6
Tetrahedron
The mechanism of the Cu(I)-catalyzed azide-alkyne
References and notes
cycloaddition reaction is proposed (shown in Scheme 1),
referring to the literature.16,18 The Cu(II) salt is first reduced to
Cu(I) by the thiourea ligand, forming a Cu(I) complex (5).7,16 The
Cu(I) catalyst first coordinates to an alkyne substrate to form a
complex (6). The latter reacts with a second Cu(I) catalyst to
generate a copper-acetylide species (7). An intermolecular
cyclization between 7 and an azide leads to metallacycle 8, which
1.
2.
Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004-2021.
(a) Namitharan, K.; Kumarraja, M.; Pitchumani, K. Chem. Eur. J.
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3.
4.
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Veerakumar, P.; Velayudham, M.; Lu, K.-L.; Rajagopal, S. Catal. Sci.
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Islam, R. U.; Taher, A.; Choudhary, M.; Witcomb, M. J.; Mallick, K.
Dalton Trans. 2015, 44, 1341-1349.
forms copper triazolide
Protonolysis of 9 forms triazole 4 and regenerates Cu(I) catalyst.
9
after reductive elimination.
(a) Mekhzoum, M. E. M.; Benzeid, H.; Qaiss, A. E. K.; Essassi, E. M.;
Bouhfid, R. Catal. Lett. 2016, 146, 136-143; (b) Ladomenou, K.;
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O
O
X
O
Cu(II)
S
Cu(I)
(X = couteranion)
NH
NH
HN
HN
2
6.
(a) Kushwaha, D.; Tiwari, V. K. J. Org. Chem. 2013, 78, 8184-8190;
(b) Zhao, X.-L.; Yang, K.-F.; Zhang, Y.; Xu, L.-W.; Guo, X.-Q. Catal.
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Biomaterials. 2008, 29, 1118-1126; (d) Dige, N. C.; Patil, J. D.; Pore,
D. M. Catal. Lett. 2017, 147, 301-309.
S
S
N
N
H
H
5
R1
7.
8.
9.
Barman, M. K.; Sinha, A. K.; Nembenna, S. Green Chem. 2016, 18,
2534-2541.
N
N
N
Cu(I)
Cu(I)
R1
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596-2599.
R2
N
N
N
R1-N3
Cu(III)
Cu(I)
Ali, A. A.; Chetia, M.; Sarma, D. Tetrahedron Lett. 2016, 57, 1711-
1714.
R2
8
Cu(I)
10. (a) Semakin, A. N.; Agababyan, D. P.; Kim, S.; Lee, S.; Sukhorukov,
A. Y.; Fedina, K. G.; Oh, J.; Ioffe, S. L. Tetrahedron Lett. 2015, 56,
6335-6339; (b) Tale, R. H.; Gopula, V. B.; Toradmal, G. K.
Tetrahedron Lett. 2015, 56, 5864-5869.
N
R1
Cu(I)
N
N
R2
Cu(I)
R2
11. Diez-Gonzalez, S. Catal. Sci. Technol. 2011, 1, 166-178.
12. Mirjafary, Z.; Ahmadi, L.; Moradi, M.; Saeidian, H. RSC Adv. 2015, 5,
78038-78046.
Cu(I)
7
9
H+
13. Campbell-Verduyn, L. S.; Mirfeizi, L.; Dierckx, R. A.; Elsinga, P. H.;
Feringa, B. L. Chem. Commun. 2009, 16, 2139-2141.
H+
Cu(I)
Cu(I)
H
Cu(I)
R2
H
14. (a) Wang, F.; Fu, H.; Jiang, Y.; Zhao, Y. Green Chem. 2008, 10, 452-
456; (b) Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.;
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6244-6247.
N
R1
6
N
N
R2
R2
H
4
*Note: the thiourea ligands and counteranions on Cu(I) center were omitted in the catalytic cycle.
Scheme 1. Proposed mechanism of the Cu(I)-catalyzed azide-alkyne
cycloaddition reaction.
16. Yuan, Y. F.; Wang, J. T.; Gimeno, M. C.; Laguna, A.; Jones, P. G.
Inorg. Chim. Acta. 2001, 324, 309-317.
3. Conclusion
17. Wang, D.; Li, N.; Zhao, M.; Shi, W.; Ma, C.; Chen, B. Green Chem.
2010, 12, 2120-2123.
In conclusion, 1-(4-methoxyphenyl)-3-phenylthiourea served
both as a reductant and a ligand in the CuAAC reaction. The
reported synthetic method is a simple and efficient complement
protocol to the literature procedures for the CuAAC reaction,
with special advantages including mild reaction conditions, green
and environmentally friendly solvents, no need of extra additives,
and excellent chemical yields with a broad spectrum of
substrates. It is worth noting 1-(4-methoxyphenyl)-3-
phenylthiourea is inexpensive and readily available through a
simple synthetic method. Further investigation of the thiourea
ligands in copper mediated catalysis is currently underway in our
group and will be reported in due course.
18. (a) Worrell, B. T.; Malik, J. A.; Fokin, V. V. Science 2013, 340, 457-
460. (b) Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255, 2933-
2945.
Acknowledgments
Financial support from the National Natural Science
Foundation of China (No. 21372043 ) and Fuzhou University
(022537) is gratefully acknowledged.