Tetrabutylammonium tribromide (TBATB): A mild and efficient catalyst for O-isopropylidenation of carbohydrates

Article abstract of DOI:10.1016/j.carres.2010.12.018

A wide range of O-isopropylidene derivatives can be prepared from the sugars and their derivatives on reaction with acetone at room temperature by employing 2 mol % of tetrabutylammonium tribromide (TBATB) as a catalyst. Good yields, low catalyst loading, mild reaction conditions, and a non-aqueous workup procedure are some major advantages of this protocol.

Full text of DOI:10.1016/j.carres.2010.12.018

Carbohydrate Research 346 (2011) 673–677
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Carbohydrate Research
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Note
Tetrabutylammonium tribromide (TBATB): a mild and efficient catalyst for
O-isopropylidenation of carbohydrates
⇑
Abu T. Khan , Md. Musawwer Khan, Anubendu Adhikary
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2010
Received in revised form 20 December 2010
Accepted 21 December 2010
Available online 30 December 2010
A wide range of O-isopropylidene derivatives can be prepared from the sugars and their derivatives on
reaction with acetone at room temperature by employing 2 mol % of tetrabutylammonium tribromide
(TBATB) as a catalyst. Good yields, low catalyst loading, mild reaction conditions, and a non-aqueous
workup procedure are some major advantages of this protocol.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
Acetals
O-Isopropylidenation
Tetrabutylammonium tribromide (TBATB)
Acetone
The O-isopropylidene acetal group is a common protecting
group extensively used in carbohydrate chemistry for the prepara-
tion of valuable building blocks.1,2 Especially, acetonation of an
aldohexose results in the formation of an O-isopropylidene deriva-
tive with a selective unmasked hydroxyl group, depending upon
with anhydrous acetone in the presence of a catalytic amount of
acid or Lewis acid, for example, concd H2SO4 or a combination
10
of anhydrous ZnCl2 and H3PO4.11 Literature reports reveal that a
number of catalysts have been utilized for acetonation, including
anhydrous copper(II) sulfate,12 FeCl3,13 pyridinium p-toluenesulfo-
nate (PPTS),14 iodine,15 ceric ammonium nitrate (CAN),16 Zeolite
HY,17 and montmorillonite clay.18 Recently, some methods have
also been reported using triphenylphosphine polymer-bound/io-
dine complex,19 sulfuric acid immobilized on silica,20 vanadyl tri-
the nature of the sugar. For example,
with acetone in presence of a catalyst provides 2,3:5,6-di-O-isopro-
pylidene- -mannofuranose (15) with an unprotected hydroxyl
group at the anomeric position. However, -glucose (2) gives
-glucofuranose (16) on acetona-
D-mannose (1) on reaction
a
-D
D
1,2:5,6-di-O-isopropylidene-
a-
D
flate (VO(OTf)2ꢀxH2O)21
, or bromodimethylsulfonium bromide
tion, leaving a free OH group at the C-3 position.3 These com-
pounds serve as glycosyl acceptors,4 glycosyl donors5 and
valuable starting materials for the synthesis of various natural
(BDMS).22 However, many of these procedures have one or more
drawbacks such as an excessive amount of catalyst,18 harsh reac-
tion conditions,20 and inert atmospheric reaction conditions.19,21
Although a large number of methods have been developed over
the years, there is still a need to find better alternatives by explor-
ing new reagents as catalysts for the preparation of O-isopropyli-
dene derivatives.
products.6 For example, 2,3:4,5-di-O-isopropylidene-
D-xylose
diethyl dithioacetal (24) has been utilized for the total synthesis
of (+)-phorboxazole A, a potent cytostatic agent.7 Recently, the O-
isopropylidene derivative of galactose, 1,2:3,4-di-O-isopropyli-
dene-
a
-
D
-galactopyranose (17), has been used for conformational
A few years ago, Chaudhuri et al. reported23 the environmen-
tally benign synthesis of various organic ammonium tribromides
and their application in bromination reactions. Later on, we have
shown the efficacy of these solid organic ammonium tribromides
for the deprotection of dithioacetals,24 the interconversion of car-
bonyl compounds into 1,3-oxathiolanes and vice-versa,25 as well
studies as well as in theoretical calculations.8 In addition, some
of these isopropylidene derivatives, namely 1,2:5,6-di-O-isopro-
pylidene-a-D-glucofuranose (16), exhibits antipyretic and anti-
inflammatory activities with a low toxicity.9 Therefore, there is a
continuous research interest to prepare these important class of
compounds in a large quantities.
as the synthesis of a
-bromo enones26 and various naturally occur-
Conventionally, the O-isopropylidene acetal derivatives of sug-
ars are usually prepared from the corresponding sugar on reaction
ring flavone derivatives.27 A wide variety of organic transforma-
tions have also been developed by others involving
tetrabutylammonium tribromide (TBATB).28–33 Knowing the un-
ique behavior, properties, and stabilities of these reagents, we con-
ceived the idea that tetrabutylammonium tribromide (TBATB)
⇑
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.12.018

674
A. T. Khan et al. / Carbohydrate Research 346 (2011) 673–677
might be a useful catalyst for the preparation of various O-isopro-
pylidene derivatives from sugars. In this paper, we report our suc-
cessful results as depicted in Scheme 1.
nation products from disaccharides, which will be reported in
due course.
Interestingly, we note that the conversion of the various free
sugars to the respective O-isopropylidene derivatives can be
achieved on a larger scale (100 mmol) without any difficulty by
using only 1 mol % of the catalyst. For example, the reaction of
For our present study, we prepared TBATB by following the
standard literature procedure.23 Initially, the reaction of
D-man-
nose (1) was carried out in anhydrous acetone in presence of
0.5 mol % TBATB. The reaction was incomplete even after 8 h of
stirring. Again, the same reaction was performed with 1, 2, and
5 mol % of catalyst, respectively. The best results (see Table 1) were
obtained using 2 mol % catalyst with complete conversion within
2 h that furnished the product in 96% yield. The product was ob-
the diethyl dithioacetal of L-arabinose (entry 9, 25.6 g, 100 mmol)
was investigated in dry acetone (400 mL) in the presence of TBATB
(1 mmol). The reaction was complete within 2 h, and the desired
product 23 was obtained in 91% yield. The above result indicates
that a large-scale reaction is also feasible using a lesser amount
of catalyst.
tained as 2,3:5,6-di-O-isopropylidene-a-D-mannofuranose (15), a
thermodynamically controlled product, which was characterized
by the usual spectroscopic data, melting point, and specific rota-
tion. These data closely matched with the reported data.19 It is
worthwhile to mention that the same transformation was also
achieved within 1 h using 5 mol % catalyst.
The formation of the product may be explained as follows: It
was proposed earlier that benzyltrimethylammonium tribromide
can react with alcohol to generate dry HBr in the medium.34 We
thus propose that dry HBr generated in situ catalyzes the O-isopro-
pylidenation reaction of sugars or other sugar derivatives to the
After optimizing the reaction conditions, other aldohexoses such
corresponding O-isopropylidene compounds. The reaction of
mannose (1) and acetone was also examined with aqueous 48%
HBr (5 L) at room temperature. It was found that it requires a
longer reaction time and provides a relatively low yield (64%) of
product. Furthermore, the efficiency of TBATB in comparison with
other catalysts is shown in Table 3. All products were fully charac-
terized by IR, 1H and 13C NMR spectroscopy, specific rotation, and
elemental analysis.
D-
as
reaction andyieldedtheproducts16(88%) and17(89%)respectively.
Next, a range of aldopentoses such as -arabinose, -xylose and
-ribose (entries 4–6, Table 2) were smoothly converted into the
corresponding O-isopropylidene derivatives 18–20 in good yields.
To explore further the scope of this reaction, -rhamnose (7) and
-mannitol (8) were transformed into the corresponding aceto-
D-glucose (2) and D-galactose (3) were tried for isopropylidenation
l
L
D
D
L
D
nides 21 and 22 under similar reaction conditions. It is important
to mention here that a wide variety of diethyl dithioacetal deriva-
tives of various sugars such as L-arabinose, D-xylose, and L-rham-
nose (entries 9–11, Table 2) were also converted into the
corresponding products 23–25 in good yields without any effect
on the dithioacetal group. Further, we have extended our protocol
In summary, we have demonstrated a simple and efficient
method for the preparation of O-isopropylidene derivatives from
free sugars as well as from acyclic sugar derivatives by employing
TBATB as catalyst. The notable advantages of the present protocol
are the following: good yields, short reaction times, a stable and
easy to handle catalyst, as well as a lower amount of catalyst load-
ing. Due to its operational simplicity, generality, and efficacy, this
method is expected to have wider applicability for the preparation
of various O-isopropylidene derivatives of sugars.
for the O-isopropylidenation of methyl a-glucopyranoside (12) and
uridine (13) and have provided the desired products 26 and 27 in
good yields as shown in Table 2. Unfortunately, we did not get the
desired product while the reaction was carried out with disaccha-
ride derivative 14 in acetone using TBATB as catalyst under identi-
cal reaction reactions. However, we are trying to find out the
suitable reaction conditions to obtain the desired O-isopropylide-
1. Experimental
1.1. General methods
Starting materials and reagents used were of commercial grade.
The progress of all reactions was monitored by TLC using plastic
sheets precoated with Silica Gel 60 F254 to a thickness of 0.2 mm
(E. Merck). Spots were detected by MOSTAIN solution (by dissolv-
ing 20 g ammonium heptamolybdate and 0.4 g cerium(IV) sulfate
in 400 mL 10% H2SO4 solution). Column chromatography was car-
ried out using silica gel (60–120 mesh, E. Merck, or Qualigen).
Melting points were determined on a Büchi melting point appara-
tus and are uncorrected. Optical rotations were measured with a
Perkin–Elmer 343 Polarimeter at 25 °C. IR spectra were recorded
on a Perkin–Elmer IR spectrophotometer. 1H and 13C NMR spectra
were recorded on a Varian (400 MHz) spectrometer using TMS as
the internal standard. Chemical shifts are expressed in parts per
million (d in ppm) in the order of multiplicity, coupling constant
(in Hz), no. of protons and signal assignment. Elemental analysis
was performed using a Perkin–Elmer CHNS/O-2400 Series II ele-
mental analyzer.
Sugar
Sugar
TBATB
dry acetone
rt
O
O
OH OH
(85-96%)
Scheme 1. O-Isopropylidenation of sugars.
Table 1
Screening of amount of TBATB for the O-isopropylidation of D-mannose at room
temperature
O
O
O
H
O
O
HO
HO
HO
O
TBATB (2 mol%)
dry acetone, rt
O
OH
OH
1.2. General experimental procedure
Entry
Catalyst (mol %)
Time (h)
Conversiona (%)
Yieldb (%)
1
2
3
4
5
No catalyst
0.5
1
2
5
12
8
5
2
1
0
50
70
100
100
0
75
80
96
94
To a stirred solution of the sugar (2 mmol) in dry acetone
(10 mL) tetrabutylammonium tribromide (TBATB) (19 mg,
0.04 mmol) was added at room temperature. The reaction was
monitored by TLC as mentioned in Table 2. After completion of
the reaction, one drop of NEt3 was added to reaction mixture,
and then acetone was removed on a rotary evaporator. Then the
a
The reactions were performed with 2 mmol scale in 10 mL of dry acetone.
Isolated yield based on starting material recovery.
b

A. T. Khan et al. / Carbohydrate Research 346 (2011) 673–677
675
Table 2
Results of the O-isopropylidenation of free sugars and their derivatives using TBATB as catalyst
Entry
Substrate
Product
Time (h)
Yielda,b (%)
Reference
HO
O
O
HO
HO
HO
O
O
O
O
1
OH
2
96
19
19
OH
O
1
15
OH
O
O
O
HO
HO
O
OH
2
8
88c
OH
OH
O
2
16
OH
O
OH
O
OH
O
O
HO
3
4
5
8
5
3
89c
19
19
22
OH
OH
O
O
3
17
OH
O
O
O
O
HO
86
OH
OH
O
O
4
18
O
HO
HO
O
O
O
O
OH
OH
89
5
O
O
19
HO
O
OH
OH
HO
OH
OH
OH
OH
6
1.5
86
19
O
O
O
6
20
O
O
HO
HO
HO
Me
HO
O
7
8
OH
1
2
88
94
22
22
7
21
OH OH
O
O
OH
O
O
OH OH
O
O
8
22
OH SEt
SEt
O
SEt
SEt
HO
HO
O
9
1.5
1.5
91
85
22
22
OH OH
O
O
23
O
9
OH SEt
SEt
SEt
SEt
O
10
O
O
OH OH
10
24
OH SEt
O
SEt
SEt
OH
OH
SEt
11
1
87
22
O
OH
OH OH
11
25
(continued on next page)

676
A. T. Khan et al. / Carbohydrate Research 346 (2011) 673–677
Table 2 (continued)
Entry
Substrate
Product
Time (h)
10
Yielda,b (%)
Reference
34
OH
O
O
HO
HO
O
O
12
13
72c
HO
OH
OH
OMe
OMe
12
26
O
O
HN
HN
O
N
O
N
O
O
O
6
76
35
HO
HO
HO
HO
OH
27
O
13
OH
O
O
O
O
OH
O
OH
O
HO
HO
HO
14
HO
24
0.0
O
O
STol
STol
HO
HO
OH
OH
28
14
a
All products were characterized by 1H NMR and 13C NMR spectroscopy and by specific rotation and elemental analysis.
The reaction was carried out with the sugar (2 mmol) in dry acetone (10 mL) using 2 mol % of catalyst TBATB.
A trace amount of sugar remains undissolved.
b
c
Table 3
O-Isopropylidenation of D-glucose and D-mannose using various catalysts and their amount of loading
Entry
1
Substrate
Catalyst
Amount (mol %)
Time (h)
Yielda (%)
FeCl3
Iodine
)–Ph2P–I2
VO(OTf)2
BDMS
>10
>10
200
5
6
4
8313
D-Glucose
8015
30 min
10
10
9519
8921
5
8422
TBATB
FeCl3
Iodine
)–Ph2P–I2
VO(OTf)2
BDMS
2
8
1
88 (in this work)
2
>10
>10
200
5
5
2
9013
D-Mannose
25 min
30 min
3
2
2
8515
9519
9221
9022
TBATB
96 (in this work)
a
Isolated yields.
crude residue was passed through a silica gel column to obtain the
desired product in pure form. Compounds 15, 16, and 22 were iso-
lated from the crude mixture by direct recrystallization after
removing excess acetone. The spectral data of the compounds
15–18 and 20 have previously been reported,19 and the spectral
data are in good agreement with our data. Similarly, the spectral
data of the compounds 19 and 21–25 have recently been
reported.22
1.2.2. 20,30-O-Isopropylideneuridine (27)
White solid: mp 145–146 °C (lit.35 146–1147 °C); IR (KBr):
3430, 3316, 2984, 1691, 1586, 1375, 1221, 1031, 847 cmꢂ1 1H
;
NMR (400 MHz, CDCl3): d 1.37 (s, 3H, CH3), 1.58 (s, 3H, CH3),
2.99 (br s, 1H, NH), 3.81 (br d, J = 11.6 Hz, 1H, H-50), 3.92 (br d,
J = 11.6 Hz, 1H, H-50), 4.30 (d, J = 3.2 Hz, 1H, H-40), 4.96 (dd,
J = 3.6, 6.4 Hz, 1H, H-20), 5.04 (dd, J = 2.8, 6.4 Hz, 1H, H-30), 5.59
(d, J = 1.6 Hz, 1H, H-10), 5.74 (d, J = 8.0 Hz, 1H, H-5), 7.39 (d,
J = 8.0 Hz, 1H, H-6), 9.11 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3):
d 25.3, 27.2, 62.1, 80.6, 84.4, 86.9, 94.2, 102.3, 114.4, 142.4, 150.7,
164.3; Anal. Calcd for C12H16N2O6 (284.27): C, 50.70; H, 5.67; N,
9.85. Found: C, 50.53; H, 5.51, N, 9.96.
1.2.1. Methyl 4,6-O-isopropylidene-a-D-glucopyranoside (26)
White solid: mp 112–114 °C (lit.34 116 °C); ½a D25
ꢁ
+108.6 (c 1.0,
H2O) [lit.34
½
a 2D5
+111 (c 1.0, H2O]; IR (KBr): 3436, 2975, 2948,
ꢁ
1371, 1228, 1201, 1068, 974, 835 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d 1.42 (s, 3H, CH3), 1.49 (s, 3H, CH3), 2.59 (d, J = 2.0 Hz, 1H, OH),
3.41 (s, 3H, CH3), 3.52 (q, J = 9.6 Hz, 1H, H-5), 3.54–3.64 (m, 2H,
H-2, and H-4), 3.73 (t, J = 10.8 Hz, 1H, H-60), 3.77 (t, J = 10.0 Hz,
1H, H-3), 3.86 (dd, J = 10.8 Hz, J = 5.6 Hz, 1H, H-6), 4.74 (d,
J = 3.6 Hz, 1H, H-1); 13C NMR (100 MHz, CDCl3): d 19.3, 29.3,
55.6, 62.5, 63.5, 72.1, 73.2, 73.7, 99.9, 100.0; Anal. Calcd for
Acknowledgments
M.M.K. is thankful to UGC, New Delhi, India for his research fel-
lowship. The authors are grateful to the Director, IIT Guwahati, for
providing the general facilities to carry out this work. The authors
are thankful to Professor M. K. Chaudhuri, Vice-chancellor, Tezpur
University for the method of preparation of tetrabutylammonium
C10H18O6 (234.25): C, 51.27; H, 7.75. Found: C, 51.16; H, 7.58.

A. T. Khan et al. / Carbohydrate Research 346 (2011) 673–677
677
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valuable comments and suggestions.
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