Accepted Manuscript

I2 mediated one-pot synthesis of 1,2,4-triazoles from amidines and imidates

Surendra Babu Inturi, Biswajit Kalita, A. Jafar Ahamed
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S0040-4039(16)30365-3
http://dx.doi.org/10.1016/j.tetlet.2016.04.015
TETL 47515

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Tetrahedron Letters

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Please cite this article as: Inturi, S.B., Kalita, B., Jafar Ahamed, A., I2 mediated one-pot synthesis of 1,2,4-triazoles
from amidines and imidates, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.015

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I2 mediated one-pot synthesis of 1,2,4-triazoles

from amidines and imidates
Surendra Babu Inturi, Biswajit Kalita, A. Jafar Ahamed

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Tetrahedron Letters

I2 mediated one-pot synthesis of 1,2,4-triazoles from amidines and imidates

Surendra Babu Inturia, Biswajit Kalitaa, and A. Jafar Ahamedb,
a

Medicinal Chemistry Division, Jubilant Biosys Ltd, #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560022, Karnataka, India

Post Graduate and Research Department of Chemistry, Jamal Mohamed College (Autonomous), Tiruchirappalli - 620020, Tamil Nadu, India

A RT I C L E I N F O

A BS T RA C T

Article history:
Received
Received in revised form
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Available online

A one-pot facile synthesis of 3,5-disubstituted-1H-1,2,4-triazole derivatives using I2/Cs2CO3 has

been described. The method involves readily available inexpensive reagents and is applicable to
a wide range of substrates. The transformation involves a one-pot sequential C-N and N-N bond
forming reactions with high product yields and selectivity, and offers a new and useful strategy
for synthesis of 3,5-disubstituted-1H-1,2,4-triazole derivatives.

Keywords:
Amidine
Imidate
Triazole
One-pot synthesis
Bioactive molecules

Introduction
Triazoles are a unique class of nitrogen-rich heterocycles and
have appeared as one of the key pharmacophores in many
bioactive molecules1 including major applications in the area of
material sciences and organocatalysis.2 1,2,4-triazole derivatives,
in particular, have been a key focus in multiple therapeutic areas
like anticancer, antibacterial, antifungal, antimicrobial, antiviral,
antidepressant, anticonvulsant, anti-inflammatory and central
nervous system modulators.3,4
Several methods to construct 1,2,4-trazoles have been
developed over the years.5 Transition metal catalyzed reactions
have also been emerging which employ CuCl or CuCl2 in
presence of O2,6 Cu(OAc)2,7 CuBr,8 Cu powder9 and Cu(OTf)210
as catalysts. Metal catalyzed reactions, although have wide
applications, may impose limitations to aryl halides because of
possible metal-halogen exchange reactions. Also use of an
external oxidant could lead to substrate specific side reactions.
In the recent past, molecular iodine has been utilized as an
inexpensive and environmentally benign reagent in many organic
transformations11 including some of the well-developed
methodologies such as construction of C-C, C-N, C-O and C-S
bonds.12 This has prompted us to investigate and develop a metalfree system using I2 for the direct synthesis of 1,2,4-triazoles
having a broad substrate scope.

2009 Elsevier Ltd. All rights reserved .

Herein we have disclosed a simple and inexpensive reagent

system consisting of I2/Cs2CO3 in o-DCB for a one-pot direct
synthesis of 3,5-disubstituted-1H-1,2,4-triazole derivatives from
amidines and imidates. The reagent system is well tolerated over
a wide range of substrates with good to excellent yields and does
not require any external oxidant or additive.
Results and discussions
In an effort to develop a metal-free reagent system to
synthesize 1,2,4-trazoles, we utilized molecular I2 as a promoter
using benzimidamide hydrochloride (1a) as a test substrate,
toluene as a solvent and Cs2CO3 as a base under heating at 120
o
C (Table 1, entry 1). To our delight, the reaction yielded 28% of
3,5-diphenyl-1H-1,2,4-triazole (2a). From the solvent screening
studies, we found that under an un-optimized condition,
I2/Cs2CO3/o-DCB system was superior to all other systems that
we had tested giving 39% yield of the corresponding 3,5diphenyl-1H-1,2,4-triazole (2a) (Table 1, entry 6). These initial
findings along with the uniqueness of the method have prompted
us to investigate and optimize the novel transformation to
synthesize 1,2,4-triazole derivatives. The optimization conditions
are summarized in Table 1.
Based on these initial outcomes, we planned to further
optimize the reaction condition to improve yields and
demonstrate the novelty of the methodology. To this effort, we
decided to evaluate the loading of I2 at different molar ratios
followed by base equivalents.

Corresponding author. Tel.: +91-80-6662-8645; e-mail: biswajit_kalita@jubilantbiosys.com

Corresponding author. Tel.: +91-431-242-0333; e-mail: agjafar@yahoo.co.in

Tetrahedron

Table 1. Optimization of reaction conditions for the one-pot

cyclization of benzamidine hydrochloride (1a) to 3,5diphenyl-1H-1,2,4-triazole (2a)a

Entry

Base

Solvent

Temp (C)

Yieldb (%)

Cs2CO3

Toluene

120

28

Cs2CO3

1,2-DCE

86

Traces

Cs2CO3

o-Xylene

130

15

Cs2CO3

DMSO

130

Cs2CO3

DMF

120

Traces

Cs2CO3

o-DCB

130

39

Cs2CO3

o-DCB

rt

Cs2CO3

o-DCB

50

NaHCO3

o-DCB

130

22

10

K2CO3

o-DCB

130

19

11

Na2CO3

o-DCB

130

12

NaOMe

o-DCB

130

13

DBU

o-DCB

130

All reactions were carried out by using 1a (1 mmol), base (2 mmol) and
iodine (1 mmol) in solvent (3.0 mL) stirred for 16 h at the specified
temperature.
b
Isolated yields.

(<10%) was observed in presence of 20 mol% of I2 and 2

equivalents of Cs2CO3 under the given reaction conditions. Table
2 summarizes the results of a set of multi-parameter optimization
reactions.
To test the versatility of I 2/Cs2CO3/o-DCB system, it was used
to synthesize a wide variety of 3,5-disubstituted-1H-1,2,4triazoles with a broad substrate scope (see Table 3). A range of
functional groups were tolerated with this reagent system with
good to excellent yields. Electronic effect of the substituents
seem to play a key role in the kinetics of the transformation and
hence on the yields. Aryl rings with electron withdrawing
substituents (Table 3, 2b, 2f and 2g) gave a better yield than the
corresponding ones with electron donating substituents (Table 3,
2e and 2i). Meta substituted electron withdrawing substrate gave
slightly lower yield (Table 3, entry 11) compared to that with a
para substituted one (Table 3, entry 6). With a methyl
substitution at the meta position (Table 3, entry 12) a relatively
lower yield was obtained compared to the meta -CF3 substituted
compound (Table 3, entry 11). To our observation, aliphatic
amidine (acetimidamide hydrochloride) did not produce the
corresponding triazole. The excellent tolerance of the halogens
(Table 3, 2c, 2d and 2h) and good yield with NO2 substitution
in the transformation provide an access to generate a 1,2,4triazole based library of compounds for further applications. The
substrate scope is generalized in Table 3.

Table 3. Substrate scope for the synthesis of 3,5-diaryl-1H1,2,4-triazole 2a

Table 2. Optimization results of I2 and Cs2CO3 equivalents in

the formation of 2aa
Entry

R1

R2

R3

R4

Product

Yieldb (%)

2a

78

2b

85

Br

2c

71

Cl

2d

78

Entry

I2 (equiv)

Cs2CO3 (equiv)

Time (h)

Yieldb (%)

18

CH3

2e

50

37

CF3

2f

82

16

Traces

OCF3

2g

74

16

Traces

2h

65

16

21

OCH3

2i

30

16

78

10

Cl

2j

73

16

32

11

CF3

2k

65

16

12

CH3

2l

47

16

13

NO2

2m

43

10

0.2

16

14

2n

46

15

CF3

2o

80

16

CH3

2p

58

17

Br

CH3

2q

67

18

Cl

2r

61

19

Br

Br

2s

60

20

2t

54

All reactions were carried out by using 1a (1 mmol), Cs2CO3 and iodine
(equiv as specified in table) in o-DCB (3.0 mL) stirred at 130 C for the
specified time (h).
b
Isolated yields.

From a set of optimization reactions, it was found that a

combination of 2 equivalents of I2 and 2 equivalents of Cs2CO3 in
o-DCB at 130 oC afforded product 2a in 78% yield (Table 2,
entry 6). It was also found that increase in either I2 or Cs2CO3
alone beyond 2 equivalents and both up to 3 equivalents while
keeping rest of the reaction conditions same did not improve the
product yield of 2a. Absence of either I2 or Cs2CO3 did not
produce 2a (Table 2, entry 8 and 9). Trace amount of triazole 2a

All reactions were carried out by using 1 (1.0 mmol), Cs2CO3 (2.0 mmol)
and iodine (2.0 mmol) in o-DCB (3.0 mL) stirred at 130 C for 16 h.
b
Isolated yields.

3
To test the broader applicability, the metal free I2 promoted
reaction was applied for synthesis of the unsymmetrical triazole
4a (see Table 4). Reaction between an equimolar ratios of ethyl
cyclopropanecarbimidate hydrochloride (3a) and benzimidamide
hydrochloride (1a) using 4 equivalents of I2 and 4 equivalents of
Cs2CO3 in o-DCB at 130 oC over 16 h afforded 10% of 4a along
with 15% of 2a (Table 4, entry 1).
To improve the yield and selectivity of 4a, we used various
equivalence of 3a and I2 and it was found that 1 equivalent of I2
in presence of 2 equivalent of 3a and 4 equivalent of Cs2CO3
gave the best yield of 44% of 4a while the triazole 2a was
formed in 7% under the reaction condition (Table 4, entry 3). To
minimize the formation of 2a, an altered protocol was adopted
where 1a (1 equivalent) was added to the imidate 3a (1
equivalent) in three portions (0.4, 0.3 and 0.3 equivalents) over a
period of 5 h under the reaction condition and observed <5%
product formation. Optimization results are summarized in Table
4.

Table 4. Optimization results of I2 promoted unsymmetrical

3,5-disubstituted-1H-1,2,4-triazole formation a

Scheme 1. Synthesis of 5-(4-methoxyphenyl)-3-phenyl-1H1,2,4-triazole (4h).

Moderate to good yields were achieved for more complex
unsymmetrical 3,5-disubstituted-1H-1,2,4-triazoles using an
amidine and an imidate as reactants (Table 5). In case of 3 with
R2 as cyclopropyl, minor amount of the symmetrical triazole 2a
(R1=H) was observed (7%) because of a parallel competing
reaction by the amidine 1 (R1=H), which could be easily removed
during purification. There was no 3,5-dicyclopropyl-1H-1,2,4triazole product observed from imidate 3 when R2 was
cyclopropyl. However, with substituted aryl imidates 3 (Table 5,
entries 8, 9 and 10), symmetrical triazoles derived from imidates
alone were isolated up to 9% yields along with the products
derived from the amidines 1 up to 10% yields.

Table 5. Substrate scope for the synthesis of unsymmetrical

3,5-disubstituted-1H-1,2,4-triazoles 4a
Entry

3a (equiv)

I2 (equiv)

Cs2CO3 (equiv)

Yieldb 4a/2a (%)

10/15

20/12

44/7

25/8

1.5

30/9

17/6

15/8

Entry

All reaction were carried out by using 1a (1 mmol), 3a, Cs2CO3 and iodine
(equiv as specified in table) in o-DCB (4.0 mL) stirred at 130 C for 16 h .
b
Isolated yields.

The assigned triazole structure of 4a was confirmed by X-ray

crystallography (Figure 1).

R1
H

R2
Cyclopropyl

Yieldb (%)

Product
d

44/7

4a/2a

4-F

Cyclopropyl

4b/2b

49/5

4-CH3

Cyclopropyl

4c/2ed

38/10

40/8
38/9

4-Br

Cyclopropyl

4d/2c

4-I

Cyclopropyl

4e/2hd
d

4-CF3

Cyclopropyl

4f/2f

3-Cl

Cyclopropyl

4g/2jd
c

46/7
41/6
d

4-OCH3 -C6H4

4h /2a /2i

32/6/8

4-OCF3-C6H4

4ic/2ad/2gd

36/10/9

10

4-I

4-OCH3 -C6H4

4j /2h /2i

42/6/7

Figure 1. X-ray crystal structure (ORTEP) of 4a (CCDC No.

1427079); ellipsoids drawn at 40% probability level.

However to our observation, with aromatic imidate 3b using 1

equivalent of I2 4h was formed in 20% yield along with 2a and 2i
(Scheme 1). To overcome this limitation, we increased I2 up to 2
equivalence to afford 4h in 32% isolated yield along with 2a
(6%) and 2i (8%).

All reactions were carried out by using 1 (1.0 mmol), 3 (2.0 mmol), Cs2CO3
(4.0 mmol) and iodine (1.0 mmol) in o-DCB (4.0 mL) stirred at 130 C for 16
h.
b
Isolated yields.
c
2.0 mmol of iodine was used.
d
Refer to Table 3.

In Scheme 2, it is proposed that the oxidative iodination of

amidine A generates the transient intermediate B which
undergoes an in-situ addition-elimination sequential reaction via
intermediate D to deliver product 2a. A second hypothesis that a
nucleophilic attack of 1a by itself shown in Scheme 3 did not
produce intermediate E as evidenced from LCMS supports that
the Scheme 3 does not operate in the pathway.

Tetrahedron

Scheme 2. Proposed reaction pathway for the formation of 2a.

Scheme 3. Studies on the mechanism of formation of 2a.

In conclusion, we have developed a I2/Cs2CO3 mediated metal
free methodology to synthesize symmetrical and unsymmetrical
3,5-disubstituted-1H-1,2,4-triazole derivatives from amidines and
imidates involving one-pot C-N and N-N bond formation. The
reaction proceeds with high yields and selectivities over a wide
range of substrates including halogen containing aromatic
substrates. Importantly, the method does not require any external
oxidant, additive and a dry atmosphere, and offers a highly cost
effective way to synthesize this novel class of pharmaceutically
important heterocycles.

Acknowledgments
The authors thank Dr. Sriram Rajagopal, CSO; Dr. Pravin
Iyer, Dr. Raghava Reddy Kethiri and the senior management of
Jubilant Biosys Ltd., Bangalore for providing facilities and
support to conduct the research work. Authors are thankful to
SAIF of Indian Institute of Technology, Madras, Chennai, India
for providing the single crystal X-ray data.
References and notes
1.

2.

(a) Yasger, P. D. et. al. U.S. Patent 43066241, June 10, 2010. (b)
Aster, S. D.; Graham, D. W.; Kharbanda, D.; Patel, G.; Ponpipom,
M.; Santorelli, G. M.; Szymonifka, M. J.; Mundt, S. S.; Shah, K.;
Springer, M. S.; Thieringer, R.; Hermanowski-Vosatka, A.;
Wright, S. D.; Xiao, J.; Zokian, H.; Balkovec, J. M. Bioorg. Med.
Chem. Lett. 2008, 18, 2799-2804. (c) He, Q.; Yang, B.; Wang, W.;
Wu, H.-H.; Fang, R. Contraception 2003, 68, 289-295. (d) Bo, Y.;
Lin, C.; Ruiying, F.; Zhiping, G. Eur. J. Pharmacol. 1999, 380,
145-152. (e) Yang, B.; Fang, R. Acta Pharm. Sin. 1996, 17, 361365. (f) Galliani, G.; Luzzani, F.; Colombo, G.; Conz, A.;
Mistrello, L.; Barone, D.; Lancini, G. C.; Assandri, A.
Contraception 1986, 33, 263-283.
(a) Hull, J. W.; Romer, D. R.; Adaway, T. J.; Podhorez, D. E. Org.
Process Res. Dev. 2009, 13, 1125-1129. (b) Al-Masoudi, I. A.; Al-

Soud, Y. A.; Al-Salihi, N. J.; Al-Masoudi, N. A. Chem.

Heterocycl. Compd. (N.Y.) 2006, 42, 1377-1403.
3.
For reviews on the biological activity of 1,2,4-triazoles, see: (a)
Sahoo, S.; Veliyath, S. K.; Kumar, M. C. B. Int. J. Res. Pharm.
Sci. 2012, 3, 326-333. (b) Kathiravan, M. K.; Salake, A. B.;
Chothe, A. S.; Dudhe, P. B.; Watode, R. P.; Mukta, M. S.;
Gadhwe, S. Bioorg. Med. Chem. 2012, 20, 5678-5698. (c) Wahi,
A. K.; Singh, A. Asian J. Biochem. Pharm. Res. 2011, 1, 193-205.
(d) Lass-Florl, C. Drugs 2011, 71, 2405-2419. (e) Kumar, S. S.;
Kavitha, H. P. Mini-Rev. Org. Chem. 2013, 10, 40-65.
4.
For selected examples of 1,2,4-triazoles with biological activities,
see: (a) Singh. R. J. Der. Pharma Chem. 2009, 1, 141-145. (b)
Chu, Y.; Xu, M. X.; Lu, D. Chin. Chem. Lett. 2004, 15, 10111014. (c) Desai, S.; Laddi, U.; Bennur, R.; Bennur, S. Indian J.
Chem. 2013, 52B, 1176-1181. (d) Holla, B. S.; Poojary, K. N.;
Rao, B. S.; Shivananda, M. K. Eur. J. Med. Chem. 2002, 37, 511517. (e) Plech, T.; Luszczki, J. J.; Wujec, M.; Flieger, J.; Pizori,
M. Eur. J. Med. Chem. 2013, 60, 208-215.
5.
(a) Holm, S. C.; Straub, B. F. Org. Prep. Proced. Int. 2011, 43,
319-347. (b) Moulin, A.; Bibian, M.; Blayo, A.-L.; Habnouni, S.
E.; Martinez, J.; Fehrentz, J.-A. Chem. Rev. 2010, 110, 1809-1827.
(c) Castanedo, G. M.; Seng, P. S.; Blaquiere, N.; Trapp, S.;
Staben, S. T. J. Org. Chem. 2011, 76, 1177-1179. (d) Staben, S.
T.; Blaquiere, N. Angew. Chem., Int. Ed. 2010, 49, 325-328. (e)
Pellizzari, G. Gazz. Chim. Ital. 1911, 41, 20. (f) Yeung, K.-S.;
Farkas, M. E.; Kadow, J. F.; Meanwell, N. A. Tetrahedron Lett.
2005, 46, 3429-3432. (g) Potts, K. T. J. Chem. Soc. 1954, 34613464. (h) Omodei-Sale, A.; Consonni, P.; Galliani, G. J. Med.
Chem. 1983, 26, 1187-1192. (i) Francis, J. E.; Gorczyca, L. A.;
Mazzenga, G. C.; Meckler, H. Tetrahedron Lett. 1987, 28, 51335136. (j) Haddadin, M. J.; Zadeh, H. G. Tetrahedron Lett. 2010,
51, 1654-1656. (k) Samanta, S. K.; Yli-Kauhaluoma, J. J. Comb.
Chem. 2005, 7, 142-146. (l) Wang, J.-K.; Zong, Y.-X.; Yue, G.-R.
Synlett 2005, 1135-1136. (m) Brunn, E.; Funke, E.; Gotthardt, H.;
Huisgen, R. Chem. Ber. 1971, 104, 1562-1572.
6.
Kauffmann, T.; Albrecht, J.; Berger, D.; Legler, J. Angew. Chem.,
Int. Ed. Engl. 1967, 6, 633-634.
7.
(a) Li, Z.; Zhang, Z.; Zhang, W.; Liu, Q.; Liu, T.; Zhang, G.
Synlett 2013, 24, 2735-2739. (b) Xu, H.; Ma, S.; Xu, Y.; Bian, L.;
Ding, T.; Fang, X.; Zhang, W.; Ren, Y. J. Org. Chem. 2015, 80,
1789-1794.
8.
Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 1508015081.
9.
Xu, H.; Jiang, Y.; Fu, H. Synlett 2013, 24, 125-129.
10. Sudheendran, K.; Schmidt, D.; Frey, W.; Conrad, J.; Beifuss, U.
Tetrahedron, 2014, 70, 1635-1645.
11. For reviews on reactivities of iodine in organic synthesis, see: (a)
Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979-999. (b)
Ren, Y.-M.; Cai, C.; Yang, R.-C. RSC Adv. 2013, 3, 7182-7204.
(c) Zhao, J.; Gao, W.; Chang, H.; Li, X.; Liu, Q.; Wei, W. Youji
Huaxue 2014, 34, 1941 (in Chinese). (d) Parvatkar, P. T.;
Parameswaran, P. S.; Tilve, S. G. Chem. -Eur. J. 2012, 18, 54605489
, D.; Zupan, M. Tetrahedron 2011, 67,
1355-1387. (f) Mphahlele, M. J. Molecules 2009, 14, 5308-5322.
(g) Banerjee, A. K.; Vera, W.; Mora, H.; Laya, M. S.; Bedoya, L.;
Cabrera, E. V. J. Sci. Ind. Res. 2006, 65, 299-308. (h) Togo, H.;
Iida, S. Synlett 2006, 2006, 2159-2175. (i) Gogoi, P.; Konwar, D.
Org. Biomol. Chem. 2005, 3, 3473-3475.
12. For I2 mediated oxidative CX (X = O, S and N) bond formation
reactions, see: (a) Niu, P.; Kang, J.; Tian, X.; Song, L.; Liu, H.;
Wu, J.; Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 1018-1024. (b)
Zhang, X.; Kang, J.; Niu, P.; Wu, J.; Yu, W.; Chang, J. J. Org.
Chem. 2014, 79, 10170-10178. (c) Yu, W.; Huang, G.; Zhang, Y.;
Liu, H.; Dong, L.; Yu, X.; Li, Y.; Chang, J. J. Org. Chem. 2013,
78, 10337-10343.

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Highlights

Iodine is used to synthesize 3,5disubstituted-1H-1,2,4-triazoles.

One-pot sequential C-N and N-N bond

formation.

No external oxidant, additive and dry

atmosphere is needed.

Good yields and substrate compatibilities.