A facile one-pot metal-free synthesis of 1,4-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/ejoc.201500360

Abstract A 1,3-dipolar cycloaddition reaction of commercially available aldehydes with azides and secondary amines through a one-pot strategy has been developed. This method furnishes 1,4-disubstituted 1,2,3-triazoles in good to excellent yields and high

Full text of DOI:10.1002/ejoc.201500360

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500360
A Facile One-Pot Metal-Free Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
Qianfa Jia,[a] Gongming Yang,[a] Lei Chen,[a] Zhiyun Du,*[a] Jia Wei,[a] Yanqiong Zhong,[a]
and Jian Wang*[a]
Keywords: Metal-free synthesis / Triazoles / Azides / 1,3-Dipolar cycloaddition
A 1,3-dipolar cycloaddition reaction of commercially avail- 1,4-disubstituted 1,2,3-triazoles in good to excellent yields
able aldehydes with azides and secondary amines through a
one-pot strategy has been developed. This method furnishes
and high levels of regioselectivity.
one century to make 1,2,3-triazoles and further developed
by Huisgen,[7] these compounds came into the limelight
only in the last two decades due to their excellent copper-
catalyzed regioselective synthesis developed by the
Sharpless[6] and Meldal[8a] groups. Cu-catalyzed azide–alk-
yne cycloaddition (CuAAC) reaction provides an advantage
of straightforward and powerful approaches to prepare 1,4-
disubstituted 1,2,3-triazoles with high yields and regioselec-
tivities.[8] However, CuI can cause oxidative DNA degrada-
tion[9] and is potentially toxic for living organisms.[10]
Therefore, the development of precise syntheses of 1,2,3-
triazoles without use of metals is a significant responsibility
for organic chemists.
Introduction
1,2,3-Triazoles were considered as useful synthons to
transform into various medicinally important molecules.[1]
Figure 1 shows TSAO (“tert-butyldimethylsilylspiroamino-
oxathioledioxide”), a non-nucloside reverse-transcriptase
inhibitor,[2] and CAI (“carboxyamidotriazole”), which exhi-
bits anticancer activity.[3] 1,2,3-Tiazole moieties are also
known as HIV protease inbibitors[4] and demonstrate po-
tential antituberculosis bioactivity.[5] Therefore, the devel-
opment of rapid and efficient protocols for the construction
of diversified triazoles tends to be extremely demanded.
In recent years, Ramachary,[11] Bressy,[12] our group[13]
and other groups[14] independently reported the use of small
organic molecules as catalysts to react with organic azides
and carbonyl compounds to afford substituted 1,2,3-tri-
azoles with high levels of regioselectivities (Scheme 1a).[14]
As part of our continued interest in extending substrate
scope and diversity of 1,2,3-triazoles, we present our new
results of azides with commercially available aldehydes and
Figure 1. Selected biologically important 1,2,3-triazoles.
Even though the thermally induced 1,3-dipolar cyclo-
addition of alkynes with azides has been known for over
[a] Allan H. Conney Laboratory for Anticancer Research,
Institute of Natural Medicine and Green Chemistry,
School of Chemical Engineering and Light Industry,
Guangdong University of Technology,
Guang Dong 510006, China
E-mail: zhiyundu@gdut.edu.cn
wangjian1999@hotmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500360.
Scheme 1. Organocatalytic strategies in the preparation of 1,2,3-
triazoles.
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Q. Jia, G. Yang, L. Chen, Z. Du, J. Wei, Y. Zhong, J. Wang
SHORT COMMUNICATION
secondary amines (via the enamine intermediate formed in Table 1. Optimization of the reaction conditions.[a]
situ) to construct 1,4-disubstituted 1,2,3-triazole com-
pounds[15] (Scheme 1b), even though the Ramachary group
had recently reported an elegant progress in the organo-
catalytic enolate-mediated synthesis of 1,2,3-triazoles from
aldehydes or ketones with aryl azides.[11c,11d]
Entry Solvent T [°C] Ratio of 1a/2a/3a t [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
CH3CN
CHCl3
MeOH
THF
toluene
DCE
THF
THF
THF
THF
50
50
50
50
50
50
50
50
50
50
r.t.
1.0:2.0:1.0
1.0:2.0:1.0
1.0:2.0:1.0
1.0:2.0:1.0
1.0:2.0:1.0
1.0:2.0:1.0
2.0:1.0:1.0
1.0:1.1:1.0
1.0:1.1:2.0
1.0:1.1:1.0
1.0:2.0:1.0
60
60
60
12
60
60
12
12
12
12
12
77
85
76
98
95
90
98
99
98
93
78
Results and Discussion
We began our initial investigation by a two-step synthesis
employing phenyl azide (1a), propionaldehyde (2a) and pyr-
rolidine (3a) in DMSO. After 12 h, 4-methyl-1-phenyl-5-
(pyrrolidin-1-yl)-4,5-dihydro-1H-1,2,3-triazole (4a) was suc-
cessfully obtained after flash chromatography; then 4a was
submitted to Cope elimination in the presence of m-chloro-
peroxybenzoic acid (m-CPBA) to afford the desired 1,4-di-
substituted 1,2,3-triazole 4aa. The two-step synthesis pro-
vided 4aa in an overall 60% yield. To further improve the
efficiency, we propose a one-pot strategy merging step 1 and
step 2 to form 4aa in high yield without isolating intermedi-
ate 4a (Scheme 2).
10[c]
11
THF
[a] Reaction conditions: A mixture of 1a (0.2 mmol, 1.0 equiv.), 2a
(0.4 mmol, 2.0 equiv.), 3a (0.2 mmol, 1.0 equiv.) in solvent (0.5 mL)
was stirred at 50 °C for 12 h. After the reaction was complete as
monitored by TLC, m-CPBA (1.5 equiv.) was added at 0 °C and
the mixture warmed up to room temperature for 1 h. [b] Yield of
isolated product after column chromatography. [c] Concentration
of 1a: 0.1 m.
Table 2. Effect of the secondary amine.[a]
Scheme 2. Synthesis of 1,4-disubstitued 1,2,3-triazoles in one pot.
To test the feasibility of this hypothesis, the reaction be-
tween phenyl azide (1a), propionaldehyde (2a) and pyr-
rolidine (3a) was chosen as the model to optimize the reac-
tion parameters. As shown in Table 1, the reaction was
carried out in various solvents (Table 1, Entries 1–6). To
our delight, excellent yields were achieved in THF (Entry 4,
12 h, 98%). Then we examined the effect of the substrate
ratio of 1a/2a/3a. The results indicated that a ratio of 1a/
2a/3a = 1.0:1.1:1.0 resulted in both, a quantitative yield and
a short reaction time (Table 1, Entry 8). Lowering of the
concentration of starting material 1a to 1.0 mol/L showed
no significant drop in yield (Table 1, Entry 10). Although
conducted at room temperature, a 78% yield was still
achieved in 12 h (Table 1, Entry 11). It is also worth noting
that the desired product 4aa was obtained as a single re-
gioisomer. The configuration was assigned unambiguously
by X-ray analysis of the product 4aa.[16]
Then we turned our attention to investigate the effect of
secondary amines in the reaction (Table 2). Other five- and
six-membered cyclic and acyclic secondary amines were
screened, and it was found that five-membered cyclic
amines (especially pyrrolidine 3a) gave the best yield (99%;
Table 2, Entry 1). Reactions in the presence of 3b, 3c and
3f as the catalysts did not afford the desired product.
Entry
Amine
Yield [%][b]
99
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
[c]
–
–
[c]
60
55
[c]
–
3g
3h
72
16
[a] Reaction conditions: A mixture of 1a (0.2 mmol, 1.0 equiv.), 2a
(0.4 mmol, 2.0 equiv.), 3a–h (0.2 mmol, 1.0 equiv.) in THF (0.5 mL)
was stirred at 50 °C for 12 h. After the reaction was complete as
monitored by TLC, m-CPBA (1.5 equiv.) was added at 0 °C and
the mixture warmed up to room temperature for 1 h. [b] Yield of
isolated product after column chromatography. [c] No reaction.
phenyl azide (1a), acetaldehydes 2 and pyrrolidine (3a) were
With the optimized reaction conditions in hand, we then allowed to react in one pot under optimal conditions to
examined the scope of azides 1 and acetaldehydes 2 in the give the desired 1,4-disubstitued 1,2,3-triazols in moderate
presence of pyrrolidine 3a. As summarized in Table 3, to high yields. Acetaldehydes bearing aliphatic and aro-
2
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1,4-Disubstituted 1,2,3-Triazoles
matic groups also reacted smoothly to afford the desired azide 1q, 3-phenylpropanal (2g) and pyrrolidine (3a) was
products in satisfying yields (Table 3, 4aa–4ah, 67–99%). To allowed to react under the standard conditions to lead to
our delight, various substituted azides, regardless of the an intermediate, which was easily converted in the presence
substitution patterns (with electron-withdrawing or -donat- of sodium methoxide into the target TcTS inhibitor 4qg
ing groups), afforded the corresponding products in good (Scheme 3, 90% yield). Consequently, the presented method
to excellent yields (Table 3, 4bg–4 mg, 85–97%). It is note- provides a convenient and high-yielding process for the syn-
worthy that heterocycles such as pyridine and naphthalenes thesis of 1,4-disubstituted triazole derivatives.
were also tolerated as substrates to afford the desired prod-
ucts in high yields (Table 3, 4ng and 4og, 96% and 98%,
respectively). In addition, the less reactive benzyl azide (1p)
produced 1,4-dibenzyl-1,2,3-triazole in moderate yield
(Table 3, 4pg, 60%).
Table 3. Scope of substrate.[a]
Scheme 3. Synthesis of Trypanosoma cruzi trans-sialidase (TcTS)
inhibitor.
To approve the proposed structure of the enamine inter-
mediate, a reaction of phenylacetaldehyde (2i) and pyrrol-
idine (3a) was conducted in the presence of TsOH and suc-
ceeded to form the enamine intermediate,[18] which was fol-
lowed by reaction with phenyl azide (1a) to afford the de-
sired product in 96% yield (Scheme 4). Build upon these
data, a mechanism is proposed and depicted in Scheme 5.
Condensation of acetaldehyde and pyrrolidine generates en-
amine A, which then reacts with phenyl azide (1a) through
a Huisgen 1,3-dipolar cycloaddition to afford the key inter-
mediate B. A subsequent oxidation of B leads to N-oxide
C. Finally, intermediate C is converted into the expected
triazole D by an elimination process.[13a]
Scheme 4. Reaction of the in situ formed enamine with azide.
Scheme 5. Plausible mechanism.
Conclusions
We have developed a new method to efficiently prepare
1,4-disubstituted 1,2,3-triazoles from organic azides, com-
mercially available aldehydes and cheap secondary amines
by a one-pot strategy in good to high yields and excellent
levels of regioselectivities. To demonstrate the utility of this
chemistry, several biologically important molecules were
[a] Reaction conditions: A mixture of 1a (0.2 mmol, 1.0 equiv.), 2a
(0.4 mmol, 2.0 equiv.), 3a (0.2 mmol, 1.0 equiv.) in THF (0.5 mL)
was stirred at 50 °C for 12 h. After the reaction was complete, m-
CPBA (1.5 equiv.) was added at 0 °C and the mixture warmed up
to room temperature for 1 h.
To further investigate the generality and potential of our synthesized. Considering the ready availability of the start-
protocol, we undertook the formal synthesis of Trypano- ing materials and the operational simplicity, we believe that
soma cruzi trans-sialidase (TcTS) inhibitor.[17] A mixture of this method will have a broad application both in academy
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Q. Jia, G. Yang, L. Chen, Z. Du, J. Wei, Y. Zhong, J. Wang
SHORT COMMUNICATION
13C NMR (100 MHz, CDCl3): δ = 148.43, 138.86, 137.16, 129.67,
128.80, 128.73, 128.53, 126.65, 120.38, 119.72, 77.48, 77.16, 76.85,
32.29 ppm.
and industry. Further mechanistic studies and applications
of this methodology are in progress, and more results will
be reported in due course.
4ag: White solid (yield 67%). 1H NMR (400 MHz, CDCl3): δ =
7.98 (s, 2 H), 7.73 (d, J = 8.0 Hz, 4 H), 7.51 (t, J = 15.2 Hz, 4 H),
7.43 (t, J = 14.8 Hz, 2 H), 4.38 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.80, 137.10, 129.74, 128.70, 120.49, 120.20, 77.35,
77.24, 77.04, 76.72, 22.91 ppm.
4ah: White solid (yield 93%). 1H NMR (400 MHz, CDCl3): δ =
7.73 (s, 1 H), 7.71 (s, 2 H), 7.52–7.49 (m, 2 H), 7.43–7.35 (m, 1 H),
1.42 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.34,
137.36, 129.60, 128.31, 120.41, 116.81, 77.41, 77.09, 76.77, 30.85,
30.32 ppm.
4bg: White solid (yield 85%). 1H NMR (400 MHz, CDCl3): δ =
7.67–7.60 (m, 2 H), 7.57 (s, 1 H), 7.34–7.28 (m, 4 H), 7.26–7.19 (m,
1 H), 7.18–7.09 (m, 2 H), 4.14 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.49, 161.02, 148.58, 138.76, 133.47, 133.44, 128.78,
128.75, 126.68, 122.37, 122.29, 119.89, 116.70, 116.47, 77.48, 77.16,
76.84, 32.25 ppm.
Experimental Section
1
General: H and 13C NMR spectra were recorded with a Mercury-
Plus 300 (300 MHz) or a Bruker ACF400 spectrometer (400 MHz
and 101 MHz). Chemical shifts for protons are reported in ppm
downfield from the tetramethylsilane signal and are referenced to
residual 1H in the NMR solvent (CHCl3: δ = 7.26 ppm). Chemical
shifts for carbons are reported in ppm downfield from the tetra-
methylsilane signal and are referenced to the carbon resonance of
the solvent (CDCl3: δ = 77.16 ppm). Data are represented as fol-
lows: chemical shift, multiplicity (br. = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constant
in Hertz (Hz), integration. For thin layer chromatography (TLC),
Merck pre-coated TLC plates (Merck 60 F254) were used, and
compounds were visualized with UV light of 254 nm. Further visu-
alization was achieved by staining with iodine. Flash chromatog-
raphy separations were performed on Merck 60 mesh (0.040–
0.063 mm) silica gel.
1
4cg: Light yellow solid (yield 94%). H NMR (400 MHz, CDCl3):
δ = 7.90 (td, J = 7.8, 1.7 Hz, 1 H), 7.72 (d, J = 2.9 Hz, 1 H), 7.40–
7.33 (m, 1 H), 7.33–7.18 (m, 7 H), 4.17 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.53, 152.04, 147.99, 138.77, 130.03,
129.95, 128.76, 128.71, 126.63, 125.21, 125.17, 124.82, 122.81,
122.73, 117.05, 116.85, 77.49, 77.17, 76.85, 32.19 ppm.
4dg: White solid (yield 85%). 1H NMR (400 MHz, CDCl3): δ =
7.61 (dt, J = 4.0, 2.4 Hz, 3 H), 7.46–7.38 (m, 2 H), 7.35–7.27 (m,
4 H), 7.26–7.17 (m, 1 H), 4.14 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.73, 138.68, 135.63, 134.21, 129.82, 128.78, 128.77,
126.72, 121.50, 119.59, 77.47, 77.15, 76.83, 32.26 ppm.
Typical Procedure for the Synthesis of 4aa: To a solution of THF
(0.5 mL) were added amine 3a (0.20 mmol), aldehyde 2a
(0.22 mmol), and azide 1a (0.20 mmol). The reaction mixture was
stirred at 50 °C for 12 h. After the reaction was complete, 1.5 equiv.
of m-CPBA was added to the reaction mixture at 0 °C and the
mixture warmed up to room temperature for 1 h. The reaction mix-
ture was then concentrated under reduced pressure, and the crude
product was purified by column chromatography on silica gel (hex-
ane/EtOAc, 10:1 to 5:1) to afford the desired product 4aa.
4aa: White solid (yield 99%). 1H NMR (400 MHz, CDCl3): δ =
7.76 (s, 1 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.47 (t, J = 15.6 Hz, 2 H),
7.38 (t, J = 14.8 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 144.00, 137.13, 129.63, 128.38, 120.24, 119.46, 77.55,
77.23, 76.91, 10.78 ppm.
1
4eg: Light yellow solid (yield 87%). H NMR (400 MHz, CDCl3):
δ = 7.62 (s, 1 H), 7.52 (dd, J = 8.2, 5.4 Hz, 2 H), 7.37 (dd, J = 8.8,
2.4 Hz, 1 H), 7.34–7.27 (m, 4 H), 7.26–7.19 (m, 1 H), 4.17 (s, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 147.64, 138.66, 135.99,
133.73, 130.51, 129.29, 128.75, 128.73, 128.48, 128.23, 126.68,
123.51, 77.49, 77.17, 76.85, 32.16 ppm.
4ab: White solid (yield 96%). 1H NMR (400 MHz, CDCl3): δ =
7.76–7.68 (m, 3 H), 7.48 (t, J = 7.2 Hz, 2 H), 7.42–7.32 (m, 1 H),
3.23–3.10 (m, 1 H), 1.37 (d, J = 7.2 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.22, 137.29, 129.60, 128.32, 120.33,
117.54, 77.49, 77.17, 76.85, 29.67, 25.87, 22.48 ppm.
4ac: White solid (yield 96%). 1H NMR (400 MHz, CDCl3): δ =
7.76–7.68 (m, 3 H), 7.54–7.45 (m, 2 H), 7.44–7.36 (m, 1 H), 2.83
(q, J = 22.8 Hz, 2 H), 1.34 (t, J = 15.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 150.52, 137.28, 129.64, 128.39, 120.37,
118.48, 77.42, 77.10, 76.78, 19.05, 13.63 ppm.
4fg: White solid (yield 90%). 1H NMR (400 MHz, CDCl3): δ =
7.60–7.49 (m, 3 H), 7.31 (d, J = 4.4 Hz, 4 H), 7.27–7.16 (m, 1 H),
7.01–6.89 (m, 2 H), 4.14 (s, 1 H), 3.81 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.66, 148.19, 138.96, 130.66, 128.79,
128.70, 126.60, 122.02, 119.87, 114.69, 77.45, 77.13, 76.82, 55.60,
32.31 ppm.
1
4gg: Light yellow solid (yield 96%). H NMR (400 MHz, CDCl3):
δ = 7.60 (s, 1 H), 7.36–7.27 (m, 6 H), 7.26–7.19 (m, 1 H), 7.19–7.14
(m, 1 H), 6.90 (dd, J = 8.4, 2.4 Hz, 1 H), 4.14 (s, 2 H), 3.81 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.56, 148.36, 138.85,
138.17, 130.43, 128.79, 128.73, 126.64, 119.79, 114.37, 112.25,
106.20, 77.49, 77.18, 76.86, 55.60, 32.27 ppm.
1
4ad: Light yellow oil (yield 89%). H NMR (400 MHz, CDCl3): δ
= 7.78–7.67 (m, 3 H), 7.53–7.45 (m, 2 H), 7.44–7.36 (m, 1 H), 2.77
(t, J = 15.2 Hz, 2 H), 1.71–1.76 (m, 2 H), 1.01 (t, J = 14.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.92, 137.27, 129.63,
128.37, 120.33, 118.88, 77.43, 77.11, 76.79, 27.65, 22.64, 13.78 ppm.
1
4hg: Light yellow solid (yield 94%). H NMR (400 MHz, CDCl3):
δ = 7.76 (s, 1 H), 7.72 (dd, J = 7.9, 1.6 Hz, 1 H), 7.39–7.26 (m, 5
H), 7.26–7.16 (m, 1 H), 7.09–6.95 (m, 2 H), 4.17 (s, 2 H), 3.80 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.15, 146.80, 139.20,
1
4ae: Light yellow oil (yield 87%). H NMR (400 MHz, CDCl3): δ
= 7.79–7.67 (m, 3 H), 7.49 (t, J = 15.6 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 129.95, 128.78, 128.61, 126.47, 125.47, 123.74, 121.15, 112.26,
1 H), 2.85–2.72 (m, 2 H), 1.72 (dt, J = 15.3, 7.6 Hz, 2 H), 1.43 (dq,
J = 14.6, 7.4 Hz, 2 H), 0.95 (t, J = 14.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.15, 137.30, 129.64, 128.37, 120.36,
118.79, 77.39, 77.07, 76.76, 31.50, 25.35, 22.31, 13.81 ppm.
77.49, 77.17, 76.86, 55.95, 32.25 ppm.
1
4ig: Light yellow solid (yield 97%). H NMR (400 MHz, CDCl3):
δ = 7.83 (s, 1 H), 7.37 (d, J = 3.2 Hz, 1 H), 7.34–7.27 (m, 4 H),
7.26–7.17 (m, 1 H), 6.92 (dt, J = 9.1, 6.0 Hz, 2 H), 4.16 (s, 2 H),
3.77 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
1
4af: Light yellow solid (yield 98%). H NMR (400 MHz, CDCl3):
δ = 7.68–7.62 (m, 2 H), 7.60 (s, 1 H), 7.44 (t, J = 15.2 Hz, 2 H), 153.86, 146.88, 144.90, 139.17, 128.76, 128.61, 126.47, 123.71,
7.37 (d, J = 7.3 Hz, 1 H), 7.33–7.18 (m, 5 H), 4.15 (s, 1 H) ppm. 115.43, 113.67, 110.36, 77.51, 77.19, 76.87, 56.53, 55.93, 32.23 ppm.
4
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1,4-Disubstituted 1,2,3-Triazoles
1
4jg: Light yellow solid (yield 88%). H NMR (400 MHz, CDCl3):
δ = 7.56 (s, 1 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 4.4 Hz, 4
H), 7.26–7.18 (m, 3 H), 4.14 (s, 2 H), 2.36 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 148.25, 138.94, 138.57, 134.90, 130.15,
128.80, 128.71, 126.61, 120.28, 119.69, 77.49, 77.17, 76.85, 32.31,
21.06 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods and characterization data.
Acknowledgments
The s acknowledge the financial support from the National Natural
Science Foundation of China (21272043), the Science and Technol-
ogy Planning Project of Guangdong Province (2007A020300007-
10, 2011B090400573) and the Guangdong Natural Science Foun-
dation (S2011010004967)
1
4kg: Light yellow solid (yield 94%). H NMR (400 MHz, CDCl3):
δ = 7.55 (s, 1 H), 7.45 (d, J = 1.9 Hz, 1 H), 7.36–7.27 (m, 5 H),
7.26–7.20 (m, 1 H), 7.17 (d, J = 8.1 Hz, 1 H), 4.14 (s, 2 H), 2.27
(d, J = 6.8 Hz, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
148.17, 138.98, 138.22, 137.23, 135.10, 130.54, 128.81, 128.70,
126.59, 121.53, 119.72, 117.67, 77.49, 77.17, 76.86, 32.32, 19.86,
19.43 ppm.
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1
4lg: Light yellow solid (yield 92%). H NMR (400 MHz, CDCl3):
δ = 7.56 (s, 1 H), 7.34–7.26 (m, 6 H), 7.26–7.19 (m, 1 H), 7.00 (s,
1 H), 4.15 (s, 2 H), 2.34 (s, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 148.22, 139.57, 138.94, 137.06, 130.13, 128.81, 128.71,
126.60, 119.78, 118.19, 77.47, 77.15, 76.83, 32.33, 21.28 ppm.
4mg: White solid (yield 60%). 1H NMR (400 MHz, CDCl3): δ =
7.36–7.31 (m, 3 H), 7.28 (m, 1 H), 7.26–7.16 (m, 6 H), 7.10 (s, 1
H), 5.44 (s, 2 H), 4.05 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 148.08, 139.06, 134.86, 129.06, 128.71, 128.61, 127.96, 126.48,
121.36, 77.41, 77.10, 76.78, 54.05, 32.32, 29.72 ppm.
4ng: White solid (yield 97%). 1H NMR (400 MHz, CDCl3): δ =
7.62–7.51 (m, 3 H), 7.38–7.26 (m, 6 H), 7.26–7.19 (m, 1 H), 7.13
(t, J = 7.4 Hz, 1 H), 7.08–6.98 (m, 4 H), 4.14 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 157.63, 156.44, 148.41, 138.89,
132.44, 130.04, 128.82, 128.75, 126.67, 124.10, 122.13, 119.89,
119.35, 119.31, 77.51, 77.19, 76.87, 32.31 ppm.
4og: White solid (yield 96%). 1H NMR (400 MHz, CDCl3): δ =
8.94 (s, 1 H), 8.64 (d, J = 3.5 Hz, 1 H), 8.20–7.97 (m, 1 H), 7.71
(s, 1 H), 7.44 (dd, J = 8.2, 4.7 Hz, 1 H), 7.38–7.28 (m, 4 H), 7.27–
7.20 (m, 1 H), 4.17 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 149.67, 149.00, 141.41, 138.51, 128.77, 128.75, 127.85, 126.75,
124.20, 119.65, 77.51, 77.19, 76.87, 32.20 ppm.
4pg: Brown solid (yield 98%). 1H NMR (400 MHz, CDCl3): δ =
7.97–7.91 (m, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.59 (d, J = 8.3 Hz,
1 H), 7.54–7.44 (m, 5 H), 7.33 (dt, J = 15.1, 7.4 Hz, 4 H), 7.22 (dd,
J = 8.1, 6.1 Hz, 1 H), 4.23 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 147.67, 138.95, 134.15, 133.88, 130.24, 128.85, 128.77,
128.56, 128.27, 127.82, 127.02, 126.67, 124.97, 124.25, 123.47,
122.44, 77.51, 77.19, 76.87, 32.34 ppm.
Procedure for Synthesis of Trypanosoma cruzi trans-Sialidase (TcTS)
Inhibitor: To THF (0.5 mL) were added pyrrolidine 3a (0.20 mmol),
3-phenylpropanal (2g) (0.22 mmol) and (2R,3S,4S,5R,6R)-2-(acet-
oxymethyl)-6-azidotetrahydro-2H-pyran-3,4,5-triyltriacetate (1q)
(0.20 mmol). The reaction mixture was stirred at 50 °C for 12 h.
After the reaction was complete, m-CPBA (1.5 equiv.) was added
at 0 °C and the mixture warmed up to room temperature for 1 h.
The reaction mixture was concentrated under reduced pressure,
and the crude product was purified by flash column chromatog-
raphy (hexane/EtOAc, 10:1 to 5:1) to afford the desired product
4qg.
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1
4qg: White solid (yield 94%). H NMR (400 MHz, CD3OD): δ =
7.91 (s, 1 H), 7.33–7.25 (m, 4 H), 7.25–7.18 (m, 1 H), 5.57 (d, J =
9.2 Hz, 1 H), 4.08 (s, 2 H), 3.93–3.84 (m, 2 H), 3.71 (dd, J = 12.2,
5.2 Hz, 1 H), 3.61–3.53 (m, 2 H), 3.53–3.44 (m, 1 H), 3.33 (dd, J
= 3.1, 1.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CD3OD): δ =
147.10, 138.87, 128.31, 128.26, 126.16, 121.67, 88.14, 79.68, 77.10,
72.54, 69.46, 60.96, 47.85, 47.64, 47.42, 31.21 ppm.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O50360
/KAP1
Date: 20-04-15 14:59:11
Pages: 7
Q. Jia, G. Yang, L. Chen, Z. Du, J. Wei, Y. Zhong, J. Wang
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Received: March 18, 2015
Published Online: ᭿
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50360
/KAP1
Date: 20-04-15 14:59:11
Pages: 7
1,4-Disubstituted 1,2,3-Triazoles
Triazole Synthesis
Q. Jia, G. Yang, L. Chen, Z. Du,* J. Wei,
Y. Zhong, J. Wang* .......................... 1–7
A Facile One-Pot Metal-Free Synthesis of
1,4-Disubstituted 1,2,3-Triazoles
A one-pot synthesis of 1,4-disubstituted
1,2,3-triazoles by 1,3-dipolar cycloaddition
reaction has been developed. This strategy
provides a rapid and efficiency way to con-
struct 1,4-disubstitued 1,2,3-triazoldes in
good to excellent yields and high levels of
regioselectivity (r.r. = ratio of regioiso-
mers).
Keywords: Metal-free synthesis / Triazoles /
Azides / 1,3-Dipolar cycloaddition
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