Facile one-pot synthesis of N-fused 1,2,4-triazoles via oxidative cyclization using manganese dioxide

Article abstract of DOI:10.1007/s10593-019-02400-0

[Figure not available: see fulltext.] A facile one-pot synthesis of N-fused 1,2,4-triazoles from heterocyclic hydrazines and aldehydes is reported. The reaction is efficiently promoted by manganese dioxide to afford the desired products mostly in high yields and in relatively short times. The mild nature of the synthesis, cheap oxidizing agent, and short reaction time are notable advantages of the developed protocol. This protocol is effective toward various substrates having different functionalities.

Full text of DOI:10.1007/s10593-019-02400-0

DOI 10.1007/s10593-019-02400-0
Chemistry of Heterocyclic Compounds 2018, 54(12), 1111–1116
Facile one-pot synthesis of N-fused 1,2,4-triazoles
via oxidative cyclization using manganese dioxide
Ashish Bhatt1*, Rajesh K. Singh2, Ravi Kant1
1 Department of Chemistry, Mewar University,
Chittorgarh (Rajasthan) 312901, India; е-mail: itsbhatt2007@yahoo.co.in
2 Department of Pharmacy, Mewar University,
Chittorgarh (Rajasthan) 312901, India
Submitted September 25, 2018
Accepted November 23, 2018
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(12), 1111–1116
A facile one-pot synthesis of N-fused 1,2,4-triazoles from heterocyclic hydrazines and aldehydes is reported. The reaction is efficiently
promoted by manganese dioxide to afford the desired products mostly in high yields and in relatively short times. The mild nature of the
synthesis, cheap oxidizing agent, and short reaction time are notable advantages of the developed protocol. This protocol is effective
toward various substrates having different functionalities.
Keywords: manganese dioxide, toluene, 1,2,4-triazole, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo-
[4,3-a]pyridine, [1,2,4]triazolo[4,3-a]pyrimidine.
N-Fused aromatic nitrogen heterocycles are among the
most important compound classes in drug discovery and
also play a pivotal role in living organisms.1,2 In particular,
such scaffolds can be used as building blocks for DNA
(guanine, adenine), they are also found in many approved
drugs, including zolpidem and trazodone, and are featured
in medicinal chemistry studies3–6 (e.g., tyrosine kinase
c-Src inhibitors7,8 or p38α kinase inhibitors,9 Fig. 1).
1,2,4-Triazoles have elicited considerable interest
among medicinal chemists because they are considered to
be privileged structural constituents of many pharma-
ceutical agents as well as natural products. In particular,
compounds containing N-fused 1,2,4-triazoles substructu-
res, such as triazolopyridine and triazolopyrazine moieties,
exhibit a wide spectrum of biological activity including
antifungal,10 antimicrobial,11 antiviral,12 anti-inflamma-
tory,13 antiasthmatic,14 antiproliferative,15 and hypotonic.16
In addition, they have often been used as bioisosteres of
esters and amides, and as dipeptidomimetics in a number of
pharmacologically important molecules.17 On the other
hand, they also play important roles as ligands in organo-
metallic compounds, as precursors for N-heterocyclic
Figure 1. Representative bioactive molecules comprising fused
heterocycles related to 1,2,4-triazoles.
carbenes, as ionic liquids, and as corrosion inhibitors.18
0009-3122/18/54(12)-1111©2018 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2018, 54(12), 1111–1116
Table 1. Optimization of the reaction conditions
Due to their importance, many efficient methods have
been developed to access N-fused 1,2,4-triazoles.19 Among
them, coupling of carboxylic acids or their derivatives with
amidrazones, followed by cyclodehydration is the most
common explored strategy (Scheme 1).20 However, some
of these protocols suffer from the limitations of harsh
conditions, tedious synthetic procedures, time-consuming
reactions, and unsatisfactory yields. Hence, the develop-
ment of milder and more general procedures to access
N-fused 1,2,4-triazoles with high yields in short reaction
time remains desirable.
for synthesis of compound 3a
NH2
HN
N
MnO2, p-TsOH
O
N
+
N
N
Solvent
80°C
Ph
H
Ph
2a
3a
1a
Solvent
MnO2,
equiv
p-TsOH,
mol %
Entry
Time, h Yield, %
1
2
3
4
5
6
7
8
EtOH
1,4-Dioxane
PhMe
1
1
1
1
1
2
4
5
2
3.5
3.5
2
65
60
80
55
50
90
95
82
2
2
Scheme 1. General synthesis of N-fused 1,2,4-triazoles
DCE
2
4
MeCN
PhMe
2
4
5
1.5
0.75
0.5
PhMe
5
PhMe
10
The described oxidative cyclization has previously been
reported for the preparation of triazoloquinoxalines.21–27
Other methods reported in the literature for the cyclization
of the triazole ring usually require a combination of NBS
and base,28 refluxing orthoesters,29,30 acids,30,31 desulfuriza-
tion of thiosemicarbazides,32 or cyclization of hydrazides in
polyphosphoric acid.30 A few examples of oxidative cycliza-
tions using chloramine-T have previously been reported.33
MnO2 has been used for the oxidation of varieties of
functional groups in various organic solvents and also in
aqueous solution. MnO2 is a cheap oxidant, therefore,
studies for the development of the new methods for using
this reagent in a more efficient way are of practical
importance. Our continued interest in the development of
useful synthetic methodologies prompted us to explore the
feasibility of MnO2 for the one-pot synthesis of N-fused
1,2,4-triazoles. However, it has not been investigated as a
catalyst in the synthesis of 1,2,4-triazoles until now.
Our preliminary investigation began with the reaction of
2-hydrazinopyridine (1a) and benzaldehyde (2a) in the
presence of MnO2 (1 equiv) and a catalytic amount of
p-TsOH (2 mol %) in ethanol at 80°C. We were delighted
to observe the formation of the desired fused heterocyclic
product 3-phenyl[1,2,4]triazolo[4,3-a]pyridine (3a), albeit
in a moderate yield of 65% (Table 1, entry 1). Next, we
optimized the reaction conditions in order to increase the
yield. Thus, different solvents were screened, and the
results are summarized in Table 1. It was found that
toluene was the best solvent in terms of the reaction time
and yield of the product (Table 1, entry 3).
decided to perform the subsequent reactions of the
heterocyclic hydrazines with different aldehydes in the
presence of MnO2 (4 equiv) and p-TsOH (5 mol %) as the
catalyst in toluene at 80°C. The effect of temperature on
the yields of the products was also investigated, but
increasing the temperature did not produce satisfactory yields.
With optimized conditions in hand, the scope of the
reaction was investigated, and the results are summarized
in Table 2. As expected, aldehydes 2a–k gave with
pyridine derivative 1a the corresponding N-fused 1,2,4-tri-
azoles: [1,2,4]triazolo[4,3-a]pyridines 3a–k, [1,2,4]triazolo-
[4,3-a]pyrazine 3l, [1,2,4]triazolo[4,3-b]pyridazine 3m, and
[1,2,4]triazolo[4,3-a]pyrimidine 3n in good to excellent
yields. Benzaldehydes with electron-donating groups such
as o-tolualdehyde (2b) and p-anisaldehyde (2f) gave the
desired [1,2,4]triazolo[4,3-a]pyridines 3b,f in very good
yields. Aromatic aldehydes with an electron-withdrawing
groups 2c–e,h and heteroaryl aldehydes 2i–k gave only
slightly lower yields. Pyrazine, pyridazine, and pyrimidine
derivatives 1b–d have also been successfully coupled with
benzaldehyde (2a) affording the corresponding N-fused
1,2,4-triazoles 3l–n in good yields.
In conclusion, we have developed a short and efficient
synthesis of N-fused 1,2,4-triazoles using a mild and
straightforward one-pot condensation/oxidative cyclization
of aldehydes and hetaryl hydrazines with manganese
dioxide as oxidant. A variety of substituents are tolerated
allowing the synthesis of diverse products in good to excellent
yields at short reaction times. The newly developed
synthetic route is believed to be valuable not only for the
construction of building blocks, but also for medicinal
chemistry studies of N-fused 1,2,4-triazole moiety.
Once we had established a suitable solvent for the
synthesis of N-fused 1,2,4-triazoles, we then focused on the
quantity of MnO2 and p-TsOH. An increase in the amount
of MnO2 (from 1 to 4 equiv) and p-TsOH (from 2 to 5 mol %)
not only decreased the reaction time from two hours to
45 min, but also increased the product yield from 80 to
95% (Table 1, entry 7). Further increasing the quantity of
MnO2 to 5 equiv and that of p-TsOH to 10 mol % led to a
decrease in the yield (Table 1, entry 8). Therefore, we
Experimental
1H and 13C NMR spectra were recorded on an AV-500
Bruker spectrometer (500 and 126 MHz, respectively) in
CDCl3 or DMSO-d6 with TMS as internal standard. High-
resolution mass spectra were recorded on a Thermo
Finnigan MAT95XP microspectrometer using electron
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Chemistry of Heterocyclic Compounds 2018, 54(12), 1111–1116
Table 2. Synthesis of [1,2,4]triazolo[4,3-a(b)]azines 3a–n
HetNHNH2
ArCHO
Product
Yield, %
95
HetNHNH2
ArCHO
Product
Yield, %
85
PhCHO
2a
98
85
80
88
N
N
N
Me
3b
90
91
82
92
2a
N
N
N
Br
3e
2a
2a
98
90
90
86
1113

Chemistry of Heterocyclic Compounds 2018, 54(12), 1111–1116
1
impact ionization. Elemental analyses were performed on a
197°C34d). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
6.91 (1H, ddd, J = 7.5, J = 6.6, J = 1.1, H Py); 7.31 (1H,
ddd, J = 9.3, J = 6.5, J = 1.1, H Py); 7.53–7.60 (2H, m,
H Ar); 7.76–7.81 (2H, m, H Ar); 7.84 (1H, dt, J = 9.3,
J = 1.2, H Py); 8.25 (1H, dt, J = 7.0, J = 1.2, H Py).
13C NMR spectrum (CDCl3), δ, ppm: 114.6; 116.9; 122.4;
125.1; 127.3; 129.5; 129.7; 136.4; 145.8; 150.6. Found, m/z:
229.0404 [M]+. C12H8ClN3. Calculated, m/z: 229.0401.
Found, %: C 62.73; H 3.47; N 18.26. C12H8ClN3.
Calculated, %: C 62.76; H 3.51; N 18.30.
VarioEL analyzer. Melting points were determined on a
Stuart SMP3 melting point apparatus. The progress of the
reactions was monitored by TLC on silica gel 60 F254
(Merck) TLC plates, eluent hexane–EtOAc, 6:4. Column
chromatography was carried out using Merck silica gel
(200–300 mesh), eluent hexane–EtOAc, 6:4. All solvents
and reagents were purchased from commercial sources and
used without further purification.
Synthesis of N-fused 1,2,4-triazoles 3a–n (General
method). p-TsOH (9.5 mg, 55 μmol, 5 mol %) and MnO2
(348 mg, 4.00 mmol) were added to a stirred solution of
heterocyclic hydrazine 1a–d (1 mmol) and aldehyde 2a–k
(1.2 mmol) in PhMe (10 ml). The mixture was heated at
80°C until the starting material was completely consumed
(monitored by TLC, 40–55 min) and then cooled down to
room temperature. After filtration and evaporation of solvent
from the filtrate, the resulting residue was purified by silica
gel column chromatography affording pure products.
3-Phenyl[1,2,4]triazolo[4,3-a]pyridine (3a).Yield 85 mg
(95%), white solid, mp 171–173°C (mp 175–176°C34a).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 6.89 (1H, td,
J = 6.8, J = 1.1, H Py); 7.31 (1H, ddd, J = 9.3, J = 6.5,
J = 1.1, H Py); 7.55–7.63 (3H, m, H Ph); 7.82–7.88 (3H,
m, 1H Py, 2H Ph); 8.30 (1H, dt, J = 7.0, J = 1.2, H Py).
13C NMR spectrum (CDCl3), δ, ppm: 114.5; 116.7; 122.7;
126.5; 127.5; 128.3; 129.4; 130.3; 146.8; 150.3. Found, m/z:
195.0792 [M]+. C12H9N3. Calculated, m/z: 195.0791.
Found, %: C 73.80; H 4.61; N 21.48. C12H9N3. Calculated, %:
C 73.83; H 4.65; N 21.52.
3-(4-Bromophenyl)[1,2,4]triazolo[4,3-a]pyridine (3e).
Yield 114 mg (91%), white solid, mp 200–202°C (mp 198–
1
200°C34e). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
6.92 (1H, ddd, J = 7.4, J = 6.6, J = 1.1, H Py); 7.32 (1H,
ddd, J = 9.3, J = 6.5, J = 1.1, H Py); 7.74 (4H, s, H Ar);
7.86 (1H, d, J = 9.3, H Py); 8.26 (1H, d, J = 7.1, H Py).
13C NMR spectrum (CDCl3), δ, ppm: 114.6; 117.0; 122.4;
124.7; 125.6; 127.2; 129.6; 132.6; 145.8; 150.7. Found, m/z:
272.9899 [M]+. C12H8BrN3. Calculated, m/z: 272.9896.
Found, %: C 52.55; H 2.91; N 15.29. C12H8BrN3.
Calculated, %: C 52.58; H 2.94; N 15.33.
3-(4-Methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine (3f).
Yield 101 mg (98%), white solid, mp 122–124°C (mp 123–
1
125°C34d). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
3.89 (3H, s, OCH3); 6.84 (1H, td, J = 6.8, J = 1.0, H Py);
7.09 (2H, d, J = 8.7, H Ar); 7.26 (1H, ddd, J = 9.3, J = 6.5,
J = 1.1, H Py); 7.73–7.77 (2H, m, H Ar); 7.80 (1H, d,
J = 9.3, H Py); 8.23 (1H, dt, J = 7.0, J = 1.2, H Py).
13C NMR spectrum (CDCl3), δ, ppm: 55.5; 114.0; 114.8;
116.8; 118.9; 122.6; 126.9; 129.8; 146.7; 150.4; 161.1.
Found, m/z: 225.0901 [M]+. C13H11N3O. Calculated, m/z:
225.0897. Found, %: C 69.29; H 4.89; N 18.62.
C13H11N3O. Calculated, %: C 69.32; H 4.92; N 18.66.
4-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)phenol (3g). Yield
87 mg (90%), white solid, mp 248–250°C (mp 249–250°C34f).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 6.95–7.03
(3H, m, 2H Ar, 1H Py); 7.64–7.76 (2H, m, H Ar); 7.39
(1H, ddd, J = 9.2, J = 6.5, J = 1.1, H Py); 7.81 (1H, dd,
J = 9.3, J = 1.2, H Py); 8.48 (1H, dd, J = 7.1, J = 1.2,
H Py); 10.03 (1H, s, OH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 114.1; 115.6; 116.0; 117.1; 123.8; 127.5; 129.7;
146.2; 149.6; 159.0. Found, m/z: 211.0743 [M]+.
C12H9N3O. Calculated, m/z: 211.0740. Found, %: C 68.21;
H 4.25; N 19.87. C12H9N3O. Calculated, %: C 68.24;
H 4.29; N 19.89.
3-(2-Methylphenyl)[1,2,4]triazolo[4,3-a]pyridine (3b).
Yield 94 mg (98%), white solid, mp 148–150°C (mp 149–
1
150°C34b). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2.27 (3H, s, CH3); 6.84 (1H, td, J = 6.7, J = 1.1, H Py);
7.30 (1H, ddd, J = 9.3, J = 6.5, J = 1.2, H Py); 7.37 (1H, td,
J = 7.3, J = 1.4, H Ar); 7.40–7.45 (1H, m, H Ar); 7.45–7.51
(2H, m, H Ar); 7.80 (1H, d, J = 7.0, H Py); 7.84 (1H, d,
J = 9.3, H Py). 13C NMR spectrum (CDCl3), δ, ppm: 19.8;
113.9; 116.6; 122.7; 125.6; 126.3; 127.1; 130.3; 130.6;
131.1; 138.6; 146.4; 149.8. Found, m/z: 209.0949 [M]+.
C13H11N3. Calculated, m/z: 209.0948. Found, %: C 74.59;
H 5.28; N 20.05. C13H11N3. Calculated, %: C 74.62;
H 5.30; N 20.08.
3-[3-(Trifluoromethyl)phenyl][1,2,4]triazolo[4,3-a]-
pyridine (3c). Yield 103 mg (85%), light-yellow solid,
mp 154–156°C (mp 154–155°C34c). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 6.97 (1H, td, J = 6.8, J = 1.1,
H Py); 7.36 (1H, ddd, J = 9.3, J = 6.5, J = 1.1, H Py); 7.76
(1H, t, J = 7.8, H Ar); 7.84 (1H, d, J = 7.9, H Ar); 7.89
(1H, d, J = 9.3, H Py); 8.05–8.11 (1H, m, H Ar); 8.14 (1H,
d, J = 1.7, H Ar); 8.28 (1H, d, J = 7.0, H Py). 13C NMR
spectrum (CDCl3), δ, ppm (J, Hz): 114.9; 117.0; 122.3;
125.1 (q, JCF = 3.9); 126.9 (q, JCF = 3.9); 127.5; 127.6;
130.0; 131.3; 131.9 (q, JCF = 33.1); 145.4; 150.7. Found, m/z:
263.0668 [M]+. C13H8F3N3. Calculated, m/z: 263.0665.
Found, %: C 59.30; H 3.01; N 15.93. C13H8F3N3.
Calculated, %: C 59.32; H 3.06; N 15.96.
4-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)benzonitrile (3h).
Yield 86 mg (85%), white solid, mp 261–263°C (mp 258–
1
260°C34d). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
6.99 (1H, td, J = 6.8, J = 1.1, H Py); 7.38 (1H, ddd, J = 9.3,
J = 6.6, J = 1.1, H Py); 7.90 (3H, dd, J = 8.8, J = 1.8,
2H Ar, 1H Py); 8.01–8.06 (2H, m, H Ar); 8.31–8.35 (1H,
m, H Py). 13C NMR spectrum (CDCl3), δ, ppm: 113.8;
115.1; 117.2; 118.0; 122.3; 127.7; 128.5; 131.1; 133.1;
145.0; 151.0. Found, m/z: 220.0744 [M]+. C13H8N4.
Calculated, m/z: 220.0744. Found, %: C 70.88; H 3.62;
N 25.41. C13H8N4.Calculated, %: C 70.90; H 3.66; N 25.44.
3-(4-Methyl-1,3-thiazol-5-yl)[1,2,4]triazolo[4,3-a]-
pyridine (3i). Yield 79 mg (80%), brown solid, mp 127–
3-(4-Chlorophenyl)[1,2,4]triazolo[4,3-a]pyridine (3d).
Yield 95 mg (90%), white solid, mp 198–200°C (mp 196–
1
129°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.58
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Chemistry of Heterocyclic Compounds 2018, 54(12), 1111–1116
1
(3H, s, CH3); 6.97 (1H, td, J = 6.7, J = 1.0, H Py); 7.38
184°C34d). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
6.98 (1H, dd, J = 7.0, J = 3.8, H pyrimidine); 7.55–7.64
(3H, m, H Ph); 7.81–7.87 (2H, m, H Ph); 8.64 (1H, dd,
J = 7.0, J = 1.9, H pyrimidine); 8.70 (1H, dd, J = 3.8,
J = 1.9, H pyrimidine). 13C NMR spectrum (CDCl3), δ, ppm:
110.2; 125.9; 128.0; 129.5; 130.7; 130.8; 145.7; 153.9;
154.1. Found: 196.0745 [M]+. C11H8N4. Calculated, m/z:
196.0744. Found: C 67.31; H 4.09; N 28.52. C11H8N4.
Calculated, %: C 67.34; H 4.11; N 28.55.
(1H, ddd, J = 9.3, J = 6.5, J = 1.1, H Py); 7.89 (1H, dt,
J = 9.3, J = 1.2, H Py); 8.01 (1H, dt, J = 6.9, J = 1.1, H Py);
9.00 (1H, s, H thiazole). 13C NMR spectrum (CDCl3),
δ, ppm: 16.6; 114.8; 115.0; 116.9; 122.6; 127.7; 139.2;
150.5; 154.1; 155.7. Found, m/z: 216.0467 [M]+. C10H8N4S.
Calculated, m/z: 216.0464. Found, %: C 55.51; H 3.71;
N 25.88. C10H8N4S. Calculated, %: C 55.54; H 3.73;
N 25.91.
3-(Furan-2-yl)[1,2,4]triazolo[4,3-a]pyridine (3j). Yield
75 mg (88%), light-brown solid, mp 92–94°C (mp 92–
1
Supplementary information file containing H and 13C
1
93°C34b). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 6.66
NMR spectra of all synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
(1H, dd, J = 3.5, J = 1.8, H Py); 6.94 (1H, td, J = 6.8,
J = 1.1, H Py); 7.20–7.34 (2H, m, H furan, H Py); 7.67–
7.70 (1H, m, H furan); 7.83 (1H, d, J = 9.3, H Py); 8.75
(1H, d, J = 7.1, H furan). 13C NMR spectrum (CDCl3), δ,
ppm: 111.2; 112.1; 114.6; 116.6; 124.3; 127.5; 139.6;
143.0; 143.6; 149.9. Found, m/z: 185.0585 [M]+.
C10H7N3O. Calculated, m/z: 185.0584. Found, %: C 64.82;
H 3.79; N 22.65. C10H7N3O. Calculated, %: C 64.86; H
3.81; N 22.69.
References
1. Bhadoriya, U.; Jain, D. K.; Int. J. Pharm. Sci. Res. 2016, 7,
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Trans. 1 2000, 33.
3-(1H-Indol-3-yl)[1,2,4]triazolo[4,3-a]pyridine (3k).
Yield 88 mg (82%), pinkish-white solid, mp 244–246°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.03 (1H,
td, J = 6.7, J = 1.1, H Py); 7.19 (1H, ddd, J = 8.0, J = 7.0,
J = 1.1, H Py); 7.26 (1H, ddd, J = 8.1, J = 7.0, J = 1.3,
H indole); 7.40 (1H, ddd, J = 9.3, J = 6.5, J = 1.1, H Py);
7.55 (1H, dt, J = 8.0, J = 0.9, H indole); 7.84 (1H, dt,
J = 9.3, J = 1.2, H Py); 8.16 (1H, dd, J = 7.8, J = 1.0,
H indole); 8.26 (1H, d, J = 2.8, H indole); 8.65 (1H, dt,
J = 7.1, J = 1.1, H indole); 11.89 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 101.3; 111.9; 113.8; 115.6;
120.3; 120.8; 122.5; 124.3; 125.0; 125.6; 127.1; 136.1;
142.8; 148.8. Found, m/z: 234.0901 [M]+. C14H10N4.
Calculated, m/z: 234.0900. Found, %: C 71.75; H 4.28;
N 23.89. C14H10N4. Calculated, %: C 71.78; H 4.30;
N 23.92.
5. Nagamatsu, T.; Yamasaki, H.; Fujita, T.; Endo, K.; Machida, H. J.
Chem. Soc., Perkin Trans. 1 1999, 3117.
6. Kobe, B.; Kobe, J.; Smee, D. F.; Jerman-Blazic-Dzonova, B.;
Solmajer, T. Eur. J. Med. Chem. 1992, 27, 259.
7. Mukaiyama, H.; Nishimura, T.; Kobayashi, S.; Ozawa, T.;
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3-Phenyl[1,2,4]triazolo[4,3-a]pyrazine (3l). Yield 82 mg
(92%), white solid, mp 161–163°C (mp 160–162°C34d).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.61–7.66 (3H,
m, H Ph); 7.86–7.90 (2H, m, H Ph); 7.95 (1H, d, J = 4.8,
H pyrazine); 8.23 (1H, dd, J = 4.9, J = 1.7, H pyrazine);
9.43 (1H, d, J = 1.6, H pyrazine). 13C NMR spectrum
(CDCl3), δ, ppm: 115.2; 125.6; 128.1; 129.6; 130.4; 130.9;
145.1; 146.0; 147.2. Found, m/z: 196.0745 [M]+. C11H8N4.
Calculated, m/z: 196.0744. Found, %: C 67.31; H 4.09;
N 28.51. C11H8N4. Calculated, %: C 67.34; H 4.11; N 28.55.
6-Chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine (3m).
Yield 72 mg (90%), white solid, mp 197–199°C (mp 199–
15. Saha, A. K.; Liu, L.; Simoneaux, R.; Decorte, B.; Meyer, C.;
Skrzat, S.; Breslin, H. J.; Kukla, M. J.; End, D. W. Bioorg.
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1
201°C34g). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
18. Dash, C.; Shaikh, M. M.; Ghosh, P. J. Chem. Sci. 2011, 123, 97.
19. Holm, S. C.; Straub, B. F. Org. Prep. Proced. Int. 2011, 43,
319.
7.17 (1H, d, J = 9.6, H pyridazine); 7.54–7.61 (3H, m,
H Ph); 8.17 (1H, d, J = 9.6, H pyridazine); 8.45–8.49 (2H,
m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm: 121.8;
125.5; 126.6; 127.7; 128.8; 130.7; 143.6; 148.1; 149.4.
Found, m/z: 230.0357 [M]+. C11H7ClN4. Calculated, m/z:
230.0354. Found, %: C 57.25; H 3.02; N 24.26.
C11H7ClN4. Calculated, %: C 57.28; H 3.06; N 24.29.
3-Phenyl[1,2,4]triazolo[4,3-a]pyrimidine (3n). Yield
77 mg (86%), white solid, mp 174–176°C (mp 182–
20. Meanwell, N. A.; Romine, J. L.; Rosenfeld, M. J.; Martin, S. W.;
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