Sono-transition-metal catalysis of one-pot three-step synthesis of glycosyl-1,2,3-triazoles

Article abstract of DOI:10.1080/00397911.2012.673043

As a continuation of our studies directed at the development of straightforward and sustainable methodologies, we describe herein an original example of a combined effect of ultrasonic activation and iron-copper dual catalysis that allows an efficient and ecofriendly one-pot, three-step route to a new series of nucleoside-substituted triazoles. The reactions were carried out under both conventional and ultrasonic irradiation conditions. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.673043

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Sono-Transition-Metal-Catalysis of One Pot Three-Step
Synthesis of Glycosyl-1,2,3-Triazoles
Mohsine Driowya a b , Khalid Bougrin a & Rachid Benhida b
a Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, Université
Mohammed V-Agdal, Faculté des Sciences B.P., Rabat, Maroc
b Laboratoire de chimie des molécules bioactives et des arômes UMR-CNRS, Université de
Nice-Sophia Antipolis, Parc Valrose, 06108 Nice Cedex, France
Accepted author version posted online: 02 Jan 2013.
To cite this article: Mohsine Driowya , Khalid Bougrin & Rachid Benhida (2013): Sono-Transition-Metal-Catalysis of One
Pot Three-Step Synthesis of Glycosyl-1,2,3-Triazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.673043
To link to this article: http://dx.doi.org/10.1080/00397911.2012.673043
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ACCEPTED MANUSCRIPT
Sono-Transition-Metal-Catalysis of One pot Three-stepSynthesis of glycosyl-1,2,3-
triazoles
Mohsine Driowya1,2, Khalid Bougrin1, Rachid Benhida2
1Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, Université
Mohammed V-Agdal, Faculté des Sciences B.P., Rabat, Maroc, 2Laboratoire de chimie
des molécules bioactives et des arômes UMR-CNRS, Université de Nice-Sophia
Antipolis, Parc Valrose, 06108 Nice Cedex, France.
E-mail: kbougrin@yahoo.fr
Abstract
As a continuation of our studies directed at the development of straightforward and
sustainable methodologies, we describe herein a first and original example of cooperative
effect of ultrasonic activation and iron-copper dual catalysis that allows an efficient and
eco-friendly one pot three-step route to new series of nucleosides substituted triazoles.
The reactions were carried out under both conventional and ultrasonic irradiation
conditions.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: Nucleosides, 1,2,3-triazoles, acetylation, azidation, 1,3-dipolar
cycloaddition, one-pot, ultrasound, iron-copper catalysis
INTRODUCTION
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The Huisgen cycloaddition using azides and alkynes is an important method for the
synthesis of 1,2,3-triazoles.[1] It’s the highest possible atom economy and simple
purification has led to various applications for pharmaceuticals, agrochemicals, polymers,
biochemicals, and functional materials.[2] In general, this cycloaddition reaction requires
harsh conditions and usually leads to a mixture of 1,4- and 1,5-regioisomers.[3] In 2002,
K. B. Sharpless and M. Meldal improved the regioselectivity of the cycloaddition by
Cu(I)-catalyzed ligation (click chemistry) of organic azides and terminal alkynes.[4]
Recently, several examples of Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition
under mild conditions have been described.[5] Most recently, Then, Kacprzak developed
an efficient one-pot method for the synthesis of 1,4-disubstituted-1,2,3-triazoles from
benzyl or alkyl halides, sodium azide, and alkynes in the presence of Cu(I) in DMF.[6]
The glycosylazide derivatives serve as important synthetic precursors in the preparation
of numerous natural and synthetic compounds with significant biological activities.[7] In
addition, these products can be converted to antiviral and anticancer analogues with
nucleosides-based triazole moiety by employing click chemistry,[8] i.e., copper(I)-
catalyzed azide-alkyne [3+2] cycloaddition.[9] Since 1,2,3-triazole nucleosides have
become increasingly useful and important in drugs and pharmaceuticals, the development
of improved methods for their synthesis with structural diversity is highly desirable.
Though there are reports on the synthesis of triazoles from azide via click reaction, the
synthesis of nucleosides-based triazoles still remains a challenge. In addition, analogues
of the purine and pyrimidine nucleosides have been studied extensively as antiviral
agents[10] and a triazole moiety has been used as surrogate of the pyrimidine (or purine)
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ring to give compounds (e.g., A; Fig. 1) which were reported to have both antiviral and
cytotoxic properties.[11] Similar analogues, bearing a good leaving group (B) (Fig. 1),
were synthesized to be used as alkylating agents in cancer chemotherapy.[12]
Thus, Ribavirin (C) (Fig.1) is a synthetic nucleoside endowed with a broad-spectrum of
antiviral activity against many RNA and DNA viruses.[13] It is the unique small molecule
drug currently used for the treatment against hepatitis C virus, in combination with
interferon- -peg. Therefore, the search for more suitable preparation of triazolyl-
nucleosides analogues of ribavirin continues today.
The chemical applications of ultrasound, ‘‘sonochemistry”, have become an exciting field
of research during the past two decades.[14] Compared with conventional methods, the
procedure is more convenient. A large number of organic reactions can be carried out in
higher yield, shorter reaction time and milder conditions under ultrasound irradiation than
at classical conditions.[15] The sonochemical methods are potentially useful in
carbohydrate chemistry.[16] First, the mechanical effect of the acoustic waves improves
heterogeneous reactions of liquid-liquid or liquid-solid systems, e.g., of simple or
polymeric sugars, in terms of smoother experimental conditions reducing the need of
expensive or polluting solvents. Second, due to the easy formation of transient reactive
species (radicals), new transformations can be designed. Earlier data clearly show that
ultrasound irradiation can activate the surface of metal powder and reduce the particle
size, and brings about an effective surface modification. Many metal-involved organic
reactions have been accelerated under ultrasound.[17]
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Sonochemical one-pot multistep (MSP) reactions, present significant advantages over
conventional linear step synthesis by reducing reaction time period and saving money,
energy, and raw materials, thus resulting in both economical and environmental benefits.
One-pot MSP sequential synthetic methods, in which a number of synthetic steps
involving two or more reactants are carried out in the same flask without the isolation of
any intermediate, feature a high degree of reaction mass efficiency and are especially
suitable in diversity oriented synthetic programs. Methods based on ultrasound assisted
multicomponent reactions have proved quite efficient for the construction of different
arrays of heterocyclic compounds. Sonochemical one-pot MSP, indoles via Sonogashira
reaction,[18] carbohydrates chemistry,[16] and others heterocyclic reactions.[19] In our
knowledge, the ultrasound-assisted synthesis of triazolyl-nucleosides has not yet been
reported.[20]
In continuation of our investigations for the development of original methods to
heterocycles,[21] we wish to report an efficient and practical procedure for the synthesis of
nucleosides-1,2,3-triaroles with sugar, Lewis acid, acetic anhydride, TMSN3, copper
iodide and alkyne via one-pot regioselective method (Scheme 1).
RESULTS AND DISCUSSION
Many recent papers describing the use of ultrasound in carbohydrate transformations
pointed out that its use due to enhance the reaction rates, formation of purer products in
high yields, easier manipulation and considered a processing aid in terms of energy
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conservation and waste minimization which compared with traditional methods [15g,
17e-g, 22]. In continuation of our work to develop new and efficient synthetic
methodologies [11a, 23], we envisioned that by fine-tuning the reaction conditions, both
sugar-acyl and azide partners can be generated in situ, which thereafter may undergo
Huisgen’s cycloaddition under the same Lewis acidic condition to make it practically a
four-component reaction. During the course of our investigations on the catalytic
activation of acylation reaction (i), we first attempted the coupling of -D-glucose (1a)
with acetic anhydride in the presence of 10 mol% of various Lewis acids under ultrasonic
irradiation at ambient temperature (Scheme 2) and (Table 1, entries 1-10).
Preliminary results showed that an intense short ultrasonication of the anhydrous FeCl3
powder (10%)[24] sufficed to accelerate the reaction at room temperature under solvent-
free conditions in comparison to magnetically stirring (Table 1, entry 2). The reaction
proceeded efficiently to afford the acylated -D-glucose product 2a in 95% yield. The
best results were also obtained using ZnCl2, FeCl2, SnCl2 and BF3OMe2 (Table 1, entries
1, 3-5), but our reason-based choice of FeCl3 catalyst as an inexpensive, stability and
environmentally friendly Lewis acid. In all the reactions including acylation (entries 1-5)
the yields were very good (> 86%); the nature of metal cation of the catalyst had
negligible effect on the rate as well as the regioselectivity of the reaction (entries 1-4).
The relative proportion of the reactants and the reaction time were also tested and the best
result was obtained by using 5.5 equiv of acetic anhydride, witch plays the dual role of
reagent and solvent in this reaction. Under these mild conditions, the reaction was very
rapid (15 min) and the acylated -D-glucose was obtained in high yield (95%). A larger
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excess of FeCl3 was not required and did not change the results. Other iron(III) salts such
as Fe(acac)3 and Fe(NO3)3 were not so effective for conversions. In contrast, for the
others catalysts (entries 6-10), the conversion rate of the starting sugar is low and
therefore the reaction is incomplete even after several hours of ultrasonication.
In the second step, the ultrasonication was continued until acylated -D-glucose (2a) had
disappeared as indicated by TLC, and transformed to acylated -D-glucose azide (3a) by
addition of TMSN3 under iron catalyst used in the first step with ultrasound irradiation. In
this case, we also observe an evident acceleration of the reaction under ultrasonic
irradiation in comparison to conventional method, and the best results were obtained with
iron (FeCl2 and FeCl3) as catalysts for the azidation (entries 1 and 2). We noticed that a
larger excess of FeCl3 was not required and did not change the results. During the course
of azidation (ii), we have tried to optimise the reaction conditions. When the molar ratio
of acylated -D-glucose and TMSN3 was 1:1, the acylated -D-glucose azide was
obtained in a lower yield. By increasing the molar ratio to 1:2, the yield of product was
increased to 95% (Table 2, entry 2). The second step necessitated an addition of a solvent
in small amount. So, the reaction was carried out in various solvents such as ether,
cyclohexane, toluene and THF and gave only the best results with CH2Cl2. The best result
obtained in CH2Cl2 as hydrophobic solvent; and the mechanical effect of the acoustic
waves improves heterogeneous reactions. The cavitation also accelerates mass transport
and the much easier contact between immiscible or poorly soluble reactants such as -D-
glucose non soluble in the beginning of reaction. Second, due to the easy formation of
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transient reactive species (radicals), we have considered the possible contribution of the
acetyl radical can be produced by ultrasound excitation of acetic anhydride.
The 1,3-dipolar cycloaddition step was carried out using the azido-sugar 3a and the ethyl
propiolate as a model reaction. After optimization of the reaction conditions, the best
results were obtained using alkyne/CuI/DIEA in 2/2/3 molar ratio. Under these
conditions, the cycloadduct 4a [9b] was obtained in high yield under ultrasonication
(84%, 20 min) compared to conventional activation (75% after 120 min, Scheme 3 and
Table 3).
Considering the efficiency of the procedure described above with iron and copper
catalysts, the scope of these transformations was examined with a range of sugars and
alkynes under ultrasound activation (Table 3). Furthermore, to avoid storage and
manipulation of organic azide known for their low stability a one-pot process was
explored. The results are summarized in Table 3.
As shown in the Table 3, all experiments were performed in relatively short global times
(50-190 min) and in good global yields (50-86%). However, some cycloaddition
reactions require a mild heating at 35 °C with ultrasound assisted to complete (entries 3,
5, 7, 9), due to the poor reactivity of the dipolarophiles (alkynes) used. The best results
are obtained with the use of ethyl propiolate as alkyne (entries 1 and 4) for the global
times and yields of 55 min, 84% (entry 1) and 50 min, 86% (entry 4) respectively.
Indeed, the presence of an electron-withdrawing group (CO2Et) facilitates the dipolar
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cycloaddition between the azido-sugar and the alkyne. In contrast, the presence of
electron-donating or bulky groups, such as p-Pr-phenyl and bi-phenyl (entries 3, 5, 7),
reduces partially the efficiency of the click chemistry step and therefore the reactions
times and yields for these tests are between 120-190 min (35°C) and 50-65%
respectively.
Furthermore, no epimerization of the anomeric stereocenter was observed since the
anomeric stereochemistry of all products remained unchanged during this one-pot three-
step process, as attested by 1H NMR and 13C NMR data.
All results clearly show that ultrasonic irradiation accelerates the reactions compared to
the magnetic stirring. Indeed, by classical method the yields are lower to moderate after
two hours of stirring, except for the reactions carried out with ethyl propiolate (entries
1,4). Therefore, the ultrasound can activate the surface of the iron and copper powders
catalysts by reducing the particle size resulting in an efficient modification of the surface,
which enables the catalysts and thus accelerate the reaction. Many metal-involved
organic reactions have been accelerated under ultrasound. In the absence of catalyst, the
reaction failed to give the desired product.
General Procedure For The Synthesis Of Products (4a-J)
To a 1 mmol of sugar 1a-c, 0.1 mmol (16.2 mg) of FeCl3 and 5.5 mmol (0.52 mL) of
Ac2O were added. The reaction mixture was irradiated with ultrasound irradiation at 25
°C for 15 minutes (the reaction mixture became a clear solution), then 2 mmol (0.26 mL)
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of TMSN3 and 5 ml of CH2Cl2 were added to continue the irradiation for 20 minutes.
When the azidation was finished (indicated by TLC), 2 mmol of alkyne, 2 mmol (0.38 g)
of CuI and 3 mmol (0.52 mL) of DIEA were added and the mixture was sonicated further
at room temperature, except for the compounds (4c, 4e, 4g, 4i) in which the
ultrasonication is accompanied by a moderate heating of the ultrasonic bath at 35°C. The
termination of the reaction was monitored by TLC using cyclohexane:AcOEt (1:1) as
eluent. Finally, the reaction was quenched by the addition of CH2Cl2 (50 mL) and sat. aq
NH4Cl (20 mL), the organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (2×20 mL). After that the organic layer was washed with water (20 mL) and
an aqueous solution of saturated brine (20 mL) before dried over MgSO4 and
concentrated in vacuum to give the crude product, which was purified by flash silica gel
chromatography (cyclohexane-EtOAc : 70/30) to afford the pure desired adducts 4a-j.
Complete experimental details are available online in the Supplementary Information.
CONCLUSION
In this work, we have developed a clean, efficient and rapid protocol for the synthesis of
triazolyl-4-substituted nucleosides which may have important biological activities. This
new methodology is based on a one-pot procedure that involves a cooperative effect of
iron-copper catalysis and ultrasound activation starting from available starting materials.
The evaluation of the potential antileukemic effect of these analogues towards the chronic
myelogenous leukemia (CML) K562 cell line, is under investigation.
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ACKNOWLEDGEMENTS
The authors thank Egide for financial support (Action intégrée) and PhD grant to M.
Driowya (Bourse Eiffel). We also thank CNRS, CNRST-Morocco (RS1), MAEE, Région
PACA, ARCUS-CERES, AUF, University of Nice Sophia-Antipolis, and University of
Mohammed V-Agdal for their financial contributions of this work.
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23. (a) Guezguez, R.; Bougrin, K.; El Akri, K.; Benhida, R. Tetrahedron Lett. 2006, 47,
4807-4811. (b) Malnuit, V.; Duca, M.; Manout, A.; Bougrin, K.; Benhida, B. Synlett
2009, 13, 2123-2128.
24. Sharma, G. V. M.; Mahalingam, A. K.; Nagarajan, M.; Llangovan, A.;
Radhakrishna, P. Synlett 1999, 8, 1200-1202.
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Table 1. The effect of catalysts and ultrasound in the acetylation reaction.
Entry a,c
Catalyst
Time
Yield (%)b
Stirring
(min)
Stirring (h)
(min)
)))
)))
1
FeCl2
1.5
15
93
94
2
3
4
5
6
7
8
9
FeCl3
SnCl2
ZnCl2
1
15
20
15
15
30
45
60
45
45
93
87
95
94
43
21
17
25
26
95
86
95
93
68
40
29
38
38
1.5
1.5
1
BF3OMe2
CuCl2
24
48
48
24
24
Cu(OAc)2
CoCl2
NiCl2
10
NiSO4
a catalyst (10 mol%), Ac2O (5.5 equiv.). b yields based on the isolated product. c entries 6-
10 : incomplete reactions.
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Table 2. The effect of catalysts and ultrasound in the azidation reaction.
Entry a
Catalyst
Time
Yield (%)b
Siirring(h)
(min)
Siirring(h)
))) (min)
)))
1
2
FeCl2
3
25
20
76
92
95
FeCl3
SnCl2
ZnCl2
2.5
78
3
4
5
3
3
2
25
25
20
70
74
88
72
78
87
BF3OMe2
a catalyst (10 mol%), TMSN3 (2 equiv.).
b yields based on the isolated product.
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Table 3. Extension of the one-pot three-step reaction by ultrasonication.
Entry Sugar
Alkyne
Product
Time (min)b
55
Yield (%)b
84[9b]
a
CO2Et
1
2
80
77[9b]
56
3c
120
O
OH
OH
HO
CO2Et
4
50
86
53
76
50
64
HO
O
OH
OH
5c
120
70
HO
HO
O
OH
OH
HO
6
HO
O
OH
OH
7c
190
100
N
N
N
HO
O
AcO
HO
4g
AcO
OAc
O
OH
OH
HO
8
HO
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O
OH
9c
120
75
65
78
HO
HO
OH
O
OH
10d
HO
HO
a Ac2O (5.5 equiv.), FeCl3 (10 mol%), TMSN3 (2 equiv.), Alcyne/CuI/DIEA (2:2:3). b
global times and yields (yields based on the isolated product). c heating of click chemistry
step (35 °C). d
/
.
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Figure 1.
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Scheme 1.
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20

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Scheme 2.
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Scheme 3.
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