Synthesis of [1,2-a] benzimidazolo-1,3,5-triazin-2-thione, [1,2-a] benzimidazolo-1,3,5-thiadiazin-2-thione, [1,2-a] benzimidazolo-1,3,5-triazin-2- amine, and [1,2-a] benzimidazol-2-yl amidrazone

Article abstract of DOI:10.1002/hc.20618

N-benzimidazol-2-yl imidate type 1 reacts with thiourea, carbon disulfide, cyanamide, and hydrazide to give, respectively, [1,2-a] benzimidazolo-1,3,5- triazin-2-thione 2, [1,2-a] benzimidazolo-1,3,5-thiadiazin-2-thione 3, [1,2-a] benzimidazolo-1,3,5-tria

Full text of DOI:10.1002/hc.20618

Heteroatom Chemistry
Volume 21, Number 5, 2010
Synthesis of [1,2-a]
Benzimidazolo-1,3,5-triazin-2-thione, [1,2-a]
Benzimidazolo-1,3,5-thiadiazin-2-thione,
[1,2-a] Benzimidazolo-1,3,5-triazin-2-amine,
and [1,2-a] Benzimidazol-2-yl Amidrazone
A. Hajri and R. Abderrahim
Chemistry Department, Faculty of Sciences Bizerte, Zarzouna 7021 Tunisia
Received 19 May 2009; revised 21 December 2009
as diuretics [10]. In the literature, we noticed that
ABSTRACT: N-benzimidazol-2-yl imidate type 1 re-
[1,2-a] benzimidazolo-1,3,5-triazin-2-thione deriva-
acts with thiourea, carbon disulfide, cyanamide, and
tives were prepared mainly by condensation of
hydrazide to give, respectively, [1,2-a] benzimidazolo-
N-benzimidazoyl imidate or N-benzimidazol-2-yl
1,3,5-triazin-2-thione 2, [1,2-a] benzimidazolo-1,3,5-
amidine with thioisocyanate [11,12]. On the other
thiadiazin-2-thione 3, [1,2-a] benzimidazolo-1,3,5-
hand, to date only a limited number of studies on
triazin-2-amine 4, and [1,2-a] benzimidazol-2-yl
the synthesis of [1,2-a] benzimidazolo-1,3,5-triazin-
amidrazone 5 with good yields. Structures eluci-
2-amine derivatives have been reported [13–15].
dation of all newly synthesized heterocyclic com-
Whereas the synthesis of [1,2-a] benzimidazolo-
1
pounds was based on the data of IR, H NMR, 13C
1,3,5-thiadiazin-2-thione and [1,2-a] benzimidazol-
NMR, elemental analysis, and MS of some prod-
2-yl amidrazone was not reported in the literature.
ꢀ
C
ucts.
2010 Wiley Periodicals, Inc. Heteroatom Chem
21:279–283, 2010; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20618
For all these reasons, we continue our lab-
oratory work on the synthesis of fused benz-
imidazoles [11,12, 16–18]. So herein we report
the synthesis of [1,2-a] benzimidazolo-1,3,5-triazin-
2-thione, [1,2-a] benzimidazolo-1,3,5-thiadiazin-2-
thione, [1,2-a] benzimidazolo-1,3,5-triazin-2-amine,
and [1,2-a] benzimidazol-2-yl amidrazone.
INTRODUCTION
Benzimidazoles and their polycyclic derivatives have
been found to be of pharmacological [1] and bio-
logical activities such as anti-inflammatory agents
[2], antidiabetics [3], antirheumatics [2], antihyper-
tensives [3], antimicrobial [4,5], and as antibiotics
against Staphylococcus [6]. They also have herbi-
cidal activities [7,8] and antidepressant effects [9];
they act as bactericides [10], fungicides [10], and
RESULTS AND DISCUSSION
In extension of our previous studies of the reactiv-
ity of N-benzimidazol-2-yl iminoester 1, we describe
here an efficient and operationally simple method
for the synthesis of fused benzimidazoles (benzim-
idazole thiadiazine benzimidazole triazine deriva-
tives and benzimidazol-2-yl amidrazone).
Correspondence to: R. Abderrahim; e-mail: Abderrahim
N-benzimidazol-2-yl imidate derivatives 1 were
obtained as described previously [16]. Treatment
raoudha@Yahoo.fr.
c
ꢀ
2010 Wiley Periodicals, Inc.
279

280 Hajri and Abderrahim
a
OEt
R1
S
N
N
S
OEt
R
N
NH2-C
Route b
N
Toluene
N
C
+
b
N
C
N
H N
C
NH2
+
2
N
1
N
H
R
H
N
H
,
MeOH
2
1
a
Route
2a
2b
R = Me
R = Et
OEt
R1
R1
N
C
SCHEME 1
N
C
NH
C
N
C
N
H
A
NH2
N
H N
of compound 1 with thiourea in dry toluene un-
der reflux for 48 h afforded 1,3,5-triazino [1,2-a]
benzimidazolo-2-thione (Scheme 1). The structure
B
N
N
of compounds 2 was confirmed by IR, 1H NMR, 13
C
N
N
NMR, and MS spectral data.
R1
IR spectra of compounds 2 showed absorption
bands at 1635, 1240, 3350, and 1570–1590 cm−1 re-
lated to C N, C S, NH, and C C, respectively.
H2
4
N
1
The H NMR spectra showed the peaks of all
4c
R1 = Ph
hydrogen set of the expected compounds and the
disappearance of the ethoxy group. The 13C NMR
confirmed the 1H NMR spectroscopy by the appear-
ing of signal at 184 ppm corresponding to the C S
group present in compound 2 and the absence of two
signals at δC = 13 and 62 ppm corresponding to the
ethoxy group. The spectroscopic properties and MS
spectra were found to be in good agreement with the
assigned structure of 2.
The chemical reactivity of iminoester 1 was fur-
ther investigated through its reaction with carbon
disulfide in the presence of triethylamine and un-
der reflux of ethanol afforded thiadiazine thione 3
(Scheme 2).
A reasonable mechanism of the reaction of 1
with carbon disulfide involves an initial elimination
of the proton of NH by triethyl amine. The second
step is the nucleophilic attack of the nitrogen atom
of iminoester 1 (acted as nucleophilic reagents) onto
the C S group. Finally, intramolecular cyclization
afforded the thiadiazine thione 3. The structure of
the latter products 3 was established with help of
the spectral data. The IR spectra of compounds 3 re-
vealed the absorption bands corresponding to C S
and C N at 1250 and 1620 cm−1, respectively, and
4a
R1= Me
4b
R1 = Et
SCHEME 3
revealed the absence of the absorption band of the
NH group. The H NMR spectrum of compound 3
revealed the disappearance of the signals of NH and
the ethoxy group.
1
13C NMR spectra of compound 3 exhibit a signal
at 168.9 ppm (3a), and at 171.8 ppm (3b) attributed
to the carbon of thiocarbonyl group (C S) and dis-
played the characteristic signals of all carbons.
On the other hand, the reaction of N-
benzimidazol-2-yl imidate 1 with cyanamide un-
der reflux of methanol gave benzimidazolo triazine
amine 4 (Scheme 3).
The formation of product 4, proceeded via the
nonisolable product A or B, which was followed by
two separate routes for heterocyclic ring closure fur-
nishing products 4 (Scheme 3). A was obtained by
the attack of the carbon of imidate 1 by the nitrogen
atom of cyanamide. B was obtained by the attack of
the central atom of cyanamide by the nitrogen atom
of 1. The latter undergoes intramolecular cyclization
to give the benzimidazolo triazine amine 4.
The IR, 1H NMR, 13C NMR, and elemental anal-
ysis of the reaction product 4 were found to be in a
good agreement with the assigned structures (cf. the
section Experimental).
N
N
S
OEt
N
EtOH
N
S
C
N
Et3N
S=C=S
+
R
+
N
H
R
1
3
The IR spectrum of compounds 4 exhibited ab-
sorption bands for NH2 at 3120–3210 cm−1, for C N
3a
3b
R = Me
R = Et
1
at 1620 cm−1, and for C C at 1600 cm−1. The H
NMR spectrum of 4 showed signals for aryl protons
at δ = 7–7.8 ppm and signals for two aryl protons
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Various Fused Benzimidazole Derivatives 281
R1
R1
R1
N
N
N
R1
N
NH2-NH-CO-R
NH-C
NH-C
N=C
N=C
N
N
H
N
H
N-NH-COR
H
N
NH-NH-COR
OEt
N-NH-COR
5
H
1
5
C
Δ
5
5b
5c
5d
5 e
Et
5f
Et
Py
5a
R1
R
Me
Ph
Me
Me
Me
Ph
R1
N
N
Py* Me
Ph
N
N
N
R1
NH
Py* :3-Pyridyl
N
N
N
H
6
R
7
N
SCHEME 4
R
SCHEME 5
each one of which gives a multiplet at δ = 7.6 ppm
(4c). The presence of the amino group in the struc-
ture was supported by D2O exchangeable signals at
δ = 7.5 ppm (4a), 6.0 ppm (4b), 7.0 ppm (4c), and
the disappearance of ethoxy peaks and the NH peak.
Analogously, compound 1 was proved to be a
key of other subsequent conversions. Thus, when it
allowed to react with hydrazide, the reaction per-
formed to produce benzimidazol-2-yl amidrazone
derivatives 5. The structure of compounds 5a–f was
deduced from their 1H NMR and IR spectra and
elemental analysis of 5f and mass spectra of com-
pounds 5a–e.
1H and 13C NMR spectra were recorded with
(CD3)2SO or CDCl3 solvent containing TMS (tetram-
ethylsilane) on a Bru¨ker 300 spectrometer (1H:
300 MHz, 13C: 75.47 MHz). The chemical shifts (δδ
are reported in ppm relative to TMS (internal refer-
1
ence). For the H NMR, the multiplicities of signals
are indicated by the following abbreviations: s: sin-
glet, d: doublet, t: triplet, q: quartet, and m: multiplet.
Melting points were obtained using a Bu¨chi
melting point apparatus and are uncorrected. Ele-
mental microanalysis was performed on a Perkin-
Elmer CHN-2400 analyzer apparatus.
The absorption band for the C N group showed
that the structure of compound 5 is an hydrazine-
amine (amidrazone), which tautomerized to the less
stable form of imine hydrazine (C). This result con-
forms to the literature [19] (Scheme 4). The IR spec-
troscopy of 5 showed absorption bands at 3120–
3470, 1690, and 1610–1630 cm−1 related to the NH,
carbonyl group (C O), and C N group, respectively.
Mass spectra were recorded on a HP-5890 A us-
ing the impact mode (70 eV).
Synthesis of [1,2-a]Benzimidazolo-1,3,5-triazin-
2-thione 2
1
The H NMR spectra showed disappearance of the
To a solution of imidate 1 (2 mmol), in anhydrous
toluene (30 mL), thiourea (2 mmol) was added. The
reaction mixture was stirred and heated under reflux
for 48 h. The solvent was removed under vacuum,
and the resulting solid was filtered off, dried, and
crystallized from ethanol.
signals of the ethoxy group and appearance of the
signals of protons of the R introduced by hydrazide
and the signal of the protons NH.
A mixture of compound 1 and hydrazide was
kept at room temperature until a solid precipitated.
The solid was and separated was identified as the
amidrazone 5. Whereas the intracyclization of 5
failed to give compounds 6 or 7 (Scheme 5). The in-
tracyclization to give 6 is possible, but we can explain
that the cyclization was failed because the doublet
of the NH was conjugated with two aromatic sys-
tems. Then, it explains the lower nucleophilicity of
this nitrogen atom.
2a: Yield: 55%. mp: 176◦C. IR (KBr, ν (cm−1)):
1635 (C N), 1240(C S). 1H NMR (DMSO-d6) δ: 1.90
(s, 3H, CH3), 6.90–7.30 (m, 5H, NH deuterium ex-
changeable, 4Harom). 13C NMR (DMSO d6) δ: 18.07,
113.69, 120.62, 137.74, 154.86, 167.56, 183.75. MS
(m/z, %): 202 (18), 158 (32), 133 (100), 90 (13), 78
(20), 59 (33).
2b: Yield: 48%. mp: 172◦C. IR (KBr, ν (cm−1)):
1630 (C N), 1240 (C S). 1H NMR (DMSO-d6) δ: 1.34
(t, 3H, CH3), 2.61 (q, 2H, CH2), 7.05–7.40 (m, 5H, NH
deuterium exchangeable, 4Harom). 13C NMR (DMSO
d6) δ: 10.58, 24.96, 113.51, 120.73, 137.89, 155.04,
171.01, 184.05. MS (m/z, %): 189 (20), 160 (42), 133
(100); 105 (12); 90 (3); 78 (25); 57 (4).
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer Paragon
1000 PC spectrometer as potassium bromide pellets
or in CHCl3 solution.
Heteroatom Chemistry DOI 10.1002/hc

282 Hajri and Abderrahim
126.00, 128.00, 128.80, 130.10, 131.00, 145.10,
148.00, 153.10, 171.00. Anal. Calcd for C15H11N5: C
68.96, H 4.21, N 26.83; Found: C 68.82, H 4.14, N
27.01.
Synthesis of [1,2a]Benzimidazolo-1,3,5-
thiadiazin-2-thione 3
A mixture of 1 (2 mmol) and carbon disulfide
(2.2 mmol) in ethanol (10 mL) containing triethy-
lamine (2.2 mmol) was refluxed for 24 h. After cool-
ing, the solvent was evaporated in vacuum and the
resulting solid was collected by filtration, washed
with ether, and crystallized from methanol.
Synthesis of Benzimidazol-2-yl Amidrazone 5
To a solution of imidate (10 mmol) 1 dissolved in
methanol, hydrazide (10 mmol) was added. The mix-
ture was left at room temperature until a solid pre-
cipitated (7–10 days); the solid product was filtered
and purified by recrystallization from CCl4.
3a: Yield: 70%. mp: 158◦C. IR (CHCl3, ν (cm−1)):
1620 (C N), 1251 (C S). 1H NMR (DMSO-d6) δ: 1.94
(s, 3H, CH3), 7.05–7.30 (m, 4H, Harom). 13C NMR
(DMSO-d6) δ: 13.96, 25.60, 113.99, 121.47, 137.99,
154.52, 168.69. Calcd for C10H7N3S2 C 51.50, H 3.00,
N 18.02; Found: C 51.39; H 3.10, N 17.95.
5a: Yield: 75%. mp: 145◦C. IR (CHCl3, ν (cm−1)):
3320–3470 (NH), 1690 (C O), 1630 (C N). 1H NMR
(CDCl3 + DMSO-d6) δ: 1.80 (s, 3H, CH3), 7.80 (broad
s, 3H, NH), 7.00 (m, 9H, Harom). MS (m/z, %): 293
(18), 173 (45), 158 (35), 132 (56), 120 (31), 77 (45).
5b: Yield: 70%. mp: 140◦C. IR (CHCl3, (ν cm−1)):
3220-3330–3400 (NH), 1690 (C O), 1620 (C N). 1H
NMR (CDCl3 + DMSO-d6) δ: 2.00 (s, 3H, CH3), 2.20
(s, 3H, CH3), 5.90 (broad s, 3H, NH), 7.20 (m, 4H,
Harom). MS (m/z, %): 231(9), 173 (45), 77 (20), 58 (33).
5c: Yield: 72%. mp: 155◦C. IR (KBr) ν (cm−1)):
3100–3230 (NH), 1690 (C O), 1630 (C N). 1H NMR
(CDCl3 + DMSO-d6) δ: 1.90 (s, 3H, CH3), 7.60 (broad
s, 3H, NH), 7.10 (m, 8H, Harom). MS (m/z, %): 294
(10), 173 (25), 135(33), 121 (37), 92 (40), 77 (15).
5d: Yield: 65%. mp: 170◦C. IR (CHCl3, ν (cm−1)):
3100–3230 (NH), 1690 (C O); 1620 (C N); 1H NMR
(CDCl3 + DMSO-d6) δ: 2.00 (s, 3H, CH3); 8.00 (broad
s, 3H, NH); 7.10 (m, 9H, Harom). MS (m/z, %): 293 (5),
235 (43), 132 (35), 135(23), 77 (40), 58 (65).
3b: Yield: 75%. mp: 165◦C. IR (CHCl3, ν (cm−1)):
1620 (C N), 1251 (C S). 1H NMR (DMSO-d6) δ: 1.18
(t, 3H, CH3), 2.55 (q, 2H, CH2), 7.05–7.30 (m, 4H,
Harom). 13C NMR (DMSO-d6) δ: 10.54, 25.21, 113.95,
121.30, 123.96, 136.36, 149.42, 171.80. Calcd for
C11H9N3S2: C 53.44, H 4.45, N 17.00; Found: C 53.39,
H 4.20, N 16.95.
Synthesis of [1,2-a]Benzimidazolo-1,3,5-triazin-
2-amine 4
To a solution of 1 (3 mmol) in methanol (10 mL),
cyanamide (3 mmol) dissolved in methanol (5 mL)
was added in dropwise. The reaction mixture was
heated under reflux for 24 h. The solvent was re-
moved under vacuum, and the formed solid prod-
uct was collected by filtration and crystallized from
ethanol.
5e: Yield: 70%. mp: 201◦C. IR (KBr, ν (cm−1)):
3110–3220 (NH), 1690 (C O), 1620 (C N). 1H NMR
(CDCl3 + DMSO-d6) δ: 1.30 (t, 3H, CH3); 2.20 (q, 2H,
CH2), 8.00 (broad s, 3H, NH); 7.10 (m, 9H, Harom).
MS (m/z, %): 307 (8), 287 (43), 132 (25), 120(45),
77 (32).
4a: Yield: 75%. mp: 295◦C. IR (KBr, ν (cm−1)):
3120–3210 (NH2), 3030 (CHarom), 1615 (C N), 1600
(C C). 1H NMR (DMSO-d6) δ: 1.90 (s, 3H, CH3), 7.00–
7.30 (mu, 4H, Harom), 7.50 (broad s, 2H, NH2). 13C
NMR (DMSO-d6) δ: 20.30, 113.10, 117.10, 119.00,
125.30, 126.00, 144.50, 149.20, 150.00, 169.00. Anal.
Calcd for C10H9N5: C 60.30, H 4.52, N 35.18; Found:
C 60.22, H 4.44, N 35.30.
5f: Yield: 65%. mp: 170◦C. IR (CHCl3, ν (cm−1)):
3100–3230 (NH), 1690 (C O), 1610 (C N). 1H NMR
(CDCl3 + DMSO-d6), δ: 1.30 (t, 3H, CH3), 2.20 (q, 2H,
CH2), 7.80 (broad s, 3H, NH), 7.10 (m, 8H, Harom).
Anal. Calcd for C16H16N6O: C 62.33, H 5.19, N 27.27;
Found: C 62.22, H 5.06, N 27.21.
4b: Yield: 70%. mp: 265◦C. IR (KBr, ν (cm−1)):
3120–3210 (NH2), 3030 (CHarom), 1615 (C N), 1600
(C C). 1H NMR (DMSO-d6) δ: 1.3 (t, 3H, CH2 CH3),
2.30 (q, 2H, CH3 CH2), 6.00 (broad s, 2H, NH2 deu-
terium exchangeable), 7.00–7.30 (mu, 4H, Harom).
13C NMR (DMSO-d6) δ: 11.00, 29.00, 113.20, 116.10,
121.10, 126.00, 126.20, 137.10, 144.00, 148.00,
169.10. Anal. Calcd for C11H11N5: C 61.97, H 5.16,
N 32.86; Found: C 61.82, H 5.14, N 32.72.
REFERENCES
[1] Gates, L. A.; Li, V. S. J Pharm Sci 1982, 71, 308.
[2] Yanchenko, V. A.; Demchenko, A. M.; Lozinski, M. O.
Chem Heterocycl Compd 2004, 40, 4.
[3] White, A. C.; Black, R. M. Chem Abstr 1997, 86,
72694c.
[4] Madhukar, S. C.; Dravid, N. D.; Nandita, P. S. Ind
Acd Sci 1988, 100, 1.
4c: Yield: 70%. mp: 265◦C. IR (KBr, ν (cm−1)):
3120–3220 (NH2), 3030 (CHarom), 1615 (C N), 1600
(C C). 1H NMR (DMSO-d6:) δ: 7.00 (broad s, 2H, NH2
deuterium exchangeable), 7.80 (mu, 9H, Harom). 13C
NMR (DMSO-d6) δ: 113.10, 117.00, 122.00, 125.00,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Various Fused Benzimidazole Derivatives 283
[5] Katiyar, D.; Tiwari, V. K.; Tripathi, R. P.; Srivastava,
A.; Chaturvedi, V.; Srivastava, R. S. Srivastava, B.
Biorg Med Chem 2003, 20, 11.
[6] Asobo, P. F.; Wahe, H.; Mbafor, J. T.; Fomum, Z. T.;
Sopbue, E. F.; Doepp, D. J Chem Soc, Perkin Trans
2001, 1, 457.
[7] Kreutzberger, A.; Egger, M. Arch Pharm 1982, 315,
438.
[8] Ward Carl, E.; Berthold Robert, V. J Agric Food Chem
1986, 34, 1005.
[12] Abderrahim, R.; Hajjem, B.; Baccar, B. J Soc Chim
Tunisie 1994, 3, 423.
[13] Dolzhenko, A. V.; Chui, W.-K.; Dolzhenko,
A. V.; Chan. L.-W. J Fluorine Chem 2005, 126,
759.
[14] Gulyas, G.; Emri, T.; Simon, A.; Gyorgydeak, Z. Folia
Microbiol 2002, 47, 29.
[15] Martin, D.; Graubaum, H.; Kepter, G.; Ehrlichmann,
W. J Prakt Chem 1981, 323, 303.
[16] Abderrahim, R.; Hajjem, B.; Baccar, B. J Soc Chim
Tunisie 1993, 3(6), 367.
[17] Abderrahim, R.; Hajjem, B.; Zantour, H.; Baccar, B.
Synth Commun 1997, 27, 3039.
[9] Wahe, H.; Asobo, P. F.; Cherkasov, R. A.; Nkengfack,
A. E.; Folefoc, G. N.; Fomum, Z. T.; Doepp, D. Arkivoc
2003, 170.
[10] Goto, K. Jpn Kokai Tokkyo Koho JP03, 215, 488;
Chem Abstr 1992, 116, 128962.
[11] Abderrahim, R.; Raouafi, N.; Ben Khoud, M. L. J Soc
Chim Tunisie 2003, 5, 245.
[18] Abderrahim, R.; Baccar, B.; Ben Khoud, M. L. Phos-
phorus Sulfur Silicon Relat Elem 2002, 177, 1.
[19] Baccar, B.; Mathis, R.; Secches, A.; Barrans, J.;
Mathis, F. J Mol Struct 1971, 4, 252.
Heteroatom Chemistry DOI 10.1002/hc