A new, high-yield synthesis of 3-aryl-1,2,4-triazoles

Article abstract of DOI:10.1016/j.tet.2016.10.045

A convenient new synthetic approach to 3-aryl-1,2,4-triazoles has been developed. Chloralamides were obtained by high yield reactions between benzamides and chloral hydrate. These reacted with a phosphorus pentachloride/phosphorus oxychloride mixture unde

Full text of DOI:10.1016/j.tet.2016.10.045

Accepted Manuscript
A new, high-yield synthesis of 3-aryl-1,2,4-triazoles
Antonio Guirado, Libertad López-Caracena, José I. López-Sánchez, José Sandoval,
María Vera, Delia Bautista, Jesús Gálvez
PII:
S0040-4020(16)31080-8
10.1016/j.tet.2016.10.045
TET 28186
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 July 2016
Accepted Date: 17 October 2016
Please cite this article as: Guirado A, López-Caracena L, López-Sánchez JI, Sandoval J, Vera M,
Bautista D, Gálvez J, A new, high-yield synthesis of 3-aryl-1,2,4-triazoles, Tetrahedron (2016), doi:
10.1016/j.tet.2016.10.045.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A new, high-yield synthesis of 3-aryl-1,2,4-triazoles
Antonio Guiradoa,*, Libertad López-Caracenaa, José I. López-Sáncheza, José Sandovala ,
María Veraa, Delia Bautistaa, Jesús Gálvezb,*
aDepartamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de
Espinardo, 30071 Murcia, Spain.
bDepartamento de Química Física, Universidad de Murcia, Spain.
*Corresponding authors. Tel.: +34 868 887 490; fax: +34 868 884 148 (A.G.).
E-mail addresses: anguir@um.es (A. Guirado), jgalvez@um.es (J. Gálvez).
Keywords:Triazoles; Chloral; Chloralamides; Benzimidoyl chlorides; Hydrazine
Abstract- A convenient new synthetic approach to 3-aryl-1,2,4-triazoles has been
developed. Chloralamides were obtained by high yield reactions between benzamides
and chloral hydrate. These reacted with a phosphorus pentachloride/phosphorus
oxychloride mixture undergoing a near quantitative conversion to N-(1,2,2,2-
tetrachloroethyl)benzimidoyl chlorides, which were treated with hydrazine hydrate to
directly give 3-aryl-1,2,4-triazoles in high to quantitative yields. The formation of these
products involves a double condensation process followed by a spontaneous
β-
elimination of chloroform. The molecular structure of 1-(4-chlorobenzoyl)-3-(4-
methoxyphenyl)-1,2,4-triazole was determined by X-ray crystallography. Theoretical
computational studies on aromatization of 3-aryl-5-trichloromethyl-1,2,4-triazolines via
chloroform elimination and to determine relative stabilities of 3-phenyl-1,2,4-triazole
tautomers were performed using ab initio, density functional (B3LYP), Moller-Plesset
(MP2), and the thermochemical recipe T1.
1. Introduction
The synthesis and properties of 1,2,4-triazoles have been thoroughly reviewed,1-24
showing that the presence of a triazole nucleus is essential for a wide assortment of
biological activities and pharmacological applications. It should also be noted that 3-
aryl-1,2,4-triazoles are currently being used as intermediates in a variety of chemical
and medicinal chemistry works.25-33 Regarding the synthesis of these substances, the
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first preparation34,35 of the parent compound, 3-phenyl-1,2,4-triazole, was carried out by
oxidation of 2-benzylidene-1-methylhydrazinecarboxamide to 5-hydroxy-1-methyl-3-
phenyl-1,2,4-triazole, which was treated with phosphorus pentasulfide to give the final
product in a very unsatisfactory yield.36 Reactions between benzoylhydrazides and
formamide or between formylhydrazide and benzamides were also found to be of little
synthetic utility.37 3-Phenyl-1,2,4-triazole and some other similar ones were obtained
through a fairly efficient procedure involving reactions of aroylisothiocyanates with
hydrazines to give the corresponding 3-aryl-1,2,4-triazol-5-thioles, which were
subjected to desulfuration with Raney nickel leading to the targeted products.36
Reactions of benzamides with N,N-dimethylformamide dimethyl acetal gave N’-
benzoyl-N,N-dimethylamidines, whose treatment with hydrazines led to isolable
intermediates that when they were subjected to high temperature cyclized giving the
corresponding triazoles in better yields.38,39 In this paper we report a new, high-yield
synthetic approach to 3-aryl-1,2,4-triazoles starting from chloral, which is an
inexpensive multipurpose starting material for organic synthesis.40
On studying reactions of trichloroethylideneacetophenones with benzamidines, we
noticed the formation of isolable 2,4-diaryl-6-trichloromethyl-1,6-dihidropyrimidines,
whose treatment with potassium tert-butoxide promoted aromatization processes via β-
elimination of chloroform to give 2,4-diarylpyrimidines in high yields.41,42 These
successful results strongly suggested continuing this promising line of work. Thus, we
envisioned a new preparative methodology for 3-aryl-1,2,4-triazoles based on
chloralamides 2, which are available by facile near quantitative reactions43,44 between
chloral and carboxamides 1 (Scheme 1). First, compounds 2 would be converted to N-
(1,2,2,2-tetrachloroethyl)benzamides 3 by treatment with phosphorous pentachloride.44
Secondly reactions of compounds 3 with hydrazine were found to be unsuccessful for
generating trichloromethyltriazolines 5 neither aryltriazoles 6, leading to a complex
mixture of unidentified products. Alternatively, intermediates 2 were efficiently
transformed to N-(1-chloro-2,2,2-trichloroethyl)benzimidoyl chlorides 4, which reacted
with hydrazine directly yielding 3-aryl-1,2,4-triazoles 6 in whose formation undetected
3-aryl-5-trichloromethyl-2-triazolines 5 intermediates would participate.
2

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N
NH
O
Cl
H2O
H2N-NH2
HCl
Ar
CCl3
N
H
Ar
CCl3
N
H
5
3
CHCl3
PCl5
O
(A)
N
NH
OH
O
Ar
N
Cl3CCHO
Ar
CCl3
N
H
Ar
NH2
6
2
1
CHCl3
N
(B)
PCl5/POCl3
NH
Cl
Cl
H2N-NH2
2 HCl
Ar
CCl3
N
Ar
CCl3
N
H
4
5
Scheme 1. Synthesis of compounds 2, 4 and 6.
2. Results and discussion
Chloralbenzamides 2 and N-(1,2,2,2-tetrachloroethyl)benzamides 3 were sequentially
synthesized in high yields as previously reported44 by heating of benzamides and
chloral hydrate mixtures followed by treatment of the obtained reaction adducts with
phosphorous pentachloride. In an earlier work, we had recognized that compounds 3
undergo clean and efficient reactions with primary amines leading to N-(1-amino-2,2,2-
trichloroethyl)benzamides.45 On the other hand, it was take into account that thermal
cyclodehydration of N-(2-aminoethyl)benzamides are able to produce the corresponding
2-arylimidazolines.46 Therefore, one would expect that reactions of compounds 3 with
hydrazine might provide 3-aryl-5-trichloromethyl-1,2,4-triazolines 5 (Scheme 1, route
A), whose chemical behaviour could be expected to be similar to that we observed in
the synthesis of 2,4-diarylpyrimidines,41,42 in this case chloroform eliminations giving
3-aryl-1,2,4-triazoles 6. Nevertheless, this possibility of conversion was discarded since
experiments led to a complex mixture of unidentified reaction products. These
disappointing results could perhaps be caused by a relatively low electrophilic activity
3

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at the carbonyl centre, thus offering an opportunity for adverse competitive reactions. In
order to overcome this difficulty we designed an alternative synthesis (route B),
involving more active electrophilic that a carbonyl amide group, such as imidoyl
chloride
function.
Focusing
the
work
on
preparing
N-(1,2,2,2-
tetrachloroethyl)benzimidoyl chlorides 4, reaction of chloralamides 2 with phosphorus
pentachloride carried out in carbon tetrachloride solutions has been the only reported
preparing method.47 In spite of the attractive structure of compounds 4, clearly
favourable to undergo reactions with dienucleophiles to close heterocyclic rings, these
reagents remain scarcely exploited, perhaps due to the lack of a good preparative
procedure for them. Low to moderate yields, generation of impurities, and difficulty of
purification were the main problems we found when working with this method.
However, we improved it by treatment of compounds 2 with a mixture of phosphorus
pentachloride and phosphorus oxychloride in the absence of carbon tetrachloride.
Fortunately, this more active chlorinating agent was found to be able to obtain the
targeted compounds in high to near quantitative yields (Table 1). Advantageously, a
simple extraction allows the isolation of intermediates 4 in a high pure state, sufficient
for use without needing any purification.
Table 1. Products 4,6 and yields.
6 (%)
entry
Ar
4 (%)
98
98
95
91
81
86
93
94
88
90
a
b
c
d
e
f
C6H5
82
87
95
75
95
84
77
86
79
93
2-ClC6H4
3-O2NC6H4
3,5-(O2N)2C6H3
2-CH3C6H4
3-FC6H4
g
h
i
4-CH3OC6H4
4-O2NC6H4
4-CH3C6H4
4-ClC6H4
j
When compounds 4 were treated with hydrazine hydrate at room temperature the
progressive formation of single products was observed in all cases. After isolation and
purification they were identified as the corresponding 3-aryl-1,2,4-triazoles 6 instead of
the expected triazolines 5. Yields ranged from high to near quantitative (Table 1). As far
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as we know, this is the first time that triazoles have been synthesized starting from
chloral. Single crystals suitable for an X-ray diffraction analysis of any of the prepared
aryltriazoles 6 could not be obtained despite intensive effort. Instead, we were
successful in analyzing a 4-chlorobenzoyl derivative of 6g. The molecular structure
determined corresponds to 1-(4-chlorobenzoyl)-3-(4-methoxyphenyl)-1,2,4-triazole 7
(Fig. 1).
Figure 1. Thermal ellipsoid plot (50% level) of compound 7 in the crystal.
It should be noted that in a previous work we reported that reactions of
trichloroethylideneacetophenones with benzamidines followed by dehydration lead to
isolable 2,4-diaryl-6-trichloromethyl-1,6-dihidropyrimidines, which needed treatment
with a strong base, such as potassium t-butoxide, to promote aromatization by
chloroform elimination.41,42 However, 3-aryl-5-trichloromethyl-1,2,4-triazolines 5 were
non detectable intermediates in the direct synthetic process of triazoles 6 described here.
This contrast evidences a greater proclivity to undergo loss of chloroform from 5 than
from trichloromethyldihidropyrimidines. This experimental observation has been found
to be fully consistent with a comparative theoretical DFT computational study48 carried
out at the B3LYP/6-311++G(d,p) level, where aromatization by chloroform elimination
from 5a is a more exothermic process (-15.77 kcal/mol) than from 2,4-diphenyl-6-
trichloromethyl-1,6-dihidropyrimidine (-9.24 kcal/mol).
5

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N
NH
HN
N
N
N
Ar
Ar
Ar
N
N
N
H
6(1)
6(2)
6(3)
Scheme 2. Tautomeric forms of 3-aryl-1,2,4-triazoles 6.
In order to gain further insights into the structure and relative populations of tautomers
(Scheme 2) in samples of triazoles 6 subjected to NMR spectroscopy, computational
calculations48 were carried out on the parent compound 6a (Ar= Ph) using different
methods: ab initio (HF), density functional (B3LYP), Moller-Plesset (MP2), and the
thermochemical recipe T1. Two basis sets of different sizes, 6-31G(d) and 6-
311++G(d,p), were applied. All procedures gave similar results, showing completely
planar structures for the three tautomeric forms, but with significant differences in
stability. Thus, at the B3LYP/6-311++G(d,p) level 6a(1) is the most stable tautomer
(rel. E= 0 kcal/mol) exhibiting a relative stability very close to 6a(2) (rel. E= 0.2
kcal/mol), whereas 6a(3) is the most unstable tautomer (rel. E= 7.17 kcal/mol). From
the Boltzmann distribution law it can be concluded that, at room temperature, isomers
6a(1) and 6a(2) would be in a comparable ratio (about 58% and 42%, respectively),
whereas the presence of 6a(3) would be negligible.
Finally, the accuracy of the above computational methodology was checked by
comparing the molecular structure obtained by X-ray crystallography of 7 (Figure 1)
and the corresponding calculated molecular structure. An excellent agreement for bond
lengths and bond angles was found, as is shown in Table 2.
Table 2. Selected bond lengths and bond angles of crystal and calculated structures in crystal structure of
compound 7
Bond
Calculateda(Å)
1.371
1.370
1.426
1.322
1.303
1.384
1.754
1.361
1.423
1.212
1.426
1.463
Crystalb(Å)
1.367
1.328
1.415
1.310
1.305
1.392
1.739
1.367
1.430
1.209
1.415
1.467
Angle
Calculateda(º) Crystalb(º)
N1-C8
N1-N2
N1-C7
N2-C9
N3-C8
N3-C9
Cl1-C4
O1-C14
O1-C17
O2-C7
C1-C17
C9-C11
C9-N2-N1
C8-N3-C9
C14-O1-C17
O2-C7-C1
O2-C7-C1
N1-C7-C1
N3-C8-N1
N2-C9-N3
N2-C9-C11
C6-C1-C2
O1-C14-C15
O1-C14-C13
103.19
103.72
118.79
117.49
122.85
119.67
110.39
113.89
123.49
119.15
124.68
115.70
102.79
102.85
116.71
117.99
122.42
119.58
110.78
114.75
122.67
119.28
123.98
116.01
a) Geometry optimized at the B3LYP/6-311++G(d,p) level; b) Crystal structure
6

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3. Conclusions
To conclude, an excellent new synthetic method on 1,2,4-triazole chemistry is reported.
Versatility, good yields, easy availability of starting materials, mildness and a simple
experimental procedure are noteworthy advantages of this approach. The development
of syntheses for some other classes of heterocycles by applying a similar strategy also
appears feasible.
4. Experimental Section
4.1. General
NMR spectra were determined on Bruker AV-200, Bruker AV-300 or Bruker AV-400
with tetramethylsilane as internal reference. High-resolution mass spectra (HRMS) were
obtained using a time-of-flight (TOF) instrument equipped with electrospray ionization
(ESI). IR spectra were recorded on a Nicolet Impact 400 Spectrometer. Microanalyses
were performed on a Carlo Erba EA- 1108 analyzer. Melting points were determined on
a Büchi Melting point B-540, and are uncorrected. Chloralbenzamides 2 and N-(1,2,2,2-
tetrachloroethyl)benzamides 3 were prepared as previously described.44
All computations were performed with the Spartan’14 package program.48 The most
stable conformers were determined with the MMFF molecular mechanics method. Next,
these conformers were used as input for ab initio molecular orbital and density
functional theory calculations of geometry optimizations at the HF, B3LYP, and MP2
levels of theory with the 6-31G(d) and 6-311++G(d,p) basis sets. There were no
significant differences between the results obtained with the different procedures.
4.2. General procedure for the synthesis of N-(1,2,2,2-tetrachloroethyl)benzimidoyl
chlorides 4
To a solution of compound 2 (16 mmol) in phosphorus oxychloride (25 mL) phosphorus
pentachloride (39 mmol) was added in small portions. The reaction mixture was
refluxed for 2 h, cooled, and carefully added to crushed ice-water (300 mL). Then,
chloroform (300 mL) was added and the mixture was vigorously stirred for 5 min, the
organic layer was separated, dried, and evaporated under low pressure, leaving
compound 4 as a highly pure pale green oil.
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1
4.2.1. N-(1,2,2,2-tetrachloroethyl)benzimidoyl chloride (4a). C9H6Cl5N (305.42). H
NMR δ (CDCl3, 200 MHz): 6.17 (s, 1H), 7.44-7.64 (m, 3H), 8.14-8.18 (m, 2H); 13C
NMR δ (CDCl3, 50.4 MHz): 83.30 (CH), 99.87 (C), 128.73 (CH), 129.90 (CH), 133.46
(CH), 134.39 (C), 153.61 (C); MS (EI) m/z (%): 268 (M+ -Cl, 7), 198 (26), 188 (43),
186 (42), 149 (25), 104 (100); IR (Nujol): 1642, 1448, 1306, 1225, 1065, 1030, 904,
832, 767, 749, 685, 665, 623, 542 cm-1.
4.2.2. N-(1,2,2,2-tetrachloroethyl)-3-chlorobenzimidoyl chloride (4b). C9H5Cl6N
(339.86). 1H NMR δ (CDCl3, 200 MHz): 6.14 (s, 1H), 7.34-7.49 (m, 3H), 7.58-7.61 (m,
1H); 13C NMR δ (CDCl3, 50.4 MHz): 83.03 (CH), 99.22 (C), 126.90 (CH), 130.37
(CH), 130.77 (CH), 132.15 (CH), 132.27 (C), 135.70 (C), 151.25 (C); MS (EI) m/z (%):
302 (M+ -Cl, 3), 270 (21), 268 (16), 232 (19), 222 (56), 167 (16), 138 (100); IR (Nujol):
1660, 1590, 1471, 1438, 1304, 1269, 1224, 1058, 1023, 905, 831, 756, 727, 709, 647
cm-1.
4.2.3. N-(1,2,2,2-tetrachloroethyl)-3-nitrobenzimidoyl chloride (4c). C9H5Cl5N2O2
(350.41). 1H NMR δ (CDCl3, 200 MHz): 6.15 (s, 1H), 7.68-7.75 (m, 1H), 8.43-8.53 (m,
2H), 8.95-8.97 (m, 1H); 13C NMR δ (CDCl3, 50.4 MHz): 82.86 (CH), 99.39 (C), 124.73
(CH), 127.72 (CH), 129.98 (CH), 135.08 (CH), 136.00 (C), 148.46 (C), 151.26 (C); MS
(EI) m/z (%): 313 (M+ -Cl, 8), 243 (19), 231 (100), 197 (23), 149 (87); IR (Nujol):
1645, 1612, 1577, 1532, 1473, 1348, 1223, 1067, 951, 849, 835, 751, 705, 676, 649 cm-
1
.
4.2.4. N-(1,2,2,2-tetrachloroethyl)-3,5-dinitrobenzimidoyl chloride (4d). C9H4Cl5N3O4
(395.41). 1H NMR δ (CDCl3, 200 MHz): 6.16 (s, 1H), 9.26 (s, 3H); 13C NMR δ (CDCl3,
50.4 MHz): 82.59 (CH), 98.98 (C), 122.48 (CH), 129.17 (CH), 137.78 (C), 148.83 (C),
149.21 (C); MS (EI) m/z (%): 358 (M+ -Cl, 7), 280 (18), 278 (91), 276 (99), 196 (15),
167 (40); IR (Nujol): 1647, 1593, 1546, 1343, 1309, 1244, 1118, 1071, 994, 918, 834,
753, 732, 715, 669, 545 cm-1.
4.2.5. N-(1,2,2,2-tetrachloroethyl)-2-methylbenzimidoyl chloride (4e). C10H8Cl5N
1
(319.44). H NMR δ (CDCl3, 300 MHz): 2.54 (s, 3H), 6.07 (s, 1H), 7.17-7.20 (m, 2H),
7.21-7.29 (m, 1H), 7.33 (dd, 1H, J= 7.4, J= 1.4 Hz, Hz); 13C NMR δ (CDCl3, 75.4
MHz): 21.86 (CH3), 83.57 (CH), 99.49 (C), 125.93 (CH), 130.54 (CH), 131.57 (CH),
134.89 (C), 138.37 (C), 153.19 (C); MS (EI) m/z (%): 282 (M+ -Cl, 19), 166.8 (26), 149
8

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(59), 118 (100); IR (Nujol): 1646, 1569, 1457, 1303, 1222, 1069, 1025, 898, 830, 762,
750, 717, 658, 629, 573 cm-1.
4.2.6. N-(1,2,2,2-tetrachloroethyl)-3-fluorobenzimidoyl chloride (4f). C9H5Cl5FN
(323.41). 1H NMR δ (CDCl3, 300 MHz): 6.11 (s, 1H), 7.24-7.47 (m, 2H), 7.80-7.94 (m,
13
2H); C NMR δ (CDCl3, 75.4 MHz): 83.07 (CH), 99.68 (C), 116.716 (CH, d, J= 24.4
Hz), 120.49 (CH, d, J= 21.3 Hz), 125.63 (CH, d, J= 2.9 Hz), 130.31 (CH, d, J= 8.0 Hz),
136.46 (C, d, J= 8.0 Hz), 152.22 (C, d, J= 3.4 Hz), 162.63 (C, d, J= 247.5 Hz); MS (EI)
m/z (%): 286 (M+ -Cl, 19), 218 (15), 216 (25), 204 (100), 167 (17), 122 (66); IR
(Nujol): 1697, 1644, 1588, 1483, 1439, 1311, 1275, 1261, 1172, 1151, 1066, 1032, 967,
879, 833, 803, 750, 684, 661 cm-1.
4.2.7. N-(1,2,2,2-tetrachloroethyl)-4-methoxybenzimidoyl chloride (4g). C10H8Cl5NO
(335.44): 1H NMR δ (CDCl3, 300 MHz): 3.89 (s, 3H), 6.16 (s, 1H), 6.96 (d, 2H, J= 9.1
Hz), 8.12 (d, 2H, J= 9.1 Hz); 13C NMR δ (CDCl3, 75.4 MHz): 55.69 (CH3), 83.65 (CH),
100.10 (C), 114.04 (CH), 126.82 (C), 132.01 (CH), 152.90 (C), 163.97 (C); MS (EI)
m/z (%): 298 (M+ -Cl, 32), 230 (26), 228 (42), 219 (18), 165 (14), 135 (36), 134 (100),
119 (18), 90 (27); IR (Nujol): 1633, 1598, 1506, 1460, 1441, 1310, 1269, 1169, 1062,
1026, 905, 822, 750, 664, 608, 544 cm-1.
4.2.8. N-(1,2,2,2-tetrachloroethyl)-4-nitrobenzimidoyl chloride (4h). C9H5Cl5N2O2
1
(350,41) H NMR δ (CDCl3, 200 MHz): 6.12 (s, 1H), 8.30 (br s, 4H); 13C NMR δ
(CDCl3, 75.4 MHz): 82.71 (CH), 99.32 (C), 123.73 (CH), 130.71 (CH), 139.42 (C),
150.49 (C), 151.42 (C); MS (EI) m/z (%): 313 (M+ -Cl, 3), 243 (45), 231 (100), 197
(35), 150 (84); IR (Nujol): 3453, 3101, 2947, 1666, 1610, 1573, 1529, 1443, 1310,
1229, 1062, 1030, 909, 831, 751, 644, 630, 558 cm-1.
4.2.9. N-(1,2,2,2-tetrachloroethyl)-4-methylbenzimidoyl chloride (4i). C10H8Cl5N
1
(319.44); H NMR δ (CDCl3, 400 MHz): 2.43 (s, 3H), 6.16 (s, 1H), 7.25-7.29 (m, 2H),
13
8.03-806 (m, 2H); C NMR δ (CDCl3, 100.8 MHz): 21.70 (CH3), 83.48 (CH), 100.00
(C), 129.45 (CH), 129.95 (CH), 131.77 (C), 144.46 (C), 153.53 (C), MS (EI) m/z (%):
282 (M+ - Cl, 3), 182 (13), 149 (29), 119 (100), 65(53); IR (KBr): 3269, 1630, 1525,
1503, 1247, 1182, 1069, 1034, 905, 821, 786, 739, 706, 621, 612, 586 cm-1.
9

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4.2.10. N-(1,2,2,2-tetrachloroethyl)-4-chlorobenzimidoyl chloride (4j). C9H5Cl6N
(339,86); 1H NMR δ (CDCl3, 200 MHz): 6.16 (s, 1H), 7.44 (d, 2H, J= 8.7 Hz), 8.08 (d,
13
2H, J= 8.7 Hz); C NMR δ (CDCl3, 75.4 MHz): 83.09 (CH), 99.64 (C), 128.97 (CH),
131.01 (CH), 132.69 (C), 139.99 (C), 152.31 (C), MS (EI) m/z (%): 302 (M+ -Cl, 3),
270 (21), 268 (16), 232 (19), 222 (56), 167 (16), 138 (100); IR (KBr): 3070, 2938,
1661, 1590, 1471, 1438, 1304, 1269, 1224, 1058, 1023, 905, 831, 727, 709, 647,558
cm-1.
4.3. General procedure for the synthesis 3-aryl-1,2,4-triazoles 6
A mixture of compound 4 (10 mmol) and hydrazine hydrate (50-60%, 5.0 mL), in
chloroform (25 mL), was stirred at room temperature for 24 h and washed twice with
water (50 mL). The organic solvent was removed under low pressure, leaving crude
product 6 as a solid residue, which was purified by crystallization from the appropriate
solvent.
4.3.1. 3-Phenyl-1,2,4-triazole (6a). C8H7N3 (145.16).Crystallization from isopropanol
gave white needles; mp 118 ºC (Lit34, mp 118.5-119 °C).1H NMR δ (CDCl3, 400 MHz):
7.36-7.43 (m, 3H), 7.98-8.02 (m, 2H), 8.23 (s, 1H), 11.48 (br s, 1H); 13C NMR δ
(CDCl3, 50.4 MHz): 126.50 (CH), 128.36 (C), 128.89 (CH), 130.11 (CH), 147.51 (CH),
158.74 (C); IR (Nujol): 3445, 2918, 2776, 2724, 1563, 1474, 1407, 1272, 1112, 964,
866, 715, 687, 663, 495 cm-1. HRMS (ESI) calcd for C8H8N3 (M+H)+: 146.0713. Found
146.0712.
4.3.2. 3-(3-Chlorophenyl)-1,2,4-triazole (6b). C8H6ClN3 (179.61). Crystallization from
1
acetonitrile/toluene gave a beige powder; mp 153-154 ºC. H NMR δ (DMSO-d6, 70 ºC,
300 MHz): 7.42-7.57 (m, 3H), 7.80-7.83 (m, 1H), 8.39 (s, 1H), 13.95 (br s, 1H); 13C
NMR δ (DMSO-d6, 70 ºC, 100.8MHz): 126.60 (CH), 129.18 (C), 129.85 (CH), 130.03
(CH), 130.89 (CH), 131.36 (C), 145.62 (CH), 156.64 (C); IR (Nujol): 3054, 2898, 2751,
2704, 1609, 1571, 1492, 1459, 1399, 1273, 1194, 1126, 1036, 997, 909, 767, 744, 671,
458 cm-1. HRMS (ESI) calcd for C8H7ClN3 (M+H)+: 180.0323. Found 180.0322.
4.3.3. 3-(3-Nitrophenyl)-1,2,4-triazole (6c). C8H6N4O2 (190.16). Crystallization from
methanol gave pale yellow needles; mp 214 ºC. 1H NMR δ (DMSO-d6, 200 MHz): 7.74
(t, 1H, J= 8.0 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.21-8.43 (m, 1H), 8.73 (s, 2H), 14.36 (br s,
10

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1H); 13C NMR δ (DMSO-d6, 50.4MHz): 120.09 (CH), 123.51 (CH), 130.56 (CH),
131.89 (CH), 132.85(C), 145.14 (CH), 148.18 (C), 159.18 (C); IR (Nujol): 3318, 3132,
1534, 1508 1349, 1274, 1117, 1089, 981, 874, 743, 725, 672, 618, 463 cm1. HRMS
(ESI) calcd for C8H5N4O2 (M-H)-: 189.0418. Found 189.0409.
4.3.4. 3-(3,5-Dinitrophenyl)-1,2,4-triazole (6d). C8H5N5O4 (235.16). Crystallization
from methanol gave brown prisms; mp 252-254 ºC. 1H NMR δ (DMSO-d6 + TFA-d, 70
ºC, 400 MHz): 7.54-7.55 (m, 1H), 7.75-7.76 (m, 1H), 8.03-8.04 (m, 1H), 8.56 (s, 1H);
13C NMR δ (DMSO-d6 + TFA-d, 70 ºC, 100.8 MHz): 109.15 (CH), 109.34 (CH),
118.05 (CH), 131.72 (C), 145.62 (CH), 148.40 (C), 149.40 (C), 157.62 (C); IR (Nujol):
3456, 3375, 3219, 3113, 1629, 1617, 1528, 1502, 1484, 1346, 1266, 1013, 975, 861,
737, 662, 577, 452 cm-1. HRMS (ESI) calcd for C8H4N5O4 (M-H)-: 234.0269. Found
234.0261.
4.3.5. 3-(2-Methylphenyl)-1,2,4-triazole (6e). C9H9N3 (159.19). Crystallization from
1
isopropanol gave a pale yellow powder; mp 158-160 ºC. H NMR δ (Pyr-d5 + D2O, 90
13
ºC, 200 MHz): 4.15 (s, 3H), 8.67-8.76 (m, 3H), 9.51-9.56 (m, 1H), 9.97 (s, 1H); C
NMR δ (DMSO-d6 + TFA-d, 90 ºC, 100.8 MHz): 20.40 (CH3), 125.79 (CH), 127.21
(C), 129.45 (CH), 129.75 (CH), 131.02 (CH), 136.94 (C), 144.86 (CH), 156.58 (C); IR
(Nujol): 3090, 1611, 1565, 1534, 1516, 1456, 1403, 1185, 1169, 955, 870, 772, 729,
627, 631, 449 cm-1. HRMS (ESI) calcd for C9H10N3 (M+H)+: 160.0869. Found
160.0876.
4.3.6. 3-(3-Fluorophenyl)-1,2,4-triazole (6f). C8H6FN3 (163.15). Crystallization from
1
isopropanol gave a beige powder; mp 111-113 ºC. H NMR δ (DMSO-d6 70 ºC, 200
MHz): 7.17-7.56 (m, 2H), 7.72-7.89 (m, 2H), 8.40 (s, 1H); 13C NMR δ (DMSO-d6,
100.8 MHz): 112.93 (CH, d, J= 23.0 Hz), 116.21 (CH, d, J= 21.0 Hz), 122.41 (CH),
131.22 (CH, d, J= 8.0 Hz), 133.24 (C), 146.90 (CH), 158.51 (C), 162.9 (C, d, J= 244.0
Hz); IR (Nujol): 3441, 3059, 2815, 2759, 1559, 1501, 1463, 1386, 1280, 1226, 1189,
1097, 1006, 860, 799, 738, 665, 527, 454 cm-1. HRMS (ESI) calcd for C8H7FN3
(M+H)+: 164.0619. Found 164.0621.
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4.3.7. 3-(4-Methoxyphenyl)-1,2,4-triazole (6g). C9H9N3O (175.19). Crystallization from
1
isopropanol gave white needles; mp 186 ºC (Lit,36 mp 186 °C). H NMR δ (DMSO-d6
90 ºC, 400 MHz): 3.82 (s, 3H), 7.03 (d, 2H J= 9.2 Hz), 7.95 (d, 2H J= 9.2 Hz), 8.22 (s,
1H), 9.97 ( br s, 1H); 13C NMR δ (DMSO-d6 90 ºC, 100.8 MHz): 54.85 (CH3), 113.86
(CH), 122.08 (C), 127.09 (CH), 146.62 (CH), 157.10 (C), 159.98 (C); IR (Nujol): 3442,
2998, 2932, 2836, 2664, 1614, 1512, 1474, 1427, 1289, 1256, 1177, 1115, 1026, 991,
963, 836, 748, 613, 530 cm-1. HRMS (ESI) calcd for C9H10N3O (M+H)+: 176.0818.
Found 176.0819.
4.3.8. 3-(4-Nitrophenyl)-1,2,4-triazole (6h). C8H6N4O2 (190,16). Crystallization from
1
ethanol gave a yellow powder; mp 226-229 ºC (Lit,38 mp 228-229 °C). H NMR δ
13
(DMSO-d6 90 ºC, 300 MHz): 8.27 (br, 4H), 8.54 (s, 1H); C NMR δ (DMSO-d6, 90
ºC, 75.4 MHz): 123.42 (CH), 126.40 (CH), 136.15 (C), 145.62 (CH), 147.31 (C),
157.57 (C); IR(KBr): 3354, 3318, 2940, 1602, 1577, 1514, 1436, 1337, 1317, 1097,
1066, 900, 865, 855, 778, 716, 696, 682,cm-1. HRMS (ESI) calcd for C8H5N4O2 (M-H)-:
189.0418. Found 189.0416.
4.3.9. 3-(4-Methylphenyl)-1,2,4-triazole (6i). C9H9N3 (159,19). Crystallization from
isopropanol gave a light grey powder; mp 169-171 ºC. 1H NMR δ (DMSO-d6, 90 ºC,
400 MHz): 2.34 (s, 3H), 7.26 (d, 2H, J= 8.0 Hz), 7.90 (d, 2H, J= 8.0 Hz), 8.24 (s, 1H);
13C NMR δ (DMSO-d6 90 ºC, 100.8 MHz): 20.26 (CH3), 125.51 (CH), 126.68 (C),
128.70 (CH), 138.31 (C), 146.64 (CH), 157.60 (C); IR (KBr): 3152, 3094, 2769, 2653,
1732, 1615, 1569, 1510, 1470, 1422, 1397, 1271, 1202, 1111, 992, 963, 821, 737, 701,
663 cm-1. HRMS (ESI) calcd for C9H10N3 (M+H)+: 160.0869. Found 160.0873.
4.3.9. 3-(4-Chlorophenyl)-1,2,4-triazole (6j). C8H6ClN3 (179,61). Crystallization from
chloroform/petroleum ether gave a white powder; mp 180-181 ºC (Lit,36 mp 182 °C).
1H NMR δ (DMSO-d6 90 ºC, 400 MHz): 7.51 (d, 2H J= 8.4 Hz), 8.02 (d, 2H J= 8.4 Hz),
13
8.49 (s, 1H); C NMR δ (DMSO-d6 90 ºC, 100.8 MHz): 127.07 (CH), 127.96 (CH),
128.67 (C), 133.31 (C), 145.77 (CH), 157.34 (C); IR (KBr): 3431, 3085, 3043,2905,
2766, 2650, 1610, 1495, 1472, 1424, 1406, 1275, 1116, 1094,1013, 993, 960, 878, 830,
741, 698, 664 cm-1. HRMS (ESI) calcd for C8H7ClN3 (M+H)+: 180.0323. Found
180.0321.
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4.4. Preparation of 1-(4-chlorobenzoyl)-3-(4-methoxyphenyl)-1,2,4-triazole 7
To a stirred solution of 3-(4-methoxyphenyl)-1,2,4-triazole 6g (0.57 mmol) and
triethylamine (0.93 mmol) in dichloromethane (1 mL) a solution of p-chlorobenzoyl
chloride (1.2 mmol) in dichloromethane (1 mL) was added. After 16 h the solvent was
removed under reduced pressure leaving a residue that was washed with aqueous
solution of sodium bicarbonate and crystallized from ethanol. (92%), white needles; mp
1
125-126 ºC. H NMR δ (CDCl3, 400 MHz): 3.82 (s, 3H), 6.95 (m, 2H), 7.50 (m, 2H),
8.07 (m, 2H), 8.28 (m, 2H), 9.03 (s, 1H); 13C NMR δ (CDCl3, 100.8 MHz): 55.46,
114.24, 122.02, 128.62, 128.75, 128.93, 133.42, 140.96, 146.52, 161.61, 163.64,
164.16; MS (EI) m/z (%): 313 (M+, 35), 141 (63), 139 (100), 119 (9), 113 (20), 111
(53), 76 (11), 75 (18); IR (Nujol): 3121, 2972, 2839, 1703, 1614, 1507, 1372, 1249,
1170, 1092, 909, 838, 744, 657, 594, 516, 482 cm-1.
4.5. X-ray structure determination of compound 7
C16H12ClN3O2, M = 313.74, orthorhombic, a = 17.567(2) Å, b = 20.530(3) Å, c =
3.9152(5) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V = 1412.0(3) Å3, T = 100(2) K, space
group Pna2(1), Z = 4, 9038 reflections measured, 2980 independent reflections (Rint
=
0.0296). Data collection: A colourless needle 0.43 × 0.12 × 0.08 mm was mounted in
inert oil on a glass fibre and transferred to the cold gas stream of the diffractometer
(Bruker SMART APEX). Measurements were performed to 2θmax 52° with
monochromated Mo-K
α radiation. Of 9038 measured reflections, 2980 were unique
(Rint = 0.0296) and were used for all calculations. Structure refinement: The structures
49
2
were refined anisotropically against F (program SHELXL-97). Hydrogen atoms were
included with a riding model. The final wR(F2) values were 0.0927 for all data and 200
parameters, with a final R1 value of 0.0395 (I > 2σ(I)). ꢀr 0.431 e/Å3, S 1.125. Complete
crystallographic data (excluding structure factors) have been deposited at the Cambridge
Crystallographic Data Centre under the number CCDC 933675. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
We gratefully acknowledge the financial support of the Fundación Séneca of the
Comunidad Autónoma de la Región de Murcia (project 19249/PI/14).
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