Efficient multicomponent synthesis of mono-, bis-, and tris-1,2,3-triazoles supported by hydroxybenzene scaffolds

Article abstract of DOI:10.1055/s-0033-1339376

A versatile one-pot synthesis of a series of mono-, bis- and tris-1,2,3-triazoles supported by commercially available hydroxybenzene scaffolds has been developed employing click chemistry. The multicomponent copper(I)-catalyzed 1,3-dipolar cycloaddition of sodium azide, propargyl bromide, and a para-substituted benzyl derivative yields N-benzyl-functionalized triazoles featuring several electron-donating or electron-withdrawing groups. Despite the preparation of highly substituted molecules, reaction conditions that provides good yields involved room temperature, times that oscillate between 16 and 24 hours, and catalyst loads ranging from 5-10 mol%. The present methodology could be useful for the building up of multi-triazole libraries easily tunable with donor or attractor functional groups.

Full text of DOI:10.1055/s-0033-1339376

PAPER
▌2431
paper
Efficient Multicomponent Synthesis of Mono-, Bis-, and Tris-1,2,3-triazoles
Supported by Hydroxybenzene Scaffolds
Multi-Triazoles Supported by Hydroxybenzene Scaffolds
Daniel Mendoza-Espinosa,a Guillermo E. Negrón-Silva,*a Leticia Lomas-Romero,b Atilano Gutiérrez-Carrillo,b
Delia Soto-Castroc
a
Departamento de Ciencias Básicas, Universidad Autónoma Metropolitana-Azcapotzalco, Avenida San Pablo No. 180, C.P. 02200, México
D.F., México
b
Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Av. San Rafael Atlixco No. 186, C.P. 09340, México D.F.,
México
c
Departamento de Química, CINVESTAV-IPN, Apdo. Postal 14-740, 07000, México D.F., México
Fax +52(55)53189000; E-mail: gns@correo.azc.uam.mx
Received: 02.05.2013; Accepted after revision: 17.06.2013
pathways take place in these cycloadditions. As a result, a
Abstract: A versatile one-pot synthesis of a series of mono-, bis-
mixture of 1,4- and 1,5-dibustituted 1,2,3-triazoles is ob-
and tris-1,2,3-triazoles supported by commercially available hy-
tained when an alkyne is unsymmetrically substituted. In
2001, Sharpless reported the outstanding efficiency and
droxybenzene scaffolds has been developed employing click chem-
istry. The multicomponent copper(I)-catalyzed 1,3-dipolar
cycloaddition of sodium azide, propargyl bromide, and a para-sub- selectivity achieved with Cu-catalyzed alkyne-azide cy-
stituted benzyl derivative yields N-benzyl-functionalized triazoles
featuring several electron-donating or electron-withdrawing
groups. Despite the preparation of highly substituted molecules, re-
now as a landmark in organic synthesis, the formation of
action conditions that provides good yields involved room temper-
ature, times that oscillate between 16 and 24 hours, and catalyst
loads ranging from 5–10 mol%. The present methodology could be
useful for the building up of multi-triazole libraries easily tunable
with donor or attractor functional groups.
cloaddition (CuAAC) reaction unveiling the widely
known click methodology.10 In this process, considered
1,4-disubstituted 1,2,3-triazoles is easy to carry out with
access to high yields, negligible or no by-products are
formed, several functional groups are tolerated, and the
reaction is highly atom economical.
Key words: click chemistry, multi-triazoles, one-pot synthesis, hy-
droxybenzene, catalysis
Because of the breakthrough of click chemistry in the
1,2,3-triazole motif, most of the work reported in the last
ten years has focused on the synthesis optimization and
functionalization of the monocyclic derivatives. Surpris-
ingly, little attention has been placed in the preparation of
bis-, and tris-1,2,3-triazole counterparts despite their evi-
dent potential as building blocks, ligands, and material
precursors.
1,2,3-Triazole derivatives are an important class of het-
erocycles constantly attracting attention due to their
chemical properties, synthetic versatility, pharmacologi-
cal, and agrochemical applications.1 Even though the
1,2,3-triazole structural moiety does not occur in nature, it
is located in diverse biologically active substances, dis-
playing anti HIV,2 antimicrobial,3 antifungal,4 antitumor,5
and selective β3-adrenergenic6 and cannabinoid CB1 re-
ceptor antagonists.7 Furthermore, compounds containing
1,2,3-triazoles have found industrial applications as dyes,
photostabilizers, and corrosion inhibitors.1
As part of our ongoing program in triazole chemistry, we
have envisioned the synthesis of multi-triazoles as poten-
tial steel corrosion inhibitors and/or transition metal li-
gands. In the present report, we disclose an efficient
general approach for the one-pot synthesis of a series of
mono-, bis-, and tris-1,2,3-triazoles supported by hy-
droxybenzene scaffolds. The modular synthesis described
herein, allows for the preparation of 1,2,3-triazoles under
mild conditions, high yields, featuring several electron-
attracting or -donating functional groups, and a wide
range of structural topologies.
The most conventional method for the preparation of tri-
azoles relies in the Huisgen 1,3-dipolar cycloaddition of
azides and terminal alkynes.8 Even though the classical
Huisgen reaction is highly exothermic (ca. 50 to 60
kcal/mol), its high activation barrier (25–26 kcal/mol for
methyl azide and propyne)9 results in slow reaction rates
and conversions that occurs mostly at elevated tempera-
tures. In addition, since the difference in HOMO-LUMO
levels for both azides and alkynes are of similar magni-
tude, both dipole-HOMO and dipole-LUMO-controlled
To prove the viability of the envisioned multi-triazole
synthesis, the preparation of mono-1,2,3-triazoles was
first explored using phenol as the starting scaffold. The
first synthetic step involved the preparation of propargy-
loxybenzene (I) by deprotonation of phenol with potassi-
um carbonate in dimethylformamide at 60 °C, followed
by the addition of equimolar amounts of propargyl bro-
mide. After workup and purification through column
chromatography on silica gel, alkyne I was isolated in
73% yield.11 The click reaction between I and sodium
SYNTHESIS 2013, 45, 2431–2437
Advanced online publication: 23.07.2013
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1
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DOI: 10.1055/s-0033-1339376; Art ID: SS-2013-M0333-OP
© Georg Thieme Verlag Stuttgart · New York

2432
D. Mendoza-Espinosa et al.
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azide was carried out in a water–ethanol mixture (4:1) us- in Table 1, the methodology proceeds smoothly in good
ing CuSO4·5H2O and sodium ascorbate as the reagents to yields and under mild reaction conditions.
render the Cu(I) active catalyst. After the addition of ben-
zyl chloride to the reaction mixture and stirring at room
temperature for 20 hours, the expected 1,2,3-triazole 1a
was obtained in only 30% yield. Targeting the process
Triazoles 1a–f were conveniently characterized by FT-IR,
1H and 13C NMR spectroscopy, and also by high-resolu-
tion mass spectrometry. The formation of the 1,2,3-tri-
azoles was apparent from the absorption band in the
yield improvement and taking advantage of our previous-
3120–3140 cm–1 region due to the =CH (stretching) of the
ly reported methodology for 1,2,3-triazoles synthesis,12
triazole ring in the IR spectra. In addition, the presence of
we switched the copper(II) source to Cu(OAc)2·H2O and
included the addition of 1,10-phenanthroline to stabilize
the in situ generated Cu(I) catalyst. Performing the one-
pot reaction under the new click conditions allowed for
1
the characteristic singlet in H NMR due to the triazolyl
protons in the region of δ = 7.52–7.74, and the peaks at
δ = 121.5–122.6 in 13C NMR belonging to the C-5 atom,
confirm the structure of the expected five-membered
rings.
the synthesis of 1a in 83% isolated yield (Table 1).
Table 1 Synthesis of Mono-1,2,3-triazoles 1a–fa
Recently, the preparation of multi-triazoles has attracted
the attention of the chemical community due to their po-
tential in areas such as materials, catalysis, and biochem-
istry. For instance, bis-triazole based size-specific mRNA
hairpin loop binding agents have been developed target-
ing mRNAs coding for proteins,13 which can be a suitable
approach in drug discovery. Also, recent studies have dis-
closed a series of 1,2,3-bis-triazoles as potent HIV-1 pro-
tease inhibitors.2c The reported synthetic routes to access
this highly functionalized molecules include oxidative
conditions using inorganic bases,14 sequential functional-
ization of mono-triazoles,15 and one-pot click chemistry
conditions.16 Unfortunately, some of these processes pres-
ent important drawbacks such as the need of several syn-
thetic steps, difficult purification procedures, formation of
secondary products, and functionalization is not always
accessible. In conjunction with our interest in sustainable
chemistry and encouraged by the discovery of the optimal
reaction conditions for 1,2,3-triazoles formation, we de-
cided to turn our efforts in the multicomponent one-pot
synthesis of bis- and tris-1,2,3-triazoles.
O
O
I
N
Cu(OAc)2•H2O (5 mol%)
N
+
NaN3
+
1,10-Phen•H2O (5 mol%)
N
EtOH–H2O (4:1)
sodium ascorbate
r.t., 16 h
Y
1a–f
X
Y
Entry
X
Y
Product
Yield (%)
1
2
3
4
5
6
Cl
Cl
Cl
Br
Br
Cl
H
1a
1b
1c
1d
1e
1f
83
81
75
79
69
74
F
Cl
Br
I
OMe
a Reaction conditions: I (0.7 mmol), Cu(OAc)2·H2O (5 mol%), 1,10-
phenanthroline (5 mol%), sodium ascorbate (0.7 mmol), NaN3 (0.77
mmol), para-substituted benzyl halogenide (0.77 mmol), EtOH–H2O
(5 mL, 4:1), stirring at r.t. for 16 h.
The selected approach to install bis- and tris-triazoles
within the same scaffold, involved the usage of 1,3-dihy-
droxy-, and 1,3,5-trihydroxybenzene moieties. Analogue
to the preparation of I and following the literature proce-
dure, 1,3-dipropargyloxybenzene (II)11 and 1,3,5-tri-
propargyloxybenzene (III)17 were obtained by
deprotonation of the benzene hydroxyl groups with excess
of potassium carbonate at 60 °C in DMF or THF, and the
subsequent treatment with the appropriate equivalents of
The scope of the method was extended with the use of sev-
eral p-halogenide or p-methoxybenzylic derivatives,
yielding 1,2,3-triazoles 1b–f, which feature several elec-
tron-donating or electron-attracting groups. As depicted
R2
OH
R1
K2CO3 (3 equiv)
(2.1 equiv)
K2CO3 (5 equiv)
(3.1 equiv)
Br
Br
DMF, 60 °C
1 = OH, R2 = H
DMF or THF, 60 °C
R1, R2 = OH
R
O
O
O
O
O
III
II
Scheme 1 Synthesis of alkynes II and III
Synthesis 2013, 45, 2431–2437
© Georg Thieme Verlag Stuttgart · New York

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Multi-Triazoles Supported by Hydroxybenzene Scaffolds
2433
propargyl bromide. After workup and purification, pre- from 1,3,5-tripropargyloxybenzene (III). In a first trial,
cursors II and III were isolated as yellow oils in 78 and the treatment of III with a slight excess of sodium azide
67% yield, respectively (Scheme 1).
and benzyl chloride and employing 5 mol% of the cop-
per(I) catalyst system yielded tris-1,2,3-triazole 3a in 32%
yield. As the conversion of the starting materials into the
final product proved low, the reaction kinetics were mon-
itored by TLC, observing that the consumption of the
starting alkyne proceeded slower compared to mono- and
bis-triazoles. Noticing this behavior, the reaction time was
increased to 24 and 36 hours and the temperature was
raised to 40 °C, but no conversion improvement was
achieved (yields were not higher than 40%). After several
optimization experiments including variable modifica-
tions such as reaction times, stoichiometry, and tempera-
ture, we found that addition of 10 mol% of the copper(I)
catalyst system (less than 3.5 mol% per triazole unit) af-
forded the best yields of the series 3a–f as depicted in Ta-
ble 3.
The preparation of bis-1,2,3-triazoles 2a–f followed sim-
ilar click reaction conditions as those for the mono-tri-
azoles, only differing in longer reaction times (20 h). The
crude materials precipitate out from the reaction mixture
after water addition, and their purification is accom-
plished through column chromatography on silica gel us-
ing a mixture of dichloromethane and methanol as eluent.
As depicted in Table 2, the reaction scope permits the in-
stallation of several electron-attracting and -donating
groups, and provides good yields employing only 2.5
mol% of the copper catalyst per each triazole formed (5
mol% overall).
Table 2 Synthesis of Bis-1,2,3-triazoles 2a–fa
O
Table 3 Synthesis of Tris-1,2,3-triazoles 3a–fa
O
O
II
Cu(OAc)2•H2O (5 mol%)
+
1,10-Phen•H2O (5 mol%)
O
O
NaN3
EtOH–H2O (4:1)
sodium ascorbate
r.t., 20 h
O
O
+
III
Y
X
Cu(OAc)2•H2O (10 mol%)
1,10-Phen•H2O (10 mol%)
+
N
N
Y
Y
N
NaN3
+
N
Y
N
N
N
N
EtOH–H2O (4:1)
sodium ascorbate
r.t., 24 h
2a–f
N
O
X
Entry
X
Y
Product
Yield (%)
Y
N
O
O
N
N
1
2
3
4
5
6
Cl
Cl
Cl
Br
Br
Cl
H
2a
2b
2c
2d
2e
2f
71
76
66
62
64
69
N
N
Y
Y
N
F
3a–f
Cl
Br
I
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
57
55
61
64
58
49
OMe
Cl
Br
I
a Reaction conditions: II (0.7 mmol), Cu(OAc)2·H2O (5 mol%), 1,10-
phenanthroline (5 mol%), sodium ascorbate (0.7 mmol), NaN3 (1.54
mmol), para-substituted benzyl halogenide (1.54 mmol), EtOH–H2O
(5 mL, 4:1), stirring at r.t. for 20 h.
OMe
a Reaction conditions: III (0.42 mmol), Cu(OAc)2·H2O (10 mol%),
1,10-phenanthroline (10 mol%), sodium ascorbate (0.84 mmol), NaN3
(1.39 mmol), of para-substituted benzyl halogenide (1.39 mmol),
EtOH–H2O (10 mL, 4:1), stirring at r.t. for 24 h.
Bis-triazoles 2a–f are highly soluble in chloroform and di-
chloromethane and slightly soluble in ethanol or metha-
nol. Interestingly, despite their complex topology, the 1H
and 13C NMR spectra of 2a–f feature highly symmetric
patterns. For instance, the two triazolyl protons are dis-
played as single sharp peaks in the region of δ = 7.52–
7.55, while the CH and quaternary triazole signals show
single peaks in the range of δ = 122.4–122.7 and 144.3–
144.7, respectively. Overall, the NMR patterns for the bis-
1,2,3-triazoles suggest a C2 symmetry in solution.
Despite the lower solubility of tris-1,2,3-triazoles 3a–f in
dichloromethane and chloroform compared with mono-
and bis-triazoles, their purification can still be performed
by column chromatography on silica gel using CH2Cl2–
MeOH. In solution, the 1H and 13C NMR spectra of 3a–f
feature C3 symmetry patterns displaying a single sharp
peak for the triazolyl-CH groups in the region of δ = 8.21–
8.27 and singlets for the two nonequivalent series of meth-
ylene bridges at δ = 5.06–5.08 (ArCH2N) and δ = 5.52–
As synthesis of 2a–f was conveniently achieved using the
CuAAC reaction, it was thought that this methodology
could be extended to produce tris-1,2,3-triazoles starting
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2431–2437

2434
D. Mendoza-Espinosa et al.
PAPER
1H NMR (500 MHz, CDCl3): δ = 5.21 (s, 2 H, ArCH2N), 5.55 (s, 2
H, ArOCH2), 6.97–7.00 (m, 3 H, CHar), 7.29–7.32 (m, 4 H, CHar),
7.38–7.40 (m, 3 H, CHar), 7.55 (s, 1 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 54.2 (ArCH2N), 62.1
(ArOCH2), 114.8 (CHar), 121.2 (CHar), 122.6 (CHtriazole), 128.1
(CHar), 128.8 (CHar), 129.1 (CHar), 129.5 (CHar), 134.5 (Car), 144.1
(Ctriazole), 158.2 (Car).
5.61 (CCH2O). Likewise, a single set of aromatic patterns
is displayed in all cases, corroborating the high symmetry
of the tris-1,2,3-triazole system (see experimental sec-
tion). It is noteworthy mentioning that the symmetry fea-
tured by the tris-triazoles 3a–f could place them as
potential G-quadruplex stabilizing ligands15a,18 or triden-
tate transition-metal ligands relevant to bio-inorganic re-
search and electron-transfer studies.19
HRMS (ESI-TOF): m/z calcd for C16H15N3O + H+: 266.1287;
found: 266.1289.
All the reported 1,2,3-triazoles are obtained as white crys-
talline solids, and their robustness is denoted by their high
stability in solution and under aerobic conditions. Addi-
tional to the wide variety of structural features, the pres-
ence of halogens at the para-position of the benzylic
moieties in each triazole carries an extra reactive position
that can be employed in further chemical transformations.
1-(4-Fluorobenzyl)-4-phenoxymethyl-1H-1,2,3-triazole (1b)
The procedure described for 1a was followed using 4-fluorobenzyl
chloride (0.78 mmol, 113 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 97:3 v/v); yield: 160 mg
(81%); white solid; mp 88–90 °C.
FT-IR (ATR): 3142, 3106, 3066, 2951, 2890, 1596, 1584, 1507,
1498, 1468 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.21 (s, 2 H, ArCH2N), 5.52 (s, 2
H, ArOCH2), 6.98–7.00 (m, 3 H, CHar), 7.07–7.10 (m, 2 H, CHar),
7.29–7.31 (m, 4 H, CHar), 7.55 (s, 1 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.5 (ArCH2N), 62.0
(ArOCH2), 114.7 (CHar), 116.1 (d, J = 21.4 Hz, CHar-F), 121.2
(CHar), 122.4 (CHtriazole), 129.5 (CHar), 129.9 (d, J = 8.8 Hz, CHar-F),
130.3 (d, J = 3.8 Hz, Car-F), 144.8 (Ctriazole), 158.1 (Car), 163.0 (d,
J = 216.4 Hz, Car-F).
In conclusion, we have reported a convenient methodolo-
gy for the synthesis of a series of mono-, bis- and tris-
1,2,3-triazoles utilizing click chemistry. Despite the prep-
aration of molecules featuring a wide variety of structural
topologies, reaction conditions that provides good yields
involved room temperature, reaction periods in the range
of 16–24 hours and catalyst loads of 5–10 mol%. Particu-
larly appealing is the possibility of using this strategy for
the synthesis of multi-triazole libraries easily tunable with
electron-donating or electron-attracting functional
groups. The possible applications of the synthesized
1,2,3-triazoles are the topic of current investigation in our
laboratory.
HRMS (ESI-TOF): m/z calcd for C16H14FN3O + H+: 284.1124;
found: 284.1198.
1-(4-Chlorobenzyl)-4-phenoxymethyl-1H-1,2,3-triazole (1c)
The procedure described for 1a was followed using 4-chlorobenzyl
chloride (0.78 mmol, 126 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 98:2 v/v); yield: 157 mg
(75%); white solid; mp 70–72 °C.
FT-IR (ATR): 3127, 3084, 3068, 2919, 2874, 1913, 1720, 1598,
1491, 1462 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.21 (s, 2 H, ArCH2N), 5.51 (s, 2
H, ArOCH2), 6.98–7.00 (m, 3 H, CHar), 7.22 (d, J = 7.7 Hz, 2 H,
CHar), 7.29–7.31 (m, 2 H, CHar), 7.37 (d, J = 7.7 Hz, 2 H, CHar), 7.57
(s, 1 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.5 (ArCH2N), 62.0
(ArOCH2), 114.8 (CHar), 121.3 (CHar), 122.5 (CHtriazole), 129.3
(CHar), 129.4 (CHar), 129.5 (CHar), 133.0 (Car), 134.9 (Car), 144.9
(Ctriazole), 158.2 (Car).
Commercially available reagents and solvents were used as re-
ceived. Alkynes I, II,11 and III18 were synthesized as reported in the
literature. Compounds 1a, 1e, and 1f have been reported elsewhere
and their spectroscopic characterization is consistent with the one
described in this article. Flash column chromatography was per-
formed on silica gel 60 (230–400 mesh). Petroleum ether used re-
fers to the fraction boiling in the 35–60 °C range. Melting points
were determined on a Fisher-Johns apparatus and are uncorrected.
IR spectra were recorded on a Bruker Alpha FT-IR/ATR spectro-
photometer. NMR spectra were obtained with a Bruker Avance
DMX-500 (500 MHz) spectrometer. Chemical shifts (δ) are given
in ppm downfield from Me4Si as an internal reference; coupling
constants are given in Hertz. High-resolution mass spectra (HRMS)
were recorded on JEOL JMS-SX 102a and Agilent-MSD-TOF-1069A
spectrometers 41.
HRMS (ESI-TOF): m/z calcd for C16H14ClN3O + H+: 300.0898;
found: 300.0905.
1-(4-Bromobenzyl)-4-phenoxymethyl-1H-1,2,3-triazole (1d)
The procedure described for 1a was followed using 4-bromobenzyl
bromide (0.78 mmol, 195 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 99:1 v/v); yield: 190 mg
(79%); white solid; mp 108–110 °C.
1,2,3-Triazoles Derived from Hydroxybenzene; 1-Benzyl-4-
phenoxymethyl-1H-1,2,3-triazole (1a); Typical Procedure
To a 20 mL round-bottomed flask equipped with a magnetic stirrer,
were charged Cu(OAc)2·H2O (7 mg, 0.035 mmol, 5 mol%), 1,10-
phenanthroline monohydrate (7 mg, 0.035 mmol, 5 mol%), and so-
dium L-ascorbate (139 mg, 0.70 mmol). After the addition of a mix-
ture of EtOH–H2O (5 mL, 4:1 v/v), the resulting suspension was
stirred for 5 min at r.t. Subsequently, I (93 mg, 0.70 mmol), NaN3
(50 mg, 0.77 mmol), and benzyl chloride (0.09 mL, 0.78 mmol)
were added to the reaction mixture and stirred for 16 h at r.t. H2O (5
mL) was added to the mixture and the precipitate was collected by
filtration, washed thoroughly with H2O, petroleum ether, and dried
under vacuum. The crude product was purified by column chroma-
tography (CH2Cl2–MeOH, 95:5 v/v); yield: 154 mg (83%); white
solid; mp 120–122 °C (Table 1).
FT-IR (ATR): 3133, 3096, 3059, 3041, 3002, 2938, 2875, 1597,
1585, 1486, 1463 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.22 (s, 2 H, ArCH2N), 5.50 (s, 2
H, ArOCH2), 6.98–7.01 (m, 3 H, CHar), 7.17 (d, J = 7.8 Hz, 2 H,
CHar), 7.29–7.32 (m, 2 H, CHar), 7.52 (s, 1 H, CHtriazole), 7.55 (d, 7.8
Hz, 2 H, CHar).
13C NMR (125.76 MHz, CDCl3): δ = 53.5 (ArCH2N), 62.0
(ArOCH2), 114.8 (CHar), 121.3 (CHar), 121.5 (CHtriazole), 123.0
(Car), 129.5 (CHar), 129.7 (CHar), 132.3 (CHar), 133.5 (Car), 145.0
(Ctriazole), 158.2 (Car).
HRMS (ESI-TOF): m/z calcd for C16H14BrN3O + H+: 344.0393;
found: 344.0396.
FT-IR (ATR): 3137, 3090, 3030, 3002, 2960, 2924, 2872, 1716,
1593 cm–1.
Synthesis 2013, 45, 2431–2437
© Georg Thieme Verlag Stuttgart · New York

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Multi-Triazoles Supported by Hydroxybenzene Scaffolds
2435
1-(4-Iodobenzyl)-4-phenoxymethyl-1H-1,2,3-triazole (1e)
The procedure described for 1a was followed using 4-iodobenzyl
bromide (0.78 mmol, 232 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 99:1 v/v); yield: 189 mg
(69%); white solid; mp 110–112 °C.
4,4′-[1,3-Phenylenebis(oxymethylene)]bis[1-(4-fluorobenzyl)]-
1H-1,2,3-triazole (2b)
The procedure described for 2a was followed using 4-fluorobenzyl
chloride (1.54 mmol, 223 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 97:3 v/v); yield: 260 mg
(76%); white solid; mp 109–111 °C.
FT-IR (ATR): 3131, 3098, 3040, 3016, 2937, 2876, 1597, 1585,
1496, 1483, 1462 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.21 (s, 2 H, ArCH2N), 5.49 (s, 2
H, ArOCH2), 6.98–7.01 (m, 3 H, CHar), 7.04 (d, J = 7.6 Hz, 2 H,
CHar), 7.29–7.32 (m, 2 H, CHar), 7.55 (s, 1 H, CHtriazole), 7.74 (d,
J = 7.6 Hz, 2 H, CHar).
13C NMR (125.76 MHz, CDCl3): δ = 53.7 (ArCH2N), 62.0
(ArOCH2), 94.6 (Car), 114.8 (CHar), 121.3 (CHar), 122.5 (CHtriazole),
129.5 (CHar), 129.8 (CHar), 134.2 (Car), 138.3 (CHar), 145.0 (Ctriazole),
158.2 (Car).
FT-IR (ATR): 3141, 3080, 3006, 2938, 2927, 2874, 1907, 1771,
1728, 1592, 1510, 1490, 1455, 1333 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.13 (s, 4 H, ArCH2N), 5.49 (s, 4
H, ArOCH2), 6.57–6.59 (m, 3 H, CHar), 7.03–7.07 (m, 4 H, CHar),
7.16 (t, J = 7.8 Hz, 1 H, CHar), 7.25–7.28 (m, 4 H, CHar), 7.53 (s, 2
H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.5 (ArCH2N), 62.0
(ArOCH2), 102.1 (CHar), 107.6 (CHar), 116.0 (d, J = 21.4 Hz, CHar-F),
122.5 (CHtriazole), 129.9 (d, J = 8.8 Hz, CHar-F), 130.3 (d, J = 3.8 Hz,
Car-F), 144.5 (Ctriazole), 159.3 (CHar), 161.8 (Car), 162.8 (d, J = 270.2
Hz, Car-F).
HRMS (ESI-TOF): m/z calcd for C16H14IN3O + H+: 392.0215;
found: 392.0257.
HRMS (ESI-TOF): m/z calcd for C26H22F2N6O2 + H+: 489.1806;
1-(4-Methoxybenzyl)-4-phenoxymethyl-1H-1,2,3-triazole (1f)
The procedure described for 1a was followed using 4-methoxyben-
zyl chloride (0.78 mmol, 122 mg). The crude product was purified
by column chromatography (CH2Cl2–MeOH, 97:3 v/v); yield: 153
mg (74%); white solid; mp 74–76 °C.
found: 489.1847.
4,4′-[1,3-Phenylenebis(oxymethylene)]bis[1-(4-chlorobenzyl)]-
1H-1,2,3-triazole (2c)
The procedure described for 2a was followed using 4-chlorobenzyl
chloride (1.54 mmol, 248 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 98:2 v/v); yield: 241 mg
(66%); white solid; mp 122–124 °C.
FT-IR (ATR): 3125, 3069, 3040, 3008, 2954, 2931, 2911, 2873,
2837, 1610, 1598, 1586, 1511, 1495, 1455 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 5.20 (s, 2 H,
ArCH2N), 5.48 (s, 2 H, ArOCH2), 6.92 (d, J = 7.9 Hz, 2 H, CHar),
6.93–6.98 (m, 3 H, CHar), 7.25 (d, J = 7.8 Hz, 2 H, CHar), 7.28–7.30
(m, 2 H, CHar), 7.52 (s, 1 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.8 (ArCH2N), 55.4 (OCH3),
62.1 (ArOCH2), 114.5 (CHar), 114.8 (CHar), 121.2 (CHar), 122.3
(CHtriazole), 126.5 (Car), 129.5 (CHar), 129.7 (CHar), 144.6 (Ctriazole),
158.2 (Car), 160.0 (Car).
FT-IR (ATR): 3127, 3088, 2996, 2948, 2879, 1590, 1489, 1464,
1438, 1409 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.13 (s, 4 H, ArCH2N), 5.49 (s, 4
H, ArOCH2), 6.56–6.58 (m, 3 H, CHar), 7.16 (t, J = 7.9 Hz, 1 H,
CHar), 7.20–7.36 (m, 4 H, CHar), 7.32–7.35 (m, 4 H, CHar), 7.54 (s,
2 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.6 (ArCH2N), 62.1
(ArOCH2), 102.2 (CHar), 107.7 (CHar), 122.7 (CHtriazole), 129.4 (2 ×
CHar), 129.5 (CHar), 133.0 (CHar), 134.9 (Car), 144.7 (Ctriazole), 159.5
(Car).
HRMS (ESI-TOF): m/z calcd for C17H17N3O2 + H+: 296.1354;
found: 296.1392.
Bis-1,2,3-triazoles Derived from 1,3-Dihydroxybenzene; 4,4′-
[1,3-phenylenebis(oxymethylene)]bis(1-benzyl)-1H-1,2,3-tri-
azole (2a); Typical Procedure
HRMS (ESI-TOF): m/z calcd for C26H22Cl2N6O2 + H+: 521.1215;
found: 521.1254.
To a 20 mL round-bottomed flask equipped with a magnetic stirrer,
were charged Cu(OAc)2·H2O (7 mg, 0.035 mmol, 5 mol%), 1,10-
phenanthroline monohydrate (7 mg, 0.035 mmol, 5 mol%), and so-
dium L-ascorbate (139 mg, 0.70 mmol). After the addition of a mix-
ture of EtOH–H2O (5 mL, 4:1 v/v), the resulting suspension was
stirred for 5 min at r.t. Subsequently, II (130 mg, 0.70 mmol), NaN3
(100 mg, 1.54 mmol), and benzyl chloride (0.18 mL, 1.54 mmol)
were added to the reaction mixture and stirred for 20 h at r.t. H2O (5
mL) was added to the mixture and the precipitate was collected by
filtration, washed thoroughly with H2O, petroleum ether, and dried
under vacuum. The crude product was purified by column chroma-
tography (CH2Cl2–MeOH, 98:2 v/v); yield: 225 mg (71%); white
solid; mp 160–162 °C (Table 2).
4,4′-[1,3-Phenylenebis(oxymethylene)]bis[1-(4-bromobenzyl)]-
1H-1,2,3-triazole (2d)
The procedure described for 2a was followed using 4-bromobenzyl
bromide (1.54 mmol, 385 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 98:2 v/v); yield: 265 mg
(62%); white solid; mp 136–138 °C.
FT-IR (ATR): 3126, 3087, 2945, 2934, 2877, 1591, 1498, 1488,
1464, 1437, 1400, 1382, 1291 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.13 (s, 4 H, ArCH2N), 5.47 (s, 4
H, ArOCH2), 6.56–6.58 (m, 3 H, CHar), 7.12–7.15 (m, 4 H, CHar),
7.16 (t, J = 7.9 Hz, 1 H, CHar), 7.47–7.49 (m, 4 H, CHar), 7.54 (s, 2
H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.6 (ArCH2N), 62.1
(ArOCH2), 102.2 (CHar), 107.7 (CHar), 122.8 (CHtriazole), 123.0
(CHar), 129.8 (CHar), 130.2 (Car), 132.4 (CHar), 133.5 (Car), 144.7
(Ctriazole), 159.5 (Car).
FT-IR (ATR): 3137, 3090, 3030, 3002, 2960, 2924, 2872, 1716,
1593 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.16 (s, 4 H, ArCH2N), 5.54 (s, 4
H, ArOCH2), 6.59–6.61 (m, 3 H, CHar), 7.18 (t, J = 7.8 Hz, 1 H,
CHar), 7.28–7.30 (m, 4 H, CHar), 7.37–7.39 (m, 6 H, CHar), 7.55 (s,
2 H, CHtriazole).
HRMS (ESI-TOF): m/z calcd for C26H22Br2N6O2 + H+: 611.0229;
found: 611.0227.
13C NMR (125.76 MHz, CDCl3): δ = 54.2 (ArCH2N), 62.1
(ArOCH2), 102.1 (CHar), 107.6 (CHar), 122.7 (CHtriazole), 128.1
(CHar), 128.8 (CHar), 129.1 (CHar), 130.0 (CHar), 134.5 (Car), 144.5
(Ctriazole), 159.4 (Car).
HRMS (ESI-TOF): m/z calcd for C26H24N6O2 + H+: 453.1994;
found: 453.2040.
4,4′-[1,3-Phenylenebis(oxymethylene)]bis[1-(4-iodobenzyl)]-
1H-1,2,3-triazole (2e)
The procedure described for 2a was followed using 4-iodobenzyl
bromide (1.54 mmol, 457 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 99:1 v/v); yield: 315 mg
(64%); white solid; mp 158–160 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2431–2437

2436
D. Mendoza-Espinosa et al.
PAPER
FT-IR (ATR) : 3130, 3089, 2955, 2946, 2908, 2872, 1614, 1585,
1484, 1459, 1435, 1402 cm–1.
FT-IR (ATR): 3130, 3079, 3012, 2939, 2873, 1723, 1589, 1518,
1509, 1498, 1458, 1436, 1419, 1403 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.14 (s, 4 H, ArCH2N), 5.46 (s, 4
H, ArOCH2), 6.57–6.59 (m, 3 H, CHar), 7.01 (d, J = 7.9 Hz, 4 H,
CHar), 7.16 (t, J = 7.9 Hz, 1 H, CHar), 7.53 (s, 2 H, CHtriazole), 7.71
(d, J = 7.8 Hz, 4 H, CHar).
13C NMR (125.76 MHz, CDCl3): δ = 53.6 (ArCH2N), 62.1
(ArOCH2), 94.6 (Car), 102.1 (CHar), 107.7 (CHar), 122.6 (CHtriazole),
129.8 (CHar), 130.1 (CHar), 134.1 (Car), 138.3 (CHar), 144.6 (Ctriazole),
159.3 (Car).
1H NMR (500 MHz, CDCl3): δ = 5.07 (s, 6 H, ArCH2N), 5.60 (s, 6
H, CCH2O), 6.31 (s, 3 H, CHar), 7.20 (dd, J = 8.5 Hz, 6 H, CHar),
7.40 (dd, J = 8.5 Hz, 6 H, CHar), 8.27 (s, 3 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 52.0 (ArCH2N), 61.1
(ArOCH2), 94.5 (CHar), 115.5 (d, J = 21.4 Hz, CHar-F), 124.5
(CHtriazole), 130.2 (d, J = 8.8 Hz, CHar-F), 132.1 (d, J = 3.8 Hz, Car-F),
142.8 (Ctriazole), 159.7 (Car), 161.8 (d, J = 246.3 Hz, Car-F).
HRMS (ESI-TOF): m/z calcd for C36H30F3N9O3 + H+: 694.2457;
found: 694.2491.
HRMS (ESI-TOF): m/z calcd for C26H22I2N6O2 + H+: 704.9927;
found: 704.9968.
4-[(3,5-Bis{[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]meth-
oxy}phenoxy)methyl]-1-(4-chlorobenzyl)-1H-1,2,3-triazole (3c)
The procedure described for 3a was followed using 4-chlorobenzyl
bromide (1.39 mmol, 224 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 96:4 v/v); yield: 190 mg
(61%); white solid; mp 155–157 °C.
4,4′-[1,3-Phenylenebis(oxymethylene)]bis[1-(4-methoxyben-
zyl)]-1H-1,2,3-triazole (2f)
The procedure described for 2a was followed using 4-methoxyben-
zyl bromide (1.54 mmol, 241 mg). The crude product was purified
by column chromatography (CH2Cl2–MeOH, 97:3 v/v); yield: 247
mg (69%); white solid; mp 132–134 °C.
FT-IR (ATR): 3129, 3085, 3064, 3029, 2934, 2875, 1724, 1590,
1492, 1455, 1438, 1430 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.08 (s, 6 H, ArCH2N), 5.61 (s, 6
H, CCH2O), 6.31 (s, 3 H, CHar), 7.35 (d, J = 8.5 Hz, 6 H, CHar), 7.43
(d, J = 8.5 Hz, 6 H, CHar), 8.28 (s, 3 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 52.0 (ArCH2N), 61.1
(ArOCH2), 94.6 (CHar), 124.6 (CHtriazole), 128.6 (CHar), 129.8
(CHar), 132.8 (Car), 134.8 (Car), 142.8 (Ctriazole), 159.7 (Car).
FT-IR (ATR): 3293, 3127, 3088, 3003, 2957, 2934, 2878, 2836,
1720, 1592, 1512, 1490, 1463 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.82 (s, 6 H, OCH3), 5.14 (s, 4 H,
ArCH2N), 5.47 (s, 4 H, ArOCH2), 6.58–6.60 (m, 3 H, CHar), 6.92
(d, J = 7.8 Hz, 4 H, CHar), 7.25 (t, J = 7.9 Hz, 1 H, CHar), 7.26 (d,
J = 8.0 Hz, 4 H, CHar), 7.52 (s, 2 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 53.8 (ArCH2N), 55.3 (OCH3),
62.1 (ArOCH2), 102.1 (CHar), 107.6 (CHar), 114.5 (CHar), 122.4
(CHtriazole), 126.4 (CHar), 129.7 (Car), 130.0 (CHar), 144.3 (Ctriazole),
159.5 (Car), 160.0 (Car).
HRMS (ESI-TOF): m/z calcd for C36H30Cl3N9O3 + H+: 744.1586;
found: 744.1589.
HRMS (ESI-TOF): m/z calcd for C28H28N6O4 + H+: 513.2206;
found: 513.2247.
4-[(3,5-Bis{[1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl]meth-
oxy}phenoxy)methyl]-1-(4-bromobenzyl)-1H-1,2,3-triazole(3d)
The procedure described for 3a was followed using 4-bromobenzyl
bromide (1.39 mmol, 347 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 95:5 v/v); yield: 236 mg
(64%); white solid; mp 115–117 °C.
Tris-1,2,3-triazoles Derived from 1,3,5-Trihydroxybenzene; 1-
Benzyl-4-({3,5-bis[(1-benzyl-1H-1,2,3-triazol-4-yl)meth-
oxy]phenoxy}methyl)-1H-1,2,3-triazole (3a); Typical Proce-
dure
FT-IR (ATR): 3139, 3115, 3070, 2931, 2873, 1722, 1593, 1487,
1458, 1432, 1407 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.08 (s, 6 H, ArCH2N), 5.60 (s, 6
H, CCH2O), 6.32 (s, 3 H, CHar), 7.28 (d, J = 8.5 Hz, 6 H, CHar), 7.57
(d, J = 8.5 Hz, 6 H, CHar), 8.28 (s, 3 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 52.0 (ArCH2N), 61.1
(ArOCH2), 94.5 (CHar), 121.4 (Car), 124.6 (CHtriazole), 130.1 (CHar),
131.6 (CHar), 135.3 (Car), 142.8 (Ctriazole), 159.7 (Car).
To a 50 mL round-bottomed flask equipped with a magnetic stirrer,
were charged Cu(OAc)2·H2O (8 mg, 0.042 mmol, 10 mol%), 1,10-
phenanthroline monohydrate (8 mg, 0.042 mmol, 10 mol%), and so-
dium L-ascorbate (166 mg, 0.84 mmol). After the addition of a mix-
ture of EtOH–H2O (10 mL, 4:1 v/v), the resulting suspension was
stirred for 5 min at r.t. Subsequently, III (100 mg (0.42 mmol),
NaN3 (90 mg, 1.39 mmol), and benzyl chloride (0.16 mL, 1.39
mmol) were added to the reaction mixture and stirred for 24 h at r.t.
H2O (10 mL) was added to the mixture and the precipitate was col-
lected by filtration, washed thoroughly with H2O, petroleum ether,
and dried under vacuum. The crude product was purified by column
chromatography (CH2Cl2–MeOH, 96:4 v/v); yield: 154 mg (57%);
white solid; mp 118–120 °C (Table 3).
HRMS (ESI-TOF): m/z calcd for C36H30Br3N9O3 + H+: 878.0059;
found: 878.0076.
4-[(3,5-Bis{[1-(4-iodobenzyl)-1H-1,2,3-triazol-4-yl]meth-
oxy}phenoxy)methyl]-1-(4-iodobenzyl)-1H-1,2,3-triazole (3e)
The procedure described for 3a was followed using 4-iodobenzyl
bromide (1.39 mmol, 413 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 95:5 v/v); yield: 248 mg
(58%); white solid; mp 183–185 °C.
FT-IR (ATR): 3138, 3090, 3065, 3011, 2937, 2875, 1589, 1496,
1456, 1435 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.07 (s, 6 H, ArCH2N), 5.61 (s, 6
H, CCH2O), 6.32 (s, 3 H, CHar), 7.31–7.33 (m, 9 H, CHar), 7.35–
7.37 (m, 6 H, CHar), 8.26 (s, 3 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 52.8 (ArCH2N), 61.1
(ArOCH2), 94.6 (CHar), 124.6 (CHtriazole), 127.8 (CHar), 128.1
(CHar), 128.7 (CHar), 135.9 (Car), 142.8 (Ctriazole), 159.8 (Car).
FT-IR (ATR) : 3137, 3119, 3076, 2933, 2874, 1718, 1677, 1592,
1484, 1458, 1432 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.07 (s, 6 H, ArCH2N), 5.57 (s, 6
H, CCH2O), 6.31 (s, 3 H, CHar), 7.13 (d, J = 8.5 Hz, 6 H, CHar), 7.74
(d, J = 8.5 Hz, 6 H, CHar), 8.26 (s, 3 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 52.2 (ArCH2N), 61.0
(ArOCH2), 94.4 (CHar), 94.5 (Car), 124.6 (CHtriazole), 130.2 (CHar),
135.6 (Car), 137.4 (CHar), 142.8 (Ctriazole), 159.7 (Car).
HRMS (ESI-TOF): m/z calcd for C36H33N9O3 + H+: 640.2740;
found: 640.2779.
4-[(3,5-Bis{[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]meth-
oxy}phenoxy)methyl]-1-(4-fluorobenzyl)-1H-1,2,3-triazole (3b)
The procedure described for 3a was followed using 4-fluorobenzyl
chloride (1.39 mmol, 201 mg). The crude product was purified by
column chromatography (CH2Cl2–MeOH, 95:5 v/v); yield: 160 mg
(55%); white solid; mp 168–170 °C.
HRMS (ESI-TOF): m/z calcd for C36H30I3N9O3 + H+: 1017.9606;
found: 1017.9696.
Synthesis 2013, 45, 2431–2437
© Georg Thieme Verlag Stuttgart · New York

PAPER
Multi-Triazoles Supported by Hydroxybenzene Scaffolds
2437
4-[(3,5-Bis{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]meth-
oxy}phenoxy)methyl]-1-(4-methoxybenzyl)-1H-1,2,3-triazole
(3f)
The procedure described for 3a was followed using 4-methoxyben-
zyl chloride (1.39 mmol, 218 mg). The crude product was purified
by column chromatography (CH2Cl2–MeOH, 97:3 v/v); yield: 150
mg (49%); white solid; mp 112–114 °C.
Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med.
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FT-IR (ATR): 3135, 3092, 3000, 2932, 2836, 1719, 1590, 1511,
1459, 1437 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.73 (s, 9 H, OCH3), 5.06 (s, 6 H,
ArCH2N), 5.52 (s, 6 H, CCH2O), 6.30 (s, 3 H, CHar), 6.92 (d, J = 8.5
Hz, 6 H, CHar), 7.30 (d, J = 8.5 Hz, 6 H, CHar), 8.21 (s, 3 H, CHtriazole).
13C NMR (125.76 MHz, CDCl3): δ = 52.3 (ArCH2N), 55.0 (OCH3),
61.1 (ArOCH2), 94.5 (CHar), 114.0 (CHar), 124.2 (CHtriazole), 127.8
(Car), 129.3 (CHar), 142.7 (Ctriazole), 159.1 (Car), 159.7 (Car).
HRMS (ESI-TOF): m/z calcd for C39H39N9O6 + H+: 730.3057;
found: 730.3103.
Acknowledgment
(11) Wang, Y.; Ji, K.; Lan, S.; Zang, L. Angew. Chem. Int. Ed.
2012, 51, 1915.
(12) Negron-Silva, G. E.; Gonzalez-Olvera, R.; Angeles, Beltran.
D.; Maldonado-Carmona, N.; Espinoza-Vazquez, A.;
Palomar-Pardave, M. E.; Romero-Romo, M. A.; Santillan-
Baca, R. Molecules 2013, 18, 4613.
We are grateful to Consejo Nacional de Ciencia y Tecnología,
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. wish to acknow-
ledge the SNI for the distinction and the stipend received.
(13) Thomas, J. R.; Liu, X.; Hergenrother, P. J. J. Am. Chem. Soc.
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Synthesis 2013, 45, 2431–2437