A metal-free three-component reaction for the regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/anie.201403453

A metal-free three-component reaction to synthesize 1,4,5-trisubstituted 1,2,3-triazoles from readily available building blocks,such as aldehydes,nitroalkanes,and organic azides,is described. The process is enabled by an organocatalyzed Knoevenagel condensation of the formyl group with the nitro compound,which is followed by the 1,3-dipolar cycloaddition of the azide to the activated alkene. The reaction features an excellent substrate scope,and the products are obtained with high yield and regioselectivity. This method can be utilized for the synthesis of fused triazole heterocycles and materials with several triazole moieties.

Full text of DOI:10.1002/anie.201403453

Angewandte
Chemie
DOI: 10.1002/anie.201403453
Triazole Synthesis
Hot Paper
A Metal-Free Three-Component Reaction for the Regioselective
Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles**
Joice Thomas, Jubi John, Nikita Parekh, and Wim Dehaen*
Abstract: A metal-free three-component reaction to synthesize
1,4,5-trisubstituted 1,2,3-triazoles from readily available build-
ing blocks, such as aldehydes, nitroalkanes, and organic azides,
is described. The process is enabled by an organocatalyzed
Knoevenagel condensation of the formyl group with the nitro
compound, which is followed by the 1,3-dipolar cycloaddition
of the azide to the activated alkene. The reaction features an
excellent substrate scope, and the products are obtained with
high yield and regioselectivity. This method can be utilized for
the synthesis of fused triazole heterocycles and materials with
several triazole moieties.
Figure 1. Organocatalytic routes to substituted 1,2,3-triazoles.
S
ubstituted 1,2,3-triazoles are among the most important
heterocyclic compounds and have found a broad spectrum of
applications in areas ranging from medicinal chemistry to
material science.[1] The amide–triazole bioequivalence of
these heterocycles has been utilized for the development of
many privileged medicinal scaffolds that exhibit, for instance,
anti-HIV, anticancer, and antibacterial activities.[2] Because of
their reliability, regioselective triazole-forming reactions have
gained much attention, particularly those that are based on
copper(I)- and ruthenium(II)-mediated azide–alkyne cyclo-
additions reactions.[3,4] However, these methods are mostly
restricted to terminal alkynes, and the toxicity of the heavy
metals makes these strategies not ideal for some biological
applications.[5] Therefore, the development of new efficient
methods that are devoid of these deficiencies would be of
great importance.
tations of these approaches are the narrow substrate scope
and the restriction to ketone or cyclic enone substrates.
Despite these advances in organocatalytic triazole syn-
thesis, some challenging issues still remain: 1) A regioselec-
tive synthesis of 1,4,5-trisubstitued 1,2,3-triazoles with con-
siderable molecular complexity and diversity to enable
structure–activity relationship studies of drug-like com-
pounds and 2) an economically viable procedure to synthesize
densely functionalized triazoles from inexpensive commer-
cially available building blocks have not been developed.
Perhaps the most promising and powerful method to reach
these goals is to rely on new multicomponent reactions
(MCRs).[7] Ideally, MCRs should be versatile so that any
combination of functional groups can be integrated into the
final products. In view of realizing such transformations, we
were prompted to consider a three-component reaction
(3CR) to construct fully functionalized triazole scaffolds
from readily available building blocks, such as aldehydes,
nitroalkanes, and organic azides (Figure 1). We hypothesized
that nitroalkene dipolarophiles prepared in situ by a Knoeve-
nagel condensation of the corresponding aldehydes and
substituted nitroalkanes may undergo a regioselective inter-
molecular Huisgen cycloaddition reaction with organic azides
to form 1,4,5-trisubstituted 1,2,3-triazoles after aromatization
by spontaneous loss of HNO2 in an atom-economic
approach.[8]
Recently, organocatalytic triazole formation has been
used as a powerful, albeit less developed, alternative to metal-
catalyzed click reactions (Figure 1).[6] The first example was
reported by Ramachary et al., who investigated the synthesis
of functionalized NH-1,2,3-triazoles from g-activated enones
and organic azides under proline catalysis.[6a,h] Recently, the
groups of Wang and Bressy independently developed a regio-
selective approach for the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles through enamide–azide cycloadditions of
b-keto esters or nitriles to azides in the presence of a catalytic
amount of a secondary amine.[6b–d,f,g] However, major limi-
The reaction conditions were optimized with benzalde-
hyde (1a), ethyl nitroacetate (2a), and benzyl azide (3a) as
the model substrates.[9] Therefore, the optimized reaction
conditions of the one-pot 3CR were found to entail the use of
1a, 2a, and 3a in a molar ratio of 1.3:1:1, morpholinium para-
toluenesulfonate (Morph/TsOH, 5 mol%) as the catalyst, and
2,6-di-tert-butyl-4-methylphenol (BHT; 5 mol%) as an addi-
tive over 4 ꢀ molecular sieves in toluene (2m) at 1008C in
a sealed tube under argon atmosphere. The desired product
[*] Dr. J. Thomas, Dr. J. John, N. Parekh, Prof. Dr. W. Dehaen
Molecular Design and Synthesis
Department of Chemistry, KU Leuven
Celestijnenlaan 200F, 3001 Leuven (Belgium)
E-mail: wim.dehaen@chem.kuleuven.be
[**] We thank the University of Leuven and the FWO-Vlaanderen for
financial support. The Erasmus Exchange program “Experts II” is
acknowledged for a fellowship to N.P.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403453.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
4a was isolated in 83% yield with a regioselectivity of > 99%
[Eq. (1)].
by further Michael addition reactions with nitroalkenes to
generate the undesired dinitroglutaric ester 6.[11] We presume
that this species is in equilibrium with the Knoevenagel
product 5, and that the formation of triazole 4 can displace
this equilibrium, so that this transformation is an example of
thermodynamically controlled dynamic covalent chemistry.[12]
Thus, the yield of the 3CR is superior to that of the 2CR
Knoevenagel condensation itself, and isolation of the nitro-
alkene prior to the cycloaddition[8] is not needed, and even
disadvantageous for the overall yield. The high regioselectiv-
ity of this reaction is clearly due to the presence of a strongly
electron-withdrawing nitro group on the dipolarophile 5,
which lowers the energy of the lowest unoccupied molecular
orbital (LUMO) and causes the b carbon atom to be the most
electrophilic.[13] Thus, dipolar reaction partners are expected
to attack the partially positively charged b position of the
nitroalkene dipolarophile in a Huisgen cycloaddition to form
a cyclic triazoline intermediate, which would then eliminate
nitrous acid to regioselectively yield a triazole with the
carboxy and the phenyl group at the C4 and the C5 position,
respectively.[8]
To get insight into the mechanism of the reaction, several
experiments were done. When 1a and 2a were reacted in the
presence of the Morph/TsOH cata-
With the optimized reaction conditions in hand, we first
studied the scope and limitations of this transformation with
Table 1: Substrate scope of the triazole synthesis.[a]
lyst (5 mol%) for a period of one
hour, nitroalkene 5 was obtained in
45% yield, together with the
expected Michael adduct, 1,3-dini-
troalkane 6, in 20% yield [Eq. (2)].
Then, two separate experiments
were conducted with the isolated
dipolarophile 5 and benzyl azide 3a
both in the absence and in the
presence of the catalyst over
a period of 48 hours. Interestingly,
both reactions led to the desired
product 4a in 84% and 86% yield,
respectively, and exhibited the same
regioselectivity as a reaction under
the optimized conditions. This
observation convincingly demon-
strated that the organocatalyst
plays no role in determining the
high regioselectivity of the final
cycloaddition step. Based on these
studies, the probable catalytic path-
way of this MCR involves the initial
formation of an activated iminium
intermediate from benzaldehyde
(1a) and the morpholine salt.[10]
This intermediate is then attacked
by ethyl nitroacetate (2a) to afford
nitroalkene 5, together with the
regeneration of the catalyst. A con-
densation reaction catalyzed by
para-toluenesulfonic acid could
constitute another reaction path-
way. However, some of these Knoe-
[a] Reaction conditions: 1 (1.3 equiv), 2 (1.0 equiv), 3 (1.0 equiv), Morph/TsOH (5 mol%), BHT
(5 mol%), 4 ꢀ M.S. (50 mg), toluene (0.2 mL), 1008C, 48 h. Yields of isolated products are given. [b] 4%
of the other regioisomer was observed. [c] BHT (30 mol%). [d] Thiophene-2-carbaldehyde (2.0 equiv).
venagel adducts will be consumed [e] 2 (2.6 equiv), 72 h. M.S.=molecular sieves.
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
a wide range of aromatic and aliphatic aldehydes (Table 1).
Both electron-donating functional groups, such as methoxy
(4b and 4c) and methyl (4d) substituents, and electron-
withdrawing groups, such as halogens (4e and 4 f), aldehyde
(4g), and ester (4h) moieties, on the aromatic rings were
compatible with this transformation, and the corresponding
products were obtained in good to excellent yields. The use of
electron-poor aldehydes led to the formation of a single
regioisomer, whereas the use of electron-rich aldehydes
resulted in a small, but noticeable amount (4%) of the
other regioisomer, which bears the ester group derived from
ethyl nitroacetate on the C5 position of the triazole ring.
These observations revealed that electron-donating groups
reduce the electrophilicity at the b carbon atom of the
corresponding dipolarophile, leading to a small amount of
the other regioisomer. Fortunately, this minor regioisomer is
effectively removed by column chromatography. The reaction
was also not affected by the steric hindrance impaired by
methoxy (4c) or methyl (4d) groups at the ortho position of
the aromatic aldehydes. Notably, a readily available fluores-
cent material, pyrene-1-carboxaldehyde, performed well in
this transformation, affording the triazole 4i in 76% yield, but
a larger amount of BHT (30 mol%) had to be employed.
Otherwise, the reaction afforded desired product 4i in only
43% yield. The reaction of the heterocyclic substrate
thiophene-2-carbaldehyde also proceeded with reduced effi-
ciency under the optimized conditions. Fortunately, when the
reaction was repeated with two equivalents of thiophene-2-
carbaldehyde, the yield of the corresponding bis(heteroaryl)
product 4j improved to 56%. Furthermore, ethyl glyoxalate
was also found to be a suitable coupling partner, which led to
the expected compound 4k in 77% yield. The reaction with
an aliphatic aldehyde afforded compound 4l in 50% yield. An
expected obstacle with the aliphatic aldehyde was the
undesired aldol condensation, which also proceeded under
the reaction conditions.
We then examined the scope of this MCR with respect to
the nitroalkane coupling partner. Differently functionalized
nitroalkanes, such as benzoylnitromethane, phenylsulfonylni-
tromethane, and nitroacetamide, were compatible with these
conditions and afforded the expected compounds once again
with excellent regioselectivity. To extend the applicability of
this transformation and to demonstrate its broad scope, we
synthesized 1,2,3-triazolyl-4-phosphonate 4q using this strat-
egy. To the best of our knowledge, a metal-free synthesis of
1,2,3-triazolyl phosphonates has not yet been described.[14] We
believe that the lower yield of this reaction is due to the
hydrolysis of the phosphonate group under the present
reaction circumstances. We next studied the use of non-
activated nitroalkanes (4r–4aa) in this transformation, and
after some optimization, we found that this multicomponent
reaction proceeded more effectively with an excess amount of
the nitro compound (2.6 equiv) and required a reaction time
of 72 hours. Several aliphatic and aromatic groups were
introduced at the C4 position of the triazole heterocycle. To
our delight, the reaction with bromonitromethane furnished
1,5-disubstituted 4-bromotriazole 4r in 64% yield, showing
that HNO2 is eliminated rather than HBr, which would be
equally plausible.[15] Generally, copper- or iridium-catalyzed
cycloaddition reactions of azides and bromoalkynes have
been employed to synthesize 1,5-disubstituted 4-bromotria-
zoles, but the lack of structural diversity in the alkynyl
building blocks has limited the application of this method.[16]
The reaction with nitromethane constitutes an additional
example of a metal-free multicomponent reaction for the
regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles.[17]
Furthermore, the reactivity of several azides was evaluated.
For aromatic azides, an electron-donating para-methoxy
group resulted in the isolation of the desired cycloadduct
4ab in good yield; however, azides with an electron-with-
drawing ester group or a phenyl substituent provided the
corresponding products in diminished yields in comparison
with benzyl azide (4ac and 4ad). This may partially be
explained by the lower thermal stability of aryl azides. Not
surprisingly, aliphatic azides were converted into the corre-
sponding products with higher efficiency than the aromatic
azides (4ae–4ag).
Interestingly, the reaction with ethyl glyoxalate (7),
benzoylnitromethane (8), and 2-azidoethanol (9) under
optimized conditions led to the formation of the novel
heterocycle-fused 1,2,3-triazole 10, which entails a six-mem-
bered lactone fused to the 1- and 5-positions of the triazole
ring system [Eq. (3)].
In a preliminary investigation, we have established that
this three-component reaction is also applicable to acetal-
protected aldehydes, thus giving access to triazole hetero-
cycles that cannot be synthesized by other methods. For
example, under the standard conditions, diethyl chloroacetal
11 yielded the desired product 12 in 52% yield with good
regioselectivity [Eq. (4)].
Bifunctional building blocks with the same functional
groups gave bis(triazole) derivatives after multiple MCRs
(Figure 2). Our initial experiments focused on the bifunc-
tional substrate terephthaldehyde, which gave the novel
bis(triazole) compound 13 in acceptable yield (40%) on
treatment with 2a and 3a (2 equiv each) under the optimized
reaction conditions. Furthermore, two diazide building
blocks, 1,2-bis(azidomethyl)benzene and 1,4-bis(azidome-
thyl)benzene, were treated with an excess of 1a and 2a to
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
21, could be shown to be the other regioisomer (with the
carbonyl group of the lactone ring connected to the 5-position
of the triazole) with respect to the preceding examples. Initial
1
evidence was obtained from the H NMR spectra of these
compounds and the unusual downfield shifts of the peaks
corresponding to the methylene groups that originate from
the organic azides compared to other trisubstituted 1,2,3-
triazoles. To obtain concrete evidence for the regiochemistry
of this product, we synthesized the regioisomer of 20, triazole
22 (with the carbonyl group of the lactone ring connected to
the 4-position of the triazole), by BBr3 mediated cleavage of
the ether moiety of triazole derivative 4c followed by
lactonization [Eq. (7)]. An upfield shift of the peaks corre-
Figure 2. Multicomponent synthesis of bis(triazole) derivatives.
furnish the desired products 14 and 15 in 69% and 75% yield,
respectively.
The versatility of these multiple MCRs was further
exemplified by synthesizing compound 17, a metal-free
tetraarylporphyrin functionalized with four fully substituted
1,2,3-triazole groups [Eq. (5)]. In earlier work, we had seen
sponding to the benzylic hydrogen
1
atoms in the H NMR spectrum of 22
relative to those of 20 confirmed the
regiochemistry of the coumarin-fused
triazole derivatives. We speculate that
with the dipolarophile 3-nitrocou-
marin, steric effects surpass electronic
preferences, to give exclusively the
opposite regioisomer.[13]
In conclusion, we have developed
a versatile organocatalytic three-com-
ponent reaction that generates fully
substituted 1,2,3-triazoles decorated
with useful functional groups, which
can be used for further manipulation
and diversification. This method fea-
tures metal-free conditions and high
regioselectivity, and it provides an easy
that unless the porphyrin is metalated (with Zn) prior to the
copper-catalyzed click reaction, we obtained a CuII metalated
porphyrinate.[18] Close inspection of the 1H NMR data of the
crude reaction mixture revealed the presence of 4% of the
other regioisomer. Ultimately, 17 was isolated as a single
regioisomer in good yield by column chromatography fol-
lowed by precipitation of the isolated compound in an excess
of heptane.
Inspired by the success of the above reactions, our efforts
were focused on the reaction of salicylaldehyde (18), ethyl
nitroacetate (2a), and organic azides to generate coumarin-
fused triazole derivatives [Eq. (6)].[9] Surprisingly, the prod-
ucts arising from these transformations, heterobicycles 20 and
access to diversely functionalized 1,2,3-triazoles that are
inaccessible by other means. Many functional groups, such as
aldehydes, ketones, esters, sulfones, halides, amides, and
phosphonates, are well tolerated under these reaction circum-
stances. A rapid search for the products reported herein
showed that less than 20% of them have been previously
described. Furthermore, most of the reported syntheses have
the disadvantage of requiring heavy metals and less available
unsymmetric internal alkynes; therefore, our method is very
convenient. Further elaboration of this chemistry to other
new reactions and the development of applications of these
transformations in the medicinal as well as the supramolec-
ular sciences are currently actively pursued within our group.
Received: March 18, 2014
Revised: May 12, 2014
Published online: && &&, &&&&
Keywords: dipolar cycloaddition · multicomponent reactions ·
.
organocatalysis · regioselectivity · triazole
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Lenard¼o, L. Savegnago, M. W. Paix¼o, D. Alves, Eur. J. Org.
Chem. 2014, 1059 – 1065.
[7] A. Dçmling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083 –
3135.
[8] a) J. C. Piet, G. Le Hetet, P. Cailleux, H. Benhaoua, R. Carrie,
Bull. Soc. Chim. Belg. 1996, 105, 33 – 44; b) T. Wang, X.-C. Hu,
X.-J. Huang, X.-S. Li, J.-W. Xie, J. Braz. Chem. Soc. 2012, 23,
1119 – 1123; c) P. S. S. Lacerda, A. M. G. Silva, A. C. Tome,
M. G. P. M. S. Neves, A. M. S. Silva, J. A. S. Cavaleiro, A. L.
Llamas-Saiz, Angew. Chem. 2006, 118, 5613 – 5617; Angew.
Chem. Int. Ed. 2006, 45, 5487 – 5491.
[1] For selected reviews on the application of 1,2,3-triazoles, see:
a) “Special issue on click chemistry”, Chem. Soc. Rev. 2010, 39,
1221 – 1408; b) T. Muller, S. Brꢁse, Angew. Chem. 2011, 123,
12046 – 12047; Angew. Chem. Int. Ed. 2011, 50, 11844 – 11845;
c) C. Chu, R. Liu, Chem. Soc. Rev. 2011, 40, 2177 – 2188; d) Y. H.
Lau, P. J. Rutledge, M. Watkinson, M. H. Todd, Chem. Soc. Rev.
2011, 40, 2848 – 2866; e) D. Astruc, L. Liang, A. Rapakousiou, J.
Ruiz, Acc. Chem. Res. 2012, 45, 630 – 640.
[2] a) R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E.
De Clercq, C.-F. Perno, A. Karlsson, J. Balzarini, M. J. Camar-
asa, J. Med. Chem. 1994, 37, 4185 – 4194; b) R. S. Bohacek, C.
McMartin, W. C. Guida, Med. Res. Rev. 1996, 16, 3 – 50; c) M. J.
Soltis, H. J. Yeh, K. A. Cole, N. Whittaker, R. P. Wersto, E. C.
Kohn, Drug Metab. Dispos. 1996, 24, 799 – 806; d) R. Kharb, P. C.
Sharma, M. S. Yar, J. Enzyme Inhib. Med. Chem. 2011, 26, 1 – 21;
e) C. Sheng, W. Zhang, Curr. Med. Chem. 2011, 18, 733 – 766;
f) S. G. Agalave, S. R. Maujan, V. S. Pore, Chem. Asian J. 2011, 6,
2696 – 2718; g) P. Thirumurugan, D. Matosiuk, K. Jozwiak,
Chem. Rev. 2013, 113, 4905 – 4979.
[3] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708 – 2711; Angew. Chem. Int. Ed.
2002, 41, 2596 – 2599; b) C. W. Tornøe, C. Christensen, M.
Meldal, J. Org. Chem. 2002, 67, 3057 – 3064; c) P. Appukkuttan,
W. Dehaen, V. V. Fokin, E. Van der Eycken, Org. Lett. 2004, 6,
4223 – 4225; d) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108,
2952 – 3015.
[4] a) L. Zhang, X. G. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
K. B. Sharpless, V. V. Fokin, G. C. Jia, J. Am. Chem. Soc. 2005,
127, 15998 – 15999; b) L. K. Rasmussen, B. C. Boren, V. V.
Fokin, Org. Lett. 2007, 9, 5337 – 5339.
[5] a) L. M. Gaetke, C. K. Chow, Toxicology 2003, 189, 147 – 163;
b) A. J. Link, D. A. Tirrell, J. Am. Chem. Soc. 2003, 125, 11164 –
11165; c) A. J. Link, M. K. S. Vink, N. J. Agard, J. A. Prescher,
C. R. Bertozzi, D. A. Tirrell, Proc. Natl. Acad. Sci. USA 2006,
103, 10180 – 10185; d) J. A. Johnson, J. M. Baskin, C. R. Ber-
tozzi, J. T. Koberstein, N. J. Turro, Chem. Commun. 2008, 3064 –
3066.
[6] For examples of organocatalytic [3+2] cycloaddition reactions,
see: a) D. B. Ramachary, K. Ramakumar, V. V. Narayana, Chem.
Eur. J. 2008, 14, 9143 – 9147; b) L. J. T. Danence, Y. Gao, M. Li,
Y. Huang, J. Wang, Chem. Eur. J. 2011, 17, 3584 – 3587; c) M.
Belkheira, D. E. Abed, J.-M. Pons, C. Bressy, Chem. Eur. J. 2011,
17, 12917 – 12921; d) L. Wang, S. Y. Peng, L. J. T. Danence, Y.
Gao, J. Wang, Chem. Eur. J. 2012, 18, 6088 – 6093; e) N. Seus,
L. C. Goncalves, A. M. Deobald, L. Savegnago, D. Alves, M. W.
Paixao, Tetrahedron 2012, 68, 10456 – 10463; f) D. K. J. Yeung, T.
Gao, J. Huang, S. Sun, H. Guo, J. Wang, Green Chem. 2013, 15,
2384 – 2388; g) W. Li, Q. Jia, Z. Du, J. Wang, Chem. Commun.
2013, 49, 10187 – 10189; h) D. B. Ramachary, A. B. Shashank,
Chem. Eur. J. 2013, 19, 13175 – 13181; i) N. Seus, B. Goldani, E. J.
[9] See the Supporting Information.
[10] a) D. W. C. MacMillan, Nature 2008, 455, 304 – 308; b) B. List,
Angew. Chem. 2010, 122, 1774 – 1779; Angew. Chem. Int. Ed.
2010, 49, 1730 – 1734; c) S.-K. Xiang, B. Zhang, L.-H. Zhang, Y.
Cui, N. Jiao, Chem. Commun. 2011, 47, 8097 – 8099; d) P. Renzi,
M. Bella, Chem. Commun. 2012, 48, 6881 – 6896.
[11] R. Ballini, S. Gabrielli, A. Palmieri, Eur. J. Org. Chem. 2014,
DOI: 10.1002/ejoc.201301531.
[12] a) P. T. Corbett, L. Vial, K. R. West, J.-L. Wietor, J. K. M.
Sanders, S. Otto, Chem. Rev. 2006, 106, 3652; b) J.-M. Lehn,
Chem. Soc. Rev. 2007, 36, 151; c) J. Thomas, G. Reekmans, P.
Adriaensens, L. Van Meervelt, M. Smet, W. Maes, W. Dehaen, L.
Dobrzanska, Angew. Chem. 2013, 125, 10427 – 10430; Angew.
Chem. Int. Ed. 2013, 52, 10237 – 10240.
[13] a) R. Huisgen, G. Szeimies, L. Mçbius, Chem. Ber. 1967, 100,
2494 – 2507; b) A. Padwa, in Comprehensive Organic Synthesis,
Vol. 4 (Ed.: B. M. Trost), Pergamon, Oxford, 1991, pp. 1069 –
1109; c) J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1302 –
1315.
[14] a) J.-M. Kee, B. Villani, L. R. Carpenter, T. W. Muir, J. Am.
Chem. Soc. 2010, 132, 14327 – 14329; b) L. Li, G. Hao, A. Zhu, X.
Fan, G. Zhang, L. Zhang, Chem. Eur. J. 2013, 19, 14403 – 14406.
[15] A referee suggested that this may be due to the cis arrangement
of the H and Br substituents in the intermediary triazoline
adduct.
[16] a) B. H. M. Kuijpers, G. C. T. Dijkmans, S. Grootuys, P. J. L. M.
Quaedflieg, R. H. Blaauw, F. L. van Delft, F. P. J. T. Rutjes,
Synlett 2005, 3059 – 3062; b) E. Rasolofonjatovo, S. Theeramun-
kong, A. Bouriaud, S. Kolodych, M. Chaumontet, F. Taran, Org.
Lett. 2013, 15, 4698 – 4701.
[17] a) S. W. Kwok, J. R. Fotsing, R. J. Fraser, V. O. Rodionov, V. V.
Fokin, Org. Lett. 2010, 12, 4217 – 4219; b) M. E. Meza-AviÇa,
M. K. Patel, C. B. Lee, T. J. Dietz, M. P. Croatt, Org. Lett. 2011,
13, 2984 – 2987; c) F. Kloss, U. Kçhn, B. O. Jahn, M. D. Hager, H.
Gçrls, U. S. Schubert, Chem. Asian J. 2011, 6, 2816 – 2824; d) G.
Cheng, X. Zeng, J. Shen, X. Wang, X. Cui, Angew. Chem. 2013,
125, 13507 – 13510; Angew. Chem. Int. Ed. 2013, 52, 13265 –
13268; e) A. Kayet, T. Pathak, J. Org. Chem. 2013, 78, 9865 –
9875.
[18] N. T. Nguyen, G. Mamardashvili, M. Gruzdev, N. Mamardashvili,
W. Dehaen, Supramol. Chem. 2013, 25, 180 – 188.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Triazole Synthesis
J. Thomas, J. John, N. Parekh,
W. Dehaen*
&&&& — &&&&
A Metal-Free Three-Component Reaction
for the Regioselective Synthesis of 1,4,5-
Trisubstituted 1,2,3-Triazoles
Fully functionalized 1,2,3-triazoles were
obtained by a metal-free three-compo-
nent reaction. Simple and readily avail-
able building blocks were employed in
this organocatalytic transformation,
which gave the desired products in good
yield and with high regioselectivity. Most
of the synthesized triazoles were previ-
ously inaccessible.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!