Facile One-Pot Synthesis of 1,2,3-Triazoles Featuring Oxygen, Nitrogen, and Sulfur Functionalized Pendant Arms

Article abstract of DOI:10.1080/00397911.2013.833628

A practical and efficient one-pot synthesis of novel 1,2,3-triazoles featuring nitrogen, oxygen, and sulfur functionalized pendant arms has been developed. The click reaction of mono-propargyl derivatives supported by aniline, thiophenol, and benzyl alcohol, with sodium azide and p-substituted benzyl halogenides, renders a series of N-substituted-1,2,3-triazoles in good yields under mild reaction conditions. The catalyst system was based in Cu(OAc)₂·H₂O, sodium L-ascorbate, and 1,10-phenanthroline monohydrate, and all reactions were performed in a mixture H₂O-ethanol (4:1 v/v). Additionally, the preparation of bis-1,2,3-triazoles supported by di-propargylated aniline was carried out, demonstrating the versatility of the present methodology. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.833628

This article was downloaded by: [Harvard Library]
On: 05 October 2014, At: 03:15
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Facile One-Pot Synthesis of 1,2,3-
Triazoles Featuring Oxygen, Nitrogen,
and Sulfur Functionalized Pendant Arms
Daniel Mendoza-Espinosa a , Guillermo Negrón-Silva a , Leticia
Lomas-Romero b , Atilano Gutiérrez-Carrillo b & Rosa Santillán c
a Departamento de Ciencias Básicas , Universidad Autónoma
Metropolitana-Azcapotzalco , Mexico City , Mexico
b Departamento de Química , Universidad Autónoma Metropolitana-
Iztapalapa , Mexico City , Mexico
c Departamento de Química , CINVESTAV-IPN , Mexico City , Mexico
Published online: 20 Feb 2014.
To cite this article: Daniel Mendoza-Espinosa , Guillermo Negrón-Silva , Leticia Lomas-Romero ,
Atilano Gutiérrez-Carrillo & Rosa Santillán (2014) Facile One-Pot Synthesis of 1,2,3-Triazoles
Featuring Oxygen, Nitrogen, and Sulfur Functionalized Pendant Arms, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:6, 807-817, DOI:
10.1080/00397911.2013.833628
To link to this article: http://dx.doi.org/10.1080/00397911.2013.833628
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 807–817, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.833628
FACILE ONE-POT SYNTHESIS OF 1,2,3-TRIAZOLES
FEATURING OXYGEN, NITROGEN, AND SULFUR
FUNCTIONALIZED PENDANT ARMS
1
Daniel Mendoza-Espinosa, Guillermo Negron-Silva,
1
´
Leticia Lomas-Romero, Atilano Gutierrez-Carrillo, and
2
2
´
3
´
Rosa Santillan
Departamento de Ciencias Basicas, Universidad Autonoma
1
´
´
Metropolitana-Azcapotzalco, Mexico City, Mexico
2
´
´
Departamento de Quımica, Universidad Autonoma
Metropolitana-Iztapalapa, Mexico City, Mexico
3
´
Departamento de Quımica, CINVESTAV-IPN, Mexico City, Mexico
GRAPHICAL ABSTRACT
Abstract A practical and efficient one-pot synthesis of novel 1,2,3-triazoles featuring nitro-
gen, oxygen, and sulfur functionalized pendant arms has been developed. The click reaction
of mono-propargyl derivatives supported by aniline, thiophenol, and benzyl alcohol, with
sodium azide and p-substituted benzyl halogenides, renders a series of N-substituted-1,2,3-
triazoles in good yields under mild reaction conditions. The catalyst system was based in
Cu(OAc)2 ꢀ H2O, sodium L-ascorbate, and 1,10-phenanthroline monohydrate, and all reac-
tions were performed in a mixture H2O–ethanol (4:1 v=v). Additionally, the preparation of
bis-1,2,3-triazoles supported by di-propargylated aniline was carried out, demonstrating the
versatility of the present methodology.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Catalysis; click chemistry; cycloaddition; multicomponent synthesis;
1,2,3-triazoles
Received July 25, 2013.
Address correspondence to Guillermo Negron-Silva, Departamento de Ciencias Basicas,
´
Universidad Autonoma Metropolitana-Azcapotzalco, Av. San Pablo No. 180, Mexico D.F., C.P.
´
´
02200, Mexico. E-mail: gns@correo.azc.uam.mx
´
´
807

808
D. MENDOZA-ESPINOSA ET AL.
INTRODUCTION
1,2,3-Triazoles and its derivatives have found numerous applications in areas
such as agrochemicals, polymers, dyes, materials, and pharmaceuticals.[1] Ever since
Sharpless and coworkers’ pivotal report[2] on the concept of ‘‘click’’ chemistry, an
enormous amount of papers based on copper(I)-catalyzed alkyne–azide cycloaddi-
tion (CuAAC) have been published. This metal-catalyzed reaction constitutes a
substantial improvement on the classical Huisgen-type thermal 1,3-dipolar
cycloaddition,[3] as it allows the regioselective preparation of 1,4-disubstituted
1,2,3-triazoles.[4]
Because of the versatility of the CuAAC methodology, significant progress has
been achieved on applying 1,2,3-triazole building blocks as either biologically active
motifs in drug discovery[5] or designed functional groups employed in new materials
preparation.[6] For instance, the functionalization tolerance of the ‘‘click’’ technique
has allowed for the preparation of a wide variety of biological model structures or
applications such as DNA labeling,[7] oligonucleotide synthesis,[8] and selective
modification of enzymes[9] and cells.[10] Furthermore, the functionalization of
1,2,3-triazoles has been applied to the design of ligands for transition-metal
complexes with potential applications in areas such as catalysts, sensors, and
light-emitting devices.[11]
Our group has a long-standing interest in the preparation of 1,2,3-triazoles
featuring diverse functional groups as they present potential as steel corrosion inhi-
bitors or suitable ligands for transition-metal chemistry. In this regard, we have
recently reported the successful synthesis of mono-, bis-, and tris-1,2,3-triazoles
supported by hydroxy benzenes moieties featuring a wide variety of structural
topologies.[12] As an expansion of that work, we describe herein the use of monopro-
pargylated derivatives supported by aniline, thiophenol, and benzylalcohol scaffolds,
which after the ‘‘click’’ reaction conditions render a series of 1,2,3-triazoles featuring
oxygen, nitrogen, and sulfur functionalized pendant arms. The modular one-pot
synthesis utilizes only 5 mol% of the copper active catalyst system and
room-temperature conditions, and permits the incorporation of several electron-
donor and electron-attractor groups. Additionally, the scope of the methodology
is further expanded by the preparation of bis-1,2,3-triazoles supported by
N,N-dipropargylated aniline, demonstrating the versatility of the procedure.
RESULTS AND DISCUSSION
The selected approach to install oxygen, sulfur, and nitrogen moieties in the
1,2,3-triazole framework was based in the preparation of monopropargyl derivatives
supported by methylaniline, thiophenol, and benzyl alcohol. Monopropargylated
methylaniline,[13] and thiophenol,[14] were achieved following the literature procedure
through deprotonation of the respective S-H and N-H groups with excess of potass-
ium carbonate in dimethylformamide (DMF) or MeCN, followed by slow addition of
equimolar amounts of propargyl bromide (Scheme 1). The propargylation of methy-
laniline (I) proceeds at room temperature under stirring for 12 h, while thiophenol
mono-propargyl derivative (II) requires heating at 60 ꢁC for half an hour before
addition of propargyl bromide. After purification through column chromatography

SYNTHESIS OF FUNCTIONALIZED TRIAZOLES
809
Scheme 1. Synthesis of monopropargylated derivatives. (Figure is provided in color online.)
on silica gel, the desired products are obtained in 81 and 70% yields, respectively.
In the case of benzyl alcohol, deprotonation of the O-H group using K2CO3 proved
inefficient as the yield of the product was not greater than 45%. In this case, excess of
NaH in DMF and addition of excess of propargyl bromide yielded 2-propynyl benzyl
ether (III) in 76% yield after purification (Scheme 1).
Owing to the fact that 1,4-disubstitued 1,2,3-triazoles prepared through ‘‘click’’
chemistry may be regarded as potential N-donor structures, a series of functionalized
mono-, bis-, and poly-1,2,3-triazoles have been synthesized during recent years.[15]
For instance, a variety of 1(pyridine-2-yl)-1,2,3-triazoles have been prepared by
base-promoted substitution between 1,2,3-triazole and 2-halopyridines,[16] or by
thermal 1,3-dipolar cyclo-additions[17] and some other multistep procedures.[18]
The one-pot preparation of bi- and tridentate pyridil-1,2,3-triazole molecules from
their corresponding halides, sodium azide, and alkynes have been reported as
well.[19] To a lesser extent, sulfur-linked triazoles have also been prepared. Some
examples include heterocycles featuring groups such as sulfonyl, sulfonamides, and
1-sulfamoyl- that have been achieved through multistep preparations[20] and ‘‘click’’
methodologies that permitted the synthesis of novel bis-heterocycles incorporating
2-mercaptobenzothiazoles and 1,2,3-triazoles.[21]
Even though CuAAC has proven the most efficient method for the assembly
and functionalization of the triazole motif,[4] some drawbacks related to the insta-
bility of the in situ–generated azides or alkynes have decreased the overall process
performance, sometimes forcing multistep syntheses. Because we are interested in
the development of environmentally friendly processes and the easy functionalization

810
D. MENDOZA-ESPINOSA ET AL.
of the triazole motif, we decided to test the click methodology for the preparation of
1,2,3-triazoles featuring nitrogen and sulfur pendant arms. We hypothesized that by
using stable alkyne derivatives, the performance of the process could be enhanced.
Experimentally, the click reaction of alkynes (I) and (II) with sodium azide in
the presence of p-substituted benzyl halogenides yields a series of mono-1,2,3--
triazoles 1a–f and 2a–f, displaying several electron-donor and electron-attractor
groups (Table 1). The crude products precipitated out from the reaction mixtures,
and after purification by chromatography column on silica gel using mixtures of
dichloromethane and methanol, all pure heterocycles presented a white crystalline
appearance. As described previously, the catalyst system employed relied on the
use of Cu(OAc)2 ꢀ H2O as the metal source, sodium ascorbate as the reducing agent,
and 1,10-phenanthroline to stabilize the Cu(I) active center. Optimal reaction times
for both nitrogen and sulfur derivatives ranged between 16 and 18 h, and
room-temperature conditions provided good yields in most cases (Table I). Through
the series preparation, we noticed that slower reaction rates and yields were obtained
when the p-methoxy benzylchloride substrate was used.
1
Triazoles 1a–f and 2a–f were fully characterized by H and 13C NMR and
Fourier transform infrared (FT-IR). In 1H NMR, the triazolyl protons are observed
as single sharp peaks in the region of d ¼ 7.18–7.21 ppm and d ¼ 7.19–7.36 ppm for
nitrogen and sulfur substituted triazoles, respectively. In 13C NMR, the CH and
quaternary triazole signals show single peaks in the range of d ¼ 120.9–121.4
and d ¼ 145.6–146.2 ppm, respectively, for 1a–f, and peaks in the range of
Table 1. Synthesis of mono-1,2,3-triazoles 1a–f and 2a–f
Entry
X
Y
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
Cl
Cl
Cl
Br
Br
Cl
H
1a
1b
1c
1d
1e
1f
70
72
71
77
83
63
2a
2b
2c
2d
2e
2f
79
75
81
80
87
70
F
Cl
Br
I
OMe
Notes. Reagents and conditions: For methylaniline: 1.03 mmol of (I), Cu(OAc)2 ꢀ H2O 5 mol%, 1,10-phe-
nanthroline 5 mol%, sodium ascorbate 1.03 mmol, 1.24 mmol of sodium azide, 1.24 mmol of p-substituted
benzyl halogenide, stirring at room temperature for 18 h, EtOH=H2O (4:1). For thiophenol: 0.61 mmol of I,
Cu(OAc)2 ꢀ H2O 5 mol%, 1,10-phenanthroline monohydrate 5 mol%, sodium L-ascorbate 0.76 mmol,
0.83 mmol of sodium azide, 0.83 mmol of p-substituted benzyl halogenide, stirring at room temperature
for 16 h, EtOH=H2O (4:1).

SYNTHESIS OF FUNCTIONALIZED TRIAZOLES
811
d ¼ 121.7–122.0 and d ¼ 145.2–145.6 ppm for 2a–f. Purity of all compounds was vali-
dated by high-resolution mass spectrometry (HRMS) analyses.
Having previously synthesized monotriazoles supported by phenol,[11] we
decided to explore the reactivity of 2-propynyl benzyl ether (III), as the oxygen atom
in this molecule was not directly connected to the aromatic ring. At first glance, when
using the same ‘‘click’’ conditions as in the sulfur and nitrogen cases, we noticed that
the resulting 1,2,3-triazoles did not precipitate from the reaction mixtures. In all
these cases, the products were extracted from the reaction mixtures with dichloro-
methane and further purified by column chromatography using dichloromethane
and ethanol. Overall, the ‘‘click’’ process yielded the desired triazoles 3a–f in yields
ranging from 35 to 59%. Because of the lower yield observed in these series, several
optimization trials were performed. While monitoring by thin-layer chromatography
(TLC), we noticed that after 24 h of reaction, a considerable amount of starting
material was still present. By increasing the reaction time to 36 h (all starting material
was consumed) and after purification, triazoles 3a–f were obtained in greater yields
(Table 2). Attempts to improve the process efficiency or reduce reaction times by
increasing amount of active catalyst were unsuccessful even with catalyst loads of
10 mol%.
Triazoles 3a–f were isolated as white waxy solids featuring high solubility in
chloroform, dichloromethane, and ethanol. The 1H NMR spectra showed the
expected triazolyl protons as single sharp peaks in the range from 7.41 to
7.51 ppm. The CH and quaternary carbons presented chemical shifts at
122.1–122.5 and 145.5–145.9 ppm, respectively, all consistent with the formation
of the monocyclic structures.
Table 2. Synthesis of 1,2,3-triazoles 3a–f
Entry
X
Y
Product
Yield (%)
1
2
3
4
5
6
Cl
Cl
Cl
Br
Br
Cl
H
F
3a
3b
3c
3d
3e
3f
77
73
73
85
79
67
Cl
Br
I
OMe
Notes. Reagents and conditions: 0.7 mmol of III, Cu(OAc)2 ꢀ H2O 5 mol%, 1,10-phenanthroline 5 mol%,
sodium ascorbate 0.7 mmol, 0.77 mmol of sodium azide, 0.83 mmol of p-substituted benzyl halogenide,
stirring at room temperature for 36 h, EtOH=H2O (4:1).

812
D. MENDOZA-ESPINOSA ET AL.
Nitrogen functionalized 1,2,3-triazoles are important scaffolds with application
in areas such as biochemistry, materials, and transition-metal chemistry.[22] With the
target of extending the scope of the multicomponent one-pot methodology, we envi-
sioned the preparation of a series of bis-triazoles utilizing N,N-diprop-2-ynylaniline
(IV) as precursor. The preparation of this bis-alkyne was accomplished by the
addition of propargyl bromide to aniline in the presence of potassium carbonate,
according to a literature procedure.[23]
The preparation of bis-1,2,3-triazoles 4a–f followed similar ‘‘click’’ reaction
conditions as those for the monotriazoles, only differing in longer reaction times
(24 h). The crude materials precipitate out from the reaction mixture after water
addition, and their purification is accomplished through chromatography column
on silica gel using a mixture of DCM and methanol as eluent. As depicted in
Table 3, the reaction scope permits the installation of several electron attractor
and donor groups and provides good yields, employing only 2.5 mol% of the copper
catalyst per each triazole formed (5 mol% overall).
Regardless of the complex topology of bis-1,2,3-triazoles 4a–f, they display
excellent solubility in dichloromethane or chloroform and their purification can be
performed by column chromatography on silica gel using DCM=MeOH as mobile
1
phase. In solution, the H and 13C NMR spectra of 4a–f feature C2 symmetry pat-
terns displaying a single sharp peak for the two triazolyl-CH groups in the region of
d ¼ 7.24–7.31 ppm, and singlets for the two nonequivalent series of methylene
bridges at d ¼ 3.78–4.65 ppm (ArCH2N) and d ¼ 4.60–5.45 ppm (C-CH2N). Simi-
larly, a single set of aromatic patterns is displayed in all cases, corroborating the high
symmetry of the bis-1,2,3-triazole system (see the experimental section).
Table 3. Synthesis of bis-1,2,3-triazoles 4a–f
Entry
X
Y
Product
Yield (%)
1
2
3
4
5
6
Cl
Cl
Cl
Br
Br
Cl
H
F
4a
4b
4c
4d
4e
4f
72
73
78
75
84
65
Cl
Br
I
OMe
Notes. Reagents and conditions: 0.59 mmol of IV, Cu(OAc)2 ꢀ H2O 5 mol%, 1,10-phenanthroline
5 mol%, sodium L-ascorbate 0.59 mmol, 1.42 mmol of sodium azide, 1.42 mmol of p-substituted benzyl
halogenide, stirring at room temperature for 24 h, EtOH=H2O (4:1).

SYNTHESIS OF FUNCTIONALIZED TRIAZOLES
813
Besides the wide variety of structural topologies and the rational functionaliza-
tion, an appealing feature of the synthesized 1,2,3-triazoles is the presence of hal-
ogens at the para position of the benzylic groups, which carries a reactive position
that could be explored in further transformations.
CONCLUSION
In conclusion, we have successfully synthesized a series of 1,2,3-triazoles
featuring nitrogen, sulfur, and oxygen functionalized pendant arms utilizing ‘‘click’’
chemistry. The use of stable propargyl derivatives allowed for the easy assembly of
1,2,3-triazoles that feature a wide variety of structural topologies under mild reaction
conditions that involved room temperature, reaction periods of 16–36 h, and catalyst
loads of 5 mol%. Reactions involving propargylated benzyl alcohol presented slower
conversion rates to products, while the use of p-methoxy benzyl chloride provided
lower yields in all the triazole series. Furthermore, the versatility of the procedure
was demonstrated by the straightforward preparation of bis-1,2,3-triazoles
constructed over N,N-diprop-2-ynylaniline. The potential of the synthetized triazoles
as corrosion inhibitors and transition-metal ligands is a focus of current research in
our laboratory.
EXPERIMENTAL
Commercially available reagents and solvents were used as received. Alkynes
I,[13] II,[14] III,[24] and IV[23] were synthesized as reported in the literature. Flash
column chromatography was performed on Kieselgel silica gel 60 (230–400 mesh).
Melting points were determined on a Fisher-Johns apparatus and are uncorrected.
IR spectra were recorded on a Bruker Alpha FT-IR=ATR spectrometer. NMR spec-
tra were obtained with a Jeol ECA-500 (500-MHz) spectrometer. Chemical shifts (d)
are given in parts per million (ppm) downfield from Me4Si as an internal reference;
coupling constants are given in hertz. High-resolution mass spectra (HRMS) were
recorded on a Jeol JMS-SX 102a and Agilent-MSD-TOF-1069A 41 spectrometers.
Typical Procedure for the Synthesis of 1,2,3-Triazoles Derived from
Methylaniline
To a 20-mL, round-bottomed flask equipped with a magnetic stirrer were
charged 11 mg (0.053 mmol, 5 mol%) of Cu(OAc)2 ꢀ H2O, 10 mg (0.053 mmol,
5 mol%) of 1,10-phenanthroline monohydrate, and 204 mg (1.03 mmol) of sodium
L-ascorbate. After addition of 7 mL of a mixture of EtOH–H2O (4:1 v=v), the result-
ing suspension was stirred for 5 min at room temperature. Subsequently, 150 mg
(1.03 mmol) of I, 81 mg (1.24 mmol) of sodium azide, and 0.14 mL (1.24 mmol) of
benzyl chloride were added to the reaction mixture, which was stirred for 18 h at
room temperature. Then 5 mL of H2O were added to the reaction mixture and the
precipitate was filtered off, washed thoroughly with H2O and petroleum ether,
and dried under vacuum. The crude product was purified by column chromato-
graphy (CH2Cl2) to afford 200 mg (70% yield) of 3a as a white solid. Mp ¼
82–84 ꢁC. 1H NMR (CDCl3, 500 MHz): d ¼ 2.96 (s, 3H, NCH3), 4.61 (s, 2H,

814
D. MENDOZA-ESPINOSA ET AL.
=
ArCH2N), 5.45 (s, 2H, NCH2C C), 6.72 (t, 7.9 Hz, 1H, CHar), 6.76 (d, 7.8 Hz, 2H,
CHar), 7.18–7.22 (m, 4H, CHar), 7.21 (s, 1H, CHtriazole), 7.33–7.35 (m, 3H, CHar).
13C NMR (CDCl3, 125.76 MHz): d ¼ 38.5 (NCH3), 48.8 (ArCH2N), 54.1
=
(NCH2C C), 113.0 (CHar), 117.2 (CHar), 121.4 (CHtriazole), 127.8 (CHar), 128.6
(CHar), 129.0 (CHar), 129.2 (CHar), 134.7 (Car), 145.9 (Ctriazole), 149.1 (Car).
FT-IR=ATR nmax cmꢂ1: 3124, 3059, 3032, 2944, 2900, 1820, 1726, 1598, 1570.
HRMS (ESI-TOF) calculated for C17H18N4 þHþ: 279.1610; found: 279.1608.
Typical Procedure for the Synthesis of 1,2,3-Triazoles Derived from
Thiophenol
To a 20-mL, round-bottomed flask equipped with a magnetic stirrer were
charged 6 mg (0.031 mmol, 5 mol%) of Cu(OAc)2 ꢀ H2O, 6 mg (0.031 mmol, 5 mol%)
of 1,10-phenanthroline monohydrate, and 150 mg (0.76 mmol) of sodium
L-ascorbate. After addition of 5 mL of a mixture of EtOH–H2O (4:1 v=v), the result-
ing suspension was stirred for 5 min at room temperature. Subsequently, 90 mg
(0.61 mmol) of II, 54 mg (0.83 mmol) of sodium azide, and 0.09 mL (0.83 mmol) of
benzyl chloride were added to the reaction mixture, which was stirred for 16 h at
room temperature. Then 5 mL of H2O were added to the reaction mixture, and
the precipitate was filtered off, washed thoroughly with H2O and petroleum ether,
and dried under vacuum. The crude product was purified by column chromato-
graphy (CH2Cl2–MeOH 99:1 v=v) to afford 136 mg (79% yield) of 2a as a white solid.
Mp ¼ 71–73 ꢁC. 1H NMR (CDCl3, 500 MHz): d ¼ 4.23 (s, 2H, ArCH2N), 5.47 (s, 2H,
ArSCH2), 7.17–7.20 (m, 3H, CHar), 7.23–7.26 (m, 3H, CHar), 7.30–7.32 (m, 2H,
CHar), 7.36–7.37 (m. 2H, CHar), 7.36 (s, 1H, CHtriazole). 13C NMR (CDCl3,
125.76 MHz): d ¼ 29.1 (ArCH2N), 54.1 (ArSCH2), 122.0 (CHtriazole), 126.5 (CHar),
127.9 (CHar), 128.7 (CHar), 128.9 (CHar), 129.1 (CHar), 129.8 (CHar), 134.6 (Car),
135.4 (Car), 145.5 (Ctriazole). FT-IR=ATR nmax cmꢂ1: 3140, 3073, 3046, 3013, 2986,
2951, 2923, 1956, 1726, 1586, 1553, 1476, 1455. HRMS (ESI-TOF) calculated for
C16H15N3S þHþ: 281.0987; found: 282.1058.
Typical Procedure for the Synthesis of Triazoles Derived from Benzyl
Alcohol
To a 20-mL, round-bottomed flask equipped with a magnetic stirrer were
charged 7 mg (0.035 mmol, 5 mol%) of Cu(OAc)2 ꢀ H2O, 7 mg (0.035 mmol,
5 mol%) of 1,10-phenanthroline monohydrate, and 139 mg (0.70 mmol) of sodium
L-ascorbate. After addition of 5 mL of a mixture of EtOH–H2O (4:1 v=v), the result-
ing suspension was stirred for 5 min at room temperature. Subsequently, 103 mg
(0.70 mmol) of I, 50 mg (0.77 mmol) of sodium azide, and 0.09 mL (0.83 mmol) of ben-
zyl chloride were added to the reaction mixture, which was stirred for 36 h at room
temperature. Then 5 mL of H2O were added to the reaction mixture, and the precipi-
tate was filtered off, washed thoroughly with H2O and petroleum ether, and dried
under vacuum. The crude product was purified by column chromatography
(CH2Cl2–MeOH 98:2 v=v) to afford 150 mg (77% yield) of 1a as a white solid.
1
Mp ¼ 53–55 ꢁC. H NMR (CDCl3, 500 MHz): d ¼ 4.58 (s, 2H, ArCH2N), 4.65 (s,
2H, C-CH2O), 5.50 (s, 2H, ArCH2O), 7.25–7.27 (m, 3H, CHar), 7.32–7.34 (m, 4H,

SYNTHESIS OF FUNCTIONALIZED TRIAZOLES
815
CHar), 7.35–7.37 (m, 3H, CHar), 7.45 (s, 1H, CHtriazole). 13C NMR (CDCl3,
125.76 MHz): d ¼ 54.2 (ArCH2N), 63.8 (ArOCH2), 72.6 (C-CH2O), 122.5 (CHtriazole),
127.8 (CHar), 127.9 (CHar), 128.1 (CHar), 128.4 (CHar), 128.7 (CHar), 129.1 (CHar),
134.6 (Car), 137.8(Car), 145.7 (Ctriazole). FT-IR=ATR nmax cmꢂ1: 3128, 3063, 3031,
2954, 2862, 1495, 1455. HRMS (ESI-TOF) calculated for C17H17N3O þHþ:
280.1450; found: 280.1443.
Typical Procedure for the Synthesis of bis-1,2,3-Triazoles Derived
from Dipropargyl Aniline
To a 20-mL, round-bottomed flask equipped with a magnetic stirrer were
charged 6 mg (0.030 mmol, 5 mol%) of Cu(OAc)2 ꢀ H2O, 6 mg (0.030 mmol,
5 mol%) of 1,10-phenanthroline monohydrate, and 117 mg (0.59 mmol) of sodium
L-ascorbate. After addition of 5 mL of a mixture of EtOH–H2O (4:1 v=v), the result-
ing suspension was stirred for 5 min at room temperature. Subsequently, 100 mg
(0.59 mmol) of IV, 92 mg (1.42 mmol) of sodium azide, and 0.16 mL (1.42 mmol)
of benzyl chloride were added to the reaction mixture, which was stirred during
24 h at room temperature. Then 5 mL of H2O were added to the reaction mixture,
and the precipitate was filtered off, washed thoroughly with H2O and petroleum
ether, and dried under vacuum. The crude product was purified by column chroma-
tography (CH2Cl2–MeOH 98:2 v=v) to afford 185 mg (72% yield) of 4a as a white
1
solid. Mp ¼ 146–148 ꢁC. H NMR (CDCl3, 500 MHz): d ¼ 4.65 (s, 4H, ArCH2N),
=
5.45 (s, 4H, NCH2C C), 6.75 (t, 7.9 Hz, 1H, CHar), 6.85 (d, 7.8 Hz, 2H, CHar),
7.18–7.20 (m, 3H, CHar), 7.21–7.22 (m. 3H, CHar), 7.31 (s, 2H, CHtriazole),
7.34–7.36 (m, 4H, CHar), 7.37–7.38 (m, 2H, CHar). 13C NMR (CDCl3,
=
125.76 MHz): d ¼ 46.9 (ArCH2N), 54.1 (NCH2C C), 113.7 (CHar), 117.8 (CHar),
121.9 (CHtriazole), 127.8 (CHar), 128.7 (CHar), 129.0 (CHar), 129.3 (CHar), 134.7
(Car), 145.8 (Ctriazole), 147.9 (Car). FT-IR=ATR nmax cmꢂ1: 3116, 3066, 3027, 3003,
3027, 3003, 2960, 2894, 1719, 1597, 1503. HRMS (ESI-TOF) calculated for
C26H25N7 þHþ: 436.2250; found: 436.2247.
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
´
We are grateful to Consejo Nacional de Ciencia y Tecnologıa, CONACyT
(Project 181448). D. M. E. also acknowledges ‘‘Beca de Retencion’’ (Application
192049) sponsored by CONACyT and UAM-Azcapotzalco. D. M. E., G. N. S.,
and L. L. R., acknowledge the SNI for the stipend.
REFERENCES
1. For general reviews on the chemistry of 1,2,3-triazoles: (a) Fan, W.-Q.; Katritzky, A. R. In
Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees, E. F. V. Scriven

816
D. MENDOZA-ESPINOSA ET AL.
(Eds.); Elsevier Science: Oxford, 1996; vol 4, pp. 1–126; (b) Denhe, H. In Methoden der
Organishen Chemie; E. Shumman, (Ed.); Thieme: Stuttgart, 1994; vol. E8d, pp. 305.
2. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
´
3. (a) L’abbe, G. Chem. Rev. 1969, 345; (b) Huisgen, R. In 1,3-Dipolar Cycloaddition
Chemistry; A. Padwa (Ed.); Wiley: New York, 1984; Chapter 1, pp. 1–176; (c) Padwa,
A. In Comprehensive Organic Synthesis; B. M. Trost, I. Fleming (Eds.); Pergamon:
Oxford, 1991; Vol. 4; (d) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863;
(e) Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439–4449.
4. For selected reviews see (a) Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255, 2933; (b)
Diez-Gonzalez, S. Catal. Sci. Technol. 2011, 1, 166; (c) Hein, J. E.; Fokin, V. V. Chem.
Soc. Rev. 2010, 39, 1302; (d) Medal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952;
(e) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
5. (a) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6, 2696; (b) Liu, J.-F.;
Sang, C.-Y.; Xu, X.-H.; Zhang, L.-L.; Yang, X.; Hui, L.; Zhang, J.-B.; Chen, S.-W. Eur. J.
Med. Chem. 2013, 64, 621; (c) Li, J.; Kaoud, T. S.; LeVieux, J.; Gilbreath, B.; Swapna, M.;
Dalby, K. N.; Kerwin, S. M. ChemBioChem. 2013, 14, 66.
6. See, for example, (a) Golas, P. L.; Matyjaszewski, K. QSAR Comb. Sci. 2007, 26, 1116; (b)
Fournier, D.; Hoogenboom, R.; Schubert, U. S. Chem Soc. Rev. 2007, 36, 1369; (c)
Nandivada, H.; Jiang, X. W.; Lahann, J. Adv. Mater. 2007, 19, 2197; (d) Binder, W.
H.; Kluger, C. Curr. Org. Chem. 2006, 10, 1791; (e) Dickschat, A. T.; Behrends, F.;
Buhner, M.; Ren, J.; Weib, M.; Eckert, H.; Studer, A. Chem. Eur. J. 2012, 18, 16689;
¨
(f) Abdulkin, P.; Moglie, Y.; Knappet, B. R.; Jefferson, D. A.; Yus, M.; Alonso, F.;
Wheatley, A. E. H. Nanoscale 2013, 5, 342; (g) Stenehjem, E. D.; Ziatdinov, V. R.; Stack,
T. D. P.; Chidsey, C. E. D. J. Am. Chem. Soc. 2013, 135, 1110.
7. (a) Gierlich, J.; Burley, G. A.; Gramlich, P. M. E.; Hammond, D. M.; Carrell, T. Org.
Lett. 2006, 8, 36–39; (b) Takei, Y.; Murata, A.; Yamagishi, K.; Arai, S.; Nakamura,
H.; Inoue, T.; Takeoka, S. Chem Commun. 2013, 49, 7313.
8. (a) Nuzzi, A.; Massi, A.; Dondoni, A. QSAR Comb. Sci. 2007, 26, 1191; (b) Ban, H.;
Nagano, M.; Gavrilyuk, J.; Hakamata, W.; Inokuma, T.; BarbasIII, C.-F. Bioconjugate
Chem. 2013, 24, 520.
9. (a) Schultz, P. G. J. Am. Chem. Soc. 2003, 125, 11782; (b) Palomo, J. M. Org. Biomol.
Chem. 2012, 10, 9309.
10. See, for example, (a) Finn, M. G.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1231; (b)
Droumaguet, C. L.; Wang, C.; Wang, Q. Chem. Soc. Rev. 2010, 39, 1233; (c) Mamidyala,
S. K.; Finn, M. G. Chem. Soc. Rev. 2010, 39, 1252; (d) Huang, H.-W.; Chen, C.-H.; Lin,
C.-H.; Wong, C.-H.; Lin, K.-I. Proc. Natl. Acad. Sci. USA 2013, 110, 10928.
11. (a) Bai, S.-Q.; Kwang, J. Y.; Koh, L. L.; Young, D. J.; Hor, T. S. A. Dalton Trans. 2010,
39, 2631; (b) Uppal, B. S.; Booth, R. K.; Ali, N.; Lockwood, C.; Rice, C. R.; Elliot, P. I. P.
Dalton Trans. 2011, 40, 7610.
12. Mendoza-Espinosa, D.; Negron-Silva, G.; Lomas-Romero, L.; Guitierrez-Carrillo, A.;
Soto-Castro, D. Synthesis 2013, 45, 2431.
13. Tayama, E.; Sugai, S. Tetrahedron Lett. 2007, 48, 61.
14. Joshi, M. C.; Joshi, P.; Rawat, D. S. Arkivoc 2006, (16), 65.
15. See, for example, (a) Badeche, S.; Daran, J. C.; Ruiz, J.; Astruc, D. Inorg. Chem. 2008, 47,
4903; (b) Mullen, K. M.; Gunter, M. J. J. Org. Chem. 2008, 73, 3336; (c) Ornelas, C.; Ruiz,
J.; Salmon, L.; Astruc, D. Adv. Synth. Catal. 2008, 350, 837; (d) Li, Y.; Huffman, J. C.;
Flood, H. C. Chem. Commun. 2007, 2692; (e) Meudtner, R. M.; Ostermeier, M.; Goddard,
R.; Limberg, C.; Hecth, S. Chem. Eur. J. 2007, 13, 9834; (f) Schuster, E. M.; Botoshansky,
M.; Gandelman, M. Angew. Chem. Int. Ed. 2008, 47, 4555; (g) Ziegler, T.; Hermann, C.
Tetrahedron Lett. 2008, 49, 2166; (h) Huang, S.; Clark, R. J.; Zhu, L. Org. Lett. 2007,
9, 4999.

SYNTHESIS OF FUNCTIONALIZED TRIAZOLES
817
16. (a) Prabakaran, K.; Manibel, P.; Khan, F. N. Tetrahedron Lett. 2010, 51, 4340; (b)
Pagoria, P. F. J. Heterocycl. Chem. 2000, 37, 1597.
17. (a) Chapyshev, S. V. Chem. Heterocycl. Comp. 2001, 37, 861; (b) Abramovitch, R. A.;
Challand, S. R.; Yamada, Y. J. Org. Chem. 1975, 40, 1541; (c) Balachari, D.; Trudell,
M. L. Tetrahedron Lett. 1997, 38, 8607.
18. (a) Keith, J. M. J. Org. Chem. 2010, 75, 2722; (b) Teyssot, M.-L.; Nauton, L.; Canet, J.-L.;
Cisnetti, F.; Chevry, A.; Gautier, A. Eur. J. Org. Chem. 2010, 3507; (c) Kaval, N.;
´
Ermolatev, D.; Appukuttan, P.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. J. Comb.
Chem. 2005, 7, 490; (d) Chen, Z.-Y.; Wu, M.-J. Org. Lett. 2005, 7, 475; (e) Beletskaya, I.
P.; Davydov, D. V.; Moreno-Maflas, M. Tetrahedron Lett. 1998, 39, 5617.
19. Crowley, J. D.; Bandeen, P. H.; Hanton, L. R. Polyhedron 2010, 29, 70.
20. (a) Thomas, K. D.; Adhikari, A. V.; Chowdhury, I. H.; Sumesh, E.; Pal, N. K. Eur. J.
Med. Chem. 2011, 46, 2503; (b) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V.
V.; Sharpless, B. K.; Chang, S. Angew. Chem. Int. Ed. 2007, 46, 1730; (c) Culhane, J.
C.; Fokin, V. V. Org. Lett. 2011, 13, 4578; (d) Wang, L.-X., Wan, W. K.; Zhou, C. -H.
Eur. J. Med. Chem. 2010, 45, 4631.
21. Shafy, S.; Alam, M. M.; Mulakayala, N.; Mulakayala, C.; Vanaja, G.; Kalle, A. M.; Pallu, R.;
Alam, M. S. Eur. J. Med. Chem. 2012, 49, 324.
22. (a) Colombano, G.; Travelli, C.; Galli, U.; Caldarelli, A.; Chini, M. G.; Canonico, P. L.;
Sorba, G., Bifulco, G.; Tron, G. C.; Genazzani, A. A. J. Med. Chem. 2010, 53, 616; (b)
Lakshman, M. K.; Singh, M.; Parrish, G.; Balachandran, R.; Day, B. W. J. Org. Chem.
2010, 75, 2461; (c) Klein, M.; Diner, P.; Dorin-Semblat, D.; Doering, C.; Grotli, M. Org.
Biol. Chem. 2009, 7, 3421; (d) Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Synlett 2007,
1591.
23. Cantet, A.-C.; Carreyre, H.; Gesson, J.-P.; Jouannetaud, M.-P.; Renoux, B. J. Org. Chem.
2008, 73, 2875.
24. Li, H.-J.; Guillot, R.; Gandon, V. J. Org. Chem. 2010, 75, 8435.