The use of glucose as alternative reducing agent in copper-catalyzed alkyne-azide cycloaddition

Article abstract of DOI:10.2174/157017811799304232

1,2,3-triazoles were synthesized using several alkynes and azides as starting materials in the presence of glucose and catalytic amounts of Fehling reagent. This process is carried out under ambient pressure and temperature with good yields.

Full text of DOI:10.2174/157017811799304232

Letters in Organic Chemistry, 2011, 8, 701-706
701
The Use of Glucose as Alternative Reducing Agent in Copper-Catalyzed
Alkyne-Azide Cycloaddition
Marco A. García, Zita G. Ríos, Jaime González, Víctor M. Pérez, Nancy Lara, Aydeé Fuentes,
Carlos González, David Corona and Erick Cuevas-Yañez*
Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM. Carretera Toluca-Atlacomulco Km 14.5.
Toluca, 52000, México
Received May 05, 2011: Revised August 19, 2011: Accepted August 19, 2011
Abstract: 1,2,3-triazoles were synthesized using several alkynes and azides as starting materials in the presence of
glucose and catalytic amounts of Fehling reagent. This process is carried out under ambient pressure and temperature with
good yields.
Keywords: Alkynes, azides, Fehling reagent, glucose, 1,2,3-triazoles.
Copper-catalyzed Alkyne-azide cycloaddition (CuAAC)
is the most used “click” reaction and one of the most
important ligation methods developed in the 21st century [1,
2]. This reaction offers the best method to obtain 1,4-
reducing sugars [6]. This reaction is widely used as an
identification test. However, as far we know, this process has
not been used like a source of copper (I) for catalysis.
Motivated by these facts, we decided to investigate the
feasibility of this idea and its possible application in
CuAAC. Herein is described a summary of our recent
endeavours in this area.
disubstituted-1,2,3-triazoles
which
have
interesting
biological activities [3]. One of the advantages of CuAAC is
the combination of mild conditions with high yields and
regioselectivities, together with high efficiency in terms of
atom economy.
In a model study, benzyl azide 2, which in turn was
prepared from benzyl chloride and sodium azide, was reacted
with phenylacetylene 1 at room temperature using a catalytic
system which was prepared in situ by successive addition of
glucose, tartrate-NaOH solution (Fehling A Solution), and
CuSO4 solution (Fehling B solution) [7]. After 2 h, a mixture
of triazole 3, and bistriazole 4 was obtained. This behaviour
The most used protocols to perform this kind of reactions
were developed by the groups of Meldal [4] and Sharpless-
Fokin [5]. Although both procedures are widespread in
application, research and developing in new copper catalysts
are important.
N
N
N
N
N
Ph
Glucose
N
Ph
+
+
Ph
N3
CuSO4
Ph
N
Ph
1
2
Tartarte-NaOH
3
N
N
MeOH-H2O
4
Scheme 1. Cu- catalyzed cycloaddition between azide 2 and alkyne 1.
In connection with other projects, some time ago we
initiated the studies on the synthesis of 1,2,3-triazoles by
CuAAC, focused on searching alternative catalytic systems,
more economical and compatible to the environment.
Inspired by the preceding works of Sharpless and Fokin [5],
we sought alternative copper bioreductants which were
suitable for click reaction.
has been observed by Angell and Burgess using diverse
inorganic bases as additives [8]. On the other hand, when the
reaction time was extended to 24 h, only triazole 3 was
obtained.
In addition, we prepared a study about the role of the
glucose concentration in the Click reaction. In previous
works with sodium ascorbate, the group of Sharpless and
Fokin discovered a significant influence between the amount
of sodium ascorbate and the reaction yield, and they realized
that this reaction proceeds with an excess of sodium
ascorbate to keep the Cu(I) ion in the reaction, which is the
catalytic species in this process. With this precedent, several
experiments were carried out using different concentrations
In this regard, we were attracted by the Fehling reaction,
a process where a copper (II) tartrate complex is reduced by
*Address correspondence to this author at the Facultad de Química,
Universidad Autónoma del Estado de México; Tel: +52 722 217 38 90 and
+52 722 276 66 11; Fax: +52 722217 51 09; E-mail: ecuevasy@uaemex.mx
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

702 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
García et al.
of glucose (Table 1). From these results, it was observed that
the amount of glucose is important, and the best results were
obtained using 0.25 molar equivalents of glucose, increasing
the yield to 79.5%.
and some reaction conditions in order to develop a selective
procedure for the synthesis of triazoles or bistriazoles.
In conclusion, this report shows that 1,2,3- triazoles are
efficiently synthesized from the appropriately constituted
alkynes and azides using a catalytic system prepared from
Fehling reagent and glucose. This procedure represents an
alternative and inexpensive methodology to obtain triazolyl
compounds, which are useful points of departure enroute to
novel libraries and compounds with triazole moiety. These
elements suggest a widespread application.
Table 1. Effect of Glucose in 1,2,3-triazole Formation
Entry
mmol glucose / mmol alkyne
% Yield
1
2
3
4
5
6
0.05
0.10
0.15
0.20
0.25
0.30
56
59.4
71.9
75
EXPERIMENTAL
79.5
78
The starting materials were purchased from Aldrich
Chemical Co. and were used without further purification.
The organic azides were prepared according to the literature
[10-12]. Solvents were distilled before use. The tartrate-
NaOH solution (Fehling B solution) was prepared dissolving
sodium hydroxide (23.5g, 0.04 mol), tartaric acid ( 18.3 g,
0.012 mol ) in H2O (100 mL). The CuSO4 solution (Fehling
On the other hand, the influence of the concentration of
basic tartrate/NaOH solution was analyzed. Burgess [8]
found a dependence of the base concentration in alkyne-
azide cycloaddition, which occurs in alkaline conditions.
Therefore, several experiments were made using different
volumes of solution of sodium tartrate/NaOH (Table 2), in
order to find the best reaction conditions. A noteworthy
feature is that using 0.1 mL of the solution/mmol alkyne, the
reaction yield was increased to 95% (see Table 2, entry 10).
The tartrate/NaOH solution is important in this process,
because it provides a buffer which stabilizes the cuprous ion
in solution.
.
A solution) was prepared dissolving CuSO4 5H2O (9.89g,
0.039 mol) in H2O (100 mL). Silica gel (230–400 mesh) was
purchased from Merck. Silica plates of 0.20 mm thickness
were used for thin layer chromatography. Melting points
were determined with a Fischer-Johns Scientific melting
1
point apparatus and they are uncorrected. H and 13C NMR
spectra were recorded using a Varian 500 MHz, The
chemical shifts (ꢀ) are given in ppm relative to TMS as
internal standard (0.00). For analytical purposes the mass
spectra were recorded on a JEOL JMS-5X 10217 in the EI
mode, 70 eV, 200 °C via direct inlet probe. Only the
molecular and parent ions (m/z) were reported. IR spectra
were recorded on a Nicolet Magna 55-X FT instrument.
Table 2. Effect of Tartrate-NaOH Solution in 1,2,3-triazole
Formation
Entry
ml tartrate-NaOH / mmol alkyne
% Yield
For the RX difraction studies, crystals of compound 1-
Benzyl-4-p-tolyloxymethyl-[1,2,3]triazole (entry 6, Table 3),
were obtained by slow evaporation of a dilute EtOH
solution, and the reflections were acquired with a Bruker
difractometer. Three standard reflections every 97 reflections
were used to monitor the crystal stability. The structure was
solved by direct methods; missing atoms were found by
difference-Fourier synthesis, and refined on F2 by a full-
1
2
3
4
5
0.025
0.05
78
81
88
95
93
0.075
0.10
0.15
matrix
least-squares
procedure
using
anisotropic
In order to explore the reaction scope, several triazoles
were synthesized using diverse alkynes and azides (Table 3).
The results show that 1,2,3-triazoles are major products and ,
in many cases, the only products. However, in some cases
(entries 1,6), the presence of bistriazole was also noted. In
these examples, the yields were not higher than 20%.
displacement parameters using SHELX-97. Crystallographic
data for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
(CCDC No. 841826 ). Copies of available materials can be
obtained free of charge on application to the Director,
CCDC, 12 Union Road, Cambridge CB2 IEZ, UK
(facsimile: (44) 01223 336033); e-mail: deposit@ccdc.ac.uk.
All compounds were fully characterized by conventional
spectroscopic techniques, and 1-Benzyl-4-p-tolyloxymethyl-
[1,2,3]triazole (entry 6, Table 3) was obtained as a
crystalline solid which was studied by X-ray crystallography,
confirming the proposed structure for this compound (Fig.
1).
Synthesis of 1,2,3-triazoles catalyzed by glucose-Fehling
Reagent
Typical procedure. The corresponding azide (1 mmol)
and alkyne (1 mmol) were added to a solution of glucose
(0.045g, 0.25 mmol) in H2O (1 mL) and MeOH (5 mL). The
mixture was treated successively with tartrate-NaOH
solution (Fehling B solution, 0.1 mL) and CuSO4 solution
(Fehling A solution, 0.25 mL, 0.1 mmol). The resulting
mixture was stirred at room temperature for 24 h. The
solvent was removed in vacuo and the final product was
Furthermore, we found that certain alkynes and azides
gave exclusively bistriazoles, whereas triazoles were not
detected. This kind of compounds might be obtained by an
oxidative process; such as Angell and Burgess have
proposed, however, the mechanistic details are not already
clear [8]. Currently, our group is studying the mechanism

The Use of Glucose as Alternative Reducing Agent
Letters in Organic Chemistry, 2011, Vol. 8, No. 10
703
Table 3. Triazoles Synthesized from Alkynes and Azides Using Catalytic Fehling-Glucose
R2
R1
N
N
N
N
N
Glucose
R1
N
R2 N3
N
R1
R2
N
+
+
N
CuSO4
R1
R2
Tartarte-NaOH
MeOH-H2O
triazole
Entry
% triazole
% bistriazole
N
1
95
2
N
N
N
N
2
57
--
N
O
O
O
O
O
N
N
O
3
4
5
6
80
53
89
72
--
--
N
N
N
Br
N
N
N
--
Cl
N
N
20
N
O
N
O
N
O
N
7
8
N
70
47
--
--
N
H
N
N
N
N
OH
N
N
9
73
65
--
--
N
O
N
N
N
10
Cl

704 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
García et al.
Fig. (1). ORTEP representation for triazole in entry 6, Table 3.
Table 4. Bistriazoles Synthesized from Alkynes and Azides Using Catalytic Fehling-Glucose
Bistriazole
Entry
% Yield
Cl
O
N
N
O
N
N
O
1
35
O
N
O
N
O
Cl
Cl
N
N
N
O
2
16
O
N
N
N
Cl
N
N
N
N
3
53
N
N
N
N
purified by crystallization or column chromatography (SiO2,
hexane/AcOEt 8:2).
MS [EI+] m/z (%) 235 [M]+ (20), 206 [M -HN2]+ (50), 116
[M - C7H7N2]+ (100), 91 [C6H5CH2]+ (85) .
1-Benzyl-4-phenyl-1,2,3-triazole (3)
3,3'- Dibenzyl -5, 5'- diphenyl - 3H, 3'H-[4,4'] bi [[1,2,3
triazolyl] (4)
White solid, mp. 65ºC (MeOH).8 IR (KBr): ꢀ= 1220,
1350, 1450, 3100 cm-1. 1H NMR (CDCl3, 500 MHz) ꢁ 7.45
(m, 4H), 7.28-7.20 (m, 6H), 7.14 (m, 2H), 7.09 (m, 4H), 6.81
(d, 4H, J = 8.0 Hz), 4.70 (d, 2H, J = 14.5 Hz), 4.64 (d, 2H, J
White solid; mp 130°C (lit. 130-130.9ºC);9 IR (KBr): ꢀ=
1220, 1350, 1450, 3100 cm-1. 1H NMR (CDCl3, 500 MHz) ꢁ
7.79 (m, 2H), 7.69 (s, 1H), 7.40-7.35 (m, 3H), 7.32-7.29 (m,
5H), 5.56 (s,2H); 13C NMR (CDCl3, 125 MHz) ꢁ 148.0,
134.5, 130.4, 128.9, 128.6, 128.6, 128.0, 127.9, 125.5, 54.0.

The Use of Glucose as Alternative Reducing Agent
Letters in Organic Chemistry, 2011, Vol. 8, No. 10
705
= 14.5 Hz); 13C NMR (CDCl3, 125 MHz) ꢀ 147.8, 132.9,
129.2, 128.9, 128.8, 128.7, 128.7, 128.1, 125.8, 119.8, 52.6.
MS [EI+] m/z (%) 468 [M]+ (40), 349 [M - C7H7N2]+ (35),
321 [M - C7H7N4]+ (35), 91 [C6H5CH2]+ (100).
144.9, 134.5, 129.9, 129.1, 128.8, 128.1, 122.4, 114.6, 62.2,
54.2, 20.4. MS [EI+] m/z (%) 279 [M]+ (40), 144 [M –
C7H7N2O]+ (70), 91 [C6H5CH2]+ (100). HRMS (EI+): for
C17H17N3O calcd. 279.1372, found 279.1377.
1-Benzyl-4-(4-methoxy-phenoxymethyl)-[1,2,3]triazole
(entry 2, Table 3)
Crystal data: formula: C17H17N3O; FW 279.34; crystal
system: Orthorhombic; space group: P212121; temp,
K=296(2); ꢀ, Å=1.54178; Unit cell dimensions a,
Å=5.7275(6); b, Å=8.1375(8); c, Å= 32.067(3); ꢁ, deg= 90;
ꢂ, deg= 90; ꢃ, deg= 90; V, Å3=1494.6(3); Z=4; ꢄcalcld., g·cm–
3=1.241; μ, mm–1=0.632; F(000)= 592; crystal size, mm3=0.2
x 0.05 x 0.05; ꢅ range for data collection, deg= 2.76 to
66.37; index ranges: – 6 ꢂ h ꢂ 5, – 9 ꢂ k ꢂ 9, – 37 ꢂ l ꢂ 38;
Reflections collected: 14063; Independent reflections (Rint)=
2582 (0.0287); no. of data / restraints / parameters=2582 / 0 /
190; GoF on F2=1.073; Final R indices [I>2ꢃ(I)] R1=0.0300,
wR2=, 0.0817; R1, wR2 (all data): 0.0303, 0.0820; largest diff.
peak / hole, e·Å–3=0.107 / –0.109.
m.p. 78°C (MeOH). IR (KBr, cm) ꢁ= 1508, 1458, 1228
1
cm-1. H-NMR (CDCl3, 300 MHz) ꢀ 7.49 (s, 1H), 7.33(m,
5H), 6.89 (d, 2H, J=8.5Hz), 6.78 (d, 2H, J=8.5Hz), 5.47 (s,
2H), 5.10 (s, 2H),3.76 (s, 3H). 13C-NMR (CDCl3, 75 MHz) ꢀ
ppm: 154.5, 154.2, 144.8, 129.1, 128.7, 128.0, 122.6, 116.1,
134.5, 115.9, 114.6, 62.8, 56.5, 55.5. MS [EI+] m/z (%): 295
[M]+ (20), 144 [M – C7H7N2O2]+ (35), 123 [M – C9H8N3]+
(100), 91 [C6H5CH2]+ (50). HRMS (EI+): for C17H17N3O2
calcd. 295.1321, found 295.1325.
4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethoxy)-benzaldehyde
(entry 3, Table 3)
In addition, the reaction afforded 3,3'-Dibenzyl-5,5'-bis-
p-tolyloxymethyl-3H,3'H-[4,4']bi[[1,2,3]triazolyl] as a White
solid (20%); 56-57°C (MeOH). IR (KBr): ꢁ = 1260, 1300,
White solid (80%); mp 79-80 °C (MeOH). IR (KBr): ꢁ=
1252, 1508, 1680 cm-1. 1H NMR (CDCl3, 500 MHz) ꢀ
9.89(s, 1H), 7.83 (d, 2H, J= 8 Hz), 7.80 (m, 2H), 7.58(s, 1H),
7.36 (m, 3H), 7.08(d, 2H, J= 8 Hz), 5.53 (s, 2H), 5.25 (s,
2H). 13C NMR (CDCl3, 125 MHz) ꢀ 190.7, 163.14, 163.1,
143.5, 134.3, 130.3, 129.1, 128.9, 128.0, 122.9, 115.1, 62.1,
55.9. MS [EI+] m/z 293 [M]+ (10), 172 [M - C7H9N2]+ (75),
144 [M – C7H7N2O]+ (80), 91 [C6H5CH2]+ (100). HRMS
(EI+): for C17H15N3O2 calcd. 293.1164, found 293.1165.
1
1560, 3125 cm-1. H NMR (CDCl3, 500 MHz) ꢀ 7.27 (m,
6H), 6.96 (d, 4H), 6.88 (d, 4H), 6.49 (m, 4H), 4.96 (d, 2H),
4.55 (d, 2H), 4.49 (d, 2H), 4.30 (d, 2H), 2.24 (s, 6H). 13C
NMR (CDCl3, 125 MHz) ꢀ 155.5, 146.0, 138.8, 130.6,
129.8, 129.0, 128.9, 128.1, 114.2, 60.9, 52.5, 20.4. [EI+] m/z
(%) 556 [M]+ (10), 91 [C6H5CH2]+ (100). HRMS (EI+): for
C34H32N6O2 calcd. 556.2587, found 556.2590.
1-Benzyl-4-(4-bromo-phenoxymethyl)-1H-[1,2,3]triazole
(entry 4, Table 3)
(1-Benzyl-1,2,3-triazol-4-yl)methyl butylcarbamate (entry 7,
Table 3)
White solid (53%); mp 109-111 °C(MeOH). IR (KBr):
White solid (43%); mp 82-83°C (MeOH). IR (KBr): ꢁ =
1536, 1610, 1710, 2954 cm-1. 1H NMR (CDCl3, 500 MHz) ꢀ
7.99 (s, 1H), 7.28-7.41 (m, 5H), 7.26 (s, 2H), 5.54 (s, 1H,
NH), 5.22 (s, 2H), 4.59 (s, 2H), 3.15 (m 2H),1.44 (m, 2H),
1.25 (m, 2H), 0.86 (t, 3H). 13C NMR (CDCl3, 125 MHz) ꢀ
156.2, 143.9, 134.6, 129.7, 128.5, 127.9, 120.4, 57.6, 52.9,
40.7, 31.9, 19.8, 13.7. MS [EI+] m/z (%) 288 [M]+ (10), 144
[M – C5H10N3O2]+ (20), 91 [C6H5CH2]+ (100). HRMS (EI+):
for C15H20N4O2 calcd. 288.1586, found 288.1583.
1
ꢁ= 1241, 1491, 1601, 3080, cm-1. H NMR (CDCl3, 500
MHz) ꢀ 7.52 (s, 1H), 7.37 (m, 2H), 7.28 (m, 2H), 7.19 (m,
1H), 6.93 (m, 2H), 6.84 (m, 2H), 5.54 (s, 2H), 5.16 (s, 2H).
13C NMR (CDCl3, 125 MHz) ꢀ 158.8, 144.0, 134.8, 134.3,
130.2, 129.1, 128.8, 128.1, 122.6, 121.4, 115.4, 113.1, 62.2,
54.2. MS [EI+] m/z 345 [M+2]+ (5), 343 [M]+ (5), 172 [M-
C6H4BrO]+ (15), 144 [M-C8H8BrO]+ (65), 91 [C6H5CH2]+
(100). HRMS (EI+): for C16H14BrN3O calcd. 343.0320,
found 343.0324.
(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-dibutyl-amine
(entry 8, Table 3)
1-benzyl-4-(4´-chlorophenoxymethyl)-1,2,3-triazole (entry
5, Table 3)
White solid (65%); mp 66-67°C °C (MeOH). IR (KBr): ꢁ
= 1577, 1473, 1276 cm-1. 1H NMR (CDCl3, 500 MHz) ꢀ 7.6
(s, 1H), 7.26-7.47 (m, 5H), 5.52 (s, 2H), 3.8 (s, 2H), 2.5 (s,
4H), 1.5 (m, 4H), 1.26 (m, 4H), 0.89 (t, 6H). 13C NMR
(CDCl3, 125 MHz) ꢀ 134.7, 132.4, 129.1, 129.0, 128.9,
127.9, 58.5, 54.1, 52.8, 27.9, 20.4,13.9. MS [EI+] m/z
(%)300 [M]+ (5), 257 [M-C3H7]+ (45), 144 [M-C10H21N]+
(45), 91 [M-C11H21N4]+ (100), 73 [M-C14H17N3]+ (65).
HRMS (EI+): for C18H28N4 calcd. 300.2314, found 300.2319.
White solid (82%); mp 102-103°C(MeOH). IR (KBr): ꢁ=
1241, 1491, 1599, 3083, cm-1. 1H NMR (CDCl3, 500 MHz) ꢀ
7.52 (s, 1H), 7.37 (m, 2H), 7.28 (m, 2H), 7.19 (m, 1H), 6.93
(m, 2H), 6.84 (m, 2H), 5.54 (s, 2H), 5.16 (s, 2H), 13C NMR
(CDCl3, 125 MHz) ꢀ 158.8, 144.0, 134.8, 134.3, 130.2,
129.1, 128.8, 128.1, 122.6, 121.4, 115.4, 113.1, 62.2, 54.2.
MS [EI+] m/z (%) 301 [M +2]+ (5), 299 [M]+ (15), 144 [M –
C6H4ClN2O]+ (50), 91 [C6H5CH2]+ (100). HRMS (EI+): for
C16H14ClN3O calcd. 299.0825, found 299.0827.
(1-Benzyl-[1,2,3]triazol-4-yl)-methanol (entry 9, Table 3)
1-Benzyl-4-p-tolyloxymethyl-[1,2,3]triazole (entry 6, Table
3)
White solid (73%); mp 76-77°C (lit. 76-77°C);10 IR
1
(KBr): ꢁ = 1276, 1475, 1572, 3330 cm-1 . H NMR (CDCl3,
White solid (75%); mp 92-93°C (MeOH). IR (KBr): ꢁ =
1572, 1475, 1276 cm-1. 1H NMR (CDCl3, 500 MHz) ꢀ
7.51(s, 1H), 7.36 (d, 2H, J=8 Hz), 7.26 (d, 2H, J=8 Hz), 7.06
(d, 2H, J=8 Hz), 6.84 (d, 2H, J=8 Hz), 5.52(s, 2H), 5.15 (s,
2H), 2.27 (s, 3H). 13C NMR (CDCl3, 125 MHz) ꢀ 156.1,
500 MHz) ꢀ 7.47(s, 1H), 7.32 (m, 3H), 7.21 (m, 2H), 5.44(s,
2H), 4.68 (s, 2H). 13C NMR (CDCl3, 125 MHz) ꢀ 148.3,
134.5, 129.0, 128.7, 128.0, 121.9, 55.9, 54.0. MS [EI+] m/z
(%) 189 [M]+ (40), 91 [C6H5CH2]+ (100).

706 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
García et al.
1-(3-Chloro-benzyl)-4-p-tolyloxymethyl-[1,2,3]triazole
(entry 10, Table 3)
(m, 2H), 2.66 (m, 2), 2.41 (m, 2H), 2.10 (m, 4H). 13C NMR
(CDCl3, 125 MHz) ꢁ 148.3, 134.6, 128.9, 128.0, 127.6,
121.1, 119.3, 52.9, 23.9, 16.49. MS [EI]+ m/z (%):450 [M]+
(5), 91 [M-C6H5CH2]+ (100). HRMS (EI+): for C26H26N8
calcd. 450.5382, found 450.5388.
White solid (65%); mp 67-69 °C(MeOH). IR (KBr): ꢀ =
1
1276, 1471, 1577 cm-1 . H NMR (CDCl3, 500 MHz) ꢁ 7.54
(s, 1H), 7.31 (m, 3H), 7.14 (dt, 1H), 7.06 (d, 2H), 6.85 (d,
2H), 5.49 (s, 2H), 5.14 (s, 2H), 2.27 (s, 3H). 13C NMR
(CDCl3, 125 MHz) ꢁ 156.0, 145.1, 136.4, 135.1, 130.6,
130.4, 129.9, 129.3, 128.1, 126.1, 122.5, 114.6, 62.2, 53.5,
20.9. MS [EI+] m/z (%) 315 [M+2]+ (10), 313 [M]+ (30),
178 [M – C8H8N3]+ (80), 125 [M – C10H10N3O]+ (100).
HRMS (EI+): for C17H16ClN3O calcd. 313.0982, found
313.0986.
ACKNOWLEDGEMENTS
Financial support from CONACYT (No. 84390) is
gratefully acknowledged. The authors would like to thank
Signa, S.A. de C.V. for some graciously donated solvents
and reagents, to Dr. Vojtech Jancik, and Dr. Marisol Reyes
(CCIQS UAEM-UNAM) for RX studies and M. C. Nieves
Zavala for the technical support.
Synthesis of Bistriazoles Catalyzed by Glucose-Fehling
Reagent
REFERENCES
Typical procedure. The corresponding azide (1 mmol)
and alkyne (1 mmol) were added to a solution of glucose
(0.045g, 0.25 mmol) in H2O (1 mL) and MeOH (5 mL). The
mixture was treated successively with tartrate-NaOH
solution (Fehling B solution, 0.1 mL) and CuSO4 solution
(Fehling A solution, 0.25 mL, 0.1 mmol). The resulting
mixture was stirred at room temperature for 48 h. The
solvent was removed in vacuo and the final product was
purified by column chromatography (SiO2, hexane/AcOEt
8:2).
[1]
Meldal, M.; Tornoe, C. W. Cu-Catalyzed Azide-Alkyne
Cycloaddition. Chem. Rev. 2008, 108, 2952-3015.
[2]
Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. CuI-Catalyzed
Alkyne–Azide “Click” Cycloadditions from a Mechanistic and
Synthetic Perspective. Eur. J. Org. Chem. 2005, 51-68.
Kolb, H. C.; Sharpless, K. B. The growing impact of click
chemistry on drug discovery. Drug Discovery Today 2003, 8, 1128-
1137.
[3]
[4]
Tornoe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on
Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-
Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to
Azides. J. Org. Chem. 2002, 67, 3057-3064.
[5]
[6]
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A
Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed
Regioselective Ligation of Azides and Terminal Alkynes. Angew.
Chem. Int. Ed. 2002, 41, 2596-2599.
Fehling, H. Die quantitative Bestimmung von Zucker und
Stärkmehl mittelst Kupfervitriol. Liebigs Ann. Chem. 1849, 72,
106-113.
Malherbe, J. S.; Meyer, C. J. A Mini-Qualitative Carbohydrate
Analysis Session. J. Chem. Educ. 1997, 74, 1304-1305.
Angell, Y.; Burgess, K. Base Dependence in Copper-Catalyzed
Huisgen Reactions: Efficient Formation of Bistriazoles. Angew.
Chem. Int. Ed. 2007, 46, 3649-3641.
Gallardo,H.; Conte,G.; Bryk, F.; Lourenço, M. C. S.; Costac, M. S.;
Ferreira, V. F. Synthesis and Evaluation of 1-Alkyl-4-phenyl-
[1,2,3]-triazole Derivatives as Antimycobacterial Agent. J. Braz.
Chem. Soc. 2007, 18, 1285-1291.
5,5'-Bis-(4-chloro-phenoxymethyl)-3,3'-bis-(2,3-dimethoxy-
benzyl)-3H,3'H-[4,4']bi[[1,2,3]triazolyl] (entry 1, Table 4)
White solid (35%); mp 103-104°C (AcOEt). IR (KBr): ꢀ
1
= 1276, 1470, 1577 cm-1 . H NMR (CDCl3, 500 MHz) ꢁ 7-
7.2 (m, 8H), 6.8-6.99 (m, 8H), 5.59 (d, 4H), 5.07 (d, 4H),
3.84 (d, 6H), 3.80 (d, 6H). 13C NMR (CDCl3, 125 MHz) ꢁ
158.0, 152.1, 146.5, 143.1, 134.0, 131.8, 130.5, 127.7, 120.5,
115.6, 112.1, 61.8, 58.3, 55.5, 48.9. MS [FAB]+ m/z (%):
718 [M+1]+ (1), 360 [M-C18H17ClN3O3]+ (40), 151 [M-
C27H23Cl2N6O4]+ (100). (100). HRMS (FAB+): for
C36H35Cl2N6O6 calcd. 717.1995, found 717.1999.
[7]
[8]
[9]
3,3'-Bis-(4-chloro-benzyl)-5,5'-bis-p-tolyloxymethyl-
3H,3'H-[4,4']bi[[1,2,3]triazolyl] (entry 2, Table 4)
[10]
de las Heras, F. G.; Alonso, R.; Alonso, G. Alkylating Nucleosides
1. Synthesis and Cytostatic Activity of N-Glycosyl(halomethyl)-
1,2,3-triazoles. A New Type of Alkylating Agent. J. Med. Chem.
1979, 22, 496-501.
White solid (16%); mp 109-110°C (AcOEt). IR (KBr): ꢀ
1
= 1276, 1473, 1577 cm-1. H NMR (CDCl3, 500 MHz) ꢁ 7-
[11]
[12]
Zhu, W.; Ma, D. Synthesis of aryl azides and vinyl azides via
7.2 (m, 8H), 6.8-6.99 (m, 8H), 5.59 (d, 4H), 5.07 (d, 4H),
3.84 (d, 6H), 3.8 (d, 6H).13C NMR (CDCl3, 125 MHz) ꢁ
155.3, 145.7, 135.0, 132.0, 130.8, 130.5, 129.4, 129.2, 122.2,
114.1, , 61.1, 51.7, 20.4. MS [FAB]+ m/z (%): 625 [M+1]+
(25), 517 [M-C7H7O]+ (30), 154 [M-C27H24ClN4O2]+ (65),
125 [M-C27H24ClN602]+ (100).HRMS (FAB+): for
C34H31Cl2N6O2 calcd. 625.1886, found 625.1888.
proline-promoted CuI-catalyzed coupling reactions.
Chem,
Commun. 2004, 888.
Liu, Q.; Yitzhac, T. Simple Conversion of Aromatic Amines into
Azides. Org. Lett. 2003, 5, 2571.
4-[3,3'-Dibenzyl-5'-(3-cyano-propyl)-3H,3'H-[4,4']bi
[[1,2,3]triazolyl]-5-yl]-butyronitrile (entry 3, Table 4)
White solid (53%); mp 56-57°C (AcOEt). IR (KBr): ꢀ =
1370, 1660, 2220, 3095 cm-1. 1H NMR (CDCl3, 500 MHz) ꢁ
7.37 (m, 6H), 7.26 (m, 4H), 5.52 (d, 4H), 3.07 (m, 2H), 2.87