A novel and facile synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from benzylic alcohols through a one-pot, three-component system

Article abstract of DOI:10.1016/j.tetlet.2014.12.019

A simple one-pot procedure has been developed to efficiently prepare 1,4,5-trisubstituted 1,2,3-triazoles from benzylic alcohols. The presence of diphenylphosphoryl azide (DPPA) and active ketones allows for an azide-enolate [3+2] cycloaddition by use of DBU.

Full text of DOI:10.1016/j.tetlet.2014.12.019

Accepted Manuscript
A novel and facile synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from benzylic
alcohols through a one-pot, three-component system
Davir González-Calderón, Itzel Santillán-Iniesta, Carlos A. González-
González, Aydeé Fuentes-Benítes, Carlos González-Romero
PII:
S0040-4039(14)02073-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.019
TETL 45543
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 October 2014
4 December 2014
5 December 2014
Please cite this article as: González-Calderón, D., Santillán-Iniesta, I., González-González, C.A., Fuentes-Benítes,
A., González-Romero, C., A novel and facile synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from benzylic alcohols
through a one-pot, three-component system, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.12.019
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A novel and facile synthesis of 1,4,5-trisubstituted
1,2,3-triazoles from benzylic alcohols through a
one-pot, three-component system
Leave this area blank for abstract info.
Davir González-Calderón*, Itzel Santillán-Iniesta, Carlos A. González-González, Aydeé Fuentes-
Benítes, and Carlos González-Romero*
O
P
N
(DPPA)
PhO
OPh
N
DBU
Ar
+
N
N
Ar
N
N
OH
DMF
O
R2
R1
R2
R1
62-82%
17 examples

1
Tetrahedron Letters
journal homepage: www.els evier.com
A novel and facile synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from benzylic
alcohols through a one-pot, three-component system
Davir González-Calderón*, Itzel Santillán-Iniesta, Carlos A. González-González, Aydeé Fuentes-Benítes,
and Carlos González-Romero∗
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.
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple one-pot procedure has been developed to efficiently prepare 1,4,5-trisubstituted 1,2,3-
triazoles from benzylic alcohols. The presence of diphenylphosphoryl azide (DPPA) and active
ketones allows for an azide-enolate [3+2] cycloaddition by use of DBU.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Triazoles
Diphenylphosphoryl azide
Benzylic alcohols
Azide–enolate cycloaddition
The triazole ring system is a key pharmacophore1 for an
increasingly important series of nitrogen heterocycles that
display a wide range of therapeutic and biological activity.2
Several methods for the synthesis of 1,4-disubstituted 1,2,3-
triazoles3 and 1,5-disubstituted 1,2,3-triazoles4 have been
described in literature. In the last decade, the 1,4,5-trisubstituted
1,2,3-triazole framework has received much attention in
medicinal chemistry due to its biological activity against cancer,5
HIV-RT,6 Cantagalo Virus,7 and Lachesis muta snake venom,8 as
well as its use as an antiplatelet agent,9 among other
applications.10 Hence, reports on synthetic methods to obtain
1,4,5-trisubstituted 1,2,3-triazole moieties are increasingly
common in literature.11 An outstanding synthetic method is
azide-enolate [3+2] cycloaddition, best known as ‘Dimroth
Cycloaddition’,12 which has been improved13 by several research
groups. Recently, Cao et al. has given versatility to this method
through an attractive three-component synthesis of 1,4,5-
trisubstituted 1,2,3-triazoles, starting from primary alcohols and
azidation procedure16 of benzyl alcohol 1 leads to the highly
regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazole 1a in
the presence of active ketone benzoylacetonitrile A (78% yield)
by a one-pot system.
O
Ph
N
DPPA
N
N
CN
Ph
OH
Ph
+
DBU
DMF
A
1
Ph
CN
1a
Consequently, we decided to investigate the coupling of 1, A
and diphenylphosphoryl azide (DPPA) in greater detail, finding
that triazolyzation was very inefficient using stoichiometric
amounts of DBU. Moreover, the evident use of only benzylic
alcohols when some alkylic alcohols (e.g. menthol, octyl alcohol,
and phenethyl alcohol) failed under our procedure is in
accordance with Thompson’s discussion. Conventional heating
(60–70 ºC upon adding ketone) and a 6 h reaction period were
adopted as the standard. The coupling reactions of various
benzylic alcohols in the presence of benzoylacetonitrile A, ethyl
acetoacetate B, dibenzoylmethane C, and/or acetylacetone D as
active ketones were then examined under these optimized
conditions (Table 1).17
using
a
NaN3/TsIm/TEA/TBAI/KOH system.14 Thus, the
development of an efficient synthesis of these valuable
heterocycles ―particularly from readily accessible and common
substrates― is of ever increasing importance.
During one of our ongoing research projects, focused on the
development of novel methodologies for the construction of
triazole carbocyclic nucleosides,15 we observed that an excess of
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in Thompson’s
———
∗ 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
O
OH
O
OH
Scheme 1. Proposed plausible mechanism for azide-
enolate [3+2] cycloaddition.
OH
Cl
1
3
2
H
N
(PhO)2PON3
N3
Bn OPO(OPh)2
Bn OH
+
OH
OH
N
1st equiv.
OH
BnO
MeO
S
6
N
N
5
OPO(OPh)2
DBU
N
H
OBn
4
+
Bn
Bn
N
N
N
N
N
R2
O
O
2nd equiv.
N
OH
R2
R2
O
S
N
R1
N
R1
[3+2]
cycloaddition
OH
R1
N
7
8
+
H
N
Bn
DBU
H2O
Table 1. Synthesis of 1,4,5-trisubstituted 1,2,3-
triazoles from benzylic alcohols by coupling with
active ketones.
N
O
DPPA
DBU
R3
+
R3
R2
N
In summary, we developed a simple one-pot, three-component
procedure for the direct conversion of alcohols to 1,4,5-
trisubstituted 1,2,3-triazoles through highly regioselective
synthesis under mild conditions.
R1
N
N
OH
DMF
1
2
A
B
: R = Ph, R = CN
2
1
: R = CH3, R = COOEt
R1
R2
C: R1= Ph, R2= COPh
1
2
D
: R = CH3, R = COCH3
Benzyl
Alcohol
Acknowledgments
Entry
Ketone
Triazolea
Yield (%)b
1
1
1
2
2
2
3
3
4
4
4
5
5
6
6
7
7
8
A
C
D
B
C
D
C
D
B
A
D
B
D
B
D
C
A
1a
1c
2d
2b
2c
3d
3c
4d
4b
4a
5d
5b
6d
6b
7d
7c
8a
78
80
82
65c
76
75
74
77
63c
72
76
62c
73
66c
82
80
75
Financial
support
from
UAEMéx
(project
No.
2
3512/2013CHT) and CONACyT (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.
3
4
5
6
7
8
9
Supplementary Material
10
11
12
13
14
15
16
17
Supplementary material (characterization data of all
compounds and copies of 1H–NMR, 13C–NMR and High
Resolution Mass spectra) associated with this article can be
found in the online version.
References and Notes
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2718
b Yields refer to chromatographically pure isolated compounds.
c
In these cases, the reactions require longer times (36 h) upon
adding ketone.
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discrete steps (Scheme 1). One DBU equiv. is necessary for an
effective Thompson azidation. The enolate generated in situ by
the action of a second DBU equiv. leads to azide-enolate [3+2]
cycloaddition.

3
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17. Experimental Procedure: To a cold solution (0 ºC) of benzyl alcohol 1
(0.108 g, 1.0 mmol) and diphenylphosphoryl azide (0.236 mL, 1.1 mmol)
in anhydrous DMF (2.5 mL) was added DBU (0.3 mL, 2.0 mmol). The
solution was stirred for 15 min at 0 ºC under nitrogen atmosphere, and
then brought to room temperature with continuous stirring for 3 h.