Copper-catalysed multicomponent click synthesis of 5-alkynyl 1,2,3-triazoles under ambient conditions

Article abstract of DOI:10.1055/s-0031-1290445

Copper(I) oxide has been found to effectively catalyse the multicomponent click synthesis of fully substituted 5-alkynyl 1,2,3-triazoles from organic halides, sodium azide, and terminal alkynes in methanol under ambient conditions. Georg Thieme Verlag Stu

Full text of DOI:10.1055/s-0031-1290445

LETTER
▌2179
lCettoerpper-Catalysed Multicomponent Click Synthesis of 5-Alkynyl
1,2,3-Triazoles under Ambient Conditions
Alkynyl Triazoles by Domino Click and Coupling
Francisco Alonso,*a Yanina Moglie,a Gabriel Radivoy,b Miguel Yusa
a
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain
Fax +34(965)903549; E-mail: falonso@ua.es
b
Departamento de Química, Instituto de Química del Sur (INQUISUR-CONICET), Universidad Nacional del Sur, Avenida Alem 1253,
8000 Bahía Blanca, Argentina
Received: 02.05.2012; Accepted after revision: 24.06.2012
Dedicated to the memory of Professor Guy Solladié
terminal alkynes with stoichiometric CuI and triethyl-
amine, using ICl as a trapping agent of the intermediate
copper(I) triazolide.8a The corresponding 5-iodo-1,2,3-tri-
azoles were further subjected to the palladium-catalysed
Sonogashira–Hagihara cross-coupling reaction with ter-
minal alkynes, giving rise to 5-alkynyl 1,2,3-triazoles.8b A
more direct strategy to access this type of compounds was
reported by Porco’s group, in which, organic azides and
terminal alkynes reacted in a catalytic system comprised
of Cu(MeCN)4PF6, N,N,N′-trimethylethylenediamine as
ligand, Hünig’s base, molecular oxygen, and 4-methyl-
morpholine N-oxide as co-oxidant in dichloromethane.9
As noted by the authors, the Glaser coupling and cycload-
dition towards the nonalkynylated 1,4-disubstituted tri-
azoles were competing reactions which accounted for the
low yields attained in many cases. Soon after, Chen et al.
presented the 1,3-dipolar cycloaddition–coupling reaction
of terminal alkynes, phenylboronic acids, and sodium
azide catalysed by CuI (10 mol%) and CuSO4·5H2O
(20 mol%) in 1,4-dioxane–water.10 Disubstituted 1-aryl-
5-alkynyl 1,2,3-triazoles have been prepared, in an indi-
rect manner, through the cycloaddition of 2-morpholino-
but-1-en-3-yne with aryl azides.11 Due to our ongoing
interest in click chemistry12 and to the scant number of
methodologies that enable the formation of 5-alkynyl
1,2,3-triazoles in an efficient manner, we want to present
herein the first general methodology for the copper-cata-
lysed multicomponent synthesis of 5-alkynyl-1,4-disub-
stituted 1,2,3-triazoles starting from organic halides,
terminal alkynes, and sodium azide under ambient condi-
tions.
Abstract: Copper(I) oxide has been found to effectively catalyse
the multicomponent click synthesis of fully substituted 5-alkynyl
1,2,3-triazoles from organic halides, sodium azide, and terminal
alkynes in methanol under ambient conditions.
Key words: alkynes, alkyl halides, azides, cycloaddition, copper,
cross-coupling, heterocycles, multicomponent reaction
In the dawn of the 21st century, we have witnessed a reviv-
al of interest in the Huisgen 1,3-dipolar cycloaddition
reaction of organic azides and alkynes1 after the pivotal
discovery by the groups of Meldal2 and Sharpless.3
Copper(I) catalysis was found to dramatically accelerate
the reaction under mild conditions while achieving a high
regioselectivity towards the 1,4-regioisomer of the tri-
azole product. This powerful, highly reliable, and selec-
tive reaction is the paradigm of a click reaction, as it meets
the set of stringent criteria required in click chemistry as
defined by Sharpless et al.4 Consequently, this protocol
has found increasing application in a variety of disciplines
such as organic chemistry, drug discovery and medicinal
chemistry, polymer and materials science, or bioconjuga-
tion.5
The copper-catalysed azide–alkyne cycloaddition (Cu-
AAC) provides a direct entry into 1,4-disubstituted 1,2,3-
triazoles, whereas the formation of the 1,4,5-trisubstituted
derivatives relies on the use of ruthenium catalysts6 or
modification of preformed 1,2,3-triazoles.7 In the latter
context, three different approaches have been devised for
the introduction of substituents at the 5-position of the tri-
azole unit, namely: (a) the interception of stoichiometri-
cally functionalised 5-cuprated-1,2,3-triazoles, (b) the use
of stoichiometrically functionalised terminal alkynes, and
(c) the catalytic direct functionalisation of C–H bonds.7
The reaction of benzyl bromide (1a), phenylacetylene
(2a), and sodium azide in the presence of a copper source
was used as a model reaction in order to optimise the cat-
alytic system and conditions (Table 1). It is worth noting
that, among the organic solvents tested (toluene, CH2Cl2,
MeCN, THF, H2O, EtOH, and MeOH), exclusively meth-
anol gave the desired product 3aa. In fact, the presence of
methanol seems to be crucial for the reaction to take place
as we never detected this product in our previous research
on click chemistry.12 Interestingly, the reaction proceeded
at room temperature irrespective of the copper source at
The synthesis of 5-alkynyl 1,2,3-triazoles has been mainly
accomplished following the first approach. Wu et al. de-
scribed thus the copper-mediated synthesis of fully substi-
tuted 1,2,3-triazoles by reacting organic azides and
SYNLETT 2012, 23, 2179–2182
Advanced online publication: 08.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290445; Art ID: ST-2012-D0385-L
© Georg Thieme Verlag Stuttgart · New York

2180
F. Alonso et al.
LETTER
Table 1 Screening of the Catalysts in the Synthesis of 3aaa
R2
Ph
R2
N
Cu2O (1 mol%)
R2
R1
X
+
NaN3, MeOH, r.t.
Cu catalyst
Ph
N
1
2
Ph
+
Ph
Br
N
NaN3, MeOH, r.t.
1a
2a
R1
Ph
X = Br, Cl
N
N
3
N
Ph
3aa
Ph
Conversion (%)b
Ph
Entry
Catalyst
Ph
Ph
N
N
1
2
3
4
5
6
7
Cu
85
83
82
70
83
90
64
N
Ph
N
N
CuCl
CuCl2
CuBr
CuI
N
N
N
N
Ph
3aa
3ba
(12 h, 88%)
3ca
(24 h, 50%)
(X = Br, 6 h, 87%)
(X = Cl, 16 h, 81%)
Ph
Ph
Cu2O
CuO
Ph
Ph
Ph
Ph
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), NaN3 (0.6 mmol),
catalyst (0.01 mmol), MeOH (2 mL), r.t.
N
N
N
N
N
N
N
N
b Conversion into 3aa after 24 h determined by GC.
N
low catalyst loading, though Cu2O exhibited the highest
performance (Table 1, entry 6).
O2N
F
OMe
3fa
3da
3ea
Following the optimised conditions, an array of 5-al-
kynyl-1,4-disusbstituted 1,2,3-triazoles were synthesised
(Scheme 1). Electronically different benzyl bromides and
chlorides 1a–f reacted with phenylacetylene (2a) to fur-
nish the corresponding products 3aa–fa in moderate to
high yields. Allylic bromides and ethyl 2-bromoacetate
reacted smoothly and high yielding, giving rise to 3ga,
3ha, and 3ia, respectively. Electron-neutral, -rich, and
-deficient aryl acetylenes 2b–d behaved similarly when
combined with benzyl bromide (1a). Moreover, triazoles
bearing two aliphatic substituents at the 4,5-positions
(3ae–ag) were also efficiently obtained.
(12 h, 68%)
(12 h, 65%)
(X = Cl, 12 h, 56%)
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
EtO2C
Ph
3ga
(8 h, 90%)
3ha
(8 h, 87%)
3ia
(8 h, 82%)
R
R
It is worth noting that products 3 can be considered the re-
sult of the Huisgen 1,3-dipolar cycloaddition over sym-
metrically substituted 1,3-diynes. This reaction has been
barely studied due to the lack of selectivity; the thermal
conditions applied require specific sterically demanding
substrates in order to prevent the double cycloaddition and
polymerisation side reactions, and even then, the yields
reported were rather poor.13 This kind of process was dis-
carded in our methodology as the reaction of 1,4-diphen-
ylbuta-1,3-diyne with benzyl bromide and sodium azide,
under the standard conditions, led to the unchanged start-
ing diyne and benzyl azide. The possibility of carbon–
hydrogen bond activation at the 5-position of the parent
1,4-disubstituted triazole was also ruled out because the
reaction of 1-benzyl-4-phenyl-1H-1,2,3-triazole with
phenylacetylene also failed. These results, together with
the experiment depicted in Scheme 2, involving equimo-
lecular amounts of 1a and 2a in CD3OD,14 point to a cop-
per(I) triazolide3,15 as the most plausible precursor of both
deuterated 4aa and compounds 3 after protonation–
deuteration or coupling with the alkyne, respectively.
R = Me, 3ab (12 h, 80%)
R = OMe, 3ac (12 h, 81%)
R = CF3, 3ad (12 h, 78%)
N
N
N
Ph
OBn
OBn
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
3ae
3af
(24 h, 54%)
3ag
(12 h, 72%)
(8 h, 83%)
Scheme 1 Multicomponent synthesis of fully substituted 5-alkynyl
1,2,3-triazoles catalysed by Cu2O. Reagents and conditions: 1 (0.5
mmol), 2 (1.0 mmol), NaN3 (0.6 mmol), Cu2O (1.4 mg, 1 mol% re-
ferred to 2), MeOH (2 mL), r.t. Reaction time and isolated yield in pa-
renthesis. X = Br unless otherwise stated
Synlett 2012, 23, 2179–2182
© Georg Thieme Verlag Stuttgart · New York

LETTER
Alkynyl Triazoles by Domino Click and Coupling
2181
click chemistry. Further research on the mechanism,
scope, and applications of this multicomponent reaction
are under way. In particular, the introduction of other sub-
stituents at the 5-position will be especially challenging.
D
Ph
Cu2O (1 mol%)
Ph
+
Ph
Br
N
N
NaN3, CD3OD, r.t.
N
1a
(1 equiv)
2a
(1 equiv)
Ph
4aa-d1
86% D
Acknowledgment
Scheme 2 Deuterium-labelling experiment
This work was generously supported by the Spanish Ministerio de
Ciencia e Innovación (MICINN; CTQ2007-65218 and Consolider
Ingenio 2010-CSD2007-00006), the Generalitat Valenciana (GV;
PROMETEO/2009/039), and Fondo Europeo de Desarrollo Regio-
nal (FEDER). Y. M. acknowledges the Instituto de Síntesis Orgáni-
ca (ISO) of the Universidad de Alicante for a grant.
In order to get an insight into the reaction mechanism, re-
agent-grade MeOH (99.8%), anhydrous MeOH (99.8%,
<0.002% water), and CD3OD were used as solvents under
different atmospheres in the title reaction. Conversions
>80% into 3aa, without byproduct formation, were only
achieved under the standard conditions (i.e., in the pres-
ence of air) independently of the methanol utilised. In
contrast, when the above solvents were subjected to de-
gasification, prior to the reaction, 3aa was produced in 1–
9%. Finally, substantial amounts of alkyne homocoupling
(21–25%) together with 3aa (67–70%) were recorded in
the presence of molecular oxygen (balloon). From these
results it can be inferred that the oxygen dissolved is ox-
idising copper in the catalytic cycle (Scheme 3). Given
that the reductive elimination from copper(II) species is
an unfavoured process,16 oxidation of copper(II) to cop-
per(III) and subsequent reductive elimination,17 with re-
generation of copper(I), is invoked as similarly suggested
by Porco et al.9 In addition, the equilibrium solubility of
oxygen in methanol seems to be the ideal one to drive the
reaction selectively toward the fully substituted triazole,
making unnecessary the use of a chemical oxidant.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) (a) Huisgen, R.; Knorr, R.; Moebius, L.; Szeimies, G. Chem.
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(2) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
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(3) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(4) For a review, see: Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2001, 40, 2004.
(5) For selected recent reviews and monographs, see:
(a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(b) Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem.
2008, 1133. (c) Amblard, F.; Cho, J. H.; Schinazi, R. F.
Chem. Rev. 2009, 109, 4207. (d) Click Chemistry for
Biotechnology and Materials Science; Lahann, J., Ed.; John
Wiley and Sons: Hoboken, 2009. (e) Finn, M. G.; Fokin, V.
V. In Catalysis Without Precious Metals; Morris Bullock, R.,
Ed.; Wiley-VCH: Weinheim, 2010, 235–260. (f) For a
special issue on applications of click chemistry, see: Chem.
Soc. Rev. 2010, 39, issue 4. (g) Quin, A.; Lam, J. W. Y.;
Tang, B. Z. Chem. Soc. Rev. 2010, 39, 2522. (h) Aragão-
Leoneti, V.; Campo, V. L.; Gomes, A. S.; Field, R. A.;
Carvalho, I. Tetrahedron 2010, 66, 9475.
(6) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.;
Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc.
2008, 130, 8923.
(7) For a perspective, including the synthesis of 5-halotriazoles,
see: Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem.
2010, 8, 4503.
[CuI]
R2
H
R2
NaX
N
N
N
R1
R2
[CuII]
R1
X
R2
+
Cu(I)
NaN3
N
N
N
R2
+
R1
R2
O2
[CuIII]
N
R2
R2
(8) (a) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005,
1314. (b) Deng, J.; Wu, Y.-M.; Chen, Q.-Y. Synthesis 2005,
2730.
(9) Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A. Jr.
Tetrahedron 2006, 62, 6405.
(10) Yang, D.; Fu, N.; Liu, Z.; Li, Y.; Chen, B. Synlett 2007, 278.
(11) Brunner, M.; Maas, G.; Klärner, F.-G. Helv. Chim. Acta
2005, 88, 1813.
H2O
R2
N
N
R1
N
N
N
R1
Scheme 3 Proposed catalytic cycle
(12) (a) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M.
Tetrahedron Lett. 2009, 50, 2358. (b) Alonso, F.; Moglie,
Y.; Radivoy, G.; Yus, M. Eur. J. Org. Chem. 2010, 1875.
(c) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Adv. Synth.
Catal. 2010, 352, 3208. (d) Alonso, F.; Moglie, Y.; Radivoy,
G.; Yus, M. Org. Biomol. Chem. 2011, 9, 6385. (e) Alonso,
F.; Moglie, Y.; Radivoy, G.; Yus, M. J. Org. Chem. 2011,
76, 8394. (f) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M.
Heterocycles 2012, 84, 1033.
In conclusion, a straightforward synthesis of fully substi-
tuted 1,2,3-triazoles with an alkynyl moiety at the 5-posi-
tion has been successfully introduced from organic
halides, terminal alkynes, and sodium azide, using a very
simple catalytic system composed of copper(I) oxide and
methanol under ambient conditions.18 This discovery will
be of great interest for the varied disciplines dealing with
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2179–2182

2182
F. Alonso et al.
LETTER
(13) (a) Stepanova, N. P.; Orlova, N. A.; Galishev, V. A.;
Turbanova, E. S.; Petrov, A. A. Zh. Org. Khim. 1985, 21,
979; Chem. Abstr. 1985, 103, 123415. (b) Bettison, M.;
Hitchcock, P. B.; Walton, D. R. M. J. Organomet. Chem.
1988, 341, 247. (c) Domnin, I. N.; Remizova, L. A.; Starova,
G. L.; Rominger, F. Russ. J. Org. Chem. 2009, 45, 1678.
(14) 1,4-Disubstituted triazoles 4 are not formed, but only
triazoles 3, when the organic halide 1 and the alkyne 2 are
used in a 1:2 molar ratio. This fact is indicative of the high
selectivity of the reaction.
and/or 1H NMR spectroscopy until total conversion of the
starting materials. H2O (2 mL) was added to the mixture,
followed by extraction with EtOAc (3 × 10 mL). The
resulting organic phase was evaporated under vacuum, and
the residue was purified by column chromatography (silica
gel, hexane–EtOAc).
1-Benzyl-4-(p-tolyl)-5-(p-tolylethynyl)-1H-1,2,3-triazole
(3ab)
Starting from benzyl bromide (1a, 60 μL, 0.5 mmol), 1-
ethynyl-4-methylbenzene (2b, 127 μL, 1.0 mmol), NaN3
(39.0 mg, 0.6 mmol), and Cu2O (1.4 mg, 0.01 mmol) in
MeOH (2 mL), 3ab was isolated as a pale orange solid (145
mg, 80%); mp 81.9–84.0 °C; Rf = 0.66 (hexane–EtOAc =
7:3). IR (neat): ν = 3034, 2919, 1518, 1496, 1455, 1362,
1001, 815, 726, 692 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.07 (d, J = 8.1 Hz, 2 H), 7.42–7.30 (m, 7 H), 7.25 (d,
J = 8.1 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 5.65 (s, 2 H), 2.39
(s, 3 H), 2.38 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 148.2,
140.2, 138.6, 134.9, 131.6, 129.6, 129.5, 128.9, 128.6,
128.2, 127.6, 126.2, 118.6, 117.2, 102.6, 77.4, 75.3, 53.0,
21.8, 21.5. MS (70 eV): m/z (%) = 364 (11) [M+ + 1), 363
(39) [M+], 334 (10), 245 (19), 244 (100), 203 (15), 127 (15),
91 (23). HRMS: m/z calcd for C25H21N3: 363.1735; found:
363.1726.
(15) Nolte, C.; Mayer, P.; Straub, B. F. Angew. Chem. Int. Ed.
2007, 46, 2101.
(16) See, for instance: Lam, P. Y. S.; Vincent, G.; Bonne, D.;
Clark, C. G. Tetrahedron Lett. 2003, 44, 4927.
(17) For the recent observation of Cu(I)/Cu(III) redox steps in
cross-coupling reactions, see: Casitas, A.; King, A. E.;
Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem. Sci.
2010, 1, 326.
(18) General Procedure for the Synthesis of 5-Alkynyl 1,2,3-
triazoles 3
The organic halide (1, 0.5 mmol), alkyne (2, 1.0 mmol), and
NaN3 (39.0 mg, 0.6 mmol) were added to a reactor tube
containing a suspension of Cu2O (1.4 mg, 0.01 mmol) in
MeOH (2 mL). The reaction mixture was stirred at r.t.
without the exclusion of air and monitored by TLC, GLC,
Synlett 2012, 23, 2179–2182
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