Synthesis, structure and transformations of 2-iminoimidazolidines into novel fused heterocyclic ring systems

Article abstract of DOI:10.3987/COM-06-10666

Reaction of 2-chloro-4,5-dihydroimidazole (1) with 2-aminobenzylamines (2a-d) afforded 2-[(imidazolidin-2-ylideneamino)methyl]-anilines (3a-d) which upon treatment with carbon disulfide gave 2,3-dihydro-12H-imidazo[2′,1′:4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thiones (4a-d) and 3,4-dihydro-1H-quinazolin-2-thiones (5a-c). Analogous reaction of 1 with 2-aminobenzyl alcohol (6) led to the formation of [2-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]methanol hydrochloride (7) which was transformed into 1-(4H-3,1-benzoxazin-2-yl)imidazolidin-2-thione (8).{A figure is presented}.

Full text of DOI:10.3987/COM-06-10666

HETEROCYCLES, Vol. 68, No. 4, 2006
687
HETEROCYCLES, Vol. 68, No. 4, 2006, pp. 687 - 699. © The Japan Institute of Heterocyclic Chemistry
Received, 4th January, 2006, Accepted, 28th February, 2006, Published online, 3rd March, 2006. COM-06-10666
SYNTHESIS, STRUCTURE AND TRANSFORMATIONS
OF 2-IMINOIMIDAZOLIDINES INTO NOVEL FUSED
HETEROCYCLIC RING SYSTEMS
Anita Kornicka,a)* Franciszek Sączewski,a) and Maria Gdaniecb)
a) Department of Chemical Technology of Drugs, Medical University of Gdańsk,
Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland, e-mail: a.kornicka@amg.gda.pl
b) Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznań, Poland
Abstract
–
Reaction of 2-chloro-4,5-dihydroimidazole (1) with
2-aminobenzylamines (2a-d) afforded 2-[(imidazolidin-2-ylideneamino)methyl]-
anilines (3a-d) which upon treatment with carbon disulfide gave 2,3-dihydro-
12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thiones (4a-d) and
3,4-dihydro-1H-quinazolin-2-thiones (5a-c). Analogous reaction of 1 with
2-aminobenzyl alcohol (6) led to the formation of [2-(4,5-dihydro-
1H-imidazol-2-ylamino)phenyl]methanol hydrochloride (7) which was
transformed into 1-(4H-3,1-benzoxazin-2-yl)imidazolidin-2-thione (8).
INTRODUCTION
Various fused heterocyclic ring systems containing 2-imidazoline moiety have been shown in Figure 1,
which act as I2 receptors ligands (structure A1), appetite depressants and cocaine abuse therapeutics
(structure B2), blockers of KATP-dependant channels (structure C3) as well as potential anticancer agents
(structure D4).
R
HO
H
N
N
Me
Me
N
N
N
N
N
N
N
N
N
H
N
H
O
A
B
C
D
Figure 1
In our recent review article5 we have shown that 2-chloro-4,5-dihydroimidazole (1) is a versatile substrate

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HETEROCYCLES, Vol. 68, No. 4, 2006
for the synthesis of novel fused heterocyclic ring systems incorporating 2-imidazoline moiety. Now, as a
part of our ongoing research program6 we have explored the reactions of 1 with anilines bearing
aminomethyl or hydroxymethyl group at position 2.
RESULTS AND DISCUSSION
Preparation of 2-(2-aminophenylimino)imidazolidines can be achieved by N-heteroalkylation reaction of
o-phenylenediamines with 2-chloro-4,5-dihydroimidazole (1).7 We found, however, that when
2-aminobenzylamines (2a-d) were treated with compound (1) in dichloromethane at ambient temperature,
the N-heteroalkylation reaction of aliphatic amine group took place leading to 2-[(imidazolidin-
2-ylideneamino)methyl]anilines (3a-d) as shown in Scheme 1. The preferential susceptibility of the
aliphatic amine group to the electrophilic attack of 1 was confirmed by X-Ray diffraction analysis of 3a
(Figure 2).
Compounds (3a-d) were further subjected to the reaction with carbon disulfide as depicted in Scheme 1.
Thus, the treatment of 3a-c with an excess of carbon disulfide in anhydrous acetone at ambient
temperature, in the presence of triethylamine gave rise to the formation of a mixture of
2,3-dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thiones (4a-c) and 3,4-dihydro-
1H-quinazolin-2-thiones (5a-c) which could be separated owing to a considerable difference in their
solubility in hot methanol. However, when compound (3d) was used as a substrate, the reaction carried
out in DMF solution gave the product (4d) as the sole product which could be isolated from the reaction
mixture (Scheme 1). Although the expected 4-methyl-3,4-dihydro-1H-quinazolin-2-thione8 was not
separated but traces of this compound were detected by means of NMR spectrum of crude product.
The mechanism of the reaction pathway was not investigated but it can be explained as follows. First,
initially formed dithiocarbamic acid (E) resulting from the addition of the 2-iminoimidazolidine (3) to
carbon disulfide undergoes a cyclocondensation with evolution of H2S giving rise to the formation of
dihydroquinazoline derivative (F), which in turn, reacts with a second molecule of carbon disulfide to
afford the corresponding imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thione (4). Alternatively,
in the presence of Et3N, the adduct (E) may form triethylammonium dithiocarbamate (G), which
undergoes intramolecular ring closure to give the intermediate (H), which then decomposes with
simultaneous loss of imidazolidine-2-thione leading to isothiocyanate (I). An intramolecular nucleophilic
attack of the nitrogen atom of the amine group at the isothiocyanate group in I gives the final product (5).
Although imidazolidine-2-thione was not separated from the reaction mixture, this side product was
identified by NMR evidence in ca 5% yield.
It should be mentioned that compounds (5a-c) were previously obtained by Spindler and Kempter,8 and
Liu9 by the reaction of 2 with carbon disulfide. On the other hand, the imidazo[2',1':4,5][1,3,5]thiadiazino-

HETEROCYCLES, Vol. 68, No. 4, 2006
689
[2,3-b]quinazolin-5-thione ring system like as the compound (4) has not been described previously in
chemical literature.
N
NH
H
N
R2
H
R2
H
N
Cl
1 / CH2Cl2 / 20 oC
R1
R1
1.
2. 10% NaOH/H2O
N
H
NH2
NH2
NH2
2a - d
3a - d
acetone or DMF / 20 oC
CS2
H
N
HN
H
N
H
_
R2
R2
R1
R1
N
N
H
N
Et3N
H
S
SH
S
N C
H
N C
H
Et3NH
S
E
G
- H2S
H
H
H
N
R2
N
R2
H
N
R1
R1
N
N
H
N
S
H
N
SH
N
Et3NH
S
F
H
CS2
-
- Et3N, HN
NH
- H2S
S
N
R2
H
N
R2
H
R1
R1
N
NH
_
2
N
S
S
N
C
4a - d
S
I
Compd.
R1
R2
R2
H
2a, 3a, 4a, 5a
2b, 3b, 4b, 5b
H
Ph
Ph
R1
NH
Cl
2c, 3c, 4c, 5c
2d, 3d, 4d
H
H
H
N
H
S
Me
5a - c
Scheme 1

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HETEROCYCLES, Vol. 68, No. 4, 2006
The structures of newly prepared compounds were confirmed by elemental analysis, IR and NMR
spectroscopic data, MS spectrometry as well as X-Ray structure analysis of 4b (Figure 3).
Figure 2. ORTEP drawing of 3a with atom labelling. Displacement ellipsoids were drawn at 40%
probability level.
Figure 3. ORTEP drawing of 4b with atom labeling. Displacement ellipsoids were drawn at 50%
probability level.
As depicted in Scheme 2, the reaction of 2-chloro-4,5-dihydroimidazole (1) with 2-aminobenzyl alcohol
(6) took a different course and [2-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]methanol hydrochloride
(7) was obtained in 50% yield as a result of N-heteroalkylation of the aromatic amino group. Then, upon
treatment of 7 with an excess carbon disulfide in the presence of 2 fold excess of triethylamine in
anhydrous acetone at ambient temperature 1-(4H-3,1-benzoxazin-2-yl)imidazolidin-2-thione (8) was
obtained in 55% yield based on 7.
A possible mechanism for this reaction is outlined in Scheme 2. We assume, that the reaction mechanism
involves the initial formation of the dithiocarbamate (J), which undergoes an intramolecular nucleophilic
addition reaction giving rise to the unstable thiazetidine (K). The later intermediate undergoes further

HETEROCYCLES, Vol. 68, No. 4, 2006
691
rearrangement upon nucleophilic attack of the hydroxyl group at the carbon atom of the thiazetidine ring
to give thiocarbamate derivative (L). This process is completed by an intramolecular cyclocondensation
with evolution of H2S leading to the formation of the final 3,1-benzoxazine (8). Structures of the
compounds (7 and 8) were confirmed by elemental analyses as well as IR and NMR spectroscopic data.
N
NH
Cl
CS2 / Et3N /
acetone
CH2OH
NH2
CH2OH
CH2OH
1
H
N
CH2Cl2 / 20 oC
- Et3N
S Et3NH
N
S
- Et3NH Cl
6
Cl
NH
HN
N
HN
7
J
_
O_
H
O
N
NH
S
O
S
_
NH2
S
S
N
NH
- H2S
N
N
N
H
S
HN
K
L
8
Scheme 2
It is well known that compounds containing 3,1-benzoxazine moiety may act as inhibitors of human
chymase, human leukocyte elastase (HLE), human cathepsin G,10 tissue factor/factor VIIa-induced
coagulation,11 HIV-1 reverse transcriptase12 as well as antimycobacterial agents,13 neuropeptide Y5
antagonists for the treatment of obesity14 or progesterone receptors modulators.15
It should also be pointed out that the product obtained 8 represents a new type of 3,1-benzoxazine
derivatives functionalized with 2-imidazolidinethione moiety at position 2. Therefore, to examine
synthetic potential of 8, we performed some representative reactions as shown in Scheme 3. As expected,
treatment of 8 with acetyl chloride afforded corresponding amide (9) in 40 % yield. On the other hand,
the reaction of 8 with benzyl bromide in the presence of NaOH led to the formation of the S-benzyl
derivative (10) in 53% yield, structure of which was confirmed by single crystal X-Ray analysis (Figure
4). We have further found that the reaction of 8 with 2 fold excess of hydrazine hydrate or
methylhydrazine, carried out in anhydrous methanol at ambient temperature gave the hydrazine derivative
(11) in 40% and 23% yield, respectively (Scheme 3). Apparently, the nucleophilic displacement of the
imidazolidin-2-thione (12) in 8 gives mono-substituted hydrazine (M), which subsequently undergoes a
condensation reaction to give bi-substituted hydrazine (11) with simultaneous elimination of hydrazine.

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HETEROCYCLES, Vol. 68, No. 4, 2006
In this context it should be pointed out that an analogous transformation of 2-pyridylcarboxamidrazone
into 1,2-bis-(2-pyridylformidoyl)hydrazine in ethanol solution was described previously.16 Structures of
the compounds (9-11) were confirmed by elemental analyses, IR and NMR spectroscopic data as well as
MS spectrometry (see Experimental).
O
O
CH3COCl
CH3
N
N
N
NH
N
N
pyridine / 0 oC - 20 oC
O
S
S
8
9
NH2NHR / MeOH /
48 h / 20 oC
PhCH2Br / NaOH / DMSO
-
HN
NH
35 - 40 oC / 1 h
S
R = H or CH3
12
O
O
N
N
NHNHR
N
N
S
10
M
- NH2NH2
or
- CH3NHNHCH3
O
O
N
N
N
N
H
H
11
Scheme 3
Figure 4. ORTEP drawing of 10 with atom labelling. Displacement ellipsoids were drawn at 50%
probability level.

HETEROCYCLES, Vol. 68, No. 4, 2006
693
Samples of the compounds (4b-d and 8-9, 11) were submitted to the US National Cancer Institute (Bethesda)
for screening against human tumour cell lines. The results of biological tests will be published elsewhere.
EXPERIMENTAL
Melting points were determined on a Büchi SMP 20 apparatus and are uncorrected. IR spectra (KBr
pellets) were measured on a Perkin Elmer 1600 FTIR spectrophotometer. NMR spectra were recorded on
a Varian Gemini 200 or Varian Unity 500 spectrometer at 200 MHz* or 500 MHz for proton and 50
MHz* or 125 MHz for carbon nuclei. Chemical shifts (δ) are expressed in ppm relative to internal
tetramethylsilane. MS were recorded on a Finningan MAT 95 spectrometer at 70 eV. The starting 2-
chloro-4,5-dihydroimidazole (1) and 2-aminobenzylamines (2a-b, d) were prepared according to
procedures described previously.17-19
Preparation of 4-R1-2-[(imidazolidin-2-ylideneamino)phenylmethyl]anilines (3a-b). To a solution of
1 (2.5 g, 24 mmol) in CH2Cl2 (30 mL) the appropriate 2-aminobenzhydrylamine (2a-b) (16 mmol) was
added and the reaction mixture was stirred at rt for 12 h. The solid that precipitated was collected by
filtration, washed with CH2Cl2 (15 mL), dried and suspended in water (1:10). The resulting suspension
was made alkaline with 10% aqueous NaOH solution (pH 10). The crude product that precipitated was
filtered off, washed with water, dried and recrystallized from suitable solvent.
The following compounds were obtained according to the above procedure.
2-[(Imidazolidin-2-ylideneamino)phenylmethyl]aniline (3a): mp 189-190 °C (acetonitrile); yield 44%. IR
(KBr): 3390, 3255, 3150, 3030, 2945, 2840, 1660, 1620, 1490, 1450, 1260 (cm-1). 1H NMR (DMSO-d6) δ
3.28 (br s, 4H, 2xCH2), 5.26 (s, 2H, NH2), 5.85 (br s, 1H, NH), 6.42-6.44 (m, 1H, ArH), 6.57-6.58 (m, 2H,
ArH), 6.74 (br s, 1H, NH), 6.87-6.9 (m, 1H, ArH), 7.14-7.21 (m, 1H, ArH), 7.27-7.3 (m, 6H, 5H Ph,
13
CH-Ph). C NMR (DMSO-d6) δ 46.27 (C-4, C-5 imidaz.), 57.07 (CH), 115.5, 115.98, 126.45, 127.33,
127.43, 128.10, 128.29, 128.46, 143.93, 146.71 (12 C aromat.), 160.99 (C=N)*. Anal. Calcd for
C16H18N4: C, 72.15; H, 6.81; N, 21.04. Found: C, 72.01; H, 6.53; N, 21.27.
4-Chloro-2-[(imidazolidin-2-ylideneamino)phenylmethyl]aniline (3b): mp 193-194 °C (acetone); yield
1
40%. IR (KBr): 3410, 3275, 3030, 2945, 2840, 1665, 1620, 1485, 1260 (cm-1). H NMR (DMSO-d6) δ
3.28 (br s, 4H, 2xCH2), 5.42 (s, 2H, NH2), 5.74 (br s, 2H, 2xNH), 6.43-6.62 (m, 1H, ArH), 6.79-6.92 (m,
2H, ArH), 7.19-7.29 (m, 6H, 5H Ph, CH-Ph). Anal. Calcd for C16H17N4Cl: C, 63.89; H, 5.70; N, 18.63.
Found: C, 64.02; H, 5.52; N, 18.32.
Preparation of 2-[(imidazolidin-2-ylideneamino)alkyl]anilines (3c-d). To a solution of 1 (2.5 g, 24
mmol) in CH2Cl2 (30 mL) the appropriate 2-aminobenzylamine (2c-d) (16 mmol) was added and the
reaction suspension was stirred at rt for 12 h. Then the suspension was extracted with water (45 mL) and

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HETEROCYCLES, Vol. 68, No. 4, 2006
the aqueous layer was made alkaline with 10% aqueous NaOH solution (pH 10) and extracted with
CH2Cl2 (50 mL). The organic layer was dried over MgSO4, evaporated under vacuum and the viscous
residue was treated with acetone (25 mL). The precipitate thus obtained was collected by filtration,
washed with acetone, dried and purified by crystallization from acetonitrile.
The following compounds were obtained according to the above procedure.
2-[(Imidazolidin-2-ylideneamino)methyl]aniline (3c): mp 206-208 °C; yield 32%. IR (KBr): 3425, 3000,
3250-2750 (ν max 3130, 3055, 2930, 2824), 1675, 1625, 1495, 1300 (cm-1). 1H NMR (DMSO-d6) δ 3.57
(s, 4H, 2xCH2), 4.24 (s, 2H, CH2), 5.12 (s, 2H, NH2), 6.51-6.54 (m, 1H, ArH), 6.65-6.67 (m, 1H, ArH),
6.98-7.05 (m, 2H, ArH), 8.57 (br s, 2H, 2xNH). 13C NMR (DMSO-d6) δ 43.18, (C-4, C-5 imidaz.), 43.26
(CH2), 115.82, 116.69, 120.46, 129.18, 129.26, 147.01 (6 C aromat.), 160.21 (C=N). Anal. Calcd for
C10H14N4: C, 63.13; H, 7.42; N, 29.45. Found: C, 63.42; H, 7.15; N, 29.11.
2-[1-(Imidazolidin-2-ylideneamino)ethyl]aniline (3d): mp 199-200 °C; yield 29%. IR (KBr): 3350, 3320,
1
3175, 3065, 3035, 2970, 1660, 1600, 1495, 1445, 1285 (cm-1). H NMR (DMSO-d6) δ 1.36 (d, J = 6.35
Hz, 3H, CH3), 3.55 (s, 4H, 2xCH2), 4.25-4.89 (m, 1H, CH-CH3), 5.0 (br s, 2H, NH2), 6.58-6.61 (m, 1H,
ArH), 6.65-6.68 (m, 1H, ArH), 6.97-6.99 (m, 1H, ArH), 7.31-7.5 (m, 1H, ArH), 8.76 (br s, 2H, 2xNH).
Anal. Calcd for C11H16N4: C, 64.68; H, 7.89; N, 27.43. Found: C, 64.43; H, 8.12; N, 27.27.
Preparation of 10-R1-12-R2-2,3-dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-
5-thiones (4a-c) and 6-R1-4-R2-3,4-dihydro-1H-quinazolin-2-thiones (5a-c). To a mixture of the
appropriate 2-[(imidazolidin-2-ylideneamino)methyl]aniline (3a-c) (2.2 mmol) in anhydrous acetone (10
mL) and carbon disulfide (1.45 g, 1.15 mL, 19 mmol) was added dropwise Et3N (0.22 g, 0.3 mL, 2.2
mmol). The resulting suspension was stirred at rt for 48-72 h (until H2S had ceased). Then the solvent and
excess of carbon disulfide were evaporated under reduce pressure, and the residue was triturated with
water (20 mL). The precipitate thus obtained was filtered off, washed with water, dried and treated with
hot methanol (1:25). The insoluble solid was separated by suction (the filtrate denoted as "T" was stored
for further workup), washed with hot methanol (3x3 mL) and dried.
The following compounds were obtained according to the above procedure.
12-Phenyl-2,3-dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thione (4a): mp
259-262 °C; yield 30%. IR (KBr): 3070, 3030, 3015, 2925, 1645, 1605, 1585, 1560, 1420, 1370 (cm-1).
1H NMR (DMSO-d6) δ 3.75-3.8 (m, 2H, CH2), 4.15-4.2 (m, 1H, CH2), 4.27-4.33 (m, 1H, CH2), 6.7 (s, 1H,
CH-Ph), 7.15-7.16 (m, 2H, ArH), 7.24-7.29 (m, 3H, ArH), 7.31-7.36 (m, 5H, Ph). Anal. Calcd for
C18H14N4S2: C, 61.69; H, 4.02; N, 15.98. Found: C, 61.73; H, 3.92; N, 15.74.
10-Chloro-12-phenyl-2,3-dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thione
(4b): mp 231-234 °C; yield 25%. IR (KBr): 3065, 3030, 2945, 2880, 1645, 1605, 1580, 1560, 1420, 1385
1
(cm-1). H NMR (DMSO-d6) δ 3.77-3.83 (m, 2H, CH2), 4.14-4.2 (m, 1H, CH2), 4.27-4.32 (m, 1H, CH2),

HETEROCYCLES, Vol. 68, No. 4, 2006
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6.73 (s, 1H, CH-Ph), 7.17 (d, J = 8.79 Hz, 1H, ArH), 7.26-7.31 (m, 2H, ArH), 7.33-7.38 (m, 4H, ArH),
7.44-7.47 (m, 1H, ArH). 13C NMR (DMSO-d6) δ 49.8, 53.55 (C-4, C-5 imidaz.), 59.43 (CH), 126.8 (two
overlapping signals), 127.03, 127.31, 127.92, 129.09, 129.54, 129.76, 131.35 (two overlapping signals),
137.28, 142.35 (12 C aromat.), 145.56 (C=N), 147.11 (C=N), 180.64 (C=S). MS (70 eV) m/z: 383.9 (M+).
Anal. Calcd for C18H13N4ClS2: C, 56.17; H, 3.40; N, 14.41. Found: C, 56.21; H, 3.27; N, 14.11
2,3-Dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thione (4c): mp 202-204 °C;
yield 30%. IR (KBr): 3030, 2960, 2925, 2870, 1650, 1610, 1575, 1435, 1390 (cm-1). 1H NMR (DMSO-d6)
δ 3.75-3.95 (m, 2H, CH2), 4.20-4.38 (m, 2H, CH2), 5.01 (s, 2H, CH2), 6.93-7.09 (m, 1H, ArH), 7.1-7.28
(m, 3H, ArH). Anal. Calcd for C12H10N4S2: C, 52.53; H, 3.67; N, 20.42. Found: C, 52.67; H, 3.34; N,
20.13.
The filtrate denoted as "T" was cooled to 0 °C and the precipitate thus obtained was separated by suction,
washed with methanol (2 mL), dried and purified by crystallization from suitable solvent.
The following compounds were obtained according above procedure.
4-Phenyl-3,4-dihydro-1H-quinazolin-2-thione (5a): mp 228-230 °C (ethanol) (ref.,8 mp 230 °C); yield
1
30%. IR (KBr): 3225, 3065, 3025, 1565, 1490 (cm-1). H NMR (DMSO-d6) δ 5.64 (d, J = 2.65 Hz, 1H,
CH-Ph), 6.95-7.06 (m, 2H, ArH), 7.18-7.25 (m, 2H, ArH), 7.28-7.42 (m, 5H, Ph), 9.25 (s, 1H, NH), 10.71
(s, 1H, NH)*. Anal. Calcd for C14H12N2S2: C, 69.97; H, 5.03; N, 11.65. Found: C, 69.64; H, 5.32; N,
11.42.
6-Chloro-4-phenyl-3,4-dihydro-1H-quinazolin-2-thione (5b): mp 221-224 °C (propan-1-ol), (ref.,8 mp
1
223-226 °C); yield 43%. IR (KBr): 3210, 3110, 2980, 1570, 1510, 1485 (cm-1). H NMR (DMSO-d6) δ
5.62 (d, J = 2.44 Hz, 1H, CH-Ph), 7.01 (d, J = 8.30 Hz, 1H, ArH), 7.24-7.28 (m, 5H, Ph), 7.35-7.38 (m,
2H, ArH), 9.31 (s, 1H, NH), 10.79 (s, 1H, NH). Anal. Calcd for C14H11N2ClS: C, 61.20; H, 4.03; N, 11.30.
Found: C, 61.47; H, 4.32; N, 11.23.
3,4-Dihydro-1H-quinazolin-2-thione (5c): mp 212-214 °C (ethanol) (ref.,9 mp 211-212 °C); yield 37%. IR
(KBr): 3195, 3135, 2990, 1590, 1225 (cm-1). 1H NMR (DMSO-d6) δ 4.33 (s, 2H, CH2), 6.9-6.95 (m, 2H,
ArH), 7.06-7.07 (m, 1H, ArH), 7.12-7.15 (m, 1H, ArH), 8.58 (s, 1H, NH), 10.35 (s, 1H, NH). Anal. Calcd
for C8H8N2S: C, 53.33; H, 4.47; N, 15.54. Found: C, 53.58; H, 4.21; N, 15.30.
12-Methyl-2,3-dihydro-12H-imidazo[2',1':4,5][1,3,5]thiadiazino[2,3-b]quinazolin-5-thione (4d). To a
suspension of 3d (0.44 g, 2.2 mmol) in DMF (10 mL) and carbon disulfide (1.45 g, 1.15 mL, 19 mmol)
was added dropwise Et3N (0.22 g, 0.3 mL, 2.2 mmol). The resulting solution was stirred at rt for 48 h
(until H2S had ceased). Then, the corresponding 4d was obtained according to the procedure described
above for 4a-c. Yield: 0.2 g (31%), mp 183-186 °C. IR (KBr): 3065, 2925, 2875, 1645, 1605, 1585, 1560,
1
1425, 1380 (cm-1). H NMR (DMSO-d6) δ 1.39 (d, J = 4.62 Hz, 3H, CH3), 3.8-3.95 (m, 2H, CH2),
4.17-4.38 (m, 2H, CH2), 5.68 (q, 1H, CH-CH3), 7.05-7.24 (m, 4H, ArH)*. Anal. Calcd for C13H12N4S2: C,

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HETEROCYCLES, Vol. 68, No. 4, 2006
54.14; H, 4.19; N, 19.43. Found: C, 54.76; H, 3.91; N, 19.27.
[2-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]methanol hydrochloride (7). 2-Aminobenzyl alcohol
(6) (1.5 g, 12.3 mmol) was added to a solution of 1 (1.25 g, 12.3 mmol) in CH2Cl2 (30 mL) and the
reaction mixture was stirred at rt for 12 h. The precipitated solid was filtered off, washed with CH2Cl2 (20
mL), dried and purified by crystallization from acetonitrile to give 7 (1.4 g, 50%), mp 165-166 °C. IR
(KBr): 3400-2550 (ν max 3275, 3190, 3010, 2975, 2925, 2885), 1655, 1600 (cm-1). 1H NMR (DMSO-d6)
δ 3.63 (s, 4H, 2xCH2), 4.53 (s, 2H, CH2), 5.48 (br s, 1H, OH), 7.25-7.31 (m, 1H, ArH), 7.33-7.42 (m, 2H,
ArH), 7.52-7.58 (m, 1H, ArH), 8.2 (br s, 2H, 2xNH⊕), 10.45 (br s, 1H, NH⊕)*. Anal. Calcd for
C10H13N3OCl: C, 52.78 ; H, 5.76; N, 18.46. Found: C, 52.52; H, 5.83; N, 18.32.
1-(4H-3,1-Benzoxazin-2-yl)imidazolidin-2-thione (8). To a mixture of the hydrochloride (7) (0.8 g, 3.4
mmol) in anhydrous acetone (15 mL) and carbon disulfide (0.2 mL, 17 mmol) was added dropwise Et3N
(0.68 g, 6.8 mmol). The resulting suspension was stirred at rt for 48 h (until H2S had ceased). Then the
solvent and excess of carbon disulfide were evaporated under reduce pressure, and the residue was treated
with water (20 mL). The precipitate thus obtained was filtered off, dried and purified by crystallization
from DMF to afford 8. Yield: 0.44 g (54%), mp 184-186 °C. IR (KBr): 3195, 3040, 2945, 2890, 1620,
1600, 1535, 1415, 1400, 1290 (cm-1). 1H NMR (DMSO-d6) δ 3.49-3.58 (m, 2H, CH2), 4.08-4.17 (m, 2H,
CH2), 5.29 (s, 2H, CH2), 7.01-7.08 (m, 1H, ArH), 7.14-7.2 (m, 2H, ArH), 7.24-7.34 (m, 1H, ArH), 9.42 (s,
1H, NH)*. 13C NMR (DMSO-d6) δ 41.44, 49.26 (C-4, C-5 imidaz.), 66.82 (CH2), 122.68, 123.04, 124.61,
125.41, 129.07, 140.47 (6 C aromat.), 151.72 (C=N), 180.4 (C=S)*. Anal. Calcd for C11H11N3OS: C,
56.63; H, 11.09; N, 18.01. Found: C, 56.45; H, 11.11; N, 17.82.
1-Acetyl-3-(4H-3,1-benzoxazin-2-yl)imidazolidin-2-thione (9). To a solution of 8 (0.4 g, 17 mmol) in
pyridine (5 mL) acetyl chloride (0.33 g, 42 mmol) was added at 0 °C. After an exothermic reaction had
subside (ca 15 min), the reaction suspension was stirred at rt for 12 h, and then the solvent was distilled
off under reduce pressure. The dry residue was treated with water (20 mL) and the resulting mixture was
neutralized to pH 7.5 with 5% aqueous Na2CO3 solution and stirred at room temperature for 30 min. The
product that precipitated was collected by filtration, washed with water, dried and purified by
crystallization from isopropanol to give 9 (0.18 g, 40%), mp 143-147 °C. IR (KBr): 3000, 2905, 2860,
1695, 1685, 1625, 1600, 1360, 1270 (cm-1). 1H NMR (CDCl3) δ 2.86 (s, 3H, OCH3), 4.09 (s, 4H, 2xCH2),
13
5.39 (s, 2H, CH2), 7.05-7.09 (m, 1H, ArH), 7.15-7.2 (m, 2H, ArH), 7.24-7.27 (m, 1H, ArH)*. C NMR
(CDCl3) δ 27.59 (CH3), 44.91, 46.21 (C-4, C-5 imidaz.), 68.23 (CH2), 122.7, 124.46, 126.25, 126.96,
129.6, 140.15 (6 C aromat.), 151.27 (C=N), 172.59 (C=O), 179.17 (C=S)*. Anal. Calcd for C13H13N3O2S:
C, 56.71; H, 4.76; N, 15.26. Found: C, 56.46; H, 5.12; N, 15.27.
2-(2-Benzylsulfanyl-4,5-dihydro-1H-imidazol-1-yl)-4H-3,1-benzoxazine (10). To a solution of 8 (0.8
mmol) and finely powdered NaOH (0.13 g, 3.2 mmol) in DMSO (6 mL) was added dropwise benzyl

HETEROCYCLES, Vol. 68, No. 4, 2006
697
bromide (0.15 mL, 1.3 mmol). The resulting suspension was stirred at 35-40 °C for 1 h. Then water (30
mL) was added to the reaction mixture, and the solid was collected by filtration, washed with water, and
crystallized from ethanol to give compound (10) (0.14 g, 53%), mp 147-150 °C. IR (KBr): 3060, 3025,
2915, 2870, 1630, 1595, 1575, 1415, 1280 (cm-1). 1H NMR (CDCl3) δ 3.99-4.05 (m, 4H, 2xCH2), 4.36 (s,
2H, CH2Ph), 5.23 (s, 2H, CH2), 6.93-7.08 (m, 3H, ArH), 7.19-7.39 (m, 6H, ArH)*. Anal. Calcd for
C18H17N3OS: C, 66.85; H, 5.30; N, 13.49. Found: C, 66.43; H, 5.12; N, 13.27.
N,N'-bis-(4H-3,1-benzoxazin-2-yl)hydrazine (11). Method A. A mixture of 8 (1.13 g, 5 mmol) and
98% hydrazine hydrate (0.5 g, 10 mmol, 0.5 mL) in anhydrous methanol (10 mL) was stirred at rt for 48 h.
The solid that precipitated was filtered off (the filtrate denoted as "T" was stored for further workup)
washed with methanol (3x5 mL), dried and crystallized from DMF/methanol to give pure product 11
(0.28 g, 40%), mp 209-210 °C (decomp). IR (KBr): 3305, 1655, 1640, 1595, 1475, 1396, 1030 (cm-1). 1H
NMR (DMSO-d6) δ 5.07 (s, 4H, 2xCH2), 6.79-6.99 (m, 2H, ArH), 7.14-7.24 (m, 6H, ArH), 9.44 (s, 2H,
2xNH)*. MS (70 eV) m/z: 294 (M+). Anal. Calcd for C16H14N4O2: C, 65.30; H, 4.79; N, 19.04. Found: C,
65.53; H, 5.02; N, 19.35.
The filtrate "T" was evaporated under reduced pressure, and the oily residue was treated with acetone (10
mL). The precipitate thus obtained, containing 12 and traces of 11 (1H NMR evidence), was collected by
suction (0.3 g) and recrystallized from isopropanol to give imidazolidin-2-thione (12) (0.07 g, 20%), mp
187-189 °C (ref.,20 mp 196-197 °C).
Method B. A mixture of 8 (0.5 g, 2.1 mmol) and methylhydrazine (0.2 g, 4.4 mmol, 0.24 mL) in
anhydrous methanol (10 mL) was stirred at rt for 48 h. Then, the resulting suspension was evaporated to
dryness, and the residue was treated with hot methanol (4 mL). The insoluble material was separated by
suction (the filtrate denoted as "T" was stored for further workup), dried and purified by crystallization
from DMF/methanol to give 8 (0.07, 23%), which was identical with the product obtained according to
the method A. The filtrate "T" was worked up as described in the method A. The crude product (12) thus
obtained (0.09 g) was not further purified.
X-Ray structure analyses. The diffraction data were collected at room temperature with a KumaCCD
diffractometer using graphite monochromated Mo Kα radiation. The intensity data were collected and
processed using Oxford Diffraction CrysAlis Software.21 The structures were solved by direct methods
with the program SHELXS-97 and refined by full-matrix least-squares method on F2 with SHELXL-97.22
X-Ray structure analysis of 3a. Crystal data for C16H18N4: triclinic, space group P1 , a= 7.9579(15), b=
8.8528(12), c= 11.3026(17) Å, α= 73.850(13), β= 86.426(14), γ= 68.765(15)°,V= 712.3(2) Å3, Z=2, dx
=1.242 g.cm-3, T=293K. Final R indices for 1613 reflections with I>2σ(I) and 200 refined parameters are:
R1=0.0597, wR2=0.1724 (R1=0.0826, wR2=0.1939 for all 2513 data.23

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HETEROCYCLES, Vol. 68, No. 4, 2006
X-Ray structure analysis of 4b. Crystal data for C18H13N4ClS2: triclinic, space group P1 , a= 8.6635(8),
b= 9.6065(10), c= 11.8111(9) Å, α= 94.271(7), β= 102.262(7), γ= 115.479(10)°, V= 851.68(14) Å3, Z=2,
dx =1.501 g.cm-3, T=293K. Final R indices for 2957 reflections with I>2σ(I) and 227 refined parameters
are: R1=0.0408, wR2=0.1115 (R1=0.0460, wR2=0.1166 for all 3428 data).23
X-Ray structure analysis of 10. Crystal data for C18H17N3OS: triclinic, space group P1 , a= 7.3689(7),
b= 10.1304(11), c= 11.6572(10) Å, α= 105.019(8), β= 95.464(8), γ= 105.781(9)°, V= 795.85(13) Å3,
Z=2, dx =1.350 g.cm-3, T=293K. Final R indices for 2371 reflections with I>2σ(I) and 473 refined
parameters are: R1=0.0391, wR2=0.1010 (R1=0.0450, wR2=0.1063 for all 2794 data).23
ACKNOWLEDGEMENTS
This work was supported by the Polish State Committee for Scientific Research (Grant 6 PO5F 03821).
REFERENCES
1. R. A. Glennon, B. Grella, R. J. Tyacke, A. Lau, J. Westaway, and A. L. Hudson, Bioorg. Med. Chem.
Lett., 2004, 14, 527.
2. W. J. Houlihan, U. F. Ahmad, J. Koletar, L. Kelly, L. Brand, and T. A. Kopajtic, J. Med. Chem.,
2002, 45, 4110; S. Kulkarni, A. H. Newman, and W. J. Houlihan, J. Med. Chem., 2002, 45, 4119.
3. F. Sączewski, E. Kobierska, J. Petrusewicz, A. Gendzwiłł, and M. Gdaniec, Farmaco, 2003, 58,
1171.
4. J. Sączewski, Z. Brzozowski, and M. Gdaniec, Tetrahedron, 2005, 61, 5303.
5. F. Sączewski and J. Sączewski, Trends Heterocycl. Chem., 2003, 9, 19.
6. A. Kornicka, F. Sączewski, and M. Gdaniec, Molecules, 2004, 9, 86; F. Sączewski, A. Kornicka, M.
Gdaniec, R. Hałasa, and W. Werel, Eur. J. Org. Chem., 2004, 3511; A. Kornicka, F. Sączewski, J.
Petrusewicz, A. Rejdych, R. J. Tyacke, A. L. Hudson, and D. J. Nutt, Pol. J. Chem., 2005, 79, 89.
7. F. Sączewski, E. Kobierska, T. Dębowski, S. Charakchiewa-Minol, M. Mokrosz, M. Gdaniec, and E.
Nowak, Arch. Pharm., 2000, 333, 425.
8. J. Spindler and G. Kempter, Z. Chem., 1987, 27, 36.
9. K.-Ch. Liu, M.-H. Yen, J.-W. Chern, and Y.-O. Lin, Arch. Pharm., 1983, 316, 379.
10. U. Neumann, N. M. Schechter, and M. Gütschow, Bioorg. Med. Chem., 2001, 9, 947.
11. P. Jakobsen, B. R. Pedersen, and E. Persson, Bioorg. Med. Chem., 2000, 8, 2095.
12. N. Masuda, O. Yamamoto, M. Fujii, T. Ohgami, T. Ohgami, J. Fujiyasu, A. Moritomo, H. Kurihara,
H. Nakahara, M. Ohta, T. Hatta, K. Sudo, Y. Shimizu, M. Matsuoka, T. Yokota, and M. Baba,
Bioorg. Med. Chem., 2004, 12, 6171.
13. K. Waisser, M. Peřina, J. Kuneš, V. Klimešovà, and J. Kaustovà, Farmaco, 2003, 58, 1137.

HETEROCYCLES, Vol. 68, No. 4, 2006
699
14. A. Torrens, J. Mas, A. Port, J. A. Castrillo, O. Sanfeliu, X. Guitart, A. Dordal, G. Romero, M. A.
Fisas, E. Sánchez, E. Hernández, P. Pérez, R. Pérez, and H. Buschmann, J. Med. Chem., 2005, 48,
2080.
15. M. A. Collins, V. Hudak, R. Bender, A. Fensome, P. Zhang, L. Miller, R. C. Winneker, Y. Zhu, J.
Cohen, R. J. Unwalla, and J. Wrobel, Bioorg. Med. Chem. Lett., 2004, 14, 2185.
16. S. Kubota, O. Kirino, Y. Koida, and K. Miyake, J. Pharm. Soc. Japan, 1972, 92, 275; E. S. H. El
Ashry, L. F. Awad, M. A. Ghani, and A. I. Atta, ARKIVOC, 2005, 15, 97.
17. A. Trani and E. Bellasio, J. Heterocycl. Chem., 1974, 11, 257.
18. G. Kempter, W. Ehrlichmann, M. Plesse, and H.-U. Lehm, J. Prakt. Chem., 1982, 324, 832.
19. G. Kempter, Z. Chem., 1971, 11, 12.
20. P. K. Mohanta, S. Dhar, S. K. Samal, H. Ila, and H. Junjappa, Tetrahedron, 2000, 56, 629.
21. Oxford Diffraction, Crysalis CCD and RED, ver.1.169. Oxford Diffraction, Oxfordshire, England,
2002.
22. G. M. Sheldrick, SHELXS-97. Program for a Crystal Structure Solution, University of Göttingen,
1997; G. M. Sheldrick, SHELXS-97. Program for the Refinement of a Crystal Structure from
Diffraction Data, University of Göttingen, 1997.
23. CCDC 290745 (compound 3a), CCDC 290746 (compound 4b) and CCDC 290747 (compound 10)
contain the supplementary crystallographic data for these compounds. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).