Trichloroisocyanuric acid (TCCA): An efficient green reagent for activation of thioglycosides toward hydrolysis

Article abstract of DOI:10.1016/j.carres.2013.01.001

Trichloroisocyanuric acid (TCCA), an inexpensive, commercially available, and non-toxic reagent has been used for the activation of thioglycosides toward their hydrolysis to the corresponding hemiacetals in high to excellent yields. The methodology provides a mild reaction condition for dealing with compounds containing acid sensitive functional groups.

Full text of DOI:10.1016/j.carres.2013.01.001

Carbohydrate Research 369 (2013) 10–13
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Note
Trichloroisocyanuric acid (TCCA): an efficient green reagent for
activation of thioglycosides toward hydrolysis
⇑
Nabamita Basu, Sajal Kumar Maity, Aritra Chaudhury, Rina Ghosh
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Trichloroisocyanuric acid (TCCA), an inexpensive, commercially available, and non-toxic reagent has been
used for the activation of thioglycosides toward their hydrolysis to the corresponding hemiacetals in high
to excellent yields. The methodology provides a mild reaction condition for dealing with compounds con-
taining acid sensitive functional groups.
Received 21 November 2012
Received in revised form 31 December 2012
Accepted 2 January 2013
Available online 9 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keyword:
Thioglycosides
Trichloroisocyanuric acid
Hemiacetals
TCCA
Hydrolysis
A careful choice of anomeric protecting group is always an
important part of planning strategy for synthesizing complex oli-
gosaccharides. Moreover, sometimes it is necessary to remove
the anomeric protecting group selectively or it is required to
transform it to an activated glycosyl donor for further glycosylation
toward the assembly of complex oligosaccharides.1 Protected
1-hydroxy sugars can be synthesized from (a) glycosyl acetates
by using hazardous hydrazine hydrate2 or by organic bases like
benzylamine or tert-butyl amine;3 (b) alkyl glycosides by hydroly-
sis of glycosidic bond under acidic conditions,4 or (c) by hydrolysis
of thioglycosides. Of which, the hydrolysis of thioglycosides is
more convenient as it opens the way for getting glycosyl hemiace-
tals having diverse functionalities under mild conditions. There-
fore, hydrolysis of thioglycosides is the first choice to chemists
for preparing glycosyl hemiacetals which can further be converted
into more reactive glycosyl donors such as trichloroacetamidate,5
fluoride,6 or can also be used as such in dehydrative glycosylation
reaction.7 Moreover, glycosyl hemiacetals have been successfully
used as synthons for the chiral synthesis of optically pure natural
products or for preparation of azasugars.8
as, use of expensive or toxic reagent,2 incompatibility of acid-
susceptible group present in the carbohydrate substrates, harsh
reaction condition, lower yields, etc. Thus, exploration of other effi-
cient reagents and metal-free conditions toward this end is worth
pursuing. Trichloroisocyanuric acid (TCCA),17 a commercially avail-
able, inexpensive, and non-toxic reagent, used in various organic
syntheses is known to be a chlorinating agent too. Very recently,
we have successfully used TCCA in the glycosylation reaction using
both armed and disarmed donors.18 Its low pKa (1.8) and high ac-
tive chlorine content (91.5%)17 indicate it to be an efficient chloro-
nium ion generator, and thus is expected to activate thioglycoside
to react with good nucleophiles without the requirement of any
other strong acids as co-activator. Our proposition was eventually
proved, as a model thioglycoside (1a) was hydrolyzed in the pres-
ence of TCCA at ambient temperature. Avoiding the use of strong
acid as co-activator could make this method more attractive for
hydrolyzing thioglycosides owing to the survival of acid-labile pro-
tecting groups present in carbohydrate derivatives. As a part of our
ongoing research to prepare hemiacetals for the synthesis of di-
verse materials, we are pleased to report herein, hydrolysis of thio-
glycosides activated by TCCA, and the results are summarized in
Schemes 1 and 2 and Tables 1–3. To the best of our knowledge, this
is the first report of thioglycoside hydrolysis by TCCA.
To date, a number of methods have been reported for hydrolysis
of thioglycosides, which include use of toxic thiophilic heavy met-
als, NIS in wet acetone, or in the presence of acid (TfOH9 or TFA10),
NBS,11 V2O5/H2O2/NH4Br,12 (NH4)6Mo7O24/H2O2–HClO4/NH4Br,13
Bu4NIO4/HClO4,14 or Bu4NIO4/TfOH,14 chloramine-T,15 and N-iodo-
saccharine.16 However, some of these suffer from limitations such
At the outset, the reaction condition was standardized from a
set of few reactions of 1a done under different conditions (Table 1).
Under the standard condition 1a reacted in aqueous acetone (1:4)
at ambient temperature in the presence of TCCA (1 equiv) generat-
ing the corresponding hemiacetal (1b) in excellent yield (Table 1,
entry 3).
⇑
Corresponding author. Fax: +91 033 2414 6266.
E-mail addresses: ghoshrina@yahoo.com, ghosh_rina@hotmail.com (R. Ghosh).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.01.001

N. Basu et al. / Carbohydrate Research 369 (2013) 10–13
11
Table 1
TCCA
Standardization of solvent and reagent load
wet (CH3)2CO
O
O
SR
OH
PO
PO
a
b
0 °C to r.t.
Scheme 1. TCCA mediated conversion of thioglycoside to the corresponding
hemiacetal.
Then the efficiency of this procedure was compared with some
reported reagents using 1a as the starting material. Though other
reagents furnished 1b in high yields, the best result was obtained
with TCCA (Table 2, entry 1).
Entry
Solvent
TCCA (equiv)
Yielda (%)
1
2
3
4
5
(CH3)2CO/H2O (9:1)
(CH3)2CO/H2O (9:1)
(CH3)2CO/H2O (9:1)
CH3CN/H2O (9:1)
CH3Cl2/H2O (9:1)
0.5
1.0
1.0
1.0
1.0
81
92
97
90
87
After the success of the initial reaction we turned our attention
to the evaluation of the hydrolyzing capability of TCCA on a series
of thioglycoside derivatives. A variety of other thioglycosides
(Fig. 1) bearing OAc, OBz, OBn, Nphth, acetal, etc. protecting groups
reacted under the standard protocol to produce the corresponding
hemiacetals in high to excellent yields (Table 3). In no case, forma-
tion of trace of sugar-isocyanuric acid adduct could be detected.
Glucose, galactose, and mannose based ester and ether pro-
tected thioglycosides (entries 1, 2, 4, 5, 6, 7, 9, 10, and 11) were
hydrolyzed within 30 min resulting in the desired products in
excellent yields (85–97%, Table 3). Acid labile benzylidene protect-
ing groups in the substrates (entries 3 and 8) remained unaffected
during the course of reaction, and no decomposition was observed,
thus the corresponding hemiacetal products (3b and 8b) were ob-
tained in excellent yields. Benzylidene and ester protected glucosa-
mine donors (entries 15–17) needed longer reaction time (1 h) for
completion of hydrolysis to furnish the corresponding hemiacetals
(14b–16b). Fuco- (entry 13) and rhamno- (entry 12) thioglycosides
also took longer reaction time (1 h) for completion of reactions; the
resulting products were obtained in high yields (85–87%, Table 3).
Hydrolysis of perbenzylated thiofucoside (13a) was complete in
30 min to give 13b in 94% yield (entry 14). Cellobiose, lactose,
and maltose derived thioglycoside donors produced the corre-
sponding hemiacetals (17b–19b, entries 18–20) in excellent yields
(91–95%) within an hour. Differentially protected disaccharide
a
Chromatographed yield.
Table 2
Hydrolysis of thioglycoside (1a) using different reagents
Entry
Solvent
mmol/1 mmol 1a
Yielda (%)
1
2
3
4
5
6
7
TCCA
1.0
97
90
95
88
90
90
87
NIS/H2SO4–Silica19
N-Iodosaccharin16
NIS/TFA10
1.2/100 mg
1.5
1.0/1.0
1.5/0.10
2.0
NIS/TfOH9
NBS11
20
NBS/CaCO3
2.0/5.0
a
Chromatographed yield.
based thioglycoside (20a25) generated from
D-glucosamine took
of thioglycosides under mild condition. A variety of commonly
used, acid labile protecting groups remain unaffected in the pres-
ence of this reagent.
2 h to afford the corresponding hydrolyzed product (20b) in 86%
yield. Finally the efficiency of this methodology was again
established by hydrolysis of 2a, 3a and 11a under a scale-up
condition (ꢀ20 times, 2 g scale, entries 2, 3 and 12, under paren-
theses,Table 3), which generated the corresponding products in
excellent yields (89-96 %).
This reaction is supposed to proceed following the pathway as
shown in Scheme 2.
In summary TCCA has been utilized as a commercially available,
non-toxic, inexpensive, and green reagent for efficient hydrolysis
1. Experimental section
1.1. General
Petroleum ether (PE, 60–80 °C) was used for chromatographic
purpose. Flash column chromatography was performed on Silica
O
Cl
Cl
O
N
N
O
N
Cl
O
Cl
R
O
SR
OH
S
PO
PO
PO
(CH3)2CO - H2O
a
RSCl
O
O
PO
b
Scheme 2. Plausible mechanism for thioglycoside hydrolysis.

12
N. Basu et al. / Carbohydrate Research 369 (2013) 10–13
Table 3
Trichlorocyanuric acid (TCCA) mediated efficient hydrolysis of thioglycosides
Entry
Thioglycosides
Time (h)
Product
Yielda (%)
Entry
Thioglycosides
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
1a
2a
3a
4a
5a
6a
7a
8a
9a
9a1
10a
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1b16
2b16
3b19
4b19
5b19
6b16
7b12
8b21
9b16
9b12
10b22
97
12
13
14
15
16
17
18
19
20
21
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
1.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
2.0
11b16
12b23
13b19
14b19
15b24
16b
87 (89)b
85
94
88
79
82
95
94
95 (96)b
90 (94)b
95
90
92
90
91
89
85
92
17b2
18b19
19b19
20b
9
10
11
91
86c
a
b
c
Chromatographed yield.
Scale-up (ꢀ20-fold) experiment.
TCCA was added at ambient temperature.
AcO
BzO
BzO
BnO
Ph
STol
O
O
O
O
O
AcO
BzO
BnO
O
STol
BzO
STol
OBn
STol
AcO
BnO
BnO
OAc
OBz
OBn
3a
OBn
1a
2a
4a
OAc
OBz
O
OAc
O
OBn
O
STol
STol
AcO
BnO
STol
BzO
OAc
OBn
OBz
6a
5a
7a
Ph
O
BnO
BnO
BnO
O
AcO
AcO
AcO
OBn
O
OAc
AcO
AcO
AcO
OAc
O
O
O
STol
BnO
SPh
SEt
OBn
SPh
10a
8a
9a
9a1
SPh
AcO
Me
STol
OAc
O
Me
O
STol
OBn
Me
AcO
O
O
AcO
SPh
NPhth
OAc
OAc
AcO
OBn
OBn
AcO
11a
OAc
Ph
12a
13a
14a
Ph
O
O
O
O
O
O
SPh
NPhth
BzO
SPh
NPhth
HO
15a
16a
OAc
AcO
AcO
AcO
AcO
AcO
AcO
O
O
O
OAc
O
O
O
AcO
AcO
SPh
AcO
SPh
OAc
OAc
OAc
18a
17a
AcO
AcO
AcO
AcO
BnO
AcO
O
O
AcO
O
OAc
O
O
O
AcO
SPh
OAc
AcO
19a
NPhth
NPhth
SPh
20a
OAc
Figure 1. Thioglycosides used for TCCA activated hydrolysis.
Gel (230–400 mesh). 1H and 13C NMR spectra were recorded on a
Bruker DPX 300 MHz and Bruker DPX 500 MHz spectrometer in
CDCl3. Chemical shifts were expressed in parts per million (d scale).
High Resolution Mass Spectra (HRMS) were measured in a QTOF I
(quadrupole–hexapole–TOF) mass spectrometer with an orthogo-
nal Z-spray-electrospray interface on Micro (YA-263) mass spec-
trometer (Manchester, UK).
1.2. 3-O-Benzoyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-
D-glucopyranose (16b)
To a solution of 16a (60 mg, 0.10 mmol) in wet (CH3)2CO (1:4,
3 mL), TCCA (23.55 mg, 0.10 mmol) was added at 0 °C. Then reac-
tion temperature was raised gradually to ambient temperature.
After 1 h stirring (CH3)2CO was evaporated in rotary evaporator at
reduced pressure. The reaction mass was diluted with CH2Cl2 and
washed subsequently with saturated NaHCO3 solution (50 ml)
Spectral data of all known products matched with those of the
reported ones.

N. Basu et al. / Carbohydrate Research 369 (2013) 10–13
13
and water (50 ml). The organic layer was dried over anhydrous
Acknowledgments
Na2SO4 and concentrated to afford the crude hydrolyzed product.
This was purified by column chromatography using PE/EtOAc 2:1
to give 16b (41.3 mg, 82%) as white foam. 1H NMR of the b-anomer
(500 MHz, CDCl3): d 7.88–7.87 (m, 3H, ArH), 7.69 (br s, 3H, ArH),
7.49 (t, 1H, J = 7.5 Hz, ArH), 7.43–7.41 (m, 2H, ArH), 7.36–7.30 (m,
5H, ArH), 6.23 (t, 1H, J = 9.8 Hz, H-3), 5.76 (t, 1H, J = 7.8 Hz, H-2),
5.57 (s, 1H, CHPh), 4.45 (d, 1H, J = 6.0 Hz, H-1) 4.42 (dd, 1H, d, 1H,
J = 10.0, 8.5 Hz, H-4), 3.97–3.88 (m, 3H, H-6, H-60, H-5), 3.29 (d,
1H, J = 7.0 Hz, OH); 13C NMR (50 MHz, CDCl3): d 168.2, 165.8,
137.0, 134.5, 133.4, 131.6, 130.0, 129.4, 129.3, 128.5, 128.4, 126.4,
123.9, 101.8, 93.5, 79.9, 70.1, 68.9, 66.8, 57.0. HRMS (ESI-TOF) calcd
for C28H23NO8Na [M+Na]+ calcd 524.1321, found: 524.1323.
Financial supports from CSIR, New Delhi, India (Scheme No. 01/
2382/10/EMR-II) to R.G. and from CAS-UGC and FIST-DST, India to
the Department of Chemistry, Jadavpur University are acknowl-
edged. N.B. (SRF) and A.C. (JRF) are grateful to CSIR for providing
fellowships.
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To a solution of 20a (115.5 mg, 0.12 mmol) in aqueous (CH3)2CO
(1:4, 5 mL), TCCA (28.26 mg, 0.12 mmol) was added at ambient
temperature. Then it was kept on stirring. After 2 h (CH3)2CO was
evaporated in rotary evaporator at reduced pressure. The reaction
mass was diluted with CH2Cl2 and washed subsequently with sat-
urated NaHCO3 solution (50 ml) and water (50 ml). The organic
layer was dried over anhydrous Na2SO4 and concentrated to afford
crude hydrolyzed product. This was purified by flash column chro-
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give 20b (90.0 mg, 86%) as white foam. 1H NMR of the b-anomer
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