Copper(i)-catalyzed benzylation of triazolopyridine through direct C-H functionalization

Article abstract of DOI:10.1039/c9ob01433k

A general and efficient copper-catalyzed benzylation reaction of triazolopyridine with N-tosylhydrazones was developed. This reaction forms a C(sp²)-C(sp³) bond through cross-coupling, and represents an exceedingly practical method t

Full text of DOI:10.1039/c9ob01433k

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DOI: 10.1039/C9OB01433K
ARTICLE
Copper(I)-Catalyzed Benzylation of Triazolopyridine Through
Direct C-H Functionalization
Received 00th January 20xx,
Accepted 00th January 20xx
Madhava Reddy Lonka, Jinquan Zhang, Thirupathi Gogula and Hongbin Zou*
DOI: 10.1039/x0xx00000x
A general and efficient copper-catalyzed benzylation reaction of triazolopyridine with N-tosylhydrazones was developed.
This reaction forms C(sp2)-C(sp3) bond through cross-coupling, and represents an exceedingly practical method to afford 3-
benzylated triazolopyridines in moderate to good yields,. A proposed mechanistic pathway underlying this reaction was
outlined. This catalytic transformation should enable borad synthetic applications in functionalization chemistry, allowing
the synthesis of new pharmaceutically relevant trizaolopyridine derivatives.
(a) Previous work
Introduction
N
I
N
N
N
CuI, Ph3P, K2CO3, 24 h
direct C-H arylation
N
N
Cross-coupling reactions mediated by transition metals have been
widely regarded as direct and excellent methods to construct C–C
bonds.1 A range of metal catalysts such as ruthenium, rhodium and
palladium have been extensively applied in these reactions to
furnish diverse molecular structures.2 Among them, copper catalyst
has attracted particular interest for being significantly active,
notably inexpensive, and commercially available.3
+
N
N
R
R
H
(b) This work
N
Ts
N
N
N
H
CuI, LitOBu, 12 h
+
N
N
direct C-H alkylation
R1
R1
H
N-tosylhydrazones, readily prepared from carbonyl compounds, are
useful synthetic intermediates that have been employed in organic
chemistry for almost 65 years. Recently, the synergistic merger of
N-tosylhydrazones and copper catalyst has been reported to enable
the direct C-H functionalization of arenes and heteroarenes.4 Zhou
et. al., reported reductive coupling of N-tosylhydrazones with H-
phosphorus oxides in the presence of copper catalyst.5 Wang and
co-workers used Cu(I) catalyst in the coupling of terminal alkynes,6
1,3-azoles,7 N-iminopyridinium ylides8 and polyfluoroarenes9 with
N-tosylhydrazones, respectively. In addition, Das and colleagues
developed copper-catalyzed direct cross-coupling of oxadiazoles
with N-tosylhydrazones.10
Triazolopyridines are ubiquitous nitrogen-containing fused
heterocycles11 with broad applications in coordination chemistry.12
They process a privileged 1,2,4-triazolo[4,3-a]pyridine skeleton that
is widely found in bioactive molecules13 as well as in herbicidal
agents14. Triazolopyridines often exhibit interesting biological
effects, through their antibacterial, anti-inflammatory, antifungal,
and antiproliferative activities.15 Thus, the development of
straightforward access to functionalized triazolopyridine has
become an attractive area of research. In 2015, You and co-workers
Scheme 1 Copper-catalyzed C(sp2)-C(sp3) cross-coupling
utilized copper catalyst to achieve successful arylation of
triazolopyridine (Scheme 1a).16
However, the direct cross-coupling of triazolopyridine with sp3
carbon centers remains challenging. Inspired by the previous
findings, we asked whether N-tosylhydrazones could react with
triazolopyridines through C(sp2)-C(sp3) bond formation via copper
catalysis. Based on the confirmative results of our investigation, we
herein report the highly efficient copper-catalyzed direct
benzylation reaction of triazolopyridine with N-tosylhydrazones in
good yields (Scheme 1b).
Results and discussion
To optimize the reaction conditions, [1,2,4]triazolo[4,3-
a]pyridine 1 and N-tosylhydrazone 2a was initially treated with
the similar previously reported reaction condition for the
copper-catalyzed direct benzylation of 1,3,4-oxadiazoles,10a
College of pharmaceutical sciences, Zhejiang University, Hangzhou 310058, P.R.
China. E-mail: zouhb@zju.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
with the presence of CuI as a catalyst and LitOBu as a base in tosylhydrazones with electron-donating alkyl ViaewndArticlaelOknolixnye
toluene. For the first 3 hours, no reaction was detected (entry groups were well-tolerated, as evidenceDdObI:y10t.h10e3f9o/Crm9OaBt0io14n33oKf
1, Table 1). However, the desired product started to form as 3b–f in good yields, ranging from 68% to 76%. Halogen-
the process continued. The product yield reached a maximum substituted N-tosylhydrazones led to slightly lowered
of 80% at the 12th hour (entry 3), and gradually decreased turnovers of products (3g‒i, 3l and 3m), a trend being
hereafter (entry 4). Raising or lowering the reaction identified with other electrophilic substituents, such as those
o
temperature from 110 C would both attenuate the product processing trifluoromethyl and cyano groups (3j, 3k).
yield (entries 5 and 6). Next, we examined the various forms of Heterocycle-substituted N-tosylhydrazones were also found
Cu-containing catalysts and found that neither CuBr nor compatible for this reaction (3n and 3o). Further reaction of 1
Cu(OAc)2.H2O gave desired product 3a (entries 7 and 8), with N-tosylhydrazone derived from phenylbutanone gave
validating the crucial role of CuI in the reaction. A survey of corresponding product 3p in 72% yield, while the N-
base and solvent was then conducted. Various base tosylhydrazone derived from benzaldehyde afforded the
substituents failed the reaction (entries 9‒11), necessitating benzylated product 3q in a similar yield. Moreover, N-
the usage of LitOBu. Switching the solvent to dioxane also tosylhydrazones derived from diaryl ketone was also proven to
diminished the reactivity (entry 12), confirming the judicious be amenable substrate for the reaction, affording 3r in
choice of toluene. Finally, reducing the loading of the catalyst moderate yield (58%). Conversely, we found that pyridine,
or the base led to a slight decrease of the yield (entries 13 and nitro and aliphatic group-substituted N-tosylhydrazones were
14).
not tolerated by this transformation.
Table 1. Optimization of reaction conditionsa
Table 2. Substrate scope of N-tosylhydrazonesa
R2
N
Ts
N
N
Ts
N
CuI (20 mol%)
LitOBu (2.5 equiv.)
N
H
CuI (20 mol%)
LitOBu (2.5 equiv.)
N
N
N
N
N
N
H
+
N
N
N
+
N
R1
R1
Toluene, 110 o
12 hrs
C
N
R2
Toluene, 110 o
12 hrs
C
1
2
3
1
2a
3a
N
N
N
N
Entry Catalyst
(mol%)
Base
Temp (oC) Time Yield
(hrs) (%)b
N
N
N
N
N
N
N
N
(equiv.)
LitOBu
LitOBu
LitOBu
LitOBu
LitOBu
LitOBu
1
2
3
4
5
6
CuI
CuI
CuI
CuI
CuI
CuI
110
110
110
110
130
80
110
110
110
110
110
110
110
110
3
6
N.Rc
Trace
80
76
60
OMe
3d, 75 %
3a, 80 %
3b ,72 %
3c, 76 %
12
24
12
12
12
12
12
12
12
12
12
12
N
N
N
N
N
N
N
N
O
N
N
N
N
O
Cl
F
35
3f, 68 %
3g, 62 %
3h, 54 %
3e, 64 %
7
Cu(OAc)2.H2O LitOBu
N.R
N.R
N.R
N.R
N.R
N.Rd
65e
70f
8
9
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
LitOBu
Cs2CO3
K2CO3
KtOBu
LitOBu
LitOBu
LitOBu
N
N
N
N
N
N
N
N
F
N
N
N
N
10
11
12
13
14
Br
CF3
CN
F
3i, 49 %
3j, 68 %
3k, 41 %
3l, 64 %
N
N
N
N
N
N
N
N
N
N
N
N
O
aReaction conditions: [1,2,4]triazolo[4,3-a]pyridine
1 (1.0
S
mmol), N-tosylhydrazone 2a (1.5 mmol), catalyst (20 mol%.),
base (2.5 equiv.) at 110 oC over 12 h in toluene (2 mL).
bIsolated yield of 3a after column chromatography. cNo
reaction. Solvent changed to dioxane. Catalyst (10 mol%.),
Base (1.5 equiv.).
Br
3m, 42 %
3o, 51 %
3n, 55 %
3p, 72 %
N
N
d
e
f
N
N
N
N
With the optimized reaction conditions in hand (entry 3,
Table 1), we then carried out direct benzylation of
[1,2,4]triazolo[4,3-a]pyridine 1 to investigate the scope of N-
tosylhydrazones. As shown in Table 2, a wide range of N-
tosylhydrazones undergo the reaction successfully, affording
the desired products (3a–r) in moderate to good yields. N-
Tosylhydrazone, derived from acetophenone, smoothly
3q, 70 %
3r, 52 %
aReaction conditions: [1,2,4]triazolo[4,3-a]pyridine 1 (1 equiv.),
2a‒r (1.5 equiv.), CuI (20 mol%), LitOBu (2.5 equiv.),
toluene(2.0 mL), 110 oC for 12 h. All yields refer to the isolated
products.
coupled with
1 to afford 3a in a yield of 80%. N-
2 | J. Name., 2012, 00, 1-3
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Next, we investigated the scope of substituted Scheme 2. Proposed reaction mechanism
ARTICLE
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DOI: 10.1039/C9OB01433K
[1,2,4]triazolo[4,3-a]pyridines
by
reaction
with
N-
tosylhydrazone 2a under optimized reaction conditions (Table
3). 8-Chloro[1,2,4]triazolo[4,3-a]pyridine afforded the desired
product 5a in 62% yield and 6-bromo[1,2,4]triazolo[4,3-
a]pyridine gave the product 5b in 58% yield, respectively. We
also tried 5-chloro[1,2,4]triazolo[4,3-a]pyridine and no product
was observed which might ascribed to the decomposition of
the substrate at high temperature. Meanwhile, the protocol
we used12e to prepare [1,2,4]triazolo[4,3-a]pyridine 1 couldn’t
afford the electron donating 5-methyl[1,2,4]triazolo[4,3-
a]pyridine which might also be due to its instability during the
preparation.
Conclusions
In summary, we developed an efficient copper(I)-catalyzed
system for the direct benzylation of triazolopyridine with N-
tosylhydrazones. A variety of benzylated triazolopyridine
derivatives have been successfully synthesized in moderate to
good yields. Given the operational ease associated with the
preparation of N-tosylhydrazones from carbonyl compounds
and the commercial availability of inexpensive copper(I)
catalyst, this reaction represents an exceedingly effective,
practical, and economical strategy to access C-H bond
functionalization of triazolopyridine by challenging the
secondary benzyl group. It broadens the field of cross-coupling
chemistry with potential applications to numerous areas of
synthetic science.
Table 3. Substrate scope of [1,2,4]triazolo[4,3-a]pyridinesa
N
Ts
N
N
CuI (20 mol%)
LitOBu (2.5 equiv.)
H
R
N
N
N
+
N
R
N
Toluene, 110 o
12 hrs
C
4
2a
5a-b
Experimental Section
Cl
General Information:
N
N
N
N
N
N
Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without further purification. The
reactions were monitored by thin-layer chromatography (TLC) with
Merck precoated silica gel 60 F254 using UV light as visualizing
agent. All the solvents were treated according to general methods.
Solvents mixture was understood as volume/ volume. Purifications
of reaction products were carried out by chromatography using
silica gel (200-300 mesh). 1H NMR spectra were recorded at 500
MHz and 13C NMR at 125 MHz. Tetramethylsilane (TMS) was used
Br
5a, 62 %
5b, 58 %
Reaction conditionsa: 4 (1 equiv.), 2a (1.5 equiv.), CuI (20
mol%), LitOBu (2.5 equiv.), toluene(2.0 mL), 110 oC for 12 h. All
yields refer to the isolated products.
Based on these experimental observations and previously
reported copper-catalyzed C-H activations,10 we propose a
plausible reaction mechanism as delineated in Scheme 2. The
copper catalytic cycle commences with deprotonation of the
acidic C−H bond of triazolopyridine by LitOBu, followed by
transmetalation by the excited Cu(I) state. The resultant
metallated triazolopyridinyl species A then captures the
reactive intermediate derived from tosylhydrazone by LitOBu,
to form a Cu(I) carbene species B. Subsequent migratory
insertion forges the desired C(sp2)-C(sp3) bond to furnish
intermediate C, followed by protonation that ultimately
liberates the benzylated product and recovers the copper
catalyst.
1
as internal standard (δ = 0) for H NMR spectra and the values are
reported as follows: chemical shift as  in ppm, and multiplicity as s
= singlet, d = doublet, t= triplet, q =quartet, m = multiplet and the
coupling constants in Hz. For 13C NMR, CDCl3 (δ = 77.00) was used
as internal standard and spectra were obtained with complete
proton decoupling.
Typical procedure for the synthesis of [1,2,4]triazolo[4,3-
a]pyridine (1):12e
A
combination of the 2-hydrazino pyridine (1.0 mmol) and
formaldehyde (1.0 mmol) in EtOH (10 mL) was heated at reflux for
30 min (TLC indicated that condensation was finished). Then, the
solvent was evaporated under reduced pressure, and the resulting
crude was redissolved in DCM (10 mL), followed by the addition of
K2CO3 (3.0 mmol) and iodine (1.2 mmol). The reaction mixture was
stirred at room temperature until TLC indicated the total
consumption of intermediate. Upon end of the reaction, it was
quenched with 5% Na2S2O3 (30 mL), and then extracted with DCM
(3 x 20 mL). The combined organic layer was washed with brine (40
mL), dried over anhydrous Na2SO4, and concentrated. The given
residue was purified by column chromatography through silica gel
to afford pure product.
TsHN
LitOBu
N
N2
N
N
Ph
Ph
N2
N
N
Cu(I)
N
Cu(I)
carben
N
A
on
i
bondt
e
N
C-H
metalla
N
N
CuI
Ph
(I)Cu
N
protona
B
N
n
N
N
t
migratory
insertio
i
on
N
N
Ph
H+
1
light brown oil, 71.6 mg (60% yield); H NMR (500 MHz, CDCl3) δ
8.86 (s, 1H), 8.20–8.15 (m, 1H), 7.80 (dd, J = 9.3, 0.6 Hz, 1H),
(I)Cu
Ph
C
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J. Name., 2013, 00, 1-3 | 3
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7.31‒7.25 (m, 1H), 6.88 (t, J = 6.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) 114.5, 113.3, 55.3, 36.6, 20.9; HRMS calcd. for C15H16N3O [M+H]+
View Article Online
DOI: 10.1039/C9OB01433K
δ 149.13, 135.63, 128.10, 123.69, 116.16, 114.38.
254.1287, found 254.1291.
Typical procedure for the synthesis of N-Tosylhydrazones (2a‒r): 7
3-(1-(2,4-Dimethylphenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3d):
A solution of 4-methylbenzenesulfonohydrazide (5.0 mmol) in White solid, 94.9 mg (75% yield); mp 121–123 °C; Rf = 0.2 (ethyl
1
methanol (5mL) was stirred and heated to 60 °C until the 4- acetate); H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 9.3 Hz, 1H), 7.36
methylbenzenesulfonohydrazide was completely dissolved. Then (d, J = 6.9 Hz, 1H), 7.17 (dd, J = 8.7, 6.7 Hz, 1H), 7.04 (s, 1H), 6.86 (d,
carbonyl compound (5.0 mmol) was added to the mixture slowly. J = 7.8 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.62 (t, J = 6.7 Hz, 1H), 4.60
After 15‒30 mins reaction, the crude product was obtained as (q, J = 7.0 Hz, 1H), 2.45 (s, 3H), 2.27 (s, 3H), 1.92 (d, J = 7.0 Hz, 3H);
precipitate which was washed by petroleum ether and then dried in 13C NMR (125 MHz, CDCl3) δ 136.9, 136.2, 134.7, 131.8, 127.8,
vacum to afford the pure product.
126.7, 122.2, 116.5, 113.3, 33.4, 20.9, 19.5, 19.3; HRMS calcd. for
C16H18N3 [M+H]+ 252.1492, found 252.1497.
General procedure for the Cu(I)-catalyzed benzylation of
triazolopyridine
3-(1-(Benzo[d][1,3]dioxol-4-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine
(3e):
A mixture of CuI (10 mol%.), LitOBu (1.25 mmol), N-tosylhydrazone
2 (0.75 mmol ) and [1,2,4]triazolo[4,3-a]pyridine 1 (0.5 mmol.) was White solid, 86.1 mg (64% yield); mp 123–125 °C; Rf = 0.2 (ethyl
0
1
stirred in toluene (2.0 mL) at 110 C for 12 h in a sealed Schlenk acetate); H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 9.2 Hz, 1H), 7.64
tube. After cooling to room temperature, the reaction mixture was (d, J = 6.9 Hz, 1H), 7.19 (dd, J = 8.7, 6.8 Hz, 1H), 6.74 (d, J = 7.9 Hz,
extracted with EtOAc (2 x 10 mL). The combined organic layer 1H), 6.71–6.64 (m, 3H), 5.94–5.90 (m, 2H), 4.39 (q, J = 7.1 Hz, 1H),
extract was dried over anhydrous Na2SO4 and evaporated to 1.94 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.4, 146.9,
remove the solvent. The residue was then purified by flash column 135.1, 126.7, 122.3, 120.3, 116.6, 113.4, 108.7, 107.5, 101.2, 37.1,
chromatography (ethyl acetate) to get benzylated triazolopyridines 21.0; HRMS calcd. for C15H14N3O2 [M+H]+ 268.1080, found
3 and 5.
268.1085.
3-(1-Phenylethyl)-[1,2,4]triazolo[4,3-a]pyridine (3a):
3-(1-m-Tolyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3f):
White solid, 89.9 mg (80% yield); mp 125–128 °C; Rf = 0.2 (ethyl White solid, 81.2 mg (68% yield); mp 130–133 °C; Rf = 0.2 (ethyl
1
1
acetate); H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 9.3 Hz, 1H), 7.58 acetate); H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 9.3 Hz, 1H), 7.60
(d, J = 7.0 Hz, 1H), 7.33–7.29 (m, 2H), 7.27–7.23 (m, 1H), 7.21 (dd, J (d, J = 7.0 Hz, 1H), 7.21–7.14 (m, 2H), 7.05 (d, J = 7.5 Hz, 1H), 7.00
= 5.2, 3.3 Hz, 1H), 7.17 (ddd, J = 9.3, 6.5, 1.0 Hz, 1H), 6.67–6.62 (m, (d, J = 6.1 Hz, 2H), 6.67–6.62 (m, 1H), 4.42 (q, J = 7.1 Hz, 1H), 2.28 (s,
1H), 4.47 (q, J = 7.1 Hz, 1H), 1.98 (d, J = 7.1 Hz, 3H); 13C NMR (125 3H), 1.96 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 150.3,
MHz, CDCl3) δ 150.4, 148.7, 141.3, 129.2, 127.4, 127.1, 126.7, 122.3, 148.8, 141.2, 139.0, 129.0, 128.2, 127.8, 126.7, 124.2, 122.3, 116.5,
116.5, 113.4, 37.4, 20.9; HRMS calcd. for C14H14N3 [M+H]+ 224.1182, 113.3, 37.3, 21.4, 20.9; HRMS calcd. for C15H16N3 [M+H]+ 238.1338,
found 228.1186.
found 238.1343.
3-(1-(p-Tolyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3b):
3-(1-(4-Fluorophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3g):
White solid, 86.0 mg (72% yield); mp 120–122 °C; Rf = 0.2 (ethyl White solid, 75.3 mg (62% yield); mp 135–138 °C; Rf = 0.2 (ethyl
1
acetate); 1H NMR (500 MHz, CDCl3) δ 7.77–7.73 (m, 1H), 7.59 (dt, J = acetate); H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 9.3 Hz, 1H), 7.60
7.0, 1.1 Hz, 1H), 7.17 (ddd, J = 9.3, 6.5, 1.1 Hz, 1H), 7.13–7.07 (m, (d, J = 7.0 Hz, 1H), 7.20 (ddd, J = 8.6, 6.7, 1.4 Hz, 3H), 7.02–6.97 (m,
4H), 6.65 (td, J = 7.0, 1.0 Hz, 1H), 4.43 (q, J = 7.1 Hz, 1H), 2.30 (s, 2H), 6.69 (t, J = 6.7 Hz, 1H), 4.48 (q, J = 7.1 Hz, 1H), 1.96 (d, J = 7.1
3H), 1.96 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 150.4, Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.9 (d, J = 246.2 Hz), 136.9
148.8, 138.2, 137.1, 129.9, 127.0, 126.7, 122.4, 116.5, 113.3, 37.0, (d, J = 3.2 Hz), 128.7 (d, J = 8.2 Hz), 126.8, 122.1, 116.6, 116.2 (d, J =
21.0, 20.9; HRMS calcd. for C15H16N3 [M+H]+ 238.1338, found 21.6 Hz), 113.5, 36.6, 21.0; 19F NMR (471 MHz, CDCl3) δ -114.89–-
238.1343.
114.96 (m, 1F); HRMS calcd. for C14H13FN3 [M+H]+ 242.1088, found
242.1092.
3-(1-(4-Methoxyphenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3c):
3-(1-(4-Chlorophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3h):
White solid, 96.9 mg (76% yield); mp 115–118 °C; Rf = 0.2 (ethyl
1
acetate); H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 9.3 Hz, 1H), 7.59 White solid, 69.9 mg (54% yield); mp 155–157 °C; Rf = 0.2 (ethyl
1
(dt, J = 7.0, 1.2 Hz, 1H), 7.18 (ddd, J = 9.3, 6.5, 1.2 Hz, 1H), 7.14–7.09 acetate); H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 6.86 Hz, 2H), 7.28
(m, 2H), 6.86–6.81 (m, 2H), 6.68-6.63 (td, J = 6.8, 1.0 Hz, 1H), 4.43 (d, J = 7.3 Hz, 2H), 7.22 (t, 1H), 7.15 (d, J = 8.1 Hz, 2H), 6.70 (t, J = 6.7
(q, J = 7.1 Hz, 1H), 3.77 (s, 3H), 1.95 (d, J = 7.1 Hz, 3H); 13C NMR (125 Hz, 1H), 4.48 (q, J = 6.6 Hz, 1H), 1.96 (d, J = 6.8 Hz, 3H); 13C NMR
MHz, CDCl3) δ 158.8, 150.3, 148.9, 133.2, 128.2, 126.8, 122.4, 116.5, (125 MHz, CDCl3) δ 139.7, 133.3, 129.4, 128.5, 126.9, 122.2, 116.7,
4 | J. Name., 2012, 00, 1-3
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113.7, 36.8, 20.9; HRMS calcd. for C14H13ClN3 [M+H]+ 258.0792, 126.7, 125.8, 123.2, 122.3, 116.8, 113.7, 37.2, 20.8; HRMS calcd. for
View Article Online
found 258.0797.
C14H13BrN3 [M+H]+ 302.0287, found 302.029D2O. I: 10.1039/C9OB01433K
3-(1-(4-Bromophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3i):
3-(1-(Furan-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3n):
1H White solid, 74.3 mg (49% yield); mp 160–163 °C; Rf = 0.2 (ethyl White solid, 59.0 mg (55% yield); mp 138–141 °C; Rf = 0.2 (ethyl
1
1
acetate); H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 9.3 Hz, 1H), 7.57 acetate); H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.0 Hz, 1H), 7.76
(d, J = 7.0 Hz, 1H), 7.45–7.42 (m, 2H), 7.20 (ddd, J = 9.3, 6.5, 1.0 Hz, (d, J = 9.3 Hz, 1H), 7.34–7.31 (m, 1H), 7.22 (ddd, J = 9.3, 6.5, 1.0 Hz,
1H), 7.11–7.07 (m, 2H), 6.71–6.68 (m, 1H), 4.44 (q, J = 7.1 Hz, 1H), 1H), 6.79–6.74 (m, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.14 (d, J = 3.3
1.96 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 140.3, 132.3, Hz, 1H), 4.75 (q, J = 7.2 Hz, 1H), 1.95 (d, J = 7.2 Hz, 3H); 13C NMR
128.9, 126.9, 122.0, 121.3, 116.7, 113.6, 36.8, 20.8; HRMS calcd. for (125 MHz, CDCl3) δ 153.7, 142.1, 126.8, 122.6, 116.6, 113.5, 110.6,
C14H13BrN3 [M+H]+ 302.0287, found 302.0291.
106.3, 31.0, 16.9; HRMS calcd. for C12H12N3O [M+H]+ 214.0974,
found 214.0980.
3-(1-(4-(Trifluoromethyl)phenyl)ethyl)-[1,2,4]triazolo[4,3-
a]pyridine (3j):
3-(1-(Thiophen-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3o):
White solid, 58.8 mg (51% yield); mp 145–148 °C; Rf = 0.2 (ethyl
1
White solid, 99.7 mg (68% yield); mp 125–128 °C; Rf = 0.2 (ethyl acetate); H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 9.3 Hz, 1H), 7.72
acetate); 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 9.3 Hz, 1H), 7.58 (t, (d, J = 6.9 Hz, 1H), 7.21 (dd, J = 7.7, 7.1 Hz, 2H), 6.93 (dd, J = 5.0, 3.6
J = 7.3 Hz, 3H), 7.36 (d, J = 8.1 Hz, 2H), 7.22 (dd, J = 8.8, 6.9 Hz, 1H), Hz, 1H), 6.82 (d, J = 3.4 Hz, 1H), 6.71 (t, J = 6.8 Hz, 1H), 4.88 (q, J =
6.72 (t, J = 6.7 Hz, 1H), 4.56 (q, J = 7.1 Hz, 1H), 2.00 (d, J = 7.1 Hz, 7.1 Hz, 1H), 2.04 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
3H); 13C NMR (125 MHz, CDCl3) δ 147.9, 145.3, 129.8 (q, J = 32.6 144.2, 127.2, 126.8, 124.8, 124.7, 122.4, 116.7, 113.5, 32.6, 21.0;
Hz), 127.6, 127.2, 126.9, 126.2 (q, J = 3.7 Hz), 125.0, 122.8, 121.8, HRMS calcd. for C12H12N3S [M+H]+ 230.0746, found 230.0751.
120.7, 116.7, 113.8, 37.1, 20.8; 19F NMR (471 MHz, CDCl3) δ -62.58
(s, 3F); HRMS calcd. for C15H13F3N3 [M+H]+ 292.1056, found 3-(1-Phenylbutyl)-[1,2,4]triazolo[4,3-a]pyridine (3p):
292.1061.
White solid, 91.1 mg (72% yield); mp 124–126 °C; Rf = 0.2 (ethyl
1
4-(1-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)ethyl)benzonitrile (3k):
acetate); H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 9.3 Hz, 1H), 7.66
(d, J = 7.0 Hz, 1H), 7.32–7.26 (m, 2H), 7.26–7.21 (m, 2H), 7.16 (dd, J
White solid, 51.2 mg (41% yield); mp 173–175 °C; Rf = 0.2 (ethyl = 8.8, 6.9 Hz, 1H), 6.65 (t, J = 6.7 Hz, 1H), 4.26 (t, J = 7.5 Hz, 1H),
1
acetate); H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 9.3 Hz, 1H), 7.64– 2.64–2.55 (m, 1H), 2.31 – 2.21 (m, 1H), 1.51–1.33 (m, 2H), 0.97 (t, J
7.60 (m, 2H), 7.58 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.24 = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 140.0, 138.0, 129.0,
(ddd, J = 9.2, 6.6, 0.9 Hz, 1H), 6.75 (t, J = 6.6 Hz, 1H), 4.55 (q, J = 7.1 127.8, 127.3, 126.6, 122.0, 116.6, 113.3, 42.7, 36.7, 20.7, 13.9;
Hz, 1H), 1.99 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 146.6, HRMS calcd. for C16H18N3 [M+H]+ 252.1492, found 252.1498.
133.0, 128.1, 127.1, 121.6, 118.4, 116.8, 114.0, 111.6, 37.3, 20.7;
HRMS calcd. for C15H13N4 [M+H]+ 249.1134, found 249.1139.
3-Benzyl-[1,2,4]triazolo[4,3-a]pyridine (3q):
3-(1-(2,4-Difluorophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3l):
White solid, 73.7 mg (70% yield); mp 164–166 °C; Rf = 0.2 (ethyl
acetate); H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 9.3 Hz, 1H), 7.71
1
White solid, 83.5 mg (64% yield); mp 139–142 °C; Rf = 0.2 (ethyl (d, J = 6.9 Hz, 1H), 7.33–7.28 (m, 2H), 7.24 (dd, J = 7.1, 5.8 Hz, 3H),
acetate); 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 9.3 Hz, 1H), 7.69 7.20 (ddd, J = 9.2, 6.6, 0.9 Hz, 1H), 6.71 (t, J = 6.7 Hz, 1H), 4.56 (s,
(d, J = 6.9 Hz, 1H), 7.22 (dd, J = 8.8, 6.9 Hz, 1H), 7.07 (td, J = 8.6, 6.5 2H); 13C NMR (125 MHz, CDCl3) δ 134.6, 129.1, 128.4, 127.4, 126.7,
Hz, 1H), 6.90–6.83 (m, 1H), 6.80–6.73 (m, 2H), 4.81 (q, J = 7.1 Hz, 122.2, 116.6, 113.6, 31.4; HRMS calcd. for C13H12N3 [M+H]+
1H), 1.96 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 163.0 (d, J 210.1025, found 210.1031.
= 12.1 Hz),160.8 (dd, J = 26.7, 12.0 Hz), 158.9 (d, J = 11.8 Hz), 129.6
(dd, J = 9.7, 5.2 Hz), 126.8, 123.9(d, J = 10.8 Hz),121.7, 116.7, 113.8, 3-Benzhydryl-[1,2,4]triazolo[4,3-a]pyridine (3r):
112.4 (dd, J = 21.2, 3.7), 104.0 (t, J = 25.9 Hz), 28.4 (d, J = 3.3 Hz),
19.8; 19F NMR (471 MHz, CDCl3) δ -110.78 (dt, J = 15.0, 7.7 Hz, 1F), - White solid, 74.7 mg (52% yield); mp 169–172 °C; Rf = 0.4 (ethyl
116.03 (dd, J = 17.4, 8.6 Hz, 1F); HRMS calcd. for C14H12F2N3 [M+H]+ acetate); 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 9.3, 1H), 7.68 (d, J
260.0993, found 260.0998.
= 7.0, 1H), 7.34 (dd, J = 11.3, 4.4, 4H), 7.30–7.28 (m, 2H), 7.26 (dd, J
= 5.4, 2.9, 4H), 7.22 (dd, J = 9.1, 6.6, 1H,), 6.70 (t, J = 6.7, 1H), 5.89
(s, 1H);.13C NMR (125 MHz, CDCl3) δ 138.7, 129.0, 128.8, 127.6,
126.8, 122.6, 116.8, 113.75, 48.6; HRMS calcd. for C19H16N3 [M+H]+
3-(1-(3-Bromophenyl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine (3m):
White solid, 63.7 mg (42% yield); mp 168–171 °C; Rf = 0.2 (ethyl 286.1338, found 286.1344.
1
acetate); H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 3.2 Hz, 2H), 7.42–
7.36 (m, 2H), 7.22 (s, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 8-chloro-3-(1-phenyethyl)-[1,2,4]triazolo[4,3-a]pyridine(5a):
1H), 6.71 (t, J = 6.7 Hz, 1H), 4.47 (d, J = 6.8 Hz, 1H), 1.96 (d, J = 7.0
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 143.6, 130.8, 130.6, 130.3,
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
5
6
L. Wu, X. Zhang, Q-Q. Chen and A-K. Zhou, VOiewrgA.rtiBclieoOmnloinle.
White solid, 79.1 mg (62% yield); mp 172–174 °C; Rf = 0.3 (ethyl
acetate); H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 6.91 1H), 7.33–
Chem., 2012, 10, 7859.
1
DOI: 10.1039/C9OB01433K
(a) Q. Xiao, Y. Xia, H. Li, Y. Zhang and J. Wang, Angew. Chem.,
Int. Ed., 2011, 123, 1146; (b) F. Ye, X.Ma, Q. Xiao, Y. Zhang
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7.30 (m, 1H), 7.29 (d, J = 2.1, 1H), 7.27–7.22 (m, 2H), 7.20 (dd, J =
5.3, 3.32, 2H), 6.62 (t, J = 7.01, 1H), 4.50 (q, J =7.1, 1H), 1.97 (d, J
7.1, 3H); 13C NMR (125 MHz, CDCl3) δ 150.3, 148.4, 140.8, 129.3,
127.5, 127.1, 125.7, 122.6, 121.1, 113.3, 37.6, 20.7; HRMS calcd. for
C14H13ClN3 [M+H]+ 258.0792, found 258.0796.
7
8
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White solid, 87.2 mg (58% yield); mp 146–148 °C; Rf = 0.3 (ethyl
acetate); H NMR (500 MHz, CDCl3) δ 7.76 (s,1H,), 7.68 (d, J = 8.8,
1H), 7.33 (t, J = 7.32, 1H), 7.30 – 7.25 (m, 2H), 7.22 (t, J = 7.73, 1H),
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20.9. HRMS calcd. for C14H13BrN3 [M+H]+ 302.0287, found 302.0292.
1
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Key R&D Program of China
(No. 2017YFE0102200), the Zhejiang Provincial Fund for
Distinguished Young Scholars (No. LR15B020001) and the National
Natural Science Foundation of China (No. 21472170).
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