D
F. Sebest et al.
Cluster
Synlett
The effect of the electronic nature of the alkene substit-
uents on the overall regioselectivity of the azide–alkene cy-
cloaddition reactions is well established;24 hence, the pres-
ent methodology can be applied to access either 1,5- or 1,4-
disubstituted triazoles. Indeed, two examples of the latter
were prepared from commercially available 1-propenyl
ethyl ether (3a) and 4-methoxybut-3-en-2-one (3b)
(Scheme 3). Pleasingly, the presence of an electron-with-
drawing group in triazole 3b obviated the need for a base in
the reaction media.25
Next, alternative leaving groups were investigated. Silyl
enol ethers, although commercially available, displayed
limited reactivity and underwent severe hydrolysis/decom-
position under most conditions tested (Table 3, entries 1–
3). This could sometimes be mitigated by using toluene as
solvent and adding TMG only once the starting azide had
been consumed (entry 2).
(4) (a) Haldón, E.; Nicasio, M. C.; Pérez, P. J. Org. Biomol. Chem.
2015, 13, 9528. (b) Díez-González, S. Catal. Sci. Technol. 2011, 1,
166. (c) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(5) For reviews, see: (a) Jalani, H. B.; Karagöz, A. Ç.; Tsogoeva, S. B.
Synthesis 2017, 49, 29. (b) Lima, C. G. S. C.; Ali, A.; van Berkel, S.
S.; Westemann, B.; Paixao, M. W. Chem. Commun. 2015, 51,
10784. (c) For a highlight on metal- and azide-free methodolo-
gies, see: Wan, J.-P.; Hu, D.; Liu, Y.; Sheng, S. ChemCatChem
2015, 7, 901; and references therein.
(6) For selected leading references, see: (a) Agard, N. J.; Prescher, J.
A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046. (b) van
Berkel, S. S.; Dirks, A. J.; Debets, M. F.; van Delft, F. L.;
Cornelissen, J. J. L.; Nolte, R. J. M.; Rutjes, F. P. J. T. ChemBioChem
2007, 8, 1504. (c) Laughlin, S. T.; Baskin, J. M.; Amacher, S. L.;
Bertozzi, C. R. Science 2008, 320, 664.
(7) For selected leading references, see: (a) Ramachary, D. B.;
Ramakumar, K.; Narayana, V. V. Chem. Eur. J. 2008, 14, 9143.
(b) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem.
Eur. J. 2011, 17, 3584. (c) Li, W.; Du, J.; Huang, J.; Jia, Q.; Zhang,
K.; Wang, J. Green Chem. 2014, 16, 3003.
In reactions with triflate enol ethers, two equivalents of
the base were used to minimise any acid-driven decompo-
sition. Two challenging substrates were tested (Table 3, en-
tries 4 and 5) and while triazole 2e was isolated in 24%
yield, a trisubstituted triflate enol ether led to severe de-
composition and a low conversion into the desired triazole.
In summary, we have developed a one-pot cycloaddi-
tion–elimination cascade in DES to access either 1,4- or 1,5-
disubstituted triazoles. This metal-free methodology does
not require any purification step and minimises the need
for volatile organic solvents. In spite of their relatively limit-
ed availability, enol ethers are the best candidates for this
methodology because they do not decompose in the reac-
tion and only produce alcohols as elimination by-products.
(8) For selected leading references, see: (a) Cheng, G.; Zeng, X.;
Shen, J.; Wang, X.; Cui, X. Angew. Chem. Int. Ed. 2013, 52, 13265.
(b) Ramachary, D. B.; Shashank, A. B.; Karthik, S. Angew. Chem.
Int. Ed. 2014, 53, 10420. (c) Li, W.; Wang, J. Angew. Chem. Int. Ed.
2014, 53, 14186.
(9) Sebest, F.; Casarrubios, L.; Rzepa, H. S.; White, A. J. P.; Díez-
González, S. Green Chem. 2018, 20, 4023.
(10) (a) Alonso, D. A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I.
M.; Ramón, D. J. Eur. J. Org. Chem. 2016, 612. (b) García-Álvarez,
J. Eur. J. Inorg. Chem. 2015, 5147. (c) Zhang, Q.; De Oliveira
Vigier, K.; Royer, S.; Jêrome, F. Chem. Soc. Rev. 2012, 41, 7108.
(11) Li, W.; Du, Z.; Zhang, K.; Wang, J. Green Chem. 2015, 17, 781.
(12) KMnO4: (a) Kadaba, P. K.; Edelstein, S. B. J. Org. Chem. 1990, 55,
5891. (b) Kadaba, P. K.; Parmley, G.; Crooks, P. A.; Agha, B. J. Het-
erocycl. Chem. 1993, 30, 1191.
(13) NiO2: Kadaba, P. K. J. Prakt. Chem. 1982, 324, 857.
(14) CuI: Janreddy, D.; Kavala, V.; Kuo, C.-W.; Chen, W.-C.; Ramesh,
C.; Kotipalli, T.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.; Yao, C.-F. Adv.
Synth. Catal. 2013, 355, 2918.
Funding Information
(15) Cu(OAc)2: Rohilla, S.; Patel, S. S.; Jain, N. Eur. J. Org. Chem. 2016,
847.
(16) Cu(OTf)2: Chen, Y.; Nie, G.; Zhang, Q.; Ma, S.; Li, H.; Hu, Q. Org.
Lett. 2015, 17, 1118.
This research was financially supported by Imperial College London
and by the Engineering and Physical Sciences Research Council (EPS-
RC) (DTP studentship to F.S. and EP/K030760).
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(17) CuO nanoparticles: Gangaprasad, D.; Raj, J. P.; Kiranmye, T.;
Sasikala, R.; Karthikeyan, K.; Rani, S. K.; Elangovan, J. Tetrahe-
dron Lett. 2016, 57, 3105.
Supporting Information
(18) See the Supporting Information for further details.
(19) (a) Huisgen, R.; Möbius, L.; Szeimies, G. Chem. Ber. 1965, 98,
1138. (b) Huisgen, R.; Möbius, L.; Szeimies, G. Chem. Ber. 1965,
98, 1153. (c) Roque, D. R.; Neill, J. L.; Antoon, J. W.; Stevens, E. P.
Synthesis 2005, 2497.
Supporting information for this article is available online at
NMR spectra, and crystallographic dat.
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References and Notes
(20) Munk, M. E.; Kim, Y. K. J. Am. Chem. Soc. 1964, 86, 2213.
(21) CCDC 1949637 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
(1) (a) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Chem. Rev. 2013,
113, 4905. (b) Themed issue on Click Chemistry: Finna, M. G.;
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The
Cambridge
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Data
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via
(22) Procedure for the Preparation of 5-methyl-1-[4-(trifluoro-
methyl)phenyl]-1H-1,2,3-triazole (2a): 1,1,3,3-Tetra-methyl-
guanidine (0.25 mL, 2 mmol) was added into a solution of 1-
azido-4-trifluoromethylbenzene (0.37 g,
2 mmol) and 2-
(3) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed.
2001, 40, 2004.
methoxypropene (0.77 mL, 8.00 mmol) in DES (4 mL) in a vial
that was fitted with a screw cap. The mixture was stirred vigor-
ously at 90 °C for 24 h before being allowed to cool to room
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E