I2/KI-Mediated Oxidative N-N Bond Formation for the Synthesis of 1,5-Fused 1,2,4-Triazoles from N -Aryl Amidines

Article abstract of DOI:10.1021/acs.joc.5b01183

An I₂/KI-mediated oxidative N-N bond formation reaction is described. This new and environmentally benign approach allows for the convenient synthesis of a variety of 1,2,4-triazolo[1,5-a]pyridines and other 1,5-fused 1,2,4-triazoles from readi

Full text of DOI:10.1021/acs.joc.5b01183

Article
pubs.acs.org/joc
I2/KI-Mediated Oxidative N−N Bond Formation for the Synthesis of
1,5-Fused 1,2,4-Triazoles from N‑Aryl Amidines
Lina Song,† Xianhai Tian,† Zhigang Lv,† Ertong Li,† Jie Wu,† Yangxue Liu,† Wenquan Yu,*,†
and Junbiao Chang*,†,‡
†College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
‡Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, P. R. China
S
* Supporting Information
ABSTRACT: An I2/KI-mediated oxidative N−N bond formation
reaction is described. This new and environmentally benign
approach allows for the convenient synthesis of a variety of 1,2,4-
triazolo[1,5-a]pyridines and other 1,5-fused 1,2,4-triazoles from
readily available N-aryl amidines in an efficient and scalable fashion.
for the synthesis of both 2-aryl and 2-alkyl substituted 1,2,4-
triazolo[1,5-a]pyridines, as well as their pyrazido- and
pyrimidotriazole derivatives, from N-aryl amidines.
1. INTRODUCTION
Owing to the numerous advantages associated with this eco-
friendly element, molecular iodine plays an important role in
organic synthesis.1 As a catalyst, iodine has been extensively
used in transformations, such as esterification, deprotection,
Michael addition, and aldol reaction. It can also mediate
iodocyclization, domino, and one-pot multicomponent reac-
tions. More importantly, a number of oxidation reactions can
be achieved by using iodine, for example, conversion of
alcohols/aldehydes to esters, nitriles, or amides,1b selective
oxidation of alcohols to aldehydes and ketones,2 and oxidative
aromatization.1e In particular, this environmentally benign
oxidizing reagent has been successfully employed to construct
C−C, C−N, C−O, and also C−S bonds.1h However, to the
best of our knowledge, there is no report of I2-mediated N−N
bond formation reactions. Encouraged by our previous work,3
in this paper, we envisioned the construction of N−N bonds by
employing molecular iodine to synthesize the biologically
important 1,2,4-triazole-fused heterocycles.4
Oxidative cyclization of N-(2-pyridyl) amidines is one of the
most straightforward strategies for the construction of the 1,2,4-
triazolo[1,5-a]pyridine framework, which previously has been
achieved by utilizing oxidants, such as NaClO/base,5 Pb-
(OAc)4,6 and MnO2.7 Nevertheless, these methods are
associated with some disadvantages, including low yields and
limited scopes. In 2009, Ueda and Nagasawa8 reported a
copper-catalyzed tandem addition−oxidative cyclization of 2-
amino pyridines and aryl nitriles to 2-aryl-1,2,4-triazolo[1,5-
a]pyridines. Alternatively, Zhao and co-workers9 developed a
recyclable Cu−Zn/Al−Ti catalyst for the same transformation.
In 2014, Du, Zhao, and co-workers10 reported a PIFA-mediated
cyclization of N-(pyridin-2-yl) amidines to 2-aryl/2-alkyl
triazolopyridines. Recently, Bartels, Fantasia, and co-workers11
described a Cu-catalyzed aerobic oxidation of guanidylpyridines
to the ones bearing 2-amino groups. Despite these elegant
achievements made, it is still of importance to develop novel
and general approaches to access this compound class. Herein,
we disclose a new and efficient I2/KI-mediated methodology
2. RESULTS AND DISCUSSION
The required substrates N-aryl amidines 2 were readily
prepared via the addition reaction of corresponding aryl amines
to substituted nitriles.8,10,11 Initial screening of a series of
laboratory commonly used solvents suggested that dimethyl
sulfoxide (DMSO) is the most suitable one for the I2-mediated
oxidative cyclization of substrates 2 to the fused [1,5-a]1,2,4-
triazoles 1 in the presence of base (e.g., K2CO3). As shown in
Table 1, full consumption of benzimidamide 2a required 2.2
equiv of iodine, affording the expected product 1a and its 6-
iodinated derivative 1a′ (confirmed by X-ray; see the
Supporting Information) in 52% and 47% yields, respectively
(entry 1). When a methyl group was incorporated to the 5-
position of the pyridine ring in the substrate, 1.5 equiv of iodine
was enough for the complete conversion of 2b to product 1b,
but still only in moderate yield with some unidentified
byproducts formed (entry 2). The reaction also worked with
weaker base (e.g., NaHCO3), which, however, slowed down the
reaction rate and decreased the yield (entry 3). During the
optimization of the reaction conditions, we were pleased to
observe that adding a catalytic amount of potassium iodide (KI)
to the reaction system is favorable for the formation of product
1b (entry 4). When a stoichiometric amount of KI was used,
the yield was significantly increased up to 92% (entry 5). On
this basis, lowering the temperature slowed down the reaction
rate with no improvement in the yield (entry 6). Then, we
started to investigate if KI would favor the formation of 1a from
substrate 2a. In the presence of 1 equiv of KI, complete
cyclization of 2a needed only 1.2 equiv of iodine. The desired
product 1a was produced in an improved yield (79%), with less
Received: May 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01183
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Table 1. Reaction Conditions Optimization for the
Oxidative Cyclization of N-Aryl Amidines 2
Scheme 1. Substrate Scope for the Synthesis of 2-Phenyl
Fused [1,5-a]1,2,4-Triazoles 1
a
a b
,
b
entry substrate I2/equiv KI/equiv temp/°C time/h product, yield
1
2a
2.2
100
1
1a, 52%
1a′, 47%
1b, 57%
1b, 43%
1b, 69%
1b, 92%
1b, 90%
1a, 79%
1a′, 20%
1a, ≥95%
1a′, trace
1a, ≥95%
1b, ≥95%
2
3
4
5
6
7
2b
2b
2b
2b
2b
2a
1.5
1.5
1.5
1.5
1.5
1.2
100
100
100
100
80
1
12
1
c
0.2
1
0.5
1
3.5
1
1
100
8
2a
1.2
5
100
2
9
2a
2b
1.2
1.2
1.5
1.5
100
100
1
1
10
a
a
Optimal reaction conditions: A well-stirred mixture of I2 (0.6 mmol)
and KI (0.75 mmol) in DMSO (5 mL) was treated with substrate 2
(0.5 mmol), followed by the addition of K2CO3 (1.5 mmol), and then
Optimal reaction conditions (entries 9−10): A well-stirred mixture of
I2 (0.6 mmol) and KI (0.75 mmol) in DMSO (5 mL) was treated with
substrate 2 (0.5 mmol), followed by the addition of K2CO3 (1.5
mmol), and then heated to 100 °C for 1 h. Isolated yields. The same
amount of NaHCO3 was used instead of K2CO3.
b
c
b
c
heated to 100 °C for 1 h. Isolated yields. Yield of gram-scale reaction
(6 mmol) in parentheses. The reaction time was 1.5 h.
d
In light of these encouraging results, we initiated further
studies by replacing the phenyl moiety in substrate 2b with a
variety of aromatic and aliphatic substituents (R2, Scheme 2).
When R2 is an aryl group, this methodology is compatible with
both electron-donating and electron-withdrawing groups at
para-, meta-, and ortho-positions of the benzene ring (1k−t).
Even the nitro-group-bearing substrate 2o was smoothly
transformed into the desired 1,2,4-triazolo[1,5-a]pyridine 1o
under the optimal reaction conditions. Ortho-substitution on
the 2-phenyl moiety did not affect either the reaction rate or
the yields of the products (1r−u). The 2,6-dichlorophenyl
substrate (2u) was completely cyclized to the expected product
1t within 1 h in excellent yield, of which the structure is further
confirmed by X-ray crystallography (see the Supporting
Information). Moreover, 2-pyridyl triazolopyridine (1v) was
obtained in decent yield from isonicotinimidamide 2v. This
protocol is also amenable to the amidines formed from aliphatic
nitriles (R2CN); however, the presence of α-hydrogens of the
R2 group may prevent the generation of the desired product, as
illustrated in the case of 2w to 1w. On the other hand,
compound 2x and 2y were successfully converted into the
target products 1x−y. Noticeably, the sensitive cyclopropane
ring in substrate 2x was untouched under the present
cyclization conditions.
byproduct 1a′ formed (20%, entry 7). Increasing the dosage of
potassium iodide to 5 equiv resulted in the formation of 1a in
excellent yield with only a trace amount of 1a′ observed (entry
8). Nevertheless, excessive KI has a negative impact on the
conversion rate (entry 8), as it is also a byproduct formed
during this oxidative cyclization process. In view of the above
results, we assume that I2 and KI may form a complex (e.g.,
KI3),2,12 which can mediate this oxidative cyclization process
more efficiently. On the basis of this hypothesis, we further
optimized the experimental protocol by adding the substrates
(2a or 2b) to a well-stirred mixture of I2 (1.2 equiv) and KI
(1.5 equiv) in DMSO. To our delight, both the reactions
finished within 1 h and afforded the desired product in excellent
yields (entries 9−10). It is noteworthy that this oxidative
cyclization reaction is insensitive to air and moisture. Taking
substrate 2b as an example, it was safely conducted on a gram
scale (Scheme 1).
Then, a range of N-aryl benzimidamides 2 were subjected to
the above optimal cyclization conditions to probe the reaction
scope and generality (Scheme 1). All the substrates with methyl
groups at the different positions of the pyridyl moiety (2b−e)
were efficiently converted to the corresponding 2-phenyl-1,2,4-
triazolo[1,5-a]pyridines (1b−e). The steric block effect of the
6-methyl group in 2e could be responsible for the slightly
decreased yield of the product (1e), and the completeness of
this transformation also required a relatively longer reaction
time. Substrates bearing electron-withdrawing groups on the
pyridine rings (2f−h) were also cyclized to the desired products
1f−h. Additionally, pyrazido- (1i) and pyrimidotriazoles (1j)
were prepared via the oxidative cyclization of N-pyrazyl (2i)
and N-pyrimidyl substituted benzimidamides (2j), respectively,
in good yields.
A plausible mechanism for the oxidative cyclization process
of N-aryl amidines 2 is proposed (Scheme 3). Taking the
formation of 1a as an example, the base-promoted oxidative
iodination of substrate 2a gives an iodide intermediate A (path
a). Then, the N−I bond in iodide A cleaves, and consequently,
an ammonium ion B is generated via an SN2′-type cyclization of
A with a new N−N bond formed. Finally, the subsequent
deprotonation and rearomatization afford the 1,2,4-triazolo[1,5-
a]pyridine framework 1a. To investigate the formation of the
B
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Scheme 2. Substrate Scope for the Synthesis of 2-Substituted
1,2,4-Triazolo[1,5-a]pyridines 1
3. CONCLUSIONS
a b
,
In summary, for the first time, an I2-mediated oxidative N−N
bond formation reaction has been developed for the synthesis
of 1,5-fused 1,2,4-triazoles. Addition of KI to the reaction
system successfully suppressed the iodination and other side
reactions. This facile and transition-metal-free synthetic process
works well with a wide range of N-aryl substituted amidines and
can be safely conducted on a gram scale. The features such as
generality, high efficiency, short reaction time, and air- and
moisture-insensitive reaction conditions make the present
method an attractive alternative for the preparation of 1,2,4-
triazolo[1,5-a]pyridines and other fused 1,2,4-triazole deriva-
tives.
4. EXPERIMENTAL SECTION
4.1. General Information. 1H and 13C NMR spectra were
recorded on a 400 MHz (100 MHz for 13C NMR) spectrometer.
Chemical shift values are given in ppm (parts per million) with
tetramethylsilane (TMS) as an internal standard. The peak patterns
are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet;
quint, quintet; sext, sextet; m, multiplet; dd, doublet of doublets; dt,
doublet of triplets. The coupling constants (J) are reported in hertz
(Hz). Melting points were determined on a micromelting point
apparatus without corrections. High-resolution mass spectra (HRMS-
ESI) were obtained on a Q-TOF mass spectrometer. For the
preparation of substrates 2, analytical grade reagents N,N-dimethyl-
formamide (DMF) and dimethyl sulfoxide (DMSO) were dried over
activated MS 4 Å prior to use; for the oxidative cyclization of 2 to 1,
analytical grade reagent DMSO was used without further treatment.
Flash column chromatography was performed over silica gel 200−300
mesh, and the eluent was a mixture of ethyl acetate (EA) and
petroleum ether (PE).
a
Optimal reaction conditions: A well-stirred mixture of I2 (0.6 mmol)
and KI (0.75 mmol) in DMSO (5 mL) was treated with substrate 2
(0.5 mmol), followed by the addition of K2CO3 (1.5 mmol), and then
4.2. Preparation of Substrates 2. 4.2.1. General Procedure A.8
A solution of substituted 2-aminopyridine (10 mmol) in DMF (5 mL)
was treated with NaH (60% dispersion in mineral oil, 0.6 g, 15 mmol)
at 0 °C and stirred at the same temperature for 30 min. The
corresponding nitrile (R2CN, 15 mmol) was then added to the
reaction mixture, which was stirred at room temperature until TLC
indicated the total consumption of the substituted 2-aminopyridine.
The reaction was quenched with 5% aqueous NaHCO3 (20 mL) and
extracted with EA (3 × 30 mL). The combined organic layers was
washed with brine (40 mL), dried over Na2SO4, concentrated, and
then purified through silica gel column chromatography using a
mixture of EA and PE as the eluent enriched with 1% of triethylamine
to afford substrates 2a−g, 2m−n, 2q, and 2s.
b
heated to 100 °C for 1 h. Isolated yields.
Scheme 3. Proposed Mechanism for the Formation of 1a and
1a′
4.2.2. General Procedure B.10 The nitrile (R2CN, 15 mmol) was
taken in a dry sealed tube, to which was added substituted 2-
aminopyridine (10 mmol) under a stream of nitrogen. The contents in
the sealed tube were stirred at 90 °C for 30 min. The above mixture
was treated with SnCl4 (1.76 mL, 15 mmol) and heated to 110 °C for
5 h. After cooling to room temperature, the resulting solid was crushed
into powder and dissolved in hot water. The aqueous suspension was
made alkaline (pH > 11) with 2 M aqueous NaOH and extracted with
CH2Cl2 (3 × 100 mL). The combined organic layer was dried over
anhydrous Na2SO4, concentrated, and then purified through silica gel
column chromatography using a mixture of EA and PE as the eluent
enriched with 1% of triethylamine to afford substrates 2h, 2k−l, 2o−p,
2r, and 2t−y.
iodinated byproduct 1a′, a control experiment was conducted
by further treating 1a with iodine in the presence of K2CO3 in
DMSO at 100 °C. It turned out that no reaction occurred at all
under the above reaction conditions. This result demonstrated
that the formation of 1a′ did not undergo 1a and the iodination
on the pyridine ring should take place before the cyclization
process (path b). When KI was added to the reaction system, it
will complex with I2 to form KI3,2,12 which can mediate the
oxidative cyclization of substrate 2a to the desired product 1a
(path a) more efficiently than free molecular iodine by
diminishing the iodination (path b) and other side reactions.
4.2.3. General Procedure C.11 Under a stream of nitrogen,
potassium tert-butoxide (2.47 g, 22 mmol) was added to a well-stirred
solution of 2-pyrazineamine (or 2-pyrimidineamine, 0.95 g, 10 mmol)
in anhydrous DMSO (5 mL). After the mixture was stirred at room
temperature for 15 min, benzonitrile (2.06 g, 20 mmol) was added
dropwise to the above mixture. The reaction mixture was stirred at
room temperature for another 30 min and then heated to 50 °C until
TLC indicated the total consumption of the aryl amine. After cooling
to room temperature, the reaction was quenched with cold water (20
mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organic
C
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layer was dried over anhydrous Na2SO4, concentrated, and then
purified through silica gel column chromatography using a mixture of
EA and PE as the eluent enriched with 1% of triethylamine to afford
substrates 2i−j.
N-(Pyridin-2-yl)benzimidamide (2a). Following General Procedure
A, 2a was obtained as a white solid: yield 1.44 g, 73%; mp 96−97 °C
(lit.8 mp 96−97 °C); Rf = 0.24 (EA/PE 20:80); 1H NMR (400 MHz,
CD3OD) δ 8.34 (dd, J = 5.2, 1.6 Hz, 1H), 7.87−7.85 (m, 2H), 7.73−
7.69 (m, 1H), 7.52−7.45 (m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 7.01−6.98
(m, 1H); 13C NMR (400 MHz, CD3OD) δ 162.3, 161.4, 146.0, 137.6,
136.9, 130.4, 128.1, 127.2, 120.2, 117.8; HRMS (m/z) [M + H]+ calcd
for C12H12N3 198.1026, found 198.1030.
(br, s, 1H), 8.62 (d, J = 1.2 Hz, 1H), 8.22 (dd, J = 2.8, 1.6 Hz, 1H),
8.14 (d, J = 2.8 Hz, 1H), 7.96−7.93 (m, 2H), 7.51−7.45 (m, 3H), 6.22
(br, s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 158.7, 145.8, 139.7,
137.1, 136.6, 131.1, 128.7, 127.0; HRMS (m/z) [M + H]+ calcd for
C11H11N4 199.0978, found 199.0979.
N-(Pyrimidin-2-yl)benzimidamide (2j). Following General Proce-
dure C, 2j was obtained as a white solid: yield 1.33 g, 67%; mp 148−
149 °C (lit.14 mp 149 °C); Rf = 0.27 (EA/PE 99:1); H NMR (400
1
MHz, CDCl3) δ 8.63 (d, J = 4.8 Hz, 2H), 8.04−8.02 (m, 2H), 7.49−
7.41 (m, 3H), 6.89 (t, J = 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 157.4, 136.3, 131.1, 128.5, 127.3, 114.6; HRMS (m/z) [M + H]+
calcd for C11H11N4 199.0978, found 199.0989.
N-(5-Methylpyridin-2-yl)benzimidamide (2b). Following General
4-Methoxy-N-(5-methylpyridin-2-yl)benzimidamide (2k). Follow-
Procedure A, 2b was obtained as a white solid: yield 1.88 g, 89%; mp
ing General Procedure B, 2k was obtained as a white solid: yield 2.08
86−87 °C (lit.13 mp 89−90 °C); Rf = 0.24 (EA/PE 20:80); H NMR
g, 86%; mp 118−119 °C; Rf = 0.32 (EA/PE 99:1); H NMR (400
1
1
(400 MHz, CDCl3) δ 8.16−8.15 (m, 1H), 7.91−7.89 (m, 2H), 7.48−
7.43 (m, 4H), 7.20 (d, J = 8.0 Hz, 1H), 2.29 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.7, 158.4, 145.8, 138.4, 137.6, 130.4, 128.5, 127.0,
126.9, 121.9, 18.0; HRMS (m/z) [M + H]+ calcd for C13H14N3
212.1182, found 212.1188.
MHz, CDCl3) δ 8.14 (d, J = 2.4 Hz, 1H), 7.88−7.86 (m, 2H), 7.46
(dd, J = 8.4, 2.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.95−6.93 (m, 2H),
3.84 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7,
156.1, 153.2, 141.0, 133.6, 125.1, 123.7, 122.0, 117.0, 109.0, 50.6, 13.2;
HRMS (m/z) [M + H]+ calcd for C14H16N3O 242.1287, found
242.1296.
N-(4-Methylpyridin-2-yl)benzimidamide (2c). Following General
Procedure A, 2c was obtained as a white solid: yield 1.54 g, 73%; mp
4-Fluoro-N-(5-methylpyridin-2-yl)benzimidamide (2l). Following
124−125 °C (lit.13 mp 125−126 °C); Rf = 0.23 (EA/PE 20:80); H
1
General Procedure B, 2l was obtained as a white solid: yield 1.67 g,
1
NMR (400 MHz, CDCl3) δ 8.19 (d, J = 5.2 Hz, 1H), 7.91 (dd, J = 7.2,
1.6 Hz, 2H), 7.45−7.44 (m, 3H), 7.12 (s, 1H), 6.77 (dd, J = 5.2, 1.2
Hz, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9, 159.0,
148.5, 145.6, 137.5, 130.4, 128.5, 126.9, 122.8, 119.2, 21.0; HRMS (m/
z) [M + H]+ calcd for C13H14N3 212.1182, found 212.1185.
73%; mp 149−151 °C; Rf = 0.25 (EA/PE 20:80); H NMR (400
MHz, CDCl3) δ 8.15 (d, J = 2.4 Hz, 1H), 7.92−7.83 (m, 2H), 7.47
(dd, J = 8.4, 2.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.13−7.09 (m, 2H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2 (d, JC−F = 248.8
Hz), 160.6, 157.3, 145.8, 138.5, 133.7, 129.0 (d, JC−F = 8.6 Hz), 127.2,
121.9, 115.4 (d, JC−F = 21.6 Hz), 18.0; HRMS (m/z) [M + H]+ calcd
for C13H13FN3 230.1088, found 230.1093.
N-(3-Methylpyridin-2-yl)benzimidamide (2d). Following General
Procedure A, 2d was obtained as a white solid: yield 1.54 g, 73%; mp
68−69 °C (lit.13 mp 68−69 °C); Rf = 0.44 (EA/PE 20:80); H NMR
1
4-Chloro-N-(5-methylpyridin-2-yl)benzimidamide (2m). Follow-
(400 MHz, CDCl3) δ 8.18 (dd, J = 4.8, 1.6 Hz, 1H), 8.00−7.97 (m,
2H), 7.50−7.44 (m, 4H), 6.84 (dd, J = 7.2, 4.8 Hz, 1H), 2.48 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.1, 157.2, 143.5, 138.0, 137.5,
130.5, 130.4, 128.5, 127.0, 117.8, 18.5; HRMS (m/z) [M + H]+ calcd
for C13H14N3 212.1182, found 212.1187.
ing General Procedure A, 2m was obtained as a white solid: yield 1.87
1
g, 76%; mp 167−168 °C; Rf = 0.28 (EA/PE 20:80); H NMR (400
MHz, CDCl3) δ 8.16−8.15 (m, 1H), 7.86−7.83 (m, 2H), 7.49−7.46
(m, 1H), 7.42−7.38 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 2.30 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.5, 157.1, 145.8, 138.5, 136.4,
136.0, 128.7, 128.3, 127.3, 122.0, 18.0; HRMS (m/z) [M + H]+ calcd
for C13H13ClN3 246.0793, found 246.0795.
N-(6-Methylpyridin-2-yl)benzimidamide (2e). Following General
Procedure A, 2e was obtained as a light yellow solid: yield 1.50 g, 71%;
mp 63−65 °C; Rf = 0.26 (EA/PE 20:80); 1H NMR (400 MHz,
CDCl3) δ 7.91−7.89 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.46−7.44 (m,
3H), 7.09 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 2.51 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 162.4, 158.9, 154.7, 137.8, 137.6,
130.4, 128.6, 126.9, 119.3, 117.2, 24.5; HRMS (m/z) [M + H]+ calcd
for C13H14N3 212.1182, found 212.1187.
4-Bromo-N-(5-methylpyridin-2-yl)benzimidamide (2n). Following
General Procedure A, 2n was obtained as a white solid: yield 2.21 g,
1
76%; mp 172−174 °C; Rf = 0.20 (EA/PE 20:80); H NMR (400
MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1H), 7.79−7.77 (m, 2H), 7.58−
7.55 (m, 2H), 7.48 (dd, J = 8.0, 2.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H),
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 157.2, 145.8,
138.5, 136.4, 131.7, 128.5, 127.3, 124.8, 122.0, 18.0; HRMS (m/z) [M
+ H]+ calcd for C13H13BrN3 290.0287, found 290.0295.
N-(5-Chloropyridin-2-yl)benzimidamide (2f). Following General
Procedure A, 2f was obtained as a white solid: yield 1.11 g, 48%; mp
155−156 °C (lit.10 mp 157−158 °C); Rf = 0.39 (EA/PE 20:80); H
1
N-(5-Methylpyridin-2-yl)-4-nitrobenzimidamide (2o). Following
General Procedure B, 2o was obtained as a yellow solid: yield 2.00
NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.4 Hz, 1H), 7.91−7.89 (m,
2H), 7.59 (dd, J = 8.8, 2.8 Hz, 1H), 7.49−7.43 (m, 3H), 7.22 (d, J =
8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.2, 159.1, 144.4,
137.3, 137.1, 130.8, 128.6, 126.9, 125.1, 123.5; HRMS (m/z) [M +
H]+ calcd for C12H11ClN3 232.0636, found 232.0647.
1
g, 78%; mp 147−148 °C; Rf = 0.31 (EA/PE 25:75); H NMR (400
MHz, CDCl3) δ 8.29−8.26 (m, 2H), 8.19−8.18 (m, 1H), 8.09−8.07
(m, 2H), 7.53−7.50 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 2.32 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.1, 155.9, 148.9, 145.9, 143.4,
138.7, 128.1, 128.0, 123.7, 122.3, 18.1; HRMS (m/z) [M + H]+ calcd
for C13H13N4O2 257.1033, found 257.1039.
N-(5-Bromopyridin-2-yl)benzimidamide (2g). Following General
Procedure A, 2g was obtained as a white solid: yield 1.44 g, 52%; mp
158−159 °C; Rf = 0.39 (EA/PE 20:80); 1H NMR (400 MHz, CDCl3)
δ 8.37 (d, J = 2.8 Hz, 1H), 7.91−7.89 (m, 2H), 7.72 (dd, J = 8.4, 2.4
Hz, 1H), 7.48−7.43 (m, 3H), 7.16 (d, J = 8.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 161.5, 159.2, 146.7, 140.0, 137.1, 130.8, 128.6, 126.9,
124.1, 113.2; HRMS (m/z) [M + H]+ calcd for C12H11BrN3 276.1031,
found 276.1034.
3-Methyl-N-(5-methylpyridin-2-yl)benzimidamide (2p). Following
General Procedure B, 2p was obtained as a white solid: yield 2.12 g,
1
94%; mp 54−55 °C; Rf = 0.28 (EA/PE 25:75); H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.6 Hz,
1H), 7.47 (dd, J = 8.4, 2.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.27 (d, J
= 7.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 2.41 (s, 3H), 2.30 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.8, 158.6, 145.7, 138.4, 138.3, 137.5,
131.2, 128.4, 127.7, 127.0, 123.7, 121.9, 21.5, 18.0; HRMS (m/z) [M +
H]+ calcd for C14H16N3 226.1339, found 226.1339.
N-(3,5-Dibromopyridin-2-yl)benzimidamide (2h). Following Gen-
eral Procedure B, 2h was obtained as a white solid: yield 2.92 g, 82%;
mp 125−126 °C (lit.10 mp 128−129 °C); Rf = 0.32 (EA/PE 89:11);
1H NMR (400 MHz, CDCl3) δ 8.30 (m, 1H), 8.06−8.02 (m, 3H),
7.53−7.45 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 157.9,
145.6, 142.9, 136.4, 131.3, 128.7, 127.3, 119.1, 111.9; HRMS (m/z)
[M + H]+ calcd for C12H10Br2N3 355.9216, found 355.9228.
N-(Pyrazin-2-yl)benzimidamide (2i). Following General Procedure
C, 2i was obtained as a white solid: yield 1.40 g, 71%; mp 160−161
3-Chloro-N-(5-methylpyridin-2-yl)benzimidamide (2q). Following
General Procedure A, 2q was obtained as a white solid: yield 2.21 g,
1
90%; mp 129−130 °C; Rf = 0.29 (EA/PE 20:80); H NMR (400
MHz, CDCl3) δ 8.16 (d, J = 2.4 Hz, 1H), 7.93 (t, J = 1.6 Hz, 1H), 7.75
(dt, J = 7.6, 1.2 Hz, 1H), 7.48 (dd, J = 8.4, 2.4 Hz, 1H), 7.44−7.41 (m,
1H), 7.36 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 2.30 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.4, 156.9, 145.8, 139.4, 138.5,
1
°C; Rf = 0.25 (EA/PE 25:75); H NMR (400 MHz, CDCl3) δ 10.28
D
DOI: 10.1021/acs.joc.5b01183
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The Journal of Organic Chemistry
Article
134.6, 130.4, 129.8, 127.4, 127.3, 124.8, 122.1, 18.0; HRMS (m/z) [M
+ H]+ calcd for C13H13ClN3 246.0793, found 246.0806.
126.8, 120.6, 113.4, 37.9, 28.5, 17.9; HRMS (m/z) [M + H]+ calcd for
C11H18N3 192.1495, found 192.1502.
2-Methyl-N-(5-methylpyridin-2-yl)benzimidamide (2r). Following
General Procedure B, 2r was obtained as a white solid: yield 0.93 g,
41%; mp 121−122 °C; Rf = 0.27 (EA/PE 99:1); 1H NMR (400 MHz,
CDCl3) δ 10.47 (br, s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.48−7.44 (m,
2H), 7.31−7.21 (m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 5.51 (br, s, 1H),
2.51 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.9,
160.6, 145.8, 138.7, 138.6, 135.6, 130.9, 129.2, 127.8, 127.3, 126.0,
121.8, 19.8, 18.1; HRMS (m/z) [M + H]+ calcd for C14H16N3
226.1339, found 226.1348.
4.3. Synthesis of Products 1. 4.3.1. Synthesis of 2-Phenyl-
[1,2,4]triazolo[1,5-a]pyridine (1a) and 7-Iodo-2-phenyl-[1,2,4]
triazolo[1,5-a]pyridine (1a′). A stirred solution of N-(pyridin-2-
yl)benzimidamide (2a, 99 mg, 0.5 mmol) in DMSO (5.0 mL) was
treated with iodine (279 mg, 1.1 mmol) and K2CO3 (311 mg, 2.25
mmol). The reaction mixture was heated to 100 °C for 1 h (TLC
indicated that the conversion was complete). After cooling to room
temperature, it was quenched with 5% Na2S2O3 (0.5 mL), followed by
the addition of brine (15 mL), and then extracted with EA (3 × 15
mL). The combined organic layer was dried over anhydrous Na2SO4,
concentrated, and purified through column chromatography using a
mixture of EA and PE as the eluent to afford products 1a (51 mg, 52%,
white solid) and 1a′ (76 mg, 47%, white solid).
2-Chloro-N-(5-methylpyridin-2-yl)benzimidamide (2s). Following
General Procedure A, 2s was obtained as a white solid: yield 1.57 g,
1
64%; mp 132−133 °C; Rf = 0.20 (EA/PE 20:80); H NMR (400
MHz, CDCl3) δ 8.16 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 5.6, 3.6 Hz,
1H), 7.47 (dd, J = 8.4, 2.4 Hz, 1H), 7.42−7.40 (m, 1H), 7.35−7.30
(m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.6, 157.8, 145.7, 138.5, 137.3, 131.3, 130.44, 130.36,
130.1, 127.4, 127.1, 121.8, 18.0; HRMS (m/z) [M + H]+ calcd for
C13H13ClN3 246.0793, found 246.0793.
7-Iodo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1a′). White solid,
1
mp 176−178 °C; Rf = 0.25 (EA/PE 10:90); H NMR (400 MHz,
CDCl3) δ 8.86 (m, 1H), 8.27−8.25 (m, 2H), 7.69 (dd, J = 9.2, 1.6 Hz,
1H), 7.55 (dd, J = 9.6, 0.8 Hz,1H), 7.51−7.48 (m, 3H); 13C NMR
(400 MHz, CDCl3) δ 164.3, 150.6, 137.7, 133.4, 130.3, 130.2, 128.7,
127.3, 117.2, 75.5; HRMS (m/z) [M + H]+ calcd for C12H9N3I
321.9836, found 321.9832.
N-(5-Methylpyridin-2-yl)-2-(trifluoromethyl)benzimidamide (2t).
Following General Procedure B, 2t was obtained as a white solid:
1
yield 1.37 g, 49%; mp 162−163 °C; Rf = 0.28 (EA/PE 25:75); H
4.3.2. Synthesis of 1,2,4-Triazolo[1,5-a]pyridines 1 (General
Procedure D). A mixture of KI (125 mg, 0.75 mmol) and iodine
(152 mg, 0.6 mmol) in DMSO (5 mL) was stirred at room
temperature for 10 min and then treated with N-substituted amidine 2
(0.5 mmol), followed by the addition of K2CO3 (208 mg, 1.5 mmol).
The reaction mixture was heated to 100 °C until TLC indicated the
total consumption of the substrate 2 (1−1.5 h). After cooling to room
temperature, the reaction was quenched with 5% Na2S2O3 (0.5 mL),
followed by the addition of brine (15 mL), and then extracted with EA
(3 × 15 mL). The combined organic layers were dried over anhydrous
Na2SO4, concentrated, and then purified through silica gel column
chromatography using a mixture of EA and PE as the eluent to afford
the desired product 1.
2-Phenyl-[1,2,4]triazolo[1,5-a]pyridine (1a). Following General
Procedure D, 1a was obtained as a white solid: yield 97 mg, ≥95%;
mp 134−136 °C (lit.8 mp 134−135 °C); Rf = 0.25 (EA/PE 17:83); 1H
NMR (400 MHz, CDCl3) δ 8.59 (dt, J = 6.8, 1.2 Hz, 1H), 8.31−8.28
(m, 2H), 7.75 (dt, J = 8.8, 0.8 Hz, 1H), 7.52−7.46 (m, 4H), 6.99 (dt, J
= 1.2, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.1, 151.7,
130.7, 130.1, 129.5, 128.7, 128.3, 127.3, 116.4, 113.6; HRMS (m/z)
[M + H]+ calcd for C12H10N3 196.0869, found 196.0873.
NMR (400 MHz, CDCl3) δ 10.55 (br, s, 1H), 8.17 (d, J = 1.6 Hz,
1H), 7.72 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6
Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.47 (dd, J = 8.0, 2.4 Hz, 1H), 7.13
(d, J = 8.4 Hz, 1H), 5.59 (br, s, 1H), 2.31 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.5, 158.2, 145.8, 138.5, 137.3, 132.1, 130.0, 129.2,
127.7 (q, JC−F = 31.3 Hz), 127.6, 126.4 (q, JC−F = 5.0 Hz), 123.9 (q,
JC−F = 272.4 Hz), 121.8, 18.0; HRMS (m/z) [M + H]+ calcd for
C14H13F3N3 280.1056, found 280.1064.
2,6-Dichloro-N-(5-methylpyridin-2-yl)benzimidamide (2u). Fol-
lowing General Procedure B, 2u was obtained as a white solid: yield
1
2.13 g, 76%; mp 179−181 °C; Rf = 0.20 (EA/PE 20:80); H NMR
(400 MHz, CDCl3) δ 8.18 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.4, 2.4
Hz, 1H), 7.36−7.34 (m, 2H), 7.26−7.22 (m, 1H), 7.16 (d, J = 8.4 Hz,
1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 155.1,
145.9, 138.5, 136.5, 133.6, 130.2, 128.2, 127.8, 121.8, 18.0; HRMS (m/
z) [M + H]+ calcd for C13H12Cl2N3 280.0403, found 280.0403.
N-(5-Methylpyridin-2-yl)isonicotinimidamide (2v). Following
General Procedure B, 2v was obtained as a white solid: yield 1.82 g,
86%; mp 144−145 °C; Rf = 0.30 (EA/PE 99:1); 1H NMR (400 MHz,
DMSO-d6) δ 8.72 (d, J = 6.0 Hz, 2H), 8.22 (s, 1H), 7.97 (d, J = 5.6
Hz, 2H), 7.58 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 2.27
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 160.7, 155.6, 150.4, 146.4,
144.2, 139.0, 127.4, 122.0, 121.7, 17.9; HRMS (m/z) [M + H]+ calcd
for C12H13N4 213.1135, found 213.1134.
6-Methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1b). Following
General Procedure D, 1b was obtained as a white solid: 0.5 mmol
scale, yield 103 mg, ≥95%; 6 mmol scale, yield 1.138 g, 91%. mp 118−
119 °C (lit.15 mp 120.5−121.0 °C); Rf = 0.28 (EA/PE 17:83); H
1
N-(5-Methylpyridin-2-yl)-2-phenylacetimidamide (2w). Following
General Procedure B, 2w was obtained as a white solid: yield 1.92 g,
85%; mp 109−110 °C; Rf = 0.28 (EA/CH3OH 83:17); 1H NMR (400
MHz, CDCl3) δ 8.07 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.4, 2.4 Hz,
1H), 7.36−7.34 (m, 4H), 7.32−7.27 (m, 1H), 7.07 (d, J = 8.0 Hz,
1H), 3.75 (s, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
161.4, 160.6, 145.7, 138.5, 136.2, 129.5, 128.9, 127.2, 126.8, 120.9,
44.9, 17.9; HRMS (m/z) [M + H]+ calcd for C14H16N3 226.1339,
found 226.1353.
N-(5-Methylpyridin-2-yl)-1-phenylcyclopropanecarboximidamide
(2x). Following General Procedure B, 2x was obtained as a colorless
oil: yield 2.18 g, 87%; Rf = 0.23 (EA/PE 34:66); 1H NMR (400 MHz,
CDCl3) δ 8.02 (m, 1H), 7.47−7.45 (m, 2H), 7.39−7.33 (m, 3H),
7.30−7.25 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 2.23 (s, 3H), 1.77−1.75
(m, 2H), 1.15−1.12 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 164.3,
160.9, 145.7, 140.9, 138.3, 130.7, 128.8, 127.5, 126.1, 120.9, 30.8, 17.9,
16.0; HRMS (m/z) [M + H]+ calcd for C16H18N3 252.1495, found
252.1496.
NMR(400 MHz, CDCl3) δ 8.38 (s, 1H), 8.28−8.26 (m, 2H), 7.64 (d,
J = 9.2 Hz, 1H), 7.51−7.45 (m, 3H), 7.33 (dd, J = 9.2, 1.6 Hz, 1H),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 150.3, 132.3,
130.9, 129.9, 128.6, 127.1, 126.3, 123.7, 115.5, 18.1; HRMS (m/z) [M
+ H]+ calcd for C13H12N3 210.1026, found 210.1034.
7-Methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1c). Following
General Procedure D, 1c was obtained as a white solid: yield 98
mg, 94%; mp 141−142 °C (lit.16 mp 140−142 °C); Rf = 0.28 (EA/PE
1
17:83); H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 7.2 Hz, 1H),
8.28−8.26 (m, 2H), 7.51−7.45 (m, 4H), 6.80 (dd, J = 7.2, 2.0 Hz,
1H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2, 151.9,
141.0, 130.9, 129.9, 128.6, 127.2, 116.0, 115.0, 21.6; HRMS (m/z) [M
+ H]+ calcd for C13H12N3 210.1026, found 210.1029.
8-Methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1d). Following
General Procedure D, 1d was obtained as a white solid: yield 100 mg,
≥95%; mp 96−97 °C (lit.10 mp 100−101 °C); Rf = 0.44 (EA/PE
1
17:83); H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 6.8 Hz, 1H),
8.31−8.29 (m, 2H), 7.51−7.45 (m, 3H), 7.26−7.22 (m, 1H), 6.87(t, J
= 6.8 Hz, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.7,
152.2, 131.0, 129.9, 128.6, 128.1, 127.3, 127.0, 125.9, 113.4, 17.0;
HRMS (m/z) [M + H]+ calcd for C13H12N3 210.1026, found
210.1033.
N-(5-Methylpyridin-2-yl)pivalimidamide (2y). Following General
Procedure B, 2y was obtained as a colorless oil: yield 0.27 g, 14%; Rf =
1
0.30 (EA/PE 50:50); H NMR (400 MHz, CDCl3) δ 8.08 (m, 1H),
7.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 2.26 (s, 3H),
1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.1, 145.7, 138.5,
E
DOI: 10.1021/acs.joc.5b01183
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The Journal of Organic Chemistry
Article
5-Methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1e). Following
General Procedure D, 1e was obtained as a white solid: yield 96 mg,
92%; mp 84−85 °C (lit.17 mp 83−85 °C); Rf = 0.33 (EA/PE 17:83);
1H NMR (400 MHz, CDCl3) δ 8.34−8.32 (m, 2H), 7.63 (d, J = 8.4
Hz, 1H), 7.52−7.40 (m, 4H), 6.81 (dt, J = 7.2, 0.8 Hz, 1H), 2.84 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.5, 151.8, 138.9, 131.2,
129.9, 129.3, 128.6, 127.3, 113.5, 112.8, 17.6; HRMS (m/z) [M + H]+
calcd for C13H12N3 210.1026, found 210.1025.
J = 9.2 Hz, 1H), 7.46−7.44 (m, 2H), 7.35 (dd, J = 9.2, 1.6 Hz, 1H),
2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8, 150.3, 135.9,
132.5, 129.5, 128.9, 128.4, 126.3, 123.9, 115.5, 18.1; HRMS (m/z) [M
+ H]+ calcd for C13H11ClN3 244.0636, found 244.0644.
2-(4-Bromophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (1n).
Following General Procedure D, 1n was obtained as a white solid:
1
yield 143 mg, ≥95%; mp 179−181 °C; Rf = 0.25 (EA/PE 17:83); H
NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.14−8.11 (m, 2H), 7.64−
7.59 (m, 3H), 7.35 (dd, J = 9.2, 1.6 Hz, 1H), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 162.9, 150.3, 132.5, 131.8, 130.0, 128.7, 126.3,
124.2, 123.9, 115.6, 18.1; HRMS (m/z) [M + H]+ calcd for
C13H11BrN3 288.0131, found 288.0128.
6-Chloro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1f). Following
General Procedure D, 1f was obtained as a white solid: yield 114
mg, ≥95%; mp 165−167 °C (lit.10 mp 168−169 °C); Rf = 0.47 (EA/
1
PE 17:83); H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.27−8.25
(m, 2H), 7.69 (d, J = 9.6 Hz, 1H) 7.52−7.46 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 164.9, 150.3, 130.9, 130.34, 130.31, 128.7, 127.3,
126.6, 121.5, 116.4; HRMS (m/z) [M + H]+ calcd for C12H9ClN3
230.0479, found 230.0481.
6-Methyl-2-(4-nitrophenyl)-[1,2,4]triazolo[1,5-a]pyridine (1o).
Following General Procedure D, 1o was obtained as a light yellow
solid: yield 126 mg, ≥95%; mp decomposed at 277−280 °C; Rf = 0.25
1
(EA/PE 17:83); H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H),
8.45−8.37 (m, 4H), 7.84 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 9.2, 1.6 Hz,
1H), 2.41 (s, 3H); 13C NMR (100 MHz, CF3COOD) δ 153.3, 150.3,
141.8, 141.4, 132.5, 128.8, 128.7, 128.4, 124.5, 110.8, 16.2; HRMS (m/
z) [M + H]+ calcd for C13H11N4O2 255.0876, found 255.0875.
6-Methyl-2-(m-tolyl)-[1,2,4]triazolo[1,5-a]pyridine (1p). Following
General Procedure D, 1p was obtained as a white solid: yield 111 mg,
6-Bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1g). Following
General Procedure D, 1g was obtained as a white solid: yield 136 mg,
≥95%; mp 165−167 °C (lit.10 mp 165−166 °C); Rf = 0.32 (EA/PE
1
11:89); H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 1.6 Hz, 1H),
8.27−8.25 (m, 2H), 7.66−7.63 (m, 1H), 7.58−7.55 (m, 1H), 7.52−
7.47 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 164.7, 150.4, 133.1,
130.34, 130.29, 128.8, 128.7, 127.3, 116.8, 107.7; HRMS (m/z) [M +
H]+ calcd for C12H9BrN3 275.9955, found 275.9955.
1
≥95%; mp 129−131 °C; Rf = 0.27 (EA/PE 17:83); H NMR (400
MHz, CDCl3) δ 8.38−8.37 (m, 1H), 8.10 (s, 1H), 8.07 (d, J = 7.6 Hz,
1H), 7.64 (d, J = 9.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.33 (dd, J =
9.2, 1.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 2.45 (s, 3H), 2.40 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.9, 150.3, 138.4, 132.4, 130.8,
130.7, 128.6, 127.8, 126.3, 124.3, 123.7, 115.5, 21.4, 18.1; HRMS (m/
z) [M + H]+ calcd for C14H14N3 224.1182, found 224.1182.
2-(3-Chlorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (1q).
Following General Procedure D, 1q was obtained as a white solid:
yield 121 mg, ≥95%; mp 153 °C; Rf = 0.31 (EA/PE 17:83); 1H NMR
(400 MHz, CDCl3) δ 8.37 (s, 1H), 8.28−8.27 (m, 1H), 8.17−8.12 (m,
1H), 7.64 (d, J = 8.8 Hz, 1H), 7.42−7.41 (m, 2H), 7.36 (dd, J = 9.2,
1.6 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5,
150.3, 134.7, 132.8, 132.6, 129.9, 129.8, 127.3, 126.3, 125.2, 124.1,
115.6, 18.1; HRMS (m/z) [M + H]+ calcd for C13H11ClN3 244.0636,
found 244.0639.
6,8-Dibromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1h).10 Fol-
lowing General Procedure D, 1h was obtained as a white solid: yield
1
176 mg, ≥95%; mp 149−151 °C; Rf = 0.32 (EA/PE 5:95); H NMR
(400 MHz, CDCl3) δ 8.70 (d, J = 1.6 Hz, 1H), 8.30−8.28 (m, 2H),
7.84 (d, J = 1.6 Hz, 1H), 7.50−7.48 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.8, 149.7, 135.0, 130.6, 129.8, 128.7, 127.9, 127.6, 110.1,
106.9; HRMS (m/z) [M + H]+ calcd for C12H8Br2N3 353.9059, found
353.9056.
2-Phenyl-[1,2,4]triazolo[1,5-a]pyrazine (1i). Following General
Procedure D, 1i was obtained as a white solid: yield 98 mg, ≥95%;
1
mp 179−180 °C; Rf = 0.33 (EA/PE 25:75); H NMR (400 MHz,
CDCl3) δ 9.30 (d, J = 1.2 Hz, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H),
8.32−8.30 (m, 2H), 8.18 (d, J = 4.4 Hz, 1H), 7.54−7.51 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 165.1, 147.3, 142.7, 131.6, 130.8, 129.8,
128.9, 127.6, 121.5; HRMS (m/z) [M + H]+ calcd for C11H9N4
197.0822, found 197.0822.
6-Methyl-2-(o-tolyl)-[1,2,4]triazolo[1,5-a]pyridine (1r). Following
General Procedure D, 1r was obtained as a white solid: yield 105 mg,
1
2-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (1j). Following General
94%; mp 95−96 °C; Rf = 0.35 (EA/PE 17:83); H NMR (400 MHz,
Procedure D, 1j was obtained as a white solid: yield 92 mg, 94%; mp
CDCl3) δ 8.41 (m, 1H), 8.06−8.03 (m, 1H), 7.66 (d, J = 9.2 Hz, 1H),
7.36−7.30 (m, 4H), 2.70 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.0, 144.8, 132.9, 127.4, 126.4, 125.6, 125.4, 124.5, 121.5,
121.0, 118.7, 110.8, 17.0, 13.3; HRMS (m/z) [M + H]+ calcd for
C14H14N3 224.1182, found 224.1194.
184−185 °C (lit.14 mp 184 °C); Rf = 0.33 (EA/PE 50:50); H NMR
1
(400 MHz, CDCl3) δ 8.86 (dd, J = 6.4, 2.0 Hz, 1H), 8.80 (dd, J = 4.4,
2.0 Hz, 1H), 8.36−8.34 (m, 2H), 7.53−7.50 (m, 3H), 7.09 (dd, J =
6.8, 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.3, 156.1, 154.4,
135.5, 130.8, 130.2, 128.8, 127.5, 110.0; HRMS (m/z) [M + Na]+
calcd for C11H8N4Na 219.0641, found 219.0656.
2-(2-Chlorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (1s).
Following General Procedure D, 1s was obtained as a white solid:
1
2-(4-Methoxyphenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine
(1k). Following General Procedure D, 1k was obtained as a white
solid: yield 104 mg, 87%; mp 166−167 °C; Rf = 0.26 (EA/PE 25:75);
1H NMR (400 MHz, CDCl3) δ 8.36−8.35 (m, 1H), 8.22−8.18 (m,
yield 121 mg, ≥95%; mp 109−110 °C; Rf = 0.22 (EA/PE 17:83); H
NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.00−7.98 (m, 1H), 7.70 (d,
J = 9.2 Hz, 1H), 7.55−7.52 (m, 1H), 7.39−7.37 (m, 3H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 162.5, 149.6, 133.1, 132.5, 132.0,
2H), 7.61 (d, J = 9.2 Hz, 1H), 7.32 (dd, J = 8.8, 1.6 Hz, 1H), 7.03−
6.99 (m, 2H), 3.87 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.7, 161.0, 150.3, 132.3, 128.6, 126.2, 123.5, 123.4, 115.3,
114.0, 55.3, 18.1; HRMS (m/z) [M + H]+ calcd for C14H14N3O
240.1131, found 240.1142.
130.7, 130.5, 130.2, 126.7, 126.4, 124.0, 115.8, 18.1; HRMS (m/z) [M
+ H]+ calcd for C13H11ClN3 244.0636, found 244.0647.
6-Methyl-2-(2-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]-
pyridine (1t). Following General Procedure D, 1t was obtained as a
white solid: yield 138 mg, ≥95%; mp 80 °C; Rf = 0.31 (EA/PE 17:83);
1H NMR (400 MHz, CDCl3) δ 8.44−8.43 (m, 1H), 7.88 (d, J = 7.6
Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.65 (t, J =
7.6 Hz 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.40 (dd, J = 9.2, 2.0 Hz, 1H),
2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 149.7, 132.6,
132.3, 131.5, 130.5 (q, JC−F = 2.0 Hz), 129.4, 129.2 (q, JC−F = 31.4
Hz), 126.6 (q, JC−F = 5.4 Hz), 126.4, 124.1, 123.8 (q, JC−F = 272.1
Hz), 115.9, 18.1; HRMS (m/z) [M + H]+ calcd for C14H11F3N3
278.0899, found 278.0909.
2-(2,6-Dichlorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine
(1u). Following General Procedure D, 1u was obtained as a white
solid: yield 138 mg, ≥95%; mp 171 °C; Rf = 0.28 (EA/PE 17:83); 1H
NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H),
7.44−7.41 (m, 3H), 7.36−7.32 (m, 1H), 2.45 (s, 3H); 13C NMR (100
2-(4-Fluorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (1l).
Following General Procedure D, 1l was obtained as a white solid:
1
yield 113 mg, ≥95%; mp 163−164 °C; Rf = 0.22 (EA/PE 17:83); H
NMR (400 MHz, CDCl3) δ 8.36 (m, 1H), 8.27−8.22 (m, 2H), 7.62
(d, J = 8.8 Hz, 1H), 7.34 (dd, J = 9.2, 1.6 Hz, 1H), 7.19−7.14 (m, 2H),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.9 (d, JC−F = 247.8
Hz), 163.0, 150.3, 132.4, 129.1 (d, JC−F = 8.4 Hz), 127.2 (d, JC−F = 3.1
Hz), 126.3, 123.8, 115.7 (d, JC−F = 21.6 Hz), 115.5, 18.0; HRMS (m/
z) [M + H]+ calcd for C13H11FN3 228.0932, found 228.0938.
2-(4-Chlorophenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (1m).
Following General Procedure D, 1m was obtained as a white solid:
1
yield 119 mg, ≥95%; mp 169−171 °C; Rf = 0.28 (EA/PE 17:83); H
NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.21−8.18 (m, 2H), 7.63 (d,
F
DOI: 10.1021/acs.joc.5b01183
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 160.2, 149.8, 136.0, 132.6, 131.0, 130.9, 127.9, 126.6,
124.2, 116.1, 18.1; HRMS (m/z) [M + H]+ calcd for C13H10Cl2N3
278.0246, found 278.0246.
(4) (a) Menet, C. J.; Fletcher, S. R.; Van Lommen, G. V.; Geney, R.;
Blanc, J.; Smits, K.; Jouannigot, N.; Deprez, P.; van der Aar, E. M.;
Clement-Lacroix, P.; Lepescheux, L.; Galien, R.; Vayssiere, B.; Nelles,
L.; Christophe, T.; Brys, R.; Uhring, M.; Ciesielski, F.; Van Rompaey,
L. V. J. Med. Chem. 2014, 57, 9323. (b) Marwaha, A.; White, J.;
El_Mazouni, F.; Creason, S. A.; Kokkonda, S.; Buckner, F. S.;
Charman, S. A.; Phillips, M. A.; Rathod, P. K. J. Med. Chem. 2012, 55,
7425. (c) Wang, X.-M.; Xu, J.; Li, Y.-P.; Li, H.; Jiang, C.-S.; Yang, G.-
D.; Lu, S.-M.; Zhang, S.-Q. Eur. J. Med. Chem. 2013, 67, 243.
(d) Oguro, Y.; Cary, D. R.; Miyamoto, N.; Tawada, M.; Iwata, H.;
Miki, H.; Hori, A.; Imamura, S. Bioorg. Med. Chem. 2013, 21, 4714.
(e) Bell, K.; Sunose, M.; Ellard, K.; Cansfield, A.; Taylor, J.; Miller, W.;
Ramsden, N.; Bergamini, G.; Neubauer, G. Bioorg. Med. Chem. Lett.
2012, 22, 5257. (f) Sunose, M.; Bell, K.; Ellard, K.; Bergamini, G.;
Neubauer, G.; Werner, T.; Ramsden, N. Bioorg. Med. Chem. Lett. 2012,
22, 4613. (g) Siu, M.; Pastor, R.; Liu, W.; Barrett, K.; Berry, M.; Blair,
W. S.; Chang, C.; Chen, J. Z.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.;
He, H.; Hurley, C. A.; Kenny, J. R.; Khojasteh, S. C.; Le, H.; Lee, L.;
Lyssikatos, J. P.; Magnuson, S.; Pulk, R.; Tsui, V.; Ultsch, M.; Xiao, Y.;
Zhu, B.-Y.; Sampath, D. Bioorg. Med. Chem. Lett. 2013, 23, 5014.
(h) Bergamini, G.; Bell, K.; Shimamura, S.; Werner, T.; Cansfield, A.;
6-Methyl-2-(pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (1v). Fol-
lowing General Procedure D, 1v was obtained as a white solid: yield
105 mg, ≥95%; mp 181−182 °C; Rf = 0.25 (EA/PE 67:33); 1H NMR
(400 MHz, CDCl3) δ 8.76−8.75 (m, 2H), 8.40 (s, 1H), 8.13−8.11 (m,
2H), 7.68 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.8, 1.6 Hz, 1H), 2.44 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 150.4, 138.4, 132.9,
126.4, 124.6, 121.2, 115.9, 18.1; HRMS (m/z) [M + H]+ calcd for
C12H11N4 211.0978, found 211.0978.
6-Methyl-2-(1-phenylcyclopropyl)-[1,2,4]triazolo[1,5-a]pyridine
(1x). Following General Procedure D, 1x was obtained as a white solid:
yield 112 mg, 90%; mp 77−78 °C; Rf = 0.25 (EA/PE 17:83); 1H NMR
(400 MHz, CDCl3) δ 8.23−8.22 (m, 1H), 7.52−7.49 (m, 3H), 7.38−
7.34 (m, 2H), 7.30−7.24 (m, 2H), 2.33 (s, 3H), 1.71−1.68 (m, 2H),
1.41−1.39 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.3, 149.8,
142.2, 132.0, 130.1, 128.4, 126.9, 126.2, 122.8, 115.0, 25.2, 18.0, 16.5;
HRMS (m/z) [M + H]+ calcd for C16H16N3 250.1339, found
250.1341.
2-(tert-Butyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (1y). Follow-
ing General Procedure D, 1y was obtained as a white solid: yield 57
Muller, K.; Perrin, J.; Rau, C.; Ellard, K.; Hopf, C.; Doce, C.; Leggate,
̈
1
mg, 60%; mp 69−70 °C; Rf = 0.30 (EA/PE 17:83); H NMR (400
D.; Mangano, R.; Mathieson, T.; O’Mahony, A.; Plavec, I.; Rharbaoui,
F.; Reinhard, F.; Savitski, M. M.; Ramsden, N.; Hirsch, E.; Drewes, G.;
Rausch, O.; Bantscheff, M.; Neubauer, G. Nat. Chem. Biol. 2012, 8,
576. (i) Dugan, B. J.; Gingrich, D. E.; Mesaros, E. F.; Milkiewicz, K. L.;
Curry, M. A.; Zulli, A. L.; Dobrzanski, P.; Serdikoff, C.; Jan, M.;
Angeles, T. S.; Albom, M. S.; Mason, J. L.; Aimone, L. D.; Meyer, S. L.;
Huang, Z.; Wells-Knecht, K. J.; Ator, M. A.; Ruggeri, B. A.; Dorsey, B.
D. J. Med. Chem. 2012, 55, 5243.
MHz, CDCl3) δ 8.32−8.31 (m, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.30
(dd, J = 8.8, 1.6 Hz, 1H), 2.38 (s, 3H), 1.48 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 174.4, 149.7, 131.9, 126.2, 122.9, 115.2, 33.2, 29.7,
18.0; HRMS (m/z) [M + H]+ calcd for C11H16N3 190.1339, found
190.1340.
ASSOCIATED CONTENT
■
S
(5) Grenda, V. J.; Jones, R. E.; Gal, G.; Sletzinger, M. J. Org. Chem.
1965, 30, 259.
(6) Potts, K. T.; Burton, H. R.; Bhattacharyya, J. J. Org. Chem. 1966,
31, 260.
* Supporting Information
Copies of 1H and 13C NMR spectra of compounds 1 and 2, and
X-ray structures and data of compounds 1a′ and 1u (CIF). The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b01183.
(7) Raval, J. P.; Desai, K. R. ARKIVOC 2005, 2005, 21.
(8) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
(9) Meng, X.; Yu, C.; Zhao, P. RSC Adv. 2014, 4, 8612.
(10) Zheng, Z.; Ma, S.; Tang, L.; Zhang-Negrerie, D.; Du, Y.; Zhao,
K. J. Org. Chem. 2014, 79, 4687.
(11) Bartels, B.; Bolas, C. G.; Cueni, P.; Fantasia, S.; Gaeng, N.; Trita,
A. S. J. Org. Chem. 2015, 80, 1249.
(12) Svensson, P. H.; Kloo, L. Chem. Rev. 2003, 103, 1649.
(13) Potts, K. T.; Burton, H. R.; Bhattacharyya, J. J. Org. Chem. 1966,
31, 260.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: changjunbiao@zzu.edu.cn (J.C.).
*E-mail: wenquan_yu@zzu.edu.cn (W.Y.).
■
Notes
The authors declare no competing financial interest.
(14) Prasad, V. S. R.; Reddy, K. K. Synth. Commun. 1990, 20, 2617.
(15) Pauchard, J. P.; Siegrist, A. E. Helv. Chim. Acta 1978, 61, 142.
(16) Kakehi, A.; Ito, S.; Uchiyama, K.; Konno, Y. Chem. Lett. 1976,
413.
(17) Gilchrist, T. L.; Harris, C. J.; Hawkins, D. G.; Moody, C. J.;
Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1976, 2166.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 81302637 and 81330075) and the China Postdoctoral
Science Foundation (Nos. 2013M530341 and 2014T70690)
for financial support.
REFERENCES
■
(1) For recent reviews on application of iodine in organic synthesis,
see: (a) Banerjee, A. K.; Vera, W.; Mora, H.; Laya, M. S.; Bedoya, L.;
Cabrera, E. V. J. Sci. Ind. Res. 2006, 65, 299. (b) Togo, H.; Iida, S.
Synlett 2006, 2006, 2159. (c) Finkbeiner, P.; Nachtsheim, B. J.
Synthesis 2013, 45, 979. (d) Ren, Y.-M.; Cai, C.; Yang, R.-C. RSC Adv.
2013, 3, 7182. (e) Mphahlele, M. J. Molecules 2009, 14, 5308.
̌
̌
(f) Jereb, M.; Vrazic, D.; Zupan, M. Tetrahedron 2011, 67, 1355.
(g) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Chem. - Eur. J.
2012, 18, 5460. (h) Zhao, J.; Gao, W.; Chang, H.; Li, X.; Liu, Q.; Wei,
W. Youji Huaxue 2014, 34, 1941 (in Chinese) .
(2) Gogoi, P.; Konwar, D. Org. Biomol. Chem. 2005, 3, 3473.
(3) For I2-mediated oxidative C−X (X = O, S and N) bond
formation reactions developed by our groups, see: (a) Yu, W.; Huang,
G.; Zhang, Y.; Liu, H.; Dong, L.; Yu, X.; Li, Y.; Chang, J. J. Org. Chem.
2013, 78, 10337. (b) Niu, P.; Kang, J.; Tian, X.; Song, L.; Liu, H.; Wu,
J.; Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 1018. (c) Zhang, X.; Kang,
J.; Niu, P.; Wu, J.; Yu, W.; Chang, J. J. Org. Chem. 2014, 79, 10170.
G
DOI: 10.1021/acs.joc.5b01183
J. Org. Chem. XXXX, XXX, XXX−XXX