A novel protocol for the regioselective bromination of primary alcohols in unprotected carbohydrates or glycosides

Article abstract of DOI:10.1002/cjoc.201200211

The regioselective and efficient bromination of primary hydroxyl groups in unprotected carbohydrates or glycosides is successfully achieved by using (chloro-phenylthio-methylene)dimethylammoniumchloride (CPMA) in the presence of tetrabutylammonium bromide

Full text of DOI:10.1002/cjoc.201200211

FULL PAPER
DOI: 10.1002/cjoc.201200211
A Novel Protocol for the Regioselective Bromination of
Primary Alcohols in Unprotected Carbohydrates or
Glycosides
Xue, Weihua*,a(薛伟华)
Zhang, Lifenb(张立芬)
a School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China
b School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
The regioselective and efficient bromination of primary hydroxyl groups in unprotected carbohydrates or gly-
cosides is successfully achieved by using (chloro-phenylthio-methylene)dimethylammoniumchloride (CPMA) in
the presence of tetrabutylammonium bromide (TBAB) in dry DMF.
Keywords regioselective, bromide, CPMA, free sugars, glycosides
Introduction
facially substituted analogues adequate candidates to
serve as scaffolds of multicovalent systems of many
bioactive molecules.[5] Although the reagents succeed in
regioselective conversion, there remain several obsta-
cles. The most significant problem concerns the unsat-
isfactory yield, in particular when monosaccharides or
disaccharides serve as substrates of the substitution re-
action. In addition, a large port of triphenylphosphine
oxide as byproduct has to be laboriously removed.
CH3SO2Br has the high toxicity and Vilsmeier salts
show fair sensitivity to moisture so that both of them are
relatively difficult to handle. Therefore, there remains a
strong need or the development of alternative ap-
proaches to address issues of reactivity, scope, and the
use or generation of undesirable reagents or byproducts.
Wagner et al. found that selective and mild conver-
sion of primary hydroxyl groups to corresponding hal-
ides could be achieved using a readily accessible re-
The conversion of alcohols into the corresponding
alkyl halides is a significant conception of broad utility
in the synthetic procedures. Halides that act as pivotal
precursors find widespread application in the prepara-
tion of other functionalized compounds such as nitriles,
azides, amines, and thioethers. Practical procedures
available, which can be widely applied to regioselec-
tively substitute primary alcohols in the presence of
secondary ones, remain fairly limited. Especially in
glycochemistry selective substitution of the primary
hydroxyl groups of polyhydroxylated substrates is much
more challenging. The control of the synthetic regiose-
lectivity is usually complicated by the requirement of
using a protection-deprotection strategy for differentia-
tion of hydroxyl groups of similar reactivity which
makes the synthetic routes lengthy, laborious, time
consuming and in low yield.[1] Therefore, the direct in-
troduction of a substituent at a specific position is more
desired. Based on higher reactivity of primary alcohols
than secondary ones, the direct replacement of primary
hydroxyls of free saccharides and their derivatives has
been successfully achieved.[2] Most of the examples
involved the use of reagent systems containing
triphenylphosphine. In addition, CH3SO2Br and diverse
Vilsmeier-Haack reagents have been applicable for the
totally monofacial bromination of the primary hydroxyl
rim in cyclodextins.[3] These halides function as build-
ing blocks for branched glyconjugates, especially the
ability of cyclodextrins (CDs) to include spatially com-
patible molecules (guest molecules) in their hydrophobic
cavity to yield inclusion complexes[4] makes these mono-
agent
(chloro-phenylthio-methylene)dimethylammo-
nium chloride (CPMA)[6] when unprotected secondary
ones are present. The protocol led us to envisage that
the reagent may be capable of direct regioselective
halogenation of primary hydroxyls in unprotected sac-
charide derivatives. We recently developed an efficient
method for the preparation of per(6-bromo-6-deoxy)-
cyclodextrins and demonstrated their usefulness in
cyclodextrin chemistry.[7] As our continuous efforts on
seeking facile and efficient regioselective methodolo-
gies in glycochemistry, we herein would like to docu-
ment our further study that the approach is extended to
the substitution of free sugars or glycosides, which have
potential significance for the total functionalization of
the primary hydroxyl groups in carbohydrates.
*
E-mail: xuewh@lzu.edu.cn; Tel.: 0086-0931-8915686
Received March 3, 2012; accepted March 22, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200211 or from the author.
Chin. J. Chem. 2012, XX, 1—4
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1

Xue & Zhang
Table 1 Synthesis of 6-brominated sugars
FULL PAPER
Results and Discussion
Entry
1
Substrate
Product
Yield/%
While CPMA was prepared, bis(trichloromethyl)-
carbonate (BTC) instead of phosgene was dissolved into
toluene, a catalytic amount of triethylamine was added
to the above solution, and BTC rapidly decomposed into
phosgene. CPMA can be stored in the solid state at am-
bient temperature for one month without appreciable
decomposition. We have successfully used the solid
reagent when stored at －80 ℃ under nitrogen for 2
months. Pure CPMA affords clear and nearly colorless
solutions when initially dissolved in dry DMF. Methyl
α-D-glucopyranoside was selected as a model in order
to explore the optimal condition for CPMA-mediated
bromination. The reaction of model substrate (2.0 equiv.)
with CPMA (2.0 equiv.) in anhydrous DMF in the pres-
ence of tetrabutylammonium bromide (TBAB) at room
temperature for 2 h, followed by one-pot acetylation,
provided the expected bromide a in 84% isolated yield.
To show the generality and scope of the protocol for
bromide synthesis, the reaction was examined with
various structurally diverse glycosides and saccharides.
These results were summarized in Table 1. In most
cases, the bromination proceeded smoothly with CPMA
(2 equiv. per monosaccharide unit) and anhydrous
TBAB (2 equiv. per monosaccharide unit) in DMF,
giving handsome isolated yields of the desired totally
brominated derivatives at the position of C-6. We also
observed that the reaction conditions neither lead to the
anomeric inversion of glycosides and disaccharides nor
cleave glycosidic bonds, so the anomeric blocking
groups or glycosidic bonds were stable against the re-
agent. No other brominated byproducts could be de-
Br
O
OH
O
AcO
AcO
HO
HO
84
AcO
HO
OCH3
OCH3
a
Br
O
OH
O
2
82[3a]
AcO
HO
O
AcO
O
HO
7
7
b
B r
O
OH
O
A c O
A c O
HO
HO
3
4
80
92
A cO
OH
OH
O A c
OAc
HO
c
Br
AcO
OAc
O
HO
HO
HO
HO
O
AcO
d
AcO
HO
Br
O
OH
AcO
AcO
O
HO
5
6
83
88
S
S
HO
HO
e
AcO
AcO
Br
HO
HO
OH
O
O
AcO
O
AcO
Br
O
O
HO
OH
O
AcO
HO
OAc
OH
f
AcO
AcO
Br
HO
HO
OH
1
tected from the crude reaction mixtures by H and 13C
O
O
AcO
Br
HO
NMR spectroscopy. The NMR spectra reflected the na-
ture of the substituents at the primary position, primary
bromides have a particular chemical shift of around δ
3.30 for methylene protons and around δ 30 for the cor-
responding carbon.
HO
7
8
95
93
O
O
O
O
AcO
HO
OH
OH
OAc
OAc
g
Br
OH
O
AcO
AcO
O
HO
HO
AcO
Experimental
HO
S
S
h
General methods
All the reagents and solvents were commercial
products and used as received, unless otherwise noted.
NMR spectra were recorded on a Varian Mercury Plus
tetrabutylammonium bromide (4 mmol) in dry DMF (8
mL) was slowly added CPMA (4 mmol) with stirring.
The reaction mixture was stirred at room temperature
for 48 h under nitrogen. Methanol (10 mL) was added,
and the solution was filtered. After evaporation under
reduced pressure and desiccation, the residue was ac-
etylated with acetic anhydride (3 equiv. of hydroxyl
group) in pyridine (10 mL). After the reactions were
complete monitored by TLC (toluene/EtOAc or petro-
leum ether/EtOAc), the solvent was removed under re-
duced pressure and the residue was dissolved in CH2Cl2
(20 mL). The organic layer was washed with HCl (20
mL, 0.1 mol/L), dried over Na2SO4, filtered, and
evaporated to dryness. The residue was purified by flash
chromatography on silica gel leading to products.
1
400 spectrometer (400 MHz for H and 100 MHz for
13C) in CDCl3 unless stated. TLC was performed with
the plates coated with silica gel 60-F254, visualization
of spots was effected by charring with a solution of 20%
(V/V) H2SO4 in ethanol or under UV light. High resolu-
tion mass spectra (HRMS) were recorded on a Bruker
APEX II high-resolution mass spectrometer with elec-
trospray ionization (ESI).
General procedure for the synthesis of per-6-bromo-
6-deoxy-carbohydrate derivatives
To a solution of the free carbohydrates or glycosides
(2 mmol of monosaccharide unit) and anhydrous
2
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Chin. J. Chem. 2012, XX, 1—4

A Novel Protocol for the Regioselective Bromination of Primary Alcohols
Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-bromo-α-D-
glucopyranoside (a) 1H NMR (400 MHz, CDCl3) δ:
2.00 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 3.36—3.41 (m,
2H), 3.41 (s, 3H), 3.98—4.03 (m, 1H), 4.89 (dd, J＝
10.0, 3.3 Hz, 1H), 4.95—4.99 (m, 2H), 5.47 (t, J＝9.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 170.1, 170.0,
169.6, 96.7, 71.2, 70.8, 69.9, 68.5, 66.5, 55.6, 31.2, 20.7,
20.6; HRMS (ESI) calcd for C13H19 O8BrNa＋ [M＋Na＋]
405.0161, found 405.0188.
1,2,3,4-Tetra-O-acetyl-6-deoxy-6-bromo-α,β-D-
mannopyranose (c) 1H NMR (400 MHz, CDCl3) δ:
1.99 (s, 3H), 2.03 (s, 3H), 2.10 (s, 3H), 3.40—3.53 (m,
2H), 4.03—4.07 (m, 1H), 5.10—5.35 (m, 3H), 5.48 (d,
J＝2.8 Hz, 1H), 6.10 (d, J＝1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 170.2, 170.0, 169.8, 169.6, 169.5,
168.3, 168.0, 90.5, 90.28, 74.4, 71.8, 70.4, 68.5, 68.4,
68.1, 68.0, 30.8, 30.2, 20.8, 20.6, 20.5; HRMS (ESI)
calcd for C14H19O9BrNa＋ [M＋Na＋] 433.0105, found
433.0104.
Phenyl 2,3,4-tetra-O-acetyl-6-deoxy-6-bromo-β-
D-thiogalactopyranoside (d) 1H NMR (400 MHz,
CDCl3) δ: 2.12 (s, 3H), 2.13 (s, 3H), 2.14 (s, 3H), 3.31
—3.46 (m, 2H), 3.90—3.93 (m, 1H), 4.73—4.76 (m,
1H), 5.04—5.08 (m, 2H), 5.56 (d, J＝10.1 Hz, 1H),
7.31—7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ:
170.0, 169.9, 169.8, 132.9, 132.7, 132.6, 132.4, 129.0,
128.9, 90.4, 81.3, 79.7, 71.9, 67.8, 28.1, 20.5, 20.6, 20.7;
HRMS (ESI) calcd for C18H21O7BrSNa＋ [M＋Na＋]
483.0105, found 483.0083.
1,2,3,4-Tetra-O-acetyl-6-deoxy-6-bromo-α-D-glu-
copyranose (e) 1H NMR (400 MHz, CDCl3) δ: 2.04 (s,
3H), 2.06 (s, 3H), 2.07 (s, 3H), 2.12 (s, 3H), 3.39—3.47
(m, 1H), 3.48—3.50 (m, 1H), 5.09—5.17 (m, 2H), 5.26
(t, J＝7.2 Hz, 1H), 5.47 (t, J＝7.2 Hz, 1H), 6.35 (d, J＝
3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 170.1,
169.6, 169.3, 169.1, 91.5, 73.4, 72.6, 70.6, 70.5, 30.2,
20.8, 20.6, 20.5; HRMS (ESI) calcd for C14H19O9BrNa＋
[M＋Na＋] 433.0105, found 433.0083.
2',3',4'-Tri-O-acetyl-6-deoxy-6-bromo-α-D-gluco-
pyranosyl-(1→4)-1,2,3-tri-O-acetyl-6-deoxy-6-bromo-
D-glucopyranose (f) 1H NMR (400 MHz, CDCl3) δ:
1.99—2.12 (m, 36H), 3.43—3.44 (m, 2H), 3.64—3.67
(m, 2H), 3.74—3.76 (m, 2H), 3.77—3.80 (m, 2H), 4.04
—4.11 (m, 2H), 4.13—4.18 (m, 4H), 4.84—4.88 (m,
2H), 5.07—5.09 (m, 4H), 5.28—5.50 (m, 6H), 5.80 (d,
J＝8.0 Hz, 1H), 6.27 (d, J＝3.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 170.5, 170.4, 170.3, 170.0, 169.9,
169.6, 169.3, 169.2, 169.1, 168.8, 95.4, 91.0, 90.9, 75.0,
74.7, 73.4, 73.1, 72.9, 72.8, 71.7, 70.5, 70.2, 70.0, 68.9,
68.6, 67.8, 33.1, 32.5, 20.3—20.8; HRMS (ESI) calcd
for C24H32O15Br2Na ＋ [M ＋Na ＋ ] 741.0010, found
741.0026.
2,2',3,3',4,4'-Hex-O-acetyl-6,6'-dideoxy-6,6'-di-
bromo-α,α-D-trehalose (g) 1H NMR (400 MHz,
CDCl3) δ: 2.00 (s, 3H), 2.02 (s, 3H), 2.08 (s, 3H), 3.29
—3.40 (m, 2H), 4.09—4.14 (m, 1H), 4.94 (t, J＝10 Hz,
1H), 5.14—5.17 (m, 1H), 5.37 (d, J＝3.6 Hz, 1H), 5.49
(t, J＝10 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
169.9, 169.6, 169.4, 91.9, 71.2, 69.9, 69.8, 69.3, 30.4,
20.9, 20.6; HRMS (ESI) calcd for C24H36O15Br2N＋ [M
＋
＋NH4 ] 736.0446, found 736.0461.
Ethyl 2,3,4-tetra-O-acetyl-6-deoxy-6-bromo-α-D-
thioglucopyranoside (h) 1H NMR (300 MHz, CDCl3)
δ: 1.27 (t, J＝7.5 Hz, 3H), 1.96 (s, 3H), 1.97 (s, 3H),
2.10 (s, 3H), 2.57—2.70 (m, 2H), 3.20—3.30 (m, 2H),
4.06 (d, J＝10.1 Hz, 1H), 4.75—4.80 (m, 1H), 5.46—
5.52 (m, 1H), 5.12 (t, J＝9.6 Hz, 1H), 6.65 (d, J＝3.9
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 170.1, 169.5,
169.3, 91.5, 73.4, 72.6, 70.6, 70.5, 30.7, 28.6, 20.6, 20.5,
20.4, 11.8; HRMS (ESI) calcd for C14H21O7BrSNa＋ [M
＋Na＋] 435.0089, found 435.0099.
Conclusions
In conclusion, a novel and convenient method has
been developed, by which brominated carbohydrate de-
rivatives have been efficiently synthesized from readily
available unprotected sugars or glycosides. The reaction
has a broad substrate scope and it proceeds with high
regioselectivity to furnish C6-substituted products in
satisfactory yields under mild conditions. This method-
ology is believed to have potential in a wider applica-
tion in glycoconjugate chemistry than conventional
ones.
Acknowledgement
The work was financially supported by the Funda-
mental Research Funds for the Lanzhou University
(lzujbky-2011-136) and the Natural Science Foundation
for Young Scientists in Gansu Province, China (Grant
No. 1107RJYA038).
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Xue & Zhang
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