Synthesis of 1,4-disubstituted 1,2,3-triazoles via click reaction in micro flow reactor

Article abstract of DOI:10.3987/COM-13-S(S)51

A Cu (I)-catalyzed three-component click reaction of alkyl bromide, terminal alkyne and sodium azide was developed in micro flow reactor. Sodium ascorbate was added as additive to prevent the oxidative coupling of desired product with terminal alkyne. Und

Full text of DOI:10.3987/COM-13-S(S)51

HETEROCYCLES, Vol. 88, No. 2, 2014
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HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1511 - 1517. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 26th June, 2013, Accepted, 20th August, 2013, Published online, 28th August, 2013
DOI: 10.3987/COM-13-S(S)51
SYNTHESIS OF 1,4-DISUBSTITUTED 1,2,3-TRIAZOLES VIA CLICK
REACTION IN MICRO FLOW REACTOR
Ming Lei,1,2* Ruijun Hu,1 Yanguang Wang,1 and Hong Zhang2,3*
1 Department of Chemistry, Zhejiang University, Hangzhou 310027, China. 2 Key
Laboratory of Medical Molecular Imaging of Zhejiang Province, Zhejiang
3
University Medical PET Centre, Hangzhou 310009, China. Department of
Nuclear Medicine, Second Affiliated Hospital of Zhejiang University, School of
Medicine, Hangzhou 310009, China. E-mail: leiming@zju.edu.cn
Abstract – A Cu (I)-catalyzed three-component click reaction of alkyl bromide,
terminal alkyne and sodium azide was developed in micro flow reactor. Sodium
ascorbate was added as additive to prevent the oxidative coupling of desired
product with terminal alkyne. Under optimized condition, various
1,4-disubstituted-1,2,3-triazoles were obtained in 85-95% yield with exclusive
1,4-regioisomeric selectivity. The present smooth procedure greatly accelerated
the reaction due to the excellent mixing and mass transfer in micro flow system.
The Huisgen 1,3-dipolar cycloaddition of azides and alkynes,1 one of the most powerful click reactions
which resulting in 1,2,3-triazoles has been widely used in various research areas, ranging from bioorganic
and medicinal chemistry to materials science for its remarkable efficiency. The recently discovered
copper catalyzed (CuAAC) version,2 which accelerates the reaction up to 107 times, has placed it in a
class of its own and has enabled many novel applications ranging from drug discovery to surface science
where rapid and reliable bond formation is required. In this fashion, a number of peptide- and
protein-based bioconjugates have been successfully prepared.3 Moreover, one pot three-component
procedure avoids isolation and handling of potentially unstable organic azides, as they are generated in
situ, making this already powerful click process even more user-friendly and safe.4 Besides the
advantages of its high efficiency, regioselectivity, and compatibility with reaction conditions, the
heterocyclic moiety of 1,4-disubstituted 1,2,3-triazoles is stable under in vivo conditions.5 The triazole
linker also introduces some degree of polarity into the tracer, adding a 1,2,3-triazole group is expected to
be advantageous with regard to the pharmacological properties of the resulting radiotracer molecules. As
a result of ongoing improvements in 1,3-dipolar cycloaddition chemistry and because of its versatility and
Dedicated with respect to Professor Victor Snieckus on the occasion of his 77th birthday.

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short reaction times, “click” radiochemistry promises to become a widely used tool for preparation of
radiotracers. Subsequently, this approach has been applied for radiolabeling of different substrates with
[18F]-fluorine and other radioisotopes.6
Combinatorial chemistry as a high-throughput synthetic technology has became a powerful tool for the
discovery of new drugs and increasing interests have been drawn onto the application of microfluidic
chips in this field.7 Automated microreactor-based (microfluidic chip) continuous flow systems have the
potential to greatly accelerate the production of small molecule libraries of drug-like structures (primarily
heterocycles).8 Our previous work had demonstrated the use of microfluidic based reactors could
eliminate the formation of the corresponding byproduct and ensure the desired transformation with very
high selectivity and efficiency.9 In comparison with the classical batch systems, especially for the
three-component cascade approach, the micro flow technique enhances accurate temperature control and
efficient mixing. As part of our ongoing research to develop new synthetic methods for the generation of
heterocycle libraries and radiolabelling imaging probes based on microfluidic reactor, we herein report
the micro flow synthesis of 1,4-disubstituted 1,2,3-triazoles derivatives from corresponding alkyl
bromides, sodium azide, and alkynes.
Our reactor is a microfluidic chip fabricated in soda-lime glass with channels produced by standard
photolithography and wet etching techniques.10 The internal geometry of the micro flow reactor is 500
µm × 100 µm × 1000 mm. The structure of the reactor is illustrated in Scheme 1. PTFE tubing (inner
diameter ID = 0.9 mm) was fitted to the inlet and outlet hole directly. The end of inlet tube was connected
to a Harvard PHD 2000 syringe pump and the end of outlet tube was connected to a sample vial, which
was used to collect the final solution.
Scheme 1
We first investigated adapting the model reaction into a continuous micro flow process for the synthesis
of 1-benzyl-4-phenyl-1H-1,2,3-triazole (3a) using benzyl bromide (1a), phenylacetylene (2a) and sodium
azide in the presence of CuI and sodium ascorbate at different flow rates and temperatures. Herein,

HETEROCYCLES, Vol. 88, No. 2, 2014
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sodium ascorbate was used as reducing agent to eliminate the formation of oxidative coupling
o
byproduct.2a,2k Preliminary test were performed at 50 C. The acetonitrile solution of benzyl bromide
(0.03 M) mixed with phenylacetylene (0.03 M) and the aqueous solution containing sodium azide (0.045
M), sodium ascorbate (0.03 M), and CuI (0.003 M) were introduced respectively through syringe pump at
identical flow rates changed from 5 μL/min to 15 μL/min. The results are summarized in Table 1. When
the flow rates were respectively set up at 5, 10, 15 μL/min, the yields of product increased from 80% to
o
94% with the increase of flow rate (Table 1, entries 1–3). At 65 C, when flow rates set up at 5, 10, 15
μL/min respectively, the reactions afforded the product with yields between 91% and 95% (Table 1,
entries 4–6). While, further increasing the flow rate to 20 μL/min led slight decrease of yield (Table 1,
entry 7). At 70 oC, significant drop of yields were observed at same flow rates (Table 1, entries 8–10). In
general, at 65 oC and 15 μL/min flow rate, the reaction could afford best yield.
Table 1. Synthesis of 1,4-disubstituted-1,2,3-triazoles in micro flow reactor at different flow rates and
temperature
Temperature
Yield
(%)b
Flow rate
(μL/min)
Residence time
(s)a
Entry
(oC)
50
1
2
5
520
260
173
520
260
173
130
520
260
173
80
93
94
91
91
95
93
84
83
88
50
50
65
65
65
65
70
70
70
10
15
5
3
4
5
10
15
20
5
6
7
8
9
10
15
10
a Average time of three runs; b Isolated yield.
Subsequently, a series of 1,4-disubstituted 1,2,3-triazole derivatives were synthesized to investigate the
scope and limitation of this reaction using the optimized micro flow procedure. As shown in Scheme 2,
various alkyl bromides and alkynes could afford corresponding products in good to excellent yields with
exclusive 1,4-regioisomeric selectivity. Benzyl bromides bearing electron-donating groups are more
reactive than those bearing electron-withdrawing group. It is noteworthy that in the present micro flow
reactor the reactions completed smoothly within several minutes. Moreover, by-product was not observed
in all cases taking the advantage of enhanced mass transfer.

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Scheme 2. Synthesis of 1,4-disubstituted 1,2,3-triazoles in micro flow reactora
CuI (10%mol)
N
R1
N
Na ascorbate
R2
R1
Br
+
N
+
NaN3
micro flow reactor
R2
1
2
3
N
N
N
N
N
N
N
N
N
Ph
Ph
N
N
N
O2N
Br
Ph
Ph
Ph
Ph
3a, 95%
3b,87%
3c, 85%
3d, 93%
N
N
N
N
Ph
N
N
Ph
N
N
Ph
N
N
N
N
CO2Me
OH
Ph
HO
3e, 90%
3f, 90%
3g, 88%
3h, 89%
N
N
N
N
N
nC7H15
N
EtO2C
N
nC7H15
N
N
Ph
N
N
N
CO2Me
Ph
Ph
3i, 92%
3j, 96%
3k, 91%
3l, 89%
a Isolated yield.
In conclusion, we have successfully developed a rapid and efficient process for the synthesis of
1,4-disubstituted 1,2,3-triazole derivatives using micro flow reactor. Under the optimized conditions, a
series of 1,4-disubstituted 1,2,3-triazole derivatives were synthesized in 85–95% isolated yields. This
process was also applied to similar reactions using aliphatic alkynes as the substrate. Compared with the
classical batch systems, the present smooth procedure greatly accelerated the reaction due to the excellent
mixing and mass transfer in micro flow system. These advances will facilitate the rapid synthesis of
biologically compounds library and radio labeled imaging probes. Further exploration of the reactivity
features of this methodology and applications to the synthesis of complex molecules and the drug
discovery process are in progress.
EXPERIMENTAL
All chemicals were reagent grade and used as purchased without further purification unless otherwise

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stated. Column chromatography was performed using silica gel 60 (300-400 mesh). Melting points were
1
obtained on a YANACO micro melting point apparatus and are uncorrected. HNMR spectra were
recorded in CDCl3 using TMS as an internal reference with a Bruker Avance-400 spectrometer operating
at 400 MHz.
Typical Procedure for the Synthesis of 1,4-Disubstituted 1,2,3-Triazoles in Microfluidic Chip.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (3a). Acetonitrile solution (3 mL) of benzyl bromide (0.03 M)
mixed with phenylacetylene (0.03 M) and the aqueous solution (3 mL) containing sodium azide (0.045
M), sodium ascorbate (0.03 M), and CuI (0.003 M) were transferred into separate gas-tight syringes. The
syringes were placed in a Harvard PHD 2000 syringe pump which was set to deliver the reactants at
identical flow rate of 15 μL/min. The output mixture was collected and then concentrated under vacuum.
The residue was subjected to silica gel column chromatography with Pet–EA (2:1) as eluent to give 3a
(20 mg, 95%); mp 128–129 ˚C (lit.,4c mp 129–129.5 ˚C); 1H NMR (400 MHz, CDCl3) δ = 5.58 (s, 2 H),
7.30–7.41 (m, 6 H), 7.68 (s, 1 H), 7.80–7.82 (m, 4 H).
1
1-(4-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (3b): mp 152–153 ˚C (lit.,4c mp 152–152.5 ˚C); H
NMR δ = 5.53 (s, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 7.22–7.41 (m, 3 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.67 (s, 1
H), 7.80 (d, J = 8.4 Hz, 2 H).
1
1-(4-Nitrobenzyl)-4-phenyl-1H-1,2,3-triazole (3c): mp 155–157 ˚C (lit.,4c mp 156–157 ˚C); H NMR δ
= 5.65 (s, 2 H), 7.33–7.37 (m, 3 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.77 (s, 1 H), 7. 79 (d, J = 8.5 Hz, 2 H),
8.21 (dd, J = 8.8, 1.9 Hz, 2 H).
1
1-(4-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (3d): mp 110–112 ˚C (lit.,4c mp 110 ˚C); H NMR δ =
2.38 (s, 3 H), 5.55 (s, 2 H), 7.28–7.43 (m, 7 H), 7.65 (s, 1 H), 7.80–7.82 (m, 2 H).
1
4-Phenyl-1-(2-phenylethyl)-1H-1,2,3-triazole (3e): mp 138–139 ˚C (lit.,4c mp 139 ˚C); H NMR δ =
3.24 (t, J = 7.2 Hz, 2 H), 4.63 (t, J = 7.2 Hz, 8 H), 7.15 (d, J = 7.6 Hz, 2 H), 7.26–7.44 (m, 6 H), 7.47 (s, 1
H), 7.66 (t, J = 8.1 Hz, 2 H), 7.78 (d, J = 7.1 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H).
2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-propanol (3f): mp 77–78 ˚C (lit.,4c mp 77 ˚C); 1H NMR δ = 1.57 (s,
6 H), 3.19 (s, 1H), 5.43 (s, 2 H), 7.21–7.36 (m, 5 H), 7.39 (s, 1 H).
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanol (3g): mp 78–79 ˚C (lit.,4c mp 78–78.5 ˚C); 1H NMR δ = 4.65
(s, 2 H), 5.41 (s, 2 H), 7.18–7.29 (m, 5 H), 7.45 (s, 1 H).
1-Benzyl-4-methoxycarbonyl-1,2,3-triazole (3h): mp 104–106 ˚C (lit.,4f mp 104–107 ˚C); 1H NMR δ =
3.81 (s, 3 H), 5.65 (s, 2 H), 7.40–7.42 (m, 5 H), 8.90 (s, 1 H).
1-Benzyl-4-butyl-1H-1,2,3-triazole (3i):4c oil; 1H NMR δ = 0.81 (t, J = 7.0 Hz, 3 H), 1.18–1.56 (m, 4 H),
2.35–2.63 (m, 2 H), 5.38 (s, 2 H), 7.02–7.26 (m, 5 H), 7.38 (s, 1 H).
1
Ethyl 2-(4-Phenyl-1H-1,2,3-triazol-1-yl)acetate (3j): mp 93–94 ˚C (lit.,2h mp 94–95 ˚C); H NMR δ =
1.32 (t, J = 7.2 Hz, 3 H ), 4.31 (q, J = 7.2 Hz, 2 H), 5.22 (s, 2 H), 7.25–7.90 (m, 5 H), 7.91 (s, 1 H).

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1-Octyl-4-phenyl-1H-1,2,3-triazole (3k): mp 77–78 ˚C (lit.,4f mp 78–79 ˚C); 1H NMR δ = 0.86 (t, J =
7.1 Hz, 3 H), 1.15–1.23 (m, 10 H), 1.89 (t, J = 7.1 Hz, 2 H), 4.42 (t, J = 7.1 Hz, 2 H), 7.35 (m, 1 H), 7.47
(m, 2 H), 7.86 (m, 2 H), 8.58 (s, 1 H).
1
4-Methoxycarbonyl-1-octyl-1H-1,2,3-triazole (3l): mp 78–80 ˚C (lit.,4f mp 78–80 ˚C); H NMR δ =
0.87 (t, J = 7.2 Hz, 3 H), 1.15–1.22 (m, 10 H), 1.89 (m, 2 H), 3.83 (s, 3 H), 4.43 (t, J = 7.2 Hz, 2 H), 8.81
(s, 1 H).
ACKNOWLEDGEMENTS
Financial support of this work from National Science and Technology Support Program (No.
2012BAI13B06) is gratefully acknowledged.
REFERENCES AND NOTES
1. R. Huisgen In 1,3-dipolar cycloaddition chemistry; ed. by A. Padwa; Wiley: New York, 1984.
2. (a) V. V. Rostovstev, L. G. Green, V. V. Fokin, and K. B. Sharpless, Angew. Chem. Int. Ed., 2002,
41, 2596; (b) V. O. Rodionov, V. V. Fokin, and M. G. Finn, Angew. Chem. Int. Ed., 2005, 44, 2210;
(c) B. H. Lipshutz and B. R. Taft, Angew. Chem. Int. Ed., 2006, 45, 8235; (d) S. Díez-González, A.
Correa, L. Cavallo, and S. P. Nolan, Chem. Eur. J., 2006, 12, 7558; (e) T. R. Chan, R. Hilgraf, K. B.
Sharpless, and V. V. Fokin, Org. Lett., 2004, 6, 2853; (f) C. Girard, E. Önen, M. Aufort, S.
Beauvière, E. Samson, and J. Herscovici, Org. Lett., 2006, 8, 1689; (g) S. Chassaing, M. Kumarraja,
A. S. S. Sido, P. Pale, and J. Sommer, Org. Lett., 2007, 9, 883; (h) F. Alonso, Y. Moglie, G. Radivoy,
and M. Yus, Eur. J. Org. Chem., 2010, 1875; (i) C. Z. Tao, X. Cui, J. Li, A. X. Liu, L. Liu, and Q. X.
Guo, Tetrahedron Lett., 2007, 48, 3525; (j) I. S. Park, M. S. Kwon, Y. Kim, J. S. Lee, and J. Park,
Org. Lett., 2008, 10, 497; (k) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302.
3. (a) A. Devadoss and C. E. D. Chidsey, J. Am. Chem. Soc., 2007, 129, 5370; (b) L. V. Lee, M. L.
Mitchell, S. J. Huang, V. V. Fokin, K. B. Sharpless, and C. H. Wong, J. Am. Chem. Soc., 2003, 125,
9588; (c) T. S. Seo, Z. Li, H. Ruparel, and J. Ju, J. Org. Chem., 2003, 68, 609; (d) Q. Wang, T. R.
Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless, and M. G. Finn, J. Am. Chem. Soc., 2003, 125, 3192;
(e) H. Struthers, B. Spingler, T. L. Mindt, and R. Schibli, Chem. Eur. J., 2008, 14, 6173; (f) J. Shen,
R. Woodward, J. P. Kedenburg, X. W. Liu, M. Chen, L. Y. Fang, D. X. Sun, and P. G. Wang, J. Med.
Chem., 2008, 51, 7417; (g) J. F. Lutz and Z. Zarafshani, Adv. Drug Delivery Rev., 2008, 60, 958.
4. (a) P. Appukkuttan, W. Dehaen, V. V. Fokin, and E. V. der Eycken, Org. Lett., 2004, 6, 4223; (b) A.
K. Feldman, B. Colasson, and V. V. Fokin, Org. Lett., 2004, 6, 3897; (c) H. Sharghi, R. Khalifeh,
and M. M. Doroodmanda, Adv. Synth. Catal., 2009, 351, 207; (d) D. Yang, N. Fu, Z. L. Liu, Y. Li,
and B. H. Chen, Synlett, 2007, 278; (e) D. Kumar and V. B. Reddy, Synthesis, 2010, 1687; (f) K.

HETEROCYCLES, Vol. 88, No. 2, 2014
1517
Kacprzak, Synlett, 2005, 943; (g) A. R. Bogdan and N. W. Sach, Adv. Synth. Catal., 2009, 351, 849;
(h) F. Alonso, Y. Moglie, G. Radivoy, and M. Yusa, Adv. Synth. Catal., 2010, 352, 3208.
5. B. H. M. Kuijpers, S. Groothuys, A. C. Soede, P. Laverman, O. C. Boerman, F. L. van Delft, and F.
P. J. T. Rutjes, Bioconjugate. Chem., 2007, 18, 1847.
6. (a) U. Sirion, H. J. Kim, J. H. Lee, J. W. Seo, B. S. Lee, S. J. Lee, S. J. Oh, and D. Y. Chi,
Tetrahedron Lett., 2007, 48, 3953; (b) M. Glaser and E. G. Robins, J. Labelled Compd. Radiopharm.,
2009, 52, 407; (c) C. Mamat, T. Ramenda, and F. R. Wuest, Mini-Rev. Org. Chem., 2009, 6, 21; (d)
M. Lei, M. Tian, and H. Zhang, Curr. Med. Imaging Rev., 2012, 8, 302.
7. (a) L. Kang, B. G. Chung, R. A. Langer, and A. Khademhosseini, Drug Discovery Today, 2008, 13,
1; (b) C. O. Kappe and D. Dallinger, Nature Rev. Drug Discovery, 2006, 5, 51; (c) C. Wiles and P.
Watts, Expert Opin. Drug Discovery, 2007, 11, 1487.
8. (a) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan, and D. T. McQuade, Chem. Rev., 2007,
107, 2300; (b) I. R. Baxendale, J. J. Hayward, S. Lanners, S. V. Ley, and C. D. Smith, 'Microreactors
in Organic Synthesis and Catalysis,' ed. by T. Wirth, Wiley-VCH, Weinheim, 2008; (c) W. Ehrfeld,
V. Hessel, and H. Lowe, 'Microreactors: New Technology for Modern Chemistry,' Wiley, Weinheim,
2000; (d) C. M. Griffiths-Jones, M. D. Hopkin, D. Jönsson, S. V. Ley, D. J. Tapolczay, E.
Vickerstaffe, and M. Ladlow, J. Comb. Chem., 2007, 9, 422.
9. (a) R. J. Hu, M. Lei, H. S. Xiong, X. Mu, Y. G. Wang, and X. F. Yin, Tetrahedron Lett., 2008, 49,
387; (b) M. Lei, W. Tian, R. J. Hu, W. Li, and H. Zhang, Synthesis, 2012, 44, 2519; (c) M. Lei, W.
Li, R. J. Hu, W. Tian, Y. G. Wang, and H. Zhang, Heterocycles, 2012, 86, 777.
10. J. Gao, X. F. Yin, and Z. L. Fang, Lab Chip, 2004, 4, 47.