Syntheses of substituted 2-(2-alkylthio-1-benzyl-5-imidazolyl)-1,3,4-oxadiazoles

Article abstract of DOI:10.1002/jhet.5570390434

Starting from the readily available benzylamine hydrochloride a series of 2-(2-alkylthio-1-benzyl-5imidazolyl)-1,3,4-oxadiazoles were prepared.

Full text of DOI:10.1002/jhet.5570390434

Jul-Aug 2002
Syntheses of Substituted 2-(2-Alkylthio-1-benzyl-
5-imidazolyl)-1,3,4-oxadiazoles
841
F. Hadizadeh* and F. I. Tafti
Faculty of Pharmacy, The Medical Sciences University of Mashhad, Mashhad, P.O.Box 91775-1365, Iran
Received September 5, 2001
Starting from the readily available benzylamine hydrochloride a series of 2-(2-alkylthio-1-benzyl-5imida-
zolyl)-1,3,4-oxadiazoles were prepared.
J. Heterocyclic Chem., 39, 841 (2002).
In view of potential biological activity of imidazolyloxa-
diazoles, it was our interest to prepare the title compounds
9a-c as posssible effective muscarinic agonists [1]. The
synthesis of the desired compounds as possible effective
muscarinic agonists were accomplished according to
Scheme 1.
Benzylamine hydrochloride (1) was stirred with 1,3-
dihydroxyacetone dimmer and potassium thiocyanate to give
5-hydroxymethyl-2-mercapto-1-benzylimidazole (2)[2].
Subsequent alkylation of compound 2 with alkyl halides
afforded 2-alkylthio-1-benzylimidazole (3)[3,4,5]. Oxidation
of 3 with manganese dioxide in chloroform gave 2-alkylthio-
1-benzyl-5-formylimidazole(4)[6], which was further oxi-
dized by alkaline solution of silver nitrate to give 2-alkylthio-
1-benzylimidazole-5-carboxylic acid (5)[7]. Esterification
of 5 with methanol gave methyl 2-alkylthio-1-benzylimida-
zole-5-carboxylate (6). Addition of hydrazine hydrate to
compound 6 gave the corresponding hydrazide (7).
Refluxing compound 7 with formic acid overnight, gave 1-
(2-alkylthio-1-benzylimidazole-5-carbonyl)-2-formylhy-
drazine in high yield (8). Compound 8 was refluxed with
thionyl chloride in the presence of a few drops pyridine as
catalyst for one hour to give the title compound 2-(2-
alkylthio-1-benzyl-5-imidazolyl)-1,3,4-oxadiazole (9)[7].
Scheme 1

842
F. Hadizadeh and F. I. Tafti
Vol. 39
EXPERIMENTAL
Anal. Calcd. for C H N OS : C, 62.06; H, 5.17; N, 12.06.
12 12 2
Found: C, 62.27; H, 5.07; N, 11.91.
Melting points were determined on Electrothermal Capillary
apparatus and are uncorrected. The ir
1-Benzyl-2-ethylthio-5-formylimidazole (4b).
This compound was obtained in 90% yield; mp 30-33°; ir
spectra were obtained usin a Perkin-Elmer Model paragon
-1
1
(potassim bromide):ν 1661cm (C=O); H nmr (deuteriochloro-
form): δ 9.6 (s, 1H, CHO), 7.76 (s, 1H, H-C imidazole), 7.25
1
1000. H nmr were obtained on Bruker Ac-80 spectrophotometer
4
and chemical shifts (δ) are in ppm relative to internal tetram-
ethylsilane. Mass spectra were obtained on a Finnigan MAT TSQ
70 spectrometre at 70 eV.
–7.12 (m, 5H, aromatic), 5.49 (s, 2H, CH N), 3.37 (q, 2H, CH S,
2
2
J = 8Hz), 1.38 ppm (t, 3H, CH , J = 8Hz).
3
Anal. Calcd. for C H N OS: C, 63.41; H, 5.69; N, 11.38.
13 14
2
General Procedure for Preparation of 2-Alkylthio-5-hydroxy-
methyl-1-benzylimidazoles (3a-c).
Found: C, 63.24; H, 5.83; N, 11.27.
1-Benzyl-2-benzylthio-5-formylimidazole (4c).
This compound was obtained in 80% yield; mp 66-68°; ir
To a stirring suspension of compound 2 (34.7 mmoles) in
methanol (500 ml) was added dropwise sodium hydroxide (1.0 N,
36 ml) at room temperature. The clear pale yellow suspension
was stirred for 10 minutes. Iodomethane (47.8 mmoles, 3ml) was
added dropwise and stirring was continued overnight. After evap-
oration of the methanol, the residue was suspended in water and
extracted with chloroform (3 x 100ml). The solvent was evapo-
rated and the residue was crystallized from ethyl acetate to give
compounds 3a-c.
-1
1
(potassim bromide):ν 1668cm (C=O); H nmr (deuteriochloro-
form): δ 9.6 (s,1H, CHO), 7.73 (s, 1H, H-C imidazole), 7.32 –6.97
4
(m, 10H, aromatic), 5.36 (s, 2H, CH N), 4.42 ppm (s, 2H, CH S).
2
2
Anal. Calcd. for C H N OS : C, 70.12; H, 5.19; N, 9.09.
18 16
2
Found: C, 69.91; H, 5.41; N, 8.81.
General Procedure for Preparation of 2-Alkylthio-1-benzylimida-
zole-5-carboxylic Acids (5a-c).
1-Benzyl-5-hydroxymethyl-2-methylthioimidazole (3a).
Compound 3 (12.93 mmoles), silver nitrate (17.65 mmoles),
sodium hydroxide (37.5 mmoles) and distilled water (100 ml) were
combined and stirred overnight. The mixture was filtered and its pH
was adjusted between 3-4 by adding HCl (2 N). A precipitate was
formed which was isolated by filtration to give compounds 5a-c.
This compound was obtained in 78% yield; mp 103-104°; ir
-1
1
(potassium bromide): ν 3110 cm (OH); H nmr (CD OD): δ
3
7.48-7.16 (m, 6H, aromatic, H-C imidazole), 5.48 (s, 2H,
4
CH N), 4.56 (s, 2H, CH O), 2.55 ppm (s, 3H, CH S).
2
2
3
Anal. Calcd. for C H N OS: C, 61.53; H, 5.98; N, 11.96.
Found: C, 61.33; H, 6.08; N, 12.20.
12 14
2
1-Benzyl-2-methylthioimidazole-5-carboxylic Acid (5a).
This compound was obtained in 75% yield; mp 205-207°; ir
1-Benzyl-2-ethylthio-5-hydroxymethylimidazole (3b).
This compound was obtained in 72% yield; mp 106-107°; ir
-1
1
(potassim bromide):ν 1700cm (C=O); H nmr (deuteriochloro-
form): δ 7.81 (s, 1H, H-C imidazole), 7.33- 7.01 (m, 5H, aro-
4
-1
1
matic), 5.47 (s, 2H, CH N), 2.67ppm (s, 2H, CH S).
(potassim bromide):ν 3109cm (OH); H nmr(CD OD): δ 7.55-
2
3
3
Anal. Calcd. for C H N O S: C, 58.06; H, 4.83; N, 11.29.
7.02 (m, 6H, aromatic, H-C imidazole), 5.44(s, 2H, CH N),
12 12
2 2
4
2
Found: C, 58.12; H, 4.96; N, 11.43.
4.60(s, 2H, CH O), 3.04 (q, 2H, CH S, J = 8Hz), 1.40 ppm (t,
2
2
3H, CH , J = 8Hz).
Anal. Calcd. for C H N OS : C, 62.90; H, 6.45; N, 11.29.
Found: C, 62.83; H, 6.55; N, 11.33.
3
1-Benzyl-2-ethylthioimidazole-5-carboxylic Acid (5b).
This compound was obtained in 91% yield; mp 158-160°; ir
13 16
2
-1
1
(potassim bromide): ν 1694cm (C=O); H nmr (deuteriochloro-
1-Benzyl-2-benzylthio-5-hydroxymethylimidazole (3c).
This compound was obtained in 72% yield; mp 108-110°; ir
form): δ 7.81 (s, 1H, H-C imidazole), 7.33- 7.01 (m, 5H, aro-
4
matic), 5.47 (s, 2H, CH N), 3.14 (q, 2H, CH S, J = 8Hz), 1.28
2
2
-1
1
ppm (t, 3H, CH , J= 8 Hz).
(potassim bromide):ν 3214cm (OH); H nmr(CD OD): δ 7.40
3
3
Anal. Calcd. for C H N O S : C, 59.54; H, 5.34; N, 10.68.
–6.81 (m, 11H, aromatic, H-C imidazole), 5.00 (s, 2H, CH N),
13 14
2 2
4
2
Found: C, 59.65; H, 5.48; N, 10.51.
4.38(s, 2H, CH O), 4.12 ppm (s, 2H, CH S).
2
2
Anal. Calcd. for C H N OS : C, 69.67; H, 5.80; N, 9.03.
Found: C, 69.90; H, 5.83; N, 8.79.
18 18
2
1-Benzyl-2-benzylthioimidazole-5-carboxylic Acid (5c).
This compound was obtained in 76% yield; mp 155-157°; ir
General Procedure for Preparation of 2-Alkylthio-1-benzyl-5-
formylimidazoles (4a-c).
-1
1
(potassim bromide): ν 1694cm (C=O); H nmr (deuteriochloro-
form): δ 7.87 (s, 1H, H-C imidazole), 7.32- 6.97 (m, 10H, aro-
4
matic), 5.47 (s, 2H, CH N), 4.42ppm (s, 2H, CH S).
A stirring suspension of compound 3 (25.62 mmoles) and
manganese dioxide (165.6 mmoles) in chloroform (100 ml) was
refluxed overnight. The reaction mixture was cooled to room
temperature and filtered. The chloroform was evaporated and the
residue was crystallized from ether to give compounds 4a-c.
2
2
Anal. Calcd. for C H N O S: C, 66.66; H, 4.93; N, 8.64.
18 16
2 2
Found: C, 66.81; H, 5.05; N, 8.53.
General Procedure for Preparation of Methyl 2-Alkylthio-1-ben-
zylimidazole-5-carboxylates (6a-c).
1-Benzyl-2-methylthio-5-formylimidazole (4a).
Compound 5 (9.68 mmoles), absolute methanol (100 ml) and
concentrated sulfuric acid (98%, 0.12 ml) were combined and
refluxed overnight. After cooling the mixture was basified with
sodium bicarbonate and extracted with chloroform (3x100ml).
Solvent was dried (sodium sulfate) and evaporated at reduced
pressure to afford oily compounds 6a-c.
This compound was obtained in 92.5% yield; mp 73-78°; ir
-1
1
(potassim bromide):ν 1655cm (C=O); H nmr (deuteriochloro-
form): δ 9.60 (s,1H, CHO), 7.77 (s, 1H, H-C imidazole), 7.25
4
–7.12 (m, 5H, aromatic), 5.48 (s, 2H, CH N), 2.67ppm (s, 3H,
2
CH S).
3

Jul-Aug 2002
Syntheses of Substituted 2-(2-Alkylthio-1-benzyl-5-imidazolyl) -1,3,4-oxadiazoles
843
Methyl 1-Benzyl-2-methylthioimidazole-5-carboxylate (6a).
This compound was obtained in 79% yield; ir (chloroform):ν
General Procedure for Preparation of 1-(2-Alkylthio-1-benzyl-5-
imidazolecarbonyl)-2-formylhydrazine (8a-c).
-1
1
1713cm (C=O); H nmr (deuteriochloroform): δ 7.80 (s, 1H, H-
C imidazole), 7.32- 7.27 (m, 5H, aromatic), 5.50 (s, 2H, CH N),
A solution of compound 7 ( 6.87mmoles ) in formic acid
(35ml) was refluxed overnight. After evaporation of the solvent,
the residue was washed with diethyl ether to give compounds 8a-
c.
4
2
3.70 (s, 3H, CH O), 2.67 ppm (s, 3H, CH S).
3
3
Anal. Calcd. for C H N O S: C, 59.54; H, 5.34; N, 10.68.
13 14
2 2
Found: C, 59.77; H, 5.54; N, 10.56.
1-(1-Benzyl-2-methylthio-5-imidazolecarbonyl)-2-formylhy-
Methyl 1-Benzyl-2-ethylthioimidazole-5-carboxylate (6b).
This compound was obtained in 81% yield; ir (chloroform): ν
drazine (8a).
This compound was prepared in 95% yield; mp 215-220°, ir
-1
1
-1
1713cm (C=O); H nmr (deuteriochloroform): δ 7.80 (s, 1H, H-
C imidazole), 7.32- 7.27 (m, 5H, aromatic), 5.50 (s, 2H, CH N),
(potassium bromide): ν 3460, 3260 (NH),1680, 1650cm (C=O);
1
H nmr (deuteriochloroform): δ 8.08(s, 1H, COH), 7.71 (s, 1H,
4
2
3.70(s, 3H, CH O),3.14 (s, 2H, CH S, J = 8Hz), 1.28 ppm (s, 3H,
H-C imidazole), 7.50 – 7.00(m, 10H, aromatic), 5.50 (s, 2H,
3
2
4
CH J = 8Hz).
CH N), 2.64ppm (s, 3H, CH S).
2 3
3,
Anal. Calcd. for C H N O S: C, 60.86; H, 5.79; N, 10.14.
Anal. Calcd. for C H N O S: C, 53.79; H, 4.82; N, 19.31.
14 16
2
2
13 14 4 2
Found: C, 60.82; H, 5.61; N, 10.28.
Found: C, 53.58; H, 4.85; N,19.22.
Methyl 1-Benzyl-2-benzylthioimidazole-5-carboxylate (6c).
This compound was obtained in 65% yield; ir (chloroform): ν
1-(1-Benzyl-2-ethylthio-5-imidazolecarbonyl)-2-formyl-
hydrazine (8b).
-1
1
1712cm (C=O); H nmr (deuteriochloroform): δ 7.80 (s, 1H, H-
imidazole), 7.32- 6.97 (m, 10H, aromatic), 5.50 (s, 2H,
This compound was prepared in 95% yield; mp 180-185°, ir
-1
C
(potassium bromide): ν 3460, 3260 (NH),1680, 1650cm (C=O);
4
1
CH N), 4.42 (s, 2H, CH S), 3.70 ppm (s, 3H, CH O).
H nmr (deuteriochloroform): δ 7.90(s, 1H, COH), 7.65 (s, 1H,
2
2
3
Anal. Calcd. for C H N O S: C, 67.45; H, 5.32; N, 8.28.
H-C imidazole), 7.50 – 7.00(m, 7H, aromatic, NHNH), 5.60 (s,
19 18
2
2
4
Found: C, 67.61; H, 5.11; N, 8.08.
2H, CH N), 3.15(q, 2H, CH S, J= 8Hz), 1.28ppm (s, 3H, CH ,
2
2
3
J = 8Hz).
General Procedure for Preparation of 2-Alkylthio-1-benzylimida-
Anal. Calcd. for C H N O S: C, 55.26; H, 5.26; N, 18.42.
Found: C, 55.57; H, 4.99; N, 18.73.
14 16
4 2
zole-5-carboxylic Acid Hydrazides (7a-c).
To a solution of compound 6 (9.06 mmoles) in ethanol (20 ml),
hydrazine hydrate (2.2ml, 45.3 mmoles) was added. After 30
minutes the precipitate was isolated by filtration and crystallized
from ethanol to give compounds 7a-c.
1-(1-Benzyl-2-benzylthio-5-imidazolecarboxyl)-2-formylhy-
drazine (8c).
This compound was prepared in 50% yield as an oil; ir (chlo-
-1
1
roform):ν 3460, 3260 (NH),1680, 1650cm (C=O); H nmr
(deuteriochloroform): δ 7.90 (s, 1H, COH), 7.65 (s, 1H, H-C
1-Benzyl-2-methylthioimidazole-5-carboxylic Acid Hydrazide
(7a).
4
imidazole), 7.32 – 7.00(m, 12H, aromatic, NHNH), 5.54 (s, 2H,
CH N), 4.42 ppm (s, 2H, CH S).
This compound was obtained in 90% yield; mp 95-98°, ir
2
2
-1
(potassium bromide):ν 3315, 3240(NH , NH), 1651cm (C=O);
Anal. Calcd. for C H N O S : C, 62.29; H, 4.91; N, 15.30.
2
19 18
4 2
1
H nmr (dimethyl sulfoxide-d ): δ 7.65 (s, 1H, H-C imidazole),
Found: C, 62.17; H, 5.16; N, 15.07.
6
4
7.33 - 7.01 (m, 5H, aromatic), 5.54 (s, 2H, CH N), 2.52 ppm (s,
2
General Procedure for Preparation of 2-(2-Alkylthio-1-benzyl-5-
imidazolyl)-1,3,4-oxadiazoles (9a-c).
3H, CH S).
3
Anal. Calcd. for C H N OS: C, 54.96; H, 5.34; N, 21.37.
12 14
4
Found: C, 54.74; H, 5.30; N, 21.17.
Compound 8 (3.45 mmoles), thionyl chloride (15 ml) and a
few drops of pyridine as catalyst were refluxed for one hour.
After cooling, this mixture was added dropwise to a cold satu-
rated solution of sodium bicarbonate (20 ml). A brown oil was
formed. The oily residue was solved in acetone (10 ml) and fil-
tered. The solvent was evaporated to give oily compounds 9a-c.
1-Benzyl-2-ethylthioimidazole-5-carboxylic Acid Hydrazide
(7b).
This compound was obtained in 95% yield; mp 72-73°, ir
-1
(potassium bromide):ν 3320, 3260 (NH , NH), 1653cm (C=O);
2
1
H nmr (dimethyl sulfoxide-d ): δ 7.65 (s, 1H, H-C imidazole),
6
4
2-(1-Benzyl-2-methylthio-5-imidazolyl)-1,3,4-oxadiazole (9a).
This compound was prepared in 42% yield; ir (chloroform): ν
7.33 - 7.01 (m, 5H, aromatic), 5.54 (s, 2H, CH N), 3.14 (q, 2H,
2
CH S, J = 8Hz), 1.28 ppm (s, 3H, CH , J = 8Hz).
2
3
-1
1
Anal. Calcd. for C H N OS : C, 56.52; H, 5.79; N, 20.28.
3050cm (H-C aromatic); H nmr (CD OD): δ 8.95 (s, 1H, H-C
13 16
4
3 5
Found: C, 56.42; H, 5.55; N, 20.35.
oxadiazole), 8.00 (s, 1H, H-C imidazole), 7.40 – 7.00 (m, 5H,
4
aromatic), 5.60 (s, 2H, CH N), 2.64 ppm (s, 3H, CH S).
2
3
1-Benzyl-2-benzylthioimidazole-5-carboxylic Acid Hydrazide
(7c).
Anal. Calcd. for C H N OS: C, 57.35; H, 4.41; N, 20.58.
13 12
4
Found: C, 57.62; H, 4.67; N, 20.41.
This compound was obtained in 60% yield; mp 75-77°, ir
2-(1-Benzyl-2-ethylthio-5-imidazolyl)-1,3,4-oxadiazole (9b).
This compound was prepared in 50% yield; ir (chloroform): ν
-1
(potassium bromide):ν 3315, 3240 (NH , NH), 1651cm (C=O);
2
1
H nmr (dimethyl sulfoxide-d ): δ 7.65 (s, 1H, H-C imidazole),
6
4
-1
1
7.32 – 6.97(m, 10H, aromatic), 5.54 (s, 2H, CH N), 4.42ppm (s,
3050cm (H-C aromatic); H nmr (CD OD): δ 8.95 (s, 1H, H-C
2
3 5
2H, CH S).
oxadiazole), 8.00 (s, 1H, H-C imidazole), 7.40 – 7.00 (m, 5H,
4
2
Anal. Calcd. for C H N OS: C, 63.90; H, 5.32, N, 16.56.
aromatic), 5.60 (s, 2H, CH N), 3.10(q, 2H, CH S, J = 8Hz), 1.20
18 18
4
2 2
Found: C, 63.58; H, 5.51; N, 16.81.
ppm (s, 3H, CH , J = 8Hz).
3

844
F. Hadizadeh and F. I. Tafti
Vol. 39
REFRENCES AND NOTES
Anal. Calcd. for C H N OS : C, 58.74; H, 4.89; N, 19.58.
14 14
4
Found: C, 58.94; H, 4.99; N, 19.37.
[1] G. Shapiro and A. Anz, Drugs of the Future, 17, 489 (1992).
[2] J. V. Duncia, A. T. Chiu, D. C. Carini, G. B. Gregory, A. L.
Johnson, W. A. Price, G. J. Wells, P. C. Wong, J. C. Calabrese and P. B.
M. W. M. Timmermans, J. Med. Chem., 33, 1330 (1990).
[3] A. Shafiee, T. Akbarzadeh, A. Foroumadi and F. Hadizadeh, J.
Heterocyclic Chem. 35, 141 (1998).
2-(1-Benzyl-2-benzylthio-5-imidazolyl)-1,3,4-oxadiazole (9c).
This compound was prepared in 45% yield; ir (chloroform): ν
-1
1
3050cm (H-C aromatic); H nmr (CD OD): δ 8.95 (s, 1H, H-C
3
5
oxadiazole), 8.00 (s, 1H, H-C imidazole), 7.32-6.97 (m, 10H,
4
aromatic), 5.60 (s, 2H, CH N), 4.42 ppm (s, 2H, CH S).
2
2
[4]
D. J. Carini and J. V. Duncia, Eur Pat. Appl. Ep 253, 310
Anal. Calcd. for C H N OS: C, 65.51; H, 4.59; N, 16.09.
(1988); Chem Abstr., 109, 129008g (1988).
19 16
4
Found: C, 65.27; H, 4.26; N, 16.37.
[5] A, Shafiee, F. Hadizadeh and S. B. Noori, J. Heterocyclic
Chem., 37, 1015 (2000).
[6] A. Shafiee and F. Hadizadeh, J. Hetrerocyclic Chem., 34, 549
(1997).
[7] F. Firoozi, K. Javidnia, M. Kamali, A. Fooladi, A. Foroumadi
and A. Shafiee, J. Heterocyclic Chem., 32, 123 (1995).
Acknowledgement.
This research was fully supported by the Research Council of
the Medical Sciences University of Mashhad.