A novel one-pot synthesis of 1,2,4-triazole-3,5-diamine derivatives from isothiocyanates and mono-substituted hydrazines

Article abstract of DOI:10.1016/S0040-4039(02)02871-X

1,2,4-Triazole-3,5-diamine derivatives were synthesized in moderate to high yields in one-pot reaction from the corresponding isothiocyanates, mono-substituted hydrazines, and sodium hydrogencyanamide, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Typically, two target compounds were obtained, but high regioselectivities to one isomer were observed when aromatic and sterically bulky hydrazines were used. A number of examples with a detailed representative procedure are given.

Full text of DOI:10.1016/S0040-4039(02)02871-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1409–1411
A novel one-pot synthesis of 1,2,4-triazole-3,5-diamine derivatives
from isothiocyanates and mono-substituted hydrazines
Chunjian Liu* and Edwin J. Iwanowicz
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 30 October 2002; revised 18 December 2002; accepted 19 December 2002
Abstract—1,2,4-Triazole-3,5-diamine derivatives were synthesized in moderate to high yields in one-pot reaction from the
corresponding isothiocyanates, mono-substituted hydrazines, and sodium hydrogencyanamide, in the presence of 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride. Typically, two target compounds were obtained, but high regioselectivities to
one isomer were observed when aromatic and sterically bulky hydrazines were used. A number of examples with a detailed
representative procedure are given. © 2003 Elsevier Science Ltd. All rights reserved.
1,2,4-Triazole-3,5-diamine derivatives have been iden-
tified as potential chemotherapeutic agents.1–4 Previous
synthetic methods involved the use of (a) N-
cyanoguanidines,5,6 which could be prepared from vari-
ous commercially available reagents, (b) S,S-dimethyl-
N-cyanodithioimidocarbonates,6,7 or (c) diphenyl
cyanocarbonimidates8–11 as starting materials. These pro-
cedures generally required two or more synthetic steps,
and overall yields were typically poor. Method b also
involved the generation of malodorous methanethiol and,
in some cases, the use of silver nitrate to ensure product
formation.6 In this communication, we report a facile,
one-pot procedure for preparation of 1,2,4-triazole-3,5-
diamines by using isothiocyanates as starting material.
Treatment of isothiocyanate with commercially available
sodium hydrogencyanamide in DMF provides the
N-cyanothiourea sodium salt 3.12 Without isolation,
3 was reacted with a hydrazine in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDC) to afford 1,2,4-triazole-3,5-diamine
derivatives 1 and 2 (Scheme 1). The reaction presumably
proceeds through intermediates 412 and/or 5.6
Either nitrogen in the hydrazine molecule may initiate
the reaction sequence by attacking the central
carbon, denoted with an arrow, in either 4 or 5 (Scheme
1). The second nitrogen initiates the formation of
the heterocycle, affording a mixture of two regio-
isomers.
Scheme 1.
* Corresponding author. Tel.: +1-(609)-252-3682; fax: +1-(609)-252-6601; e-mail: chunjian.liu@bms.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02871-X

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C. Liu, E. Iwanowicz / Tetrahedron Letters 44 (2003) 1409–1411
hydrazine may have the greater electron density, but it
suffers on a basis of accessibility to intermediate 4 or 5
when compared to the unsubstituted nitrogen. The
regioisomers were distinguished by nuclear Overhauser
effect (NOE) experiments. NOEs were observed
between 5-NH2 and 1-CH2 but not between 3-NH and
1-CH2 in 1a. In 2a, on the other hand, NOEs were
observed between 5-NH and 1-CH2 but not between
3-NH2 and 1-CH2 (Fig. 1). By utilising cyclohexyl
hydrazine hydrochloride in the presence of triethyl-
amine in the procedure, triazoles 1b15 and 2b16 were
formed in a comparable ratio of 3.0:1 (entry 2). Similar
selectivities (1g:2g=3.9:1 and 1h:2h=4.0:1) were
observed in entries 7 and 8, respectively, where elec-
tron-donating and electron-withdrawing groups were
present on the phenyl ring of the isothiocyanates. How-
ever, when the hydrazine was substituted with an
extremely bulky tert-butyl residue in entries 3 and 9,
the ratios of isomers 1c17 and 2c,18 and 1i and 2i,
As shown by examples arranged in Table 1, both the
isothiocyanate and hydrazine can be aromatic or
aliphatic. Aromatic isothiocyanates typically result in
high yields (entries 1–8), whereas aliphatic isothio-
cyanates appear to give more side products and only
moderate yields (entries 9 and 10). Both aromatic iso-
thiocyanates and aromatic hydrazines may be substi-
tuted with either electron-donating or electron-with-
drawing groups on the aromatic rings (entries 5–8).
More specifically, cyano and halogen functionalities
have been shown to be compatible with the reaction
conditions (entries 1 and 8). Sterically hindered hydrazi-
nes do not appear to hamper the reaction (entries 3 and
9). Commercially available hydrazines are often sold as
the corresponding salts. It has been demonstrated that
hydrazine hydrochloride salts may be directly used as
long as a base such as triethylamine is added (entries 2,
3, and 6–9).
Regioselectivity for the reaction sequence appears to be
determined by the nature of hydrazine, though in all
cases isomer 1 was formed in preference to isomer 2.
When the adduct of phenyl isothiocyanate and sodium
hydrogencyanamide was treated with 2-cyanoethylhy-
drazine in the presence of EDC, triazoles 1a13 and 2a14
were produced in a ratio of 3.6:1, respectively (entry 1).
The moderate regioselectivity in favour of 1a can be
understood by considering the steric environment about
the reactive centers. The substituted nitrogen of the
Figure 1.
Table 1. One-pot preparation of 1,2,4-triazole-3,5-diamine derivatives

C. Liu, E. Iwanowicz / Tetrahedron Letters 44 (2003) 1409–1411
1411
increased significantly to 20:1 and 14:1, respectively.
When the adduct of phenyl isothiocyanate and sodium
hydrogencyanamide was reacted with phenyl hydrazine
and EDC, triazoles 1d19 and 2d were obtained in a ratio
of 19:1 (entry 4). A very similar selectivity (1j:2j=20:1)
was observed in entry 10, where an aliphatic isothio-
cyanate was used. The very high preference of forma-
tion of 1d and 1j in entries 4 and 10 can be understood
because the phenyl moiety makes the directly connected
nitrogen of the hydrazine not only more hindered but
also less electron rich. Entry 5 showed that when the
phenyl was substituted with a 4-trifluoromethyl elec-
tron-withdrawing group, nucleophilicity of the more
hindered nitrogen was further reduced and conse-
quently the regioselectivity could be further improved.
In this case, triazole 1e was the only detected product.
In entry 6, an electronic donating 4-methoxy would be
expected to offset, to some extent, the electronic effect
produced by the phenyl itself. As a result, a poorer
selectivity for 1f over 2f (12:1) was encountered.
4. Gespach, C.; Menez, I.; Emami, S. Biosci. Rep. 1983, 3,
871–878.
5. Steck, E. A.; Brundage, R. P.; Fletcher, L. T. J. Am.
Chem. Soc. 1958, 80, 3929–3931.
6. Wu, M. T. J. Heterocyclic Chem. 1977, 14, 443–444.
7. Reiter, J.; Pongo´, L.; Somorai, T.; Dvortsa´k, P. J. Hete-
rocyclic Chem. 1986, 23, 401–408.
8. Webb, R. L.; Labaw, C. S. J. Heterocyclic Chem. 1982,
19, 1205–1206.
9. Webb, R. L.; Eggleston, D. S.; Labaw, C. S.; Lewis, J. J.;
Wert, K. J. Heterocyclic Chem. 1987, 24, 275–278.
10. Garratt, P. J.; Thorn, S. N.; Wrigglesworth, R. Tetra-
hedron 1993, 49, 165–176.
11. Dunstan, A. R.; Weber, H.-P.; Rihs, G.; Widmer, H.;
Dziadulewicz, E. K. Tetrahedron Lett. 1998, 39, 7983–
7986.
12. Atwal, K. S.; Ahmed, S. Z.; O’Reilly, B. C. Tetrahedron
Lett. 1989, 30, 7313–7316.
13. Compound 1a: 1H NMR (DMSO-d6): l 8.72 (1H, s), 7.51
(2H, d, J=7.9 Hz), 7.17 (2H, dd, J=7.9, 7.2 Hz), 6.74
(1H, t, J=7.2 Hz), 6.31 (2H, s), 4.08 (2H, t, J=6.4 Hz),
2.92 (2H, t, J=6.4 Hz); 13C NMR (DMSO-d6): l 157.6,
154.4, 142.6, 128.8, 119.0, 118.9, 116.0, 41.4, 17.7.
14. Compound 2a: 1H NMR (DMSO-d6): l 8.78 (1H, s), 7.57
(2H, d, J=7.7 Hz), 7.26 (2H, dd, J=7.7, 6.9 Hz), 6.89
(1H, t, J=6.9 Hz), 5.26 (2H, s), 4.17 (2H, t, J=6.0 Hz),
2.93 (2H, t, J=6.0 Hz); 13C NMR (DMSO-d6): l 161.2,
150.4, 143.2, 141.2, 129.0, 120.9, 119.0, 117.4, 41.4, 17.9.
15. Compound 1b: 1H NMR (DMSO-d6): l 8.60 (1H, s), 7.48
(2H, d, J=7.8 Hz), 7.15 (2H, dd, J=7.8, 7.8 Hz), 6.70
(1H, t, J=7.3 Hz), 6.04 (2H, s), 3.91 (1H, m), 1.83–1.64
(7H, m), 1.34 (2H, m), 1.18 (1H, m); 13C NMR (DMSO-
d6): l 156.9, 152.9, 143.0, 128.7, 118.5, 115.7, 53.8, 32.0,
25.4, 25.3.
In conclusion, we have reported a convenient synthesis
of 1,2,4-triazole-3,5-diamine derivatives from isothio-
cyanates, sodium hydrogencyanamide, and hydrazines.
This procedure has the advantage of one-pot operation
that gives the desired products in high yields. The
method has particular utility for the preparation of
triazole 1 and is far more convenient and efficient than
previously reported methods.
A representative procedure is demonstrated by the prepa-
ration of 1b and 2b: To a solution of phenyl isothio-
cyanate (0.276 g 2.00 mmol) in dry DMF was added
sodium hydrogencyanamide (0.137 g, 2.10 mmol) at
room temperature in one portion. The mixture was
heated at 60°C for 1 h before triethylamine (0.50 mL,
3.59 mmol), cyclohexyl hydrazine hydrochloride (0.452
g, 3.00 mmol), and EDC (0.479 g, 2.50 mmol) were
added at room temperature. The mixture was heated at
60°C for an additional 1 h, and diluted with ethyl
acatate (100 mL), washed with water (3×25 mL) and
10% lithium chloride solution (3×30 mL). The organic
solution was dried over anhydrous MgSO4. A mixture
of 1b and 2b (0.424 g, 82% yield) was isolated as a
white solid by chromatography (silica gel, 5%
methanol/chloroform). Analytical samples of 1b and 2b
were obtained by preparative HPLC.
16. Compound 2b: 1H NMR (DMSO-d6): l 8.50 (1H, s), 7.52
(2H, d, J=7.8 Hz), 7.23 (2H, dd, J=7.8, 7.8 Hz), 6.84
(1H, t, J=7.3 Hz), 5.04 (2H, s), 4.12 (1H, m), 1.81–1.64
(7H, m), 1.36 (2H, m), 1.16 (1H, m); 13C NMR (DMSO-
d6): l 160.5, 148.8, 141.8, 128.9, 120.4, 117.1, 53.8, 32.4,
25.4, 25.3.
17. Compound 1c: 1H NMR (DMSO-d6): l 8.57 (1H, s), 7.49
(2H, d, J=8.0 Hz), 7.14 (2H, dd, J=8.0, 7.2 Hz), 6.70
(1H, t, J=7.2 Hz), 5.78 (2H, s), 1.52 (9H, s); 13C NMR
(DMSO-d6): l 155.2, 152.9, 143.0, 128.7, 118.5, 115.7,
56.6, 28.9.
1
18. Compound 2c: H NMR (DMSO-d6): l 7.65 (1H, s), 7.18
(2H, dd, J=8.5, 7.3 Hz), 7.08 (2H, d, J=8.5, 7.2 Hz),
6.79 (1H, t, J=7.2 Hz), 5.04 (2H, s), 1.52 (9H, s); 13C
NMR (DMSO-d6): l 159.6, 148.4, 143.8, 128.9, 119.9,
116.6, 57.8, 29.6.
References
19. Compound 1d: 1H NMR (DMSO-d6): l 8.92 (1H, s),
7.60–7.48 (6H, m), 7.29 (1H, t, J=7.2 Hz), 7.20 (2H, dd,
J=7.2, 7.2 Hz), 6.77 (1H, t, J=7.2), 6.75 (2H, s); 13C
NMR (DMSO-d6): l 158.0, 153.5, 142.4, 138.1, 129.6,
128.9, 126.0, 122.0, 119.2, 116.2.
1. Liu, C.; Dhar, T. G. M.; Gu, H. H.; Iwanowicz, E. J.;
Leftheris, K.; Pitts, W. J. US Patent 6,399,773, 2002.
2. Stemp, G.; Burrell, G. US Patent 5,232,938, 1993.
3. Cornu, P.-J.; Perrin, C.; Dumaitre, B.; Streichenberger,
G. US Patent 4,569,933, 1986.