Synthesis of fused 3-amino-1,2,4-triazoles via sequential addition of aryl hydrazines to isothiocyanates and I2-mediated cyclodesulfurization

Article abstract of DOI:10.1016/j.tet.2018.05.009

A variety of fused 3-amino-1,2,4-triazole derivatives were synthesized via addition of aryl hydrazines to isothiocyanates followed by I₂-mediated oxidative cyclodesulfurization. This transition-metal-free synthetic process provides facile acces

Full text of DOI:10.1016/j.tet.2018.05.009

Accepted Manuscript
Synthesis of fused 3-amino-1,2,4-triazoles via sequential addition of aryl hydrazines
to isothiocyanates and I -Mediated cyclodesulfurization
2
Shufeng Jiao, Zhen Wang, Qiongli Zhao, Wenquan Yu, Junbiao Chang
PII:
S0040-4020(18)30517-9
10.1016/j.tet.2018.05.009
TET 29516
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 March 2018
Revised Date: 30 April 2018
Accepted Date: 3 May 2018
Please cite this article as: Jiao S, Wang Z, Zhao Q, Yu W, Chang J, Synthesis of fused 3-
amino-1,2,4-triazoles via sequential addition of aryl hydrazines to isothiocyanates and I -Mediated
2
cyclodesulfurization, Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.009.
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ACCEPTED MANUSCRIPT
Synthesis of Fused 3-Amino-1,2,4-triazoles via Sequential
Addition of Aryl Hydrazines to Isothiocyanates and I2-Mediated
Cyclodesulfurization
Shufeng Jiao,b, c Zhen Wang,a Qiongli Zhao,b, c Wenquan Yu,*, a and
Junbiao Chang*, a, b, c
a College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan
Province 450001, China
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province,
Zhengzhou University, Zhengzhou, Henan Province 450001, China
c School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001,
China
H
R2NCS; then I2, K2CO3
N
N
R1
NH2
R1
N
N
gram-scale synthesis
N
X
X
NHR2
27 examples, up to 97% yield
R1 = H, Me, Cl, CF3, CN, SMe; X = CH or N; R2 = aryl or alkyl
Abstract: A variety of fused 3-amino-1,2,4-triazole derivatives were synthesized via
addition of aryl hydrazines to isothiocyanates followed by I2-mediated oxidative
cyclodesulfurization. This transition-metal-free synthetic process provides facile
access to 1,2,4-triazolo[4,3-a]pyridines and related heterocyclic frameworks bearing a
3-amino substituent from readily accessible substrates in an efficient and scalable
fashion.
Keywords: fused 3-amino-1,2,4-triazole; aryl hydrazine; isothiocyanate; iodine;
cyclodesulfurization
1

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ꢀ Introduction
1,2,4-Triazolo[4,3-a]pyridine derivatives exhibit important biological and
pharmaceutical properties including anti-inflammatory,1 antiproliferative/anticancer,2
antibacterial3 and antiviral properties.4 In addition, these compounds also have
applications in agricultural chemistry5 and material sciences.6 To date, various
synthetic methodologies have been developed to construct this heterocyclic skeleton.7
However, few approaches provide efficient access to the biologically interesting
3-amino-1,2,4-triazolo[4,3-a]pyridines, and the existing methods suffer from the use
of toxic reagents, low yields, and limited substrate scope/scalability.8 In 2009,
Swinnen et al.9 disclosed a straightforward protocol for the synthesis of such fused
3-aminotriazoles via annulations of 2-hydrazinylpyridines and isothiocyanates
promoted by a polymer-supported Mukaiyama reagent. Recently, Gunnlaugsson,
Scanlan, and coworkers10 reported
a
similar transformation using
tetrabutylammonium fluoride (TBAF) under microwave conditions. These reactions
can produce structurally diverse 1,2,4-triazolo[4,3-a]pyridine-3-amine derivatives
from readily accessible substrates. As a continuation of our research on the synthesis
of fused 1,2,4-triazoles,11 herein we describe such a reaction employing molecular
iodine as the sole oxidant.
ꢀ Results and Discussion
The addition of 2-hydrazinylpyridine (2a) to phenyl isothiocyanate (3a) finished
within 10 min in most solvents at room temperature, generating a thiosemicarbazide
intermediate 4a. Then, I2-mediated cyclodesulfurization of 4a under basic conditions
afforded the expected product 1a (Table 1). Solvent screening indicated that the
reaction proceeds faster in DMSO (entry 6), DMF (entry 7) and EtOH (entry 8), and
2

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gives better yields in 1,4-dioxane (entry 4) and EtOH (entry 8). Replacement of EtOH
i
with MeOH or PrOH affected the yield and/or the reaction rate (entries 9−10).
Overall, EtOH is an optimal solvent for this transformation (entry 8), allowing for this
synthetic process to be conducted on a gram scale. With a weaker base or no base, the
cyclization still worked, but required longer reaction times and resulted in decreased
yields (entries 11−12).
Table 1. Reaction conditions optimization for the synthesis of
3-amino-1,2,4-triazolo[4,3-a]pyridine 1aa
entry
1
base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
−
solvent
toluene
THF
temp.
reflux
reflux
reflux
80 °C
60 °C
rt
timeb
5 h
yieldc
71%
2
2 h
76%
3
CH2Cl2
1,4-dioxane
MeCN
DMSO
DMF
1 h
79%
4
3 h
91%
5
2 h
80%
6
30 min
30 min
15 min
15 min
2 h
75%
7
rt
82%
91% (88%)d
8
EtOH
rt
9
MeOH
iPrOH
rt
80%
10
11
12
rt
79%
EtOH
rt
2 h
85%
EtOH
rt
5 h
60%
aReaction conditions: (1) 2a (0.5 mmol), 3a (0.6 mmol), EtOH (5 mL), rt, 10 min; (2)
b
c
I2 (0.55 mmol), base (1 mmol). Time for the second step. Isolated yields are given.
dYield of gram-scale (6 mmol) reaction in parentheses.
With the optimal reaction conditions (Table 1, entry 8) in hand, we examined the
3

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scope and generality of this methodology. Addition of 2-hydrazinylpyridine (2a) with
isothiocyanates (3), followed by I2-mediated cyclization, afforded a range of
3-amino-1,2,4-triazolo[4,3-a]pyridines (1) in good to excellent yields (Scheme 1).
The present synthetic method works well with both aryl and alkyl isothiocyanates. For
monosubstituted phenyl isothiocyanate substrates, the reaction was not affected by
either electron-donating or electron-withdrawing groups (EDGs and EWGs) at para-,
meta-, or ortho- positions (1b−k). The steric effect of the 2,6-dimethyl groups could
be responsible for the lower yield of 1l and 1m, thus possibly attributing to the longer
reaction times required in both the addition and cyclization steps. It is worth noting
that the reactions with aliphatic isothiocyanates gave better yields of the desired
products (1n−r) in 1,4-dioxane than in EtOH.
4

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N
H
N
(1) R2NCS (3), EtOH, rt
N
NH2
N
N
(2) I2, K2CO3, rt
NHR2
2a
1
N
N
N
N
N
N
N
N
N
N
N
N
HN
HN
Me
HN
NHPh
OMe
F
1a, 91%
(10 min,a 15 minb)
1b, 97%
(15 min, 15 min)
1c, 96%
(10 min, 25 min)
1d, 94%
(10 min, 25 min)
N
N
N
N
N
N
N
N
N
HN
HN
HN
Cl
I
CN
1e, 95%
1f, 94%
1g, 92%
(10 min, 30 min)
(10 min, 1 h)
(10 min, 30 min)
N
N
N
N
N
N
N
N
N
HN
HN
HN
CF3
NO2
Me
1h, 95%
1i, 93%
1j, 96%
(10 min, 20 min)
(5 min, 20 min)
(10 min, 20 min)
N
N
N
N
N
N
Me
Me
N
N
N
N
N
Me
N
HN
HN
HN
Me
NHMe
Me
Me
1n, 95%
(1 h, 4 h)c
1k, 96%
(10 min, 20 min)
1l, 79%
(3 h, 5 h)
1m, 77%
(2 h, 3 h)
N
N
N
N
N
N
N
N
N
N
N
N
HN
HN
HN
HN
1o, 93%
(1 h, 4 h)c
1p, 86%
(2 h, 4 h)c
1q, 90%
(1 h, 4 h)c
1r, 87%
(2 h, 4 h)c
Scheme 1. Scope of isothiocyanates. Reaction conditions: (1) 2 (0.5 mmol), 3 (0.6
mmol), EtOH (5 mL), rt; (2) I2 (0.55 mmol), K2CO3 (1 mmol), rt (isolated yields).
b
c
aTime for the first step. Time for the second step. The reaction was performed in
1,4-dioxane with the second step at 80 °C.
In light of these encouraging results, the scope of the hydrazine substrates was also
explored. 2-Hydrazinylpyridines bearing alkyl and halo groups (2) were all smoothly
5

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converted into the expected triazolopyridine products (1s‒u) when reacted with
phenyl isothiocyanate (3a) under the optimal cyclization conditions. The presence of
stronger EWGs on the pyridine ring affected both the conversion rates and the yields
(1v‒w). Moreover, quinolino- (1x) and diazino-fused (1y‒aa) 3-aminotriazoles were
also synthesized in satisfactory yields.
Scheme 2. Scope of aryl hydrazines. Reaction conditions: (1) 2 (0.5 mmol), 3 (0.6
mmol), EtOH (5 mL), rt; (2) I2 (0.55 mmol), K2CO3 (1 mmol), rt (isolated yields are
a
b
c
given). Time for the first step. Time for the second step. The reaction was
performed in MeCN. dThe second step at 60 °C.
Based on the experimental results, a plausible reaction mechanism is proposed
(Scheme 3). Using the formation of 1a as an example, addition of
2-hydrazinylpyridine (2a) to phenyl isothiocyanate (3a) yields a thiosemicarbazide 4a.
6

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Oxidative desulfurization of compound 4a by molecular iodine12 in the presence of
base generates intermediate B. Then, the nucleophilic addition of the pyridine
nitrogen to the carbodiimide group and subsequent proton translocation form the
1,2,4-triazolo[4,3-a]pyridine-3-amine framework 1a.
H
N
base
H
N
H
N
N
2a + 3a
N
Ph
N
Ph
S
I
A
N
H
S
I
N
H
I
base
4a
H
N
N
N
N
N
N
C
N
NHPh
Ph
B
1a
Scheme 3. Proposed Mechanism.
ꢀ Conclusion
In summary, we have developed a practical methodology for the synthesis of fused
3-amino-1,2,4-triazoles under transition-metal-free conditions. Under the optimal
reaction conditions, addition of aryl hydrazines to isothiocyanates followed by
I2-mediated oxidative desulfurization/cyclization produced a wide-range of
1,2,4-triazolo[4,3-a]pyridine-3-amines and related heterocyclic frameworks. This
synthetic approach is operationally simple and can be conveniently conducted on a
gram-scale.
ꢀ Experimental Section
1
13
General Information. H and C NMR spectra were recorded on a 400 MHz (100
13
MHz for C NMR spectroscopy) spectrometer. Chemical shift values are given in
ppm with tetramethylsilane (TMS) as an internal standard. The resonance patterns are
7

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indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doublet of doublets; dt, doublet of triplets. The coupling constants (J) are reported in
Hz. Melting points were determined on a micromelting point apparatus without
corrections. High-resolution mass spectra were obtained on a Q-TOF mass
spectrometer equipped with an ESI source operated in positive mode. Flash column
chromatography was performed over silica gel 200–300 mesh. EtOH, 1,4-dioxane and
MeCN was dried over 4 Å molecular sieves prior to use.
General Procedure A for the Synthesis of [1,2,4]triazolo[4,3-a]pyridin-3-amine 1.
To a solution of 2-hydrazinylpyridine (2, 0.5 mmol) in EtOH (5 mL) was added the
corresponding isothiocyanate (3, 0.6 mmol) slowly at room temperature. After the
total consumption of the substrate 2 (indicated by TLC), the reaction mixture was
treated with iodine (140 mg, 0.55 mmol) and K2CO3 (138 mg, 1 mmol) in sequence,
and then stirred at room temperature until TLC indicated the disappearance of the
addition intermediate 4. Upon the completion of the reaction, it was quenched with 5%
Na2S2O3 (5 mL), diluted with brine (10 mL) and then extracted with CH2Cl2 (enriched
5% MeOH, 4 × 10 mL). The combined organic layer was dried over anhydrous
Na2SO4, concentrated, and then purified through silica gel column chromatography
using a mixture of EtOAc/petroleum ether (PE) or MeOH/EtOAc as the eluent to
1
afford the product 1. [The structure of 4a was characterized by NMR and MS: H
NMR (400 MHz, DMSO-d6 ) δ 9.83 (br, s, 1H), 9.72 (br, s, 1H), 8.55 (br, s, 1H), 8.14
(d, J = 4.0 Hz, 1H), 7.65−7.60 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.6 Hz,
13
2H), 7.12 (t, J = 7.2 Hz, 1H), 6.81 (t, J = 5.6 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H); C
NMR (100 MHz, DMSO-d6) δ 181.7, 159.6, 148.1, 139.7, 138.3, 128.3, 125.7, 125.2,
116.2, 107.7; MS (m/z) [M + H]+ calcd for C12H13N4S 245.09, found 244.98.]
N-Phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1a). Eluent: MeOH/EtOAc 5:95;
8

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yield 0.5 mmol scale: 95 mg, 91%; 6 mmol scale: 1.11g, 88%; light-yellow solid, mp
232−233 °C (lit9 232.5−233.3 °C); 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H),
8.35 (d, J = 7.2 Hz, 1H), 7.63−7.56 (m, 3H), 7.32−7.28 (m, 2H), 7.25−7.20 (m, 1H),
13
6.93−6.87 (m, 2H); C NMR (100 MHz, DMSO-d6): δ 146.7, 144.8, 141.9, 129.4,
126.9, 123.1, 120.9, 116.7, 116.0, 112.7; HRMS (m/z) [M + H]+ calcd for C12H11N4
211.0978, found 211.0973.
N-(p-Tolyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1b).10 Eluent: MeOH/EtOAc 5:95;
yield: 108 mg, 97%; off-white solid, mp 259−260 °C; 1H NMR (400 MHz, DMSO-d6)
δ 9.11 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 8.4 Hz,
2H), 7.24−7.20 (m, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.88 (t, J = 6.4 Hz, 1H), 2.26 (s,
13
3H); C NMR (100 MHz, DMSO-d6) δ 146.6, 145.0, 139.3, 129.8, 129.6, 126.8,
123.1, 116.8, 116.0, 112.6, 20.8; HRMS (m/z) [M + H]+ calcd for C13H13N4 225.1135,
found 225.1140.
N-(4-Methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine
(1c).
Eluent:
MeOH/EtOAc 5:95; yield: 115 mg, 96%; white solid, mp 240−242 °C (lit9 240 °C);
1H NMR (400 MHz, DMSO-d6) δ 9.11 (br, s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 7.59−7.55
(m, 3H), 7.23−7.18 (m, 1H), 6.94−6.90 (m, 2H), 6.88−6.85 (m, 1H), 3.73 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 154.0, 146.4, 145.4, 135.1, 126.6, 123.2, 123.0, 118.4,
115.9, 114.7, 112.4, 55.7; HRMS (m/z) [M + H]+ calcd for C13H13N4O 241.1084,
found 241.1084.
N-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine
(1d).10
Eluent:
MeOH/EtOAc 5:95; yield: 107 mg, 94%; white solid, mp 246−247 °C; 1H NMR (400
MHz, DMSO-d6) δ 9.30 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.65−7.60 (m, 3H),
7.26−7.22 (m, 1H), 7.19−7.15 (m, 2H), 6.91 (t, J = 6.8 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 157.0 (d, J C−F = 234.8 Hz), 146.6, 144.9, 138.2 (d, J C−F = 2.2 Hz), 126.9,
9

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123.0, 118.2 (d, J C−F = 7.6 Hz), 116.0 (d, J C−F = 3.7 Hz), 115.8, 112.7; HRMS (m/z)
[M + H]+ calcd for C12H10FN4 229.0884, found 229.0887.
N-(4-Chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine
(1e).
Eluent:
MeOH/EtOAc 5:95; yield: 116 mg, 95%; white solid, mp 269−271 °C; 1H NMR (400
MHz, DMSO-d6) δ 9.45 (s, 1H), 8.36 (d, J = 6.8 Hz, 1H), 7.65−7.62 (m, 3H),
13
7.39−7.35 (m, 2H), 7.28−7.24 (m, 1H), 6.94−6.90 (m, 1H); C NMR (100 MHz,
DMSO-d6) δ 146.7, 144.5, 140.8, 129.2, 127.1, 124.3, 123.1, 118.2, 116.0, 112.8;
HRMS (m/z) [M + H]+ calcd for C12H10ClN4 245.0589, found 245.0597.
N-(4-Iodophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1f). Eluent: MeOH/EtOAc
10:90; yield: 158 mg, 94%; off-white solid, mp 274−277 °C; 1H NMR (400 MHz,
DMSO-d6) δ 9.44 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.64−7.61 (m, 3H), 7.45 (d, J =
9.2 Hz, 2H), 7.27−7.23 (m, 1H), 6.93−6.89 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 146.7, 144.4, 141.7, 137.9, 127.1, 123.1, 119.1, 116.0, 112.8, 83.1; HRMS (m/z) [M
+ H]+ calcd for C12H10IN4 336.9945, found 336.9947.
4-([1,2,4]Triazolo[4,3-a]pyridin-3-ylamino)benzonitrile (1g). Eluent: MeOH/EtOAc
5:95; yield: 108 mg, 92%; light-yellow solid, mp 282−285 °C; 1H NMR (400 MHz,
DMSO-d6) δ 9.91 (s, 1H), 8.39 (d, J = 6.8 Hz, 1H), 7.77−7.75 (m, 2H), 7.70−7.67 (m,
3H), 7.33−7.29 (m, 1H), 6.98−6.95(m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 147.1,
146.1, 143.6, 134.0, 127.5, 123.2, 120.0, 116.6, 116.0, 113.2, 102.0; HRMS (m/z) [M
+ H]+ calcd for C13H10N5 236.0931, found 236.0935.
N-(4-(Trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1h). Eluent:
MeOH/EtOAc 5:95; yield: 132 mg, 95%; white solid, mp 269−270 °C (lit9 270 °C);
1H NMR (400 MHz, DMSO-d6) δ 10.17 (br, s, 1H), 8.58 (d, J = 7.2 Hz, 1H), 7.82 (d,
J = 8.4 Hz, 2H), 7.66−7.64 (m, 3H), 7.30−7.26 (m, 1H), 6.92 (t, J = 6.4 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 146.9, 145.6, 144.3, 127.3, 126.7 (q, J C−F = 3.9 Hz),
10

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125.3 (q, J C−F = 268.8 Hz), 123.6, 120.6 (q, J C−F = 31.9 Hz), 116.4, 115.9, 112.9;
HRMS (m/z) [M + H]+ calcd for C13H10F3N4 279.0852, found 279.0847.
N-(4-Nitrophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1i).10 Eluent: MeOH/EtOAc
5:95; yield: 119 mg, 93%; yellow solid, mp > 300 °C; 1H NMR (400 MHz, DMSO-d6)
δ 10.22 (s, 1H), 8.43−8.41 (m, 1H), 8.26−8.22 (m, 2H), 7.74−7.69 (m, 3H), 7.35−7.30
13
(m, 1H), 7.01−6.96 (m, 1H); C NMR (100 MHz, DMSO-d6) δ 148.2, 147.3, 143.4,
140.4, 127.8, 126.1, 123.3, 116.0, 113.4; HRMS (m/z) [M + Na]+ calcd for
C12H9N5O2Na 278.0648, found 278.0649.
N-(o-Tolyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1j). Eluent: MeOH/EtOAc 5:95;
yield: 108 mg, 96%; light-yellow solid, mp 188−189 °C (lit9 189−189.5 °C); 1H NMR
(400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 9.6 Hz,
1H), 7.31−7.27 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.10−7.06 (m, 1H), 7.03−7.01 (m,
1H), 6.91−6.87 (m, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 147.7, 145.1,
140.9, 131.1, 127.2, 127.1, 127.0, 123.4, 121.9, 117.6, 116.0, 112.9, 18.4; HRMS (m/z)
[M + H]+ calcd for C13H13N4 225.1135, found 225.1138.
N-(m-Tolyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1k). Eluent: MeOH/EtOAc 5:95;
yield: 107 mg, 96%; white solid, mp 218−219 °C; 1H NMR (400 MHz, DMSO-d6) δ
9.15 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J
= 8.4 Hz, 1H), 7.27−7.23 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 6.8 Hz, 1H),
6.75 (d, J = 7.6 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 146.7, 144.8,
141.9, 138.6, 129.3, 126.9, 123.1, 121.7, 117.1, 116.0, 113.9, 112.7, 21.8; HRMS (m/z)
[M + H]+ calcd for C13H13N4 225.1135, found 225.1145.
N-(2,6-Dimethylphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine
(1l).10
Eluent:
MeOH/EtOAc 5:95; yield: 94 mg, 79%; light-yellow solid, mp 216−218 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.27 (d, J = 7.2 Hz, 1H), 8.13 (s, 1H), 7.53 (d, J = 9.2 Hz,
11

ACCEPTED MANUSCRIPT
13
1H), 7.20−7.16 (m, 1H), 7.12−7.04 (m, 3H), 6.88−6.85 (m, 1H), 2.11 (s, 6H); C
NMR (100 MHz, DMSO-d6) δ 146.80, 146.77, 137.8, 134.4, 128.7, 126.2, 125.7,
122.9, 116.0, 112.4, 18.5; HRMS (m/z) [M + H]+ calcd for C14H15N4 239.1291, found
239.1291.
N-Mesityl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1m). Eluent: MeOH/EtOAc 5:95;
1
yield: 97 mg, 77%; light-yellow solid, mp 258−260 °C; H NMR (400 MHz,
DMSO-d6) δ 8.25 (d, J = 6.8 Hz, 1H), 8.07 (s, 1H), 7.50 (d, J = 9.6 Hz, 1H),
7.17−7.13 (m, 1H), 6.92 (s, 2H), 6.84 (t, J = 6.4 Hz, 1H), 2.26 (s, 3H), 2.08 (s, 6H);
13C NMR (100 MHz, DMSO-d6) δ 147.0, 146.7, 135.0, 134.8, 134.6, 129.3, 126.1,
122.9, 116.0, 112.3, 20.9, 18.4; HRMS (m/z) [M + H]+ calcd for C15H17N4 253.1448,
found 253.1451.
N-Methyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1n).13 According to General
Procedure A, the reaction was performed in 1,4-dioxane at room temperature for the
first-step addition, and then 80 °C for the second-step oxidative cyclization. Eluent:
MeOH/EtOAc 10:90; yield: 70 mg, 95%; white solid, mp 182−183 °C; 1H NMR (400
MHz, DMSO-d6) δ 8.06 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.10−7.06 (m,
13
1H), 6.75−6.70 (m, 2H), 2.98 (d, J = 4.8 Hz, 3H); C NMR (100 MHz, DMSO-d6) δ
149.9, 146.5, 125.8, 122.6, 115.9, 111.7, 30.0; HRMS (m/z) [M + H]+ calcd for
C7H9N4 149.0822, found 149.0830.
N-Ethyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1o). According to General Procedure
A, the reaction was performed in 1,4-dioxane at room temperature for the first-step
addition, and then 80 °C for the second-step oxidative cyclization. Eluent:
MeOH/EtOAc 10:90; yield: 75 mg, 93%; white solid, mp 185−186 °C; 1H NMR (400
MHz, DMSO-d6) δ 8.10 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.06−7.02 (m,
13
1H), 6.70 (t, J = 6.0 Hz, 2H), 3.45−3.38 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H); C NMR
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(100 MHz, DMSO-d6) δ 149.1, 146.4, 125.8, 122.6, 115.8, 111.7, 38.2, 15.2; HRMS
(m/z) [M + H]+ calcd for C8H11N4 163.0978, found 163.0986.
N-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1p). According to General
Procedure A, the reaction was performed in 1,4-dioxane at room temperature for the
first-step addition, and then 80 °C for the second-step oxidative cyclization. Eluent:
MeOH/EtOAc 6:94; yield: 76 mg, 86%; brown solid, mp 145−146 °C; 1H NMR (400
MHz, DMSO-d6) δ 8.14 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.09−7.05 (m,
1H), 6.72 (t, J = 6.4 Hz, 1H), 6.44 (d, J = 6.8 Hz, 1H), 3.99−3.89 (m, 1H), 1.25 (d, J =
13
6.4 Hz, 6H); C NMR (100 MHz, DMSO-d6) δ 148.5, 146.2, 125.9, 122.8, 115.7,
111.7, 45.1, 23.1; HRMS (m/z) [M + H]+ calcd for C9H13N4 177.1135, found
177.1138.
N-Butyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1q). According to General Procedure
A, the reaction was performed in 1,4-dioxane at room temperature for the first-step
addition, and then 80 °C for the second-step oxidative cyclization. Eluent:
MeOH/EtOAc 5:95; yield: 86 mg, 90%; white solid, mp 89−90 °C; 1H NMR (400
MHz, DMSO-d6) δ 8.13 (dt, J = 6.8, 0.8 Hz, 1H), 7.46 (dt, J = 9.6, 0.8 Hz, 1H),
7.11−7.07 (m, 1H), 6.76−6.73 (m, 1H), 6.68 (t, J = 5.6 Hz, 1H), 3.43−3.38 (m, 2H),
1.70−1.62 (m, 2H), 1.46−1.36 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 149.2, 146.3, 125.7, 122.6, 115.8, 111.6, 43.1, 31.6, 20.1, 14.2; HRMS
(m/z) [M + H]+ calcd for C10H15N4 191.1291, found 191.1296.
N-Cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1r). According to General
Procedure A, the reaction was performed in 1,4-dioxane at room temperature for the
first-step addition, and then 80 °C for the second-step oxidative cyclization. Eluent:
MeOH/EtOAc 5:95; yield: 94 mg, 87%; brown solid, mp 158−159 °C; 1H NMR (400
MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.03−6.99 (m, 1H),
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6.58 (t, J = 6.4 Hz, 1H), 5.51 (br, s, 1H), 3.81−3.78 (m, 1H), 2.18−2.16 (m, 2H),
13
1.74−1.71 (m, 2H), 1.63−1.60 (m, 1H), 1.39−1.25 (m, 4H), 1.19−1.13 (m, 1H); C
NMR (100 MHz, CDCl3) δ 148.4, 146.9, 125.8, 122.2, 115.7, 111.7, 53.0, 33.4, 25.7,
25.1; HRMS (m/z) [M + H]+ calcd for C12H17N4 217.1448, found 217.1453.
7-Methyl-N-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1s). Eluent: MeOH/EtOAc
3:97; yield: 108 mg, 96%; off-white solid, mp 235−238 °C; 1H NMR (400 MHz,
DMSO-d6) δ 9.21 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.38 (d, J
= 1.2 Hz, 1H), 7.33−7.29 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H), 6.75 (dd, J = 7.2, 1.2 Hz,
13
1H), 2.33 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 147.1, 144.3, 142.0, 137.5,
129.4, 122.2, 120.8, 116.5, 115.5, 113.4, 21.3; HRMS (m/z) [M + H]+ calcd for
C13H13N4 225.1135, found 225.1141.
5-Methyl-N-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1t). Eluent: MeOH/EtOAc
1
3:97; yield: 108 mg, 96%; white solid, mp 235−236 °C; H NMR (400 MHz,
DMSO-d6) δ 8.47 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.25−7.18 (m, 3H), 6.80 (t, J = 7.2
13
Hz, 1H), 6.70−6.66 (m, 3H), 2.68 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 150.3,
146.6, 144.3, 135.4, 129.7, 128.3, 119.7, 114.7, 114.2, 114.2, 18.1; HRMS (m/z) [M +
H]+ calcd for C13H13N4 225.1135, found 225.1145.
8-Chloro-N-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1u). Eluent: EtOAc/PE
1
80:20; yield: 115 mg, 94%; white solid, mp 200−202 °C; H NMR (400 MHz,
DMSO-d6) δ 9.40 (s, 1H), 8.40 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J
= 7.2 Hz, 1H), 7.37−7.33 (m, 2H), 6.96 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) δ 146.2, 144.3, 141.4, 129.4, 126.0, 122.5, 121.2,
120.6, 116.9, 112.5; HRMS (m/z) [M + H]+ calcd for C12H10ClN4 245.0589, found
245.0595.
N-Phenyl-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1v). Eluent:
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EtOAc/PE 50:50; yield: 92 mg, 66%; white solid, mp 253−254 °C; 1H NMR (400
MHz, DMSO-d6) δ 9.52 (s, 1H), 9.13 (d, J = 1.2 Hz, 1H), 7.80−7.74 (m, 3H),
7.42−7.35 (m, 3H), 6.98 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 146.2,
145.6, 140.9, 129.4, 124.2 (q, J C−F = 6.2 Hz), 124.1 (q, J C−F = 269.1 Hz), 121.8 (d, J
C−F = 2.4 Hz), 121.4, 117.5, 117.1, 114.8 (q, J C−F = 33.2 Hz); HRMS (m/z) [M + H]+
calcd for C13H10F3N4 279.0852, found 279.0849.
3-(Phenylamino)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (1w). According to
General Procedure A, the reaction was performed in MeCN at room temperature for
the first-step addition, and then 60 °C for the second-step oxidative cyclization.
Eluent: MeOH/EtOAc 3:97; yield: 86 mg, 73%; yellow solid, mp 275−277 °C; 1H
NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.24 (s, 1H), 7.75−7.70 (m, 3H),
7.41−7.34 (m, 3H), 6.98 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 145.8,
144.8, 140.7, 132.4, 129.5, 125.5, 121.6, 117.2, 117.1, 97.3; HRMS (m/z) [M + H]+
calcd for C13H10N5 236.0931, found 236.0939.
N-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-1-amine (1x). Eluent: MeOH/EtOAc 3:97;
yield: 117 mg, 90%; yellow solid, mp 264−266 °C (lit8c 263−264 °C); 1H NMR (400
MHz, DMSO-d6) δ 9.12 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz,
1H), 7.76 (d, J = 9.2 Hz, 1H), 7.66−7.61 (m, 2H), 7.57−7.53 (m, 1H), 7.25−7.22 (m,
2H), 6.90−6.86 (m, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.4, 147.2, 144.4,
131.8, 129.8, 129.8, 129.7, 129.4, 126.5, 124.6, 120.7, 116.7, 116.0, 115.4; HRMS
(m/z) [M + H]+ calcd for C16H13N4 261.1135, found 261.1127.
6-Chloro-N-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine (1y). Eluent: EtOAc/PE
80:20; yield: 102 mg, 83%; yellow solid, mp 246−248 °C (lit8b 249−251 °C); 1H
NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.32 (d, J = 9.6 Hz, 1H), 7.90 (d, J = 7.6
Hz, 2H), 7.39−7.32 (m, 3H), 7.00 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
15

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δ 148.3, 146.8, 140.7, 140.1, 129.2, 127.5, 121.7, 121.5, 117.6; HRMS (m/z) [M + H]+
calcd for C11H9ClN5 246.0541, found 246.0551.
5-(Methylthio)-N-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-amine (1z). According to
General Procedure A, the reaction was performed in MeCN. Eluent: EtOAc/PE 67:33;
o
yield: 102 mg, 79%; light yellow-green solid, mp 192-193 C (lit9 197.6−198.2 °C);
1H NMR (400 MHz, DMSO-d6 ) δ 8.67 (s, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.44 (d, J =
13
6.4 Hz, 1H), 7.22−7.18 (m, 2H), 6.85−6.76 (m, 3H), 2.56 (s, 3H); C NMR (100
MHz, DMSO-d6) δ 151.5, 148.8, 145.6, 143.5, 140.9, 129.6, 120.3, 115.5, 106.3, 14.0;
HRMS (m/z) [M + H]+ calcd for C12H12N5S 258.0808, found 258.0804.
N-Phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-amine (1aa).9 According to General
Procedure A, the reaction was performed in MeCN. Eluent: EtOAc/PE 75:25
(enriched with 2.5% of MeOH); yield: 43 mg, 41%; brown solid, mp 243-244 °C; 1H
NMR (400 MHz, DMSO-d6 ) δ 9.57 (s, 1H), 9.22 (d, J = 1.6 Hz, 1H), 8.41 (dd, J =
4.8, 1.6 Hz, 1H), 7.82 (d, J = 4.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 8.0 Hz,
2H), 6.98 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 145.7, 144.6, 142.4,
140.9, 129.5, 128.0, 121.5, 117.1, 116.0; HRMS (m/z) [M + H]+ calcd for C11H10N5
212.0931, found 212.0936.
ꢀ Associated Content
Supporting Information
Copies of 1H and 13C NMR spectra of compounds 1 and 4a.
ꢀ Author Information
Corresponding Authors
*E-mail: wenquan_yu@zzu.edu.cn
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*E-mail: changjunbiao@zzu.edu.cn
Notes
The authors declare no competing financial interest.
ꢀ Acknowledgements
We thank the National Natural Science Foundation of China (No. 81773570 and
81330075), the Outstanding Young Talent Research Fund of Zhengzhou University
(No. 1521316004) for financial support.
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