Tandem synthesis of [1,2,4]-triazoles mediated by iodine - A regioselective approach

Article abstract of DOI:10.1016/j.tet.2012.04.042

A tandem regioselective one-pot synthesis of 3-amino-[1,2,4]-triazoles has been achieved from 1,3-disubstituted thioureas using molecular iodine. In this one-pot strategy, the intermediate carbodiimide generated in situ from thiourea upon reaction with HCONHNH₂ gives diaryl/ alkylhydrazinecarboximidamide or acylureidrazone, which then undergoes an intramolecular cyclodehydration to afford the corresponding 3-amino-[1,2,4]- triazole. The product regioselectivity for unsymmetrical 1,3-disubstituted thioureas correlate well with the pK_as of the parent amines attached, in which the amine having higher pK_a goes to the ring nitrogen while the other nitrogen remains flanked as an exocyclic nitrogen of the triazole core. This method is milder and environmentally sustainable giving good to excellent yields of the desired products.

Full text of DOI:10.1016/j.tet.2012.04.042

Tetrahedron 68 (2012) 5066e5074
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem synthesis of [1,2,4]-triazoles mediated by iodineda regioselective
approach
*
Srimanta Guin, Saroj Kumar Rout, Nilufa Khatun, Tuhin Ghosh, Bhisma K. Patel
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem regioselective one-pot synthesis of 3-amino-[1,2,4]-triazoles has been achieved from 1,3-
disubstituted thioureas using molecular iodine. In this one-pot strategy, the intermediate carbodiimide
generated in situ from thiourea upon reaction with HCONHNH2 gives diaryl/alkylhydrazinecarbox-
imidamide or acylureidrazone, which then undergoes an intramolecular cyclodehydration to afford the
corresponding 3-amino-[1,2,4]-triazole. The product regioselectivity for unsymmetrical 1,3-disubstituted
thioureas correlate well with the pKas of the parent amines attached, in which the amine having higher
pKa goes to the ring nitrogen while the other nitrogen remains flanked as an exocyclic nitrogen of the
triazole core. This method is milder and environmentally sustainable giving good to excellent yields of
the desired products.
Received 20 December 2011
Received in revised form 3 April 2012
Accepted 11 April 2012
Available online 19 April 2012
Keywords:
Tandem reaction
Triazole
Iodine
Regioselective
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
O
Me
S
O
HN
N
Chemistry to have its maximal effect on biology, discovery, and
development of efficient synthetic methods for the construction of
N, O, S heterocycles are in great demand in the field of chemical
genetics.1 As a privileged fragment, [1,2,4]-triazole core holds
a central position in modern heterocyclic chemistry principally due
to its prevalence in a wide variety of biologically active/relevant
molecules, which are reported to exhibit diverse biological activi-
ties in the field of medicinal and agrochemicals.2e5 Some examples
of pharmaceutically significant compounds containing [1,2,4]-
triazole nucleus are shown in Fig. 1.
N
N
N
N
H
N
N
N
N
N
Me
N
H
NH2
N
Inhibitor of Eosinophilia
Me
Essramycin
DSM1 Antimalarial
Antibiotic
agent
NMe2
CF3
F
H
F
NH
Me
N
N
N
N
N
N
S
N
H
N
N
H
F
N
Cl
[1,2,4]-Triazolo[1,5-a]pyrimidine
N
Inhibitor of Methionine
Aminopeptidase-2
HT1D Receptor
The widespread applications of such potent 3-amino-[1,2,4]-
triazoles have resulted in the development of numerous protocols
for their synthesis. The general protocols for solution phase syn-
thesis of 3-amino-[1,2,4]-triazoles involve the reaction of ami-
drazones with carbodiimides,6a,b cyclization of hydrazones,6c
reaction of aminoguanidines with carboxylic acids.6d These pro-
cesses entail direct condensation of thioamides with hydrazides,
but are disadvantageous with respect to their commercial avail-
ability and diversities. Solid-phase synthesis has emerged as an
important method for the construction of a library of organic
compounds in combinatorial science and hence several methods
are being developed in order to culminate the problems associated
with solution phase methods.7aec Stocks and co-workers have
demonstrated a one-pot three component synthesis of [1,2,4]-
Anticancer agent
Fig. 1. Some pharmaceutical products having [1,2,4]-triazole core.
triazole using acetic hydrazide, primary amine and DMFDMA (1,1-
dimethoxy-N,N-dimethylmethamine) in which the desired tri-
azole core is formed finally by a cyclodehydrative path.8 An addi-
tionedehydration path for the synthesis of 3-amino-[1,2,4]-
triazoles has been documented by Chorev et al. in which a one-pot
reaction of 1,3-disubstituted thiourea and acyl hydrazide was per-
formed in the presence of toxic Hg(OAc)2 as the thiophilic reagent.9
Kamenecka group have reported a multi-stepped synthesis of 3-
amino-[1,2,4]-triazoles through an oxidative approach. The thio-
urea or semithiocarbazide is initially oxidized to their corre-
sponding sulfonic acid, which when reacted with amine or
hydrazine followed by the treatment of trimethyl orthoformate
* Corresponding author. E-mail address: patel@iitg.ernet.in (B.K. Patel).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.042

S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
5067
afforded the corresponding triazole through
a
con-
thought of developing an environmentally benign one-pot strategy
for the synthesis of 3-amino-[1,2,4]-triazoles. In this methodology,
the in situ generated carbodiimide from 1,3-disubstituted thiourea
on treatment with formic hydrazide (HCONHNH2) would form
acylureidrazone, which is expected to undergo dehydrative cycli-
zation to afford the targeted 3-amino-[1,2,4]-triazole.
densationedehydration process.10 Recently, Castanedo et al. have
reported an intriguing synthesis of 1,3,5-substituted [1,2,4]-
triazoles using carboxylic acids, amidines and hydrazines as the
precursors.11 Further, Wong et al. have described two elegant
methods, one for the synthesis of 3,5-disubstituted [1,2,4]-triazole
from aldehydes with hydrazonoyl hydrochloride via a 1,3-dipolar
cycloaddition reaction12a and the other for the synthesis of 1,3,5-
trisubstituted [1,2,4]-triazole by reacting oxime with hydrazonoyl
hydrochloride.12b
2. Results and discussion
To test the feasibility of our envisioned route, in a typical re-
action, to a solution of 1,3-diphenylthiourea (1 equiv) 1 in ethanol
were added sequentially HCONHNH2 (1 equiv), aqueous solution of
K2CO3 (2.5 equiv) and iodine (1.1 equiv) pinch wise over a period of
10 min at room temperature. Formation of a new product along
with other minor side products was observed together with the
retention of some starting substrate 1. Isolation by usual workup
procedure followed by chromatographic purification (55% isolated
yield) and characterization revealed the product to be phenyl-(4-
phenyl-4H-[1,2,4]triazol-3-yl)-amine 1a. Further optimization
such as increasing the quantity of HCONHNH2 to 2.5 equiv and io-
dine to 2 equiv, improved the isolated yield up to 81% with com-
plete disappearance of 1. Other inorganic carbonates such as
Na2CO3 and Cs2CO3 were also found to be equally effective. Since
we wanted to develop a greener protocol the organic bases or other
environmentally non-compatible solvents were not studied for this
transformation. The mechanistic path for this transformation is
expected to be similar to the one already proposed by Chorev et al.9
The intermediacy of carbodiimide has been confirmed by per-
forming the reaction with an isolated carbodiimide.14d However, in
none of the reaction, formation of the intermediate carbodiimide
could be detected, probably due to the faster nucleophilic attack of
HCONHNH2 to intermediate carbodiimide than its formation in
a polar protic medium. Interestingly, despite the presence of water
in the medium, no urea by product was observed from the expected
carbodiimide intermediate probably owing to the more nucleo-
philic nature of the formic acid hydrazide (NH2NHCHO) compared
to water. Employing this one-pot strategy, we have successfully
prepared a series of [1,2,4]-triazol-3-yl-amines from their corre-
sponding thioureas as shown in Table 1. Symmetrical thioureas 1e7
afforded their corresponding [1,2,4]-trizol-3-yl-amines 1ae7a in
good to excellent yields (Table 1). Symmetrical thioureas 2e5
Despite the numerous procedures enumerated in literature for
the synthesis of [1,2,4]-triazoles possessing varied substitutions,
few of these describe direct synthesis of the triazole having no
substitution at the 5-position. Additionally, most of them suffer
from severe environmental concerns as they involve direct or in-
direct use of strong alkaline or acidic conditions; toxic, corrosive
and expensive reagents, which at times impede the applicability of
these methodologies. Further, the generality of these methods are
bound owing to (a) limited substrate scope, (b) not being atom-
economical and (c) low yielding. Hence it is of utmost importance
to develop a more sustainable synthesis of [1,2,4]-triazoles.
In recent years, molecular iodine has been identified as an ef-
ficient catalyst for various organic transformations pertaining to its
low cost, non-toxicity, easy availability and eco-friendly nature.13
Also as a part of our ongoing research program intended towards
greener synthesis we have developed several synthetically useful
transformations exploiting the desulfurative ability of molecular
iodine.14 So, from the ‘Green Chemistry’ perspective and our in-
cessant effort to explore the utility of molecular iodine as an effi-
cient thiophilic agent, herein, we envisaged a one-pot tandem
strategy for the synthesis of 3-amino-[1,2,4]-triazoles from 1,3-
disubstituted thioureas using molecular iodine as the desulfuriz-
ing agent. For [1,2,4]-triazoles derived from unsymmetrical thio-
ureas it would be interesting to find out the product regioselectivity
as which of the nitrogen would be part of the ring nitrogen in the
triazole core and, which one to remain as an exocyclic nitrogen.
The genesis of the work started with two of our recent works on
a green synthetic protocol for the preparation of carbodiimides14d
from 1,3-disubstituted thioureas in the presence of molecular io-
dine and the synthesis of aminotetrazoles through the intermediacy
of carbodiimide.14e Taking cues from these observations, we
Table 1
Formation of [1,2,4]-triazol-3-yl-amine from symmetrical thioureaa
H
H
N
H
N
I2 / K2CO3
N
Ar
N
Ar
Ar
N
N
NH2NHCHO
EtOH / H2O
S
Ar
Substrate
Productb
Yieldc (%)
H
N
N
N
H
N
H
N
(1a)
81
N
(1)
S
H
N
H
H
N
N
N
(2a)
N
83
N
(2)
S
(continued on next page)

5068
S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
Table 1 (continued )
Substrate
Productb
Yieldc (%)
H
H
N
H
N
N
N
(3a)
N
(3)
75
N
S
H
N
N
OMe
(4a)
H
H
N
N
N
80
N
(4)
OMe
S
MeO
OMe
MeO
H
N
OMe
OMe
H
N
H
N
N
78
N
(5a)
N
(5)
S
MeO
H
N
Br
H
H
N
N
N
N
(6a)
70
N
(6)
Br
S
Br
Br
Cl
H
N
H
N
H
N
N
N
(7a)
(7)
72
N
S
Cl
Cl
Cl
a
b
c
Reactions were monitored by TLC.
Confirmed by IR, 1H NMR and 13C NMR.
Isolated yields.
bearing electron-donating substituents underwent the reaction
smoothly to afford products 2ae5a in a slightly better yields than
those 6 and 7 bearing electron-withdrawing substituents giving
corresponding [1,2,4]-triazol-3-yl amines 6a and 7a. The structure
of the product 4a has been further confirmed by X-ray crystallo-
graphic analysis as shown in Fig. 2.
exocyclic nitrogen it has been observed that the amine having
lower pKa is part of the heterocyclic nitrogen and amine having
higher pKa goes to exocyclic nitrogen. So far this has been con-
firmed during the regioselective synthesis of thiazole-2-imine [or
Since the formation of [1,2,4]-triazole is an additionedehydra-
tion reaction, hence the effect of substituents in the phenyl ring is
expected to play an important role on reaction rates and on product
yields. It is evident from the product yields that 1,3-diphenyl
thioureas substituted with electron-donating groups gave better
yields as compared to the substrates having electron-withdrawing
groups. This observation is consistent with the observation made
by Chorev et al. using Hg(OAc)2.9
Furthermore, we have found a direct correlation between
regioselectivity with the pKas of the parent amines attached to
thioureas during the construction of various heterocycles and re-
lated transformations and have established a good correlation be-
tween them. Recently, an excellent agreement between the
regioselective N-acylation and the pKas of the precursor amines
attached to thioureas has been found.15a For heterocycles origi-
nating from unsymmetrical thioureas having ring nitrogen and an
Fig. 2. Ortep view of compound 4a.

S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
5069
2-iminothiazoline],15b 2-amino-4-thiazolidinones,15c thioamido
I
S
I
I
guanidines15d and 1,5-disubstituted tetrazoles.14e We wanted to
investigate whether the correlation of regioselectivity as a function
of pKa is applicable to the synthesis of [1,2,4]-triazol-3-yl-amine.
Although the mechanism proposed is essentially same as has
been proposed by Chorev et al.9 however with unsymmetrical
thioureas the correlation between the regioselectivity with the
pKas of the parent amines is due to be ascertained. In the present
methodology an excellent correlation between product regiose-
lectivity and pKa of the parent amines could be established, how-
ever, the effect due to steric factor of the substituents on the aryl
ring of thiourea cannot be completely ruled out. As per the mech-
anism proposed in Scheme 1, the attack of the formic hydrazide
(NH2NHCHO) to the in situ generated unsymmetrical carbodiimide
(B)14d would lead to an equilibrium where the protonation could
occur towards either of the amino/imino nitrogen to afford car-
boximidamide. However, the equilibrium of protonation would be
more favoured and shifted towards more basic nitrogen (path a,
Scheme 1) to give the intermediate (C) rather than towards the less
basic nitrogen atom (path b, Scheme 1). The carboximidamide (C)
would then undergo an intramolecular nucleophilic attack from
nitrogen atom onto the aldehydic carbonyl group to provide the
intermediate (D). In a final step (D) undergoes a dehydration step to
render the corresponding regioisomeric [1,2,4]-triazole. Thereby,
nitrogen of the amine attached to the thiourea having higher pKa
should appear in the ring while the other amine would flank as an
exocyclic nitrogen in the major product. As a typical illustration
unsymmetrical thiourea 14 has been chosen, which exclusively
gave 14a and no trace of other regioisomer 14b was obtained (Table
2). Structure of the regioselective product 14a has been confirmed
by crystal X-ray crystallography (Fig. 3).
S
O2N
N
H
N
H
O2N
N
(A)
N
H
14
OH−
OH−
Path-a
Path-b
Slow
H+
H+
Path-b
Unfavorable
Path-a
S
N
C
N
+
More favorable
O
O2N
(B)
H2N
C
N
H
H
H
C
N
C
H
N
C
HN
H
C
OH
N
N
O
HN
N
H
N
O2N
O2N
H
(
D)
(C)
Cyclo
dehydration
H
N
N
+ H2O
N
14a
N
)
(
Obtained
NO2
Scheme 1. Plausible mechanism for the regioselective formation of [1,2,4]-triazol-3-
yl-amines.
Thus, it is expected, smaller the difference in pKas of precursor
amines attached to a thiourea, lesser should be the regioselectivity
giving both the regioisomers because of the probability of pro-
tonation to either of the nitrogen atoms. A larger pKa difference
should yield exclusively one of the regioisomer due to the
Table 2
Formation of [1,2,4]-triazol-3-yl-amine from unsymmetrical thioureasa
H
N
H
N
Ar1
Ar2/alkyl
H
N
H
N
N
N
I2 / K2CO3
Ar1
Ar2/alkyl
N
N
+
N
N
NH2NHCHO
S
Ar2/alkyl
Ar1
Substrateb
(pKa2ꢀpKa1)c
Product(s)d
% Yielde (ratio)f
3.58 4.15
N
N
N
N
H
H
N
N
N
N
N
Br
0.57
80 (52:48)
Cl
+
Cl
NH
(8a)
NH
(8b)
S
Cl
Br
(8)
Br
Br
Br
N
4.63 3.86
N
N
H
N
H
N
N
N
0.77
1.22
72 (57:43)
77 (78:22)
NH
(9a)
NH
(9b)
+
S
(9)
Br
Br
N
N
N
N
5.08 3.86
H
N
H
N
N
N
Me
+
Me
Br
Br
NH
NH
S
Me
Br
(10a)
(10b)
(10)
N
N
N
N
5.34 3.86
H
N
H
N
N
N
1.48
70 (87:13)
NH
MeO
+
NH
S
MeO
Br
(11a)
(11b)
(11)
(continued on next page)
OMe
Br

5070
S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
Table 2 (continued )
Substrateb
(pKa2ꢀpKa1)c
Product(s)d
% Yielde (ratio)f
N
N
3.52 5.08
N
N
H
N
H
N
N
N
1.56
2.37
73 (95:5)
NH
Me
+
Me
NH
S
Me
(12a)
(12b)
(12)
Cl
Cl
Cl
N
N
N
2.15 4.52
OMe
N
N
MeO
F3C
OMe
H
H
N
F3C
N
N
+
60 (98:2)
CF3
NH
NH
S
(13a)
(13b)
(13)
F3C
CF3
F3C
N
N
2.46 5.28
N
N
H
H
N
N
N
N
2.82
70 (99:1)
NH
NH
S
+
(14a)
(14b)
(14)
O2N
NO2
O2N
N
N
N
3.86 10.66
N
H
N
H
N
N
N
6.80
6.86
52 (100:0)
62 (100:0)
Br
NH
+
NH
S
Br
(15a)
(15b)
(15)
Br
3.92 10.78
H
N
N
N
N
N
N
NH-nBu
Nn-Bu
+
n-BuHN
NH
(16a)
S
(16)
(16b)
2.46 10.78
H
N
N
N
N
O2N
N
NHnBu
N
NnBu
8.32
55 (100:0)
+
NO2
n-BuHN
S
NH
(17)
(17a)
(17b)
NO2
a
b
c
d
e
f
Reactions were monitored by TLC.
pKa of the parent amines.
Dissociation constants of organic acids and bases. http://www.zirchrom.com/organic.htm.
Confirmed by IR, 1H NMR and 13C NMR.
Isolated yields.
Ratio determined by 1H NMR and/or HPLC.
preferential protonation towards one of the nitrogen during the
formation of [1,2,4]-triazol-3-yl-amines. Hence a proper tuning of
the pKa would be useful to selectively form a single regioisomer. As
a further proof to our hypothesis, various unsymmetrical thioureas
were subjected to the present reaction condition with pKa differ-
ences (pKa2ꢀpKa1) ranging from 0.57 to 8.32 units. For instance,
the unsymmetrical thiourea 8 containing m-bromo aniline and p-
chloro aniline under the optimized reaction condition furnished
a mixture of triazoles 8a and 8b in the ratio of 52:48. The measured
pKa of m-bromo aniline and p-chloro anilines are 3.58 and 4.15,
respectively, a difference of 0.57 units (Table 2). Thus, as per our
proposition, the formation of the major regioisomer 8a satisfies
this. The assumption of better regioselectivity with increase in the
pKa difference has been further demonstrated with other thioureas
9 and 10 having a pKa difference of 0.77 and 1.22 units, respectively.
There is an improvement in the regioselectivity with increase in pKa
Fig. 3. Ortep view of compound 14a.

S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
5071
differences giving a pair of regioisomers 9a/9b and 10a/10b in the
ratio of (57:43) and (78:22), respectively. When the pKa difference
rose from 1.48 to 1.56, the regioisomeric ratio further improved
from 87:13 to 95:5 for the regioisomeric pairs 11a/11b and 12a/12b
derived, respectively, from substrates 11 and 12. When the differ-
ence in pKas of the parent amine is above two pKa units the ratio
improved dramatically as demonstrated for substrates 13 and 14
giving regioisomers 13a/13b and 14a/14b in the ratio of 98:2 and
99:1, where the pKa differences are 2.37 and 2.82, respectively.
Beyond a pKa difference of 1.8 or so exclusively one of the
regioisomer was obtained. Substrates 15, 16 and 17 having a pKa
difference of above 2.8 units gave regioisomers 15a, 16a and 17a
entirely and no traces of 15b, 16b and 17b regioisomers could be
detected. Structure of the regioisomer 17a has been confirmed by
crystal X-ray crystallography as shown in Fig. 4.
well with the pKas of the parent amines in which the amine having
lower pKa stays as exocyclic nitrogen and the one having higher pKa
is part of the ring nitrogen. The methodology provides access to the
formation of a single regioisomer through proper tuning of the pKas
of the parent amines in the unsymmetrical thioureas. In compari-
son to the reported methods, our method offers simple convenient
approach for the construction of this pharmaceutically important
heterocycle and thus has potential industrial application.
4. Experimental section
4.1. General remarks
Unless otherwise stated, all reagents were purchased from
commercial sources and used without further purification. Reaction
progress was monitored by TLC using silica gel 60 F254 (0.25 mm)
with detection by UV or iodine. Chromatography was performed
using silica gel (60e120 mesh size) with freshly distilled solvents.
Columns were typically packed as slurry and equilibrated with the
appropriate solvent system prior to use. 1H NMR (400 MHz) and 13
C
NMR (100 MHz) spectra were recorded on FT-400 MHz instrument
using TMS as an internal standard. Data are presented as follows:
chemical shift (ppm), multiplicity (s¼singlet, d¼doublet, t¼triplet,
quin¼quintet, m¼multiplet, b¼broad, br s¼broad singlet, br
m¼broad multiplet, coupling constant J (Hz)). Elemental analyses
were carried out on a PerkineElmer 2400 elemental analyzer and
Euro Vector EA3000. Melting points were recorded and are un-
corrected. IR spectra were recorded in KBr or neat. HPLC was per-
formed using C-18 column.
Fig. 4. Ortep view of compound 17a.
A plot of the percentage of major regioisomers against pKa dif-
ferences revealed almost a linear correlation in the lower pKa dif-
ference range as shown in Fig. 5. As the pKa difference increases
beyond 1.7, the change becomes abrupt and the linear correlation
does not fit well, giving a flattened curve thereby indicating ex-
clusive formation of one of the regioisomer, which is shown
graphically in Fig. 5.
4.2. General procedure for the preparation of N,4-
disubstituted-4H-1,2,4-triazol-3-amine from symmetrical
thioureas 1e7
To a suspension of 1,3-disubstituted thioureas 1e7 (1 mmol) in
ethanol (2 mL) were added sequentially formic hydrazide
(2.5 mmol) and aqueous K2CO3 (2.5 mmol in 0.5 mL water) and the
mixture was stirred at room temperature. Under this stirring con-
dition iodine (1.2 mmol) was added pinch wise over a period of
10 min. Disappearance of iodine colour was associated with the
precipitation of colloidal sulfur. The reaction mixture was stirred
for a further period of 20e40 min. During this period complete
disappearance of 1,3-disubstituted thiourea was observed with the
appearance of a new product having lower Rf. Precipitated ele-
mental sulfur was filtered off and the filtrate ethanol was removed
in a rotary evaporator. The reaction mixture was treated with a 5%
hypo solution (5 mL) and the product was extracted with ethyl
acetate (2ꢁ10 mL). The combined ethyl acetate layer was washed
with water (1ꢁ5 mL), dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The reaction product was purified
over a column of silica gel and eluted with hexane/ethyl acetate
mixture to give the corresponding products 1ae7a.
4.2.1. N,4-Diphenyl-4H-1,2,4-triazol-3-amine (1a). The general
procedure was followed. The product was purified by column
chromatography (90% EtOAc/hexane) to give the title compound 1a
(191 mg, 81%) as yellowish white solid; Rf (90% EtOAc/hexane) 0.23;
mp 213e216 ꢂC; nmax (KBr): 3448, 3222, 3052, 1598, 1550, 1496,
1388, 1255, 1198, 744 cmꢀ1
;
1H NMR (400 MHz, CD3OD)
d
¼8.38
Fig. 5. A plot of pKa difference and % of major regioisomer.
(1H, s, eN]CHeNe), 7.50e7.60 (5H, m, Ar. CeH), 7.32 (2H, d,
J¼7.6 Hz, Ar. CeH), 7.23 (2H, t, J¼8.4 Hz, Ar. CeH), 6.93 (1H, t,
3. Conclusions
J¼7.2 Hz, Ar. CeH) ppm; 13C NMR (100 MHz, CD3OD):
d
¼150.9,
In conclusion we have developed a tandem one-pot method for
the synthesis of 3-amino-[1,2,4]-triazoles from 1,3-disubstituted
thioureas and NH2NHCOR (R¼H, Ph) using molecular iodine. For
unsymmetrical thioureas the product regioselectivity correlates
142.7,142.5,134.6,131.4,130.8,130.2,127.0,123.0,119.0 ppm; HRMS
(ESI): MHþ, found 237.1132. C14H12N4 requires 237.1135. Elemental
analysis: found C, 71.12; H, 5.10; N, 23.79. C14H12N4 requires C,
71.17; H, 5.12; N, 23.71%.

5072
S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
4.2.2. N,4-Bis(p-tolyl)-4H-1,2,4-triazol-3-amine (2a). The general
procedure was followed. The product was purified by column
chromatography (90% EtOAc/hexane) to give the title compound 2a
(219 mg, 83%) as white solid; Rf (90% EtOAc/hexane) 0.19; mp
224e226 ꢂC; nmax (KBr): 3434, 3224, 3175, 3122, 3007, 2957, 2919,
mp 239e242 ꢂC; nmax (KBr): 3221, 3173, 3116, 3060, 3021, 2969,
2922, 1601, 1549, 1488, 1405, 1194, 1070, 1006, 835, 819 cmꢀ1 1H
NMR (400 MHz, CD3OD):
;
d
¼8.41 (1H, s, eN]CHeNe), 7.76 (2H, d,
J¼8.4 Hz, Ar. CeH), 7.46 (2H, d, J¼8.4 Hz, Ar. CeH), 7.38 (2H, d,
J¼8.8 Hz, Ar. CeH), 7.31 (2H, d, J¼8.8 Hz, Ar. CeH) ppm; 13C NMR
2857, 1610, 1586, 1552, 1513, 1383, 1258, 1196, 816, 808 cmꢀ1
;
1H
(100 MHz, CD3ODþDMSO-d6): ¼152.1, 143.2, 134.5, 133.7, 133.0,
d
NMR (400 MHz, CD3OD):
d
¼8.31 (1H, s, eN]CHeNe), 7.38 (4H, d,
129.1, 128.3, 124.4, 120.7, 141.9 ppm. Elemental analysis: found C,
42.69; H, 2.52; N, 14.17. C14H10Br2N4 requires C, 42.67; H, 2.56; N,
14.22%.
J¼2 Hz, Ar. CeH), 7.21 (2H, d, J¼8.4 Hz, Ar. CeH), 7.06 (2H, d,
J¼8.0 Hz, Ar. CeH), 2.43 (3H, s, AreCH3), 2.26 (3H, s, AreCH3) ppm;
13C NMR (100 MHz, CD3OD):
d
¼151.3, 142.7, 141.3, 139.7, 132.7,
131.9, 131.5, 130.6, 126.8, 119.4, 21.4, 20.9 ppm; HRMS (ESI): MHþ,
found 265.1454. C16H16N4 requires 265.1448. Elemental analysis:
found C, 72.72; H, 6.04; N, 21.26. C16H16N4 requires C, 72.70; H, 6.10;
N, 21.19%.
4.2.7. N,4-Bis(3-chlorophenyl)-4H-1,2,4-triazol-3-amine (7a). The
general procedure was followed. The product was purified by col-
umn chromatography (90% EtOAc/hexane) to give the title com-
pound 7a (219 mg, 72%) as white solid; Rf (70% EtOAc/hexane) 0.21;
mp 196e198 ꢂC; nmax (KBr): 3433, 3230, 3116, 3060, 2960, 1592,
4.2.3. N,4-Bis(3,4-dimethylphenyl)-4H-1,2,4-triazol-3-amine
(3a). The general procedure was followed. The product was puri-
fied by column chromatography (90% EtOAc/hexane) to give the
title compound 3a (219 mg, 75%) as white solid; Rf (90% EtOAc/
hexane) 0.21; mp 173e175 ꢂC; nmax (KBr): 3428, 3218, 3046, 2916,
1552, 1480, 1378, 1226, 1197, 1096, 1077, 909, 793 cmꢀ1
(400 MHz, CD3OD):
;
1H NMR
d
¼8.44 (1H, s, eN]CHeNe), 7.64 (1H, s, Ar.
CeH), 7.57 (2H, m, Ar. CeH), 7.47 (2H, m, Ar. CeH), 7.19e7.26 (2H, m,
Ar. CeH), 6.93 (1H, m, Ar. CeH) ppm; 13C NMR (100 MHz, CD3OD):
d
¼152.0, 143.9, 142.9, 136.8, 135.9, 135.7, 132.7, 131.4, 131.1, 127.4,
1602, 1553, 1505, 1454, 1365, 1199, 1023, 1006, 880 cmꢀ1
(400 MHz, CD3OD):
;
1H NMR
125.6, 122.7, 118.6, 117.0 ppm; HRMS (ESI): MHþ, found 305.0352.
C14H10Cl2N4 requires 305.0355. Elemental analysis: found C, 55.06,
H, 3.34, N, 18.42. C14H10N4Cl2 requires C, 55.10, H, 3.30, N, 18.36%.
d
¼8.26 (1H, s, eN]CHeNe), 7.31 (1H, d,
J¼8.0 Hz, Ar. CeH), 7.24 (1H, s, Ar. CeH), 7.17 (1H, d, J¼8.0 Hz, Ar.
CeH), 7.12 (1H, s, Ar. CeH), 7.04 (1H, d, J¼8.0 Hz, Ar. CeH), 6.97 (1H,
d, J¼8.0 Hz, Ar. CeH), 2.32 (6H, s, 2ꢁAreCH3), 2.19 (3H, s, AreCH3),
4.3. General procedure for the preparation and
determination of regioisomeric of N,4-disubstituted-4H-1,2,4-
triazol-3-amine from unsymmetrical thioureas 8e17
2.17 (3H, s, AreCH3) ppm; 13C NMR (100 MHz, CD3OD):
d¼153.1,
142.4, 140.2, 139.9, 139.8, 138.3, 132.2, 132.1, 131.3, 131.1, 127.7, 124.2,
120.8, 117.0, 20.2, 20.0, 19.7, 19.3 ppm; HRMS (ESI): MHþ found
293.1758. C18H20N4 requires 293.1761. Elemental analysis: found C,
73.91; H, 6.87; N, 19.22. C18H20N4 requires C, 73.94; H, 6.89; N,
19.16%.
For unsymmetrical thioureas (8e17) possessing two different
aryl amines, the reaction and work up procedures were exactly the
same as followed for symmetrical thiourea (1). However after work
up the crude reaction mixture containing both the inseparable
regioisomers (8a,be14a,b) was purified over a column of silica gel
and eluted as an inseparable mixture to get rid of the minor upper
impurities that formed in the reaction. Fractions containing
regioisomers were collected, combined, evaporated and were then
subjected to 1H NMR, 13C NMR and HPLC analysis in order to de-
termine their ratio in the reaction product.
4.2.4. N,4-Bis(4-methoxyphenyl)-4H-1,2,4-triazol-3-amine
(4a). The general procedure was followed. The product was puri-
fied by column chromatography (100% EtOAc) to give the title
compound 4a (237 mg, 80%) as white crystalline solid; Rf (100%
EtOAc) 0.26; mp 189e191 ꢂC; nmax (KBr): 3292, 3136, 2922, 2835,
1601, 1561, 1513, 1303, 1257, 1236, 1222, 1191, 1175, 1038, 1027, 840,
826 cmꢀ1
;
1H NMR (400 MHz, CD3OD):
d
¼8.23 (1H, s, eN]
CHeNe), 7.41 (2H, d, J¼8.8 Hz, Ar. CeH), 7.28 (2H, d, J¼8.8 Hz, Ar.
CeH), 7.11 (2H, d, J¼8.8 Hz, Ar. CeH), 6.83 (2H, d, J¼9.2 Hz, Ar. CeH),
3.86 (3H, s, AreOMe), 3.75 (3H, s, AreOMe) ppm; 13C NMR
4.3.1. N-(3-Bromophenyl)-4-(4-chlorophenyl)-4H-1,2,4-triazol-3-
amine (8a)þ4-(3-bromophenyl)-N-(4-chlorophenyl)-4H-1,2,4-
triazol-3-amine (8b). The general procedure for the un-
symmetrical thiourea was followed. The crude reaction mixture
containing both the inseparable regioisomeric products (checked
by TLC) was purified by column chromatography (80% EtOAc/hex-
ane) to give the mixture of regioisomers 8a and 8b (280 mg, 80%) as
white solid in the ratio of 52:48; Rf (70% EtOAc/hexane) 0.30; nmax
(KBr): 3234, 3023, 2965, 2970, 2922, 2850, 1608, 1555, 1491, 1437,
(100 MHz, CD3ODþDMSO-d6): ¼161.9, 156.4, 153.3, 142.7, 135.5,
d
128.8, 127.1, 121.3, 116.5, 115.5, 56.6, 56.3 ppm. Elemental analysis:
found C, 64.89; H, 5.48; N, 18.83. C16H16N4O2 requires C, 64.85; H,
5.44; N, 18.91%.
4.2.5. N,4-Bis(2-methoxyphenyl)-4H-1,2,4-triazol-3-amine
(5a). The general procedure was followed. The product was puri-
fied by column chromatography (90% EtOAc/hexane) to give the
title compound 5a (231 mg, 78%) as white solid; Rf (90% EtOAc/
hexane) 0.21; mp 149e151 ꢂC; nmax (KBr): 3388, 3106, 2924, 2841,
1410, 1383, 1195, 1092, 1010, 892, 833, 779 cmꢀ1
;
1H NMR
¼8.79 (s, eNHe), 8.77 (s, eNHe), 8.504 (s,
(400 MHz, DMSO-d6):
d
eN]CHeNe), 8.499 (s, eN]CHeNe), 7.83 (s, Ar. CeH), 7.72e7.75
(m, Ar. CeH), 7.67 (s, Ar. CeH), 7.65 (s, Ar. CeH), 7.50e7.58 (m, Ar.
CeH), 7.43 (d, J¼8 Hz, Ar. CeH), 7.28 (d, J¼9.2 Hz, Ar. CeH), 7.19 (t,
J¼8 Hz, Ar. CeH), 7.04 (d, J¼8.8 Hz, Ar. CeH) ppm; 13C NMR
1605, 1569, 1494, 1464, 1385, 1285, 1246, 1115, 1021, 988, 755 cmꢀ1
;
1H NMR (400 MHz, CD3OD):
d
¼8.30 (1H, s, eN]CHeNe), 7.81 (1H,
m, Ar. CeH), 7.58 (1H, t, J¼8.0 Hz, Ar. CeH), 7.43 (1H, d, J¼7.6 Hz, Ar.
CeH), 7.32 (1H, d, J¼8.4 Hz, Ar. CeH), 7.16 (1H, t, J¼8.0 Hz, Ar. CeH),
6.92 (3H, m, Ar. CeH), 3.92 (3H, s, AreOMe), 3.81 (3H, s, AreOMe)
(100 MHz, DMSO-d6):
d
¼149.7, 143.2, 141.4, 140.6, 134.5, 133.8,
131.9, 131.8, 130.7, 130.0, 128.6,127.8,124.9,124.2,123.1,122.3, 121.9,
119.1, 118.6, 115.8 ppm; MS (ESI): MHþ, found 351.0. C14H10BrClN4
requires 350.6.
ppm; 13C NMR (100 MHz, CD3OD):
d
¼155.3, 152.4, 149.2, 142.8,
133.0, 130.6, 129.1, 123.2, 122.9, 122.4, 122.1, 118.1, 114.1, 111.6, 56.9,
56.6 ppm. Elemental analysis: found C, 64.79; H, 5.51; N, 18.83.
C16H16N4O2 requires C, 64.85; H, 5.44; N, 18.91%.
4.3.2. N-(4-Bromophenyl)-4-phenyl-4H-1,2,4-triazol-3-amine (9a)þ
4-(4-bromophenyl)-N-phenyl-4H-1,2,4-triazol-3-amine
(9b). The
general procedure for the unsymmetrical thiourea was followed.
The crude reaction mixture containing both the inseparable
regioisomeric products as indicated by TLC was purified by column
chromatography (90% EtOAc/hexane) to give the mixture of
regioisomers 9a and 9b (227 mg, 72%) as white solid in the ratio of
4.2.6. N,4-Bis(4-bromophenyl)-4H-1,2,4-triazol-3-amine (6a). The
general procedure was followed. The product was purified by col-
umn chromatography (80% EtOAc/hexane) to give the title com-
pound 6a (276 mg, 70%) as white solid; Rf (70% EtOAc/hexane) 0.21;

S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
5073
57:43; Rf (70% EtOAc/hexane) 0.25; nmax (KBr): 3444, 3220, 3176,
reaction mixture containing both the inseparable regioisomeric
products (checked by TLC) was purified by column chromatography
(80% EtOAc/hexane) to give the mixture of regioisomers 13a and 13b
(241 mg, 60%) as white solid in the ratio of (98:2); Rf (70% EtOAc/
hexane) 0.24; nmax (KBr): 3262, 3228, 3096, 2967, 1679, 1598, 1562,
1508, 1475, 1386, 1278, 1185, 1121, 1022, 944, 878, 755, 681 cmꢀ1; 1H
3115, 2966, 2922, 1600, 1548, 1407, 1491, 1383, 1315, 1230, 1197,
1070, 1007, 959, 826, 750 cmꢀ1 1H NMR (400 MHz, CD3OD):
;
d
¼8.370 (s, eN]CHeNe), 8.366 (s, eN]CHeNe), 7.72 (d,
J¼8.8 Hz, Ar. CeH), 7.54e7.59 (m, Ar. CeH), 7.47e7.51 (m, Ar. CeH),
7.44 (d, J¼8 Hz, Ar. CeH), 7.29e7.36 (m, Ar. CeH), 7.23 (t, J¼8 Hz, Ar.
CeH), 6.93 (t, J¼7.2 Hz, Ar. CeH) ppm; 13C NMR (100 MHz, DMSO-
NMR (400 MHz, DMSO-d6):
8.06 (s, eN]CHeNe), 6.89e7.60 (br m, Ar. CeH), 3.77 (s, AreOMe)
ppm; 13C NMR (100 MHz, CD3OD):
d¼9.19 (s, eNHe), 8.38 (s, eN]CHeNe),
d6):
d¼150.0, 149.7, 141.6, 141.2, 133.2, 132.8, 132.6, 131.4, 129.9,
129.0, 128.7, 127.8, 125.5, 121.9, 120.5, 118.8, 116.8, 111.7 ppm; MS
(ESI): MHþ, found 316.0. C14H11BrN4 requires 316.1.
d
¼169.6,162.5,156.4,152.2,143.8,
133.3, 129.7, 128.1, 127.2, 122.5, 121.4, 117.9, 114.8, 114.0, 112.6,
56.5 ppm; MS (ESI): MHþ, found 403.2. C17H12F6N4O requires 403.2.
4.3.3. N-(4-Bromophenyl)-4-p-tolyl-4H-1,2,4-triazol-3-amine
(10a)þ4-(4-bromophenyl)-N-p-tolyl-4H-1,2,4-triazol-3-amine
(10b). The general procedure for the unsymmetrical thiourea was
followed. The crude reaction mixture containing both the in-
separable regioisomeric products (checked by TLC) was purified by
column chromatography (90% EtOAc/hexane) to give the mixture of
regioisomers 10a and 10b (253 mg, 77%) as white solid in the ratio
of 78:22; Rf (70% EtOAc/hexane) 0.25; nmax (KBr): 3226, 3033, 1601,
4.3.7. 4-(3,4-Dimethylphenyl)-N-(3-nitrophenyl)-4H-1,2,4-triazol-3-
amine (14a)þN-(3,4-dimethylphenyl)-4-(3-nitrophenyl)-4H-1,2,4-
triazol-3-amine (14b). The general procedure for the un-
symmetrical thiourea was followed. The crude reaction mixture
containing both the inseparable regioisomeric products (checked
by TLC) was purified by column chromatography (90% EtOAc/hex-
ane) to give the mixture of regioisomers 14a and 14b (216 mg, 70%)
as yellow solid in the ratio of (99:1 or w100% 14a); Rf (90% EtOAc/
hexane) 0.22; nmax (KBr): 3443, 3214, 3178, 2921, 1605, 1548, 1525,
1551, 1513, 1489, 1411, 1381, 1227, 1194, 1071, 1006, 957, 820 cmꢀ1
1H NMR (400 MHz, DMSO-d6):
;
d
¼8.65 (s, eNHe), 8.44 (s, NeCH]
Ne), 8.41 (s, NeCH]Ne), 7.77 (d, J¼8.4 Hz, Ar. CeH), 7.44e7.50 (m,
Ar. CeH), 7.34e7.39 (m, Ar. CeH), 7.03 (d, J¼8 Hz, Ar. CeH), 2.38 (s,
AreCH3), 2.21 (s, AreCH3) ppm; 13C NMR (100 MHz, DMSO-d6):
1295, 1251, 1234, 1196, 1020, 872, 817, 736, 667 cmꢀ1
(400 MHz, DMSO-d6):
;
1H NMR
d
¼9.10 (1H, s, eNHe), 8.57 (1H, s, eN]
CHeNe), 8.46 (1H, s, Ar. CeH), 7.97 (1H, d, J¼8 Hz, Ar. CeH), 7.71
(1H, d, J¼8 Hz, Ar. CeH), 7.52 (1H, t, J¼8 Hz, Ar. CeH), 7.36 (1H, s, Ar.
CeH), 7.33 (1H, d, J¼4.8 Hz, Ar. CeH), 7.24 (1H, d, J¼8 Hz, Ar. CeH),
2.299 (3H, s, AreCH3), 2.290 (3H, s, AreCH3) ppm; 13C NMR
d
¼149.9, 141.6, 141.3, 139.1, 138.8, 132.9, 131.4, 130.4, 129.4, 129.2,
127.8, 125.5, 122.0, 118.8, 117.1, 111.7, 20.8, 20.4 ppm; MS (ESI): MHþ,
found 329.1. C15H13BrN4 requires 329.1.
(100 MHz, CD3ODþDMSO-d6): ¼151.5, 150.3, 144.0, 143.8, 140.2,
d
4.3.4. N-(4-Bromophenyl)-4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-
amine (11a)þ4-(4-bromophenyl)-N-(4-methoxyphenyl)-4H-1,2,4-
triazol-3-amine (11b). The general procedure for the un-
symmetrical thiourea was followed. The crude reaction mixture
containing both the inseparable regioisomeric products (checked
by TLC) was purified by column chromatography (90% EtOAc/hex-
ane) to give the mixture of regioisomers 11a and 11b (242 mg, 70%)
as brown solid in the ratio of (87:13); Rf (90% EtOAc/hexane) 0.20;
nmax (KBr): 3242, 3055, 2924, 2852, 1601, 1553, 1512, 1492, 1299,
139.9, 132.3, 131.9, 131.2, 128.1, 124.5, 124.4, 116.8, 112.9, 20.2,
19.9 ppm; MS (ESI): MHþ, found 310.2. C16H15N5O2 requires 310.3.
4.3.8. N-(4-Bromophenyl)-4-cyclohexyl-4H-1,2,4-triazol-3-amine
(15a). The general procedure for the unsymmetrical thiourea was
followed. The crude product containing single regioisomer (as in-
dicated by TLC) was purifiedbycolumnchromatography(100%EtOAc)
to give the title compound 15a (167 mg, 52%) as white solid; Rf (100%
EtOAc)0.21;mp197e200 ꢂC;nmax (KBr):3301, 3188, 3138, 3086,2925,
2853, 1606, 1552, 1488, 1238, 1203, 1003, 819 cmꢀ1; 1H NMR
1244, 1196, 1179, 1111, 1073, 1031, 1001, 959, 829 cmꢀ1
(400 MHz, DMSO-d6):
;
1H NMR
d
¼8.62 (s, eNHe), 8.39 (s, eN]CHeNe),
(400 MHz,CD3OD):
d
¼8.38(1H, s,eN]CHeNe),7.37(2H,d,J¼7.6 Hz,
8.34 (s, eN]CHeNe), 7.77 (d, J¼8 Hz, Ar. CeH), 7.37e7.50 (m, Ar.
CeH), 7.11 (d, J¼8 Hz, Ar. CeH), 6.83 (d, J¼8 Hz, Ar. CeH), 3.82 (s,
AreOMe), 3.69 (s, AreOMe) ppm; 13C NMR (100 MHz, DMSO-d6):
Ar. CeH), 7.27 (2H, d, J¼7.6 Hz, Ar. CeH), 4.05 (1H, m, aliphatic CeH),
2.05 (2H, d, J¼12.0 Hz, aliphatic CeH),1.90 (2H, d, J¼12.8 Hz, aliphatic
CeH), 1.63e1.75 (4H, m, aliphatic CeH), 1.46 (2H, m, aliphatic CeH)
d
¼159.5, 153.6, 150.0, 141.5, 141.1, 134.7, 132.7, 132.6, 131.2, 127.8,
ppm; 13C NMR (100 MHz, CD3OD):
d¼152.0, 142.5, 134.6, 133.1, 120.2,
127.2, 125.7, 121.7,118.6,114.9, 113.9,111.4, 55.5, 55.2 ppm; MS (ESI):
MHþ, found 346.1. C15H13BrN4O requires 346.1.
114.6, 55.2, 34.6, 26.7, 26.2 ppm. Elemental analysis:found C, 52.39; H,
5.36; N, 17.46. C14H17BrN4 requires C, 52.35; H, 5.33; N, 17.44%.
4.3.5. N-(3-Chlorophenyl)-4-p-tolyl-4H-1,2,4-triazol-3-amine
(12a)þ4-(3-chlorophenyl)-N-p-tolyl-4H-1,2,4-triazol-3-amine
(12b). The general procedure for the unsymmetrical thiourea was
followed. The crude reaction mixture containing both the in-
separable regioisomeric products (checked by TLC) was purified by
column chromatography (90% EtOAc/hexane) to give the mixture of
regioisomers 12a and 12b (208 mg, 73%) as white solid in the ratio
of (95:5); Rf (70% EtOAc/hexane) 0.33; nmax (KBr): 3726, 3216, 3130,
3010, 2921, 2852, 1599, 1554, 1513, 1481, 1383, 1197, 1097, 906, 819,
4.3.9. 4-Butyl-N-(naphthalene-1yl)-4H-1,2,4-triazol-3-amine
(16a). The general procedure for the unsymmetrical thiourea was
followed. The crude product containing single regioisomer (as in-
dicated by TLC) was purified by column chromatography (100%
EtOAc) to give the title compound 16a (166 mg, 62%) as black gum;
Rf (100% EtOAc) 0.20; nmax (KBr): 3054, 2958, 2927, 2856,1629,1557,
1463, 1403, 1274, 792, 772 cmꢀ1 1H NMR (400 MHz, CD3OD):
;
d
¼8.32 (1H, s, eNeCH]Ne), 8.09 (1H, m, Ar. CeH), 7.86 (1H, m, Ar.
CeH), 7.59 (1H, d, J¼8.0 Hz, Ar. CeH), 7.49 (2H, m, Ar. CeH), 7.09
(1H, d, J¼7.2 Hz, Ar. CeH), 3.91 (2H, t, J¼7.2 Hz, aliphatic-CH2e),1.74
(2H, quin, J¼7.6 Hz, aliphatic-CH2e), 1.27 (2H, m, aliphatic-CH2e),
0.86 (3H, t, J¼7.2 Hz, aliphatic-CH3) ppm; 13C NMR (100 MHz,
771, 670 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6):
d
¼8.74 (s, eNHe),
8.45 (s, eN]CHeNe), 7.68 (s, Ar. CeH), 7.39 (s, Ar. CeH), 7.23 (t,
J¼8 Hz, Ar. CeH), 6.89 (d, J¼8 Hz, Ar. CeH), 2.38 (s, AreCH3), 2.21 (s,
AreCH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d¼149.5, 143.2,
CD3OD):
d¼153.5, 142.3, 137.7, 134.9, 128.3, 127.2, 126.1, 125.71,
141.5, 138.6, 133.1, 130.4, 130.2, 125.4, 119.8, 116.0, 115.1, 20.6 ppm;
125.66, 123.6, 122.0, 115.9, 43.6, 31.3, 19.4, 12.6 ppm. Elemental
analysis: found C, 72.19; H, 6.77; N, 21.06. C16H18N4 requires C,
72.15; H, 6.81; N, 21.04%.
MS (ESI): MHþ, found 285.5. C15H13ClN4 requires 285.7.
4.3.6. N-(3,5-Bis(trifluoromethyl)phenyl)-4-(2-methoxyphenyl)-4H-
1,2,4-triazol-3-amine (13a)þ4-(3,5-bis(trifluoromethyl)phenyl)-N-
(2-methoxyphenyl)-4H-1,2,4-triazol-3-amine (13b). The general
procedure for the unsymmetrical thiourea was followed. The crude
4.3.10. 4-Butyl-N-(3-nitrophenyl)-4H-1,2,4-triazol-3-amine
(17a). The general procedure for the unsymmetrical thiourea was
followed. The crude product containing single regioisomer (as

5074
S. Guin et al. / Tetrahedron 68 (2012) 5066e5074
indicated by TLC) was purified by column chromatography (100%
EtOAc) to give the title compound 17a (144 mg, 55%) as yellow
solid; Rf (100% EtOAc) 0.19; mp 127e130 ꢂC; nmax (KBr): 3252, 3142,
2961, 2930, 2851, 1630, 1613, 1553, 1531, 1353, 1251, 997, 853, 803,
References and notes
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739 cmꢀ1
;
1H NMR (400 MHz, CD3OD):
d
¼8.36 (2H, m, eNeCH]
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Ne and Ar. CeH), 7.76e7.79 (2H, m, Ar. CeH), 7.50 (1H, t, J¼8.0 Hz,
Ar. CeH), 4.02 (2H, t, J¼7.6, aliphatic-CH2e), 1.78 (2H, quin,
J¼7.6 Hz, aliphatic-CH2e), 1.37 (2H, sextet, J¼7.6 Hz, aliphatic-
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(100 MHz, CD3OD):
d
¼152.1, 150.5, 144.3, 143.2, 131.3, 123.9, 116.9,
112.5, 44.7, 33.0, 20.8, 14.0 ppm; HRMS (ESI): MHþ, found 262.1296.
C12H15N5O2 requires 262.1299. Elemental analysis: found C, 55.19;
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4.4. Crystallographic description
Crystal data were collected with a Bruker Smart Apex-II CCD
diffractometer by using graphite monochromated MoK
a
radiation
ꢀ
(l¼0.71073 A) at 298 K. Cell parameters were retrieved using
SMART16 software and refined with SAINT16 on all observed re-
flections. Data reduction was performed with the SAINT software
and corrected for Lorentz and polarization effects. Absorption
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program and refined by full-matrix least-squares methods on F2.
All non-hydrogen atomic positions were located in difference
Fourier maps and refined anisotropically. The hydrogen atoms
were placed in their geometrically generated positions. All the
crystals were isolated in rectangular shape from ethyl acetate and
hexane mixture at room temperature. CCDC numbers for com-
pounds 4a, 14a and 17a are CCDC-824581, CCDC-831538 and
CCDC-824582, respectively. These data can be obtained from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
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Acknowledgements
B.K.P acknowledges the support of this research by the De-
partment of Science and Technology (DST) (SR/S1/OC-79/2009),
New Delhi, and the Council of Scientific and Industrial Research
(CSIR) (01(2270)/08/EMR-II). S.G., S.K.R. and N.K. thank CSIR for
fellowships. Thanks are due to Arghya Basu and Sandeep Dey for
crystallographic help and Paramartha Gogoi for HPLC. Thanks are
due to Central Instruments Facility (CIF) IIT Guwahati for NMR
spectra and DST-FIST for XRD facility.
Supplementary data
16. SMART, SAINT and XPREP; Siemens Analytical X-ray Instruments: Madison, WI,
1995.
17. Sheldrick, G. M. SADABS: Empirical Absorption and Correction Software; Univer-
sity of Gottingen: Gottingen, 1999e2003.
X-ray crystallographic data (CIF file) of 4a, 14a and 17a as well as
copies of 1H and 13C NMR and HRMS spectra of products. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2012.04.042.
18. Sheldrick, G. M. SHELXS-97; University of Gottingen: Gottingen, 1997.