Easy access to triazoles, triazolopyrimidines, benzimidazoles and imidazoles from imidates

Article abstract of DOI:10.1016/j.tetlet.2008.07.134

We have described a new and easy synthesis of triazoles, triazolopyrimidines, benzimidazoles and imidazoles variously substituted based on the reaction of imidates with diamine derivatives. The products were obtained in moderate to good yields. A general mechanism for the reactions is proposed.

Full text of DOI:10.1016/j.tetlet.2008.07.134

Tetrahedron Letters 49 (2008) 5883–5886
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Easy access to triazoles, triazolopyrimidines, benzimidazoles and imidazoles
from imidates
a
c
a
b
A. Zarguil a, , S. Boukhris , M. L. El Efrit , A. Souizi , E. M. Essassi
*
a Equipe de Synthèse Organique, Organométallique et Agrochimie, Département de Chimie, Faculté des Sciences, Université Ibn Tofaïl, BP 133 Kénitra, Maroc
b Laboratoire de Chimie Organique, Département de Chimie, Faculté des Sciences, Université Mohammed V, Rabat, Maroc
c Laboratoire de Synthèse Organique, Faculté des Sciences de Tunis II, Campus Universitaire 1060 Tunis, Tunisie
a r t i c l e i n f o
a b s t r a c t
Article history:
We have described a new and easy synthesis of triazoles, triazolopyrimidines, benzimidazoles and
imidazoles variously substituted based on the reaction of imidates with diamine derivatives. The
products were obtained in moderate to good yields. A general mechanism for the reactions is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 2 June 2008
Revised 19 July 2008
Accepted 23 July 2008
Available online 29 July 2008
Keywords:
Imidates
Triazoles
Triazolopyrimidines
Benzimidazoles
Imidazoles
The study of heterocyclic systems of triazole, triazolopyrimi-
dine, benzimidazole and imidazole type has known a considerable
development due to the revealing of their varied effects in diverse
domains. These last years, research become intensified and turned
to the synthesis of this kind of compounds1 and the study of their
activities in the pharmacological and agrochemical fields.
Indeed, these compounds are widely used in agricultural chem-
istry as herbicides2 and in the biosynthesis of chlorophylls.3 They
are known for their antitumoral,4 antibiotic,2a antifungal2a,5 and
antibacterial5 properties. They also present inhibitive properties
of corrosion of metals.6
(Scheme 1). The typical experimental procedure is outlined in
Ref. 8. The yields of these reactions are collected in Table 1.
All triazoles 3 were characterized by satisfactory HRMS and by
NMR spectroscopy.8
Scheme 1 depicts a mechanism which shows the formation of
3-amino-1,2,4-triazoles 3. This reaction is comparable to mecha-
nisms described in the literature.9
The reaction was assumed to proceed by substitution of the eth-
oxy group of 1 or 2 with the hydrazines giving intermediates 4 or 5,
which then immediately yield 1,2,4-triazoles 3 by reaction of
heterocyclisation.
Owing to all these real and potential properties we established a
research program that focussed on the synthesis of new triazoles
and triazolopyrimidines, and resulted in the discovery of a simple
and general route for the preparation of 3-amino-1,2,4-triazoles
and 7-amino-1,2,4-triazolopyrimidines starting from the corre-
sponding imidates 1 and 2.
Indeed, the bis electrophilic character of easily accessible imi-
dates7 1 and 2 would allow to postulate that their reaction with
the hydrazine derivatives could constitute an easy access to new
series of 3-amino-1,2,4-triazoles 3.
In order to confirm the mechanism, we verified that the ther-
molysis of amidrazones 5, which we isolated by an independent
way,10 in methanol gives exclusively 3-amino-1,2,4-triazoles 3
(Scheme 2).
With a simple and fast synthesis of 3-amino-1,2,4-triazoles 3 in
hand, it appeared interesting to use these compounds as precur-
sors to prepare 7-amino-1,2,4-triazolopyrimidines 6. Although
the synthetic methods of triazolopyrimidines are well docu-
mented, the methods for the synthesis of 7-amino-1,2,4-triazolo-
pyrimidines 6 are limited.
When a variety of imidates 1 or 2 were treated with hydrazine
derivatives, good yields of 3-amino-1,2,4-triazoles 3 was obtained
Indeed, 7-amino-1,2,4-triazolopyrimidines 611 are easily ob-
tained, in good yields, by simple refluxing 3-amino-1,2,4-triazoles
3 in toluene for 48 hours (Scheme 3, Table 2).
The structure of these triazolopyrimidines 6 is confirmed by 1H
and 13C NMR and by mass spectrometry.
In this Letter, we also report a convenient method for the
synthesis of new benzimidazoles 7 and imidazoles 8.
* Corresponding author. Fax: +212 37329433.
E-mail address: Zarguil_abdelkebir@hotmail.fr (A. Zarguil).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.134

5884
A. Zarguil et al. / Tetrahedron Letters 49 (2008) 5883–5886
S
S
N
C
N
C
H2NNHR1
+
NHR2
NHR2
R
R
C
C
R
C
NHNHR1
OEt
NHR2
N R1
1
4
N
R
N
3
N CN
N CN
OEt
H2NNHR1
+
R
C
NHNHR1
2
5
Scheme 1. Mechanism of the formation of 1,2,4-triazoles 3.
Table 1
Prepared 3-amino-1,2,4-triazoles 3
Substrate
R
R2
R1
Conditions (°C, h)
Product (Yielda (%), mp (°C))
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
2a
2b
2c
C6H5
4-MeC6H4
C6H5
4-MeC6H4
C6H5
4-MeC6H4
C6H5CH2
C6H5CH2
C6H5CH2
C6H5
4-MeC6H4
C6H5CH2
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
CH3
CH3
C6H5
C6H5
H
CH3
25, 20
25, 20
25, 20
25, 20
25, 20
25, 20
25, 20
25, 20
25, 20
25, 24
25, 24
25, 24
Reflux, 20
Reflux, 20
Reflux, 20
3a (70, 253)
3b (67, 132)
3c (62, 265)
3d (58, 185)
3e (90, 88)
3f (67, 146)
3g (72, 112)
3h (65, 80)
3i (69, 176)
3j (79, 80)
3k (67, 145)
3l (67, 180)
3n (86, 88)
3o (71, 135)
3p (68, 142)
C6H5
CH2CH2CN
CH2CH2CN
CH2CH2CN
CH2CH2CN
CH2CH2CN
CH2CH2CN
Et
C6H5
H
H
a
Yields of isolated, purified products. The solid compounds can be recrystallised from CCl4.
tion with nucleophilic reagents, either as 1,3-difunctional agents
(ß-ketoesters, ketonitriles) or as an imidic source such as orthoes-
ters, carbon disulfide and aldehydes.
NH2
N CN
N
MeOH
R
C
N CH2CH2CN
R
reflux, 10 h
N
These conditions led us to imagine that the reaction of these
imidates with o-phenylenediamine derivatives or ethylenediamine
could constitute a new access to benzimidazoles and imidazoles
respectively.
NHNHCH2CH2CN
5
3
Scheme 2. Synthesis of 1,2,4-triazoles 3.
Effectively, good yields of benzimidazoles 712 have been
obtained by the reaction of o-phenylenediamine with imidates 2
in refluxing methanol (Scheme 4, Table 3).
NH2
N
NH2
N
N
Benzimidazoles 7 were characterised by their spectroscopic
data of NMR and by satisfactory HRMS.
The reaction proceeds by the substitution of the ethoxy group of
2 with the o-phenylenediamine, which leads the unstable amidraz-
ones 9. Then, elimination of the cyanamide molecule yields benz-
imidazoles 7.
Toluène
N CH2CH2CN
N
N
R
R
reflux, 48 h
N
3
6
Scheme 3. Synthesis of 7-amino-1,2,4-triazolopyrimidines 6.
We could not, unfortunately, obtain benzodiazepines 10
(Scheme 5). This shows that imidates 2 behave as 1,1-bis electro-
philic agents towards o-phenylenediamine.
Table 2
Preparation of 7-amino-1,2,4-triazolopyrimidines 6
Our route to imidazoles 8 is shown in Scheme 6, a key inter-
Product
R
Yielda (%)
Mp (°C)
mediate being amidrazones 11.13
6a
6b
6c
CH3
C2H5
C6H5
64
72
70
224
235
220
The typical experimental procedure is outlined in Ref. 14. The
yields of these reactions are collected in Table 3.
In conclusion, we have described a new convenient one-step
synthesis of a new series of 3-amino triazoles and 7-amino triazolo-
pyrimidines. The easy removal of the benzimidazoles and imida-
zoles makes this method competitive with other procedures.
Further studies of these reactions are under investigation.
a
Yields obtained after recrystallisation from chloroform.
Indeed, imidates 1 and 2 possess several reagent sites in parti-
cular in position 1,3. They can behave, in intermolecular condensa-

A. Zarguil et al. / Tetrahedron Letters 49 (2008) 5883–5886
5885
2006, 45, 8235–8238; (c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. 2002, 114, 2708–2711; (d) Yan, Z. Y.; Zhao, Y. B.; Fan, M. J.;
Liu, W.-M.; Liang, Y. M. Tetrahedron 2005, 61, 9331–9337; (e) Wu, Y. M.; Deng,
J.; Li, Y. L.; Chen, Q. Y. Synthesis 2005, 1314–1318; (f) Rogue, D. R.; Neill, J. L.;
Antoon, J. W.; Stevens, E. P. Synthesis 2005, 2497–2502; (g) Barral, K.;
Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809–1811; (h) Kamijo, S.;
Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786–7787; (i)
Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Zunino, E.; Vaccaro, L. J. Org.
Chem. 2005, 70, 6526–6529.
N CN
NH
R
C
X
Y
NH2
NH2
N CN
OEt
R
C
+
NH2
2
X
2. (a) Li, W.; Wu, Q.; Yu, Y.; Luo, M.; Hu, L.; Gu, Y.; Niu, F.; Hu, J. Spectrochim. Acta,
Part A 2004, 60, 2343–2354; (b) Findeisen, K.; Santel, H. J.; Eur. Pat. App. Ep 412,
358 CA, 114, 185517 n, 1991.
Y
9
3. Padmanabraham, D.; Regupathy, D. Adv. Plant Reprod. Physiol. 1976, 254–261.
4. Hiasa, Y.; Ohshima, M.; Kitahori, Y. Carcinogenesis 1982, 3, 381–384.
5. (a) Hardman, J.; Limbird, L.; Gilman, A. Goodman and Gilman’s The
Pharmacological Basis of Therapeutics, 9th ed.; McGraw-Hill: New York, 1996.
p 988; (b) Gennaro Remington, A. R. In The Science and Practice of Pharmacy;
Mack Easton: PA, 1995; Vol. II, p 1327; (c) Richardson, K; Whittle, P. J. Eur. Pat.
Appl. Ep. 115, 416, 1984; (d) Richardson, K.; Whittle, P. J. Chem. Abstr. 1984,
101, 230544; (e) Ammermann, E.; Loecher, F.; Lorenz, G.; Janseen, B.; Karbach,
S.; Meyer, N. Brighton Crop Prot. Conf. Pests. Dis 1990, 2, 407–414; (f) Heindel, N.
D.; Reid, J. R. J. Heterocycl. Chem. 1980, 17, 1087–1088.
X
N
N
R
Y
H
7
6. (a) Mernari, B.; Elattari, H.; Traisnel, M.; Bentiss, F.; Langrenee, M. Corros. Sci.
1998, 40, 391–399; (b) Bentiss, F.; Langrenee, M.; Traisnel, M.; Hornez, J. C.
Corros. Sci. 1999, 41, 789–803.
Scheme 4. Synthesis of benzimidazoles 7.
7. Imidates 1: To a solution of iminoester (10 mmol), prepared according to the
method described by Pinner,16 in ethanol and nitrile (15/15 mL) was bubbled by
dry HCl. Then, the iminoester was free of its salt, in 50 mL of ether, by a solution
of sodium carbonate. Phenylthioisocyanate (10 mmol) was added dropwise at
0 °C in the thus formed iminoester. The mixture was stirred for 2 h and the ether
was evaporated. The imidate 1 was recrystallised from petroleum ether.
Table 3
Prepared benzimidazoles 7, amidrazoles 11 and imidazoles 8
Product
R
X
Y
Yielda (%)
Mp (°C)
For example, 1 (R = C6H5, R2 = C6H5), Yield = 80%, mp = 113 °C; IR (CHCl3):
m
1120, 1655, 3395 cmÀ1
.
1H NMR (CDCl3) d ppm: 9.95 (m, 1H, NH), 7.10–8.0 (m,
7a
7b
7c
7d
8a
8b
11a
11b
CH3
C6H5
CH3
C6H5
CH3
C6H5
CH3
H
H
CH3
CH3
—
—
—
—
H
H
CH3
CH3
—
—
—
—
79
68
69
65
75
69
78
65
171 (lit.15 170)
291 (lit.15 291)
10H, Ar), 4.35 (q, 2H, CH2), 1.35 (t, 3H, CH3).
Compound 1 (R = 4-MeC6H4, R2 = C6H5), Yield = 77%, mp = 135 °C; IR (CHCl3):
m
251
221
267
183
199
181
1120, 1655, 3395 cmÀ1.1H NMR (CDCl3) d ppm: 9.60 (m, 1H, NH), 7.00–7.50 (m,
9H, Ar), 4.30 (q, 2H, CH2), 1.32 (t, 3H, CH3), 2.30 (s, 3H, CH3). Imidates 2: A
mixture of orthoester (0.12 mol), cyanamide (0.1 mol) and few drops of acetic
acid was refluxed during 6 h and distilled then under vacuum (14 mmHg).
For example,
2220 cmÀ1 1H NMR (CDCl3) d ppm: 4.01 (q, 2H, CH2), 2.02 (s, 3H, CH3), 1.25
(t, 3H, CH3).Compound 2 (R = C2H5), Yield = 84%, Eb = 120 °C; IR (CHCl3): 1655,
2220 cmÀ1 1H NMR (CDCl3) d ppm: 4.05 (q, 2H, CH2), 1.95 (q, 2H, CH2), 1.25 (t,
3H, CH3), 1.20 (t, 3H, CH3).
2 (R = CH3), Yield = 78%, Eb = 110 °C; IR (CHCl3): m 1655,
C6H5
.
m
a
Yields of isolated, purified products. The solid compounds can be recrystallised
.
from me.
8. To a solution of imidates 1 or 2 (10 mmol) in methanol (40 mL) were added
hydrazine derivatives (10 mmol). The solution was refluxed for 2 h and
concentrated under reduced pressure to afford 3-amino-1,2,4-triazoles 3.
m .
1540, 3435 cmÀ1 1H NMR (DMSO-d6) d ppm:
NH2
NH
R1
For example, 3b, IR (CHCl3):
N
N
X
Y
7.0–7.60 (m, 9H, Ar), 6.33 (s, 1H, NH), 3.67 (s, 1H, NH), 2.30 (s, 3H, CH3). Anal.
Calcd: C, 72.00; N, 22.40; H, 5.60. Found: C, 71.58; N, 22.51; H, 5.61.
Compound 3h, IR (CHCl3):
m .
1560, 3440 cmÀ1 1H NMR (CDCl3) d ppm: 7.10–
7.50 (m, 10H, Ar), 6.45 (s, 1H, NH), 3.93 (s, 2H, CH2), 3.50 (s, 3H, CH3). Anal.
Calcd: C, 72.00; N, 22.40; H, 5.60. Found: C, 71.58; N, 22.51; H, 5.61.
Compound 3o, IR (CHCl3): m .
1580, 2240, 3310, 3400 cmÀ1 1H NMR (DMSO-d6) d
10
ppm: 4.65 (s, 2H, NH2), 4.27 (t, 2H, CH2), 2.85 (t, 2H, CH2), 2.52 (q, 2H, CH2),
1.23 (t, 3H, CH3). Anal. Calcd: C, 72.00; N, 22.40; H, 5.60. Found: C, 71.58; N,
22.51; H, 5.61.
Scheme 5. Benzotriazepines 10.
9. Baccar, B.; Mathis, F. C.R. Acad. Sci. Paris 1965, 26, 174–177.
10. A mixture of imidate 2 (10 mmol), 2-cyano ethylhydrazine (10 mmol) and
methanol (40 mL) was stirred during one day at 25 °C. After evaporation of the
solvent under reduced pressure, the precipitated product 5 was recrystallised
from methanol.
NH2
N CN
OEt
N CN
25 °C, 4 h
R
R
+
For example, 5 (R = C6H5), Yield = 69%, mp = 104 °C; IR (CHCl3):
m 2142, 2223,
MeOH
NHCH2CH2NH2
3320, 3380 cmÀ1 1H NMR (CDCl3) d ppm: 9.95 (m, 1H, NH), 6.90–7.40 (m, 5H,
.
NH2
Ar), 4.66 (s, 1H, NH), 2.43 (s, 1H, NH), 3.96 (t, 2H, CH2), 2.73 (t, 2H, CH2).
11. A mixture of imidate 2 (10 mmol), 2-cyano ethylhydrazine (10 mmol) and
toluene (40 mL) was stirred efficiently under reflux for 48 h. The solution was
concentrated under reduced pressure to afford triazolopyrimidines 6.
2
11
reflux, 28 h
m .
1600, 3200, 3480 cmÀ1 1H NMR (CDCl3) d ppm:
MeOH
For example, 6a, IR (CHCl3):
4.70 (s, 2H, NH2), 4.20 (t, 2H, CH2), 3.90 (t, 2H, CH2), 2.20 (s, 3H, CH3). 13C NMR:
18.4 (s, CH3), 159.0 (s, CH3C@N), 152.6 (s, C@N), 39.4 (t, 1J = 124.1 Hz, NCH2),
31.4 (t, 1J = 124.3 Hz, CH2C=N), 163.2 (s, C–NH2). HMRS calcd for C6H9N5 (M+Å):
151.085; found, 151.087.
N
R
Compound 6b, IR (CHCl3):
m .
1610, 3200, 3480 cmÀ1 1H NMR (CDCl3) d ppm:
N
H
4.80 (s, 2H, NH2), 4.20 (t, 2H, CH2), 3.90 (t, 2H, CH2), 1.90 (q, 2H, CH2), 1.20 (t,
3H, CH3). HMRS calcd for C7H11N5 (M+Å): 165.101; found, 165.103.
12. To a solution of o-phenylenediamine (10 mmol) in methanol (40 mL) was added
a solution of imidate 2 (10 mmol). The solution was then stirred under reflux for
10 h and concentrated under reduced pressure to afford benzimidazoles 7.
8
Scheme 6. Synthesis of amidrazones 11 and imidazoles 8.
For example, 7a, IR (KBr):
m .
1620, 3100, 3220 cmÀ1 1H NMR (CDCl3) d ppm:
7.01–7.50 (m, 4H, Ar), 6.66 (s, 1H, NH), 2.51 (s, 3H, CH3). 13C NMR: 19.1 (s, CH3);
153.1 (s, CCH3); 115.2 123.0, 123.2, 138.2, 193.1 (Ar-ring C). HMRS calcd for
C8H8N2 (M+Å): 132.068; found, 132.070.
References and notes
Compound 7c, IR (KBr): m .
1605, 3100, 3300 cmÀ1 1H NMR (CDCl3) d ppm: 6.40–
7.23 (s, 2H, Ar), 5.70 (s, 1H, NH), 2.30 (s, 3H, CH3), 2.20 (s, 3H, CH3). HMRS calcd
1. (a) Barluenga, J.; Valdes, C.; Beltran, G.; Escribano, M.; Aznar, F. Angew. Chem.,
Int. Ed. 2006, 45, 6893–6896; (b) Lipshutz, B. H.; Taft, B. R. Angew. Chem., Int. Ed.
for C10H12N2 (M+Å): 160.100; found, 160.097.

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A. Zarguil et al. / Tetrahedron Letters 49 (2008) 5883–5886
13. To a solution of ethylenediamine (10 mmol) in methanol (40 mL) was added a
solution of imidate (10 mmol). The solution was then stirred at room
Compound 8a, IR (KBr): m .
1550, 3100, 3400 cmÀ1 1H NMR (DMSO-d6) d ppm:
2
2.01 (s, 3H, CH3), 3.80 (m, 4H, 2 CH2), 4.20 (s, 1H, NH). HMRS calcd for C4H8N2
temperature for 4 h and concentrated under reduced pressure to afford
(M+Å): 84.280; found, 84.277.
amidrazones 11.
For example, 11a, IR (KBr):
Compound 8b, IR (KBr): m .
1510, 1550, 3200–3400 cmÀ1 1H NMR (DMSO-d6) d
m
1550, 2160, 3100, 3400 cmÀ1
.
1H NMR (DMSO-d6)
ppm: 6.70–7.20 (m, 5H, Ar), 3.90 (m, 4H, 2 CH2), 5.70 (s, 1H, NH). HMRS calcd
d ppm: 4.40 (s, 1H, NH), 2.80 (t, 2H, CH2), 2.0 (t, 2H, CH2), 2.20 (s, 3H, CH3) 1.70
(s, 2H, NH2).
for C9H10N2 (M+Å): 146.084; found, 146.080.
15. Essassi, E. M.; Lavergne, J. P.; Vialleffont, Ph. J. Heterocycl. Chem. 1975, 12, 661–
666.
16. Pinner, A. Chem. Ber. 1894, 2861–2870 and references cited therein.
14. To a solution of ethylenediamine (10 mmol) in methanol (40 mL) was added a
solution of imidate 2 (10 mmol). The solution was then stirred under reflux for
28 h and concentrated under reduced pressure to afford imidazoles 8.