Solvent-free mechanochemical synthesis of aryl glycosides

Article abstract of DOI:10.1080/07328300802402259

Aryl glycosides have been prepared from a range of readily available glycosyl halides by a solvent-free mechanochemical procedure employing a planetary ball mill in excellent yields. Besides being a solvent-free reaction, the procedure has been successful in eliminating the need for employing any phase-transfer catalyst in the reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/07328300802402259

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Solvent-Free Mechanochemical Synthesis
of Aryl Glycosides[ ]
Premanand Ramrao Patil a & K. P. Ravindranathan Kartha a
a Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160
062, India
Published online: 29 Oct 2008.
To cite this article: Premanand Ramrao Patil & K. P. Ravindranathan Kartha (2008): Solvent-Free
Mechanochemical Synthesis of Aryl Glycosides[ ] , Journal of Carbohydrate Chemistry, 27:7, 411-419
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Journal of Carbohydrate Chemistry, 27:411–419, 2008
ꢀC
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300802402259
Solvent-Free
Mechanochemical Synthesis
of Aryl Glycosides[1]
Premanand Ramrao Patil and K.P. Ravindranathan Kartha
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, S.A.S. Nagar, Punjab 160 062, India
Aryl glycosides have been prepared from a range of readily available glycosyl halides
by a solvent-free mechanochemical procedure employing a planetary ball mill in excel-
lent yields. Besides being a solvent-free reaction, the procedure has been successful in
eliminating the need for employing any phase-transfer catalyst in the reaction.
Keywords Aryl glycoside synthesis; Mechanochemical reactions; Chemistry by ball
milling; Solvent-free synthesis
INTRODUCTION
Aryl glycosides are of significant importance to both chemists and biologists
because of their medicinal properties, because of their widespread occurrence
in nature, and because they serve as suitable substrates in various enzyme
assays.[2] They are useful in carbohydrate-lectin interaction studies[3] (serving
as inhibitors) and serve as building blocks in oligosaccharide synthesis as well
as substrates for the synthesis of C-glycosidic compounds by rearrangement.[4]
A number of methods are available for their syntheses,[5] but the one employ-
ing phase-transfer catalysis is perhaps the most convenient besides being the
most widely used in recent times.[3,6] However, the method often suffers from
drawbacks such as β-elimination and hydrolysis, leading to a decrease in yields
of the reaction.[6e] In view of our recent findings[7] that facile regioselective
tritylation of various hexosides and nucleosides as well as displacement of
anomeric halides by inorganic azides can be done under solvent-free condi-
tions in a commercially available planetary ball mill, an investigation of the
Received 7 June 2008; accepted 27 July 2008.
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
411

P. R. Patil & K. P. R. Kartha
412
mechanochemical glycosylation of phenol and substituted phenols was initi-
ated using acetylated glycosyl halides as glycosyl donors under solvent-free
conditions without the aid of phase-transfer catalyst. The results are summa-
rized below.
RESULTS AND DISCUSSION
When a mixture of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (1,
1 mmol), phenol (2 mmol), and K2CO3(2.2 mmol) was allowed to mix in a plan-
etary ball mill at 400 rpm for 45 min, complete disappearance of the bromide 1
occurred and a product identical (TLC: eluent, EtOAc:n-Hex = 2:3) to authentic
2[6e] was formed. Aqueous workup gave, without recourse to chromatography,
crystals of 2 (yield, 85%; recrystallization from Et2O:n-Hex), the structure of
1
which was confirmed by H and 13C NMR spectroscopy (entry 1, Table 1). In
sharp contrast to the observations reported by Dess et al.[6e] (as well as others
as reported by them), it was interesting to note that no by-products arising out
of the possible β-elimination and/or hydrolysis (to lead to 3 and 4, respectively)
were detected in the reaction mixture. The present method was also seen to be
faster as well as more efficient in terms of the yield observed.
Experiments with other alkali metal carbonates as possible substitutes
for K2CO3 proved less successful (results not shown in the table). Thus, the
Na2CO3-assisted reactions (at 400 rpm for 48 hr) were shown to be consider-
ably slower as a result of which the desired phenyl glycoside 2 was obtained in
poor yield (only 40%) with the hydrolytic product 4[8] preponderating (>50%).
Use of Cs2CO3 and KOH (at 400 rpm for 15 min), on the other hand, led to
the formation of partially deacetylated products, thus giving the desired prod-
uct 2 in only low yields (31% and 47%, respectively). Further, no reaction was
observed in attempts with BaCO3, and hence the unchanged starting material
1 was recovered. Among the organic bases tried, imidazole led to the forma-
tion of the hydrolytic product 4 (as the sole product) and DABCO to the enitol
derivative 3[9] (as the sole product).
The applicability of the method using K2CO3 as the base was therefore
further evaluated by extending the reaction to some of the other important
glycosyl bromides of our specific interest. Thus, the reaction of phenol with
galactosyl bromide 5 in the presence of K2CO3 was found to take place very ef-
ficiently at 400 rpm in the ball mill, giving the corresponding 1,2-trans-linked
galactopyranoside 6[6a] in 92% yield without any need for column chromato-
graphic purification (entry 2, Table 1). The reaction was also scaled up to 5 g
without affecting the yield (entry 3, Table 1). In fact, as observed in our earlier
work, the multigram scale reactions were consistently more efficient than
the mmol scale reactions.[7a] The glycosyl bromide 7, a relatively more stable
benzobromo analog of 5, under similar conditions also underwent successful
glycosylation reaction in 1 h, giving the desired product (8) in excellent yield

Mechanochemical Synthesis of Aryl Glycosides
413
Table 1: Aryl-O-glycoside synthesis by dry ball millinga
Product
(Yield, %)
Glycosyl
bromide
Reaction
time (hr)
Entry
Ar
Reference
1
2
1
5
Ph
Ph
Ph
Ph
0.75
2 (85)
6 (92)
6e, 10
6a, 6e
6a, 6e
11
0.75
3b
4
5
0.75
6 (95)
7
1
8 (96)
9 (96)
5
1
Ph-p-OMe
Ph-p-NO2
Ph-p-NO2
Ph-p-NO2
Ph-p-NO2
Ph-p-NO2
Ph-p-NHAc
Ph-p-NHBoc
Ph-m-NHBoc
Ph-p-CHO
Ph-p-CHO
0.75
6
12
6c
7
1
10 (66)
11 (82)
10 (88)
11 (93)
13 (71)
14 (82)
15 (89)
16 (87)
17 (79)
18 (81)
13
13
13
5
6
3
1
8d
9d,e
10d
11
12
13
14
15
1
5
13
12
8
3a
1
1
14
5
3
—
5
3
—
1
3
15
5
1
16
aReactions were carried out with bromide (1 mmol):ArOH:K2CO3 in the mole ratio of 1:2:2.2 at
400 rpm and the products were isolated by crystallization after aqueous workup.
bThe reaction was carried out with 5 g (12.16 mmol) of 5.
cYield after purification by column chromatography.
dReaction was carried out with bromide (2.5 mmol):ArOH:K2CO3 in the mole ratio of 1:2:1.5 at
600 rpm.
eThe reaction was also conducted on a 12-g and 25-g scale (with respect to 5) without
affecting the yields.
(96%, entry 4, Table 1). As expected, substituted phenols bearing electron
donating groups were proved equally suitable as glycosyl acceptors, which was
evident from the facile formation of the p-methoxyphenyl glucoside 9 (entry 5,
Table 1) from 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (1). Likewise,
under the above conditions, and as to be expected, the relatively “disarmed”

P. R. Patil & K. P. R. Kartha
414
p-nitrophenol (PNP-OH) was found to be more sluggish toward the reaction
with bromides such as those described here (e.g., compare entries 1 and 2 with
6 and 7, respectively, Table 1). It also must be noted that while the reaction of
PNP-OH with the relatively more reactive galactosyl bromide 5 produced only
the desired 1,2-trans-linked glycoside (in 82% yield after recrystallization from
Et2O:n-Hex after a 6 h reaction at 400 rpm), formation of the corresponding
glycoside (yield, 66% after chromatographic purification after a 6-hr reaction
at 400 rpm) in the case of reaction with glucosyl bromide 1 was accompanied
by the formation of the elimination product 4 (approx. 30% upon chromato-
graphic isolation). It was reasoned that the formation of the by-product was
at least in part, if not solely, due to the lower reactivity of the substrates.
Therefore, based on our earlier observation that increasing the speed of mixing
had led to considerably faster reactions,[7a] when the reaction of the bromide 1
with PNP-OH was carried out at 600 rpm, the corresponding 1,2-trans-linked
glycoside was obtained as the sole product in 88% yield directly after crys-
tallization following the aqueous workup (entry 8, Table 1). Here, reducing
the amount of K2CO3 employed in the reaction was also found to be fruitful
for ensuring the favored reaction as can be seen from the table. Under these
conditions the galactopyranosyl bromide (5) also underwent complete reaction
with PNP-OH in 1 h (entry 9, yield 93%), and was equally successful when
carried out at preparative scale (in two separate experiments of 12-g and 25-g
scale). Lactosyl bromide 12 also gave satisfactory results (71% yield, entry 10,
Table 1) upon mixing under these conditions to yield the corresponding
lactoside 13. The results obtained in reactions (carried out at 400 rpm; entries
11–15, Table 1) of the gluco- and galacto-configured glycosyl bromides (1 and
5, respectively) with some of the other deactivated acceptors of interest to us
are also reported. Results of further work in this area will be reported in due
course.
CONCLUSIONS
A highly efficient practical route to aryl glycosides under solvent-free con-
ditions, requiring neither chromatographic purification nor use of a phase-
transfer catalyst, is reported for the first time in synthetic carbohydrate
chemistry.
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; the values reported below are for crystals
obtained from Et2O-n-Hex unless otherwise mentioned. Specific rotations

Mechanochemical Synthesis of Aryl Glycosides
415
were obtained on AUTOPOL IV polarimeter at 20◦C. IR spectra were recorded
on a Nicolet FT-IR Impact 410 instrument either as neat or KBr pellets. Mass
spectra were obtained on an ultraflex TOF/TOF MALDI mass spectrometer,
which is equipped with a reflector and controlled by the Flex control 1.4
software package. NMR spectra were recorded on a 300/400 MHz Bruker FT
NMR (AVANCEDPX300/AVANCEIII400) spectrometer at 300/400 MHz for the
1H and at 75.47/100.62 MHz for the 13C nuclei. Chemical shifts are reported
in ppm from TMS as the internal standard. The spectral data obtained for the
compounds reported here were in accordance with the expected structures.
General Procedure for the Aryl Glycoside Synthesis Using a
Planetary Ball Mill
The desired glycosyl halide (see Table 1 for details; e.g., entry 3: 5, 5g, 12.16
mmol), the desired phenol (e.g., Ph-OH, 24.33 mmol), and K2CO3(26.76 mmol)
were allowed to mix in a stainless steel (SS, for details see ref. [7a]) jar (capac-
ity, 50 mL) containing SS balls (10 numbers, 10 mm o.d.) in a planetary ball
mill (Retsch PM-100; Retsch GmbH & Co. KG, Germany) at 400 rpm (or 600
rpm for faster reactions) until the reaction was complete (TLC, e.g., EtOAc:n-
Hex, 2:3, 45 min for 5 and Ph-OH at 400 rpm). The mixture was then taken up
in CH2Cl2 and was washed successively with cold dil. aq. Na2CO3 solution and
water in a separatory funnel. The organic layer was dried (Na2SO4) and con-
centrated to dryness under reduced pressure to yield the respective glycoside
which was recrystallized from a suitable solvent such as Et2O-n-Hex or MeOH
or EtOH as desired [e.g., 6, 4.9 g from 5, 95%; mp 116–117◦C from Et2O-n-Hex
and 119–120◦C from MeOH (lit.[6e] 120–122◦C, solvent not known); [α]D+3.9
(lit.[6e] −27.6, c 2 in CHCl3)].
Compounds 2 [mp 126–127 (lit.[10] 125–126); [α]D–22.3 (lit.[10] −22.5, c 2 in
CHCl3)], 6, 8, 9 [mp 86–87 (lit.[12] 98.5); [α]D–13.3 (lit.[12]–15.5, c 1 in CHCl3)],
10 [mp 176–177 (lit.[13] 177–178.5); [α]D–31.9 (lit.[13]–38.9, c 1 in CHCl3)], 11
[mp 143–144 (lit.[13] 146–147); [α]D–9.3 (lit.[13]–9.7, c 1 in CHCl3)], 13, 14, 17
[mp 134–135 (lit.[15]142–143); [α]D–27.8 (lit.[15]–29.5, c 0.5 in CHCl3)], and 18
[mp 102–103 (lit.[16] 121.5–122); [α]D–1.0 (lit.[16]–1.1, c 1 in CH3OH)] have been
reported before and their NMR data were in agreement with the literature
values. But the NMR spectral data/physical constants for compounds 8, 13,
and 14 were not found and therefore the data obtained in the present work
have been listed below. No literature precedence for compounds 15 and 16 was
found and hence their physical constants and NMR spectral data have also
been listed below.
Phenyl 2,3,4,6-tetra-O-benzoyl-β-D-galactopyranoside (8)
Compound 8 was prepared by the general procedure described above in
96% yield as a colorless solid; mp 68–69◦C (Et2O:n-Hex); [α]D = +139.2 (C 1 in

P. R. Patil & K. P. R. Kartha
416
1
CHCl3); H NMR (300 MHz, CDCl3) δ 8.13 (d, 2H, J = 7.2 Hz, 2,6 Bz-H), 8.06
(d, 2H, J = 7.2 Hz, 2,6 Bz-H), 7.97 (d, 2H, J = 7.3 Hz, 2,6 Bz-H), 7.83 (d, 2H,
J = 7.2 Hz, 2,6 Bz-H), 7.63–7.16 (m, 14H, 4 × 3,4,5 Bz-H, 1 × 2,6 Ph-H), 7.03
(m, 3H, 3,4,5 Ph-H), 6.07 (m, 2H, H-2, H-4), 5.69 (dd, 1H, J2,3 = 10.3 Hz, J3,4
3.3 Hz, H-3), 5.39 (d, 1H, J1,2 = 7.9 Hz, H-1), 4.70 (dd, 1H,J5,6a = 7.3, J6a,,6b
=
=
11.1 Hz H-6a), 4.57–4.46 (m, 2H, H-5, H-6b); 13C NMR (75.47, CDCl3) δ 166.5,
166.1, 165.8, 157.6, 134.2, 133.9, 130.6, 130.3, 130.0, 129.7, 129.4, 129.2, 129.0,
128.9, 128.8, 123.9, 117.8, 100.7, 72.3, 72.2, 70.0, 68.5, 62.8.
4-Nitrophenyl 4-O-(2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranoside
(13)
Compound 13 was prepared by the general procedure described above in
71% yield as a colorless solid; mp 106–107◦C (Et2O:n-Hex); [α]D = –23.3 (c 1 in
1
CHCl3); H NMR (300 MHz, CDCl3) δ 8.22 (d, 2H, J = 9.1Hz, 3,5 Ph-H), 7.07
(d, 2H, J = 7.2 Hz, 2,6 Ph-H), 5.37 (d, 1H, J3,4 = 2.8 Hz, H-4ꢁ), 5.33–5.10 (m,
4H, H-3, H-2ꢁ, H-2, H-1), 4.99 (dd, 1H, J2,3 = 10.3 Hz, H-3ꢁ), 4.51 (m, 2H, H-1ꢁ,
H-6a), 4.24–4.11 (m, 3H, H-6b, H-6aꢁ, H-6bꢁ), 3.94–3.86 (m, 3H, H-4, H-5, H-
5ꢁ), 2.16 (s, 3H, COCH3), 2.12–2.06 (m, 15H, 5 × COCH3), 1.97 (s, 3H, COCH3);
13C NMR (75.47, CDCl3) δ 170.9, 170.6, 170.2, 170.0, 169.6, 161.7, 143.7, 126.3,
117.1, 101.7, 98.3, 76.5, 73.6, 73.1, 71.7, 71.4, 71.3, 69.6, 67.1, 62.4, 61.3, 21.2,
21.1, 21.0.
4-N-Acetylaminophenyl
2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (14)
Compound 14 was prepared by the general procedure described above in
82% yield as a colorless solid; mp 110–111◦C (Et2O:n-Hex); [α]D = –11.7 (c 1
in CHCl3);1H NMR (400 MHz, CDCl3) δ 7.50 (d, 2H, J = 8.8 Hz, 3,5 Ph-H),
7.03 (d, 2H, J = 8.8 Hz, 2,6 Ph-H), 5.26 (m, 2H, H-2, H-3), 5.18 (d, 1H, J3,4
=
9.6 Hz, H-4), 5.02 (d, 1H, J1,2 = 7.2 Hz, H-2), 4.29 (dd, 1H,J5,6a = 5.6, J6a,,6b 12.4
H-6a), 4.14 (dd, 1H,J5,6a = 2.4 Hz, H-6b), 3.83 (ddd, 1H, H-5), 2.16, 2.10, 2.08,
2.06, 2.04 (5s, 15H, N-COCH3, 4 × COCH3); 13C NMR (100.62 MHz,CDCl3) δ
170.6, 170.2, 169.6, 169.4, 168.3, 153.4, 135.6, 121.9, 117.6, 99.5, 72.1, 72.0,
71.1, 68.2, 61.9, 24.4, 21.0, 20.6, 20.5.
4-tert-Butoxycarbonylaminophenyl
2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (15)
Compound 15 was prepared by the general procedure described above in
89% yield as a colorless solid; mp 156–157◦C (Et2O:n-Hex); [α]D = +4.7 (c 1
1
in CHCl3); H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H, J = 8.4 Hz, 3,5 Ph-H),

Mechanochemical Synthesis of Aryl Glycosides
417
6.95 (dd, 2H, J = 6.8, J = 2.0 Hz 1.5 Hz, 2,6 Ph-H), 6.42 (bs, 1H, NH), 5.45 (m,
2H, H-2, H-4), 5.10 (dd, 1H, J2,3 = 10.4 Hz, J3,4 = 3.2 Hz, H-3), 4.96 (d, 1H,
J1,2 = 7.6 Hz, H-1), 4.18 (m, 2H, H-6a, H-6b), 4.02 (t, 1H, H-5), 2.18, 2.07, 2.05,
t
2.01 (4s, 12H, 4 × COCH3), 1.50 (s, 9H, Bu); 13C NMR (100.62 MHz, CDCl3)
δ 170.3, 170.2, 170.1, 169.3, 152.9, 133.8, 120.1, 117.8, 115.5, 100.3, 80.5, 71.0,
70.8, 68.7, 66.9, 61.3, 28.3, 20.7, 20.6, 20.5; MALDI-TOF MS C25H33NO12 [M]+
calcd. m/z 539.539, found m/z 578.759 (M+K+), 562.770 (M+Na+), 331.519
(M-OPhNHBoc)+.
3-tert-Butoxycarbonylaminophenyl
2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (16)
Compound 16 was prepared by the general procedure described above in
87% yield as a colorless solid; mp 117–118◦C (Et2O:n-Hex); [α]D = +7.3 (c 1
1
in CHCl3); H NMR (300 MHz, CDCl3) δ 7.15 (m, 2H, 2,5 Ph-H), 7.01 (d, 1H,
J = 7.9 Hz, 6-Ph-H), 6.68 (d, 1H, J = 7.9 Hz, 4-Ph-H), 6.50 (bs, 1H, NH), 5.45
(m, 2H, H-2, H-4), 5.08 (m, 2H, H-3, H-1), 4.18 (m, 2H, H-6a, H-6b), 4.06
(t, 1H,J5,6a = 6.4, H-5), 2.18, 2.05, 2.04, 2.00 (4s, 12H, 4 × COCH3), 1.50 (s,
t
9H, Bu); 13C NMR (75.47 MHz, CDCl3) δ 170.9, 170.8, 170.6, 169.9, 158.0,
152.9, 140.2, 130.3, 113.8, 111.9, 107.9, 100.0, 81.2, 71.5, 71.4, 69.2, 67.4, 61.8,
28.8, 21.2, 21.18, 21.16; MALDI-TOF MS C25H33NO12 [M]+ calcd. m/z 539.539,
found m/z 578.863 (M+K+), 562.874 (M+Na+), 331.588 (M-OPhNHBoc)+.
ACKNOWLEDGMENTS
Premanand R. Patil would like to thank NIPER for the research fellowship.
Mr. Bharat Gadakh and Mr. Satish Malik are thanked for the multigram scale
experiments.
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