A straightforward and versatile approach to the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from alkyl halides via a one-pot, three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2015.02.049

The preparation of 1,4,5-trisubstituted 1,2,3-triazoles by the coupling of three components (alkyl halides, sodium azide, and active ketones) through an azide-enolate [3+2] cycloaddition (Dimroth cycloaddition) has been developed for the first time. A wide variety of halides (including chlorides, bromides, and iodides as well as primary and secondary derivatives) have demonstrated the versatility of this method, which is based on a one-pot system under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.02.049

Accepted Manuscript
A straightforward and versatile approach to the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles from alkyl halides via a one-pot, three-component reaction
Davir González-Calderón, José G. Aguirre-De Paz, Carlos A. González-
González, Aydeé Fuentes-Benítes, Carlos González-Romero
PII:
S0040-4039(15)00320-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.049
TETL 45918
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 January 2015
9 February 2015
13 February 2015
Please cite this article as: González-Calderón, D., Aguirre-De Paz, J.G., González-González, C.A., Fuentes-
Benítes, A., González-Romero, C., A straightforward and versatile approach to the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles from alkyl halides via a one-pot, three-component reaction, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.02.049
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A straightforward and versatile approach to the
synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from
alkyl halides via a one-pot, three-component reaction
Leave this area blank for abstract info.
Davir González-Calderón*, José G. Aguirre-De Paz, Carlos A. González-González, Aydeé Fuentes-
Benítes, and Carlos González-Romero*
Na
R3
N
N
N
DBU
DMF
R1
X
+
N
N
X= Cl, Br, I
O
N
R2
R3
R2
R1
73-82 %
14 examples

1
Tetrahedron Letters
journal homepage: www.els evier.com
A straightforward and versatile approach to the synthesis of 1,4,5-trisubstituted 1,2,3-
triazoles from alkyl halides via a one-pot, three-component reaction
Davir González-Calderón a,*, José G. Aguirre-De Paz b, Carlos A. González-González a, Aydeé Fuentes-
Benítes a, and Carlos González-Romero a,∗
a Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estado de
México, 50120, México.
b Universidad de Ixtlahuaca CUI, Carretera Ixtlahuaca-Jiquipilco km 1, Ixtlahuaca de Rayón, Estado de México, 50740, México.
ARTICLE INFO
ABSTRACT
Article history:
Received
The preparation of 1,4,5-trisubstituted 1,2,3-triazoles by the coupling of three components (alkyl
halides, sodium azide and active ketones) through an azide-enolate [3+2] cycloaddition
(Dimroth Cycloaddition) has been developed for the first time. A wide variety of halides
(including chlorides, bromides and iodides as well as primary and secondary derivatives) have
demonstrated the versatility of this method, which is based on a one-pot system under mild
reaction conditions.
Received in revised form
Accepted
Available online
Keywords:
Triazoles
2009 Elsevier Ltd. All rights reserved.
Alkyl halides
Azide–enolate cycloaddition
Dimroth Cycloaddition
In 19021 Otto Dimroth first described the azide-enolate [3+2]
cycloaddition to obtain 1,4,5-trisubstituted 1,2,3-triazoles under
strong basic conditions (NaOEt as base). For nearly 100 years
this reaction remained almost forgotten.
starting from conventional functional groups and using mild
reaction conditions.
Alkyl halides in presence of sodium azide (NaN3) have been
highly efficient in Cu-catalyzed azide-alkyne cycloaddition
(CuAAC) for the synthesis of 1,4-disubstituted 1,2,3-triazoles
through a one-pot, three-component system.6 This has proven to
be a very rapid and elegant way to access triazole building
blocks. The reasons are evident, the azide substrate generated in
situ require only a simple and rapid displacement (SN2) of a
halide by an azide ion, providing this potential functional group
in a one-pot reaction.
During the last decade several research groups2 took renewed
interest in this synthetic method and strove to improve it, because
the 1,4,5-trisubstituted 1,2,3-triazole core had shown potent
pharmacological activities.3 Although these improved protocols
have brought back this synthetic method in a new setting, there
are still certain limitations. For instance, the use of azide
substrate as the starting material requires that this uncommon
reagent be obtained from other common functional group.
Recently, Cao et al. reported a one-pot, three-component
synthesis of 1,4,5-trisubstituted 1,2,3-triazoles starting from
primary alcohols and using a NaN3/TsIm/ TEA/TBAI/KOH
system.4 Unfortunately, the exclusive use of primary substrates
and strongly basic conditions limits it use. Previously we
published the use of a BnOH/DPPA/DBU system5 as a facile
approach to the synthesis of these compounds, but its scope is
limited by the exclusive use of benzylic alcohols. Thus, there is
a need to develop new alternatives for an effective approach to
this important class of heterocycle compounds, preferably
Rationalizing these facts, we decided to investigate the use of
alkyl halides in the synthesis of 1,4,5-trisubstituted 1,2,3-
triazoles via a one-pot, three-component reaction. The aim was to
improve the synthetic strategies for the total synthesis of triazole
carbocyclic nucleosides.7
Optimization studies for this coupling synthesis were carried
out on benzyl chloride 1 and benzoylacetonitrile B. Mixing
halide with a 1.1 equivalent of sodium azide in anhydrous DMF
solution produced the desired alkyl azide in quantitative yield
with short reaction times at 50 ºC. The reaction with the enolate
substrate, which was generated in situ by the action of a 1.1
———
∗ Corresponding author: Tel: +52 722 217 5109x113; Fax: +52 722 217 3890; e-mail: cgonzalezr@uaemex.mx (C. González-Romero) and
qfb_dgonzalez@yahoo.com.mx (D. González-Calderón).

2
Tetrahedron Letters
Br
O
Br
I
O
O
Cl
BnO
BnO
Ph
Br
BnO
OBn
OCH3
1
5
OBn
3
4
2
O
I
O
CH3
OEt
Cl
CH3
7
O
9
8
I
Ph
CO2
I
6
R3
N
O
NaN3
N
R3
R1
X
+
R2
N
DBU, DMF
R2
2
3
A
: R = CH3, R = COCH3
3
R1
2
B
: R = Ph, R = CN
C: R2= Ph, R3= COPh
O
CN
O
O
O
N
N
N
O
O
O
N
N
Ph
N
N
N
N
N
N
N
O
O
CN
N
N
N
Ph
Ph
Ph
O
CH3
CH3
Ph
2b
Ph
(76 %)
2c
(78 %)
2a (82 %)
1b
(80 %)
1c
(80 %)
O
N
N
N
N
Ph
Ph
O
CH3
CH3
N
N
N
N
O
N
N
N
N
O
BnO
N
BnO
BnO
N
O
H3C
Ph
CN
Ph
3b
O
OBn
OBn
BnO
H3C
5a
(81%)
(73 %)
Ph
CO2
6a (75 %)
N
OBn
3a (75 %)
4c
(78 %)
OCH3
CH3
O
CH3
O
CH3
N
N
CN
N
N
N
N
Ph
Ph
N
N
CH3
N
N
N
N
Ph
CH3
O
Ph
(80 %)
Ph
7c
OEt
8c
Ph
Ph
(73 %)
9a
(76 %)
9b (81 %)
O
Scheme 1. Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from alkyl halides by coupling with sodium azide and active ketones. The
products were confirmed by 1H-NMR, 13C-NMR, MS and HRMS.
equivalent of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) on a
1.1 equivalent of active ketone A led the building of the desired
1,4,5-trisubstituted 1,2,3-triazole block in 80 % yield. In contrast
with Khurana’s procedure,2f the catalytic use of DBU failed
under our protocol. Optimized conditions were then used to study
the coupling of a series of halide compounds in the presence of
acetylacetone A, benzoylacetonitrile B, and/or dibenzoylmethane
C as active ketones (Scheme 1).8
obtaining of potential intermediates (1b, 2b, 3b, and 9b) for the
synthesis of rufinamide analogues.
On the other hand, the formation of 1,2,3-triazole core in
carbohydrates has become one of the most important issue in
medicinal chemistry to obtain 1,2,3-triazole nucleosides,
nucleotides and oligonucleotides.11 Triazolyl saccharide
derivative 4c obtained from halosugar 4 represent an interesting
reaction for the synthesis of aforementioned compounds.
Furthermore, this protocol is a facile alternative to obtain 4-
acetyl-5-methyl-triazole derivatives (e.g. 2a, 3a, 5a, 6a, and 9a)
which are very functionalizable intermediates to obtain anti-HIV
triazolyl sugars, previously reported by Ferreira et. al. (Scheme
3).3c
As the data in Scheme 1 indicate, acceptable yields of 1,4,5-
trisubstituted 1,2,3-triazoles were obtained by using chlorides (1
and 7), bromides (2, 4 and 5), and iodides (3, 6, 8 and 9) as well
as primary (1–6) and secondary (7–9) derivatives. The inversion
of configuration in an asymmetric center (e.g. 8→8c) must be
expected in order to a SN2 mechanism.9
In summary, we report the first one-pot procedure for the
direct conversion of alkyl halides to 1,4,5-trisubstituted 1,2,3-
triazoles vía an azide-enolate [3+2] cycloaddition. These
reactions were efficiently performed under mild conditions. The
method circumvents the problems encountered with the isolation
of organic azides, and complements the library of synthetic
methods for obtaining these valuable heterocycles.
Rufinamide is an anticonvulsant medication approved by the
FDA in 2008 which was discovered by Novartis Pharmaceuticals
and is currently manufactured by Eisai Co., Japan, and marketed
under the brand name Banzel. Classical approach to rufinamide is
described in Scheme 2.10 Synthetically, the use of
benzoylacetonitrile B under our method may represent the

3
Cl
5. González-Calderón, D.; Santillán-Iniesta, I.; González-González, C. A.;
Fuentes-Benítes, A.; González-Romero, C. Tetrahedron Lett. 2015, 56,
514–516
F
F
N
F
N
N
N
N
N
CONH2
CN
30% NaOH
CN
N3
95 ºC, 1.54 h
H2O, 80 ºC,
24 h
6. Odlo, K.; Høydahl, E. A.; Hansen, T. V. Tetrahedron Lett. 2007, 48,
2097–2099. (b) Kacprzak, K. Synlett 2005, 943–946. (c) Huang, L.; Liu,
W.; Wu, J.; Fu, Y.; Wang, K.; Huo, C.; Du, Z. Tetrahedron Lett. 2014,
55, 2312–2316. (d) Kumar, B. S. P. A.; Reddy, K. H. V.; Madhav, B.;
Ramesh, K.; Nageswar, Y. V. D. Tetrahedron Lett. 2012, 53, 4595–
4599. (e) Mukherjee, N.; Ahammed, S.; Bhadra, S.; Ranu, B. C. Green
Chem. 2013, 15, 389–397. (f) Ladouceur, S.; Soliman, A. M.; Zysman-
Colman, E. Synthesis 2011, 3604–3611. (g) Sharghi, H.; Khalifeh, R.;
Doroodmand, M. M. Adv. Synth. Catal. 2009, 351, 207–218.
F
F
Rufinamide
F
Scheme 2. Reported synthetic approach to Rufinamide.
Ph
CH3
sugar
N
N
HN
N
O
CH3SO2N3, NaH
CH3CN, 48 h, r.t.
sugar
O
7. González-González, C. A.; Fuentes-Benítez, A.; Cuevas-Yáñez, E.;
Corona-Becerril, D.; González-Romero, C.; González-Calderón, D.
Tetrahedron Lett. 2013, 54, 2726–2728.
anti-HIV triazolyl sugars
Scheme 3. Ferreira’s synthesis for anti-HIV triazolyl sugars.
8. Experimental Procedure: A 10-mL round-bottom flask was equipped
with a magnetic stir bar and a reflux condenser. Then 0.4 mmol of alkyl
halide and 0.44 mmol of sodium azide were added to 1.5 mL of
anhydrous dimethylformamide. The reaction mixture was stirred at 60 °C
for 2 h under nitrogen atmosphere. After cooling to room temperature,
TLC indicated the disappearance of the starting material. 0.44 mmol of
active ketone and 0.44 mmol of DBU were then added to the reaction
mixture, which was stirred for 3 h at 60 ºC. Brine (∼40 mL) was added to
the reaction mixture and washed with EtOAc (3×10 mL). The organic
layer was dried (Na2SO4) and the solvent evaporated under reduced
pressure. Flash column chromatography afforded the pure triazole.
9. Rablen, P. R.; McLarney, B. D.; Karlow, B. J.; Schneider, J. E. J. Org.
Chem. 2014, 79, 867–879.
Acknowledgments
Financial
support
from
UAEMéx
(project
No.
3512/2013CHT)
and CONACYT-Mexico (postgraduate
scholarship) is gratefully acknowledged. The authors would like
to thank the referee for valuable comments and suggestions,
Signa S.A. de C.V. for some graciously donated solvents and
reagents, M.N. Zavala-Segovia and L. Triana-Cruz (CCIQS
UAEMéx‒UNAM) for technical support.
10. Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; Del Pozo, C.; Sorochinsky,
A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114,
−2506
2432 and references therein.
11. (a) For representative Reviews see: Aragão-Leoneti, V.; Campo, V. L.;
Gomes, A. S.; Field, R. A.; Carvalho, I. Tetrahedron 2010, 66, 9475–
9492. (b) Amblard, F.; Cho, J. H.; Schinazi, R. F. Chem. Rev. 2009, 109,
4207–4220.
Supplementary Material
Supplementary material (characterization data of all
compounds and copies of 1H–NMR, 13C–NMR and HRMS)
associated with this article can be found in the online version.
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