Radical-mediated bromination of carbohydrate derivatives: Searching for alternative reaction conditions without carbon tetrachloride

Article abstract of DOI:10.1016/S0040-4039(02)02205-0

KBrO₃-Na₂S₂O₄ in CH₂Cl₂-H₂O or PhCF₃-H₂O biphasic solvent systems was applied to the bromination of several monosaccharide derivatives having capto-datively

Full text of DOI:10.1016/S0040-4039(02)02205-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8849–8852
Radical-mediated bromination of carbohydrate derivatives:
searching for alternative reaction conditions without
carbon tetrachloride
Katalin Czifra´k and La´szlo´ Somsa´k*
Department of Organic Chemistry, University of Debrecen, H-4010, POB 20, Debrecen, Hungary
Received 29 August 2002; revised 26 September 2002; accepted 4 October 2002
Abstract—KBrO3–Na2S2O4 in CH2Cl2–H2O or PhCF3–H2O biphasic solvent systems was applied to the bromination of several
monosaccharide derivatives having capto-datively substituted reaction centres. With less reactive compounds neat PhCF3 was
shown to be a suitable substitute of the health and environmentally hazardous carbon tetrachloride. © 2002 Elsevier Science Ltd.
All rights reserved.
Radical-mediated bromination is one major procedure
by which hydrogens at ring positions of carbohydrate
derivatives can directly be replaced.1–3 The regioselec-
tivity of the transformation depends largely on the
substituents at C-1 and C-5 (or C-4 in furanoid deriva-
tives), the hydrogens bound to these carbon atoms
being the subjects of the replacement,2 as illustrated in
Scheme 1. The brominated compounds offer several
possibilities for further transformations either by
homolytic or heterolytic pathways,2 and many useful
intermediates and biologically active products have
been prepared by using this reaction as a key step in
synthetic sequences.4
Generally bromine or NBS (methods a and b, respec-
tively, in Scheme 1 and Table 1) are used for radical-
mediated brominations either by illuminating
the reaction mixture with a tungsten or heat lamp or
by using benzoyl peroxide (Bz2O2) or AIBN as
radical initiators. Refluxing carbon tetrachloride is
the almost exclusively applied solvent which has some-
times been mixed with bromotrichloromethane or
chloroform in reactions with carbohydrate derivatives.2
However, accessibility of carbon tetrachloride has
been seriously restricted in recent years especially
because of its health hazards and ozone layer damaging
property.
Scheme 1. Reagents and conditions: (a) Br2, CCl4, hw, reflux; (b) NBS, Bz2O2, CCl4, reflux.
Keywords: carbohydrates; halogenation; radicals and radical reactions; substitution.
* Corresonding author. Fax: +36-52-512-900/2348; e-mail: somsak@tigris.klte.hu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02205-0

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K. Czifra´k, L. Somsa´k / Tetrahedron Letters 43 (2002) 8849–8852
With these concerns in mind alternative conditions
were sought for typical radical-mediated brominations
like those of aromatic side chains, and supercritical
CO2 was suggested as a solvent.5 For small scale lab-
oratory preparations the use of NaBrO3–NaHSO3 in
the EtOAc–H2O solvent mixture6 seemed more appro-
priate, and with slight modifications this method was
applied to cleave carbohydrate benzyl ethers and benz-
ylidene acetals7 as well as for the preparation of bis-
C-glycosyl-1,2,4-thiadiazole derivatives.8 The applica-
tion of CH2Cl2, PhH, and their biphasic mixtures
with water was investigated for the bromination, with
bromine or NBS, of oligopyridine benzylic-methyl
groups.9 With 2,5-anhydro-aldonic esters 1,1,1-
trichloroethane4e and with 2,6-anhydro-aldononitriles
and -amides chloroform and dichloromethane4f were
used as substitutes for CCl4.
chlorinated solvents, benzotrifluoride10 (PhCF3, BTF),
a hybrid organic-fluorous solvent was tried in a
biphasic system (method e) and also as a neat
medium (method f ); bromination with NBS in
CH2Cl2–H2O at reflux temperature could also be per-
formed (method g). Each of the tested methods gave
yields comparable to those of the classical procedures
using CCl4 (methods a and b).
Taking into account the costs of the reagents as well
as the simplicity of the protocols methods d and e
were investigated† further with other carbohydrate
derivatives (Table 2). It can be seen that bromination
of capto-datively substituted reaction centres2 (entries
1–10) gives similar yields by methods a, b, and d, and
the yields are somewhat lower with method e. Bromi-
nation of acetylated b-D-glucopyranosyl azide (entry
11) by method d resulted in a much lower yield than
with method b. Non-captodative centres (entries 12
and 13) were unreactive under conditions used in
methods d and e, while the use of neat BTF (method
f ) allowed C-5 bromination only with the benzoyl-
ated substrate.
Given the usefulness of the bromination of carbohy-
drate derivatives and the environmental and health
concerns of using CCl4 as solvent, in order to find
similar generally applicable reaction conditions, we
have started a systematic investigation whose first
results are disclosed here.
In conclusion, we have shown that bromination of a
wide range of carbohydrate derivatives is possible by
using the KBrO3–Na2S2O4/CH2Cl2–H2O reagent–sol-
vent system. The chlorinated solvent can be replaced
by benzotrifluoride which, applied as a neat solvent,
can also facilitate bromination of rather unreactive
centres.
Several protocols were tried for the bromination of
acetylated b-D-galactopyranosyl cyanide (Table 1): no
reaction was observed with KBrO3–Na2S2O4 in the
suggested6,7 EtOAc–H2O solvent system (method c),
but in CH2Cl2–H2O (method d), good to excellent
yields were achieved; in order to avoid the use of the
Table 1. Bromination of 2,3,4,6-tetra-O-acetyl-b-D
-galactopyranosyl cyanidea
Method
Reaction time (h)
Yield (%)
a
b
c
Br2, CCl4, hw, reflux
NBS, Bz2O2, CCl4, reflux
KBrO3–Na2S2O4 (6–6 equiv.) EtOAc–H2O, rt
KBrO3–Na2S2O4 (6–6 equiv.) CH2Cl2–H2O, rt
0.5
2
88
73
240
24
72b
27
1
No reaction
d
79
99b
88
69
75
e
f
g
KBrO3–Na2S2O4 (6–6 equiv.) PhCF3–H2O, rt
Br2, PhCF3, hw, K2CO3, reflux
NBS, CH2Cl2–H2O, AIBN, hw, reflux
3
a The reactions were performed with 0.1 g substrate.
b With 5 g substrate.
† General procedure: The sugar derivative (0.1 g) was dissolved in CH2Cl2 (3 ml, Method d) or BTF (3 ml, Method e), and KBrO3 (6 equiv.) and
Na2S2O4 (6 equiv.) in aqueous solutions (3 ml of each) were added in one portion (in the case of larger scale reactions as in entries 1 and 7 of
Table 2 the Na2S2O4 solution was added dropwise to the other components). The mixture was stirred at room temperature until disappearance
of the starting material (TLC), then diluted with CH2Cl2 in both Methods. A 1 M aqueous solution of Na2S2O5 (3 ml) was added, well shaken,
and then separated. The organic phase was further washed with satd. aqueous NaHCO3 (2×5 ml), and water (5 ml), then dried with MgSO4.
After filtration and removal of the solvent(s) in vacuo the residue was purified by crystallization if necessary. The materials obtained exhibited
NMR spectra identical with those reported.

K. Czifra´k, L. Somsa´k / Tetrahedron Letters 43 (2002) 8849–8852
Table 2. Bromination of carbohydrate derivativesa
8851
a
The reactions were performed on 0.1–0.3 mmol scales unless otherwise indicated.
b For methods see Table 1.
c With 5 g starting material.
d PCP=pentachlorophenyl.
e In CHCl3.
f Pure crude product (yield: 75% after crystallization from ethanol).
g Pure crude product (yield: 80% after crystallization from ethanol).
h From 2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl azide.

8852
K. Czifra´k, L. Somsa´k / Tetrahedron Letters 43 (2002) 8849–8852
N. G.; Fleet, G. W. J. Tetrahedron: Asymmetry 1996, 7,
Acknowledgements
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Campbell, N.; Ble´riot, Y.; Fleet, G. W. J. Synlett 1999,
1151–1153; (f) Somsa´k, L.; Nagy, V. Tetrahedron: Asym-
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6430–6431.
This work was supported by the Hungarian Scientific
Research Fund (Grant: OTKA T32124).
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