Indium triflate catalyzed peracetylation of carbohydrates

Article abstract of DOI:10.1016/j.carres.2008.04.009

Peracetylation is a very common protection strategy that is widely implemented in carbohydrate synthesis. Here, a method for the peracetylation of carbohydrates using catalytic In(OTf)₃ in neat acetic anhydride is reported. In(OTf)₃ has low toxicity and is mild and water tolerant, and the reactions are high yielding and efficient. Details regarding the scope and mechanism of the reaction are briefly discussed.

Full text of DOI:10.1016/j.carres.2008.04.009

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 1814–1818
Note
Indium triflate catalyzed peracetylation of carbohydrates
Nicholas P. Bizier, Shannon R. Atkins, Luke C. Helland, Shane F. Colvin,
Joseph R. Twitchell and Mary J. Cloninger*
Department of Chemistry and Biochemistry, 103 Chemistry and Biochemistry Building,
Montana State University, Bozeman, MT 59717, United States
Received 8 February 2008; received in revised form 2 April 2008; accepted 5 April 2008
Available online 10 April 2008
Abstract—Peracetylation is a very common protection strategy that is widely implemented in carbohydrate synthesis. Here,
a method for the peracetylation of carbohydrates using catalytic In(OTf)3 in neat acetic anhydride is reported. In(OTf)3 has low
toxicity and is mild and water tolerant, and the reactions are high yielding and efficient. Details regarding the scope and mechanism
of the reaction are briefly discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Acetylation; Catalysis; Indium triflate; Acetic anhydride
Acetylation reactions are among the most common
transformations in organic synthesis, and acetylation
of monosaccharides is often the first step in the synthesis
of complex carbohydrates. The peracetylation of sugars
is most often performed using acetic anhydride and
DMAP in pyridine.1 Although this reaction works well,
long reaction times (12 h) are required and pyridine is
high boiling and noxious.
Most of the conventional metal salts that are used as
Lewis acids are water sensitive and are often used in
stoichiometric amounts. Metal triflates are an attractive
alternative because of their low toxicity and non-corro-
sive nature.23 Yamamoto’s report of acetylation reac-
tions using catalytic Sc(OTf)3 in CH3CN generated
high interest in the area of metal triflate catalyzed acet-
ylations.24 In(OTf)3 is a mild, water-tolerant Lewis acid
that can be used in catalytic quantities for a variety of
organic transformations.25 Because In(OTf)3 is consid-
erably less expensive than Sc(OTf)3, we are interested
in its development as a catalyst for acetylation reactions.
Frost reported the acetylation of alcohols and amines in
acetonitrile using 0.1 mol % In(OTf)3, but a chromato-
graphic purification step was required and only one
carbohydrate was evaluated.22 Here, we report the
In(OTf)3 catalyzed peracetylation of carbohydrates
under solvent-free conditions.
We found that 0.05 equiv of In(OTf)3 catalyzed the
peracetylation of a number of sugars in acetic anhydride
when the reactions were stirred for 1 h at 0 °C. The
results are summarized in Scheme 1. For reaction work-
up, ethyl acetate was added to the flask and a 10% aque-
ous solution of Na2CO3 was added. After stirring for 20
min to1 h to hydrolyze any unreacted acetic anhydride,
the organic layer was collected and concentrated. The
Numerous ways to avoid the use of pyridine in acetyl-
ation reactions have been devised. Some notable exam-
2
ples include the use of catalytic TMSOTf in CH2Cl2
and of catalytic Bu3P in CH2Cl2.3 Use of acetic anhy-
dride as both the solvent and the acylating reagent has
been demonstrated using a wide variety of catalysts
including sodium acetate,4 montmorillonite K-10,5
molecular sieves,6 iodine,7 FeCl3,8 3-nitrobenzeneboron-
ic acid,9 LiClO4,10 HClO4–SiO2,11 CuSO4Á5H2O,12
acetonyltriphenylphosphonium bromide,13 H14[Na-
P5W30O110],14 La(NO3)3Á6H2O,15 and Mg(NTf2)2.16
Metal triflate catalysis of acetylation reactions has been
reported using Cu(OTf)2,17 Bi(OTf)3,18 V(O)(OTf)2,19
Sc(OTf)3,20 Ce(OTf)3,21 and In(OTf)3.22
*
Corresponding author. Tel.: +1 406 994 3051; e-mail: mcloninger@
chemistry.montana.edu
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.04.009

N. P. Bizier et al. / Carbohydrate Research 343 (2008) 1814–1818
1815
hydrolyzed (and the corresponding acetylated sugars
were obtained).
HO
AcO
O
O
HO
AcO
(1)
(2)
HO
AcO
99%
96%
Investigation into the mechanism of the indium tri-
flate catalyzed acetylation suggests that triflic acid is
the active catalytic species. Acetylation of galactose
occurred rapidly using 0.05 equiv of triflic acid (Table
1, entry 1). However, the reaction does not proceed
when 2,6-di-tert-butylpyridine (DTBP) is added with
In(OTf)3, nor does acetylation occur when glucosamine
is used as the substrate in a1 h reaction (Table 1, entries
2–4). Thus, our results suggest that indium triflate can
be used to provide low levels of triflic acid. Dumeunier
HO
AcO
OH
OAc
OAc
HO
AcO
OAc
OH
O
O
HO
AcO
AcO
HO
OH
OH
OH
OAc
O
HO
HO
AcO
AcO
(3)
(4)
O
88%
63%
HO
AcO
OAc
´
and Marko observed a similar triflic acid mediated acyl-
O
O
HO
HO
AcO
AcO
ation using scandium triflate in a benzoylation proce-
dure,26 and free acid has also been proposed as the
active catalyst in metal triflate mediated Friedel–Crafts
reactions.27 Loh and co-workers capitalized on the labil-
ity of the triflate on indium when forming chiral
indium(III)-pybox complexes.28 When we allowed our
In(OTf)3 catalyzed reaction with DTBP to stir at room
temperature for one day, an 11% yield of peracetylated
product was obtained (Table 1, entry 2). This result indi-
cates that an indium triflate mediated reaction pathway
may also be possible but is much slower than the triflic
acid-catalyzed process. A similar dual pathway process
HO
AcO
OH
OAc
O
O
HO
HO
AcO
(5)
(6)
(7)
AcO
96%
89%
HO
AcO
OH
OAc
AcO
AcO
AcO
HO
HO
HO
AcHN
O
O
AcHN
OAc
OH
OH
OAc
HO
HO
AcO
AcO
HO
AcO
O
O
HO
O
O
´
AcO
has been proposed by Dumeunier and Marko for
97%
O
O
Sc(OTf)3.26
HO
HO
OAc
AcO
OH
OAc
To further explore the role of the catalyst in the acetyl-
ation reactions, we investigated the effect of the choice
of ligand on the behavior of the catalyst in the reaction.
We compared In(OTf)3 to InCl3 and InBr3. The acetyl-
ation of alcohols using indium chloride and ruthenium
chloride catalysts has been reported previously.29 RuCl3
catalyzed reactions worked well without solvents for
liquid substrates and were also successful for substrates
compatible with acetonitrile (and slower in dichloro-
methane, chloroform, and tetrahydrofuran). Acetyla-
tions with carbohydrates were not explored.29a InCl3
catalyzed reactions were performed with only a small
amount of catalyst and only one equivalent of Ac2O at
room temperature, and peracetylation of glucose was
reported.29b However, acetylation of glucose at 0 °C in
our labs required 12 h using 0.05 equiv of InCl3
(Table 1, entry 5). InCl3 is a less reactive catalyst, and
In(OTf)3 may be better suited for acetylations per-
formed below room temperature. InBr3 catalyzed the
acetylation of glucose at room temperature as shown
in Scheme 1 (Table 1, entry 6). Thus, although InCl3
and InBr3 both effect the desired acetylation, the reac-
tions are considerably slower with these catalysts than
with In(OTf)3. Our results indicate that the strength of
the respective acids that are generated from the catalysts
(TfOH, HBr, and HCl) correlates well with the reaction
rate.
Scheme 1. In(OTf)3 catalyzed peracetylation of carbohydrates. Con-
ditions: In(OTf)3 (0.05 equiv) in Ac2O (30 equiv), 1 h, 0 °C (reactions
1–5) or 0 °C to rt (reactions 6 and 7).
crude products were normally of sufficient purity to be
used without further purification. The reactions using
lactose or N-acetyl glucosamine were warmed to room
temperature because of the low solubility of the sub-
strates in acetic anhydride at low temperature (reactions
6 and 7 in Scheme 1).
The compatibility of the In(OTf)3 catalyzed peracetyl-
ation reactions with a number of commonly used pro-
tecting groups was explored. The benzylidene acetal
and the TBDPS ether were stable to the reaction condi-
tions (Scheme 2), but TMS and TBS groups were readily
Ph
O
O
In(OTf)3 (5 mol %)
Ac2O, 0 ºC, 1 h
Ph
O
O
O
O
HO
AcO
(88%)
HO
AcO
OMe
OMe
HO
HO
HO
OH
TBDPSO
AcO
OAc
O
1) TBDPSCl, py
O
AcO
2) In(OTf)3 (5 mol %)
Ac2O, 0 ºC, 1 h
(86%, 2 steps)
OMe
OMe
Overall, we found that carbohydrates that were solu-
ble in acetic anhydride could be peracetylated very effec-
Scheme 2. Protecting group compatibility studies.

1816
N. P. Bizier et al. / Carbohydrate Research 343 (2008) 1814–1818
Table 1. Catalyst comparisona
Entry
Substrate
OH
Catalyst (equiv)
Time
Yield (%)
84
HO
1
TfOH (0.05 equiv)
10 min
O
HO
HO
OH
HO
O
HO
2
3
4
5
6
In(OTf)3 (0.05 equiv) with DTBPb
In(OTf)3 (0.05 equiv) without DTBP
In(OTf)3 (0.05 equiv)
24 hc
11
HO
HO
OH
HO
O
HO
1 h
99
HO
HO
OH
HO
O
HO
1 h
N.R.d
71
HO
H2N
OH
HO
O
HO
InCl3 (0.05 equiv)
12 h
6 hc
HO
HO
OH
HO
HO
HO
O
InBr3 (0.05 equiv)
86
HO
OH
a Reactions were performed in 30 equiv Ac2O.
b DTBP = di-tertbutylpyridine.
c 0 °C to rt; all other reactions 0 °C.
d N.R. = no reaction.
tively using the In(OTf)3-mediated reaction conditions
described in this report. Acetylation of sugars such as
sorbose and fructose that were insoluble in acetic anhy-
dride could not be performed using this methodology.
Carbohydrates are also generally insoluble in solvents
such as acetonitrile that are commonly reported for
In(OTf)3-mediated acetylation of simple alcohols.
Although smaller amounts of acetic anhydride could
be used for the peracetylation of carbohydrates, we
found reactions with 30 equiv of Ac2O to be most con-
venient, and excess anhydride is easily removed using
the described workup procedure.
In addition to the peracetylation reaction, the use of
In(OTf)3 to catalyze benzoylation reactions with carbo-
hydrates was also briefly explored. Unfortunately,
because benzoyl anhydride is a solid, solvent would be
required for an analogous benzoylation reaction. Frost’s
work indicated that acetonitrile would be an appropriate
solvent in which to invoke this transformation,22 but the
low solubility of carbohydrate substrates in acetonitrile
precluded product formation. In DMF, benzoyl pro-
tection of 1-methyl glucoside was performed using
0.05 equiv of In(OTf)3 and 10 equiv of benzoyl anhy-
dride at room temperature for 12 h, affording a 50%
yield of fully benzoyl-functionalized 1-methyl glucoside.
Microwave irradiation to improve carbohydrate
solubility in the perbenzoylation reactions was also eval-
uated. The use of microwave irradiation in glycosyla-
tions and in protecting group manipulations for
carbohydrates has recently been reviewed.30 We evalu-
ated reactions using glucose and 10 equiv of benzoyl
anhydride in acetonitrile with 0.05 equiv of In(OTf)3.
At temperatures ranging from 25 °C to 100 °C and with
irradiations of 150 W to 300 W (all for 5 min), we were
unable to achieve sufficient solubilization of substrates,
and product formation was not observed.
We next tested microwave irradiation of the In(OTf)3-
catalyzed peracetylation reactions. Microwave condi-
tions have been successfully applied by Limousin and
co-workers to peracetylations using ZnCl2, potassium
acetate, or sodium acetate in acetic anhydride.31 An
InCl3-catalyzed peracetylation reaction using microwave
irradiation in acetonitrile was reported by Das and co-
workers.32 We found that the reactions that were per-
formed according to our protocol described above
(5 mol % In(OTf)3, 1 h, 0 °C, neat acetic anhydride)
could also be performed under microwave irradiation.
We irradiated mannose and N-acetyl glucosamine for 5
min at room temperature in a sealed tube with 150 W to
afford peracetylated products (Scheme 3). Although the
yields we obtained were lower than those obtained with-
out microwave irradiation, our results suggest that, with
additional optimization, microwave irradiation could be
used to successfully perform the transformations shown
in Scheme 1. Reactions that were unsuccessful without
microwave irradiation due to the insolubility of the sub-

N. P. Bizier et al. / Carbohydrate Research 343 (2008) 1814–1818
1817
2. Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G.
G. A. J. Org. Chem. 1998, 63, 2342–2347.
3. (a) Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115,
3358–3359; (b) Vedejs, E.; Bennett, N. S.; Conn, L. M.;
Diver, S. T.; Gingras, M.; Lin, S.; Oliver, P. A.; Peterson,
M. J. J. Org. Chem. 1993, 58, 7286–7288.
4. Wolfrom, M. L.; Thompson, A. Meth. Carbohydr. Chem.
1963, 211–215.
5. Bhaskar, P. M.; Loganathan, D. Tetrahedron Lett. 1998,
39, 2215–2218.
In(OTf)3 (5 mol %)
HO
OH
O
Ac2O, microwave (150 W)
AcO
OAc
O
HO
AcO
HO
AcO
25 ºC, 5 min
(84%)
OH
OAc
In(OTf)3 (5 mol %)
Ac2O, microwave (150 W)
HO
AcO
O
O
HO
HO
AcO
AcO
25 ºC, 5 min
(46%)
AcHN
AcHN
OH
OAc
6. Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M.
Tetrahedron Lett. 2003, 44, 4661–4663.
Scheme 3. Peracetylation using microwave conditions.
7. Phukan, P. Tetrahedron Lett. 2004, 45, 4785–4787.
8. Dasgupta, F.; Singh, P. P.; Srivastava, H. C. Carbohydr.
Res. 1980, 80, 346–349.
9. Tale, R. H.; Adude, R. N. Tetrahedron Lett. 2006, 47,
7263–7265.
10. Lu, K.-C.; Hsieh, S.-Y.; Patkar, L. N.; Chen, C.-T.; Lin,
C.-C. Tetrahedron 2004, 60, 8967–8973.
11. Misra, A. K.; Tiwari, P.; Madhusudan, S. K. Carbohydr.
Res. 2005, 340, 325–329.
strates in acetic anhydride were equally unsuccessful
when irradiated.
In summary, the In(OTf)3-catalyzed peracetylation of
carbohydrates in acetic anhydride works well for many
carbohydrates. The new reaction conditions eliminate
the need for unpleasant solvents such as pyridine, and
In(OTf)3 has the advantage of being affordable, non-
toxic, and non-corrosive.
12. Heravi, M. M.; Behbahani, F. K.; Zadsirjan, V.;
Oskooie, H. A. J. Brazil Chem. Soc. 2006, 17, 1045–
1047.
13. Khan, A. T.; Choudhury, L. H.; Ghosh, S. Eur. J. Org.
Chem. 2005, 2782–2787.
1. Experimental
14. Heravi, M. M.; Behbahani, F. K.; Bamoharram, F. F. J.
Mol. Catal. A: Chem. 2006, 253, 16–19.
15. Reddy, T. S.; Narasimhulu, M.; Suryakiran, N.; Mahesh,
K. C.; Ashalatha, K.; Venkateswarlu, Y. Tetrahedron Lett.
2006, 47, 6825–6829.
16. Chakraborti, A. K.; Shivani J. Org. Chem. 2006, 71, 5785–
5788.
17. (a) Chandra, K. L.; Saravanan, P.; Singh, R. K.; Singh, V.
K. Tetrahedron 2002, 58, 1369–1374; (b) Tai, C.-A.;
Kulkarni, S. S.; Hung, S.-C. J. Org. Chem. 2003, 68,
8719–8722.
18. (a) Orita, A.; Tanahashi, C.; Kakudo, A.; Otera, J. Angew.
Chem., Int. Ed. 2000, 39, 2877–2879; (b) Orita, A.;
Tanahashi, C.; Kakuda, A.; Otera, J. J. Org. Chem. 2001,
66, 8926–8934.
1.1. General peracetylation procedure
Carbohydrate was added to Ac2O (30 equiv), and the
solution was cooled to 0 °C. In(OTf)3 (0.05 equiv) was
added, and the reaction was allowed to warm to room
temperature while stirring for 1 h. EtOAc and 10%
aqueous Na2CO3 solution were added, and the mixture
was stirred for 1 h. Isolation of the organic layer, wash-
ing twice with satd aq NaHCO3 solution, drying over
MgSO4, and removal of solvent in vacuo afforded the
product.
19. Chen, C.-T.; Kuo, J.-H.; Li, C.-H.; Barhate, N. B.; Hon,
S.-W.; Li, T.-W.; Chao, S.-D.; Liu, C.-C.; Li, Y.-C.;
Chang, I.-H.; Lin, J.-S.; Liu, C.-J.; Chou, Y.-C. Org. Lett.
2001, 3, 3729–3732.
Acknowledgments
20. (a) Ke, W.; Whitfield, D. M. Carbohydr. Res. 2004, 339,
2841–2850; (b) Lee, J.-C.; Tai, C.-A.; Hung, S.-C. Tetra-
hedron Lett. 2002, 43, 851–855.
21. Bartoli, G.; Dalposso, R.; De Nino, A.; Maiuolo, L.;
Nardi, M.; Procopio, A.; Tagarelli, A. Green Chem. 2004,
6, 191–192.
Support from NIGMS RO1 62444 and from NSF REU
0552959 (J.R.T.) is gratefully acknowledged. CEM Cor-
poration loaned the microwave to us.
22. Chauhan, K. K.; Frost, C. G.; Love, I.; Waite, D. Synlett
1999, 1743–1744.
23. Kulkarni, S. S.; Hung, S.-C. Lett. Org. Chem. 2005, 2,
670–677.
Supplementary data
24. (a) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto,
H. J. Am. Chem. Soc. 1995, 117, 4413–4414; (b) Ishihara,
K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560–4567.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2008.04.009.
25. (a) Ghosh, R.; Maiti, S. J. Mol. Catal. A: Chem. 2007, 264,
1–8; (b) Chauhan, K. K.; Frost, C. G. J. Chem. Soc.,
Perkin Trans. 1 2000, 3015–3019; (c) Thakur, A. J. Synlett
2003, 899–900; (d) Auge, J.; Lubin-Germain, N.; Uziel, J.
Synthesis 2007, 1739–1764.
References
´
26. Dumeunier, R.; Marko, I. E. Tetrahedron Lett. 2004, 45,
1. (a) Steglich, W.; Holfe, G. Angew. Chem., Int. Ed. Engl.
1969, 8, 981; (b) Hofle, G.; Steglich, W.; Vorbruggen, H.
Angew. Chem., Int. Ed. Engl. 1978, 17, 569–583.
825–829.

1818
N. P. Bizier et al. / Carbohydrate Research 343 (2008) 1814–1818
27. Goodrich, P.; Hardacre, C.; Mehdi, H.; Nancarrow, P.;
Rooney, D. W.; Thompson, J. M. Ind. Eng. Chem. Res.
2006, 45, 6640–6647.
28. Fu, F.; Teo, Y.-C.; Loh, T.-P. Tetrahedron Lett. 2006, 47,
4267–4269.
29. (a) De, S. K. Tetrahedron Lett. 2004, 45, 2919–2922; (b)
Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett. 2003,
44, 6749–6753.
30. Das, S. K. Synlett 2004, 915–932.
31. Limousin, C.; Cleophax, J.; Petit, A.; Loupy, A.; Lukacs,
G. J. Carbohydr. Chem. 1997, 16, 327–342.
32. Das, S. K.; Reddy, K. A.; Krovvidi, V. L. N. R.;
Mukkanti, K. Carbohydr. Res. 2005, 340, 1387–
1392.