Multi-component reaction for the preparation of 1,5-disubstituted 1,2,3-triazoles by in-situ generation of azides and nickel-catalyzed azide-alkyne cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2021.153131

An efficient one-pot procedure combining bromide conversion into azide followed by NiAAC for the preparation of 1,5-disubstituted 1,2,3-triazoles has been developed. This procedure prevents the use of isolated azides, which are insufficiently commercially

Full text of DOI:10.1016/j.tetlet.2021.153131

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Multi-component reaction for the preparation of 1,5-disubstituted
1,2,3-triazoles by in-situ generation of azides and nickel-catalyzed
azide-alkyne cycloaddition
Virgyl Camberlein a,1, Nicolas Kraupner a,1, Nour Bou Karroum a, Emmanuelle Lipka b,c
,
Rebecca Deprez-Poulain a,d, Benoit Deprez a,d, Damien Bosc a,
⇑
a Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, Lille, France
b Univ. Lille, Inserm, RID-AGE U1167, F-59000 Lille, France
c UFR Pharmacie, Laboratoire de Chimie Analytique, BP 83, F-59006 Lille, France
d European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot procedure combining bromide conversion into azide followed by NiAAC for the
preparation of 1,5-disubstituted 1,2,3-triazoles has been developed. This procedure prevents the use of
isolated azides, which are insufficiently commercially available and could be potentially unstable and dif-
ficult to handle. Moreover, this one-pot method tolerates a broad range of functional moieties including
ester, carbamate or alcohol. Diverse 1,5-disubstituted 1,2,3-triazoles can be obtained from functionalized
aryl and alkyl alkynes and bromides with modest to excellent yields and regioselectivities. This procedure
will enable the synthesis of libraries of functionalizable 1,5-disubstituted 1,2,3-triazoles particularly
helpful for diverse applications such as medicinal chemistry and chemical biology purposes.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 22 February 2021
Revised 18 April 2021
Accepted 22 April 2021
Available online xxxx
Keywords:
Click chemistry
Molecular diversity
Multicomponent reactions
Regioselectivity
Synthetic methods
Introduction
1,2,3-triazoles, which are for most of them with very limited scope.
The main methodologies use azide-alkyne cycloadditions either
Spearhead of the heterocycles generated by click chemistry,
1,2,3-triazoles are broadly found in several domains such as mate-
rials science [1], organometallic science [2] but also chemical biol-
ogy [3] and medicinal chemistry [4]. This considerable importance
is due to the favorable properties linked to this heteroaromatic ring
but also thanks to the easiness of access of the 1,4-disubstituted
1,2,3-triazoles by copper-catalyzed azide-alkyne cycloaddition
(CuAAC) [5]. This methodology is indeed powerful with excellent
regioselectivity, high yield and is easy to implement. Noteworthy,
the 1,5-disubstituted 1,2,3-triazoles are less represented. As there
is a high interest for 1,5-disubstituted regioisomers in drug discov-
ery as disulfide bond surrogate [6] or cis-peptide bond mimetic [7]
or enzyme modulator [8], it is valuable to facilitate the access of
this scaffold. Several teams have worked on this purpose and to
date there are few methods to synthesize 1,5–disubstituted
mediated by metal acetylide or metal catalysts [9]. The alkynes
can also be replaced by nitroolefins with the use of metallic addi-
tives to afford 1,5–disubstituted 1,2,3-triazoles substituted by aryl
groups [10]. Moreover, in a lesser extent, other functional moieties
have also been used for playing the role of dipolarophile in 1,5-dis-
ubstituted 1,2,3-triazole synthesis [11]. An alternative method
based on a cascade Michael addition was also described for the
construction of 1,5-disubstituted 1,2,3-triazoles [12]. Regrettably,
most of these methodologies have scope constraints. Besides, most
of them require the handling of isolated organic azides, which are
not often commercially available and are known to be unstable,
especially those of low molecular weight [13].
In order to bypass these drawbacks, only few methods, most of
them being multicomponent, have been developed [14]. These
methodologies have the advantage to be safer by preventing the
manipulation of organic azides. However, they suffer from a very
limited substrate scope, often requesting high temperatures, strict
inert atmosphere conditions or an inconvenient sequential pattern,
all of which have confined their use. In order to provide an exten-
sive procedure that circumvent all these drawbacks and that afford
functionalized 1,5-disubsituted 1,2,3-triazoles suitable for diverse
⇑
Corresponding author at: Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 -
Drugs and Molecules for Living Systems, 3 rue du Professeur Laguesse F-59000,
Lille, France.
E-mail address: damien.bosc@univ-lille.fr (D. Bosc).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tetlet.2021.153131
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: V. Camberlein, N. Kraupner, N. Bou Karroum et al., Multi-component reaction for the preparation of 1,5-disubstituted 1,2,3-tri-
azoles by in-situ generation of azides and nickel-catalyzed azide-alkyne cycloaddition, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153131

V. Camberlein, N. Kraupner, N. Bou Karroum et al.
Tetrahedron Letters xxx (xxxx) xxx
applications, we investigated the feasibility to implement an effi-
cient and safe one-pot, two-step method. This procedure would
allow the in situ bromides conversion by nucleophilic substitution
with sodium azide into azides, which react consecutively with
alkynes by NiAAC (Scheme 1).
Results and discussion
First we performed the screening of different reaction condi-
tions on the model substrates 4-tert-butylbenzyl bromide 1a and
phenylacetylene 2A (Table 1). Reaction conditions close to the
recently published NiAAC ones [9g] were applied with the
combination of bromide 1a (1.0 equiv), sodium azide (1.0 equiv),
alkyne 2A (1.2 equiv) in presence of nickelocene (Cp2Ni)
precatalyst (20 mol%), bidentate Xantphos ligand (20 mol%) and
Cs2CO3 (1.0 equiv) at room temperature for 2 h in water. Under
these conditions, the bromide 1a was converted into azide but
the cycloaddition was not observed (entry 1). To facilitate the
triazole formation, several conditions were screened. First,
dimethylformamide, often used as a solvent for azide formation
from bromide and shown to be efficient for the NiAAC, was
evaluated (entry 2). Pleasantly, this solvent allowed the triazole
formation with good yield (71%) contrary to other solvents such
as dichloromethane, ethanol and tetrahydrofuran (entries 2–5).
In order to improve the reaction conversion into triazole, the
reaction vessel was slightly heated at 50 °C under microwave
irradiation for 1 h (entry 6). This heating condition was beneficial
for the regioselectivity (from 88:12 to 93:7) without
compromising the yield (entries 2 vs 6). Higher temperature
Scheme 1. Strategies for the synthesis of 1,5-disubstituted 1,2,3-triazoles.
(80 °C or 100 °C) resulted to
a lower yield and a poorer
order to isolate and characterize properly the 1,5-regioisomers 3,
the reaction crude mixtures were also purified by semi-preparative
supercritical fluid chromatography (SFC) and comparable isolated
yields (24% to 72%) were obtained.
regioselectivity (entries 7 and 8), probably due to the catalyst
degradation. Increasing reaction time to 4 h improved yield (86%,
entry 9) but slightly decreased the regioselectivity (from 93:7 to
92:8). In the attempt to improve the yield of the 1,5-disubsituted
1,2,3-triazole 3aA, the bromide 1a and the sodium azide were
defined as excess reagents (1.2 equiv and 1.5 equiv respectively)
(entries 10). Appealingly, after 4 h under microwave irradiation
at 50 °C, the calculated yield for triazole 3aA was excellent (89%)
with no secondary products and excellent regioselectivity (92:8).
To investigate the mechanism of this multicomponent method,
4-tert-butylbenzyl bromide 1a was submitted to sodium azide at
The regioselectivity of the reactions was determined by super-
critical fluid chromatography (SFC) analysis of the crude reaction
mixtures obtained after the work-up of the reactions carried out
with alkynes 2A–2E and 2H, or according to the 1H NMR spectra
for reactions carried out with alkynes 2F and 2G, whose separation
of the two regioisomers by SFC was not optimal. Modest to excel-
lent regioselectivities were obtained. Considering the regioselec-
tivity obtained with the p-nitrophenylacetylene 2B (ratio 66:34)
compared to the phenylacetylene 2A (ratio 89:11) and then the
p-fluorophenylacetylene 2C (ratio 91:9) and the p-methoxypheny-
lacetylene 2D (ratio > 99:1), a positive mesomeric effect on the
phenyl ring seems to induce a positive contribution to the regios-
electivity without having an effect on the yield. Noteworthy, het-
eroaryl and alkyl chains are accepted for this procedure (2E–2H).
Interestingly, the scope was widened by hydroxyl and carbamate
moieties, which were compatible with this process.
The substrate scope was also examined with various bromides
(Table 3). Aromatic benzyl bromides possessing either electron-
donating (1a and 1b) or electron-withdrawing (1c–1 g) groups
are tolerated and afforded the 1,5-regioisomers (3aA–3gA) with
modest to high yields both after flash chromatography purification
(calculated yield: 64%–79%) and after semi-preparative SFC purifi-
cation (isolated yield: 31%–84%). The ortho isomer 3gA was
obtained with the lowest yield in the series, probably due to steric
effect. Besides, regioisomerism of the phenyl substitution (1e–1g)
has only minor impact on the yield and does not influence the
regioselectivity. Strikingly, high to excellent regioselectivities from
85:15 to 97:3 ratios were also obtained. Interestingly, the scope of
this one-pot procedure could be efficiently enlarged with non-sat-
urated bromide (1i–1l). Noteworthy, functional groups such as car-
bamate-protected amine and ester are well tolerated with these
room temperature for
2 h in DMF with or without the
Cp2Ni/Xantphos catalytic system. For both conditions,
4-tert-butylbenzyl azide was formed in quantitative yield. Thus,
the nickelocene precatalyst in association with its Xantphos
ligand has no influence on the SN2 event and only has positive
effect for the azide-alkyne cycloaddition and its regioisomerism.
After determining the optimized conditions for this one-pot
procedure, we explored the scope with various alkynes and bro-
mides. The integrity of the 1,5-disubstituted 1,2,3-triazole tem-
plate was validated by NMR NOESY and HSQC experiments to
corroborate the distinctive 13C chemical shift of the triazole CH
at ~133 ppm [15].
The evaluation of substrate scope with various aromatic (2A–
2E) and aliphatic alkynes (2F–2H) in reaction with bromide 1a is
summarized in Table 2. Except for alkynes 2D and 2E, the attempts
to separate and isolate the two regioisomers 3 and 4 were not fruit-
ful either by classical flash column chromatography, or by C-18
reversed-phase flash column chromatography with the use of clas-
sical or pentafluorophenyl columns. However, because of the high
regioselectivity rates associated with this methodology (from
66:34 to > 99:1), flash chromatography was still performed to
afford 3 in mixture with 4 in order to evaluate the efficiency of this
one-pot multicomponent procedure. Modest to excellent calcu-
lated yields ranging from 27% to 84% were obtained. Besides, in
2

Table 1
Condition screening.a
Entry
Solvent
Temp (°C)
Time (h)
cYield (%)c
Ratio 3aA/4aAd
e
e
1
2
3
4
5
6
7
8
H2O
rt
rt
rt
rt
2
2
2
2
2
1
1
1
4
4
–
–
DMF
EtOH
DCM
THF
DMF
DMF
DMF
DMF
DMF
71
88:12
e
e
–
–
–
–
e
e
–
e
e
rt
–
50 °C (MW)
80 °C (MW)
100 °C (MW)
50 °C (MW)
50 °C (MW)
73
49
93:7
64:36
e
e
–
–
9
86
89
92:8
92:8
10b
a
Reaction conditions: Run on a 0.5 mmol scale of alkyne 2A (1.2 equiv), bromide 1a (1.0 equiv), NaN3 (1.0 equiv), solvent (2 mL), Cp2Ni (20 mol%), Xantphos (20 mol%), Cs2CO3 (1.0 equiv).
Run on a 0.5 mmol scale of alkyne 2A (1.0 equiv), bromide 1a (1.2 equiv), NaN3 (1.5 equiv), solvent (2 mL), Cp2Ni (20 mol%), Xantphos (20 mol%), Cs2CO3 (1.0 equiv).
Calculated yield of 3aA determined by LCMS analysis from the crude product.
Determined by LCMS analysis from the crude product.
No triazole formation. Cp, cyclopentadienyl; cYield, calculated yield; DCM, dichloromethane; DMF, dimethylformamide; MW, microwave irradiation; temp, temperature; rt, room temperature.
b
c
d
e

V. Camberlein, N. Kraupner, N. Bou Karroum et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 2
Substrate scope with various alkynes.a
aReaction conditions: Run on a 0.3–0.6 mmol scale of alkyne 2 with 1a (1.2 equiv), NaN3 (1.5 equiv), Cp2Ni (20 mol%), Xantphos (20 mol%), Cs2CO3 (1.0 equiv), DMF (2.0 mL),
50 °C (MW), 4 h. Isolated yields (%) of 3 obtained after SFC purification; 3/4 ratio determined from the crude product by SFC analysis unless noted otherwise; in brackets:
calculated yields (%) of 3 obtained after flash column chromatography purification (in mixture with 4).
bIsolated yield (%) of 3 obtained after flash column chromatography purification; cDetermined by 1H NMR. Boc, tert-butoxycarbonyl; Cp, cyclopentadienyl; t-Bu, tert-butyl.
Table 3
Substrate scope with various bromides.a
aReaction conditions: Run on a 0.49 mmol scale of alkyne 2A with 1 (1.2 equiv), NaN3 (1.5 equiv), Cp2Ni (20 mol%), Xantphos (20 mol%), Cs2CO3 (1.0 equiv), DMF (2.0 mL),
50 °C (MW), 4 h. Isolated yields (%) of 3 obtained after SFC purification; 3/4 ratio determined from the crude product by SFC analysis unless noted otherwise; in brackets:
calculated yields (%) of 3 obtained after flash column chromatography purification (in mixture with 4).
bIsolated yield (%) of 3 obtained after flash column chromatography. Boc, tert-butoxycarbonyl; Cp, cyclopentadienyl; Me, methyl; Ph, phenyl; t-Bu, tert-butyl.
reaction conditions (1k–1l) providing the related 1,5-disubstituted
1,2,3-triazoles with high to excellent yields and regioselectivities.
Briefly, we succeeded in providing a procedure to efficiently
access diverse 1,5-disubstitued 1,2,3-triazoles in a fast and simple
manner. Remarkably, one of the advantages of this one-pot reac-
tion is the in situ generation of azides from bromides, which are
commercially available with a large diversity. Thus, this one-pot
method prevents the sequential and time-consuming synthesis
and isolation of azides, which could be unstable and are rarely
commercially available. It makes this procedure very convenient,
especially when sensitive low-molecular weight azides are
required. A diverse range of functional moieties including N-pro-
tected amines, hydroxyls and esters are tolerated by these reaction
conditions. This method will enable the synthesis of libraries of
functionalizable 1,5-regioisomers especially useful for drug discov-
ery and chemical biology purposes.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
We are grateful to the institutions that support our laboratory:
Université de Lille, Institut Pasteur de Lille, INSERM. The authors
thank Nicolas Lefebvre for technical assistance. The authors thank
´
the members of the Laboratoire d’Application de Resonance Mag-
´
´
netique Nucleaire (LARMN), Lille, France for NMR acquisitions
and for their technical assistance. The postdoctoral fellowship of
N.B.K. is funded by I-SITE-ULNE (contract CSB0120_ I-SITE
4

V. Camberlein, N. Kraupner, N. Bou Karroum et al.
Tetrahedron Letters xxx (xxxx) xxx
b) S.C.C. Lucas, S.J. Atkinson, P. Bamborough, H. Barnett, C.-W. Chung, L.
Gordon, D.J. Mitchell, A. Phillipou, R.K. Prinjha, R.J. Sheppard, N.C.O.
Tomkinson, R.J. Watson, E.H. Demont, J. Med. Chem. 63 (2020) 5212–5241.
[9] a) G. Himbert, D. Frank, M. Regit, Ber. 109 (1976) 370–394;
b) A. Krasin´ ski, V.V. Fokin, K.B. Sharpless, Org. Lett. 6 (2004) 1237–1240;
c) C.D. Smith, M.F. Greaney, Org. Lett. 15 (2013) 4826–4829;
d) B.C. Boren, S. Narayan, L.K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia, V.V.
Fokin, J. Am. Chem. Soc. 130 (2008) 8923–8930;
Molecular Design For Health). V.C. is a recipient of a doctoral fel-
lowship from Université de Lille and Universität des Saarlandes.
N.K. is a recipient of a doctoral fellowship from Université de Lille.
Appendix A. Supplementary data
e) L. Zhang, X. Chen, P. Xue, H.H.Y. Sun, I.D. Williams, K.B. Sharpless, V.V. Fokin,
G. Jia, J. Am. Chem. Soc. 127 (2005) 15998–15999;
f) L. Hong, W. Lin, F. Zhang, R. Liu, X. Zhou, Chem. Commun. 49 (2013) 5589;
g) W.G. Kim, M.E. Kang, J.B. Lee, M.H. Jeon, S. Lee, J. Lee, B. Choi, P.M.S.D. Cal, S.
Kang, J.-M. Kee, G.J.L. Bernardes, J.-U. Rohde, W. Choe, S.Y. Hong, J. Am. Chem.
Soc. 139 (2017) 12121–12124.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153131.
References
[10] a) L. Maiuolo, B. Russo, V. Algieri, M. Nardi, M.L. Di Gioia, M.A. Tallarida, A. De
Nino, Tetrahedron Lett. 60 (2019) 672–674;
[1] a) P. Nezhad-Mokhtari, M. Ghorbani, L. Roshangar, J. Soleimani Rad, Eur.
Polym. J. 117 (2019) 64–76;
b) M. Arslan, G. Acik, M.A. Tasdelen, Polym. Chem. 10 (2019) 3806–3821.
[2] a) P.-Z. Li, J. Wang, Y. Zhao, Coord. Chem. Rev. 380 (2019) 484–518;
b) D. Huang, P. Zhao, D. Astruc, Coord. Chem. Rev. 272 (2014) 145–165.
[3] a) B.L. Kenry, Trends Chem. 1 (2019) 763–778;
b) E. Kim, H. Koo, Chem. Sci. 10 (2019) 7835–7851.
[4] a) A. Rani, G. Singh, A. Singh, U. Maqbool, G. Kaur, J. Singh, RSC Adv. 10 (2020)
5610–5635;
b) Y.-C. Wang, Y.-Y. Xie, H.-E. Qu, H.-S. Wang, Y.-M. Pan, F.-P. Huang, J. Org.
Chem. 79 (2014) 4463–4469;
c) H.M. Nanjundaswamy, H. Abrahamse, Synth. Commun. 45 (2015) 967–974;
d) A. De Nino, P. Merino, V. Algieri, M. Nardi, M. Di gioia, B. Russo, M. Tallarida,
L. Maiuolo, Catalysts 8 (2018) 364.
[11] a) Ahsanullah, P. Schmieder, R. Kühne, J. Rademann, Angew. Chem. Int. Ed. 48
(2009) 5042–5045;
b) X. Zhang, K.P. Rakesh, H.-L. Qin, Chem. Commun. 55 (2019) 2845–2848;
c) L. Wu, Y. Chen, J. Luo, Q. Sun, M. Peng, Q. Lin, Tetrahedron Lett. 55 (2014)
3847–3850;
d) A. Banday, V. Hruby, Synlett 25 (2014) 1859–1862;
e) N. Kumar, M.Y. Ansari, R. Kant, A. Kumar, Chem. Commun. 54 (2018) 2627–
2630.
b) E. Bonandi, M.S. Christodoulou, G. Fumagalli, D. Perdicchia, G. Rastelli, D.
Passarella, Drug Discov. Today 22 (2017) 1572–1581;
c) D. Bosc, V. Camberlein, R. Gealageas, O. Castillo-Aguilera, B. Deprez, R.
Deprez-Poulain, J. Med. Chem. 63 (2020) 3817–3833;
d) R. Deprez-Poulain, N. Hennuyer, D. Bosc, W.G. Liang, E. Enée, X. Marechal, J.
Charton, J. Totobenazara, G. Berte, J. Jahklal, T. Verdelet, J. Dumont, S.
Dassonneville, E. Woitrain, M. Gauriot, C. Paquet, I. Duplan, P. Hermant, F.-X.
Cantrelle, E. Sevin, M. Culot, V. Landry, A. Herledan, C. Piveteau, G. Lippens, F.
Leroux, W.-J. Tang, P. van Endert, B. Staels, B. Deprez, Nat. Commun. 6 (2015)
8250.
[12] G. Cheng, X. Zeng, J. Shen, X. Wang, X. Cui, Angew. Chem. Int. Ed. 52 (2013)
13265–13268.
[13] S. Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed. 44 (2005)
5188–5240.
[14] a) H.-W. Bai, Z.-J. Cai, S.-Y. Wang, S.-J. Ji, Org. Lett. 17 (2015) 2898–2901;
b) J.-P. Wan, S. Cao, Y. Liu, J. Org. Chem. 80 (2015) 9028–9033;
c) S. Cao, Y. Liu, C. Hu, C. Wen, J. Wan, ChemCatChem 10 (2018) 5007–5011;
d) W. Huang, C. Zhu, M. Li, Y. Yu, W. Wu, Z. Tu, H. Jiang, Adv. Synth. Catal. 360
(2018) 3117–3123;
[5] a) V.V. Rostovtsev, L.G.V. Green, V. Fokin, K.B. Sharpless, Angew. Chem. Int. Ed.
Engl. 41 (2002) 2596–2599;
b) C.W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 67 (2002) 3057–3064.
[6] A.M. White, S.J. Veer, G. Wu, P.J. Harvey, K. Yap, G.J. King, J.E. Swedberg, C.K.
Wang, R.H.P. Law, T. Durek, D.J. Craik, Angew. Chem. Int. Ed. 59 (2020) 11273–
11277.
[7] O. Kracker, J. Góra, J. Krzciuk-Gula, A. Marion, B. Neumann, H.-G. Stammler, A.
Nieß, I. Antes, R. Latajka, N. Sewald, Chem. - Eur. J. 24 (2018) 953–961.
[8] a) D.P. Becker, M.R. Lutz, S. Flieger, A. Colorina, J. Wozny, N.S. Hosmane,
ChemMedChem 15 (2020) 1897–1908;
e) S. Dey, T.A. Pathak, RSC Adv. 4 (2014) 9275;
f) J.R. Johansson, P. Lincoln, B. Nordén, N. Kann, J. Org. Chem. 76 (2011) 2355–
2359.
[15] X. Creary, A. Anderson, C. Brophy, F. Crowell, Z. Funk, J. Org. Chem. 77 (2012)
8756–8761.
5