Synthesis of 1,2,4-Triazolo[4,3-a]pyridines and Related Heterocycles by Sequential Condensation and Iodine-Mediated Oxidative Cyclization

Article abstract of DOI:10.1002/chem.201601744

A facile and efficient approach to access 1,2,4-triazolo[4,3-a]pyridines and related heterocycles has been accomplished through condensation of readily available aryl hydrazines with corresponding aldehydes followed by iodine-mediated oxidative cyclizatio

Full text of DOI:10.1002/chem.201601744

DOI: 10.1002/chem.201601744
Full Paper
&
Synthesis Design
Synthesis of 1,2,4-Triazolo[4,3-a]pyridines and Related
Heterocycles by Sequential Condensation and Iodine-Mediated
Oxidative Cyclization
Ertong Li, Zhiyuan Hu, Lina Song, Wenquan Yu,* and Junbiao Chang*[a]
Abstract: A facile and efficient approach to access 1,2,4-tri-
azolo[4,3-a]pyridines and related heterocycles has been ac-
complished through condensation of readily available aryl
hydrazines with corresponding aldehydes followed by
iodine-mediated oxidative cyclization. This transition-metal-
free synthetic process is broadly applicable to a variety of ar-
omatic, aliphatic, and a,b-unsaturated aldehydes, and can be
conveniently conducted on the gram scale.
Introduction
A survey of the literature indicated that 1,2,4-triazolo[4,3-
a]pyridines could be prepared by the following strategies
(Scheme 1): a) cyclodehydration of acylated 2-hydrazinopyri-
Triazolopyridines are an important class of fused-ring heterocy-
clic compounds.[1] Among the various triazolopyridine deriva-
tives, the 1,2,4-triazolo[4,3-a]pyridine skeleton widely exists in
many compounds with diverse pharmaceutical properties,
such as anti-inflammatory,[2] antithrombotic,[3] antiprolifera-
tive,[4] antidepressant/antipsychotic,[5] antibacterial,[6] and antivi-
ral activities.[7] For example, selective p38a inhibitor 5 exhibited
significant anti-inflammatory activity in a rat model of arthritis
(Figure 1).[2c] As a positive allosteric modulator (PAM) of the
Scheme 1. Synthetic strategies for the preparation of 1,2,4-triazolo[4,3-a]pyri-
dines.
dines in acetic acid under microwave irradiation[10] or by using
Lawesson’s reagent;[11] b) tandem/one-pot reaction of 2-hydra-
zinopyridines with carboxylic acids in the presence of reagents
such as POCl3/PCl5,[12] polystyrene-bound triphenylphosphine
(PS-PPh3)/CCl3CN,[13] and 1,1’-carbonyldiimidazole (CDI);[14] with
isothiocyanates promoted by polymer-supported Mukaiyama’s
reagent;[15] or with aryl iodides through [Mo(CO)6]-mediated
carbonylation;[16] c) oxidative cyclization of 2-pyridylhydrazones
with oxidants such as hypervalent iodine reagents,[17] N-bromo-
succinimide (NBS),[18] chloramine T,[19] ceric ammonium nitrate
(CAN),[20] and CuCl2;[21] and d) Cu-catalyzed direct CÀH (hetero)-
arylation of preformed 1,2,4-triazolo[4,3-a]pyridines.[9]
Figure 1. Representative bioactive 1,2,4-triazolo[4,3-a]pyridine derivatives.
metabotropic glutamate 2 receptor, compound 6 showed
good antipsychotic activity in mice.[5a] 1,2,4-Triazolo[4,3-a]quin-
oline 7 was demonstrated to have good inhibitory activity
against several bacterial strains.[6a] Moreover, 1,2,4-triazolo[4,3-
a]pyridines can also be used as herbicidal agents in agricul-
ture.[8] Owing to their excellent deep-blue emission and stabili-
ty properties, 3-aryl[1,2,4]triazolo[4,3-a]pyridines could be po-
tential candidates for applications in high-performance organic
light-emitting diodes (OLEDs).[9]
Nevertheless, there are still disadvantages associated with
the existing methods due to harsh reaction conditions, the use
of expensive and/or hazardous reagents, and limited substrate
scope and/or scalability. Therefore, it is of great importance to
develop practical and eco-friendly approaches to access this
compound class. Previously, utilizing molecular iodine as the
sole oxidant,[22] we have successfully constructed nitrogen-con-
taining heterocyclic frameworks, such as pyrazoles, quinazoli-
nones, and benzimidazoles, through oxidative CÀN bond for-
[a] E. Li, Z. Hu, L. Song, Dr. W. Yu, Prof. Dr. J. Chang
College of Chemistry and Molecular Engineering
Zhengzhou University, Zhengzhou, 450001 (P.R. China)
E-mail: wenquan_yu@zzu.edu.cn
changjunbiao@zzu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601744.
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mation.[23] Recently, we disclosed an I2-mediated oxidative cycli-
zation reaction of N-aryl amidines 8 to prepare 1,5-fused 1,2,4-
triazoles 9.[24] As a continuation of this research into the syn-
thesis of fused 1,2,4-triazoles, herein we envisioned a sequential
synthetic method for the preparation of 1,2,4-triazolo[4,3-a]pyr-
idines and related heterocycles through condensation of aryl
hydrazines and aldehydes followed by iodine-mediated oxida-
tive cyclization.
With the optimal reaction conditions (Table 1, entry 8) in
hand, we sought to examine the scope and generality of this
sequential synthesis. Condensation of 2a with substituted
benzaldehydes 3, followed by I2-mediated oxidative cyclization,
produced a series of 3-aryl[1,2,4]triazolo[4,3-a]pyridines (1b–m)
in good to excellent yields (Scheme 2). This synthetic method
Results and Discussion
First, we investigated the oxidative cyclization of the purified
hydrazone 4a, obtained in 89% yield through the condensa-
tion of 2-hydrazinopyridine (2a) and benzaldehyde (3a). Treat-
ment of 4a with molecular iodine in the presence of K2CO3 in
1,4-dioxane at 808C resulted in the desired triazolopyridine
(1a) in 91% yield (Table 1, entry 1). Next, we attempted to
Table 1. Optimization of the reaction conditions for the synthesis of 3-
phenyl[1,2,4]triazolo[4,3-a]pyridine (1a).[a]
Entry Substrate Base
Solvent
T
t
Yield[b] [%]
1
2
3
4
5
6
7
8
9
10
4a
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DBU[d]
1,4-dioxane 808C
1,4-dioxane 808C
1,4-dioxane reflux 2 h
5 h
5 h
91
90
90
81
71
Scheme 2. Scope of aromatic aldehydes tested. Optimal reaction conditions:
1) 2a (0.5 mmol), 3 (0.5 mmol), EtOH, reflux; 2) I2 (0.6 mmol), K2CO3
(1.5 mmol), CH2Cl2, RT (isolated yields are given). [a] The second step was
performed at reflux.
2a+3a
2a+3a
2a+3a
2a+3a
2a+3a
2a+3a
2a+3a
2a+3a
2a+3a
DMSO
DMF
1008C 1 h
1008C 10 min
EtOH
RT
RT
RT
RT
RT
1 h
3 h
1 h
30 min
1 h
89
69
is compatible with both electron-donating and -withdrawing
groups (EDGs and EWGs, respectively) at the para, meta, and
ortho positions of the benzene ring of the aldehydes (3b–m).
It is worth mentioning that good functional group tolerance
allows the preparation of the product containing a phenolic
hydroxy group (1d). Additionally, a-naphthylaldehyde, pyri-
dine-2-aldehyde, and 2-furaldehyde were converted into the
expected triazolopyridines (1n–p) in satisfactory yields as well.
In light of these encouraging results, we further explored
the substrate scope by replacing the aromatic aldehydes with
aliphatic ones (3q–s; Scheme 3). The desired products (1q–s)
were obtained in good yields under the optimal reaction con-
ditions. The reaction of paraformaldehyde with 2a gave the
unsubstituted 1,2,4-triazolo[4,3-a]pyridine (1t) in 60% yield.
This synthetic process also worked well with a,b-unsaturated
aldehydes (3u,v), which afforded products 1u and 1v, respec-
tively. Furthermore, triazolopyridines containing both EDGs
and EWGs on the pyridine ring (1w–z) and other 4,3-fused
1,2,4-triazoles (1aa–ad) were prepared in excellent yields by
using the corresponding aryl hydrazines (Scheme 4).
MeCN
CH2Cl2
CH2Cl2
ꢀ95[c]
82
NaHCO3 CH2Cl2
24
[a] Optimal reaction conditions: 1) 2a (0.5 mmol), 3a (0.5 mmol), EtOH,
reflux; 2) I2 (0.6 mmol), K2CO3 (1.5 mmol), CH2Cl2, RT. [b] Yields of products
isolated are given. [c] Yields for both 0.5 and 6 mmol scale reactions.
[d] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
probe the feasibility of the sequential synthesis of triazolopyri-
dine 1a without purification of intermediate 4a. Upon comple-
tion of the first condensation step, the solvent was removed
and the resulting crude product 4a was directly subjected to
the above oxidative cyclization conditions; this gave product
1a in equally good yield (Table 1, entry 2). Raising the reaction
temperature accelerated the conversion rate and did not affect
the yield (Table 1, entry 3). Further screening of a series of
commonly used laboratory solvents (Table 1, entries 3–8) sug-
gested that CH2Cl2 was the optimal solvent for the cyclization
step. By taking the synthesis of 1a as an example, the reaction
was conveniently carried out on a gram scale (6 mmol; Table 1,
entry 8). Replacement of K2CO3 with either an organic base
(Table 1, entry 9) or a weaker inorganic base (Table 1, entry 10)
decreased the yield of the product.
A plausible reaction mechanism for the formation of 1,2,4-
triazolo[4,3-a]pyridine is proposed (Scheme 5). Taking the for-
mation of 1a as an example, the base-promoted oxidative iodi-
nation of hydrazone 4a produces a plausible iodo species A.[25]
Then, the pyridine nitrogen attacks the iodo-substituted
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Under the optimal sequential reaction conditions, readily avail-
able aryl hydrazines and the corresponding aldehydes were
smoothly converted into the desired triazolopyridines without
purification of the condensation intermediates. This operation-
ally simple synthetic process is broadly applicable to a variety
of aromatic, aliphatic, and a,b-unsaturated aldehydes; this
allows the efficient and scalable preparation of a variety of
1,2,4-triazolo[4,3-a]pyridines and related heterocycles.
Experimental Section
Scheme 3. Scope of aliphatic and a,b-unsaturated aldehydes tested. Optimal
reaction conditions: 1) 2a (0.5 mmol), 3 (0.5 mmol), EtOH, reflux; 2) I2
(0.6 mmol), K2CO3 (1.5 mmol), CH2Cl2, RT (isolated yields are given). [a] The
second step was performed at reflux.
General
1H and 13C NMR spectra were recorded on a 400 MHz (100 MHz for
13C NMR spectroscopy) spectrometer. Chemical shift values are
given in ppm with tetramethylsilane (TMS) as an internal standard.
The resonance patterns are indicated as follows: s, singlet; d, dou-
blet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet;
dd, doublet of doublets; dt, doublet of triplets. The coupling con-
stants (J) are reported in Hz. Melting points were determined on
a micromelting point apparatus without corrections. High-resolu-
tion 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 by using a mixture of EtOAc and petroleum ether (PE) (or
MeOH and EtOAc) as the eluent.
General procedure for the synthesis of 1,2,4-triazolo[4,3-a]-
pyridines 1
A mixture of the hydrazine (2; 0.5 mmol) and aldehyde (3;
0.5 mmol) in EtOH (6 mL) was heated at reflux for 30 min (TLC indi-
cated that condensation was complete). Then, the solvent was
evaporated under reduced pressure, and the resulting residue was
redissolved in CH2Cl2 (6 mL), followed by the sequential addition of
K2CO3 (207 mg, 1.5 mmol) and iodine (152 mg, 0.6 mmol). The reac-
tion mixture was stirred at room temperature (for the synthesis of
products 1d, 1i, 1s, 1x, and 1ab, the reaction was performed at
reflux) until TLC indicated the total consumption of intermediate 4
(0.5–4 h). Upon completion of the reaction, it was quenched with
5% Na2S2O3 (15 mL), and then extracted with CH2Cl2 (3”10 mL).
The combined organic layer was washed with brine (20 mL), dried
over anhydrous Na2SO4, and concentrated. The given residue was
purified by column chromatography through silica gel to afford
pure product 1.
Scheme 4. Scope of hydrazines tested. Optimal reaction conditions: 1) 2
(0.5 mmol), 3 (0.5 mmol), EtOH, reflux; 2) I2 (0.6 mmol), K2CO3 (1.5 mmol),
CH2Cl2, RT (isolated yields are given). [a] The second step was performed at
reflux.
Compound 1a: Yield: 94 mg, ꢀ 95% (0.5 mmol scale); 1.15 g, ꢀ
95% (6 mmol scale); off-white solid, m.p. 171–1738C (lit.[19] m.p.
172–1748C); Rf =0.3 (EtOAc); H NMR (400 MHz, CDCl3): d=8.29 (d,
Scheme 5. Proposed mechanism for the formation of 1,2,4-triazolo[4,3-a]pyr-
idine 1a.
1
J=7.2 Hz, 1H), 7.85–7.81 (m, 3H), 7.61–7.55 (m, 3H), 7.31–7.27 (m,
1H), 6.88 (t, J=6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=150.5,
146.7, 130.2, 129.3, 128.2, 127.1, 126.6, 122.6, 116.8, 114.2; HRMS
(m/z) [M+H]+ calcd for C12H10N3, 196.0869; found: 196.0874.
carbon in A to generate intermediate B through a SN2’-type
cyclization, which forms a new CÀN bond. Finally, the subse-
quent deprotonation and rearomatization by a base affords
the 1,2,4-triazolo[4,3-a]pyridine framework 1a.
Compound 1b: Yield: 102 mg, ꢀ95%; white solid; m.p. 162–
1648C (lit.[6a] m.p. 1578C); Rf =0.3 (EtOAc); 1H NMR (400 MHz,
CDCl3): d=8.27 (dt, J=7.2, 1.2 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.72
(d, J=8.0 Hz, 2H), 7.39 (d, J=7.6 Hz, 2H), 7.29–7.25 (m, 1H), 6.86
(td, J=6.8, 0.8 Hz, 1H), 2.46 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=150.5, 146.9, 140.5, 130.0, 128.2, 127.0, 123.7, 122.7,
116.8, 114.1, 21.5 ppm; HRMS: m/z calcd for C13H12N3 [M+H]+:
210.1026; found: 210.1031.
Conclusion
We have developed a practical and environmentally benign
approach for the synthesis of 1,2,4-triazolo[4,3-a]pyridine deriv-
atives through I2-mediated oxidative CÀN bond formation.
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133.1, 131.1, 128.5, 127.7, 122.3, 118.1, 117.2, 115.2, 113.8 ppm;
HRMS: m/z calcd for C13H8N4Na [M+Na]+: 243.0641; found:
243.0636.
Compound 1c: Yield: 111 mg, ꢀ95%; off-white solid; m.p. 121–
1
1238C (lit.[19] m.p. 123–1258C); Rf =0.3 (EtOAc); H NMR (400 MHz,
CDCl3): d=8.24 (d, J=6.8 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.76 (d,
J=8.8 Hz, 2H), 7.26 (dd, J=10.0, 7.2 Hz, 1H), 7.10 (d, J=8.8 Hz,
2H), 6.85 (t, J=6.8 Hz, 1H), 3.90 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=161.0, 150.4, 146.7, 129.7, 126.9, 122.6, 118.8, 116.8,
114.8, 114.1, 55.5 ppm; HRMS: m/z calcd for C13H12N3O [M+H]+:
226.0975; found: 226.0980.
Compound 1j:[19] Yield: 108 mg, 90%; brown solid; m.p. >3008C;
Rf =0.4 (MeOH/CH2Cl2 2:98); H NMR (400 MHz, CF3CO2D): d=8.98
(d, J=6.8 Hz, 1H), 8.84–8.81 (m, 2H), 8.50–8.38 (m, 4H), 7.91 ppm
(td, J=7.2, 0.8 Hz, 1H); 13C NMR (100 MHz, CF3CO2D): d=150.1,
145.5, 145.0, 139.0, 130.3, 128.1, 124.9, 119.9, 111.3 ppm; HRMS:
m/z calcd for C12H9N4O2 [M+H]+: 241.0720; found: 241.0722.
1
Compound 1d: Yield: 86 mg, 81%; off-white solid; m.p. 247–
2498C (lit.[21] m.p. 249–2508C); Rf =0.4 (MeOH/CH2Cl2 5:95); H NMR
1
Compound 1k: Yield: 126 mg, ꢀ95%; off-white solid; m.p. 157–
(400 MHz, [D6]DMSO): d=10.06 (s, 1H), 8.48 (d, J=7.2 Hz, 1H), 7.81
(d, J=9.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.39 (dd, J=9.2, 6.4 Hz,
1H), 7.01–6.97 ppm (m, 3H); 13C NMR (100 MHz, [D6]DMSO): d=
159.1, 149.7, 146.3, 129.8, 127.7, 123.9, 117.1, 116.1, 115.6,
114.2 ppm; HRMS: m/z calcd for C12H10N3O [M+H]+: 212.0818;
found: 212.0820.
1
1598C; Rf =0.3 (MeOH/EtOAc 5:95); H NMR (400 MHz, CDCl3): d=
8.29 (d, J=7.2 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.35–7.26 (m, 2H),
7.06–7.04 (m, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.98 ppm (s, 6H);
13C NMR (100 MHz, CDCl3): d=150.7, 150.4, 149.8, 146.7, 127.0,
122.7, 120.3, 119.1, 116.8, 114.1, 111.8, 111.3, 56.2, 56.1 ppm; HRMS:
m/z calcd for C14H13N3O2Na [M+Na]+: 278.0900; found: 278.0895.
Compound 1e: Yield: 90 mg, 85%; white solid; m.p. 108–1098C;
Rf =0.4 (EtOAc); 1H NMR (400 MHz, CDCl3): d=7.98–7.95 (m, 1H),
7.87–7.82 (m, 2H), 7.61–7.55 (m, 1H), 7.41–7.27 (m, 3H), 6.92–
6.88 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=159.8 (d, J(C,F)=
249.0 Hz), 150.7, 143.0, 132.6 (d, J(C,F)=8.3 Hz), 132.4 (d, J(C,F)=
2.8 Hz), 127.4, 125.3 (d, J(C,F)=3.4 Hz), 123.6 (d, J(C,F)=7.0 Hz),
116.5, 116.3 (d, J(C,F)=20.8 Hz), 114.7 (d, J(C,F)=14.3 Hz),
114.1 ppm; HRMS: m/z calcd for C12H9FN3 [M+H]+: 214.0775;
found: 214.0778.
Compound 1l: Yield: 131 mg, ꢀ95%; off-white solid; m.p. 134–
1368C (lit.[26] m.p. 1378C); Rf =0.5 (EtOAc); 1H NMR (400 MHz,
CDCl3): d=7.87 (dt, J=9.2, 1.2 Hz, 1H), 7.79 (dt, J=7.2, 1.2 Hz, 1H),
7.65–7.63 (m, 2H), 7.48 (dd, J=8.4, 2.4 Hz, 1H), 7.36 (ddd, J=9.2,
6.4, 1.2 Hz, 1H), 6.92 ppm (td, J=6.8, 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=150.4, 144.1, 137.7, 134.8, 134.1, 130.2, 128.0,
127.5, 124.6, 123.3, 116.7, 114.1 ppm; HRMS: m/z calcd for
C12H7Cl2N3Na [M+Na]+: 285.9909; found: 285.9909.
Compound 1m:[10] Yield: 110 mg, 92%; off-white solid; m.p. 142–
1448C; Rf =0.5 (EtOAc); H NMR (400 MHz, CDCl3): d=7.83 (d, J=
Compound 1 f: Yield: 110 mg, ꢀ95%; off-white solid; m.p. 123–
1
1
1258C (lit.[19] m.p. 125–1278C); Rf =0.4 (EtOAc); H NMR (400 MHz,
9.2 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.31–7.27 (m, 1H), 7.03 (s, 2H),
6.82–6.78 (m, 1H), 2.38 (s, 3H), 1.99 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=149.7, 145.8, 140.6, 139.1, 128.7, 127.0, 122.4,
122.2, 116.6, 113.9, 21.3, 19.6 ppm; HRMS: m/z calcd for C15H15N3Na
[M+Na]+: 260.1158; found: 260.1159.
CDCl3): d=7.86 (dt, J=9.6, 1.2 Hz, 1H), 7.81 (dt, J=6.8, 1.2 Hz, 1H),
7.69 (dd, J=7.6, 1.6 Hz, 1H), 7.61–7.46 (m, 3H), 7.34 (ddd, J=9.2,
6.8, 1.2 Hz, 1H), 6.89 ppm (td, J=6.8, 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=150.3, 145.0, 134.1, 133.3, 132.0, 130.2, 127.5,
127.4, 125.9, 123.5, 116.6, 113.9 ppm; HRMS: m/z calcd for
C12H9ClN3 [M+H]+: 230.0480; found: 230.0468.
Compound 1n:[9] Yield: 121 mg, ꢀ95%; off-white solid; m.p. 120–
1
1218C; Rf =0.5 (EtOAc); H NMR (400 MHz, CDCl3): d=8.06 (d, J=
Compound 1g: Yield: 109 mg, 95%; off-white solid; m.p. 199–
1
2018C (lit.[19] m.p. 198–1998C); Rf =0.4 (EtOAc); H NMR (400 MHz,
8.0 Hz, 1H), 7.97–7.95 (m, 1H), 7.89–7.86 (m, 1H), 7.77–7.75 (m,
2H), 7.69–7.67 (m, 1H), 7.65–7.61 (m, 1H), 7.58–7.54 (m, 1H), 7.50–
7.46 (m, 1H), 7.33–7.28 (m, 1H), 6.80–6.76 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=150.3, 145.8, 133.9, 131.5, 131.1, 129.0, 128.7,
127.5, 127.3, 126.7, 125.3, 125.0, 123.5, 123.0, 116.6, 114.0 ppm;
HRMS: m/z calcd for C16H11N3Na [M+Na]+: 268.0845; found:
268.0834.
CDCl3): d=8.26 (d, J=7.2 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.79 (d,
J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.31 (dd, J=8.8, 6.8 Hz, 1H),
6.91 ppm (t, J=6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=150.7,
145.8, 136.4, 129.7, 129.5, 127.2, 125.1, 122.4, 117.0, 114.6 ppm;
HRMS: m/z calcd for C12H8ClN3Na [M+Na]+: 252.0299; found:
252.0292.
Compound 1o:[11] Yield: 65 mg, 66%; black solid; m.p. 117–1198C;
Rf =0.5 (EtOAc); 1H NMR (400 MHz, CDCl3): d=9.75 (d, J=7.2 Hz,
1H), 8.63–8.62 (m, 1H), 8.45 (d, J=8.4 Hz, 1H), 7.82–7.77 (m, 2H),
7.31–7.26 (m, 2H), 6.89 ppm (t, J=6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=151.2, 148.7, 148.3, 144.4, 137.1, 128.0, 127.1, 123.7,
122.6, 116.0, 114.3 ppm; HRMS: m/z calcd for C11H9N4 [M+H]+:
197.0822; found: 197.0830.
Compound 1h: Yield: 123 mg, 93%; light yellow solid; m.p. 154–
1558C; Rf =0.5 (EtOAc); H NMR (400 MHz, CDCl3): d=8.28 (d, J=
1
7.2 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.88 (d, J=9.6 Hz,
1H), 7.83–7.73 (m, 2H), 7.35 (ddd, J=9.2, 6.4, 0.8 Hz, 1H), 6.96 ppm
(td, J=7.2, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=150.8, 145.4,
131.9 (q, J(C,F)=32.8 Hz), 131.4 (d, J(C,F)=11.3 Hz), 130.0, 127.6,
127.5, 126.9 (q, J(C,F)=3.7 Hz), 125.0 (q, J(C,F)=3.7 Hz), 122.2,
117.1, 114.9 ppm; HRMS: m/z calcd for C13H9F3N3 [M+H]+:
264.0743; found: 264.0747.
Compound 1p: Yield: 80 mg, 86%; light brown solid; m.p. 92–
1
948C (lit.[26] m.p. 928C); Rf =0.4 (EtOAc); H NMR (400 MHz, CDCl3):
Compound 1i: Yield: 108 mg, ꢀ95%; off-white solid; m.p. 261–
d=8.74 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.67 (s, 1H),
7.32–7.26 (m, 2H), 6.94 (t, J=6.8 Hz, 1H), 6.65 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=149.9, 143.6, 142.9, 139.6, 127.4,
124.2, 116.5, 114.5, 112.1, 111.0 ppm; HRMS: m/z calcd for C10H8N3
[M+H]+: 186.0662; found: 186.0665.
1
2628C (lit.[19] m.p. 258–2608C); Rf =0.3 (MeOH/CH2Cl2 2:98); H NMR
(400 MHz, CDCl3): d=8.33 (d, J=7.2 Hz, 1H), 8.04–8.02 (m, 2H),
7.91–7.89 (m, 3H), 7.37 (ddd, J=9.2, 6.4, 0.8 Hz, 1H), 6.99 ppm (td,
J=6.8, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=151.1, 145.0,
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128.5, 126.2, 125.9, 123.0, 121.4, 114.0 ppm; HRMS: m/z calcd for
C12H8ClN3Na [M+Na]+: 252.0299; found: 252.0296.
Compound 1q:[27] Yield: 78 mg, ꢀ95%; light brown oil; Rf =0.2
1
(EtOAc); H NMR (400 MHz, CDCl3): d=7.92 (d, J=7.2 Hz, 1H), 7.74
(d, J=9.2 Hz, 1H), 7.26–7.22 (m, 1H), 6.86 (t, J=6.8 Hz, 1H), 3.07 (t,
J=7.4 Hz, 2H), 1.95 (sext, J=7.4 Hz, 2H), 1.08 ppm (t, J=7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=149.7, 146.7, 126.6, 121.9, 116.6,
113.5, 26.4, 20.0, 13.9 ppm; HRMS: m/z calcd for C9H12N3 [M+H]+:
162.1026; found: 162.1026.
Compound 1y: Yield: 92 mg, 84%; white solid; m.p. 193–1958C;
Rf =0.4 (EtOAc); 1H NMR (400 MHz, CDCl3): d=8.73 (s, 1H), 7.92
(dd, J=9.6, 0.4 Hz, 1H), 7.83–7.80 (m, 2H), 7.68–7.64 (m, 3H),
7.36 ppm (dd, J=9.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
149.0, 147.8, 131.2, 129.9, 129.7, 128.4, 126.4, 125.1, 118.3, 115.5,
101.2 ppm; HRMS: m/z calcd for C13H8N4Na [M+Na]+: 243.0641;
found: 243.0642.
Compound 1r:[10] Yield: 80 mg, ꢀ95%; light brown oil; Rf =0.2
1
(EtOAc); H NMR (400 MHz, CDCl3): d=7.95–7.93 (m, 1H), 7.75 (td,
J=9.2, 1.2 Hz, 1H), 7.22 (ddd, J=9.2, 6.4, 1.2 Hz, 1H), 6.86–6.82 (m,
1H), 3.39 (heptet, J=6.8 Hz, 1H), 1.54 ppm (d, J=6.8 Hz, 6H);
13C NMR (100 MHz, CDCl3): d=151.3, 150.1, 126.5, 122.0, 116.9,
113.4, 25.3, 20.3 ppm; HRMS: m/z calcd for C9H11N3Na [M+Na]+:
184.0845; found: 184.0845.
Compound 1z: Yield: 124 mg, 94%; white solid; m.p. 93–958C;
Rf =0.5 (EtOAc); H NMR (400 MHz, CDCl3): d=8.61 (s, 1H), 7.95 (d,
1
J=9.6 Hz, 1H), 7.84–7.82 (m, 2H), 7.67–7.62 (m, 3H), 7.42 ppm (dd,
J=9.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=149.9, 148.0,
130.9, 129.7, 128.4, 125.6, 123.0 (q, J(C,F)=2.2 Hz), 122.9 (q, J(C,F)=
270.0 Hz), 122.2 (q, J(C,F)=6.0 Hz), 119.0 (q, J(C,F)=34.2 Hz),
118.1 ppm; HRMS: m/z calcd for C13H8F3N3Na [M+Na]+: 286.0563;
found: 286.0566.
Compound 1s:[10] Yield: 87 mg, ꢀ95%; off-white solid; m.p. 90–
958C; Rf =0.4 (EtOAc); 1H NMR (400 MHz, CDCl3): d=8.20 (d, J=
7.2 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.23–7.19 (m, 1H), 6.81 (t, J=
6.8 Hz, 1H), 1.62 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=153.0,
151.0, 126.1, 123.9, 117.1, 113.1, 32.5, 27.88 ppm; HRMS: m/z calcd
for C10H14N3 [M+H]+: 176.1182; found: 176.1187.
Compound 1aa: Yield: 109 mg, 89%; light yellow solid; m.p. 180–
1
1838C (lit.[19] mp181–1838C); Rf =0.3 (MeOH/CH2Cl2 2:98); H NMR
(400 MHz, CDCl3): d=8.80–8.78 (m, 1H), 7.98 (d, J=7.6 Hz, 1H),
7.85–7.83 (m, 2H), 7.75–7.66 (m, 3H), 7.62–7.54 (m, 3H), 7.08 ppm
(d, J=7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=149.3, 148.7,
130.4, 130.2, 129.9, 129.4, 129.3, 128.7, 127.2, 126.8, 124.3, 121.8,
119.7, 115.6 ppm; HRMS: m/z calcd for C16H11N3Na [M+Na]+:
268.0845; found: 268.0845.
Compound 1t:[9] Yield: 36 mg, 60%; light brown oil; Rf =0.2
(MeOH/EtOAc 5:95); 1H NMR (400 MHz, CDCl3): d=8.87 (s, 1H),
8.19 (d, J=6.8 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.32–7.28 (m, 1H),
6.89 ppm (t, J=6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=149.4,
135.6, 127.8, 123.5, 116.5, 114.3 ppm; HRMS: m/z calcd for C6H6N3
[M+H]+: 120.0556; found: 120.0539.
Compound 1ab: Yield: 115 mg, 94%, light yellow solid; m.p. 134–
1
1368C (lit.[19] m.p. 135–1378C); Rf =0.5 (EtOAc); H NMR (400 MHz,
CDCl3): d=7.80 (dd, J=7.6, 0.8 Hz, 1H), 7.71–7.69 (m, 3H), 7.64–
7.54 (m, 5H), 7.46 (t, J=7.6 Hz, 1H), 7.36–7.32 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=150.0, 149.1, 132.0, 130.6, 130.0,
129.8, 129.7, 129.4, 129.2, 129.0, 126.2, 124.7 ppm; HRMS: m/z
calcd for C16H11N3Na [M+Na]+: 268.0845; found: 268.0838.
Compound 1u: Yield: 105 mg, 95%; yellow solid; m.p. 185–1878C
1
(lit.[27] m.p. 185–1878C); Rf =0.5 (EtOAc); H NMR (400 MHz, CDCl3):
d=8.17 (d, J=6.8 Hz, 1H), 7.89 (d, J=16.4 Hz, 1H), 7.78 (d, J=
9.2 Hz, 1H), 7.60–7.58 (m, 2H), 7.43–7.33 (m, 3H), 7.26 (m, 1H,
overlapped with the chloroform signal), 7.16 (d, J=16.0 Hz, 1H),
6.92 ppm (t, J=6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=150.2,
145.2, 135.8, 135.4, 129.2, 129.0, 127.2, 127.0, 122.1, 116.9, 114.3,
109.4 ppm; HRMS: m/z calcd for C14H11N3Na [M+Na]+: 244.0845;
found: 244.0840.
Compound 1ac: Yield: 114 mg, ꢀ95%; off-white solid; m.p. 197–
1
1998C (lit.[19] m.p. 199–2018C); Rf =0.4 (MeOH/CH2Cl2 2:98); H NMR
(400 MHz, CDCl3): d=8.47–8.44 (m, 2H), 8.16 (d, J=9.6 Hz, 1H),
7.60–7.52 (m, 3H), 7.16 ppm (d, J=9.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=149.5, 148.2, 143.8, 130.8, 129.0, 127.8, 126.8, 125.6,
122.0 ppm; HRMS: m/z calcd for C11H7ClN4Na [M+Na]+: 253.0251;
found: 253.0252.
Compound 1v: Yield: 56 mg, 70%; off-white solid; m.p. 143–
1
1458C; Rf =0.2 (EtOAc); H NMR (400 MHz, CDCl3): d=8.04 (d, J=
7.2 Hz, 1H), 7.74 (d, J=9.6 Hz, 1H), 7.25–7.21 (m, 1H), 7.06–6.97
(m, 1H), 6.86 (t, J=6.6 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 2.05 ppm
(d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=149.8, 145.0,
134.9, 126.7, 122.1, 116.8, 113.9, 113.7, 19.2 ppm; HRMS: m/z calcd
for C9H9N3Na [M+Na]+: 182.0689; found: 182.0698.
Compound 1ad: Yield: 110 mg, 91%; off-white solid; m.p. 169–
1
1718C (lit.[19] m.p. 169–1718C); Rf =0.4 (MeOH/CH2Cl2 2:98); H NMR
(400 MHz, CDCl3): d=7.82 (d, J=6.8 Hz, 1H), 7.63–7.60 (m, 3H),
7.53–7.49 (m, 2H), 7.44 (d, J=6.4 Hz, 1H), 2.53 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=151.5, 150.1, 146.3, 140.4, 131.8,
131.0, 127.9, 127.0, 106.5, 15.2 ppm; HRMS: m/z calcd for
C12H10N4SNa [M+Na]+: 265.0518; found: 265.0506.
Compound 1w: Yield: 96 mg, 91%; light yellow solid; m.p. 184–
1
1868C (lit.[27] m.p. 187–1888C); Rf =0.3 (EtOAc); H NMR (400 MHz,
CDCl3): d=8.05 (s, 1H), 7.83 (d, J=6.8 Hz, 2H), 7.74 (d, J=9.2 Hz,
1H), 7.61–7.53 (m, 3H), 7.15 (d, J=9.2 Hz, 1H), 2.34 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=150.0, 146.4, 130.6, 130.1, 129.3,
128.3, 126.9, 124.2, 119.6, 116.1, 18.3 ppm; HRMS: m/z calcd for
C13H11N3Na [M+Na]+: 232.0845; found: 232.0842.
Acknowledgements
Compound 1x: Yield: 113 mg, ꢀ95%; off-white solid; m.p. 157–
We thank the National Natural Science Foundation of China
(nos. 81302637 and 81330075) and the Outstanding Young
Talent Research Fund of Zhengzhou University (no.
1521316004) for financial support.
1
1598C (lit.[19] m.p. 152–1548C); Rf =0.5 (MeOH/CH2Cl2 2:98); H NMR
(400 MHz, CDCl3): d=8.22 (d, J=6.8 Hz, 1H), 7.82–7.80 (m, 2H),
7.62–7.55 (m, 3H), 7.35 (d, J=6.8 Hz, 1H), 6.84 ppm (t, J=7.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=148.6, 148.3, 130.6, 129.4,
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Published online on June 29, 2016
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim