Iron(III) chloride catalyzed glycosylation of peracylated sugars with allyl/alkynyl alcohols

Article abstract of DOI:10.1590/S0103-50532012005000070

In this work, the use of ferric chloride as an efficient catalyst in glycosylation reactions of sugars in the presence of allyl and alkynyl alcohols is described. The corresponding glycosides were obtained with moderate to good yields. This new procedure presented greater selectivity when compared to classic methods found in the literature. Principal features of this simple method include non-hazardous reaction conditions, low-catalyst loading, good yields and high anomeric selectivity.

Full text of DOI:10.1590/S0103-50532012005000070

J. Braz. Chem. Soc., Vol. 23, No. 11, 1982-1988, 2012.
Printed in Brazil - ©2012 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
A
Iron(III) Chloride Catalyzed Glycosylation of Peracylated Sugars
with Allyl/Alkynyl Alcohols
Senthil Narayanaperumal, Rodrigo César da Silva, Julia L. Monteiro,
Arlene G. Corrêa and Márcio W. Paixão*
Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos-SP, Brazil
Neste trabalho, o emprego de cloreto férrico como um eficiente catalisador em reações de
glicosilação de açúcares na presença de álcoois alílicos e propargílicos é descrito. Os glicosídios
correspondentes foram obtidos com rendimentos de moderados a bons. Este novo procedimento
apresenta maior seletividade quando comparado a métodos clássicos encontrados na literatura.
As principais características desse método simples incluem condições de reação não perigosas,
quantidade de catalisador baixa, bom rendimento e seletividade anomérico elevada.
In this work, the use of ferric chloride as an efficient catalyst in glycosylation reactions of
sugars in the presence of allyl and alkynyl alcohols is described. The corresponding glycosides
were obtained with moderate to good yields. This new procedure presented greater selectivity
when compared to classic methods found in the literature. Principal features of this simple
method include non-hazardous reaction conditions, low-catalyst loading, good yields and high
anomeric selectivity.
Keywords: glycosylation, iron(III) chloride, stereoselective, carbohydrate, green chemistry
Introduction
HClO4-SiO2,6 InCl3/IBX (iodoxybenzoic acid),7 InBr38 and
SnCl4.9 Glycosides have been also synthesized via
Ferrier rearrangement starting from the corresponding
unsaturated glycosides with alcohols in presence of InCl3,10
Bi(OTf)3/SiO2-Bi(OTf)311 and other acid catalysts.12
Many carbohydrate-containing complex natural
compounds are found in nature as important biological
substances. Recent biological studies on these glycosides,
such as proteoglycans, glycoproteins, glycolipid and
antibiotics at the molecular level have shed light on the
biological significance of their carbohydrate parts (glycons)
in molecular recognition for the transmission of biological
information.1
With the stimulant biological background, the
synthesis of carbohydrate-containing compounds is
becoming more and more important in the field of organic
chemistry and chemical biology.2 On the other hand,
glycosylation is a key reaction for the introduction of a
carbon chain into the anomeric position of a glycal or a
sugar derivative bearing a leaving group at C-1. Due to the
importance of glycosylic compounds, the present subject
has received considerable attention in recent years.3
Substantial number of reports has appeared in
the literature on glycosylation reaction employing
common reagents such as BF3.OEt2,4 indium metal,5
In an environmentally benign chemistry on
carbohydrates, i.e., green carbohydrate chemistry requires
for clean, efficient and selective processes have increased
the demand for such metal-based reaction promoters,
especially in catalytic amounts. However, many catalysts
are derived from heavy or rare metals and their toxicity and
prohibitive prices constitute severe drawbacks for large-
scale applications. In contrast, iron is one of the most
abundant metals on earth, and consequently one of the most
inexpensive and environmentally friendly ones. Moreover,
many iron salts and complexes are commercially available,
or their applications are well described in the literature.13
Despite its advantages, it is surprising that, until recently,
iron was relatively underrepresented in the field of catalysis
including nucleophilic additions/substitutions, reductions,
oxidations, hydrogenations, cycloadditions, isomerizations,
rearrangements, as well as polymerizations.14 However,
iron(III) chloride has been extensively utilized for
glycosylation reactions with different sugar moieties like
*e-mail: mwpaixao@ufscar.br

Vol. 23, No. 11, 2012
Narayanaperumal et al.
1983
2-acylamido-2-deoxy-β-D-glucopyranose-1-acetates, etc.,
with the use of a quantitative amount of iron(III) chloride.15
In addition, iron chloride was successfully employed for
the Ferrier rearrangement.16
Whilst there are several published procedures4-12 for
the glycosylation reactions, many of these methods require
the use of expensive reagents and have limitations in
terms of yields, stereoselectivities, reaction temperature,
the catalyst/reagents used and their quantitative amounts.
Therefore, our aim was to find a method that utilized mild,
relatively cheap reagents and flexible enough to allow the
synthesis of glycosides.
Henceforth, it was focused our attention towards the use
of iron salts for this transformation.
The influence of different iron salts was further studied
to check the reaction course.All these catalysts provide the
corresponding glycoside 3 in traces, whereas FeCl3 was
the only one to provide isolable yields of product (Table 2,
entries 1-6). It was observed the formation of 3a as a pure
isomer (assigned by nuclear magnetic resonance, NMR)
in 26% yield.
In continuation of our optimization, it was next
studied other factors including catalyst loading,
reaction temperature and solvent. Analyzing Table 3,
it was possible to verify that the amount of catalyst
loading (from 5 to 20 mol%) has the influence of the
glycosylation reaction. When the amount of catalyst
loading was decreased from 20 to 10 mol%, the yield got
increased to 64% (Table 3, entries 1-3). This is due to the
catalyst concentration which plays a fundamental role
in this glycosylation reaction.17 Also, catalyst loadings
7 and 5 mol% gave the corresponding product in low yield
as compared with the use of 10 mol% (Table 3, entries
3-5). In all cases, the uncharacterizad polymerization
products or side products were also observed, whereas
using 10 mol% FeCl3, comparative low amounts of
byproduct formation was observed. Finally, to further
optimize the protocol, it was necessary to examine the
effect of the solvent in promoting the reaction efficiency.
Results and Discussion
Considering all these aspects, herein, it is reported an
efficient, mild, cost-effective procedure for glycosylation
of peracetylated-β-D-sugar catalyzed by FeCl3 (Scheme 1).
Togainsomepreliminaryinformationofthissynthetically
useful reaction, screening experiments were performed. It
was carried out the reaction employing 1.0 equivalent of
β-D-glucose pentaacetate (1), 1.2 equivalent of allyl alcohol
(2), 20 mol% of catalyst in dry dichloromethane at room
temperature under different conditions to get the glycoside
(Table 1). Firstly, it was tested different catalysts, among
these, FeCl3 showed a positive result in terms of yield
as compared with other catalysts (Table 1, entries 1-6).
Iron catalyst (10 mol%)
8 h, room temperature
AcO
O
AcO
O
OAc
O
+
R OH
R
Scheme 1. Synthesis of glycosides catalyzed by FeCl3.
Table 1. Screening of catalysta
AcO
AcO
O
O
Catalyst (20 mol%)
OAc
O
AcO
AcO
AcO
HO
+
AcO
DCM, 8 h
room temperature
OAc
3a
OAc
2
1
entry
Catalyst
ZnO
Yieldb / %
traces
traces
traces
-
1
2
3
4
5
6
ZnCl2
CuBr2
InI
SnCl2
FeCl3
traces
26
aUnless otherwise mentioned, reactions were performed using: alcohol (1.2 equivalent) to a stirred suspension of peracetylated sugar (1 equivalent) and
FeCl3 (20 mol%) in ultra-dry conditions; bisolated yield.

1984
Iron(III) Chloride Catalyzed Glycosylation of Peracylated Sugars with Allyl/Alkynyl Alcohols
J. Braz. Chem. Soc.
Table 2. Screening of iron catalysta
AcO
AcO
Fe salts
O
O
AcO
AcO
O
HO
AcO
AcO
OAc
+
DCM, 8 h
room temperature
OAc
3a
OAc
2
1
entry
Iron catalyst
FeCl3
Catalyst loading / mol%
Yieldb / %
1
20
26
2c
3
Fe2O3 (nano)
Fe(NO3)3.9H2O
20
traces
traces
traces
traces
traces
20
25% (m/m)
20
4d
5
Aerosil 200-FeCl3
Fe(III) acetate
Fe(acac)3
6
20
aUnless otherwise mentioned, reactions were performed using: alcohol (1.2 equivalent) to a stirred suspension of peracetylated sugar (1 equivalent) and
FeCl3 (20 mol%) in ultra-dry conditions; bisolated yield; cnanoparticles; dsilica crafted with FeCl3.
Table 3. Screening of the catalyst loading, solvent and temperaturea
AcO
AcO
FeCl3
O
O
AcO
AcO
O
HO
AcO
AcO
OAc
+
Solvent, 8 h
room temperature
OAc
3a
OAc
2
1
entry
1
FeCl3 / mmol%
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Et2O
Temperature
Yieldb / %
20
15
10
7
rt
rt
26
22
64
28
18
bpc
2
3
rt
4
rt
5
5
rt
6c
7d
8
10
10
10
10
rt
d
rt
-
CH2Cl2:Et2O
CH2Cl2
rt
26
bp
9c
reflux
aUnless otherwise mentioned, reactions were performed using: alcohol (1.2 equivalent) to a stirred suspension of peracetylated sugar (1 equivalent) and
FeCl3 (20 mol%) in an ultra-dry conditions; bisolated yield; cbyproducts were observed; dno reaction; rt: room temperature.
The use of dichloromethane gave the higher yields as
compared with other solvents (Table 3, entries 6-8). Also,
elevated temperature exhibited negative effect, which
affords the byproduct formation as compared with room
temperature (Table 3, entries 9 and 3).
With the optimized conditions in hands, it was
subsequently used this approach to synthesize different
glycosides derived from β-D-glucose, β-D-mannose,
β-D-maltose, β-D-galactose using FeCl3 catalyst.
The results were summarized in Table 4. Our general
reaction conditions involve the addition of alcohol
(1.2 equivalent) to a stirred suspension of peracetylated
sugar (1 equivalent) and FeCl3 (10 mol%) in dry
dichloromethane at room temperature. In all cases, the
product formation was observed as a single isomer in
moderate to good yield (Table 4, entries 1-9).
It was speculated that FeCl3 would function as Lewis
acid and thus promote the glycosylation. By using the
standard reaction conditions, it was then tested α-D-glucose
pentaacetate as the sugar partner with allyl alcohol in
presence of FeCl3 catalyst. Unfortunately, however, our
methodology fails.
The mechanism of FeCl3 mediated glycosylation is
still an intriguing subject of study. Based on the literature
report,18 it was proposed the plausible reaction pathways
of the glycosylation (Scheme 2). FeCl3 would behave as
Lewis acid and the initial step of the reaction is a Lewis
acid promoted of β-D-glucose pentaacetate (1), involving

Vol. 23, No. 11, 2012
Narayanaperumal et al.
1985
Table 4. Glycosylation of sugars with alcohols catalyzed by iron(III) chloridea
RO
O
RO
O
FeCl3 (10 mol%)
OAc
O
HO
+
Solvent, 8 h
room temperature
1a-d
3a-h
Sugar
Product
Yieldb / %
1
2
64
53
48
3
4
58
5
6
51
53
7c
64
39
8c
aDetails in general experimental procedure; bisolated yield; cthe starting material and desired product showed the same α/β relationship (1:10). The anomeric
ratios were determined by comparison of the integral intensities of the corresponding signals in NMR spectra.

1986
Iron(III) Chloride Catalyzed Glycosylation of Peracylated Sugars with Allyl/Alkynyl Alcohols
J. Braz. Chem. Soc.
OAc
OAc
O
O
AcO
AcO
AcO
AcO
OAc
OR
OAc
OAc
A
3
OAc
O
LA (FeCl3)
AcO
AcO
ROH
(rearrangement)
LA
OAc
OAc
OAc
OAc
O
1
AcO
AcO
OAc
O
AcO
AcO
O
O
O
O
LA: Lewis acid
R : allyl, alkynyl
OR
B
4 (orthoester)
Scheme 2. Plausible reaction pathways.
AcO
O
O
OAc
1.0 eq (3a),
NaIO4(1 eq)
O
H
AcO
AcO
RuCl3.xH2O (2 mol%)
DCM:CH3CN:H2O (2:2:3)
4a; 74%
AcO
O
AcO
O
1.0 eq (3a),
NaIO4 (8 eq)
O
O
O
OH
AcO
AcO
AcO
OAc
AcO
OAc
3a
RuCl3.xH2O (2 mol%)
DCM:CH3CN:H20 (2:2:3)
4b; 92%
AcO
O
OH
PdCl2, AcOH,H2O, AcONa
AcO
AcO
OAc
Details in general experimental
procedure
4c
Scheme 3. Functionalization of allyl glycoside.
the participation of the C-2 acetoxy group, to give an
oxocarbenium acetate ion pair (A) or dioxolenium ion (B).
The carbenium ion would react with the allyl/alkynyl
alcohol to give the desired 1,2-trans-glucoside (3) and
1,2-orthoester (4). Furthermore, the orthoester (4) would
rearrange19 to give the glycosylated product (3).
A great deal of interest has been laid in the application
of synthesized compounds. Especially allyl glycoside, 3a is
attractive due to the presence of the terminal double bond
that is amenable to easy further functionalization leading
to other molecules20 or selective deprotection of allyl group
from glycoside 3a without affecting other functional groups
on glycosides, which afford the anomeric alcohol 4c and
this would be used as building blocks on carbohydrate
arrays (Scheme 3).21 The synthesized compound 4a and 4b
have to be used as starting material for the Ugi four
component reactions which demonstrates the synthetic
utility of this class of compounds.22
Experimental
13
1H and C NMR spectra were recorded at 400 MHz
with tetramethylsilane as internal standard. Column
chromatography was performed using Merck silica gel (230-
400 mesh). Thin layer chromatography (TLC) was performed
using Merck silica gel GF254, 0.25 mm thickness. For
visualization, TLC plates were placed under acidic vanillin.
All solvents were used in dry conditions.
General experimental procedure (3a-h)
Allyl or propargyl alcohol (1.2 equivalent) was
added to a stirred suspension of peracetylated sugar
(1 equivalent) and FeCl3 (10 mol%) in dry dichloromethane
(1 mL) at room temperature in ultra-dry conditions under
inert atmosphere. After completion of the reaction as
monitored by thin-layer chromatography (TLC), the

Vol. 23, No. 11, 2012
Narayanaperumal et al.
1987
reaction was diluted with dichloromethane and washed
with water, and worked up in the usual manner. The crude
product was purified by chromatography on silica gel (ethyl
acetate:hexane 1:1) to afford the corresponding glycoside
in good yield and with high selectivity.
6. Agarwal, A.; Rani, S.; Vankar, Y. D.; J. Org. Chem. 2004, 69,
6137.
7. Yadav, J. S.; Reddy, B. V. S.; Reddy, R. C.; Tetrahedron Lett.
2004, 45, 4583.
8. Yadav, J. S.; Reddy, B.V. S.; Raju,A. K.; Rao, C.V.; Tetrahedron
Lett. 2002, 43, 5437.
Conclusions
9. Boryski, J.;Grynkiewicz, G.;Synthesis2001, 14, 2170;Xue, J. L.;
Cecioni, S.; He, L.;Vidal, S.; Praly, J. P.; Carbohydr. Res. 2009,
344, 1646 and references therein.
In conclusion, our methodology has several notable
advantages such as mild reaction conditions that make
use of a reagent of relatively low toxicity, low-catalyst
loading, good yields and high anomeric selectivity. Efforts
to construct a library of compounds with this method are
still underway in our laboratory.
10. Nagaraj, P.; Ramesh, N. G.; Tetrahedron Lett. 2009, 59, 3970;
Mukherjee, D.; Yousuf, S. K.; Taneja, S. C.; Tetrahedron Lett.
2008, 49, 4944; Das, S. K.; Reddy, K.A.;Abbineni, C.; Roy, J.;
Rao, K. V. L. N.; Sachwani, R. H.; Iqbal, J.; Tetrahedron Lett.
2003, 44, 4507; Ghosh, R.; De, D.; Shown, B.; Maiti, S. B.;
Carbohydr. Res. 1999, 321, 1.
Supplementary Information
11. Babu, J. L.; Khare, A.; Vankar,Y. D.; Molecules 2005, 10, 884.
12. Tilve, R. D.;Alexander, M.V.; Khandekar,A. C.; Samant, S. D.;
Kanetkar, V. R.; J. Mol. Catal. A: Chem. 2004, 223, 237;
Churchill, D. G.; Rojas, C. M.; Tetrahedron Lett. 2002, 43, 7225.
13. Zettler, M. W. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., ed.; Wiley: New York, NY, USA,
1995; White, A. D. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., ed.; Wiley: NewYork, NY, USA, 1995;
King, B. R.; Encyclopedia of Inorganic Chemistry; Wiley:
New York, NY, USA, 1994.
Experimental details and spectral data are available free
of charge at http://jbcs.sbq.org.br as a PDF file.
Acknowledgments
S. N. and J. L. M. thank Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP) for Postdoctoral and
doctoral fellowships, respectively, while R. C. S is a
Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq) fellowship holder for the PhD and
cordially acknowledge their financial support. We are also
obliged to CNPq (INCT-Catálise and INBEQMeDI) and
FAPESP (2009/07281-0) for their financial support.
14. Beller, M.; Bolm, C.; Transition Metals for Organic Synthesis,
2nd ed.; Wiley-VCH: Weinheim, Germany, 2004; Thomas,
S. E. G.; Transition Metals in Organic Synthesis, a Practical
Approach; Oxford University Press: Oxford, USA, 1997;
Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
104, 6217; Addis, D.; Shaikh, N.; Zhou, S.; Das, S.; Junge, K.;
Beller, M.; Asian. J. Chem. 2010, 5, 1687; Driller, K. M.;
Prateeptongkum, S.; Jackstell, R.; Beller, M.; Angew. Chem.,
Int. Ed. 2011, 50, 537.
References
1. Ernst, B.; Hart, G.; Sinay, P. In Carbohydrates in Chemistry and
Biology; Wiley-VCH: NewYork, NY, USA, 2000; Fraser-Reid,
B. O.; Tatsuta, K.; Thiem, J. In Glycoscience: Chemistry and
Chemical Biology I-III; Springer: Berlin, Germany, 2001.
2. Nicolaou, K. C.; Mitchell, H. J.; Angew. Chem., Int. Ed. 2001,
40, 1576; Lehnert, T.; Özüduru, G.; Grugel, H.; Albrecht, F.;
Telligmann, S. M.; Boysen, M. M. K.; Synthesis 2011, 17,
2685 and references there in; Crich, D.; J. Org. Chem. 2011,
76, 9193.
15. Kiso, M.;Anderson, L.; Carbohydr. Res. 1979, 72, C12; Kiso, M.;
Anderson, L.; Carbohydr. Res. 1979, 72, C15; Hasegawa, A.;
Kiso,M.;Carbohydr.Res.1979,74,341;Kiso,M.;Nishiguchi,H.,
Hasegawa, A.; Carbohydr. Res., 1980, 81, C13; Kiso, M.,
Anderson, L.; Carbohydr. Res. 1985, 136, 309; Dasgupta, F.;
Anderson, L.; Carbohydr. Res. 1990, 202, 239; Charbonnier, F.;
Penades, S.; Eur. J. Org. Chem. 2004, 3650; Seibel, J.;
Hillringhaus, L.; Moraru, R.; Carbohydr. Res. 2005, 340, 507.
16. Masson, C.; Soto, J.; Bessodes, M.; Synlett 2000, 9, 1281;
Churchill, D. G.; Rojas, C. M.; Tetrahedron Lett. 2002, 43,7225;
Tilvea, R. D.;Alexander, M.V.; Khandekar,A. C.; Samant, S. D.;
Kanetkar, V. R.; J. Mol. Catal. A: Chem. 2004, 223, 237.
17. Rulli, G.; Duangdee, N.; Baer, K.; Hummel, W.; Berkessel, A.;
Gröger, H.; Angew. Chem., Int. Ed. 2011, 50, 7944.
3. Ayed, C.; Palmier, S.; Lubin-Germain, N.; Uziel, J.; Augé, J.;
Carbohydr. Res. 2010, 345, 2566; Levy, D. E.; Fügedi, P. In
Organic Chemistry of Sugars; CRC Press.: Boca Raton, FL,
USA, 2006, p. 269.
4. Lin,Y.A.; Chalker, J. M.; Davis, B. G.; J. Am. Chem. Soc. 2010,
132, 16805 and references therein.
5. Lubin-Germain, N.; Baltaze, J. P.; Coste, A.; Hallonet, A.;
Lauréano, H.; Legrave, G.; Uziel, J.; Augé, J.; Org. Lett. 2008,
10, 725.
18. Banoub, J.; Bundle, D. R.; Can. J. Chem. 1979, 57, 2091;
Aich, U.; Loganathan, D.; Carbohydr. Res. 2006, 341, 19;
Murakami, T.; Hirono, R.; Sato, Y.; Furusawa, K.; Carbohydr.

1988
Iron(III) Chloride Catalyzed Glycosylation of Peracylated Sugars with Allyl/Alkynyl Alcohols
J. Braz. Chem. Soc.
Res. 2007, 342, 1009; Xue, L. J.; Cecioni, S.; Vidal, S.; Praly,
J. P.; Carbohydr. Res. 2009, 344, 1646.
21. Ban, L.; Mrksich, M.; Angew. Chem., Int. Ed. 2008, 47, 3396.
22. Westermann, B.; Dörner, S.; Chem. Commun. 2005, 2116.
19. Ogawa, T.; Beppu, K.; Nakabayashi, S.; Carbohydr. Res. 1981,
93, C6; Kong, F. Carbohydr. Res. 2007, 342, 345.
Submitted: August 21, 2012
20. Synthetic procedure for aldehyde and acid derivative of 4a-b:
Buskas, T.; Söderberg, T.; Konradsson, P.; Reid, B. F.; J. Org.
Chem. 2000, 65, 958; Virta, P.; Karskela, M.; Lönnberg, H.;
J. Org. Chem. 2006, 71, 1989.
Published online: November 6, 2012
FAPESP has sponsored the publication of this article.