Synthesis of benzimidazole ketene N,S-acetals and their reactions with nucleophiles

Article abstract of DOI:10.1081/SCC-120015809

The novel ketene thioacetal 4 and ketene N,S-acetal 5 were readily prepared by the reaction of 2-cyanomethylbenzimidazole with either carbon disulfide or phenyl isothiocyanate in the presence of a base, followed by alkylation of the produced salts with methyl iodide. The reaction of compounds 4 and 5 with hydrazines afforded different benzimidazolyl substituted pyrazoles.

Full text of DOI:10.1081/SCC-120015809

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Synthesis of Benzimidazole Ketene N , S -Acetals and
Their Reactions with Nucleophiles
Galal H. Elgemeie a , Hosny A. Ali b , Ahmed H. Elghandour b & Ahmed M. Hussein b
a Chemistry Department , Faculty of Science , Helwan University , Helwan, Cairo, Egypt
b Chemistry Department , Faculty of Science , Cairo University , Bani Suef Branch, Bani Suef,
Egypt
Published online: 16 Aug 2006.
To cite this article: Galal H. Elgemeie , Hosny A. Ali , Ahmed H. Elghandour & Ahmed M. Hussein (2003) Synthesis of
Benzimidazole Ketene N , S -Acetals and Their Reactions with Nucleophiles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:4, 555-562, DOI: 10.1081/SCC-120015809
To link to this article: http://dx.doi.org/10.1081/SCC-120015809
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 555–562, 2003
Synthesis of Benzimidazole Ketene N,S-Acetals
and Their Reactions with Nucleophiles
2
Galal H. Elgemeie,1, Hosny A. Ali,
*
Ahmed H. Elghandour,2 and Ahmed M. Hussein2
1Chemistry Department, Faculty of Science,
Helwan University, Helwan, Cairo, Egypt
2Chemistry Department, Faculty of Science,
Cairo University, Bani Suef Branch, Bani Suef, Egypt
ABSTRACT
The novel ketene thioacetal 4 and ketene N,S-acetal 5 were readily
prepared by the reaction of 2-cyanomethylbenzimidazole with either
carbon disulfide or phenyl isothiocyanate in the presence of a base,
followed by alkylation of the produced salts with methyl iodide. The
reaction of compounds 4 and 5 with hydrazinesafforded different
benzimidazolyl substituted pyrazoles.
Key Words: Benzimidazole ketene N,S-acetals; Nucleophiles;
Phenyl isothiocyanate; Pyrazoles; Benzimidazole derivatives.
*Correspondence: Galal H. Elgemeie, Chemistry Department, Faculty of
Science, Helwan University, Helwan, Cairo, Egypt; Fax: þ00202 5870668;
E-mail: rughe@rusys.eg.
555
DOI: 10.1081/SCC-120015809
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556
Elgemeie et al.
Heterocyclic ketene dithioacetals are versatile starting materials for
the synthesis of a wide variety of fused heterocyles.[1–3] Although their
synthesis and reactions have received much attention,[4] the synthesis and
reactionsof their correpsonding S,N- and S,O-acetalshave only been
studied in a few cases.[5] Recently, the synthesis and some reactions of
[6]
heterocyclic ketene S,S- and N,S-acetalshave been reported by u.s
Here, we describe the synthesis of benzimidazole ketene N,S-acetals
and their reactions with nucleophiles. Using the latter reactions, several
benzimidazolyl substituted pyrazole derivatives can be synthesized. Thus,
it hasbeen found that 2-cyanomethylbenzimidazole 1[7] reacted with
carbon disulfide in the presence of sodium ethoxide to give the corre-
sponding sodium monothiolate derivative 2 in high yields. The latter on
treatment with 1 eqv. of methyl iodide givesthe novel thioetser 4. The
structure of 4 (Sch. 1) has been established on the basis of its elemental
Scheme 1.

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Benzimidazole Ketene N,S-Acetals
557
analysis and spectral data (IR, 1H NMR, 13C NMR and MS). Thus,
structure 4 is supported by its mass spectrum which showed a molecular
formula C11H9N3S2 (Mþ ¼ 247). Compound 4 can potentially exist
in three tautomeric forms 4a–c. Spectral studies, however, indicated the
presence of the thione tautomer 4a in solutions. Thus, the 13C NMR
signal at 200.25 ppm indicated the presence of a thione carbon rather
than ¼C–SH. No significant amounts of the alternative tautomers 4b
and 4c could be detected. 1H NMR revealed a singlet band at ꢀ ¼
2.49 ppm assignable to a methylsulfanyl group and another multiplet at
ꢀ ¼ 7.34–7.69 ppm assignable to aromatic protons. Another broad singlet
appeared at ꢀ ¼ 13.61 ppm assignable to NH group. The course of the
reaction between 1 and carbon disulfide prompted us to investigate this
reaction between 1 and phenyl isothiocyanate under a basic reaction
condition. Thus, in a typical experiment, 2-cyanomethylbenzimidazole
1 reacted with phenyl isothiocyanate in DMF–KOH to give the corre-
sponding stable potassium salt 3. The latter on alkylation with methyl
iodide in methanol afforded the novel benzimidazole ketene N,S-acetal 5.
The structure of 5 was established on the basis of elemental analysis and
spectral data (IR, MS and 1H NMR). The analytical data for 5 revealed a
molecular formula C17H14N4S (Mꢀ ¼ 306). The 1H NMR spectrum
revealed a multiplet at ꢀ ¼ 7.17–7.62 ppm assigned to the aromatic
protonsand two broad isngletsat
ꢀ ¼ 12.49 and 12.57 ppm assignable
for two NH groups. Reaction of compound 4 with substituted hydrazines
in a molar ratio 1:1 in refluxing DMF containing a catalytic amount of
piperidine gave the corresponding 4-benzimidazolyl-5-aminopyrazole
derivatives 6. The structures of 6 (Sch. 2) were established on the basis
of their elemental analysis and spectral data (IR, MS, 1H NMR and
13C NMR). Thus, structure 6 is supported by its mass spectrum which
showed a molecular formula C10H9N5S (Mꢀ ¼ 231). Compound 6 can
potentially exist in two tautomeric forms, 5-aminopyrazolin-3-thione and
5-amino-3-mercaptopyrazole. The mercapto form would be expected to
be more stable, because of the weakened basicity of the ring N atom at
the 2-position, in turn arising from the adjacent heteroatom and the
sulfur atom at the 3-position. Spectral studies proved the mercapto
form and indicated the presence of the SH tautomer in solution (e.g.,
the 13C NMR signal at 150 ppm indicates a ¼C–SH rather than a thione
carbon). Similarly, the benzimidazole ketene N,S-acetal 5 reacted with
substituted hydrazines in refluxing ethanol containing a catalytic amount
of piperidine to give the corresponding pyrazole derivatives 8 in good
yields(method a). Structure 8a was supported by its mass (Mꢀ ¼ 290),
which agreeswith itsmolecular formula C 16H14N6; its 1H NMR spectrum
displayed signals at ꢀ ¼ 7.16–7.50 ppm related to the aromatic protons,

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558
Elgemeie et al.
Scheme 2.
a broad signal at ꢀ ¼ 7.92 ppm corresponding to the NH2 group and
another three singlets at ꢀ ¼ 7.99, 9.63 and 10.46 ppm assignable to the
three NH groups. Compounds 8 could also be prepared by alkylation of
the pyrazole derivatives 6 with methyl iodide followed by reaction with
aniline (Method B).

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Benzimidazole Ketene N,S-Acetals
559
In summary, we have achieved a highly regioselective synthesis of
interesting benzimidazole ketene N,S-acetalsand their converisonsto
several benzimidazolyl substituted pyrazole derivatives. The compounds
obtained seem promising as high potential antimetabolite agents.
EXPERIMENTAL
All melting pointsare uncorrected on a Gallenkamp melting point
apparatus. The IR spectra were recorded (KBr disk) on a Perkin Elmer
11650 FT-IR instrument. The 1H NMR spectra were measured on a
Varian 400 MHz spectrometer for solutions in (CD3)2SO using
Si(CH3)4 as an internal standard. Mass spectra were recorded on a
Varian MAT 112 spectrometer. Analytical data were obtained from the
Microanalytical Data Center at Cairo University.
Sodium Thiolate Derivative (2)
A mixture of 2-cyanomethylbenzimidazole 1 (0.01 mol) and sodium
ꢁ
ethoxide (0.02 mol) in ethanol (50 mL) wasgently heated at 40–50 C for
20 min. After the solution has become cold, carbon disulfide (0.01 mol) was
added gradually and the reaction mixture wasthen refluxed for 15 min.
The solvent was concentrated by evaporation over water bath. The per-
formed sodium salt was separated by filtration and recrystallized from
ethanol.
2: Yellow; m.p. >300ꢁC; yield, 58%; ꢁmax/cmꢀ1 (KBr) 3323, 3199
(NH); 2208 (CN); Found: C, 47.41; H, 2.01; N, 16.52%; Calcd. for
C10H6N3S2Na (255): C, 47.06; H, 2.35; N, 16.47%.
2-[(1-Cyano-2-methylsulfanyl-2-mercapto)ethylene]-
(1H )-benzimidazole (4)
To a cold solution of compound 2 (0.01 mol) in ethanol (30 mL),
methyl iodide (0.01 mol) was added dropwise and stirring was continued
for 1 h. The reaction mixture waspoured over ice-water mixture (50 mL).
The resulting solid product was collected by filtration and recrystallized
from ethanol.
4: Brown; m.p. >300ꢁC; from ethanol; yield, 78%; ꢁmax/cmꢀ1 (KBr)
3200 (NH); 2192 (CN); ꢀH [(CD3)2SO] 2.49 (s, 3H, CH3); 3.70 (s, 1H, CH);
7.34–7.69 (m, 4H, C6H4); 13.61 (s, 1H, NH); 13C NMR: 16.88 (SCH3);

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Elgemeie et al.
80.51(CH), 117.81 (CN); 124.27–129.80 (aromatic carbons); 149.45 (C-2);
200.25 (C¼S); m/z (248); Found: C, 53.02; H, 3.78; N, 16.94%; Calcd.
for C11H9N3S2 (247): C, 53.44; H, 3.64; N, 17.00%.
Potassium Thiolate Derivative (3)
A solution of compound 1 (0.01 mol) and phenyl isothiocyanate
(0.01 mol) in DMF (30 mL) wastreated with a oslution of KOH
(0.01 mol in 5 mL H2O). The mixture was stirred for 1 h and the resulting
salt product was collected by filtration and recrystallized from ethanol.
3: Yellow; m.p. >300ꢁC; yield, 91%; ꢁmax/cmꢀ1 (KBr) 3340, 3195
(NH); 2206 (CN); Found: C, 58.61; H, 2.88; N, 17.26%; Calcd. for
C16H11N4SK (330); C, 58.18; H, 3.33; N, 16.97%.
2-[(1-Cyano-2-methylthio-2-anilino)ethylene]-
(1H )-benzimidazole (5)
Methyl iodide (0.01 mol) wasadded gradually to a cooled solution of
the potassium salt 3 (0.01 mol) in DMF (30 mL). The reaction mixture
was left under stirring overnight and the resulting product was collected
by filtration and recrystallized from ethanol.
5: Brown; m.p. 219ꢁC; yield, 88% (according to Method A); 61%;
ꢁ
max/cmꢀ1 (KBr) 3450–3250 (NH); 2220 (CN); ꢀH [(CD3)2SO] 2.21 (s, 3H,
CH3); 7.17–7.62 (m, 9H, C6H5, C6H4); 12.49 (s, br, 1H, NH), 12.57 (s, br,
1H, NH); m/z (304); Found: C, 66.23; H, 4.72; N, 17.96%; Calcd. for
C17H14N4S (306): C, 66.66; H, 4.57; N, 18.30%.
4-[(1H )-Benzimidazolo-2-yl]-3-mercapto-
5-aminopyrazoles (6a,b)
A mixture of compounds 4a,b (0.01 mol) and hydrazine hydrate or
phenyl hydrazine (0.01 mol) wasrefluxed in DMF (30 mL) containing
a catalytic amount of piperidine for 4 h. The solvent was evaporated
and the resulting product was collected by filtration and recrystallized
from ethanol.
6a: Colorless; m.p. 230ꢁC; yield, 65%; ꢁmax/cmꢀ1 (KBr) 3214,
1
3460, 3370 (NH, NH2); H NMR: 4.56 (s, 2H, NH2); 7.23–7.81 (m, 4H,
C6H4), 10.49 (s, br, 1H, NH), 12.00 (s, br, 1H, SH); Found: C, 52.12;

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Benzimidazole Ketene N,S-Acetals
561
H, 3.58; N, 30.61%; Calcd. for C10H9N5S (231): C, 51.94; H, 3.89;
N, 30.30%.
6b: Yellow; m.p. 206ꢁC; from ethanol; yield, 69%; ꢁmax/cmꢀ1 (KBr)
1
3468–3215 (NH, NH2); H NMR: 4.99 (s, 2H, NH2); 7.05–7.76 (m, 9H,
C6H5, C6H4), 9.89 (s, br, 1H, NH); Found: C, 62.00; H, 4.61, N, 23.11%;
Calcd. for C16H13N5S (307); C, 62.54; H, 4.23, N, 22.80%.
1-Substituted-3-methylthio-4-[(1H )-benzimidazolo-2-yl]-
5-aminopyrazoles (7a,b)
A mixture of 6 (0.01 mol), KOH (0.01 mol) and methyl iodide
(0.01 mol) in ethanol (30 mL) wasrefluxed for 30 min and then diluted
with cold water (50 mL). The resulting solid product was collected by
filtration and recrystallized from ethanol.
7a: Colorless; m.p. 258ꢁC; yield, 48%; ꢁmax/cmꢀ1 (KBr) 3124, 3186,
3435 (NH, NH2); 1H NMR: 2.55 (s, 3H, SCH3), 4.89 (s, 2H, NH2);
7.11–7.67 (m, 4H, C6H4), 11.00 (s, br, 1H, NH); m/z (245); Found:
C, 53.97; H, 4.01; N, 28.33%; Calcd. for C11H11N5S (245): C, 53.88;
H, 4.48; N, 28.57%.
7b: Yellow; m.p. 243ꢁC; yield, 61%; ꢁmax/cmꢀ1 (KBr) 3195, 3296
(NH, NH2); m/z (321); Found: C, 63.97; H, 4.20; N, 21.55%; Calcd.
for C17H15N5S (321): C, 63.55; H, 4.67; N, 21.81%.
1-Substituted-3-phenylamino-4-[2-(1H )benzimidazolo-yl]-
5-amino-pyrazoles (8a,b)
Method A
To a mixture of 5 (0.01 mol) and hydrazine or phenylhydrazine
(0.01 mol) in ethanol (50 mL), pipridine (3 drops) was added. The mixture
washeated under reflux for 3–6 h. The resultant precipitate wasisolated
by suction and recrystallized from ethanol.
Method B
A mixture of compound 7a,b (0.01 mol) and aniline (0.01 mol) was
refluxed in ethanol for 6 h. The solvent was concentrated by evaporation

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Elgemeie et al.
and the formed product wascollected by filtration and recrytsallized
from ethanol.
8a: Yellow; m.p. >300ꢁC; from ethanol; yield, 78%; ꢁmax/cmꢀ1
(KBr)ꢀ 3480–3230 (NH, NH2); 1H NMR: 7.16–7.50 (m, 9H, C6H5,
C6H4), 7.92 (s, br, 2H, NH2), 7.99 (s, br, 1H, NH), 9.63 (s, br, 1H,
NH), 10.46 (s, br, 1H, NH); m/z (291); Found: C, 65.97; H, 4.58;
N, 28.57% Calcd. for C16H14N6 (290); C, 66.20; H, 4.82; N, 28.96%.
8b: Yellow; m.p. 287ꢁC; from ethanol; yield, 79%; ꢁmax/cmꢀ1 (KBr)
3330, 3340, 3450 (NH, NH2); 1H NMR: 7.00–7.77 (m, 14H, 2C6H5,
C6H4), 7.92 (s, br, 2H, NH2), 9.76 (s, br, 1H, NH), 10.34 (s, br, 1H, NH);
m/z (291); found: C, 72.42; H, 4.68; N, 23.10%. Calcd. for C22H18N6
(366): C, 72.13; H, 4.92; N, 22.95%
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Chem. Soc. Jpn. 1994, 67, 738.
2. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Ahmed, S.A.
J. Chem. Soc. Perkin Trans. 1 1997, 3285.
3. Tominaga, Y. J. Heterocyclic Chem. 1989, 26, 1167.
4. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Hussein, A.M.
J. Chem. Research (S) 1997, 256.
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Received in the UK August 16, 2001