Effective friedel-crafts acylations of O- and C-arylglycosides with triflic acid

Article abstract of DOI:10.3987/COM-08-S(F)39

Triflic acid is well known not only as a Friedel-Crafts promoter, but also as a deglycosidation reagent. In this study, we promote effective Friedel-Crafts acylations for O- or C-arylglucosides without deglycosidation and check their inhibitory activities for β-glucosidase.

Full text of DOI:10.3987/COM-08-S(F)39

HETEROCYCLES, Vol. 77, No. 1, 2009
227
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 227 - 231. © The Japan Institute of Heterocyclic Chemistry
Received, 4th July, 2008, Accepted, 22nd August, 2008, Published online, 25th August, 2008.
DOI: 10.3987/COM-08-S(F)39
EFFECTIVE FRIEDEL-CRAFTS ACYLATIONS OF O- AND
C-ARYLGLYCOSIDES WITH TRIFLIC ACID
Makoto Hashimoto* and Miho Takahashi
Department of Agricultural and Life Science, Obihiro University of Agriculture
and Veterinary Medicine, Inada-cho, Obihiro 080-8555, Hokkaido, Japan. E-mail;
hasimoto@obihiro.ac.jp
Abstract – Triflic acid is well known not only as a Friedel-Crafts promoter, but
also as a deglycosidation reagent. In this study, we promote effective
Friedel-Crafts acylations for O- or C-arylglucosides without deglycosidation and
check their inhibitory activities for β-glucosidase.
Carbohydrates carrying aromatic aglycons are important compounds; examples of which promote many
biological functions (antibiotics, etc).1 The aromatic substitutions of these compounds have been
performed by glycosidation of glycosyl donors and appropriate aromatic compounds. These
methodologies required several steps for protection, glycosidation and deprotection to synthesize each
glycoside. Although Friedel-Crafts reactions are one of the most popular means of derivatization for
aromatic compounds, few applications of the reactions for the derivatization of aryl-O-glycosides have
been reported. There are several reasons to explain the low solubility of unprotected aromatic glycosides
in reaction media and competitive deglycosidation in the acidic conditions for O-glycosides.
Trifluoromethanesulfonic acid (triflic acid) is widely used as a de-O-glycosidation reagent for
glycoprotein and glycolipids.2 Carbohydrate analysis of the reaction mixture indicated that triflic acid can
dissolve carbohydrates easily without decomposition of each carbohydrate unit occurring. The results
promoted the notion that selective Friedel-Crafts acylation of arylglucosides with triflic acid might be
applied as a competitive reaction against de-O-glycosidation. Phenyl-β-D-glucoside (1) was suspended in
excess acetyl chloride, and then triflic acid was added, dropwise, at 0 °C. The suspension became a
solution and was stirred for 10 min., then poured into cold water. A colorless solid formed immediately
and was filtered and no sugar moiety was included in the aqueous solution. The filtrate was subjected to
NMR analysis in CDCl3 and the analysis indicated both Friedel-Crafts reaction for the benzene ring and
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

228
HETEROCYCLES, Vol. 77, No. 1, 2009
acetylation for hydroxyl groups (2) occurred, but deglycosidation of O-aryl group was not observed.
These results indicated that triflic acid promoted the acylation of hydroxyl groups and the benzene ring
(this occurred within 10 minutes), over de-O-glycosidation in the presence of excess acetyl chloride. The
long incubation caused de-O-glycosidation and afforded a complex mixture within an hour. The
effectiveness of the triflic acid equivalents was examined for Friedel-Crafts acylations. Compound 1 was
treated with 1.6 equivalents of triflic acid afforded only O-acetylated compound 3 in 88% yield.
OAc
O
OH
O
i)
O
AcO
AcO
HO
HO
O
O
AcO
HO
ii)
iii)
2
1
OAc
O
AcO
AcO
O
3
AcO
Scheme 1. Friedel-Crafts acylations and O-acetylation of phenyl-β-D-glucoside 1.
i) TfOH (16 equivalents), 90%/. ii) TfOH (1.6 equivalents), 98%. iii) TfOH (16
equivalents), 90%, common conditions: AcCl (solvent), 0 °C, 10 min.
Compound 3 was re-treated with 16 equivalents of triflic acid, which afforded Friedel-Crafts product (2)
in 90% yield. The results indicated O-acylation was faster than Friedel-Crafts acylations. (Scheme 1)
Table 1 shows summarized proportions of compounds 2 and 3 and phenol derivatives, which were
derived from de-O-glycosidation of aglycon, in various amounts of triflic acid. This demonstrates that
five equivalents of triflic acid facilitated equivalent amounts of compounds 2 and 3 being detected and
compound 2 being reduced in a reaction mixture with over 12.5 equivalents of triflic acid.
Table 1. Effect of TfOH quantities for Friedel-Crafts acylations, O-acetylation and
de-O-glycosidation of phenyl-β-D-glucoside 1.
2
(Friedel-Crafts
TfOH
(equivalent) and O-acylated)
3
(O-acetylated)
phenol
derivatives
1
2
1
98
95
35
20
5
1
3
2
5
35
45
80
90
30
35
15
5
8
12.5
16
5

HETEROCYCLES, Vol. 77, No. 1, 2009
229
The acylations with triflic acid were applied to other O-arylglucosides. 4-hydroxyphenyl β-glucoside 4
afforded per-O-acetylated compound 5 in 63% yield and no Fries rearrangement products were detected.
4-Methoxyphenyl β-glucoside 6 afforded 3-acetyl-4-methoxypheyl tetra-O-acetyl β-glucoside 73 in 66%
and no regioisomer of acetyl group on the aromatic ring was detected from NOE measurement.
O-Arylglucosides which have electron-withdrawing groups (CHO, COOH and NO2) on the benzene ring
afforded a complex mixture, because acidic hydrolysis was preferred to a Friedel-Crafts reaction.
OAc
O
OH
O
i)
O
AcO
AcO
HO
HO
O
O
AcO
HO
ii)
iii)
2
1
OAc
O
AcO
AcO
O
3
AcO
Scheme 2. Friedel-Crafts acylations and O-acetylation of phenyl-β-D-glucoside
derivatives 4 and 6. TfOH (30 equivalents), AcCl (solvent), 0 °C, 10 min, 63 and 66%
for 5 and 7, respectively.
OH
O
OH
O
OH
O
HO
HO
HO
HO
HO
HO
i)
OH
ii)
HO
HO
HO
O
10
9
8
iii)
iv)
O
OAc
O
OAc
O
AcO
AcO
AcO
AcO
11
12
AcO
AcO
Scheme 3. Synthesis of phenylethyl C-glucoside and its Friedel-Crafts acylations.
i) 1-phenyl 1,3-butanedione, NaHCO3, 80 °C, 3 h, 24%. ii) H2, Pd/C, CF3COOH,
rt, 10 h, 70%. iii) TfOH (30 equivalents), AcCl (solvent), 0 °C, 20 min, 90%.
iv) TfOH (10 equivalents), AcCl (solvent), 0 °C, 20 min, 13 and 87% for 11 and 12,
respectively.
Post-functionalizations for aryl glucoside were applied to C-glycoside, which is one of the major foci for
the glycobiology. Glucose 8 was treated with 1-phenyl 1,3-butanedione in the presence of NaHCO3 in
accordance with the literature,4 then 9 was subjected to reduction of aryl carbonyl group with
hydrogenation to afford phenylethyl C-glycoside 10. Acylations of hydroxyl and aromatics were achieved
with slightly large amounts of triflic acid (30 equivalents) and a long incubation time (20 min) with good
yield (115, 90%), because there was less activation of aromatic moiety than that of aryl-O-glycosides.

230
HETEROCYCLES, Vol. 77, No. 1, 2009
Less triflic acid (10 eq) was required to afford a mixture of per-O-acetyl glucoside with (11) and without
(12) acylated on the aromatic ring in proportions of 13 and 87, respectively. (Scheme 3)
OAc
O
OH
O
AcO
AcO
HO
HO
R
R
AcO
HO
O
2, 7, 11
O
O
R=
15
13
95%
14
98%
O
O
OMe
82%
Scheme 4. De-O-acetylation of alkaline labile compounds. Bu2SnO, methanol, reflux,
12 h.
The synthesized products should be de-O-acetylated to measure the inhibition for β-glycosidase activities
and subjected to de-O-acetylation methods for alkaline labile compounds, because these compounds have
α-hydrogene of acetophenone moiety. Bu2SnO in methanol with refluxing6 was very effective for these
compounds.7 (Scheme 4) Preliminary experiments for inhibition of β-glucosidase from sweet almond
were performed as indicated below. In 96 well plate, the assay mixture, which consisted of p-nitrophneyl
β-D-glucoside (1 mM) and synthesized aryl glucoside (20 mM) in 100 mM acetate buffer (pH 5.0), was
pre-incubated at 37 °C for 5 min. The enzymatic reactions were initiated by addition of β-glucosidase
(1.25 units) and terminated by the addition of 0.2 M Na2CO3 after 15 min. Inhibitions were calculated by
measurement of free p-nitrophenol at 400 nm with a titer plate reader. The results indicated C-glycosides
(9, 10, 15) have more inhibition potential than O-glycosides 13, 14, and triazole derivative 16; the last of
which was synthesized with click chemistry of azide glycosides and acetylene derivatives.
O
13
10
O
O
34 ± 1.4%
R=
49 ± 0.6%
O
O
15
14
OH
45 ± 0.6%
19 ± 1.4%
O
OMe
HO
HO
R
O
9
N
HO
16
30 ± 1.1%
N
29 ± 1.2%
O
N
Scheme 5. Inhibition rates of synthetic aryl O- or C-β-glycosides (20 mM) for the
β-glucosidase from sweet almond in the presence of p-nitorophenyl-β-glucoside (1 mM).

HETEROCYCLES, Vol. 77, No. 1, 2009
231
The Friedel-Crafts reactions for aromatic glycosides in this paper were simplified for the preparation of
many aromatic glycosides and were able to examine their biological activities more easily.
ACKNOWLEDGEMENTS
This research was partially supported by a Ministry of Education, Science, Sports and Culture
Grant-in-Aid for Scientific Research on a Priority Area, 18032007 and for Scientific Research (C),
19510210. M.H. also thanks the Fugaku Foundation and Research for Promoting Technological Seeds for
financial support for the study.
REFERENCES
1. M. Jacobsson, J. Malmberg, and U. Ellervik, Carbohydr. Res., 2006, 341, 1266.
2. A. S. B. Edge, C. R. Faltynek, L. Hof, L. E. Reichert, Jr, and P. Weber, Anal. Biochem., 1981, 118,
131.
3. Compound 7; FAB-MS m/z: 497 (MH+), 1H-NMR (CDCl3) 7.41 (1H, d, J = 2.9 Hz), 7.13 (1H, dd, J
= 9.2, 2.9 Hz), 6.90 (1H, d, J = 9.2 Hz), 5.30 – 5.23 (1H, m), 5.15 (1H, t, J = 9.2 Hz), 5.03 (1H, d, J
= 7.4 Hz), 4.26 (1H, dd, J = 12.0, 5.1 Hz), 4.18 (1H, dd, J = 12.0, 2.3 Hz), 3.90 (3H, s), 3.87 - 3.84
(1H, m), 2.41 (3H, s), 2.08 (3H, s), 2.05 (3H, s), 2.03 (3H, s), 2.00(3H, s).
4. I. Riemann, M. A. Papadopoulos, M. Knorst, and W.-D. Fessner, Aust. J. Chem., 2002, 55, 147.
5. Compound 11; FAB-MS m/z: 479 (MH+), 1H-NMR (CDCl3) 7.89 (2H, d, J = 8.0 Hz), 7.27 (2H, d, J
= 8.0 Hz), 5.14 (1H, t, J = 9.2 Hz), 5.06 (1H, t, J = 9.7 Hz), 4.93 (1H, t, J = 9.7 Hz), 4.26 (1H, dd, J
= 12.0, 6.0 Hz), 4.15 (1H, dd, J = 12.0, 3.2 Hz), 4.08 (1H, m) 3.63 - 3.59 (1H, m), 2.77 – 2.71 (2H,
m), 2.43 (3H, s), 2.05 (3H, s), 2.03 (3H, s), 2.02 (3H, s), 2.00(3H, s), 1.83-1.79 (2H, m).
6. H. –M. Liu, X. Yan, W. Li, and C. Huang, Carbohydr. Res., 2002, 337, 1763.
7. Compound 14; FAB-MS m/z: 329 (MH+), 1H-NMR (CD3OD) 7.42 (1H, d, J = 3.4 Hz), 7.30 (1H, dd,
J = 9.2, 3.4 Hz), 7.07 (1H, d, J = 9.2 Hz), 4.80 (1H, d, J = 8.0 Hz), 3.89 (3H, s), 3.87 (1H, m), 3.70
(1H, dd, J = 11.7, 4.9 Hz), 3.68 (1H, dd, J = 11.7, 2.3 Hz), 3.45 - 3.39 (2H, m), 2.57(3H, s).
Compound 15; FAB-MS m/z: 311 (MH+), 1H-NMR (CD3OD) 7.91 (2H, d, J = 8.0 Hz), 7.36 (2H, d,
J = 8.0 Hz), 4.32-4.24 (2H, m), 4.05-3.92 (3H, m), 3.89 (1H, dd, J = 12.0, 2.3 Hz), 3.66 (1H, dd, J =
12.0, 6.0 Hz), 2.84 – 2.78 (2H, m), 2.57(3H, s), 1.83-1.79 (2H, m).