Synthesis and characterization of [1,2,4,6]thiatriazino[2,3-a][1,3] benzimidazol-1(2H)-one and [1,3,5]thiadiazino[3,4-a][1,3]benzimidazol-2-imine

Article abstract of DOI:10.1080/10426507.2010.506453

The reaction of thionyl chloride with amidines 2, derived from N-benzimidazol-2-yl imidates 1, leads to [1,2,4,6]thiatriazino[2,3-a][1,3] benzimidazol-1(2H)-one 3 in good yields. [1,3,5]Thiadiazino[3,4-a][1,3] benzimidazol-2-imine 4 was prepared by conden

Full text of DOI:10.1080/10426507.2010.506453

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Phosphorus, Sulfur, and Silicon and the
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Synthesis and Characterization
of [1,2,4,6]Thiatriazino[2,3-a]
[1,3]benzimidazol-1(2H)-one
and [1,3,5]Thiadiazino[3,4-a]
[1,3]benzimidazol-2-imine
A. Hajri a & R. Abderrahim a
a Laboratory of Physics of Lamellaires Materials and Hybrids
Nanomaterials, Faculty of Sciences of Bizerte , University of
Carthage , Bizerte, Tunisia
Published online: 07 Mar 2011.
To cite this article: A. Hajri & R. Abderrahim (2011) Synthesis and Characterization of
[1,2,4,6]Thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one and [1,3,5]Thiadiazino[3,4-a]
[1,3]benzimidazol-2-imine, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:3, 520-525,
DOI: 10.1080/10426507.2010.506453
To link to this article: http://dx.doi.org/10.1080/10426507.2010.506453
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Phosphorus, Sulfur, and Silicon, 186:520–525, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.506453
SYNTHESIS AND CHARACTERIZATION OF [1,2,4,6]
THIATRIAZINO[2,3-a][1,3]BENZIMIDAZOL-1(2H)-ONE AND
[1,3,5]THIADIAZINO[3,4-a][1,3]BENZIMIDAZOL-
2-IMINE
A. Hajri and R. Abderrahim
Laboratory of Physics of Lamellaires Materials and Hybrids Nanomaterials,
Faculty of Sciences of Bizerte, University of Carthage, Bizerte, Tunisia
GRAPHICAL ABSTRACT
N
N
NaSCN
R2-NH2/EtOH
N
N
N
SOCl2/2 pyridine
NHR2
N
N
N
N
OEt
N
N
H
R1
N
H
R1
R1
N
S
4
1
R1
2
3
S
R2
O
HN
Abstract The reaction of thionyl chloride with amidines 2, derived from N-benzimidazol-
2-yl imidates 1, leads to [1,2,4,6]thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one 3 in good
yields. [1,3,5]Thiadiazino[3,4-a][1,3]benzimidazol-2-imine 4 was prepared by condensation
of NaSCN with benzimidazol-2-yl imidate 1. The isolated compounds 3 and 4 were identified
by spectroscopic methods including IR, 1H NMR, and 13C NMR as well as elemental analyses
and MS of 3d and 4b.
Keywords Amidines; imidates; [1,3,5]thiadiazino[3,4-a][1,3]benzimidazol-2-imine; [1,2,
4,6]thiatriazino[2,3-a][1,3]benzimidazol-1 (2H)-one; thionyl chloride
INTRODUCTION
The chemistry of benzimidazole attracts much research because of its wide applica-
tions in several domains. Compounds derived from benzimidazole have diverse biocidal
activities and pharmaceutical applications.1–3 In particular, tricyclic benzimidazole deriva-
tives have been investigated as potential inhibitors of dihydrofolate reductase in the search
for anticancer and antibacterial agents4–6 and for DNA intercalating agents.6 As a con-
tinuation of our previous work,7–9 we aimed, in this manuscript, to combine both nuclei,
namelybenzimidazole and thiatriazine or thiadiazine, in a new series of benzimidazoles
having the thiatriazine or thiadiazine ring directly linked to the benzimidazole moiety. It
is important to note that substituted 1,3,5,2-thiatriazine-S-oxide derivatives are known for
their useful proprieties from pharmacological and biological activities. They are used as an-
ticoagulant,10–12 anti-imflamatory,13 antiviral,14,15 antitumor,16–19 and fungicidal agents,20
Received 14 May 2010; accepted 2 July 2010.
Address correspondence to R. Abderrahim, Chemistry Department, Faculty of Sciences Bizerte, Zarzouna
7021, Tunisie. E-mail: Abderrahim raoudha@yahoo.fr
520

NEW THIATRIAZINO-BENZIMIDAZOL-1(2H)-ONE
521
whereas 1,3,5-thiadiazine derivatives have a wide spectrum of antimicrobial activity. Sev-
eral studies related to the antifungal, antiviral, antihelmintic, and tuberculostatic activity
of these compounds has been extensively reported.21,22 We report in this article a new
method for the synthesis of [1,2,4,6]thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one 3 and
[1,3,5]thiadiazino[3,4-a][1,3]benzimidazol-2-imine 4.
RESULTS AND DISCUSSION
[1,2a]Benzimidazol-2-yl iminoesters 1 and [1,2a]benzimidazol-2-yl amidines 2 pre-
viously described by our group7–9 were used as starting compounds to prepare the thiatri-
azine and thiadiazine benzimidazole derivatives.
Reaction of thionyl chloride with compound 2 derivatives in the presence of
two equivalents of pyridine under reflux for 3 h yielded [1,2,4,6]thiatriazino [2,3-
a][1,3]benzimidazol-1(2H)-one 3 in good yields. The structures of the isolated products
were established on the basis of elemental analyses and the MS of 3d and spectral data. For
example, the 1H NMR spectrum of compound 3a displayed a singlet at δ 2.42 due to methyl
protons, a triplet signal at δ 3.38 and quartet at δ 1.60 due to ethyl protons, in addition to
aromatic multiplets in the region δ 7.50–8.10.
The formation of compounds 3 was confirmed by the IR spectra showing a strong
band in the region 1080–1086 cm–1 assigned to the S O group and another band in the
region 1615–1622 cm–1 corresponding to C N cyclic. The 13C NMR spectra display the
characteristic signals of all carbons. From a mechanistic viewpoint, the condensation of
thionyl chloride and compound 2 under reflux gives 3; we did not isolate intermediates A
(Scheme 1).
R2-NH2/ EtOH
N
N
NHR2
SOCl /
2 pyridine
N
2
N
O-CH2-CH3
N
H
N
H
R1
R1
2
1
N
N
N
N
H
N
1
R
R1
N
S
Cl
N
S
R2
N
R2
O
O
3
A
3
3a
Me
Et
3b
Et
Et
3c
3d
Et
Pr
3e
3f
R1
R2
Me
Pr
Me
Et
Ph-CH2 Ph-CH2
Pr : CH3-CH2CH2 ; Ph : C6H5
Scheme 1
Treatment of [1,2a]benzimidazol-2-yl as iminoesters derivatives 1 with NaSCN in
dioxane/H2O under reflux gave only the product (Scheme 2). The formation of compound

522
A. HAJRI AND R. ABDERRAHIM
4 was confirmed by 1H NMR, 13C NMR, IR spectrum, and elemental analyses. The isolated
products were identified as [1,3,5]thiadiazino[3,4-a][1,3]benzimidazol-2-imine derivatives
1
4a and 4b (Scheme 2). The H NMR spectrum of compound 4a, taken as an example,
revealed two singlet signals at δ 1.70 and δ 4.96 due, respectively, to methyl and NH
protons, in addition to aromatic multiplets in the region δ 6.71–7.30. The 13C NMR spectra
recorded for compound 4a and 4b confirmed the formation of 4 and the total absence of
compound 5. The IR spectra showed the presence of a band in the region 1630–1638 cm–1
(C N) and 3445–3460 cm–1 (C NH) and total absence of absorption band corresponding
to a C S group, all of which support the formation of 4.
N
N
N
R
S
N
4
EtOH/ H2O
HN
N
NaSCN
O-CH2-CH3
+
N
H
R
1
1
N
N
S
N
R
N
H
5
4a
4b
R
Me
Et
Scheme 2
EXPERIMENTAL
IR spectra were recorded in CHCl3 solution on a Perkin Elmer Paragon 1000 PC
spectrometer. 1H, 13C NMR spectra were recorded with CDCl3 or a mixture of CDCl3 and
(CD3)2SO as the solvents containing TMS on a Bruker 300 spectrometer. The chemical
shifts were reported in δ values relative to TMS (internal reference). For the 1H NMR, the
multiplicities of signals are indicated by the following abbreviations: s: singlet, d: doublet,
t: triplet, q: quartet, m: multiplet.
Melting points were obtained using a Bu¨chi melting point apparatus. Elemental
microanalysis was performed on a Perkin-Elmer CHN-2400 analyser apparatus. Mass
spectra were recorded on a HP-5890 A using the impact mode (70 eV).
Synthesis of [1,2,4,6]Thiatriazino [2,3-a][1,3]benzimidazol-1(2H)-one 3
To a solution of compound 2 (1 mmol) in dioxane (10 mL) containing pyridine
(2 mmol), thionyl chloride (1 mmol) was added dropwise. The reaction mixture was
heated under reflux for 3 h and then left to cool. The solvent was evaporated to dryness
under vacuum, and the solid obtained was filtered off and recrystallized from a mixture of
chloroform and ethanol (v/v 9:1) to give 3.

NEW THIATRIAZINO-BENZIMIDAZOL-1(2H)-ONE
523
2-Ethyl-3-methyl [1,2,4,6] thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one
(3a). Yield = 54%, mp = 186–188◦C, IR (CHCl3, ν (cm−1)): 1615 (C N), 1086 (S O). 1H
NMR (CDCl3) δ 2.42 (s, 3H), 3.38 (q, 3JHH = 8.8 Hz, CH3 CH2 N , 2H), 1.60 (t, 3JHH
=
8.8 Hz, CH3 CH2 N , 3H), 7.50–8.10 (m, 4Harom). 13C NMR (CDCl3) δ 11.4 (CH3),
18.3 (CH3 CH2 N ), 42.1 (CH3 CH2 N ), 115.3 (HC CH C N C ), 116.4
( HC CH C NSO), 123.0 (HC CH C N SO), 123.8 (HC CH C N C ),
129.3 (HC CH C N SO), 130.4 (HC CH C N C ), 157.3 ( N C(N) N ),
162.7 ( N C(CH3) N ). Calcd for C11H12N4SO: C, 53.22; H, 4.83; N, 22.58. Found:
C, 53.23; H, 4.80; N, 22.55.
2,3-Diethyl [1,2,4,6]thiatriazino [2,3-a][1,3]benzimidazol-1(2H)-one (3b).
Yield = 61%, mp = 192–193◦C, IR (CHCl3 ν (cm−1)): 1618 (C N), 1081(S O). 1H NMR
3
3
(CDCl3) δ 2.82 (q, JHH = 9.0 Hz, CH3 CH2, 2H), 1.05 (t, JHH = 9.0 Hz, CH3 CH2,
3
3
3H), 3.70 (q, JHH = 9.0 Hz, CH3 CH2 N, 2H), 1.30 (t, JHH = 9 Hz, CH3 CH2 N,
3H), 7.20–7.80 (m, 4Harom). 13C NMR (CDCl3) δ 10.1 (CH3 CH2), 16.5 (CH3 CH2),
20.5 (CH3 CH2 N ), 43.3 (CH3 CH2 N ), 112.6 (HC CH C N C ), 112.8
( HC CH C NSO), 116.0 (HC CH C N SO), 117.0 (HC CH C N C ),
139.4 (HC CH C N SO), 140.6 (HC CH C N C ), 156.1 ( N C(N) N ),
164.0 ( N C( CH2 CH3) N ). Calcd for C12H14N4SO: C, 54.96; H, 5.34; N, 21.37.
Found: C, 54.93; H , 5.32; N, 21.35.
3-Methyl-2-propyl[1,2,4,6] thiatriazino [2,3-a][1,3]benzimidazol-1(2H)-
one (3c). Yield = 66%, mp = 178–180◦C, IR (CHCl3, ν (cm−1)): 1622 (C N), 1087
(S O). 1H NMR (CDCl3) δ 2.33 (s, 3H), 3.91 (t, 3JHH = 6.0 Hz, CH3 CH2 CH2 N ,
3
2H), 2.20 (m, 2H), 1.11 (t, JHH = 6.0 Hz, CH3 CH2 CH2 N , 3H), 7.54 8.60
(m, 4Harom). 13C NMR (CDCl3) δ 10.8 (CH3), 11.5 (CH3 CH2 CH2 N ), 21.9
(CH3 CH2 CH2 N), 45.6 (CH3 CH2 CH2 N), 111.3 (HC CH C N C ), 112.2
( HC CH C NSO), 124.8 (HC CH C N SO), 125.0 (HC CH C N C ),
139.8 (HC CH C N SO), 144.6 (HC CH C N C ), 159.1 ( N C(N) N ),
170.7 ( N C(CH3) N ) Calcd for C12H14N4SO: C, 54.96; H, 5.34, N, 21.37. Found:
C, 54.93; H, 5.31; N, 21.40.
3-Ethyl-2-propyl[1,2,4,6] thiatriazino [2,3-a][1,3]benzimidazol-1(2H)-one
(3d). Yield = 73%, mp = 166–168◦C, IR (CHCl3, ν (cm−1)): 1620 (C N), 1085
1
3
(S O). H NMR (CDCl3) δ 1.40 (t, , 3JHH = 9.0 Hz, CH3 CH2, 3H), 2.71 (q, JHH
=
3
6.0 Hz, CH3 CH2, 2H), 3.47 (t, JHH = 6.0 Hz, CH3 CH2 CH2 N, 2H), 1.83 (m,
2H), 1.03 (t, JHH = 6.3 Hz, CH3 CH2 CH2 N, 3H), 8.24–9.09 (m, 4Harom). 13C
3
NMR (CDCl3) δ 11.1 (CH3 CH2), 11.2 (CH3 CH2 CH2 N), 20.3 (CH3 CH2), 21.1
(CH3 CH2 CH2 N), 46.0 (CH3 CH2 CH2 N), 110.8 (HC CH C N C ), 114.6
( HC CH C NSO), 125.1 (HC CH C N SO), 125.3 (HC CH C N C ),
141.2 (HC CH C N SO), 146.6 (HC CH C N C ), 155.2 ( N C(N) N ),
170.1 ( N C( CH2 CH3) N ). Calcd for C13H16N4SO: C, 56.52; H, 5.79; N, 20.28.
Found: C, 56.53; H, 5.79; N, 20.30. MS (m/z, %): 190 (33%), 145 (120%), 118 (96%),
131 (15%), 91 (25%).
2-Benzyl-3-methyl[1,2,4,6]thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one
(3e). Yield = 80%, mp = 154–156◦C, IR (CHCl3, ν (cm−1)): 1620 (C N), 1080
1
(S O). H NMR (CDCl3) δ 2.40 (s, 3H), 4.73 (s, 2H), 7.09-7.43 (m, 9H). 13C NMR
(CDCl3) δ 21.0(CH3), 45.9 (Ph CH2 N ), 115.0 (HC CH C N C ), 115.2
( HC CH C NSO), 124.1 (HC CH C N SO), 124.3 (HC CH C N C ),
127.1, 128.0, 131.2, 133.0 (Carom,C6H5 ), 136.7 (HC CH C N SO), 137.0

524
A. HAJRI AND R. ABDERRAHIM
(HC CH C N C ), 155.7 ( N C(N) N ), 166.9 ( N C(CH3) N ). Calcd. for
C16H14N4SO: C, 61.90; H, 4.50; N, 18.00. Found: C, 62.03; H, 4.51; N, 18.03.
2-Benzyl-3-ethyl[1,2,4,6]thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one
(3f). Yield = 71%, mp = 143–145◦C, IR (CHCl3, ν (cm−1)): 1620 (C N),
3
1083 (S O). 1H NMR (CDCl3) δ 1.30 (t, JHH = 9.0 Hz, CH3 CH2, 3H),
3
2.65 (q, JHH = 6.1 Hz, CH3 CH2, 2H), 4.65 (s, 2H), 7.15–7.50 (m, 9H). 13C
NMR (CDCl3) δ. 11.8 (CH3 CH2), 26.4 (CH3 CH2), 40.5 (Ph CH2 N), 107.4
(HC CH C N C ), 110.5 ( HC CH C NSO), 125.2 (HC CH C N SO),
125.8 (HC CH C N C ), 126.2, 127.9, 130.4, 134.0 (Carom, C6H5 ), 138.5
(HC CH C N SO), 139.3 (HC CH C N C ), 154.5 ( N C(N) N ), 167.4
( N C( CH2 CH3) N ).Calcd for C17H16N4SO: C, 62.96; H, 4.93; N, 17.28. Found:
C, 62.94; H, 4.90; N, 17.32.
Synthesis of [1,3,5]Thiadiazino[3,4-a][1,3]benzimidazol-2-imine 4
Equimolecular amounts (1 mmol) of 1 and NaSCN were dissolved under vigorous
stirring in a mixture of ethanol (16 mL) and water (4 mL). After complete dissolution of the
reagents, the solution was heated under reflux for 3 h. After cooling to room temperature,
the organic solution was extracted with CHCl3 (3 × 15 mL). The organic phase was dried
over anhydrous MgSO4. Evaporation of the solvent under reduced pressure yielded crude
compound. The product was recrystallized from methanol to give 4a, 4b.
6-Methyl[1,3,5]thiadiazino[3,4-a][1,3]benzimidazol-2-imine (4a). Yield =
1
57%, mp = 226–227◦C, IR (CHCl3, ν (cm−1)): 1630(C N), 3445 (NH). H NMR
(DMSO-d6 + CDCl3) δ 1.70 (s, 3H), 4.96 (s, 1H), 6.71-7.30 (m, 4Harom). 13C
NMR (DMSO-d6 + CDCl3), δ: 19.1(CH3), 111.6 (HC C N C(NH S), 114.0
(HC C N C(N) N ), 118.1 (HC CH C N C ), 120.6 (HC CH C N
(NH) S ), 121.0 (HC C N C(NH) S), 136.8 (HC C N C(N) N ), 153.8
( N C(N) N ), 154.2 ( N C(S) NH), 173.0 ( N C( CH3) S ). Calcd for
C10H8N4S: C, 55.55; H, 3.70; N, 26.01. Found: C, 55.57; H, 3.65; N, 26.05.
6-Ethyl[1,3,5]thiadiazino[3,4-a][1,3]benzimidazol-2-imine (4b). Yield =
1
61%, mp = 212–214◦C, IR (CHCl3, ν (cm−1)): 1638 (C N), 3460 (NH). H NMR
3
(DMSO-d6 + CDCl3), δ 1.18 (t, 3JHH = 9.0 Hz, CH3 CH2, 3H), 2.70 (q, JHH
=
9.0 Hz, CH3 CH2, 2H), 5.80 (s, 1H), 7.00–7.50 (m, 4Harom). 13C NMR (DMSO-d6
+ CDCl3) δ 10.2 (CH3 CH2), 24.7 (CH3 CH2), 111.5 (HC C N C(NH S),
113.4 (HC C N C(N) N ), 119.4 (HC CH C N C ), 120.4 (HC CH C N
(NH) S ), 121.0 (HC C N C(NH) S), 137.7 (HC C N C(N) N ), 154.0
( N C(N) N ), 154.8 ( N C(S) NH), 174.1 ( N C( CH2 CH3) S ). MS
(m/z, %): 170 (20), 143 (42), 133 (100); 105 (12); 90 (3); 78 (25); 57 (11). Calcd for
C11H10N4S: C, 57.39; H, 4.38; N, 24.33. Found: C, 57.40; H, 4.35; N, 24.35.
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