Efficient synthesis of deuterated 1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2010.09.097

A wide variety of 1-monosubstituted 1,2,3-triazoles were synthesized efficiently via a copper-catalyzed click-reaction between azides and acetylene gas, generated in situ from CaC₂ with the addition of H₂O or D₂O.

Full text of DOI:10.1016/j.tetlet.2010.09.097

Tetrahedron Letters 51 (2010) 6275–6277
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of deuterated 1,2,3-triazoles
⇑
}
Zsombor Gonda, Krisztián Lorincz, Zoltán Novák
Institute of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/a, Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Revised 30 August 2010
Accepted 20 September 2010
Available online 25 September 2010
A wide variety of 1-monosubstituted 1,2,3-triazoles were synthesized efficiently via a copper-catalyzed
click-reaction between azides and acetylene gas, generated in situ from CaC2 with the addition of H2O
or D2O.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Acetylene
Copper
Click-reaction
Deuterium
Triazoles
Since the independent reports of Meldal1 and Sharpless2 on the
copper-catalyzed azide-alkyne cycloaddition (CuAAC), several
improvements and applications have proved the efficiency and
importance of this synthetic transformation.3 Besides utilization
of the CuAAC click-reaction in organic synthesis4 and materials sci-
ence,5 ligand-affected reaction rate acceleration is one of the most
important research directives in this field of organic chemistry.6
However, the CuAAC reaction provides an excellent tool for the
selective synthesis of 1,4-disubstituted 1,2,3-triazoles, while
procedures for the preparation of 1-monosubstituted triazole
derivatives are under developed.7 As a monoprotected acetylene
surrogate, trimethylsilyl acetylene is applicable for the click-reac-
tion, and subsequent deprotection of the formed triazoles at posi-
tion 4 provided the desired 1-monosubstituted triazole.8 There are
two recent examples of the direct addition of acetylene gas to the
azide moiety in the presence of 10–30 mol % copper catalysts.9
Kuang and co-workers demonstrated, for the first time, the appli-
cability of CaC2 as an acetylene source, but only aromatic azides
proved to be suitable substrates in the reported procedure.9a
As 1-monosubstituted triazoles possess important antibacterial
and other biological activity10 we aimed to develop a simple and
efficient procedure for the synthesis of various 1-monosubstituted
triazoles based on in situ generated acetylene from H2O and a car-
bide source. The utilization of CaC2 offers the possibility for intro-
duction of deuterium atoms instead of hydrogen when D2O is used
for the generation of acetylene gas. Isotope-labeled molecules have
important roles in mechanistic studies both from chemistry and
biology.
As we found previously, bis-triphenylphosphano complexes of
Cu(I) salts demonstrate prominent activity in the CuAAC reac-
tion.6h Therefore, we first used CuOAc(PPh3)2 and CuNO3(PPh3)2
complexes as catalysts for the synthesis of 1-monosubstituted tri-
azoles. Among the catalysts tested the copper(I) nitrate complex
showed higher activity and the reaction of benzyl azide and acet-
ylene gas generated in situ from CaC2 and water gave full conver-
sion in eight hours at 25 °C (Table 1, entries 1 and 2). On
replacing the water with D2O, we found that the reaction took
place with the same efficiency affording the expected triazole ring
(entry 3). The mass spectra of the products showed high incorpo-
ration of deuterium atoms into the benzyl triazole. The ratio of
the 4,5-dihydro 2a, the monodeuterated isomers 3a,b and the
4,5-dideutero compound 4a was found to be approximately
2:13:85.11 However, the aforementioned copper complexes gave
full conversions to 2a. Utilization of simple CuSO4Á5H2O
(40 mol %) also provided the benzyl triazole with almost the same
efficiency in the presence of KOAc.
As was expected, the high water content of the copper salt caused
a significant change in the isomeric ratio of the deuterated products
(20:52:28). Although, anhydrous CuSO4 in toluene resulted in only
39% conversion (entry 6), EtOH and DMSO were suitable solvents
for the CuSO4-catalyzed click-reaction (entries 7 and 8).
However, in these solvents the deuterium incorporation was
lower due to the presence of the OH hydrogen in the alcohol, and
supposedly the minor water content present in DMSO.
Organic bases usually accelerate the CuAAC reaction. Applica-
tion of triethylamine as the solvent for the cycloaddition of acety-
lene and benzyl azide in the presence of anhydrous CuSO4 gave full
conversion and a high amount of the dideutero triazole product
was obtained (entry 9). Additionally, CuI as the catalyst was also
⇑
Corresponding author. Tel.: +36 1 372 2500x1610; fax: +36 1 372 2909.
E-mail address: novakz@elte.hu (Z. Novák).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.097

6276
Z. Gonda et al. / Tetrahedron Letters 51 (2010) 6275–6277
Table 1
Table 2
Optimization of the copper-catalyzed click-reaction of acetylene and benzyl azidea
Synthesis of 1-monosubstituted 1,2,3-triazolesa
N
N
N
N
N
N
N
N
N
5% CuI, CaC2
5% CuI, CaC2
Cu(I), CaC2
Bn
Bn
Bn
R
N
H
N
H
N
D
N
H
N
R
N
D
Bn N3
R
N3
H2O or D2O,
solvent, 6 h
H2O,
Et3N, 55 ºC
D2O,
Et3N, 55 ºC
H
1
H
D
D
1
D
3
4
2
2
N
4
N
Bn
N
H
Entry
1
Product
Time (h)
6
Yieldb (%)
90
D
N
N
N
N
N
Entry
Catalyst
Solvent
H2O/D2O
Conv.b (%)
Ratio, 2:3:4c
N
H
N
H
N
H
N
H
2a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuOAc(PPh3)2
CuNO3(PPh3)2
CuNO3(PPh3)2
CuSO4Á5H2Od
CuSO4Á5H2Od
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
EtOH
DMSO
Et3N
EtOH
DMSO
Toluene
Et3N
CH2Cl2
Acetone
Et3N
H2O
H2O
D2O
H2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
25
100
100
90
100:0:0
100:0:0
2:13:85
100:0:0
20:52:28
1:6:93
12:48:40
3:28:69
1:5:94
12:48:40
7:27:66
1:5:94
1:5:94
n.a.
H
H
H
H
N
2
3
4
2b
2c
2d
6
6
6
57
74
79
98
39
NO2
d
CuSO4
d
CuSO4
100
100
100
100
100
16
N
N
d
CuSO4
d
CuSO4
Br
I
CuI
CuI
CuI
CuI
100
0
CuIe
CuIe
CuIe
CuIe,f
CuIf,g
20
73
100
100
21:49:30
2:11:87
1:5:94
N
N
N
H
Et3N
Et3N
5
6
2e
2f
40
6
92
67
0:17:83
H
a
Reaction conditions: 0.25 mmol BnN3, 1 mmol CaC2, 40 mol % Cu(I), 200
solvent, 200 l H2O/D2O.
Conversions were determined by GC–MS.
ll
l
b
N
N
N
N
N
N
N
N
S
c
d
e
f
N
H
N
H
N
H
N
H
Approximate ratio calculated on the basis of the MS spectra of the products.
0.5 mmol KOAc was added.
10 mol % CuI was used.
Reaction was carried out at 55 °C.
5 mol % CuI was used.
H
H
H
H
CN
g
7
8
9
2g
2h
2i
6
6
81
59
69
tested in toluene, EtOH, DMSO and Et3N and provided similar re-
sults with CuSO4 regarding the conversions and distributions of
the triazole isomers (entries 10–13).
Solvents such as CH2Cl2 and acetone were not effective in the
presence of 10 mol % CuI (entries 14 and 15). When a reduced
amount of CuI (10 mol %) was used in Et3N the reaction took place
with only 73% conversion (entry 16) but with this catalyst loading
at 55 °C the deuterated triazole was formed with full conversion
(entry 17). Decreasing the amount of copper to 5% was optimal
for the transformation (entry 18).
To assess the scope of the conditions developed we aimed to
synthesize several 1-monosubstituted triazoles. We also intended
to prepare the fully deuterated analogs of the target molecules.
Benzyl azide reacted smoothly both with acetylene gas and deuter-
ated acetylene in the presence of 5 mol % CuI in triethylamine at
55 °C. The products (2a and 4a) were isolated in good yields (Table
2, entries 1 and 11). Nitro, bromo and iodo substituents on the phe-
nyl ring of the benzyl azide had no influence on the click-reaction
and the corresponding triazoles were obtained in fair to good
yields (entries 2–4 and 12–14). It is of note that deuterium incor-
poration also occurred at the benzylic position during the forma-
tion of 1-(4-nitrobenzyl)-1,2,3-triazole (4b) due to the enhanced
benzylic C–H acidity of this substrate. Secondary azide 1e was
transformed into triazole 2e in excellent yield both with C2H2 (en-
try 5, 92%) and C2D2 (entry 15, 86%). Reaction of azidomethyl-phe-
nylsulfide with acetylene also afforded the desired products
containing hydrogen or deuterium atoms in the triazole ring in
67% and 68% yields, respectively (entries 6 and 16). Various ali-
phatic azides bearing cyano 1g, chloro 1h or alkene 1i functional
groups also proved to be good substrates for the click-reaction un-
der the developed conditions. The 1,2,3-triazole derivatives
Cl
16
OMe
N
N
N
N
10
2j
16
64
N
H
N
D
H
D
11
12
4a
4b
6
6
81
84
D
D
N
N
N
N
N
N
N
D
N
D
N
D
NO2
D
D
D
13
14
4c
6
6
81
86
Br
I
4d
N
N
N
D
15
4e
40
86
D

Z. Gonda et al. / Tetrahedron Letters 51 (2010) 6275–6277
6277
edged. The European Union and the European Social Fund have
provided financial support to the project under the Grant agree-
ment no. TÁMOP 4.2.1./B-09/KMR-2010-0003.
Table 2 (continued)
Entry
Product
Time (h)
6
Yieldb (%)
N
Supplementary data
N
S
16
4f
68
N
D
D
Supplementary data (procedures, optimization studies and
characterization of the materials) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.09.097.
CN
N
N
N
N
N
N
N
D
N
D
N
D
17
18
19
4g
4h
4i
6
16
16
91
66
70
D
D
References and notes
Cl
1. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
2. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596–2599.
3. (a) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018–1025; (b) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51–68; (c) Gil, M. V.;
Arévalo, M. J.; López, Ó. Synthesis 2007, 1589–1620; (d) Hein, C. D.; Liu, X.-M.;
Wang, D. Pharm. Res. 2008, 25, 2216–2230; (e) Meldal, M.; Tornøe, C. W. Chem.
Rev. 2008, 108, 2952–3015; (f) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39,
1302–1315.
D
OMe
}
4. (a) Lorincz, K.; Kele, P.; Novák, Z. Synthesis 2009, 3527–3532; (b) Detz, R. J.;
N
N
20
4j
16
42
N
D
Heras, S. A.; de Gelder, R.; van Leeuwen, P. W. N. M.; Hiemstra, H.; Reek, J. N. H.;
van Maarseveen, J. H. Org. Lett. 2006, 8, 3227–3230; (c) Alza, E.; Cambeiro, X. C.;
Jimeno, C.; Pericàs, M. A. Org. Lett. 2007, 9, 3717–3720; (d) Mason, B. P.;
Bogdan, A. R.; Goswami, A.; McQuade, D. T. Org. Lett. 2007, 9, 3449–3451.
5. (a) Cavalli, S.; Tipton, A. R.; Overhand, M.; Kros, A. Chem. Commun. 2006, 3193–
3195; (b) O’Reilly, R. K.; Joralemon, M. J.; Hawker, C. J.; Wooley, K. L. Chem. Eur.
J. 2006, 12, 6776–6786; (c) White, M. A.; Johnson, J. A.; Koberstein, J. T.; Turro,
N. J. J. Am. Chem. Soc. 2006, 128, 11356–11357; (d) Saha, A.; Ramakrishnan, S.
Macromolecules 2009, 42, 4028–4037; (e) Saha, A.; Ramakrishnan, S.
Macromolecules 2009, 42, 4956–4959; (f) Zhang, J.; Wang, X.; Wu, D.; Liu, L.;
Zhao, H. Chem. Mater. 2009, 21, 4012–4018.
D
a
Reaction conditions: 0.44 mmol azide, 0.022 mmol (5 mol %) CuI, 0.22–0.23 g
(techn. grade, P2.6 mmol) calcium carbide, 170
l
l H2O or D2O, 335
l
l Et3N.
b
Yield of isolated product.
containing hydrogens at positions 4 and 5 were isolated in 81%,
59% and 69% yields, respectively (entries 7–9). The alkylated 4,5-
deuterated triazoles were obtained in similarly good yields (entries
17–19). As demonstrated earlier by Kuang and co-workers,9a the
click-reaction of aryl azides and acetylene generated from carbide
provided the appropriate monosubstituted triazoles. Under our
reaction conditions, 4-azidoanisole was easily transformed into
1,2,3-triazole derivatives bearing hydrogen 2j and deuterium
atoms 4j at positions 4 and 5 in moderate yields (entries 10 and
20).
Although, the click-reactions of different azides with deuterated
acetylene all afforded the appropriate 4,5-dideutero triazoles, the
total deuterium incorporation was in the range 90–94%. This phe-
nomenon can be attributed to the kinetic isotope effect.
In conclusion, we have developed a synthetic procedure for the
copper-catalyzed synthesis of 1-monosubstituted triazoles from
structurally diverse organic azides utilizing cheap and easily acces-
sible calcium carbide as an acetylene surrogate. The strategy en-
ables the easy and simple introduction of deuterium atoms into
the heterocyclic core of the product providing important isotope-
labeled derivatives.
6. (a) Ozcubukcu, S.; Ozkal, E.; Jimeno, C.; Pericas, M. A. Org. Lett. 2009, 11, 4680–
4683; (b) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6,
2853–2855; (c) Donelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.;
Williams, S. J. Chem. Commun. 2008, 2459–2461; (d) Rodionov, V. O.; Presolski,
S. I.; Gardinier, S.; Lim, Y.-H.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12696–
12704; (e) Candelon, N.; Lastécouéres, D.; Diallo, A. K.; Ruiz Aranzaes, J.; Astruc,
D.; Vincent, J.-M. Chem. Commun. 2008, 741–743; (f) Díez-González, S.; Nolan,
S. P. Angew. Chem., Int. Ed. 2008, 47, 8881–8884; (g) Campbell-Verduyn, L. S.;
Mirfeizi, L.; Dierckx, R. A.; Elsinga, P. H.; Feringa, B. L. Chem. Commun. 2009,
2139–2141; (h) Gonda, Z.; Novák, Z. Dalton Trans. 2010, 39, 726–729.
7. de Oliveira, R. N.; Sinou, D.; Srivastava, R. M. J. Carbohydr. Chem. 2006, 25, 407–
425.
8. (a) Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Tetrahedron Lett. 2008, 49, 7030; (b)
Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J. Org. Lett. 2005, 7, 1469; (c) Gunji,
H.; Vasella, A. Helv. Chim. Acta 2000, 83, 3229.
9. (a) Jiang, Y.; Kuang, C.; Yang, Q. Synlett 2009, 3163–3166; (b) Wu, L.-Y.; Xie, Y.-
X.; Chen, Z.-S.; Niu, Y.-N.; Liang, Y.-M. Synlett 2009, 1453–1456.
10. (a) Fan, H.; Xu, G.; Chen, Y.; Jiang, Z.; Zhang, S.; Yang, Y.; Ji, R. Eur. J. Med. Chem.
2007, 42, 1137–1143; (b) Chan, D. C. M.; Laughton, C. A.; Queener, S. F.;
Stevensa, M. F. G. Bioorg. Med. Chem. 2002, 10, 3001–3010; (c) Tremblay, M. R.;
Lescarbeau, A.; Grogan, M. J.; Tan, E.; Lin, G.; Austad, B. C.; Yu, L.-C.; Behnke, M.-
L.; Nair, S. J.; Hagel, M.; White, K.; Conley, J.; Manna, J. D.; Alvarez-Diez, T. M.;
Hoyt, J.; Woodward, C. N.; Sydor, J. R.; Pink, M.; MacDougall, J.; Campbell, M. J.;
Cushing, J.; Ferguson, J.; Curtis, M. S.; McGovern, K.; Read, M. A.; Palombella, V.
J.; Adams, J.; Castro, A. C. J. Med. Chem. 2009, 52, 4400–4418; (d) Kim, J.-Y.;
Boyer, F. E.; Choy, A. L.; Huband, M. D.; Pagano, P. J.; Prasad, J. V. N. V. Bioorg.
Med. Chem. Lett. 2009, 19, 550–553; (e) Komine, T.; Kojima, A.; Asahina, Y.;
Saito, T.; Takano, H.; Shibue, T.; Fukuda, Y. J. Med. Chem. 2008, 51, 6558–6562;
(f) Reck, F.; Zhou, F.; Eyermann, C. J.; Kern, G.; Carcanague, D.; Ioannidis, G.;
Illingworth, R.; Poon, G.; Gravestock, M. B. J. Med. Chem. 2007, 50, 4868–4881;
(g) Gajewski, M.; Seaver, B.; Esslinger, C. S. Bioorg. Med. Chem. Lett. 2007, 17,
4163–4166; (h) Cosyn, L.; Palaniappan, K. K.; Kim, S.-K.; Duong, H.-T.; Gao, Z.-
G.; Jacobson, K. A.; van Calenbergh, S. J. Med. Chem. 2006, 49, 7373–7378; (i)
Phillips, O. A.; Udo, E. E.; Ali, A. A. M.; Samuel, S. M. Bioorg. Med. Chem. 2005, 13,
4113–4123; (j) Liu, J.; Numa, M. M. D.; Liu, H.; Huang, S.-J.; Sears, P.; Shikhman,
A. R.; Wong, C.-H. J. Org. Chem. 2004, 69, 6273–6283.
Acknowledgments
The authors thank Professor K. Torkos, Dr. Zs. Eke and Mr. Sz.
Nász for providing analytical support. Financial support and a Re-
}
search Grant (Z.N.) from the Magyary Zoltán Felsooktatási Köza-
lapítvány, EEA and Norway Grants are gratefully acknowledged.
The financial support of OTKA-NKTH CK 80763 is also acknowl-
11. Approximate ratio based on the MS spectrum of the product.