Application of ball milling technology to carbohydrate reactions-II. Solvent-free mechanochemical synthesis of glycosyl azides

Article abstract of DOI:10.1080/07328300802161897

Glycosyl azides have been prepared from a range of readily available glycosyl halides by a solvent-free mechanochemical procedure employing a planetary ball mill in good to excellent yields.

Full text of DOI:10.1080/07328300802161897

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Application of Ball Milling Technology to
Carbohydrate Reactions‐II. Solvent‐Free
Mechanochemical Synthesis of Glycosyl
Azides
G. Mugunthan a & K. P. Ravindranathan Kartha a
a Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Punjab, India
Published online: 24 Jul 2008.
To cite this article: G. Mugunthan & K. P. Ravindranathan Kartha (2008) Application of Ball Milling Technology
to Carbohydrate Reactions‐II. Solvent‐Free Mechanochemical Synthesis of Glycosyl Azides , Journal of
Carbohydrate Chemistry, 27:5, 294-299
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Journal of Carbohydrate Chemistry, 27:294–299, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802161897
Application of Ball Milling
Technology to
Carbohydrate Reactions-II.
Solvent-Free
Mechanochemical
Synthesis of Glycosyl
Azides‡
G. Mugunthan and K. P. Ravindranathan Kartha
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Punjab, India
Glycosyl azides have been prepared from a range of readily available glycosyl halides by
a solvent-free mechanochemical procedure employing a planetary ball mill in good to
excellent yields.
Keywords Glycosyl azides, Ball mill, Solvent-free synthesis
INTRODUCTION
Synthetic carbohydrate chemistry relies heavily on the use of expensive pro-
tecting group manipulations, which is largely unavoidable, for carrying out
selective reactions on polyfunctional molecules such as sugars. While on the
Received March 3, 2008; accepted April 24, 2008.
‡We have performed several (at least 25 including four 5-g scale reactions) preparative
grinding experiments employing NaN3 during this work and no untoward incidents of
any kind were observed. Even though sodium azide is considered safe to handle, see
reference [13], due caution must be exercised during all experiments involving NaN3.
For Part I see Ref. [8].
Address correspondence to K. P. Ravindranathan Kartha, Department of Medicinal
Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S.
Nagar, Punjab 160 062, India. E-mail: rkartha@niper.ac.in
294

Solvent-free Mechanochemical Synthesis of Glycosyl Azides
295
one hand the high expenditure of chemicals, time, and work involved tends to
greatly restrict the broad industrial use of carbohydrate derivatives, the
advent of glycobiology and better understanding of the role of glyconjugates
in various diseases have, on the other, led to greater demand for synthetic
carbohydrates and their derivatives.[1] Hence, there is an increased need for
more efficient and environment friendly ways of making carbohydrate deriva-
tives. Glycosyl azides, for example, are highly useful in synthesizing various
neoglycoconguates, which serve as mimics for glycoconjugates, by click chem-
istry.[2,3] Further, azides are good starting materials for preparing other
nitrogen-containing functionalities such as amines, amides, ureas, carbodii-
mides, and others.
Different methods for the preparation of glycosyl azides have recently been
reviewed by Gyorgydeak.[4] One of the early methods of synthesis, which is still
in use, involves the reaction of a glycosyl halide with an inorganic azide, like
sodium/silver azide, often using DMF as the solvent.[3] Variations of this
method include the use of a phase transfer catalyst in a two-phase system.[5]
Glysosyl azides can also be prepared by treating the corresponding per-O-
acetylated sugars with TMSN3 in the presence of a Lewis acid such as
SnCl4.[6,7] Also, treatment of the protected cyclic 1,2-sulfites of monosacchar-
ides with NaN3 in DMF has resulted in the formation of the corresponding
1,2-trans-linked glycosyl azides with a free 2-OH group.[4] However, to date
no solvent free, greener synthesis of glycosyl azides has been reported.
We have recently observed that a commercially available planetary ball
mill is very convenient for carrying out solvent-free reactions under standar-
dized and reproducible conditions;[8] and the regioselective protection of the
primary -OH group of various hexosides and a nucleoside was successfully
carried out with high efficiency.[8] Further to this, we now report our findings
on the displacement of different glycosyl halides by sodium azide under dry
milling conditions.
´
¨
RESULTS AND DISCUSSION
Initial studies for the optimization of the reaction conditions were carried out
using acetobromoglucose (1) as the substrate. It was found that on treatment
with 10 mol equiv of NaN3 the reaction was complete in 8 h at 500 rpm
giving the corresponding glycosyl azide 2 in virtually quantitative yield
(entry 1, Table 1). Without the need for purification by column chromatography,
neat product was obtained directly by crystallization after the aqueous workup.
Use of less than 10 mol equiv of the inorganic azide required significantly
longer reaction time (results not shown). The reaction was subsequently
extended to other halide substrates (3, 5, 7, and 9) derived, respectively, from
D-galactose (another common hexose), N-acetyl-D-glucosamine (an aminosugar
derivative), D-lactose (a disaccharide), and L-arabinose (a pentose sugar), and

Table 1: Preparation of glycosyl azides from glycosyl bromides by dry ball milling.
Melting point (8C)
Yield
(%) Observed Reported Observed
Optical rotation [a]D
Halide substrate
(1 mmol)
Entry
Product
Reported
1
2,3,4,6-Tetra-O-acetyl–a-D-
glucopyranosyl bromide (1)
2,3,4,6-Tetra-O-acetyl–b-D-
glucopyranosyl azide (2)
99
98
98
75
87
133–136a
131.8–
135[10]
237.5
(C ¼ 1)
MeOH
28.0
237.4[10]
(C ¼ 1)
MeOH
213.8[10]
(C ¼ 1)
MeOH
246.3[11]
(C ¼ 1.1)
CHCl3
218[12]
(C ¼ 0.64)
CHCl3
2
3
4
5
2,3,4,6-Tetra-O-acetyl–a-D-
galactopyranosyl bromide (3)
2,3,4,6-tetra-O-acetyl–b-D-
galactopyranosyl azide (4)
90–91
90.9[10]
(C ¼ 1)
MeOH
2-Acetamido-3,4,6-tri-O-acetyl– 2-Acetamido-3,4,6-tri-O-acetyl
2-deoxy-b-D-glucopyranosyl
chloride (5)
Hepta-O-acetyl-a-Dlactosyl
bromide (7)
168–170a
72–75a
68–70
170–
244.1
–2-deoxy-b-D-glucopyranosyl
azide (6)
Hepta-O-acetyl-b-D-lactosyl
azide (8)
171[11]
(C ¼ 1.1)
CHCl3
74–76[12] 216.6
(C ¼ 0.6)
CHCl3
219.0
2,3,4-Tri-O-acetyl-b-
L-arabinopyranosyl bromide
(9)
2,3,4-Tri-O-acetyl-b-
L-arabinopyranosyl azide (10)
—
—
(C ¼ 1)
CHCl3)
6
7
2,3,4,6-Tetra-O-acetyl–b-D-
glucopyranosyl chloride (11)
Bromide 1 (5 g, 12.2 mmol
approximately)
Glycosyl azide (2)
Glycosyl azide (2)
95
See entry
1
See entry
1
.99
aRecrystallized from EtOAc/Petroleum ether (60–808C).

Solvent-free Mechanochemical Synthesis of Glycosyl Azides
297
the corresponding 1,2-trans-linked glycosyl azides (4, 6, 8, and 10) were
obtained in very good yields (see Table 1). Although 1,2-trans-linked
products 4, 6, and 8 were obtained from the respective 1,2-cis-linked glycosyl
bromides 3, 5, and 7, this cannot prove whether the reaction proceeds by a
direct displacement mechanism or via neighboring group participation by the
C-2 substituent on the respective sugar ring. However, the exclusive formation
of the b-L-arabinoside 10 from bromide 9 clearly indicated a reaction involving
the cyclic oxocarbonium ion intermediate (the latter course) of general struc-
ture 12. In order to further investigate the involvement of anchimeric assist-
ance by the C-2-acyl group in the reaction, acetochloro- b-D-glucose (11)[9]
was allowed to mix in the ball mill in the presence of NaN3 (entry 6, Table 1)
as described above. The product obtained was indentical with 2 in all
respects, thus confirming the involvement of the cyclic oxocarbonium ion inter-
mediate 12 formed from 11 via the C-2-acetoxy group participation. Further
evidence for this mechanism was obtained from the reaction of acetobromo-
mannose with NaN3 wherein, again, the 1,2-trans-linked a-azide was the
sole product obtained. No by-products were ever detected by TLC/NMR spec-
troscopy in any of these reactions. The reaction of bromide 1 was scaled up to
the 5-g level without affecting the yield or quality of the product (entry 7,
Table 1). In all the experiments described above the products obtained were suf-
ficiently pure the for next chemical transformation.
Solvent-free reactions of glycosyl halides with other nucleophilic reagents
such as KSCN and KSAc, phenols, and mercaptans are currently under way,
with the results showing a wide scope for making a range of sugar derivatives
employing the greener, solvent-free ball milling technique.
CONCLUSION
We have developed a solvent-free highly efficient method for the synthesis of
1,2-trans-linked glycosyl azides that can be applied on multigram quantities.
EXPERIMENTAL
All reagent chemicals were purchased from Aldrich Chemical Co. (Milwaukee,
WI, USA). TLC was performed on 0.2-mm Merck precoated silica gel 60 F254
aluminum sheets. Melting points were recorded on a capillary melting point
apparatus and are uncorrected. Specific rotations were obtained on

G. Mugunthan and K. P. R. Kartha
298
AUTOPOL IV polarimeter at 208C. IR spectra were recorded on a Nicolet FT-IR
Impact 410 instrument either as neat or KBr pellets. Mass spectra were
obtained on ultraflex TOF/TOF MALDI mass spectrometer, which is
equipped with a reflector and controlled by Flexcontrol 1.4 software package.
NMR spectra were recorded on 300-MHz Bruker FT-NMR (Avance DPX300)
spectrometer at 300 MHz for 1H and at 75.47 MHz for the 13C nucleus.
Chemical shifts are reported in ppm from TMS as the internal standard.
General Procedure for the Glycosyl Azide Synthesis using
a Planetary Ball Mill
The appropriate glycosyl halide (1 mmol) and NaN3 (10 mmol) were
allowed to mix in a stainless steel (SS) jar (capacity, 50 mL) containing SS
balls (10 numbers, 10 mm o.d) for 8 h in a planetary ball mill (Retsch PM-
100; Retsch GmbH & Co. KG, Germany) at 500/600 rpm. The mixture was
then taken up in dichloromethane and was washed in a separatory funnel
with cold water. The organic layer was dried (Na2SO4) and concentrated to
syrup under reduced pressure; addition of ether resulted in the rapid crystal-
lization, giving glycosyl azides suitable for subsequent synthetic reactions.
Preparation of 2 in multigram (5 g and above) quantities from acetobromoglu-
cose (1) resulted in the direct crystallization of 2 upon removal of solvent after
the aqueous workup. All the compounds reported here have been reported pre-
viously. Their spectral data were in accordance with the expected structures
and in agreement with literature values. The physical constants obtained are
shown in Table 1.
ACKNOWLEDGMENTS
G. Mugunthan likes to thank NIPER for the award of a research fellowship.
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