
N
i
ii
7g
N
N
N
S
N
O
H
H
6c
3d
Scheme 6. Transformation of 3d into 6c: (i) NaOH, MeI; (ii) glacial AcOH,
H2O2.
The reaction of 5-thiomethoxy-6H-imidazo[1,2-c]quinazo-
lines 7g and 7j with hydrazine afforded the 5-hydrazino-
6H-imidazo[1,2-c]quinazolines 9a and 9b in good yields
(Scheme 7, Table 5). Reflux of 9a, 9b with formic or acetic
R1
N
H2N-NH2
N
7g,j
NH2
i
N
9a,b
N
H
R1
O
ii
N
R2
OH
N
Figure 4. ORTEP plot of 7k.
N
N
N
R2
10a-d
Reflux of 5-thiomethoxy-6H-imidazo[1,2-c]quinazolines
7a, 7g and 7j with an excess of various secondary amines
(neat) afforded the 5-amino-6H-imidazo[1,2-c]quinazolines
8a–8j in very good yields (Scheme 5, Table 4).
Scheme 7. Synthesis of 10a–10d: conditions: (i) EtOH, reflux, 16 h; (ii)
neat, reflux, 4 h.

A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
11291
Table 5. Synthesis of 10a–10d
precipitate were suspended in EtOH (200 mL) and the mix-
ture was refluxed for 12 h. The product 3f, which crystallized
upon cooling, was filtered off and dried in vacuo. The filtrate
was concentrated at reduced pressure to give an additional
amount of 3f (combined yield: 1.48 g, 78%).
9,10
R1
R2
% (9)a
% (10)a
a
b
c
4-BrC6H4
4-ClC6H4
4-BrC6H4
4-ClC6H4
H
H
Me
Me
79
95
86
84
79
95
86
84
d
4.2.1. 2-Phenyl-6H-imidazo[1,2-c]quinazoline-5-thione
(3a). From ITCB (1.00 g, 6.4 mmol) and a-aminothioaceto-
phenone hydrochloride (0.95 g, 6.4 mmol), 8 h reflux. Yield:
1.30 g (73%), colourless prisms (2-propanol), mp 300–
304 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3175, 3136, 3111,
3027, 2970, 1630 (m), 1537 (s), 1478, 1420 (m), 1357,
1302, 1190 (s), 1070, 973 (w), 774, 736, 695 (m). 1H
NMR (DMSO-d6, 300 MHz): d¼7.34–7.71 (m, 6H, Ar),
8.08–8.12 (m, 2H, Ar), 8.29–8.32 (m, 1H, Ar), 8.66 (s, 1H,
3-H, Hetar), 13.81 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼112.6 (C-3), 113.6 (C, 10a), 116.4 (Ar-H,
C-10), 123.0 (Ar-H, C-9), 125.5 (Ar-H, C-7), 125.8 (Ar-H,
C-30, C-50), 128.3 (Ar-H, C-40), 128.8 (Ar-H, C-20, C-60),
131.0 (Ar-H, C-8), 132.5 (C, C-10), 134.5 (C, C-2), 139.9
(C, C-6a), 143.9 (C, C]N), 166.9 (C, C]S). MS (EI,
70 eV): m/z (%)¼277 ([M]+, 2), 261 (3), 245 (3), 127 (9),
105 (4). UV–vis (CH3CN): lmax (log 3)¼213 (4.27), 225
(4.21), 259 (4.60), 285 (4.54), 323 (4.12), 340 (4.12), 354
(4.02). Anal. Calcd for C16H11N3S (277.35): C, 69.24; H,
4.00; N, 15.15; found: C, 69.55; H, 3.72; N, 15.12.
a
Yields of isolated products.
acid afforded the 1,2,4-triazolo[4,3-a]-imidazo[1,2-c]quin-
azolines 10a–10d. The synthesis of this heterocyclic core
structure has, to the best of our knowledge, not yet been
reported.
3. Conclusions
5-Thioxo-6H-imidazo[1,2-c]quinazolines and 5-oxo-6H-
imidazo[1,2-c]quinazolines were prepared by sequential
reactions of a-aminoketones with 2-isothiocyanatobenzo-
nitrile (ITCB) and 2-isocyanatobenzonitrile (ICB), respec-
tively. The functionalization of the thioxo moiety allowed
the synthesis of 5-amino-6H-imidazo[1,2-c]quinazolines
and of what are, to the best of our knowledge, the first
1,2,4-triazolo[4,3-a]-imidazo[1,2-c]quinazolines.
4. Experimental section
4.1. General
4.2.2. 2-Tolyl-6H-imidazo[1,2-c]quinazoline-5-thione
(3b). From ITCB (1.00 g, 6.4 mmol) and a-amino-4-methyl-
acetophenone hydrochloride (1.17 g, 6.4 mmol), 12 h reflux.
Yield: 1.79 g (96%), colourless needles (2-propanol), mp
328–330 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3179, 3133,
3118, 3084, 3025, 2972, 1630 (m), 1536 (s), 1499 (w),
1474, 1418 (m), 1356 (s), 1324 (w), 1299 (m), 1186 (s),
All solvents were dried by standard methods and all
reactions were carried out under an inert atmosphere. For
1H and 13C NMR, the deuterated solvents indicated
were used. The 1H NMR (300.13 MHz) and 13C NMR
(75.9 MHz) were recorded with a Bruker spectrometer
1
772, 746 (m). H NMR (DMSO-d6, 300 MHz): d¼2.36 (s,
1
ARX 300. In addition to the routine measurements, the H
3H, CH3), 7.28–7.31 (d, J¼8.0 Hz, 2H, Ar), 7.48–7.71 (m,
3H, Ar), 7.97–8.00 (d, J¼8.0 Hz, 2H, Ar), 8.29–8.31 (m,
1H, Ar), 8.60 (s, 1H, 3-H), 13.85 (br s, 1H, NH). 13C
NMR (DMSO-d6, 75.5 MHz): d¼20.8 (CH3), 111.9 (Ar-H,
C-3), 113.5 (C, 10a), 116.3 (Ar-H, C-10), 122.9 (Ar-H,
C-9), 125.4 (Ar-H, C-7), 125.6 (Ar-H, C-30, C-50), 129.3
(Ar-H, C-20, C-60), 129.6 (C, C-10), 130.8 (Ar-H, C-8),
134.3 (C, C-2), 137.6 (C, C-40), 139.7 (C, C-6a), 143.9 (C,
C]N), 166.7 (C, C]S). MS (EI, 70 eV): m/z (%)¼292
(23), 291 ([M]+, 100), 290 (76), 275 (7), 103 (11). UV–vis
(CH3CN): lmax (log 3)¼219 (5.03), 262 (4.64), 286 (4.62),
325 (4.17), 341 (4.16), 355 (4.05). Anal. Calcd for
C17H13N3S (291.38): C, 70.08; H, 4.50; N, 14.42; found:
C, 69.80; H, 4.82; N, 14.52.
NMR (500.13 MHz) and 13C NMR (125.8 MHz) spectra
of 7f, 7k were recorded on a Bruker spectrometer AVANCE
500 in CDCl3 and DMSO-d6, respectively, as solvents. Cal-
ibration of spectra was carried out on the solvent signals
1
1
(CDCl3: d H¼7.25, d 13C¼77.0; DMSO-d6: d H¼2.50,
d
13C¼39.7). The NMR signals were assigned by DEPT
and two-dimensional 1H,1H COSY, 1H,1H NOESY and
1H,13C correlation spectra (HSQC, HMBC). Mass spectro-
metric data (MS) were obtained by electron ionization
(70 eV), chemical ionization (CI, H2O) or electrospray ion-
ization (ESI). For preparative scale chromatography, silica
gel (60–200 mesh) was used. Melting points are uncorrected.
4.2. Typical procedure for the synthesis of 5-thioxo-5,6-
dihydro-imidazo[1,2-c]quinazolines (3a–3j)
4.2.3. 2-(4-Methoxyphenyl)-6H-imidazo[1,2-c]quin-
azoline-5-thione (3c). From ITCB (0.50 g, 3.2 mmol) and
a-amino-4-methoxyacetophenone hydrochloride (0.64 g,
3.2 mmol) and sodium carbonate (0.91 g), 16 h reflux. Yield:
0.66 g (67%), yellow prisms (2-propanol), mp 274–280 ꢀC
(decomp.). IR (KBr, cmꢂ1): ~n¼3176, 3138, 3108, 3028,
2971 (w), 1628, 1615, 1537 (m), 1496 (s), 1475, 1421,
1355, 1301 (m), 1248, 1189 (s), 1172 (m), 1070 (w), 1030,
To a CH2Cl2 suspension (40 mL) of isothiocyanatobenzo-
nitrile (ITCB, 1.00 g, 6.4 mmol) and 4-(a-aminoacetyl)-1-
fluorobenzene hydrochloride (1.21 g, 6.4 mmol) was added
an aqueous solution (12 mL) of sodium carbonate (1.38 g)
with stirring. The mixture was stirred for 10 min at 20 ꢀC
and for 10 min under reflux. After cooling to room temper-
ature a colourless precipitate formed (intermediate B) which
was filtered off. The organic and the aqueous layers of the
filtrate were separated and the aqueous layer was extracted
with CH2Cl2 (2ꢁ20 mL). The combined organic layers
were concentrated at reduced pressure. The residue and the
1
748 (m). H NMR (DMSO-d6, 300 MHz): d¼3.82 (s, 3H,
CH3), 7.02–7.05 (d, J¼8.8 Hz, 2H, Ar), 7.46–7.66 (m, 3H,
Ar), 7.99–8.03 (d, J¼8.8 Hz, 2H, Ar), 8.27–8.30 (m, 1H,
Ar), 8.53 (s, 1H, 3-H), 13.77 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼55.1 (OCH3), 111.2 (Ar-H,

11292
A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
C-3), 113.4 (C, 10a), 114.1 (Ar-H, C-30, C-50), 116.4 (Ar-H,
C-10), 122.9 (Ar-H, C-9), 125.0 (C, C-10), 125.3 (Ar-H, C-
7), 127.1 (Ar-H, C-20, C-60), 130.7 (Ar-H, C-8), 134.4 (C,
C-2), 139.7 (C, C-6a), 143.8 (C, C]N), 159.3 (C, C-40),
166.5 (C, C]S). MS (EI, 70 eV): m/z (%)¼308 (18), 307
([M]+, 100), 306 (236), 293 (11), 265 (19). UV–vis
(CH3CN): lmax (log 3)¼267 (4.52), 289 (4.57), 300 (4.54),
327 (4.09), 342 (4.06). HRMS calcd for C17H13N3OS
(307.37): [M]+¼307.0779; found: 307.0779.
temperature a colourless precipitate formed. After filtration,
the layers were separated and the aqueous layer was ex-
tracted with dichloromethane (2ꢁ20 mL). The organic
layers were collected and the solvent was removed at re-
duced pressure. The residue and the precipitate were sus-
pended in 2-propanol (200 mL) and the mixture was
refluxed for 12 h. The product crystallized upon cooling.
Concentration of the solution at reduced pressure gave a fur-
ther amount of the product. Yield: 1.48 g (78%), colourless
prisms (2-propanol), mp 327–332 ꢀC (decomp.). IR (KBr,
cmꢂ1): ~n¼3179, 3141, 3113 (m), 3092, 3033, 2975 (m),
1634 (s), 1608 (m), 1566 (w), 1540, 1494, 1477 (s), 1467
(w), 1416, 1359, 1316 (s), 1303, 1295 (m), 1283 (w),
4.2.4. 2-(4-Bromophenyl)-6H-imidazo[1,2-c]quinazoline-
5-thione (3d). From ITCB (1.00 g, 6.4 mmol) and a-amino-
4-bromoacetophenone hydrochloride (1.60 g, 6.4 mmol),
16 h reflux. Yield: 1.82 g (80%), colourless prisms (2-prop-
anol), mp 344–346 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3177,
3143, 3114, 3029, 2975, 1630 (m), 1536, 1477 (s), 1418,
1404 (m), 1354 (s), 1315 (m), 1297 (s), 1266 (w), 1190
1
1230, 1219 (m), 1208 (w), 1193, 1156, 842, 747 (s). H
NMR (DMSO-d6, 300 MHz): d¼7.27–7.71 (m, 5H, Ar),
8.12–8.31 (m, 3H, Ar), 8.67 (s, 1H, 3-H), 13.82 (br s, 1H,
NH). 13C NMR (DMSO-d6, 75.5 MHz): d¼112.6 (Ar-H,
C-3), 113.5 (C, 10a), 115.7 (Ar-H, d, JC,F¼21 Hz, C-30, C-
50), 116.4 (Ar-H, C-10), 123.1 (Ar-H, C-9), 125.5 (Ar-H,
C-7), 127.8 (Ar-H, 2d, JC,F¼8 Hz, C-20, C-60), 129.0 (C, d,
JC,F¼3 Hz, C-10), 131.0 (Ar-H, C-8), 134.5 (C, C-2), 139.9
(C, C-6a), 142.9 (C, C]N), 162.1 (C, d, JC,F¼245 Hz, C-
40), 166.8 (C, C]S). MS (EI, 70 eV): m/z (%)¼296
([M+H]+, 22), 295 (M+, 100), 294 (83), 262 ([MꢂHS]+,
3), 108 (17), 107 (16). UV–vis (CH3CN): lmax (log 3)¼
220 (4.18), 259 (4.60), 283 (4.52), 323 (4.09), 340 (4.09),
354 (3.99). Anal. Calcd for C16H10FN3S (295.34): C,
65.07; H, 3.41; N, 14.23; found: C, 65.19; H, 3.54; N, 14.14.
1
(s), 1070, 974, 833 (w), 748 (m). H NMR (DMSO-d6,
300 MHz): d¼7.49–7.69 (m, 5H, Ar), 8.06–8.31 (m, 3H,
Ar), 8.73 (s, 1H, 3-H), 13.82 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz, Cr(acac)3): d¼113.3 (Ar-H, C-3),
113.6 (C, 10a), 116.5 (Ar-H, C-10), 121.3 (C, C-10), 123.1
(Ar-H, C-9), 125.5 (Ar-H, C-7), 127.8 (Ar-H, C-30, C-50),
131.1 (Ar-H, C-8), 131.8 (Ar-H, C-20, C-40, C, C-60), 134.7
(C, C-2), 140.1 (C, C-6a), 142.7 (C, C]N), 166.8 (C,
C]S). MS (EI, 70 eV): m/z (%)¼358 (25), 357 ([M]+
(81Br), 100), 356 (82), 355 ([M]+ 79Br, 97), 354 (68), 275
(25), 138 (38), 116 (21), 102 (21), 89 (47), 64 (12). UV–
vis (CH3CN): lmax (log 3)¼220 (4.92), 263 (4.61), 287
(4.59), 324 (4.19), 340 (4.15), 354 (4.02). Anal. Calcd for
C16H10BrN3S (356.24): C, 53.95; H, 2.83; N, 11.80; found:
C, 53.88; H, 2.98; N, 11.61.
4.2.7. 2-(4-Nitrophenyl)-6H-imidazo[1,2-c]quinazoline-
5-thione (3g). From ITCB (1.00 g, 6.4 mmol) and a-amino-
4-nitroacetophenone hydrochloride (1.39 g, 6.4 mmol), 24 h
reflux. Yield: 0.70 g (34%), yellow prisms (2-propanol), mp
349–352 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3176, 3141,
3111, 3087, 3025, 2972, 1630, 1601 (m), 1534, 1514 (s),
1476, 1412 (m), 1336 (s), 1306, 1280 (m), 1292 (s), 1109,
4.2.5. 2-(4-Chlorophenyl)-6H-imidazo[1,2-c]quin-
azoline-5-thione (3e). From ITCB (1.00 g, 6.4 mmol) and
a-amino-4-chloroacetophenone hydrochloride (1.32 g,
6.4 mmol), 24 h reflux. Yield: 1.81 g (91%), colourless
prisms (2-propanol), mp 342–345 ꢀC (decomp.). IR (KBr,
cmꢂ1): ~n¼3176, 3144, 3115, 3090, 3029, 2974 (m), 1632,
1537, 1481, 1476 (s), 1422, 1405 (m), 1355, 1315, 1302,
1290 (s), 1267, 1205 (w), 1190 (s), 1089, 1070, 974, 836
1
856, 747 (m). H NMR (DMSO-d6, 300 MHz): d¼7.49–
7.70 (m, 3H, Ar), 8.30–8.41 (m, 5H, Ar), 8.95 (s, 1H,
3-H), 13.89 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz, Cr(acac)3): d¼113.5 (Ar-H, C-3), 113.5 (C, C-
10a), 116.5 (Ar-H, C-10), 123.0 (Ar-H, C-9), 125.4 (Ar-H,
C-7), 127.4 (Ar-H, C-30, C-50), 128.8 (Ar-H, C-20, C-60),
131.0 (Ar-H, C-8), 131.4 (Ar-H, C-40), 132.6 (Ar-H, C-10),
134.6 (C, C-2), 140.0 (C, C-6a), 142.6 (C, C]N), 166.8
(C, C]S). MS (EI, 70 eV): m/z (%)¼323 (20), 322 ([M]+,
100), 321 (41), 276 ([MꢂNO2]+, 20), 275 (20), 116 (17),
89 (26). UV–vis (CH3CN): lmax (log 3)¼223 (4.00), 243
(4.23), 279 (4.12), 334 (4.17). Anal. Calcd for
C16H10N4O2S (322.34): C, 59.62; H, 3.19; N, 17.38; found:
C, 59.25; H, 3.33; N, 17.32.
1
(m), 749 (s), 698 (w). H NMR (DMSO-d6, 300 MHz):
d¼7.48–7.71 (m, 5H, Ar), 8.12–8.31 (m, 3H, Ar), 8.73 (s,
1H, 3-H), 13.83 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz, Cr(acac)3): d¼113.1 (Ar-H, C-3), 113.5 (C,
10a), 116.5 (Ar-H, C-10), 123.0 (Ar-H, C-9), 125.4 (Ar-H,
C-7), 127.4 (Ar-H, C-30, C-50), 128.8 (Ar-H, C-20, C-60),
131.0 (Ar-H, C-8), 131.4 (Ar-H, C-40), 132.6 (Ar-H, C-10),
134.6 (C, C-2), 140.0 (C, C-6a), 142.6 (C, C]N), 166.8
(C, C]S). MS (EI, 70 eV): m/z (%)¼313 ([M]+ (37Cl),
41), 312 (45), 311 ([M]+ (35Cl), 100), 310 (74), 275 (14),
138 (18), 89 (25). UV–vis (CH3CN): lmax (log 3)¼220
(4.88), 262 (4.62), 286 (4.59), 324 (4.18), 340 (4.16), 354
(4.04). Anal. Calcd for C16H10ClN3S (311.79): C, 61.64;
H, 3.23; N, 13.48; found: C, 61.92; H, 3.33; N, 13.51.
4.2.8. 2-(Naphth-2-yl)-6H-imidazo[1,2-c]quinazoline-5-
thione (3h). From ITCB (0.50 g, 3.2 mmol) and 2-(a-ami-
noacetyl)naphthalene hydrochloride (0.71 g, 3.2 mmol),
16 h reflux. Yield: 0.80 g (76%), colourless prisms (2-prop-
anol), mp 328–335 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3177,
3142, 3111, 3056, 3024, 2973, 2939 (w), 1684, 1631, 1529
(m), 1476, 1419, 1418 (w), 1350, 1307 (m), 1285 (w),
1183, 1153, 749 (m). 1H NMR (DMSO-d6, 300 MHz):
d¼7.54–8.37 (m, 10H, Ar), 8.68, 8.81 (2s, 2H, 3-H, Ar),
13.81 (br s, 1H, NH). 13C NMR (DMSO-d6, 75.5 MHz):
d¼113.5 (C, Ar-H), 116.4, 123.0, 123.9, 124.2, 125.4,
126.2, 126.4, 127.6, 128.1, 128.3 (Ar-H), 129.9 (C), 130.9
4.2.6. 2-(4-Fluorophenyl)-6H-imidazo[1,2-c]quinazoline-
5-thione (3f). ITCB (1.00 g, 6.4 mmol) and a-amino-4-
fluoroacetophenone hydrochloride (1.21 g, 6.4 mmol) were
suspended in dichloromethane (40 mL). A solution of
sodium carbonate (1.83 g in 12 mL of water) was added
and the mixture was stirred for 10 min at ambient tempera-
ture and for 10 min at reflux. After cooling to room

A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
11293
(Ar-H), 132.7, 133.1, 134.5, 140.0 (C), 143.7 (C, C]N),
166.7 (C, C]S). MS (EI, 70 eV): m/z (%)¼328 (23), 327
([M]+, 100), 326 (59), 295 (4), 139 (14), 127 (4). UV–vis
(CH3CN): lmax (log 3)¼248 (4.83), 283 (4.20), 331 (3.59).
HRMS (EI, 70 eV): calcd for C20H13N3S (327.41):
[M]+¼327.0830; found: 327.0830.
(33), 91 (30), 32 (22). UV–vis (CH3CN): lmax (log 3)¼259
(4.58), 286 (4.50), 328 (4.14), 346 (4.16), 358 (4.10).
Anal. Calcd for C22H15N3S (353.45): C, 74.76; H, 4.28; N,
11.89; found: C, 74.37; H, 4.57; N, 11.97.
4.3. Typical procedure for the synthesis of 5-oxo-5,6-
dihydroimidazo[1,2-c]quinazolines (6a–6d)
4.2.9. 2-Methyl-6H-imidazo[1,2-c]quinazoline-5-thione
(3i). From ITCB (1.00 g, 6.4 mmol) and aminoacetone hy-
drochloride (0.70 g, 6.4 mmol), 24 h reflux. Yield: 0.51 g
(37%), colourless prisms (2-propanol/water), mp 263–
273 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3171, 3029, 2954,
2930, 2865 (w), 1629, 1577, 1534, 1477, 1445, 1357,
To a CH2Cl2 suspension (40 mL) of isocyanatobenzonitrile
(ICB, 325 mg, 2.4 mmol) and a-amino-4-methylacetophe-
none hydrochloride (520 mg, 2.4 mmol) was added drop-
wise a CH2Cl2 solution (10 mL) of NEt3 (246 mg). The
mixture was stirred for 10 min at 20 ꢀC and for 40 min under
reflux. Upon cooling to ambient temperature a colourless
solid formed, which was filtered off and dried by exposure
to air to give 5b as a colourless solid (630 mg, 88%). An
i-PrOH (100 mL) suspension of 5b (360 mg, 1.2 mmol)
and of ammonium hydroxide (20 mL) was refluxed for
20 h. The solution was cooled to ambient temperature and
concentrated in vacuo to give a colourless precipitate which
was filtered off and dried in vacuo. The solid was recrystal-
lized from i-PrOH to give 6b (255 mg, 78%) as colourless
needles. 13C NMR spectra of compounds 5a–5d could not
be obtained, due to their low solubility.
1
1300, 1169 (m), 762 (w), 747 (m). H NMR (DMSO-d6,
300 MHz): d¼2.36 (d, 4J¼0.9 Hz, 3H, CH3), 7.44–7.65
4
(m, 3H, Ar), 7.97 (d, J¼0.9 Hz, 1H, 3-H), 8.17–8.20 (m,
1H, Ar), 13.65 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼13.8 (CH3), 113.4 (C, 10a), 113.6 (Ar-H,
C-3), 116.3 (Ar-H, C-10), 122.8 (Ar-H, C-9), 125.3 (Ar-H,
C-7), 130.5 (Ar-H, C-8), 134.1 (C, C-2), 138.8 (C, C-6a),
142.0 (C, C]N), 166.5 (C, C]S). MS (EI, 70 eV): m/z
(%)¼216 (16), 215 ([M]+, 100), 214 (40), 182 (17), 161
(10), 102 (10), 54 (11). UV–vis (CH3CN): lmax (log 3)¼
239 (4.48), 278 (4.45), 296 (4.08), 308 (4.03), 336 (4.12),
351 (4.03). Anal. Calcd for C11H9N3S (215.28): C, 61.37;
H, 4.21; N, 19.52; found: C, 61.00; H, 4.53; N, 19.42.
4.3.1. 2-Phenyl-6H-imidazo[1,2-c]quinazoline-5-one
(6a). From ICB (0.72 g, 5.0 mmol), a-aminoacetophenone
hydrochloride (0.85 g, 5.0 mmol) and triethylamine
(0.50 g). Yield (5a): 0.95 g (90%). Data of 5a: IR (KBr,
cmꢂ1): ~n¼3334 (s, NH), 2224 (w, CN), 1692, 1652 (s),
1604 (m), 1576, 1554 (s), 1477, 1448, 1359, 1301, 1223,
4.2.10. 2-tert-Butyl-6H-imidazo[1,2-c]quinazoline-5-thi-
one (3j). From ITCB (1.00 g, 6.4 mmol) and 1-amino-3,3-
dimethylbutan-2-one hydrochloride (1.00 g, 6.4 mmol),
24 h reflux. Yield: 0.87 g (53%), colourless prisms (2-prop-
anol), mp 227–234 ꢀC (decomp.). IR (KBr, cmꢂ1): ~n¼3173,
3028 (w), 2963 (m), 1627 (s), 1563 (w), 1532 (s), 1475 (m),
1457, 1417 (w), 1352 (s), 1308 (m), 1287 (s), 1223, 1192,
1
761 (m), 688, 651 (w). H NMR (DMSO-d6, 300 MHz):
d¼4.72 (d, J¼5.1 Hz, 2H, CH2), 7.10–7.15 (m, 1H, Ar-H),
7.43 (t, J¼5.1 Hz, 1H, NHCH2), 7.56–7.72 (m, 4H, Ar-H),
8.01–8.04 (m, 3H, Ar-H), 8.98 (br s, 1H, NH). Reflux of
5a (0.51 g, 1.8 mmol) in a mixture of 2-propanol (30 mL)
and ammonium hydroxide (7 mL) for 2 h gave 6a (0.35 g,
74%) as colourless prisms (2-propanol), mp 295–296 ꢀC
(decomp.). Data of 6a: IR (KBr, cmꢂ1): ~n¼3211, 3152,
3084, 3059, 3001, 2938 (w), 1714 (s), 1598, 1557 (m),
1
1132, 748 (m). H NMR (DMSO-d6, 300 MHz): d¼1.36
(s, 9H, 3CH3), 7.44–7.65 (m, 3H, Ar), 7.87 (s, 1H, 3-H),
8.20–8.23 (m, 1H, Ar), 13.71 (br s, 1H, NH). 13C NMR
(DMSO-d6, 75.5 MHz): d¼29.5 (CH3), 31.9 (C(CH3)3),
110.5 (Ar-H, C-3), 113.5 (C, 10a), 116.3 (Ar-H, C-10),
122.8 (Ar-H, C-9), 125.3 (Ar-H, C-7), 130.5 (Ar-H, C-8),
134.1 (C, C-2), 138.9 (C, C-6a), 155.4 (C, C]N), 166.8
(C, C]S). MS (EI, 70 eV): m/z (%)¼258 (8), 257 ([M]+,
51), 242 ([MꢂCH3]+, 100), 202 (13). UV–vis (CH3CN):
lmax (log 3)¼239 (4.52), 278 (4.45), 295 (4.09), 308
(4.05), 335 (4.13), 349 (4.04). Anal. Calcd for C14H15N3S
(257.36): C, 65.34; H, 5.87; N, 16.33; found: C, 64.89; H,
6.25; N, 16.29.
1
1480 (w), 1408 (m), 1369 (w), 736 (m), 694 (w). H NMR
(DMSO-d6, 300 MHz): d¼7.31–7.61 (m, 6H, Ar-H), 8.05–
8.23 (m, 3H, Ar-H), 8.41 (s, 1H, 3-H), 12.01 (br s, 1H,
NH). 13C NMR (DMSO-d6, 75.5 MHz): d¼109.7 (Ar-H,
C-3), 112.2 (C, 10a), 116.1 (Ar-H, C-10), 123.1 (Ar-H,
C-9), 123.6 (Ar-H, C-7), 125.6 (Ar-H, C-30, C-50), 127.9
(Ar-H, C-40), 128.8 (Ar-H, C-20, C-60), 130.7 (Ar-H, C-8),
133.0 (C, C-10), 135.4 (C, C-2), 143.2 (C, C-6a), 143.7 (C,
C]N), 145.0 (C, C]O). MS (EI, 70 eV): m/z (%)¼262
(27), 261 ([M]+, 100), 260 (10), 115 (10), 90 (20), 89 (18).
UV–vis (CH3CN): lmax (log 3)¼241 (4.61), 270 (4.20),
280 (4.18), 298 (4.12), 310 (4.12), 323 (4.13). Anal. Calcd
for C16H11N3O (261.28): C, 73.55; H, 4.24; N, 16.08; found:
C, 73.31; H, 4.41; N, 16.14.
4.2.11. 2,3-Diphenyl-6H-imidazo[1,2-c]quinazoline-5-
thione (3k). From ITCB (0.78 g, 5.0 mmol), a-amino-a-
phenylacetophenone hydrochloride (1.24 g, 5.0 mmol) and
sodium carbonate (1.43 g), 20 h reflux. Yield: 1.40 g
(79%), colourless prisms (2-propanol), mp 283–288 ꢀC (de-
comp.). IR (KBr, cmꢂ1): ~n¼3183, 3123, 3028 (m), 2971 (w),
1631 (m), 1532 (s), 1479 (m), 1393, 1370 (w), 1324, 1276
1
(s), 1173, 774 (w), 749, 696 (m). H NMR (DMSO-d6,
4.3.2. 2-Tolyl-6H-imidazo[1,2-c]quinazoline-5-one (6b).
Starting with ICB (0.32 g, 2.4 mmol), a-amino-4-methyl-
acetophenone hydrochloride (0.52 g, 2.4 mmol) and tri-
ethylamine (0.25 g), 5b (0.63 g, 88%) was isolated. Data
of 5b: IR (KBr, cmꢂ1): ~n¼3322 (s, NH), 2226 (w, CN),
1682, 1649, 1607, 1571, 1538 (s), 1476, 1450, 1414, 1358,
300 MHz): d¼7.22–7.68 (m, 13H, Ar), 8.34–8.37 (m, 1H,
Ar), 13.34 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz, Cr(acac)3): d¼114.0 (C, 10a), 116.0 (Ar-H,
C-10), 123.0 (Ar-H, C-9), 124.9 (Ar-H, C-7), 127.3, 127.5,
128.1, 128.3, 130.8, 132.1 (Ar-H), 133.3 (C), 140.4 (C,
C-6a), 141.3 (C, C]N), 168.1 (C, C]S). MS (EI, 70 eV):
m/z (%)¼354 (18), 353 ([M]+, 76), 352 (45), 321 (5), 165
1
1298 (m), 1232 (s), 1184, 994, 815, 759, 639, 563 (m). H
NMR (DMSO-d6, 300 MHz): d¼2.40 (s, 3H, CH3), 4.70

11294
A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
(d, J¼5.1 Hz, 2H, CH2), 7.09–7.14 (m, 1H, Ar-H), 7.36–
7.38 (m, 2H, Ar-H), 7.42 (t, J¼5.1 Hz, 1H, NHCH2),
7.56–7.62 (m, 1H, Ar-H), 7.69–7.72 (m, 1H, Ar-H), 7.90–
7.93 (m, 2H, Ar-H), 8.03–8.06 (m, 1H, Ar-H), 8.98 (br s,
1H, NH). Starting with an i-PrOH (100 mL) suspension of
5b (360 mg, 1.2 mmol) and of ammonium hydroxide
(20 mL) (reflux 20 h), 6b (255 mg, 78%) was isolated as
colourless prisms (2-propanol), mp 301–302 ꢀC (decomp.).
IR (KBr, cmꢂ1): ~n¼3213 (w), 3155, 3077, 3064, 3053,
3015, 2943, 2923, 2894 (m), 1710, 1599, 1556 (s), 1497,
1483 (m), 1416 (s), 1371 (m), 1330 (w), 1296 (m), 1253,
1147, 830 (w), 822 (m), 747 (s), 737 (m). 1H NMR
(DMSO-d6, 300 MHz): d¼2.35 (s, 3H, CH3), 7.25–8.22
(m, 8H, Ar-H), 8.34 (s, 1H, 3-H), 12.00 (br s, 1H, NH).
13C NMR (DMSO-d6, 75.5 MHz): d¼20.8 (CH3), 108.9
(Ar-H, C-3), 112.0 (C, 10a), 115.8 (Ar-H, C-10), 122.8
(Ar-H, C-9), 123.3 (Ar-H, C-7), 125.4 (Ar-H, C-30, C-50),
129.2 (Ar-H, C-20, C-60), 130.1 (C, C-10), 130.4 (Ar-H,
C-8), 135.2 (C, C-2), 137.0 (C, C-40), 143.1 (C, C-6a),
143.3 (C, C]N), 144.8 (C, C]O). MS (EI, 70 eV): m/z
(%)¼276 (19), 275 ([M]+, 100), 247 ([MꢂCO]+, 4), 130
(11). UV–vis (CH3CN): lmax (log 3)¼242 (4.62), 249
(4.60), 273 (4.30), 312 (4.11), 324 (4.19). Anal. Calcd for
C17H13N3O (275.31): C, 74.17; H, 4.76; N, 15.26; found:
C, 74.14; H, 4.78; N, 15.14.
chloroacetophenone hydrochloride (1.03 g, 5.0 mmol) and
triethylamine (0.50 g). Yield (5d): 1.17 g (75%). IR (KBr,
cmꢂ1): ~n¼3330 (m, NH), 2224 (w, CN), 1689, 1649, 1586,
1551 (s), 1480, 1449, 1358, 1299, 1223, 1094, 994, 761
(m). 1H NMR (DMSO-d6, 300 MHz): d¼4.74 (d, J¼
5.1 Hz, 2H, CH2), 7.09–7.15 (m, 1H, Ar-H), 7.44 (t, J¼
5.1 Hz, 1H, NHCH2), 7.53–7.72 (m, 4H, Ar-H), 8.00–8.06
(m, 3H, Ar-H), 8.98 (br s, 1H, NH). Reflux of 5d (0.56 g,
1.8 mmol) in a mixture of 2-propanol (140 mL) and ammo-
nium hydroxide (20 mL) for 32 h afforded 6d. Yield: 0.32 g
(61%), colourless prisms (2-propanol), mp 334–335 ꢀC (de-
comp.). IR (KBr, cmꢂ1): ~n¼3217, 3155, 3080, 3057, 3010,
2942, 2894 (w), 1708 (s), 1598, 1556, 1484, 1478 (m),
1407 (s), 1370 (m), 1295, 1147, 1089 (w), 835 (m), 750
1
(s). H NMR (DMSO-d6, 300 MHz): d¼7.33–7.64 (m, 5H,
Ar-H), 8.07–8.25 (m, 3H, Ar-H), 8.48 (s, 1H, 3-H), 11.79
(br s, 1H, NH). 13C NMR (DMSO-d6, 75.5 MHz):
d¼110.1 (Ar-H, C-3), 111.9 (C, 10a), 115.9 (Ar-H, C-10),
122.9 (Ar-H, C-9), 123.4 (Ar-H, C-7), 127.1 (Ar-H, C-30,
C-50), 128.6 (Ar-H, C-20, C-60), 130.6 (Ar-H, C-8), 131.8
(C, C-10), 132.1 (Ar-H, C-40), 135.3 (C, C-2), 141.8 (C,
C-6a), 143.6 (C, C]N), 144.7 (C, C]O). MS (EI,
70 eV): m/z (%)¼298 ([M]+ (37Cl), 32), 297 (16), 296
([M]+ (35Cl), 100), 89 (16). UV–vis (CH3CN): lmax (log 3)¼
245 (4.59), 274 (4.27), 286 (4.26), 310 (4.16), 323 (4.15).
Anal. Calcd for C16H10ClN3O (295.73): C, 64.98; H, 3.41;
N, 14.21; found: C, 65.00; H, 3.55; N, 14.13.
4.3.3. 2-(4-Bromophenyl)-6H-imidazo[1,2-c]quinazoline-
5-one (6c). Method A. To a hot solution of 7g (60 mg,
0.16 mmol) in glacial acetic acid (10 mL) was added H2O2
(5 mL). The mixture was stirred for 14 h at 20 ꢀC and subse-
quently diluted with water to 50 mL to give a precipitate
which was filtered off. Yield: 50 mg (91%). Method B.
From ICB (0.72 g, 5.0 mmol), a-amino-4-chloroacetophe-
none hydrochloride (1.25 g, 5.0 mmol) and triethylamine
(0.5 g). Yield (5c): 1.40 g (78%). IR (KBr, cmꢂ1): ~n¼3341
(m, NH), 2223 (w, CN), 1690, 1651, 1584, 1546 (s), 1478,
1448, 1399, 1358, 1299, 1220, 1071, 992, 761 (m). 1H
NMR (DMSO-d6, 300 MHz): d¼4.72 (d, J¼5.1 Hz, 2H,
CH2), 7.10–7.15 (m, 1H, Ar-H), 7.43 (t, J¼5.1 Hz, 1H,
NHCH2), 7.56–7.79 (m, 4H, Ar-H), 7.94–8.05 (m, 3H,
Ar-H), 8.98 (br s, 1H, NH). Reflux of 5c (0.79 g,
2.2 mmol) in a mixture of 2-propanol (60 mL) and ammoni-
um hydroxide (10 mL) for 24 h afforded 6c. Yield: 0.56 g
(75%), colourless prisms (2-propanol), mp 334–335 ꢀC (de-
comp.). IR (KBr, cmꢂ1): ~n¼3155, 3081, 3057, 3004, 2942
(w), 1712 (s), 1599, 1554, 1479 (m), 1406 (s), 1368, 829,
748 (m). 1H NMR (DMSO-d6, 300 MHz): d¼7.32–7.67
(m, 5H, Ar-H), 8.00–8.22 (m, 3H, Ar-H), 8.49 (s, 1H,
3-H), 12.02 (br s, 1H, NH). 13C NMR (DMSO-d6,
75.5 MHz): d¼110.2 (Ar-H, C-3), 112.1 (C, 10a), 116.1
(Ar-H, C-10), 120.9 (C-10), 123.0 (Ar-H, C-9), 123.6
(Ar-H, C-7), 127.6 (Ar-H, C-30, C-50), 130.8 (Ar-H, C-8),
131.7 (Ar-H, C-20, C-60), 132.3 (C, C-10), 135.5 (C, C-40),
135.3 (C, C-2), 142.0 (C, C-6a), 143.8 (C, C]N), 144.9
(C, C]O). MS (EI, 70 eV): m/z (%)¼343 (16), 342 ([M]+
(81Br), 94), 341 (19), 340 ([M]+ (79Br), 100), 261 (7), 130
(18), 116 (14), 89 (25). UV–vis (CH3CN): lmax
(log 3)¼245 (4.58), 275 (4.30), 287 (4.30), 323 (4.19), 354
(3.99). Anal. Calcd for C16H10BrN3O (340.18): C, 56.49;
H, 2.96; N, 12.35; found: C, 56.27; H, 3.35; N, 12.23.
4.4. General procedure for the preparation of the
alkylsulfanyl-imidazo[1,2-c]quinazolines (7a–7l)
Method A. Compounds 3a, 3b, 3d, or 3e (10.0 mmol) was
dissolved in an aqueous solution of sodium hydroxide
(0.02 M, 120 mL). The mixture was heated to 60 ꢀC and
methyl iodide (2.5 g, 16 mmol) was added dropwise over
a period of 5 min. The colourless solid, which precipitated
upon cooling, was filtered off and washed with water.
Method B. Compounds 3a, 3d, or 3e (10.0 mmol) was dis-
solved in an aqueous solution of sodium hydroxide
(0.02 M, 120 mL). Allyl bromide (1.44 g, 12.0 mmol) was
added dropwise and the solution was stirred for 45 min at
room temperature. The colourless solid, which precipitated
upon cooling, was filtered off and washed with water.
Method C. A mixture of compound 3a, 3b, 3d, or 3e
(10.0 mmol) and of NaOMe (0.54 g, 10.0 mmol) was dis-
solved in dry methanol (200 mL) and the solution was
refluxed for 1 h. The alkyl halide (12.0 mmol) was added
and the solution was heated at reflux for further 2 h. Upon
cooling, a crystalline precipitate was formed, which was
filtered off and washed with water.
4.4.1. 2-Phenyl-5-methylsulfanyl-imidazo[1,2-c]quinazo-
line (7a). Yield: method A: 2.18 g (75%); method C:
2.30 g (79%), yellow needles (EtOH), mp 182 ꢀC. IR
(KBr, cmꢂ1): ~n¼724 (s), 768 (s), 955 (m), 1197 (s), 1273
(m), 1373 (s), 1474 (s), 1507 (s), 1593 (s). 1H NMR
(300 MHz, CDCl3): d¼2.87 (s, 3H, Me), 7.53–7.91 (m,
9H, Ar-H), 8.56 (s, 1H, Hetar). 13C NMR (75 MHz,
CDCl3): d¼13.7, 106.3, 117.3, 123.0, 126.2, 126.8, 126.9,
128.2, 128.8, 130.0, 133.1, 141.5, 143.4, 145.0, 147.2. MS
(EI, 70 eV): m/z¼291 (M+, 100), 258 (25), 244 (20), 142
4.3.4. 2-(4-Chlorophenyl)-6H-imidazo[1,2-c]quinazolin-
5-one (6d). From ICB (0.72 g, 5.0 mmol), a-amino-4-

A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
11295
3
4
5
(4), 89 (12), 28 (9). Anal. Calcd for C17H13N3S (291.37): C,
70.08; H, 4.50; N, 14.42; found: C, 70.12; H, 4.65; N, 14.51.
7.86 (ddd, 1H, J6,7¼8.2 Hz, J6,8¼1.2 Hz, J6,9¼0.6 Hz,
3
3
4
H-6), 7.75 (ddd, 1H, J6,7¼8.2 Hz, J7,8¼7.1 Hz, J7,9
¼
¼
1.6 Hz, H-7), 7.68 (m, 2H, m-C6H4Br), 7.64 (ddd, 1H, 3J8,9
3
4
4.4.2. 2-Phenyl-5-allylsulfanyl-imidazo[1,2-c]quinazo-
line (7b). Yield: method B: 2.41 g (76%); method C:
2.55 g (80%), yellow needles (EtOH), mp 90 ꢀC. IR (KBr,
cmꢂ1): ~n¼766 (s), 955 (m), 1195 (s), 1372 (s), 1594 (s).
1H NMR (300 MHz, CDCl3): d¼4.14 (d, 2H, CH2), 5.48
(d, 2H, CH2), 6.03–6.09 (m, 1H, CH), 7.32–7.99 (m, 9H,
Ar-H), 8.57 (s, 1H, Hetar). 13C NMR (300 MHz, CDCl3):
d¼33.9, 106.4, 117.4, 119.3, 123.0, 126.2, 126.9, 128.2,
128.8, 130.0, 132.4, 133.1, 141.4, 143.5, 145.1, 146.0. MS
(EI, 70 eV): m/z¼317 (M+, 100), 301 (51), 284 (44), 275
(27), 121 (12), 89 (15), 41 (11), 28 (35). Anal. Calcd for
C19H15N3S (317.10): C, 71.48; H, 4.76; N, 13.29; found:
C, 71.53; H, 4.81; N, 13.35.
8.0 Hz, J7,8¼7.1 Hz, J6,8¼1.2 Hz, H-8), 2.86 (s, 2H,
SCH3). 13C NMR (125.8 MHz, DMSO-d6): d¼148.0
(C-5), 143.2 (C-3a), 142.7 (C-1), 141.0 (C-5a), 132.3
(i-C6H4Br), 131.8 (m-C6H4Br), 130.6 (C-7), 128.1
(o-C6H4Br), 127.3 (C-8), 127.0 (C-6), 122.6 (C-9), 121.4
(p-C6H4Br), 116.8 (C-9a), 108.6 (C-2), 13.6 (SCH3). MS
(70 eV): m/z¼370 (M+, 100), 368 (97), 274 (23), 256 (25),
144 (14), 102 (12), 88 (18), 28 (48). Anal. Calcd for
C17H12N3S1Br (370.28): C, 55.15; H, 3.27; N, 11.35; found:
C, 55.18; H, 3.32; N, 11.38.
4.4.7. 2-(4-Bromophenyl)-5-allylsulfanyl-imidazo[1,2-
c]quinazoline (7g). Yield: method B: 3.02 g (76%); method
C: 3.20 g (81%), yellow prisms (EtOH), mp 145 ꢀC. IR
(KBr, cmꢂ1): ~n¼736 (m), 768 (m), 955 (m), 1194 (m),
4.4.3. 2-Phenyl-5-benzylsulfanyl-imidazo[1,2-c]quinazo-
line (7c). Yield: method A: 65%; method C: 2.60 g (71%),
yellow prisms (EtOH), mp 188 ꢀC. IR (KBr, cmꢂ1):
~n¼766 (s), 956 (m), 1195 (s), 1374 (s), 1453 (s), 1474 (s),
1
1374 (s), 1475 (s), 1508 (s), 1594 (s). H NMR (300 MHz,
CDCl3): d¼4.15 (d, 2H, CH2), 5.23–5.25 (d, 2H, CH2),
6.12–6.15 (m, 1H, CH), 7.51–7.90 (m, 8H, Ar-H), 8.51 (s,
1H, Hetar). 13C NMR (50 MHz, DMSO-d6): d¼
33.1, 108.2, 116.6, 119.2, 121.1, 122.3, 126.7, 127.1, 127.8,
130.3, 131.5, 132.0, 132.6, 140.6, 142.5, 142.9, 146.3. MS
(EI, 70 eV): m/z¼397 (M+, 100), 380 (53), 364 (35), 275
(97), 146 (11), 102 (11), 88 (11), 41 (14), 28 (23). Anal.
Calcd for C19H15N3SBr (397.32): C, 57.88; H, 3.56; N,
10.60; found: C, 57.61; H, 3.62; N, 10.71.
1
1506 (s), 1594 (s). H NMR (300 MHz, CDCl3): d¼4.70
(s, 2H, CH2, Bn), 7.30–7.98 (m, 14H, Ar-H), 8.52 (s, 1H,
Hetar). 13C NMR (75 MHz, CDCl3): d¼35.4, 106.4, 117.4,
123.0, 126.1, 126.8, 128.9 127.8, 128.2, 128.7, 128.7,
129.3, 130.0, 133.0, 136.3, 141.3, 143.5, 145.1, 146.2. MS
(EI, 70 eV): m/z¼367 (M+, 100), 276 (13), 245 (14), 91
(71), 59 (9), 28 (27). Anal. Calcd for C23H17N3S (367.47):
C, 75.18; H, 4.66; N, 11.49; found: C, 75.07; H, 4.72; N,
11.51.
4.4.8. 2-(4-Bromophenyl)-5-benzylsulfanyl-imidazo[1,2-
c]quinazoline (7h). Yield: method C: 3.20 g (72%), colour-
less needles (EtOH), mp 195 ꢀC. IR (KBr, cmꢂ1): ~n¼701 (s),
768 (s), 955 (m), 1194 (s), 1373 (s), 1475 (s), 1508 (s), 1593
(m). 1H NMR (300 MHz, DMSO-d6): d¼4.79 (s, 2H, CH2),
7.28–8.10 (m, 13H, Ar-H), 8.56 (s, 1H, Hetar). 13C NMR
(50 MHz, DMSO-d6): d¼34.4, 108.3, 116.6, 121.2, 122.3,
126.7, 127.2, 127.5, 127.8, 128.4, 129.2, 130.4, 131.6,
132.0, 136.6, 140.7, 142.5, 142.9, 146.5. MS (EI, 70 eV):
m/z¼446 (M+, 64), 412 (22), 322 (7), 275 (37), 91 (100),
66 (10), 28 (44). Anal. Calcd for C23H16BrN3S (445.36):
C, 61.89; H, 3.61; N, 9.41; found: C, 62.02; H, 3.34; N, 9.43.
4.4.4. 2-Phenyl-5-phenylethylsulfanyl-imidazo[1,2-c]quin-
azoline (7d). Yield: method C: 3.12 g (82%), yellow
prisms (EtOH), mp 221 ꢀC. IR (KBr, cmꢂ1): ~n¼759 (s),
9.56 (m), 1055 (m), 1192 (s), 1301 (s), 1475 (s), 1594 (m).
1H NMR (300 MHz, CD3OD): d¼3.22–3.23 (t, 2H, CH2),
3.31–3.32 (t, 2H, CH2), 7.29–7.99 (m 14H, Ar-H), 8.08 (s,
1H, Hetar). 13C NMR (300 MHz, CD3OD): d¼30.7, 36.6,
108.5, 116.4, 118.0, 123.1, 123.8, 125.4, 127.0, 128.2,
128.9, 129.8, 131.2, 134.1, 141.2, 142.1, 143.6, 144.1,
148.4, 166.5. MS (EI, 70 eV): m/z¼381 (M+, 16), 277
(100), 105 (13), 77 (11), 44 (11), 32 (13), 28 (54). Anal.
Calcd for C24H19N3S (381.49): C, 75.56; H, 5.02; N,
11.01; found: C, 75.61; H, 5.21; N, 11.20.
4.4.9. 2-(4-Chlorophenyl)-5-methylsulfanyl-imidazo[1,2-
c]quinazoline (7i). Yield: method A: 2.34 g (72%); method
C: 2.50 g (77%), colourless needles (EtOH), mp 135 ꢀC. IR
(KBr, cmꢂ1): ~n¼737 (s), 765 (s), 955 (m), 1196 (s), 1272
(m), 1374 (s), 1475 (s), 1507 (s), 1593 (s). 1H NMR
(300 MHz, CDCl3): d¼2.87 (s, 3H, Me), 7.41–7.97 (m,
8H, Ar-H), 8.56 (s, 1H, Hetar). 13C NMR (50 MHz,
DMSO-d6): d¼13.3, 108.2, 116.5, 122.3, 126.7, 127.0,
127.5, 128.6, 130.3, 131.7, 132.5, 140.7, 142.4, 142.8, 147.7.
MS (EI, 70 eV): m/z¼325 (M+, 71), 205 (100), 145 (12),
123 (15), 107 (12), 95 (35), 81 (17), 55 (18), 28 (25).
Anal. Calcd for C17H12N3SCl (325.82): C, 62.67; H, 3.71;
N, 12.90; found: C, 62.66; H, 3.70; N, 12.89.
4.4.5. 2-(4-Tolyl-5-benzylsulfanyl)-imidazo[1,2-c]quin-
azoline (7e). Yield: method C: 2.86 g (75%), yellow prisms
(EtOH), mp 121 ꢀC. IR (KBr, cmꢂ1): ~n¼756 (m), 1018 (m),
1248 (m), 1402 (s), 1443 (s), 1474 (s), 1532 (s), 1628 (s),
1
1702 (m). H NMR (300 MHz, DMSO-d6): d¼2.35 (s, 3H,
Me), 4.26 (s, 2H, CH2), 7.21–7.97 (m, 13H, Ar-H), 8.39
(s, 1H, Hetar). MS (EI, 70 eV): m/z¼381 (M+, 14), 288
(100), 259 (44), 130 (30), 103 (29), 77 (17), 28 (4). Anal.
Calcd for C24H19N3S (381.50): C, 75.56; H, 5.02; N,
11.01; found: C, 75.61; H, 5.08; N, 11.08.
4.4.6. 2-(4-Bromophenyl)-5-methylsulfanyl-imidazo[1,2-
c]quinazoline (7f). Yield: method A: 2.74 g (74%); method
C: 2.85 g (77%), colourless prisms (EtOH), mp 187 ꢀC. IR
(KBr, cmꢂ1) ~n¼735 (m), 768 (m), 1197 (m), 1375 (s),
4.4.10. 2-(4-Chlorophenyl)-5-allylsulfanyl-imidazo[1,2-
c]quinazoline (7j). Yield: method B: 2.96 g (84%); method
C: 3.10 g, (88%), colourless needles (EtOH), mp 117 ꢀC. IR
(KBr, cmꢂ1):~n¼736 (s), 768 (s), 634 (m), 955 (m), 1091 (m),
1
1
1475 (s), 1507 (s), 1593 (s). H NMR (500 MHz, DMSO-
1195 (s), 1375 (s), 1476 (s), 1508 (s), 1595 (s). H NMR
3
d6): d¼8.58 (s, 1H, H-2), 8.42 (ddd, 1H, J8,9¼8.0 Hz,
(300 MHz, CDCl3): d¼4.15–4.18 (d, 2H, CH2), 5.23–5.26
5
4J7,9¼1.6 Hz, J6,9¼0.6 Hz, H-9), 8.11 (m, 2H, o-C6H4Br),
(d, 2H, CH2), 6.07–6.13 (m, 1H, CH), 7.40–7.98 (m, 8H,

11296
A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
Ar-H), 8.55 (s, 1H, Hetar). 13C NMR (300 MHz, CDCl3):
d¼34.1, 106.7, 117.5, 119.5, 123.1, 127.1, 127.2, 127.6,
129.1, 130.3, 131.8, 132.5, 134.2, 141.6, 147.6, 144.1,
146.1. MS (EI, 70 eV): m/z¼351/353 (M+, 100/39), 318
(47), 275 (84), 123 (11), 102 (9), 32 (14), 28 (75). Anal.
Calcd for C19H14N3SCl (351.85): C, 64.84; H, 4.01; N,
11.94; found: C, 64.91; H, 4.20; N, 11.81.
1414 (s), 1483 (m), 1522 (s), 1564 (s), 1600 (s), 2873 (m),
2969 (m). 1H NMR (300 MHz, CDCl3): d¼1.98–2.03
(m, 4H, 2ꢁCH2), 3.81–3.85 (t, 4H, 2ꢁCH2), 7.31–7.97
(m, 9H, Ar-H), 8.46 (s, 1H, Hetar). 13C NMR (75 MHz,
CDCl3): d¼25.6, 49.9, 107.4, 115.8, 122.7, 123.7, 125.9,
127.8, 128.6, 130.0, 133.4, 142.8, 143.9, 144.5, 146.6. MS
(EI, 70 eV): m/z¼314 (M+, 90), 285 (86), 259 (38), 245
(70), 244 (56), 142 (26), 115 (28), 102 (24), 91 (15), 90
(30), 77 (17), 71 (14), 28 (100). Anal. Calcd for C20H18N4
(314.38): C, 76.41; H, 5.77; N, 17.82; found: C, 76.45; H,
5.81; N, 17.81.
4.4.11. 2-(4-Chlorophenyl)-5-benzylsulfanyl-imidazo-
[1,2-c]quinazoline (7k). Yield: method C: 3.06 g (76%).
1H NMR (500 MHz, DMSO-d6): d¼13.80 (br s, 1H, NH),
3
8.72 (s, 1H, H-2), 8.28 (dd, 1H, J8,9¼8.0 Hz,
4J7,9¼1.5 Hz, H-9), 8.13 (m, 2H, o-C6H4Cl), 7.67 (ddd,
4.5.4. 2-(4-Bromophenyl)-5-piperidino-imidazo[1,2-
c]quinazoline (8d). Yield: 3.22 g (79%), colourless rods
(EtOH), mp 196 ꢀC. IR (KBr, cmꢂ1): ~n¼766 (m), 834 (m),
1235 (m), 1394 (s), 1523 (s), 1606 (s), 2838 (s), 2933 (m).
1H NMR (300 MHz, CDCl3): d¼1.64–1.90 (m, 6H,
3ꢁCH2), 3.44–3.47 (t, 4H, 2ꢁCH2), 7.45–7.92 (m, 8H,
Ar-H), 8.52 (s, 1H, Hetar). 13C NMR (75 MHz, CDCl3):
d¼24.9, 25.6, 50.1, 107.1, 117.0, 121.9, 122.8, 125.8,
126.7, 127.6, 130.1, 131.8, 132.4, 142.0, 143.4, 146.0,
147.2. MS (EI, 70 eV): m/z¼406/408 (M+ 74/70), 350
(11), 325 (21), 323 (20), 244 (7), 114 (5), 84 (21), 41 (11),
32 (29), 28 (100). Anal. Calcd for C21H19BrN (407.31): C,
61.93; H, 4.70; N, 13.76; found: C, 61.90; H, 4.70; N, 13.75.
3
3
4
1H, J6,7¼8.2 Hz, J7,8¼7.0 Hz, J7,9¼1.2 Hz, H-7), 7.62
3
4
(dd, 1H, J6,7¼8.2 Hz, J6,8¼1.2 Hz, H-6), 7.52 (m, 2H,
3
3
m-C6H4Cl), 7.50 (ddd, 1H, J8,9¼8.0 Hz, J7,8¼7.0 Hz,
4J6,8¼1.2 Hz, H-8). 13C NMR (125.8 MHz, DMSO-d6):
d¼166.9 (C-5), 142.7 (C-1), 140.3 (C-3a), 135.0 (C-5a),
132.8 (p-C6H4Cl), 131.7 (i-C6H4Cl), 131.1 (C-7), 129.0
(m-C6H4Cl), 127.6 (o-C6H4Cl), 125.5 (C-8), 123.1 (C-9),
116.9 (C-6), 113.2 (C-2), 113.8 (C-9a). Anal. Calcd for
C23H16ClN3S (401.92): C, 68.73; H, 4.01; N, 10.45; found:
C, 68.62; H, 4.21; N, 10.43.
4.5. General procedure for the preparation of
5-amino-imidazo[1,2-c]quinazolines (8a–8j)
4.5.5. 2-(4-Bromophenyl)-5-morpholino-imidazo[1,2-
c]quinazoline (8e). Yield: 3.90 g (95%), yellow prisms
(EtOH), mp 235 ꢀC. IR (KBr, cmꢂ1) ~n¼767 (m), 1004
(m), 1114 (s), 1391 (s), 1476 (s), 1525 (s), 1609 (s), 2857
Compound 8a, 8g, or 8j (10.0 mmol) was dissolved at 70 ꢀC
in the respective secondary amine (10–12 mL) and the solu-
tion was refluxed for 16 h. After cooling to room tempera-
ture, the precipitated product was filtered off and washed
with methanol.
1
(m). H NMR (300 MHz, DMSO-d6): d¼3.47–3.48 (t, 8H,
4ꢁCH2), 7.51–8.37 (m, 8H, Ar-H), 8.46 (s, 1H, Hetar).
13C NMR (75 MHz, CDCl3): d¼49.2 (CH2), 66.4 (CH2),
106.6, 117.7, 122.2, 122.9, 126.3, 126.9, 127.7, 130.3,
131.9, 132.2, 141.6, 143.8, 146.0, 146.1. MS (EI, 70 eV):
m/z¼410 (M+, 100), 408 (95), 364 (23), 351 (60), 322
(24), 243 (14), 142 (28), 129 (15), 102 (34), 89 (24), 28
(25). Anal. Calcd for C20H17N4BrO (409.28): C, 58.69; H,
4.19; N, 13.69; found: C 58.21; H, 4.20; N, 13.70.
4.5.1. 2-Phenyl-5-piperidino-imidazo[1,2-c]quinazoline
(8a). Yield: 2.92 g (89%), colourless rods (EtOH), mp
152 ꢀC. IR (KBr, cmꢂ1): ~n¼727 (m), 767 (m), 994 (m),
1235 (m), 1392 (s), 1452 (m), 1524 (s), 1562 (m), 1606 (s),
2838 (m), 2934 (m). 1H NMR (300 MHz, CDCl3): d¼1.75–
1.89 (m, 6H, 3ꢁCH2), 3.44–3.47 (t, 4H, 2ꢁCH2), 7.35–8.02
(m, 9H, Ar-H), 8.55 (s, 1H, Hetar). 13C NMR (75 MHz,
CDCl3): d¼24.4, 25.5, 50.0, 106.9, 117.1, 122.8, 125.5,
126.0, 126.6, 128.0, 128.6, 129.8, 133.4, 141.9, 144.4,
145.7, 147.2. MS (EI, 70 eV): m/z¼328 (M+, 100), 299 (24),
285 (20), 272 (36), 259 (23), 245 (62), 218 (9), 102 (4), 84
(9), 41 (5), 28 (3). Anal. Calcd for C21H20N4 (328.41): C,
76.80; H, 6.14; N, 17.06; found: C, 76.80; H, 6.14; N, 17.10.
4.5.6. 2-(4-Bromophenyl)-5-pyrrolidino-imidazo[1,2-
c]quinazoline (8f). Yield: 3.07 g (81%), yellow needles
(EtOH), mp 201 ꢀC. IR (KBr, cmꢂ1): ~n¼764 (m), 834 (m),
1010 (m), 1277 (m), 1407 (s), 1480 (m), 1522 (s), 1599
(s), 2876 (m), 2908 (m). 1H NMR (300 MHz, CDCl3):
d¼2.06–2.11 (m, 4H, 2ꢁCH2), 3.89–3.94 (t, 4H, 2ꢁCH2),
7.19–7.90 (m, 8H, Ar-H), 8.46 (s, 1H, Hetar). 13C NMR
(75 MHz, CDCl3): d¼25.7 (CH2), 50.1 (CH2), 107.6 (C-3),
115, 121.8, 122.8, 124.0, 125.5, 127.5, 130.2, 131.8, 132.4,
142.8, 142.9, 144.6, 146.8. MS (70 eV): m/z¼392 (M+,
100), 364 (54), 339 (17), 324 (24), 284 (15), 244 (14), 142
(6), 102 (4). Anal. Calcd for C20H17BrN4 (393.28): C,
61.08; H, 4.36; N, 14.25; found: C, 61.10; H, 4.41; N, 14.25.
4.5.2. 2-Phenyl-5-morpholino-imidazo[1,2-c]quinazoline
(8b). Yield: 2.81 g (85%), yellow prisms (EtOH), mp
205 ꢀC. IR (KBr, cmꢂ1): ~n¼769 (s), 1115 (s), 1231 (m), 1393
(s), 1455 (m), 1523 (s), 1611 (s). 1H NMR (300 MHz,
CDCl3): d¼3.49–3.52 (t, 4H, 2ꢁCH2), 3.94–3.97 (t, 4H,
2ꢁCH2), 7.31–8.01 (m, 9H, Ar-H), 8.54 (s, 1H, Hetar). 13
C
NMR (50 MHz, DMSO-d6): d¼49.1, 66.3, 106.4, 117.2,
122.8, 126.06, 126.07, 126.7, 128.1, 128.7, 130.0, 133.1,
141.5, 144.8, 145.7, 146.1. MS (EI, 70 eV): m/z¼330 (M+,
100), 285 (27), 273 (65), 245 (34), 143 (3), 116 (6), 90 (6),
28 (5). Anal. Calcd for C20H18N4O (330.38): C, 72.71; H,
5.49; N, 16.96; found: C, 72.77; H, 5.51; N, 16.91.
4.5.7. 2-(4-Chlorophenyl)-5-piperidino-imidazo[1,2-
c]quinazoline (8g). Yield: 3.08 g (85%), colourless needles
(EtOH), mp 180 ꢀC. IR (KBr, cmꢂ1): ~n¼765 (m), 836 (m),
994 (m), 1094 (m), 1235 (m), 1273 (m), 1393 (m), 1476
1
(m), 1524 (s), 1606 (s), 2838 (m), 2933 (m). H NMR
(300 MHz, CDCl3): d¼1.76–1.87 (m, 6H, 3ꢁCH2), 3.44–
3.48 (t, 4H, 2ꢁCH2), 7.41–7.97 (m, 8H, Ar-H), 8.52 (s,
1H, Hetar). 13C NMR (50 MHz, DMSO-d6): d¼23.8, 24.8,
49.5, 108.6, 116.2, 122.1, 125.3, 126.2, 127.5, 128.4,
4.5.3. 2-Phenyl-5-pyrrolidino-imidazo[2,1-c]quinazoline
(8c). Yield: 2.61 g (83%), colourless rods (EtOH), mp
211 ꢀC. IR (KBr, cmꢂ1): ~n¼718 (s), 765 (m), 1341 (m),

A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
11297
129.9, 132.0, 132.2, 141.3, 142.0, 144.7, 146.8. MS (EI,
70 eV): m/z¼362 (M+, 100), 333 (20), 319 (16), 306 (28),
279 (45), 84 (25), 28 (5). Anal. Calcd for C21H19N4Cl
(362.86): C, 69.51; N, 5.28; N, 15.44; found: C, 69.62; H,
5.35; N, 15.47.
122.8, 124.3, 127.2, 129.2, 131.3, 132.6, 142.0, 143.2,
144.1. MS (EI, 70 eV): m/z¼354 (M+), 339 (82), 258 (25),
129 (33), 102 (18), 32 (23), 28 (100). Anal. Calcd for
C16H12N5Br (354.20): C, 54.25; H, 3.41; N, 19.77; found:
C, 54.31; H, 3.52; N, 19.82.
4.5.8. 2-(4-Chlorophenyl)-5-morpholino-imidazo[1,2-
c]quinazoline (8h). Yield: 3.40 g (93%), yellow needles
(EtOH), mp 217 ꢀC. IR (KBr, cmꢂ1): ~n¼767 (m), 837 (m),
1114 (s), 1230 (m), 1359 (m), 1390 (s), 1478 (s), 1526 (s),
1609 (s), 2858 (m), 3140 (m). 1H NMR (300 MHz,
DMSO-d6): d¼3.26–3.49 (m, 8H, 4ꢁCH2), 7.51–8.37 (m,
8H, Ar-H), 8.47 (s, 1H, Hetar). 13C NMR (50 MHz, DMSO-
d6): d¼48.8, 65.6, 113.4, 125.7 (Ar), 126.3 (Ar), 127.3 (Ar),
128.5 (Ar), 128.6 (Ar), 130.0 (Ar), 131.3 (Ar), 132.0 (Ar),
134.4 (Ar), 141.0, 142.2, 146.2, 166.7. MS (EI, 70 eV):
m/z¼364 (M+, 100), 321 (18), 319 (30), 311 (35), 307
(76), 279 (46), 149 (19), 142 (22), 129 (8), 102 (14), 89
(11), 28 (19). Anal. Calcd for C20H17N4OCl (364.83): C,
65.85; H, 4.70; N, 15.36; found: C, 65.81; H, 4.70; N, 15.40.
4.5.12. 2-(4-Chlorophenyl)-5-hydrazino-imidazo[1,2-
c]quinazoline (9b). Compound 7j (3.25 g, 10.0 mmol)
was refluxed in an ethanol solution (160 mL) of hydrazine
hydrate (30 mL) for 16 h. After cooling, a precipitate formed
which was separated by filtration, washed with water and
dried in vacuo. Yield: 2.50 g (81%), colourless prisms
(EtOH), mp 231 ꢀC. IR (KBr, cmꢂ1): ~n¼763 (m), 835 (m),
1091 (m), 1283 (m), 1386 (m), 1431 (m), 1477 (s), 1526
1
(s), 1565 (m), 1620 (s), 1650 (s), 3061 (m), 3328 (m). H
NMR (300 MHz, CDCl3): d¼7.33–7.97 (m, 8H, Ar-H),
8.49 (s, 1H, 3-H, Hetar). 13C NMR (50 MHz, DMSO-d6):
d¼114.6, 122.8, 124.5, 126.9, 128.79, 128.83, 129.9,
132.1, 132.2, 142.0, 143.2, 144.2. MS (EI, 70 eV):
m/z¼309 (M+, 15), 293 (100), 258 (18), 129 (25), 117
(12), 102 (13), 90 (22), 32 (15), 28 (69). Anal. Calcd for
C16H12N5Cl (309.75): C, 62.04; H, 3.90; N, 22.61; found:
C, 62.15; H, 4.01; N, 22.81.
4.5.9. 2-(4-Chlorophenyl)-5-pyrrolidino-imidazo[1,2-
c]quinazoline (8i). Yield: 2.99 g (86%), yellow rods
(EtOH), mp 221 ꢀC. IR (KBr, cmꢂ1): ~n¼765 (m), 1012
(m), 1091 (m), 1278 (m), 1408 (s), 1481 (s), 1523 (s), 1599
(s), 2877 (m), 2969 (m). 1H NMR (300 MHz, CDCl3):
d¼2.06–2.10 (m, 4H, 2ꢁCH2), 3.91–3.92 (t, 4H, 2ꢁCH2),
7.32 (m, 8H, Ar), 8.46 (s, 1H, Hetar). 13C NMR (75 MHz,
CDCl3): d¼25.7 (CH2), 50.1 (CH2), 107.6 (C-2), 115.8
(Ar), 122.8 (CH, Ar), 124.0 (CH, Ar), 125.5 (CH, Ar),
127.2 (CH, Ar), 128.9 (CH, Ar), 130.2 (CH, Ar), 132.0
(Ar), 133.6 (Ar), 142.8 (C-7a), 142.9 (C-2), 144.6 (C-5),
146.8 (C-10a). MS (EI, 70 eV): m/z¼348 (M+, 100), 319
(69), 293 (22), 279 (49), 149 (20), 142 (26), 123 (15), 113
(15), 101 (15), 89 (35), 71 (52), 41 (25), 28 (14). Anal. Calcd
for C20H17N4Cl (348.83): C, 68.86; H, 4.91; N, 16.06;
found: C, 68.86; H, 4.92; N, 16.05.
4.5.13. 6-(4-Bromophenyl)-1,2,4-triazolo[4,3-a]-imid-
azo[1,2-c]quinazoline (10a). Compound 9a (3.54 g,
10.0 mmol) was refluxed in formic acid (30 mL) for 4 h.
The solution was concentrated under reduced vacuum to
10 mL. On cooling, a colourless solid precipitated, which
was filtered off. The product was washed with water and
recrystallized from EtOH. Yield: 2.98 g (82%), colourless
prisms (EtOH), mp 246 ꢀC. IR (KBr, cmꢂ1): ~n¼747 (s),
1071 (m), 1135 (m), 1229 (s), 1478 (s), 2801 (s), 2916 (s),
1
3113 (s). H NMR (300 MHz, CDCl3): d¼7.55–7.93 (m,
8H, Ar-H), 8.35 (s, 1H, Hetar), 8.99 (s, 1H, 3-H, Hetar).
13C NMR (50 MHz, DMSO-d6): d¼116.5, 120.9, 127.3,
127.3, 127.4, 128.7, 131.6, 131.8, 140.5, 142.5, 142.9,
158.9, 161.5, 166.7, 167.0. MS (EI, 70 eV): m/z¼363/365
(M+ 100/96), 337, 339 (46/46), 257 (38), 129 (12), 102
(12), 28 (4). Anal. Calcd for C17H10N5Br (364.20): C,
56.06; H, 2.77; N, 19.23; found: C, 56.12; H, 2.98; N, 19.25.
4.5.10. 2-(4-Chlorophenyl)-5-(N-methylpiperazino)-
imidazo[1,2-c]quinazoline (8j). Yield: 3.17 g (84%), yel-
low needles (EtOH), mp 284 ꢀC. IR (KBr, cmꢂ1): ~n¼
748 (m), 833 (m), 1092 (m), 1191 (s), 1296 (m), 1355 (s),
1478 (s), 1533 (s), 1630 (m), 3027 (m), 3178 (m). 1H NMR
(300 MHz, DMSO-d6): d¼3.29–3.45 (m, 4H, 2ꢁCH2),
4.37 (s, 1H, CH3), 7.51–8.31 (m, 8H, Ar-H), 8.72 (s, 1H, He-
tar). 13C NMR (75 MHz, DMSO-d6): d¼113.0, 113.4, 116.3,
122.9, 125.3, 127.3, 128.7, 130.9, 131.3, 132.6, 134.5, 139.9,
142.6, 166.8. MS (EI, 70 eV): m/z¼377 (M+, 39), 311 (99),
307 (82), 294 (28), 142 (12), 102 (17), 83 (69), 71 (100), 42
(50), 28 (67). Anal. Calcd for C21H20HN5 (377.87): C,
66.75; H, 5.33; N, 18.53; found: C, 66.71; H, 5.30; N, 18.51.
4.5.14. 6-(4-Chlorophenyl)-1,2,4-triazolo[4,3-a]-imid-
azo[1,2-c]quinazoline (10b). Compound 9b (3.09 g,
10.0 mmol) was refluxed in formic acid (30 mL) for 4 h.
The workup was carried out as described for compound
10a. Yield: 2.78 g (87%), colourless needles (EtOH), mp
295 ꢀC. IR (KBr, cmꢂ1): ~n¼742 (s), 765 (s), 837 (m), 1091
(m), 1476 (s), 1503 (s), 1609 (s). 1H NMR (300 MHz,
CDCl3): d¼7.43–7.96 (m, 8H, Ar-H), 8.34 (s, 1H, Hetar),
8.99 (s, 1H, 3-H, Hetar). MS (EI, 70 eV): m/z¼319 (M+,
100), 257 (24), 129 (6), 101 (3), 28 (24). Anal. Calcd for
C17H10N5Cl (319.75): C, 63.86; H, 3.15; N, 21.90; found:
C, 63.81; H, 3.70; N, 21.91.
4.5.11. 2-(4-Bromophenyl)-5-hydrazino-imidazo[1,2-
c]quinazoline (9a). Compound 7g (1.85 g, 5.0 mmol) was
refluxed in an ethanol solution (80 mL) of hydrazine hydrate
(15 mL) for 16 h. After cooling, a precipitate formed which
was separated by filtration, washed with water and dried in
vacuo. Yield: 1.45 g (82%), yellow rods (EtOH), mp
254 ꢀC. IR (KBr, cmꢂ1): ~n¼759 (s), 830 (m), 1008 (m),
1284 (m), 1427 (s), 1475 (s), 1521 (s), 1653 (s), 3139 (m).
1H NMR (300 MHz, DMSO-d6): d¼7.31–7.91 (m, 8H,
Ar-H), 8.56 (s, 1H, 3-H, Hetar), 10.15 (s, br, 2H, NH2).
13C NMR (50 MHz, DMSO-d6): d¼114.6, 120.7, 122.2,
4.5.15. 1-Methyl-6-(4-bromophenyl)-1,2,4-triazolo-
[4,3-a]-imidazo[1,2-c]quinazoline (10c). Compound 9a
(3.54 g, 10.0 mmol) was refluxed in glacial AcOH (30 mL)
for 4 h. The workup was carried out as described for com-
pound 10a. Yield: 3.21 g (85%), colourless prisms (EtOH),
mp 338 ꢀC. IR (KBr, cmꢂ1): ~n¼743 (m), 834 (m), 1007
(m), 1443 (m), 1476 (s), 1549 (s), 1593 (m), 1615 (s),
1
1638 (s), 3102 (m). H NMR (300 MHz, CDCl3): d¼2.17

11298
A. Bodtke et al. / Tetrahedron 63 (2007) 11287–11298
13. Pazdera, P.; Ondracek, D. Czech. CS 270,981, 1991; Chem.
Abstr. 1992, 117, 69590u.
14. Besson, T.; Guillard, J.; Rees, C. W.; Thiery, V. J. Chem. Soc.,
Perkin Trans. 1 1998, 889.
15. Morgenstern, O.; Schuster, R.; Finke, M.; Richter, P. H.
Pharmazie 1996, 51, 458.
€
16. Pfeiffer, W. D.; Pazdera, P.; Hetzheim, A.; Mucke, J.
Pharmazie 1995, 50, 21.
(s, 1H, Me), 7.59–7.90 (m, 8H, Ar-H), 8.50 (s, 1H, 3-H,
Hetar). 13C NMR (50 MHz, DMSO-d6): d¼21.0, 107.3
114.6, 120.7, 12.2, 122.9, 124.5, 127.2, 130.0, 131.8,
132.6, 142.0, 143.2, 144.2, 144.3, 171.8. MS (EI, 70 eV):
m/z¼377 (M+, 100), 257 (84), 129 (16), 114 (7), 102 (22),
77 (10), 28 (2). Anal. Calcd for C18H12N5Br (378.23): C,
57.16; H, 3.10; N, 18.52; found: C, 57.18; H, 3.23; N, 18.52.
17. (a) Besson, T.; Guillard, J.; Rees, C. W.; Therisod, M. Chem.
Commun. 1997, 881; (b) Besson, T.; Dozias, M.-J.; Guillard,
J.; Jacquault, P.; Legoy, M.-D.; Rees, C. W. Tetrahedron
1998, 54, 6475.
18. Calestani, G.; Capella, L.; Leardini, R.; Minozzi, M.; Nanni,
D.; Papa, R.; Zanardi, G. Tetrahedron 2001, 57, 7221.
19. Ludocici, D. W.; Kukla, M. J.; Grous, P. G.; Krishnan, S.;
Andries, K.; de Bethune, M.-P.; Azijn, H.; Pauwels, R.; De
Clercq, E.; Arnold, E.; Janssen, P. A. J. Bioorg. Med. Chem.
Lett. 2001, 17, 2225.
20. Pazdera, P.; Ondracek, D.; Novacek, E. Chem. Pap. 1989, 43, 771.
€
21. Pfeiffer, W.-D.; Hetzheim, A.; Pazdera, P.; Bodtke, A.; Mucke,
J. J. Heterocycl. Chem. 1999, 36, 1327.
22. Albrecht, U.; Reinke, H.; Langer, P. Synthesis 2006, 3067.
23. Blank, J.; Kandt, M.; Pfeiffer, W.-D.; Hetzheim, A.; Langer, P.
Eur. J. Org. Chem. 2003, 182.
4.5.16. 1-Methyl-6-(4-chlorophenyl)-1,2,4-triazolo-
[4,3-a]-imidazo[1,2-c]quinazoline (10d). Compound 9b
(3.54 g, 10.0 mmol) in glacial AcOH (30 mL) was refluxed
for 4 h. The workup was carried out as described for com-
pound 10a. Yield: 2.86 g (86%), yellow needles (EtOH),
mp 267 ꢀC. IR (KBr, cmꢂ1): ~n¼762 (m), 834 (m), 1013
(m), 1090 (m), 1431 (s), 1475 (s), 1527 (s), 1648 (s), 3263
1
(m). H NMR (300 MHz, CDCl3): d¼2.12 (s, 3H, Me),
7.42–8.08 (m, 8H, Ar-H), 8.31 (s, 1H, 3-H, Hetar). 13C
NMR (50 MHz, DMSO-d6): d¼107.8, 114.5, 122.1, 122.8,
124.4, 126.9, 127.1, 128.6, 128.8, 129.9, 132.2, 142.0,
143.0, 144.1, 144.2. MS (EI, 70 eV): m/z¼334 (M+, 7),
332 (29), 294 (9), 293 (16), 292 (21), 256 (10), 123 (21),
82 (10), 44 (44), 28 (100). Anal. Calcd for C18H12N5Cl
(333.72): C, 64.77; H, 3.62; N, 20.98; found: C, 64.68; H,
3.75; N, 21.01.
24. Bodtke, A.; Reinke, H.; Michalik, D.; Langer, P. Tetrahedron
2006, 62, 7653.
25. Langer, P.; Bodtke, A. Tetrahedron Lett. 2003, 5965.
26. 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.
Acknowledgements
Financial support by the state of Mecklenburg-Vorpommern
(scholarship for A.B.) and by the Deutsche Forschungsge-
meinschaft is gratefully acknowledged.
27. (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,
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31. CCDC-645678 (3b), CCDC-645679 (3i) and CCDC-645680
(7l) contain all crystallographic details of this publication
and are available free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or can be ordered from the following address:
Cambridge Crystallographic Data Centre, 12 Union Road,
GB-Cambridge CB21EZ; fax: (+44)1223 336 033 or deposit@
ccdc.cam.ac.uk).