Synthesis of bitriazolyl compounds via Huisgen reaction

Article abstract of DOI:10.3987/COM-04-10202

Bitriazolyl compounds were synthesized via Huisgen 1,3-cyclcoaddition starting with an azidotriazole and various alkynes. Good yields were obtained with terminal alkynes using copper(I) as a catalyst in the THF/H₂O system.

Full text of DOI:10.3987/COM-04-10202

HETEROCYCLES, Vol. 65, No. 2, 2005
345
HETEROCYCLES, Vol. 65, No. 2, 2005, pp. 345 - 352
Received, 17th August, 2004, Accepted, 15th December, 2004, Published online, 17th December, 2004
SYNTHESIS OF BITRIAZOLYL COMPOUNDS VIA HUISGEN
REACTION
Yi Xia1, Fanqi Qu1, Wei Li1, Qiongyou Wu1 and Ling Peng1, 2,
*
1College of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
2
430072, P. R. China; Département de Chimie, AFMB CNRS UMR 6098,
Université Aix-Marseille II, 163, avenue de Luminy, 13288 Marseille cedex,
France; ling@afmb.cnrs-mrs.fr
Abstract
–
Bitriazolyl compounds were synthesized via Huisgen
1,3-cyclcoaddition starting with an azidotriazole and various alkynes. Good yields
were obtained with terminal alkynes using copper(I) as a catalyst in the THF/H2O
system.
INTRODUCTION
Triazoles are attractive construction units because of their unique structure and properties. Although they
are not present in the natural products, they are of considerable significance in medicinal chemistry and in
material sciences. Ribavirin1 (Scheme 1) is the first synthetic nucleoside showing a broad-spectrum of
antiviral activity against many RNA and DNA viruses. Alprazolam2 (Scheme 1), a member of the
benzodiazepines drug family, is one of the main drugs used at present for the treatment of anxiety and
panic disorders. A 1,2,3-triazole ligand (syn-1 in Scheme 1) was recently found to be the most potent
acetylcholinesterase inhibitor.3 Triazoles also provide useful components for constructing molecular
memory devices4 and fuel cell drives.5 However, triazole compounds have not received as much attention
as they deserve, propably because of the lack of convenient and practical methods of synthesis.
We are interested in the potential applications of triazole compounds in the fields of medicine and
material sciences. For this purpose, we wanted to obtain bitriazolyl unit (1) (Scheme 1) for use as a
surrogate for the current biaryl motif, which is being widely applied in a range of pharmaceutics,
herbicides, and natural products, as well as in conducting polymers, molecule wires and liquid-crystalline
materials.6 One of the most convenient and attractive approach to the synthesis of the 1,2,3-triazoles is the
Huisgen 1,3-dipolar cycloaddition using azides and alkynes.7 In a recent attempt to synthesize

346
HETEROCYCLES, Vol. 65, No. 2, 2005
photolabeling probes of ribavirin, we developed a convenient and practical method of synthesizing
azidotriazole (2) (Scheme 2) on a large scale.8 We are interested in using this molecule as the starting
material for synthesizing bitriazolyl compounds (1) with various alkynes via the Huisgen reaction. Here
we report on the synthesis and characterisation of these bitriazolyl compounds.
H2N
NH2
N
O
N
N
NH2
N
N
O
Ph
N
N
N
N
HN
R1
R2
HO
N
N
OCH3
O
N
N
N
Me
N
N
N
Cl
H
OH OH
Ribavirin
Alprazolam
syn-1
1
Scheme 1: Ribavirin, Alprazolam, the most potent AChE inhibitor syn-1 and bitriazolyl compound (1).
RESULTS AND DISCUSSION
Scheme 2 shows the synthesis of the bitriazolyl constructs. Methyl 5-azido-1,2,4-triazole-3-carboxylate (2)
was synthesized from methyl 5-amino-1,2,4-triazole-3-carboxylate by diazotization with HNO2 at –3 °C
followed by substitution with NaN3. This two-step procedure yields readily 2 in a scale of 20 g, which can
serve as the starting material for Huisgen reaction to obtain the bitriazolyl building blocks.
O
O
O
R1
R2
N
1) NaNO2, H2SO4
2) NaN3
R1
R2
N
N
OCH3
OCH3
OCH3
N3
H2N
N
N
N
N
N
N
H
2
N
N
H
N
H
1
Scheme 2: Synthesis of bitriazolyl units (1), starting with 5-amino-1,2,4-triazole-3-carboxylate, using the
Huisgen reaction via 2.
When the Huisgen reaction was carried out with 2 and various alkynes by simply heating, the results were
not very satisfactory (Table 1), since low yields and several by-products were obtained. Most of the
reactions were not complete, with the starting materials being recovered in yields of up to 90% (data not
shown). There was one exception in the case of methyl propiolate, which gave a yield of 74.6%, and only
1,4-disubstituted 1,2,3-triazole isomer was isolated and identified (Entry 1 in Table 1). It is known that

HETEROCYCLES, Vol. 65, No. 2, 2005
347
strong electron-withdrawing substituents on the alkynes and strong electron-donating substituents on the
azides favor the reaction.9 However, the triazole ring is highly electron-deficient, which makes 2 less
reactive in Huisgen reactions. Only the most electron-deficient and least sterically hindered alkynes
(Entries 1, 2, 3 in Table 1) react readily with 2 via Huisgen reactions. We noticed that there is big
difference in the reaction yield when the substituent on the alkynes is changed from COOMe to COOEt.
This might be explained that the ethyl group is larger than the methyl group and therefore more sterically
demanding, leading to less product formation. It is important to point out further that the bulky aromatic
alkynes (Entries 4, 5 in Table 1) are not ready to participate in this reaction.
Table 1: 1,3-Dipolar cycloaddition reaction between methyl 5-azido-1,2,4-triazole-3-carboxylate (2) and
alkynes by direct heating.
O
O
O
R1
R2
R2
R1
N
N
OCH3
OCH3
N
OCH3
R1
R2
+
N
N
N
N
N
N
N3
N
N
N
N
N
N
toluene, 120 °C
H
H
H
1'
2
1
a
a
a
a
a
Entry
R1
R2
Time (h)
Yield (%)
O
a
a
a
a
CH3OC
1
H
H
55
74.6
O
a
a
a
a
CH3CH2OC
2
76
22.5
O
O
a
a
a
CH3CH2OC
CH3CH2OC
3
20
30.5
a
a
a
a
CH3
4
H
72
1.8
b
5
b
b
b
CH3O
H
52
5.1
a:
b:
Yield of isolated regioisomer (1). Yield of the isolated mixture of regioisomers (1) and (1’)
Sharpless et al. recently reported on the copper(I)-catalyzed synthesis of 1,2,3-triazole from azides and
terminal alkynes.10 The copper(I)-catalyzed Huisgen reaction can be carried out under mild conditions

348
HETEROCYCLES, Vol. 65, No. 2, 2005
and give regioselective 1,4-disubstituted 1,2,3-triazole products, and thus has found a wide range of
applications in medicinal science.11 During our efforts to optimize the synthesis of bitriazolyl units via
Huisgen reaction using azidotriazole and alkynes, we observed that the copper(I)-catalyzed route
efficiently and regiospecifically unites the azidotriazole (2) and terminal acetylenes, giving only
1,4-disubstituted 1,2,3-triazoles isomers in good yields in a mixed THF/H2O solvent system.
Azidotriazole (2) readily engaged in a copper(I)-catalyzed Huisgen reaction with a variety of terminal
acetylenes (Table 2). Triazole products (1) were obtained by stirring 2 and the corresponding alkynes in
.
the presence of CuSO4 5H2O and ascorbic acid or sodium ascorbate at 80 °C for 1-5 h in the mixed
THF/H2O solvent system, followed by a chromatographic purification step. Only the 1,4-disubstituted
1,2,3-triazoles were obtained, while no 1,5-disubstituted triazole isomer was obtained upon performing
either TLC or column separation. This regioselectivity is in agreement with previous findings and the
proposed reaction mechanism, where the formed copper(I) acetylide undergoes stepwise addition with the
azide.10 It has also been reported that a number of copper(I) sources can catalyze this reaction. However,
among the various catalysts (CuCl, CuBr, and CuBr2, Cu(OAc)2, CuSO4 in the presence of a reductant)
.
we tested, the best results were obtained with the catalyst prepared in situ by reducing CuSO4 5H2O in the
presence of ascorbic acid or sodium ascorbate. Although both ascorbic acid and sodium ascorbate were
reported to be excellent reductant in the copper(I)-catalyzed Huisgen cycloaddition procedure,10 we noted
that sodium ascorbate led to better and more reproducible yields (Conditions B and C in Entries 5, 6,
Table 2). Further, higher loading of the copper(I) catalyst could also improve the reaction yield and
reduce the reaction time to some extent (Conditions A and B in Entries 5, 6, Table 2). Meanwhile, a
judicious choice of solvent is crucial to the outcome of the reaction. In comparison with THF alone, the
use of THF/H2O co-solvent significantly reduces the reaction time and improves the reaction yield (data
not shown). The best results were obtained with a THF/H2O 1/2 co-solvent system. The beneficial effect
of co-solvent system might be attributable to the enhanced hydrophobic interactions occurring between
the substrates during the activation process, which favors the reaction.12 We also ran the reaction at room
temperature, but the reaction obtained under these conditions was not complete, even when the reaction
time was extended. It is necessary to maintain the temperature at around 80 °C in order to obtain good
product yields in short reaction time. With the various alkyne substituents tested, no significant effects on
the outcome of the reaction were observed, whether these substituents were alkyl (Entries 3, 4 in Table 2),
aromatic (Entries 5, 6, 7 in Table 2) or electron-withdrawing groups or not (Entries 1, 2, 8 in Table 2).
It is worth noting that the aromatic protons in the triazole rings of 1a-b and 1e-h are strongly deshielded
when compared with those of normal triazoles. This may be explained that the protons in the triazole
rings of 1a-b are in the deshielding regions of the oxygen atoms, while those of 1e-h the adjacent benzene
rings. We also observed important solvent effect for the aromatic proton in the triazole ring of 1b, with its

HETEROCYCLES, Vol. 65, No. 2, 2005
349
Table 2: Copper(I)-catalyzed Huisgen reaction using methyl 5-azido-1,2,4-triazole-3-carboxylate (2) and
terminal alkynes.
O
O
R1
N
OCH3
N
OCH3
Cu(I)
N3
+ R1 C CH
N
N
N
N
N
H
80 °C
N
N
H
2
1
a
a
a
a
a
a
Entry
1
R1
Product
Condition
Time (h)
4.0
Yield (%)
O
1a
1b
A
A
81.2
CH3OC
O
2
1.5
85.3
CH3CH2OC
O
3
4
1c
A
A
1.0
2.0
92.4
77.7
CH3COCH2
1d
OH
A
B
C
5.0
6.0
6.0
84.5
69.3
61.4
CH3
5
6
1e
1f
A
B
C
2.5
5.5
5.0
82.5
75.2
53.9
CH3O
F
7
8
1g
1h
A
A
4.0
1.5
70.0
76.1
O
S
CH3
O
a:
.
.
Condition: (A): THF/H2O 1/2, CuSO4 5H2O (0.16 eq.)/sodium ascorbate. (B): THF/H2O 1/2, CuSO4 5H2O (0.08
.
eq.)/sodium ascorbate; (C): THF/H2O 1/2, CuSO4 5H2O (0.08 eq.)/ascorbic acid。
chemical shift being 8.98 ppm in CDCl3 and 9.30 ppm in DMSO-d6. This might be due to the
conformational change induced by a change of solvent. Unfortunately, we were not able to further

350
HETEROCYCLES, Vol. 65, No. 2, 2005
confirm the solvent effect with other compounds or other solvents because all the compounds 1a-h are
soluble only in DMSO-d6 with exception that 1b is well soluble in CDCl3.
In conclusion, the results of the present study show that the copper(I)-catalyzed Huisgen reaction is an
efficient and regiospecific method of synthesizing bitriazolyl units starting with the azidotriazole (2) and
terminal alkynes in a mixed solvent THF/H2O synthesis. Since the bitriazolyl units (1) synthesized here
have different functional groups, they should provide useful scaffolds for further synthesis or for setting
up libraries of biologically active compounds and functional molecular materials.
EXPERIMENTAL
General: The 1H NMR and 13C NMR spectra were recorded at 300 MHz and 150 MHz, respectively, on
Varian Mercury-VX300 and Varian Inova-600 spectrometers. The chemical shifts were recorded in parts
per million (ppm) with TMS as the internal reference. FAB and ESI MS were determined using
ZAB-HF-3F or Finnigan LCQ Advantage mass spectrometer. UV spectral analysis was performed with a
Perkin Elmer Lambda 35 UV/VIS spectrophotometer. All the compounds were purified by performing
flash chromatography on silica gel (200-300 mesh). Element analysis (EA) was measured on a Vario
ELIII Chnso elemental analyzer.
Preparation of methyl 5-azido-1,2,4-triazole-3-carboxylate (2). 5-Amino-1,2,4-triazole-3-carboxylate
(30.0 g, 0.21 mol) was suspended in a mixture of water (120 mL) and conc.H2SO4 (3 mL). Then an
aqueous solution of NaNO2 (16.4 g, 0.23 mol) was added portionwise to the suspension at -3 °C. After
allowing 20 min. for the reaction, NaN3 (16.7 g, 0.25 mol, freshly prepared solution in water) was added
dropwise. The mixture was extracted with ethyl acetate after stirring it for about 3 h at 25 °C. The pure
product was obtained after being evaporated under reduced pressure, yielding 2 (18.8 g, 53.1%) as white
1
solid, which can be further purified by crystallization in ethyl acetate. H NMR (300 MHz, CDCl3): δ =
13
3.89 (s, 3H). C NMR (150 MHz, CDCl3): 158.8, 155.6, 150.0, 53.7. IR (KBr, cm-1): 2145. FAB-MS:
m/z 169.0 [M+H]+. UV: (MeOH) λmax 231.4 nm (ε 5132). Anal. Calcd for C4H4N6O2: C, 28.58; H, 2.40;
N, 49.99. Found: C, 28.51; H, 2.45; N, 50.10.
General procedure for preparing 1 via Huisgen reaction by simply heating. Heating mixture of azide
(2, 0.4 mmol) and alkynes (0.48 mmol) in toluene (10 mL) at 120 °C for 20-75 h afforded the
corresponding products. The product was purified by column chromatography with CH2Cl2/MeOH 30/1
and dried in vacuo to afford 1.
General procedure for preparing 1 via copper(I)-catalyzed Huisgen reaction. The azide (2, 0.4 mmol)
and alkynes (0.48 mmol) were dissolved in a mixed solvent system (THF/H2O = 1/2, 9 mL). Sodium

HETEROCYCLES, Vol. 65, No. 2, 2005
351
.
ascorbate (0.2 mmol, freshly prepared solution in water) was added, followed by CuSO4 5H2O (0.064
mmol, freshly prepared solution in water). The yellowish mixture was stirred at 80 °C, at which point
TLC analysis indicated complete consumption of 2. The solvent in the reaction mixture was evaporated
and the residue was purified by column chromatography with CH2Cl2/MeOH 30/1. The product was dried
in vacuo to afford 1.
1
13
1a: White solid. H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 3.95 (s, 3H), 3.88 (s, 3H,). C NMR
(150 MHz, DMSO-d6): δ 163.0, 159.8, 156.8, 150.4, 142.1, 131.1, 56.0, 55.0. ESI-MS: m/z 251.0 [M-H]-.
UV: (MeOH) λmax 244.6 nm (ε 5771). Anal. Calcd for C8H8N6O4: C, 38.10; H, 3.20; N, 33.32. Found: C,
37.89; H, 3.32; N, 33.13.
1
1b: White solid. H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 4.34 (q, 2H, J = 7.0 Hz), 3.95 (s, 3H),
1
1.32 (t, 3H, J = 7.0 Hz). H NMR (300 MHz, CDCl3 ): δ 8.98 (s, 1H), 4.48 (q, 2H, J = 7.0 Hz), 4.10 (s,
13
3H), 1.45 (t, 3H, J = 7.2 Hz). C NMR (150 MHz, CDCl3): δ 160.1 157.1, 154.5, 147.8, 140.5, 126.7,
61.9, 53.8, 14.2. ESI-MS: m/z 265.0 [M-H]-. UV: (MeOH) λmax 237.6 nm (ε 5867). Anal. Calcd for
C9H10N6O4: C, 40.61; H, 3.79; N, 31.57. Found: C, 40.79; H, 3.73; N, 31.89.
1c: White solid. 1H NMR (300 MHz, DMSO-d6): δ 8.79 (s, 1H), 5.22 (s, 2H), 3.96 (s, 3H), 2.07 (s, 3H).
13C NMR (150 MHz, DMSO-d6): δ 171.2, 158.1, 144.0, 125.1, 57.7, 54.1, 21.5, ESI-MS: m/z 264.9
[M-H]-. UV: (MeOH) λmax 235.6 nm (ε 6217). Anal. Calcd for C9H10N6O4: C, 40.61; H, 3.79; N, 31.57.
Found: C, 40.89; H, 3.98; N, 31.31.
1d: White solid. 1H NMR (300 MHz, DMSO-d6): δ 8.41 (s, 1H), 5.07 (br s, 1H), 3.93 (s, 3H), 1.89-1.96
13
(m, 2H), 1.66-1.77 (m, 3H), 1.42-1.50 (m, 3H), 1.21-1.30 (m, 2H). C NMR (150 MHz, DMSO-d6): δ
157.9, 157.2, 121.0, 68.6, 53.7, 38.2, 25.8, 22.3. ESI-MS: m/z 291.1 [M-H]-. UV: (MeOH) λmax 236.6 nm
(ε 4268). Anal. Calcd for C12H16N6O3: C, 49.31; H, 5.52; N, 28.75. Found: C, 49.61; H, 5.25; N, 29.06.
1e: White solid. 1H NMR (300 MHz, DMSO-d6): δ 9.26 (s, 1H), 7.89 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, J =
8.1 Hz), 3.95 (s, 3H), 2.33 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 156.8, 146.5, 137.5, 129.0, 126.3,
125.1, 119.5, 52.6, 20.4. FAB-MS: m/z 285.0 [M+H]+. UV: (MeOH) λmax 247.5 nm (ε 12427). Anal.
Calcd for C13H12N6O2: C, 54.93; H, 4.25; N, 29.56. Found: C, 54.98; H, 4.13; N, 29.87.
1f: White solid. 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.93 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J =
8.7 Hz), 3.95 (s, 3H), 3.79 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 160.2, 157.8, 147.7, 127.8, 122.8,
120.1, 115.1, 55.9, 53.7. FAB-MS: m/z 301.0 [M+H]+. UV: (MeOH) λmax 255.1 nm (ε 11156). Anal.
Calcd for C13H12N6O3: C, 52.00; H, 4.03; N, 27.99. Found: C, 52.27; H, 4.21; N, 28.34.
1g: White solid. 1H NMR (300 MHz, DMSO-d6): δ 9.33 (s, 1H), 8.04 (dd, 2H, 4JHF = 5.4, 3JHH =8.7 Hz),
7.31 (dd, 2H, 3JHF = 8.7 Hz, 3JHH = 8.7 Hz), 3.94 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 162.8 (1JCF

352
HETEROCYCLES, Vol. 65, No. 2, 2005
= 245.2 Hz), 157.7, 146.8, 128.3 (3JCF = 8.3 Hz), 126.8, 121.1, 116.6 (2JCF = 20.4 Hz), 53.7. FAB-MS:
m/z 289.0 [M+H]+. UV: (MeOH) λmax 242.4 nm (ε 12506). Anal. Calcd for C12H9FN6O2: C, 50.00; H,
3.15; N, 29.16. Found: C, 50.34; H, 3.26; N, 29.42.
1h: White solid. 1H NMR (300 MHz, DMSO-d ): δ 9.59 (s, 1H), 7.92 (d, 2H, J = 8.7 Hz), 7.47 (d, 2H, J =
8.1 Hz), 3.93 (s, 3H), 2.38 (s, 3H).13C NMR (150 MHz, DMSO-d6): δ 170.9, 157.4, 149.3, 146.0, 137.5,
131.0, 128.4, 128.1, 53.8, 21.8. ESI-MS: m/z 349.1 [M+H]+. UV: (MeOH) λmax 237.4 nm (ε 5758). Anal.
Calcd for C13H12N6O4S: C, 44.82; H, 3.47; N, 24.13. Found: C, 44.54; H, 3.48; N, 23.84.
ACKNOWLEDGEMENTS
We thank Dr. Jessica Blanc for revising the English manuscript. Financial support from the CNRS, the
State Key Program of Basic Research of China (2003CB114400), the Hi-Tech Research and
Development Programm of China (2003AA2Z3506), Cheung Kong Scholar Foundation and Wuhan
University is gratefully acknowledged.
REFERENCES
1. R. W. Sidwell, J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski, and R. K. Robins, Science,
1972, 177, 705.
2. ‘Heterocyclic Chemistry’, Fourth Edition, ed. by J. A. Joule and K. Mills, Blackwell Science, 2000, p.
504.
3. W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radić, P. R. Carlier, P. Taylor, M. G. Finn, and K. B.
Sharpless, Angew. Chem., Int. Ed., 2002, 41, 1053; Y. Bourne, H. C. Kolb, Z. Radić, K. B. Sharpless, P.
Taylor, and P. Marchot, Proc. Natl. Acad. Sci. USA, 2004, 101, 1449.
4. O. Kahn and C. J. Martinez, Science, 1998, 279, 44.
5. M. A. B. H. Susan, A. Noda, S. Mitsushima, and M. Watanabe, Chem. Comm., 2003, 938.
6. S. P. Stanforth, Tetrahedron, 1998, 54, 263.
7. R. Huisgen, Angew. Chem., Int. Ed., 1963, 2, 565; R. Huisgen, Angew. Chem., Int. Ed., 1963, 2, 633.
8. Q. Wu, F. Qu, J. Wan, X. Zhu, Y. Xia, and L. Peng, Helv. Chim. Acta, 2004, 87, 811.
9. A. R. Katritzky, Y. Zhang, and S. K. Singh, Heterocycles, 2003, 60, 1225.
10. V. V. Rostovtsev, L. G. Green., V. V. Fokin., and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41,
2596.
11. H. C. Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128.
12. D. v. Mersbergen, J. W. Wijnen, and J. B. F. N. Engberts, J. Org. Chem., 1998, 63, 8801.