A simple and efficient synthesis of 3,4,5-trisubstituted/N-fused 1,2,4-triazoles via ceric ammonium nitrate catalyzed oxidative cyclization of amidrazones with aldehydes using polyethylene glycol as a recyclable reaction medium

Article abstract of DOI:10.1055/s-0034-1378909

An environmentally benign protocol is described for the synthesis of 3,4,5-trisubstituted 1,2,4-triazoles and N-fused 1,2,4-triazoles via ceric ammonium nitrate catalyzed oxidative cyclization of amidrazones and aldehydes using polyethylene glycol as recyclable reaction medium. This protocol is effective toward various substrates having different functionalities. The easy recyclability of the reaction medium makes the process economic and potentially viable for commercial applications.

Full text of DOI:10.1055/s-0034-1378909

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 517–525
paper
517
M. Nakka et al.
Paper
Synthesis
A Simple and Efficient Synthesis of 3,4,5-Trisubstituted/N-Fused
1,2,4-Triazoles via Ceric Ammonium Nitrate Catalyzed Oxidative
Cyclization of Amidrazones with Aldehydes Using Polyethylene
Glycol as a Recyclable Reaction Medium
NH2
NH2
HN
N
Mangarao Nakka
Ramu Tadikonda
N
Ph
NH
R2
Srinuvasarao Rayavarapu
Prasanthi Sarakula
Siddaiah Vidavalur*
N
O
N
N
Z
Z
N
R1
N
R1
H
Ph
N
CAN, PEG, 80 °C
CAN, PEG, 80 °C
R1
R2
Z = CH, N
Department of Organic Chemistry & FDW, Andhra University,
Visakhapatnam - 530 003, India
sidduchem@gmail.com
+
9
1
8
(
9
1
2
)
7
1
3
8
1
3
Received: 23.07.2014
Due to their importance, many efficient methods have
been developed to access 3,4,5-trisubstituted/N-fused
1,2,4-triazoles.11 Among them, coupling of carboxylic acids
or their derivatives with amidrazones, followed by cyclode-
hydration is the most common explored strategy (Scheme
1).12 However, some of these protocols suffer from the lim-
itations of harsh conditions, tedious synthetic procedures
and unsatisfactory yields. Hence, the development of milder
and more general procedures to access 3,4,5-trisubstituted
1,2,4-triazoles and N-fused 1,2,4-triazoles remains desir-
able.
Accepted after revision: 06.10.2014
Published online: 20.11.2014
DOI: 10.1055/s-0034-1378909; Art ID: ss-2014-n0460-op
Abstract An environmentally benign protocol is described for the syn-
thesis of 3,4,5-trisubstituted 1,2,4-triazoles and N-fused 1,2,4-triazoles
via ceric ammonium nitrate catalyzed oxidative cyclization of amidra-
zones and aldehydes using polyethylene glycol as recyclable reaction
medium. This protocol is effective toward various substrates having dif-
ferent functionalities. The easy recyclability of the reaction medium
makes the process economic and potentially viable for commercial ap-
plications.
Key words polyethylene glycol, ceric ammonium nitrate, 1,2,4-tri-
azoles, [1,2,4]triazolo[4,3-a]pyridines, [1,2,4]triazolo[4,3-a]pyrazines
R1
NH2
N
N
N
N
N
O
Δ
R1
O
Ph
+
N
R2
R1
X
Ph
NH
R2
NH
R2
Ph
– H2O
1,2,4-Triazoles have elicited considerable interest
among medicinal chemists because they are considered to
be privileged structural constituents of many pharmaceuti-
cal agents as well as natural products (Figure 1).1 In particu-
lar, compounds containing 3,4,5-trisubstituted 1,2,4-tri-
azoles and N-fused 1,2,4-triazoles, such as triazolopyridine
and triazolopyrazine substructures exhibit a wide spec-
trum of biological activity including antifungal,2 antimicro-
bial,3 antiviral,4 anti-inflammatory,5 antiasthmatic,6 anti-
proliferative7 and hypotonic.8 In addition, they have often
been used as bioisosteres of esters and amides, and as di-
peptidomimetics in a number of pharmacologically import-
ant molecules.9 On the other hand, they also play important
roles as ligands in organometallic compounds, as precur-
sors for N-heterocyclic carbenes, as ionic liquids and as cor-
rosion inhibitors.10
H
N
R1
NH2
HN
HN
N
O
Δ
Z
O
+
N
N
N
R1
X
N
– H2O
Z
Z
R1
Scheme 1 General synthesis of 3,4,5-trisubstituted 1,2,4-triazoles and
N-fused 1,2,4-triazoles
Ceric ammonium nitrate (CAN) has received consider-
able attention as an easily available and inexpensive cata-
lyst for various synthetically useful reactions such as oxida-
tion, oxidative addition, photooxidation, nitration, graft po-
lymerization, deprotection, etc.13 In addition, its many
advantages such as excellent solubility in water, ecofriendly
nature, high reactivity, ease of handling, fast conversions
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F
F
F
F
F
F
F
N
N
N
N
NH
O
NH2
O
N
N
N
F
N
maraviroc
sitagliptin
N
N
N
N
N
N
HOOC
N
N
Cl
Et
N
N
H
Cl
OH
OMe
penipanoid A
DL111-IT
triazolam
Figure 1 Examples of biologically active and natural compounds possessing a 1,2,4-triazole core
and convenient work-up procedures make ceric ammoni-
um nitrate a potent catalyst in organic synthesis. 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 N-phenylbenzamidrazone (1a) and benzaldehyde (2a) in
the presence of a catalytic amount of ceric ammonium ni-
trate (2 mol%) in ethanol at 80 °C. We were delighted to ob-
serve the formation of the desired product 3a, albeit in a
low yield of 61% (Table 1, entry 1). Next, we optimized the
reaction conditions in order to increase the yield. Thus, dif-
ferent solvents were screened and the results are summa-
rized in Table 1. It was found that polyethylene glycol was
the most superior solvent in terms of the reaction time and
yield of the product (Table 1, entry 4). Once we had estab-
lished a suitable solvent for the synthesis of 3,4,5-trisubsti-
tuted 1,2,4-triazoles, we then focused on the quantity of ce-
ric ammonium nitrate. An increase in the amount of ceric
ammonium nitrate (from 2 mol% to 5 mol%) not only de-
creased the reaction time from two hours to one hour, but
also increased the product yield from 82% to 96% (Table 1,
entry 6). Further increasing the quantity of ceric ammoni-
um nitrate to 10 mol% led to a decrease in the yield to 71%
(Table 1, entry 7). Therefore, we decided to perform the
subsequent reactions of the amidrazones with different al-
dehydes in the presence of ceric ammonium nitrate (5
mol%) as the catalyst in polyethylene glycol at 80 °C. The ef-
fect of temperature on the reaction rate as well as on the
yields of the products was also investigated. Faster reactions
occurred on increasing the temperature but the product
yields were not satisfactory. The progress of the reactions
was monitored by TLC analysis (using EtOAc–hexane as the
eluent).
Polyethylene glycol (PEG) has been found to be an inter-
esting, ecofriendly solvent in synthetic organic chemistry.14
It is non-toxic, inexpensive and can function as a non-ionic
liquid solvent of low volatility, all of which represent bene-
ficial properties. Recently, we described the use of polyeth-
ylene glycol as a reaction medium for the synthesis of 1,2,4-
triazoles,15 1,2,4-oxadiazoles,15 2-(N-acyl)aminobenzimid-
azoles,16 2-(N-acyl)aminobenzothiazoles16 and dihydropyr-
idines.17 In continuation of our studies on developing inex-
pensive and environmentally benign methodologies for the
synthesis of bioactive molecules,15–17 herein we report a
novel, convenient and efficient ceric ammonium nitrate
catalyzed synthesis of 3,4,5-trisubstituted 1,2,4-triazoles
via oxidative cyclization of amidrazones with aldehydes in
PEG (Scheme 2).
NH2
N
N
N
O
CAN
R1
Ph
R1
H
+
Ph
NH
R2
N
PEG, 80 °C
R2
1
2
3
Scheme 2 Synthesis of 3,4,5-trisubstituted 1,2,4-triazoles
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Table 1 Optimization of the Reaction Conditions
With optimized conditions in hand, the scope of the re-
action was investigated and the results are summarized in
Table 2. As expected, all of the aldehydes employed gave the
corresponding 3,4,5-trisubstituted 1,2,4-triazoles in good
to excellent yields. Benzaldehydes with electron-donating
groups such as 4-tolualdehyde (2b) and 4-anisaldehyde (2c)
gave the desired products in very good yields (Table 2, en-
tries 3 and 4). An aromatic aldehyde with an electron-
withdrawing group, 4-bromobenzaldehyde (2d), gave the
corresponding triazole 3e in 97% yield (Table 2, entry 5).
However, the use of 4-nitrobenzaldehyde (2e) did not lead
to the desired product (Table 2, entry 6). The heteroaryl al-
dehyde, 3-formylpyridine (2h), reacted smoothly, affording
the desired product 3i in good yield (Table 2, entry 9). Ali-
phatic aldehydes including propanal (2f) and cyclohexanal
(2g) underwent the addition reaction to give the corre-
sponding products 3g and 3h in 89% and 90% yields, respec-
tively (Table 2, entries 7 and 8).
NH2
N
N
N
O
CAN
Ph
Ph
+
N
Ph
NH
Ph
Ph
H
solvent, 80 °C
Ph
3a
1a
2a
Entry
Solvent
EtOH
CAN (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
2%
2%
2%
2%
2%
5%
10%
3
61
53
48
82
28
96
71
1,4-dioxane
MeCN
3
3.5
2
PEG-300
toluene
4
PEG-300
PEG-300
1
0.5
a Yield of isolated product after column chromatography.
Table 2 Synthesis of 3,4,5-Trisubstituted 1,2,4-Triazoles from Different Amidrazones and Aldehydes
NH2
N
N
N
O
CAN
R1
Ph
+
R1
H
Ph
NH
R2
N
PEG, 80 °C
R2
1
2
3
Entry
R
R1
Product
Time (h)
Yield (%)a
N
N
N
N
N
N
1
Ph
Ph (2a)
1
96
3a
2
4-BrC6H4
Ph (2a)
1
95
Br
3b
N
N
N
3
3-ClC6H4
4-MeC6H4 (2b)
1.5
94
Cl
3c
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Table 2 (continued)
Entry
R
R1
Product
Time (h)
Yield (%)a
N
N
N
OMe
4
4-MeC6H4
4-MeOC6H4 (2c)
1.5
93
3d
N
N
N
Br
5
6
7
4-BrC6H4
4-BrC6H4 (2d)
4-O2NC6H4 (2e)
n-Pr (2f)
1
–
2
97
Br
N
3e
N
N
NO2
Ph
–
3f
N
N
N
4-ClC6H4
89
Cl
N
3g
3h
N
N
8
9
Ph
Cy (2g)
2
2
90
88
N
N
N
N
3-ClC6H4
3-pyridyl (2h)
Cl
3i
a Yield of isolated product after column chromatography.
Encouraged by these promising results, we turned our
attention toward the synthesis of N-fused 1,2,4-triazoles
such as [1,2,4]triazolo[4,3-a]pyridines and [1,2,4]triazo-
lo[4,3-a]pyrazines. Gratifyingly, following the above proto-
col, we were able to prepare triazolopyridines and triazolo-
pyrazines very efficiently using 2-hydrazinopyridines and
2-hydrazinopyrazines, respectively. Table 3 shows the
scope of the aldehydes employed, demonstrating that aro-
matic, aliphatic and heteroaromatic substituents furnished
the expected adducts in and efficient manner. However, the
electron-deficient aromatic aldehyde, 4-nitrobenzaldehyde
(2e), was not a suitable substrate for this process (Table 3,
entry 5).
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Table 3 (continued)
Table 3 Synthesis of Various [1,2,4]Triazolo[4,3-a]pyridines and
[1,2,4]Triazolo[4,3-a]pyrazines
Entry
R1
Product
Time (h) Yield (%)a
H
N
N
O
N
Z
CAN
Z
NH2
N
N
+
N
N
8
n-Bu (2k)
2
2
88
87
R1
H
PEG, 80 °C
N
R1
5h
5i
4 Z = CH
6 Z = N
2
5 Z = CH
7 Z = N
N
N
N
Entry
R1
Product
Time (h) Yield (%)a
9
n-Hex (2l)
N
N
N
N
1
Ph (2a)
1.5
97
N
N
10
2-furyl (2m)
2.5
91
89
5a
O
N
N
5j
N
N
N
2
4-MeC6H4 (2b)
1.5
95
N
N
N
11
Ph (2a)
2
5b
N
7a
N
N
N
N
N
N
N
3
4-MeOC6H4 (2c)
1.5
94
98
–
12
4-MeC6H4 (2b)
2
89
OMe
5c
5d
5e
7b
N
N
N
N
N
N
N
N
4
4-ClC6H4 (2i)
1
13
4-MeOC6H4 (2c)
2
87
Cl
OMe
7c
N
N
N
N
N
5
4-O2NC6H4 (2e)
–
14
4-BrC6H4 (2d)
1.5
93
NO2
Br
7d
N
N
N
N
N
N
6
7
2-MeC6H4 (2j)
1.5
96
88
15
2-ClC6H4 (2n)
1.5
88
Cl
5f
7e
N
a Yield of isolated product after column chromatography
N
N
n-Pr (2f)
2
5g
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To check the reusability of polyethylene glycol, a mix-
ture of N-phenylbenzamidrazone (1a), benzaldehyde (2a)
and ceric ammonium nitrate in polyethylene glycol was
stirred at 80 °C for one hour. After the completion of the re-
action (monitored by TLC), the mixture was extracted with
diethyl ether (3 × 20 mL). The retained polyethylene glycol
phase was reused three consecutive times with only a slight
variation in the yields of the obtained products (96%, 94%
and 92%).
ppm). Mass spectra were recorded on an Agilent 1100 LC/MSD. Ele-
mental analyses were obtained using an Elementar Vario EL III ana-
lyzer.
3,4,5-Triphenyl-4H-1,2,4-triazole (3a);15 Typical Procedure
A mixture of amidrazone 1a (1.00 g, 0.0047 mol), benzaldehyde (2a)
(0.50 g, 0.0047 mol), PEG-300 (5 mL) and CAN (5 mol%) was heated at
80 °C for 1 h (Table 2). After completion of the reaction as monitored
by TLC, the mixture was cooled to r.t. and extracted with Et2O (3 × 20
mL). The combined organic layers were washed with H2O (2 × 30 mL)
and aq NaHCO3 solution (2 × 30 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude residue was pu-
rified by silica gel column chromatography (EtOAc–hexane, 1:1) to af-
ford pure 3a.
According to the literature,18 a plausible mechanism has
been proposed for this oxidative cyclization reaction as
shown in Scheme 3. It is clear that ceric ammonium nitrate
acts as both a Lewis acid and an oxidant.
Yield: 1.35 g (96%); off-white solid; mp 287–289 °C.
IR (KBr): 3014, 1632, 1498, 769 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.40–7.33 (m, 6 H), 7.30–7.19 (m, 7 H),
.
[CAN]
[CAN]
7.09–7.06 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 154.8, 135.2, 129.9, 129.5, 128.9,
128.8, 128.3, 127.8, 126.9.
LC–MS: m/z = 298 [M + H]+.
[CAN]
N
NH2
[CAN]
O
N
R1
NH2
H
O
N
C
H
R1
+
H
+
R1
H
N
H
Ph
NH
R2
Ph
N
R2
OH
R2
[CAN]
H
N
Ph
Anal. Calcd for C20H15N3: C, 80.78; H, 5.08; N, 14.13. Found: C, 80.72;
H, 5.11; N, 14.11.
[CAN]
[CAN]
4-(4-Bromophenyl)-3,5-diphenyl-4H-1,2,4-triazole (3b)15
Yield: 1.23 g (95%); light gray solid; mp 236–238 °C.
[CAN]
R1
IR (KBr): 3031, 1638, 1492, 761 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.4 Hz, 2 H), 7.41–7.36 (m, 5
H), 7.34–7.26 (m, 5 H), 7.00 (d, J = 8.4 Hz, 2 H).
H
N
N
N
N
N
C H
H
R1
N
R1
Ph
13C NMR (100 MHz, CDCl3): δ = 154.6, 134.2, 133.2, 129.8, 129.3,
N
Ph
H
N
N
R2
128.9, 128.5, 126.7, 123.6.
[CAN]
Ph
R2
H2
R2
LC–MS: m/z = 376 [M + H]+.
[CAN]
Anal. Calcd for C20H14BrN3: C, 63.84; H, 3.75; N, 11.17. Found: C,
63.81; H, 3.80; N, 11.15.
Scheme 3 A plausible mechanism for the preparation of 3,4,5-trisub-
stituted 1,2,4-triazoles
4-(3-Chlorophenyl)-3-phenyl-5-(p-tolyl)-4H-1,2,4-triazole (3c)15
In summary, we have developed a new, mild and effi-
cient approach for the synthesis of 3,4,5-trisubstituted
1,2,4-triazoles and N-fused 1,2,4-triazoles via oxidative cy-
clization of amidrazones with aldehydes using polyethylene
glycol as the solvent and employing ceric ammonium ni-
trate as the catalyst. The advantages of this procedure are
the use of an environmentally benign solvent and cheap ox-
idant, the wide scope of the reactants and satisfactory
product yields, which should make it a useful addition to
previously reported strategies.
Yield: 1.32 g (94%); off-white solid; mp 197–199 °C.
IR (KBr): 3031, 2933, 1641, 1470, 740 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.28 (m, 9 H), 7.16–7.11 (m, 3 H),
7.06–7.03 (m, 1 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.6, 153.5, 134.0, 133.2, 129.5,
129.2, 128.44, 128.41, 126.9, 123.7, 26.0.
LC–MS: m/z = 346 [M + H]+.
Anal. Calcd for C21H16ClN3: C, 72.93; H, 4.66; N, 12.15. Found: C,
72.90; H, 4.70; N, 12.12.
3-(4-Methoxyphenyl)-5-phenyl-4-(p-tolyl)-4H-1,2,4-triazole (3d)15
Yield: 1.40 g (93%); light gray solid; mp 200–202 °C.
Standard substrates and reagents were obtained from commercial
suppliers and were used without further purification. TLC analysis
was performed on Merck silica gel 60 F254 plates. Column chromatog-
raphy was performed on Merck silica gel (100–200 mesh). Melting
points were recorded on an Equiptronics capillary digital melting
point apparatus. IR spectra were obtained using a Perkin Elmer FT-IR
spectrophotometer. 1H and 13C NMR spectra were recorded on a
Bruker AMX 400 MHz spectrometer and referenced to Me4Si (δ = 0
IR (KBr): 3034, 2935, 1608, 1071, 832 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.41 (m, 2 H), 7.36 (d, J = 8.8 Hz, 2
H), 7.33–7.26 (m, 3 H), 7.20 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 8.4 Hz, 2 H),
6.80 (d, J = 8.8 Hz, 2 H), 3.78 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.5, 154.7, 154.5, 139.6, 132.8,
130.4, 130.1, 129.3, 128.7, 128.3, 127.6, 127.3, 119.5, 113.8, 55.2, 21.2.
LC–MS: m/z = 342 [M + H]+.
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Anal. Calcd for C22H19N3O: C, 77.40; H, 5.61; N, 12.31. Found: C, 77.37;
H, 5.67; N, 12.29.
IR (KBr): 3030, 1631, 1494, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 6.8 Hz, 1 H), 7.84 (dd, J = 5.6,
6.4 Hz, 3 H), 7.60–7.52 (m, 3 H), 7.27 (dd, J = 6.8, 9.2 Hz, 1 H), 6.88 (t,
J = 6.8 Hz, 1 H).
3,4-Bis(4-bromophenyl)-5-phenyl-4H-1,2,4-triazole (3e)
13C NMR (100 MHz, CDCl3): δ = 150.5, 146.7, 130.2, 129.3, 128.2,
126.9, 126.7, 122.6, 116.9, 114.2.
Yield: 1.51 g (97%); light gray solid; mp 180–182 °C.
IR (KBr): 3027, 1638, 1489, 833 cm–1
.
LC–MS: m/z = 196 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4
Hz, 2 H), 7.40 (d, J = 6.4 Hz, 3 H), 7.35–7.29 (m, 2 H), 7.26 (d, J = 6.4 Hz,
2 H), 7.02 (d, J = 8.4 Hz, 2 H).
Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C, 73.76; H,
4.76; N, 21.48.
13C NMR (100 MHz, CDCl3): δ = 154.8, 153.6, 133.9, 133.3, 131.8,
130.1, 129.2, 129.1, 128.8, 128.5, 126.3, 125.5, 124.5, 123.9.
3-(4-Tolyl)[1,2,4]triazolo[4,3-a]pyridine (5b)
LC–MS: m/z = 453 [M + H]+.
Yield: 1.80 g (95%); off-white solid; mp 110–112 °C.
Anal. Calcd for C20H13Br2N3: C, 52.78; H, 2.88; N, 9.23. Found: C, 52.77;
H, 2.97; N, 9.22.
IR (KBr): 3026, 2916, 1629, 1494, 744 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 7.2 Hz, 1 H), 7.85 (d, J = 9.2
Hz, 1 H), 7.75 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.30–7.26 (m,
1 H), 6.88–6.84 (m, 1 H), 2.48 (s, 3 H).
4-(4-Chlorophenyl)-3-ethyl-5-phenyl-4H-1,2,4-triazole (3g)15
13C NMR (100 MHz, CDCl3): δ = 150.4, 146.8, 140.4, 129.9, 128.1,
126.9, 123.7, 122.6, 116.7, 114.0, 21.4.
Yield: 1.02 g (89%); off-white solid; mp 136–138 °C.
IR (KBr): 3036, 2957, 1634, 1489, 826 cm–1
.
LC–MS: m/z = 210 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 2 H), 7.39–7.26 (m, 5
H), 7.08 (d, J = 8.0 Hz, 2 H), 2.66 (q, J = 7.2 Hz, 2 H), 1.28 (t, J = 8.0 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 156.8, 153.8, 134.0, 133.3, 129.6,
128.9, 128.5, 128.3, 126.8, 123.7, 19.0, 11.7.
Anal. Calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found: C, 74.58;
H, 5.41; N, 20.01.
3-(4-Methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine (5c)19
LC–MS: m/z = 284 [M + H]+.
Yield: 1.92 g (94%); off-white solid; mp 122–124 °C.
Anal. Calcd for C16H14ClN3: C, 67.72; H, 4.97; N, 14.81. Found: C,
67.70; H, 5.01; N, 14.78.
IR (KBr): 3031, 2981, 1613, 1498, 1130, 837 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 1.2 Hz, 1 H), 7.80–7.75 (m, 3
H), 7.28–7.24 (m, 1 H), 7.11 (dd, J = 2.0, 6.0 Hz, 2 H), 6.85 (m, 1 H),
3.90 (s, 3 H).
3-Cyclohexyl-4,5-diphenyl-4H-1,2,4-triazole (3h)15
13C NMR (100 MHz, CDCl3): δ = 160.6, 149.9, 146.0, 129.8, 127.7,
123.9, 118.9, 115.7, 114.8, 114.3, 55.5.
Yield: 1.29 g (90%); light gray solid; mp 147–149 °C.
IR (KBr): 3028, 2935, 1637, 1468, 833 cm–1
.
LC–MS: m/z = 226 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.53–7.51 (m, 3 H), 7.49–7.38 (m, 2 H),
7.29–7.23 (m, 3 H), 7.22–7.19 (m, 2 H), 2.53–2.50 (m, 1 H), 1.89–1.75
(m, 6 H), 1.68–1.64 (m, 1 H), 1.31–1.15 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 153.6, 135.1, 129.9, 129.6,
129.2, 128.4, 128.3, 127.6, 127.2, 34.7, 31.6, 26.0, 25.6.
Anal. Calcd for C13H11N3O: C, 69.32; H, 4.92; N, 18.66. Found: C, 69.29;
H, 4.99; N, 18.62.
3-(4-Chlorophenyl)[1,2,4]triazolo[4,3-a]pyridine (5d)19
LC–MS: m/z = 304 [M + H]+.
Yield: 2.00 g (98%); off-white solid; mp 196–199 °C.
Anal. Calcd for C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C, 79.16;
H, 7.01; N, 13.82.
IR (KBr): 3039, 1633, 1473, 826 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.57 (d, J = 7.2 Hz, 1 H), 7.95 (d, J =
8.8 Hz, 2 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.46–7.42
(m, 1 H), 7.04 (t, J = 7.2 Hz, 1 H).
3-[4-(3-Chlorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl]pyridine
(3i)
13C NMR (100 MHz, DMSO-d6): δ = 150.5, 145.5, 135.1, 130.3, 129.7,
128.5, 125.9, 124.4, 116.1, 115.0.
LC–MS: m/z = 230 [M + H]+.
Yield: 1.19 g (88%); light gray solid; mp 200–202 °C.
IR (KBr): 3029, 1597, 1485, 838 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.63 (t, J = 4.0 Hz, 2 H), 7.86 (d, J = 8.0
Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.45–7.40 (m, 4 H), 7.37–7.20 (m, 3
H), 7.20 (s, 1 H), 7.10 (d, J = 8.0 Hz, 1 H).
Anal. Calcd for C12H8ClN3: C, 62.76; H, 3.51; N, 18.30. Found: C, 62.71;
H, 3.59; N, 18.28.
13C NMR (100 MHz, CDCl3): δ = 155.0, 152.0, 150.5, 148.8, 135.9,
135.8, 135.6, 131.0, 130.3, 130.0, 128.6, 128.5, 127.7, 125.9, 125.8,
123.2, 122.9.
3-(2-Tolyl)[1,2,4]triazolo[4,3-a]pyridine (5f)
Yield: 1.82 g (96%); off-white solid; mp 148–150 °C.
IR (KBr): 3028, 2921, 1626, 1498, 752 cm–1
.
LC–MS: m/z = 333 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.83–7.76 (m, 2 H), 7.45–7.35 (m, 4 H),
7.30–7.26 (m, 1 H), 6.83–6.79 (dd, J = 0.4, 6.4 Hz, 1 H), 2.24 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.7, 146.2, 138.5, 133.8, 130.6,
Anal. Calcd for C19H13ClN4: C, 68.57; H, 3.94; N, 16.84. Found: C,
68.56; H, 3.99; N, 16.83.
130.5, 130.2, 127.0, 126.2, 125.5, 122.6, 116.5, 19.6.
LC–MS: m/z = 210 [M + H]+.
3-Phenyl[1,2,4]triazolo[4,3-a]pyridine (5a)19
Yield: 1.71 g (97%); off-white solid; mp 171–173 °C.
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Anal. Calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found: C, 74.61;
H, 5.33; N, 20.06.
1H NMR (400 MHz, DMSO-d6): δ = 9.44 (s, 1 H), 8.18 (d, J = 5.0 Hz, 1
H), 7.97–7.91 (m, 2 H), 7.77–7.57 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 147.5, 146.6, 144.8, 130.5, 130.0,
129.7, 128.1, 125.9, 117.1.
3-Ethyl[1,2,4]triazolo[4,3-a]pyridine (5g)
LC–MS: m/z = 197 [M + H]+.
Yield: 1.18 g (88%); light orange solid; mp 121–123 °C.
IR (KBr): 3041, 2981, 1631, 1489 cm–1
.
Anal. Calcd for C11H8N4: C, 67.34; H, 4.11; N, 28.55. Found: C, 67.29; H,
4.22; N, 28.49.
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.0
Hz, 1 H), 7.27–7.20 (m, 1 H), 6.83 (t, J = 8.0 Hz, 1 H), 1.92 (q, J = 8.2 Hz,
2 H), 1.05 (t, J = 8.0 Hz, 3 H).
3-(4-Tolyl)[1,2,4]triazolo[4,3-a]pyrazine (7b)
13C NMR (100 MHz, CDCl3): δ = 149.6, 146.7, 129.5, 121.8, 116.5,
Yield: 1.69 g (89%); off-white solid; mp 164–166 °C.
113.3, 20.0, 13.7.
LC–MS: m/z = 148 [M + H]+.
IR (KBr): 3091, 2978, 1660, 1427, 815 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.47 (d, J = 1.6 Hz, 1 H), 8.60 (dd, J =
1.6, 4.8 Hz, 1 H), 7.95 (d, J = 4.8 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.47
(d, J = 8.0 Hz, 2 H), 2.43 (s, 3 H).
Anal. Calcd for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.27; H,
6.20; N, 28.53.
13C NMR (100 MHz, DMSO-d6): δ = 147.1, 146.0, 144.6, 140.8, 130.3,
129.7, 128.4, 123.3, 117.4, 21.5.
3-Propyl[1,2,4]triazolo[4,3-a]pyridine (5h)
LC–MS: m/z = 211 [M + H]+.
Yield: 1.29 g (88%); light orange solid; mp 122–124 °C.
IR (KBr): 3044, 2983, 1627, 1482 cm–1
.
Anal. Calcd for C12H10N4: C, 68.56; H, 4.79; N, 26.65. Found: C, 68.51;
H, 4.88; N, 26.61.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.0
Hz, 1 H), 7.24–7.20 (m, 1 H), 6.83 (t, J = 8.0 Hz, 1 H), 3.04 (t, J = 8.0 Hz,
2 H), 1.92 (m, 2 H), 1.05 (t, J = 8.0 Hz, 3 H).
3-(4-Methoxyphenyl)[1,2,4]triazolo[4,3-a]pyrazine (7c)
13C NMR (100 MHz, CDCl3): δ = 149.7, 146.7, 126.6, 121.9, 116.6,
Yield: 1.77 g (87%); off-white solid; mp 148–150 °C.
113.5, 26.4, 20.0, 13.8.
LC–MS: m/z = 162 [M + H]+.
IR (KBr): 3041, 1610, 1498, 1140, 810 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.39 (d, J = 1.6 Hz, 1 H), 8.19 (dd, J = 1.6,
4.8 Hz, 1 H), 7.91 (d, J = 4.8 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 2 H), 7.26 (d, J =
8.0 Hz, 2 H), 3.84 (s, 3 H).
Anal. Calcd for C9H11N3: C, 67.06; H, 6.88; N, 26.07. Found: C, 67.04; H,
6.95; N, 26.04.
13C NMR (100 MHz, CDCl3): δ = 147.3, 145.8, 145.0, 130.23, 130.20,
129.6, 129.0, 127.9, 115.2, 56.5.
3-Pentyl[1,2,4]triazolo[4,3-a]pyridine (5i)
LC–MS: m/z = 227 [M + H]+.
Yield: 1.50 g (87%); light orange solid; mp 111–114 °C.
IR (KBr): 3040, 2980, 1632, 1504 cm–1
.
Anal. Calcd for C12H10N4O: C, 63.71; H, 4.46; N, 24.76. Found: C, 63.68;
H, 4.52; N, 24.71.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 6.8 Hz, 1 H), 7.67 (d, J = 8.0
Hz, 1 H), 7.18 (m, 1 H), 6.79 (t, J = 6.8 Hz, 1 H), 3.01 (t, J = 7.6 Hz, 2 H),
1.85 (t, J = 6.8 Hz, 2 H), 1.37–1.32 (m, 4 H), 0.85 (t, J = 7.2 Hz, 3 H).
3-(4-Bromophenyl)[1,2,4]triazolo[4,3-a]pyrazine (7d)
13C NMR (100 MHz, CDCl3): δ = 149.7, 146.9, 126.5, 121.9, 116.5,
Yield: 2.30 g (93%); off-white solid; mp 168–171 °C.
113.5, 31.4, 26.2, 24.4, 22.2, 13.8.
LC–MS: m/z = 190 [M + H]+.
IR (KBr): 3039, 1628, 1502, 818 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.47 (d, J = 1.2 Hz, 1 H), 8.62 (dd, J =
1.6, 4.8 Hz, 1 H), 7.95 (d, J = 4.8 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.47
(d, J = 8.0 Hz, 2 H).
Anal. Calcd for C11H15N3: C, 69.81; H, 7.99; N, 22.20. Found: C, 69.79;
H, 8.02; N, 22.19.
13C NMR (100 MHz, DMSO-d6): δ = 146.0, 145.9, 144.3, 132.4, 130.29,
130.25, 125.1, 124.1, 117.2.
3-(Furan-2-yl)[1,2,4]triazolo[4,3-a]pyridine (5j)
LC–MS: m/z = 276 [M + H]+.
Yield: 1.54 g (91%); off-white solid; mp 132–134 °C.
IR (KBr): 3039, 1631, 1420, 1082 cm–1
.
Anal. Calcd for C11H7BrN4: C, 48.02; H, 2.56; N, 20.37. Found: C, 48.00;
H, 2.64; N, 20.34.
1H NMR (400 MHz, DMSO-d6): δ = 8.75 (d, J = 8.0 Hz, 1 H), 8.01 (d, J =
4.0 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.47–7.42 (m, 1 H), 7.29 (t, J = 4.0
Hz, 1 H), 7.29–7.08 (m, 1 H), 6.79 (dd, J = 1.6, 2.0 Hz, 1 H).
3-(2-Chlorophenyl)[1,2,4]triazolo[4,3-a]pyrazine (7e)
13C NMR (100 MHz, DMSO-d6): δ = 149.7, 145.0, 142.0, 139.1, 128.5,
Yield: 1.82 g (88%); off-white solid; mp 164–165 °C.
124.9, 116.0, 115.3, 112.4, 111.0.
LC–MS: m/z = 186 [M + H]+.
IR (KBr): 3033, 1636, 1484, 744 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.47 (d, J = 1.6 Hz, 1 H), 8.66 (d, J =
1.2 Hz, 1 H), 8.44 (s, 1 H), 8.15–8.03 (m, 2 H), 7.50–7.47 (m, 1 H),
7.41–7.35 (m, 1 H).
Anal. Calcd for C10H7N3O: C, 64.86; H, 3.81; N, 22.69. Found: C, 64.84;
H, 3.90; N, 22.68.
13C NMR (100 MHz, DMSO-d6): δ = 153.0, 142.4, 137.1, 135.9, 132.57,
132.54, 131.3, 130.7, 130.2, 127.9, 126.9.
3-Phenyl[1,2,4]triazolo[4,3-a]pyrazine (7a)19
LC–MS: m/z = 231 [M + H]+.
Yield: 1.57 g (89%); off-white solid; mp 161–163 °C.
IR (KBr): 3036, 1614, 1450, 707 cm–1
.
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Anal. Calcd for C11H7ClN4: C, 57.28; H, 3.06; N, 24.29. Found: C, 57.24;
H, 3.19; N, 24.25.
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Acknowledgment
The authors thank the Department of Science and Technology (DST),
New Delhi for financial assistance (through project SB/EMEQ-348/2013)
and UGC, New Delhi for the award of SRF to N.M. and T.R.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 517–525