Synthesis of substituted 2-(β-d-glucopyranosyl)-benzimidazoles and their evaluation as inhibitors of glycogen phosphorylase

Article abstract of DOI:10.1016/j.carres.2013.01.011

Microwave assisted condensation of O-perbenzoylated C-(β-d- glucopyranosyl)formic acid with 1,2-diaminobenzenes in the presence of triphenylphosphite gave the corresponding O-protected 2-(β-d- glucopyranosyl)-benzimidazoles in moderate yields. O-Perbenzoy

Full text of DOI:10.1016/j.carres.2013.01.011

Carbohydrate Research 381 (2013) 179–186
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Carbohydrate Research
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Synthesis of substituted 2-(b-D-glucopyranosyl)-benzimidazoles and
their evaluation as inhibitors of glycogen phosphorylase
a
a
b
b
a,
⇑
}
Éva Bokor , Eniko Szilágyi , Tibor Docsa , Pál Gergely , László Somsák
a Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary
b Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave assisted condensation of O-perbenzoylated C-(b-D-glucopyranosyl)formic acid with 1,2-
Received 3 November 2012
Received in revised form 15 January 2013
Accepted 16 January 2013
Available online 29 January 2013
diaminobenzenes in the presence of triphenylphosphite gave the corresponding O-protected 2-(b-
glucopyranosyl)-benzimidazoles in moderate yields. O-Perbenzoylated C-(b- -glucopyranosyl)formamide
and -thioformamide were transformed into the corresponding ethyl C-(b- -glucopyranosyl)formimidate
and -thioformimidate, respectively, by Et3OꢀBF4. Treatment of the formimidate with 1,2-diaminobenz-
enes afforded O-protected 2-(b- -glucopyranosyl)-benzimidazoles in good to excellent yields. Similar
reaction of the thioformimidate gave these compounds in lower yields. The O-benzoyl protecting groups
were removed by the Zemplén protocol. These test compounds were assayed against rabbit muscle gly-
cogen phosphorylase (GP) b, the prototype of liver GP, the rate limiting enzyme of glycogen degradation.
D-
D
D
D
Keywords:
C-Glycopyranosyl-formimidate
C-Glycopyranosyl-thioformimidate
2-C-Glycopyranosyl benzimidazole
Glycogen phosphorylase
Inhibitor
The best inhibitors were 2-(b-D-glucopyranosyl)-4-methyl-benzimidazole (Ki = 2.8 lM) and 2-(b-D-gluco-
pyranosyl)-naphtho[2,3-d]imidazole (Ki = 2.1
unsubstituted parent compound.
lM) exhibiting a ꢁ3–4 times stronger binding than the
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
mediated H-bonds between the protein and the heteroaromatic
ring, and van der Waals interactions of the large aromatic part in
the so-called b-channel of the enzyme.27 The higher affinity of 1F
in comparison with its thio counterpart 1E can be attributed to
the direct H-bond of the imidazole NH with the His377 main chain
carbonyl group of the enzyme which is certainly absent for benzo-
thiazole 1E.27 Analogous NH-(His377)CO interactions were identi-
fied in other GP enzyme-inhibitor complexes (e.g., in cases of spiro
Inhibition of glycogen phosphorylase (GP) has been considered
as an effective therapeutic approach in combating type 2 diabetes
(for the biochemical and pharmacological background of targeting
liver GP as a validated concept for lowering blood glucose levels,
please survey recent review articles1–6). Furthermore, the pharma-
ceutical utility of GP inhibitors in the intervention of other dis-
eased states associated with GP activity (e.g., cardiovascular
(thio)hydantoin28,29 and N-acyl-b-
D-glucopyranosylamine type
disorders,7–9 ischaemic lesions,10–13 and tumorous growth11,14–16
has also been under investigation.
)
inhibitors30) indicating the prominent importance of this special
H-bridge, as well. Additionally, X-ray crystallographic investigation
of 1F in complex with RMGPb revealed that besides the active site
the compound also occupied the new allosteric site, and a new
binding cleft called the benzimidazole site was also discovered.27
To get an insight into the structure–activity relationship of this
type of inhibitors the aim of our present work has been to synthe-
A large array of compounds were shown to have an inhibitory
effect against this enzyme17–19 including glucose derivatives20,21
which primarily bind to the catalytic site of the enzyme. In the
course of searching for potent glucose based inhibitors, several
C-b-D
-glucopyranosyl heterocycles (Chart 1), such as tetrazole22
1A, 1,3,4-oxadiazoles22–24 1B, 1,2,4-oxadiazoles23,25,26 1C,D, benzo-
thiazole22 1E and benzimidazole22 1F have been synthesized and
some of them proved to be efficient against rabbit muscle glycogen
phosphorylase b (RMGPb, the prototype of GP enzymes for enzy-
size a series of substituted 2-(b-D-glucopyranosyl)-benzimidazoles
and to evaluate their effect on RMGPb.
For the formation of 2-C-glycosyl-benzimidazoles several syn-
thetic methods are known from the literature most of which have
been described for furanose based derivatives. Furanosyl benzimi-
dazoles were prepared (a) by acid catalysed condensation of C-
glycofuranosyl formic acids and o-phenylenediamine (OPD),31,32
(b) by coupling of C-glycofuranosyl formic acids or their chlorides
with 1,2-diaminobenzenes, followed by acid or POCl3 mediated
ring closure of the resulting amide type intermediates,33,34 (c) in
the reaction of C-glycofuranosyl formaldoximoyl chlorides (actually
matic tests2). In this class, 2-(b-
D-glucopyranosyl)-benzimidazole
(1F) was the first compound to have a Ki value in the low micromo-
lar range.22,27 As evidenced by X-ray crystallography, the strong
binding in the catalytic centre is the result of direct and water
⇑
Corresponding author. Tel.: +36 52512900x22348; fax: +36 52512744.
E-mail address: somsak@tigris.unideb.hu (L. Somsák).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.01.011

180
Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
esters
benzimidazoles.
Previously, hydrochloride salt of O-perbenzoylated ethyl C-(b-
6
and
7
was envisaged for the construction of
OH
R
Het
O
HO
HO
C
D-
OH
1
glucopyranosyl)thioformimidate obtained from glucopyranosyl
cyanide 2 by an acid catalysed addition of EtSH to the nitrile group
was used for this purpose.22 Since these conditions were rather
unpleasant and subsequent transformation of the salt gave benz-
imidazole 8a in a 34% yield only, we set out to produce and use
the free form of this type of precursor. Free thioimidate 7 was ob-
tained from thioamide 4 by Et3OꢀBF4. The preparation of 446 was
also modified to avoid the use of H2S; thus, cyanide 2 was reacted
with P4S10 in refluxing EtOH as described for the synthesis of ali-
phatic and aromatic thioamides.47 Similarly to 7, imidate 6 was ob-
tained from amide 3 by Et3OꢀBF4.
Het
R
-
Ki [μM]
N
NH
A
B
No inhibition22
N
N
14527
CH3
21222
N
N
N
R
2-naphthyl 10 % at 625 μM23
O
O
N
C
D
2-naphthyl 3825
R
R
N
Next, the preparation of benzimidazole 8a from either 6 or 7
was compared in preliminary experiments. Reaction of 6 or 7 with
OPD gave 8a in 89% and 62% yields, respectively. Therefore, also
taking into account the instability of 7 (decomposition was ob-
served on storage at rt after a few days), further reactions to get
the desired benzimidazoles were performed with 6.
O
N
2-naphthyl
-
2.423
N
7627
E
F
22922
S
Similarly to 8a, high yields were also achieved in reactions of 6
with methyl-substituted 1,2-diaminobenzenes f–h and 2,3-diami-
nonaphthalene i, respectively (Table 1). A comparison of the yields
for 8a,f,h obtained from acid 5 under conditions v and from imi-
date 6 under conditions vi, respectively, showed the ring closure
of 6 with 1,2-diaminobenzenes to be superior to that of 5.
On treatment of imidate 6 with 1,2-diaminobenzenes containing
electron withdrawing substituents (b–e) benzoic acid elimination
was also observed, and beside the 2-glucopyranosyl benzim-
8.627
N
-
1122
N
H
Chart 1. Inhibitory potency (Ki) of C-glucosyl heterocyclic derivatives against rabbit
muscle glycogen phosphorylase b (RMGPb).
the nitrile oxide obtained by base induced dehydrochlorination)
with OPD,35 (d) by intramolecular ring closure of suitably pro-
tected 2-(pentitol-10-yl)-benzimidazoles obtained from 2-lithiated
benzimidazoles and sugar lactone or acyclic pentose derivatives,36–38
and (e) by acid induced cyclodehydration of unprotected 2-(tetritol-
10-yl)-benzimidazoles.39
For the synthesis of 2-C-glycopyranosyl-benzimidazoles three
procedures were reported: (a) acid catalysed condensation of
unprotected C-glycopyranosylmethanals (generated in situ from
the appropriate dimethyl acetals) with OPD, followed by spontane-
ous oxidation of the intermediate benzimidazolines,40 (b) reaction
idazoles 8b–e 4-substituted-2-(30,40,60-tri-O-benzoyl-20-deoxy-
D-
arabino-hex-1-enopyranosyl)-benzimidazoles (1-C-benzimidazolyl
glucals, 9b–e) were also isolated. Furthermore, total consumption
of the starting material 6 in reaction with 4-nitro-1,2-diaminoben-
zene (e) required higher temperature, thus cyclization was per-
formed in boiling ethanol to yield benzimidazole 8e together
with 9e. This tendency for elimination might be attributed to an in-
creased acidity of the C-1–H proton in the 2-glucosyl-benzimidazoles
probably due to the presence of the electron withdrawing substitu-
ent in the aromatic ring system.
For enzymatic studies removal of the benzoyl protecting groups
of 8b–i was effected by the Zemplén method to give test com-
pounds 10b–i in good yields.
of O-perbenzoylated ethyl C-(b-D-glucopyranosyl)thioformimidate
hydrochloride (prepared from the corresponding glycosyl cyanide)
with OPD,22 and (c) treatment of O-peracetylated C-glycopyranosyl
formaldoximoyl chlorides with OPD.41 In addition, a 2-benzimidazolyl
The structure of the new compounds was determined by 1H and
13C NMR spectroscopy. The presence of a b-
D-configured glucopyr-
moiety was also attached to C-1 of D-galactal in the reaction of
anosyl moiety in the 4C1 conformation was confirmed by the vici-
nal proton–proton coupling constants for compounds 6, 7, 8b–i
and 10b–i, respectively. In the 1H NMR spectra of 1-C-hetaryl glu-
cals 9b–e the observed small couplings between the vicinal ring
protons (3–6 Hz) suggested a conformational change of the pyra-
nose ring (from chair to half chair).48 In the 13C NMR spectra of
9b–e characteristic resonances appeared for C-10 (143–145 ppm)
and C-20 (99–101 ppm) providing evidence for the unsaturated
nature of the pyranoid ring.48 Among 13C NMR signals of the benz-
imidazole units only those for C-2 appeared as sharp peaks at 146–
158 ppm, the others usually gave broad signals. These observations
are in accord with the literature experiences,35,41 and may be ex-
plained by the rapid proton exchange between N-1 and N-3 of
the benzimidazole moiety.35,41,49 Additionally, in the 13C NMR
spectra duplication of certain carbon peaks was also observed (pri-
marily for the benzimidazole carbon signals for example, in 8b, 9c,
9e and 10b), which may refer to the coexistence of the tautomeric
pairs. For the fluoro-benzimidazole 8b this phenomenon seemed
quite clear as 14 resonances were observed in the 13C NMR spec-
trum which could be tentatively assigned on the basis of the char-
acteristic C–F couplings50 as illustrated in Figure 1.
methyl C-(2-deoxy-D-lyxo-hex-1-enopyranosyl)formimidate and
the dihydrochloride salt of OPD.42
In this paper, we disclose further synthetic possibilities to con-
struct benzimidazole at the anomeric centre of the pyranose unit.
2. Results and discussion
2.1. Syntheses
C-(b-D-Glucopyranosyl)formic acid 5, prepared from cyanide 2
via amide 343 by the literature protocol44 (Table 1), was reacted
with 1,2-diaminobenzenes (a, f, h) in the presence of trip-
henylphosphite in pyridine under microwave irradiation (condi-
tions were adapted from a published procedure applied for non-
sugar based compounds45). Although the conversions were com-
plete at 140 °C in 20 min, the desired products could be isolated
only in moderate yields (8a: 45%, 8f: 53%, 8h: 43%). Nevertheless,
it has to be noted, that earlier attempts to transform 5 into benz-
imidazole 8a by the classical acid catalysed procedure with con-
ventional heating brought about no reaction even at elevated
temperatures.22 Therefore, application of the more reactive imino-

Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
181
Table 1
Synthesis of 2-(b-D-glucopyranosyl)-benzimidazoles
OBz
OBz
O
OBz
O
iii
O
i to 3
ii to 4
BzO
BzO
BzO
BzO
CXNH2
COOH
CN
BzO
BzO
OBz
3 X = O (94 %)
4 X = S (66 %)
OBz
OBz
2
5 (76 %)
R2
iv
v
H2N
H2N
R3
R4
a-i
R2
R3
R2
OBz
R4
OBz
NH
R3
R4
OR1
N
O
N
BzO
BzO
BzO
R1O
R1O
O
O
vi
C
+
BzO
N
H
XEt
OR1
8a-i R1 = Bz
N
H
OBz
9a-i
6 X = O (96 %)
7 X = S (90 %)
vii
10a-i R1 = H
i) HBr-AcOH, rt;43 ii) P4S10, abs. EtOH, reflux; iii) NO2, abs. CH2Cl2, rt;44 iv) Et3O·BF4, abs. CH2Cl2,
Ar, rt; v) P(OPh)3 (1.2 equiv.), a or f or h (1.0 equiv), abs. pyridine, μW, 140 ºC, 20 min; vi) a-i (2
equiv.), abs. CH2Cl2, reflux; vii) ~1 M NaOMe in abs. MeOH, rt.
Reagent
R2
H
R3
R4
Conditions and yields (%)
8
9
10
c,d
a
H
H
v
45
—
—
vii
—
vi
vi
vi
vi
vi
vib
v
vi
vi
v
89 (from 6)
62a (from 7)
b
c
d
e
f
H
H
H
H
H
F
Cl
Br
NO2
Me
H
H
H
H
H
46
76
54
46
53
83
79
43
81
35
24
29
20
—
—
—
—
—
vii
vii
vii
vii
vii
54
89
58
53
87
g
h
Me
H
H
Me
H
Me
vii
vii
73
78
vi
i
H
vi
79
—
vii
77
a
b
c
Reported yield of 8a by the earlier method from perbenzoylated b-D
-glucopyranosyl cyanide via the thioimidate hydrochloride salt: 34%.22
Modified reaction conditions were necessary for complete consumption of the starting material 6: abs. EtOH, reflux.
Debenzoylation of 8a by the Zemplén protocol was carried out earlier. Reported yield of 10a: 84%.22
Reported yield of 10a by a different method: 54%.40
d
104.5 (d, 2JC-F = 24 Hz)
98.0 (d, 2JC-F = 27 Hz)
and the obtained inhibitor constants are given in Table 2. The
new compounds showed inhibitory effects in the micromolar
range and some of them proved equivalent or somewhat better
inhibitors than 10a (=1F in Chart 1).
142.8 (d, 3JC-F ~ 9 Hz)
134.2 (d, 3JC-F ~ 9 Hz)
1
158.9 (d, JC-F = 237 Hz)
1
158.2 (d, JC-F = 237 Hz)
4(7)
7(4)
3(1)(H)
N
F
Among benzimidazoles with a halogen substituent in the 5-
position fluoro derivative 10b exhibited modest activity, while the
chloro (10c) as well as bromo (10d) compounds were as good inhib-
itors as 10a. Substitution of the benzimidazole ring in the same posi-
tion by a nitro group (10e) brought about a significant decrease of
the inhibition. Among the alkyl substituted derivatives the 5-
methyl- (10f) and 4-methyl-benzimidazoles (10g) displayed similar
and slightly better (ꢁ3-fold increase) potency than 10a, respec-
tively. However, introduction of two methyl groups into the 5- and
6-positions of the heterocycle (10h) resulted in a remarkable weak-
ening of the inhibition. Finally, the naphtho[2,3-d]imidazole 10i
showed ꢁ4 times stronger binding than 10a and proved to be the
most effective inhibitor of this series. To elucidate the nature of
the binding modes of the new compounds to GP enzyme X-ray crys-
tallographic studies are in progress and will be reported elsewhere.
3a(7a)
7a(3a)
5(6)
interchangable
assignments
2(2)
Bz -β- -Glc
D
4
p
6(5)
1(3)
N
H
110.9 (d, 2JC-F = 23 Hz)
109.7 (d, 2JC-F = 23 Hz)
151.1 (s)
150.3 (s)
139.0 (s)
130.8 (s)
3
120.0 (d, JC-F ~ 7 Hz)
3
112.3 (d, JC-F ~ 6 Hz)
Figure 1. Tentative assignment of 13C NMR signals for tautomers of compound 8b.
2.2. Enzyme kinetic studies
Enzyme kinetic measurements with rabbit muscle glycogen
phosphorylase b were performed as described previously,51,52

182
Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
-glucopyranosyl)formamide43 and C-(2,3,4,6-tetra-O-benzoyl-
Table 2
b-
b-
D
D
-glucopyranosyl)formic acid44 were synthesized according to
Kinetic data on the inhibition of rabbit muscle glycogen phosphorylase b by the new
compounds 10b–i
published procedures.
R2
R3
4.2. C-(2,3,4,6-Tetra-O-benzoyl-b-D-glucopyranosyl)-
thioformamide (4)
R4
OH
N
O
HO
HO
N
H
OH
A solution of phosphorus pentasulfide (2.23 g, 10 mmol) in
anhydrous EtOH (20 mL) was stirred at rt for 1.5 h, then 2,3,4,6-
10
a
R2
H
R3
H
R4
H
Ki (lM)
tetra-O-benzoyl-b-D
-glucopyranosyl cyanide43 (2, 3.02 g, 5 mmol)
8.627
1122
55
9.7
7.5
179
12
2.8
152
was added and the mixture was heated at reflux temperature for
2 h. After cooling the heterogenous mixture to rt, the precipitate
was filtered off and washed with EtOH to yield 2.1 g (66%) of 4
as a pale yellowish solid. Mp: 199–201 °C (Lit.46 mp: 198–
200 °C). 1H and 13C NMR data correspond to the reported spectra.46
b
c
H
H
F
Cl
Br
NO2
Me
H
H
H
H
H
H
H
Me
d
e
f
H
H
H
g
h
Me
H
4.3. Ethyl C-(2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyl)-
formimidate (6)
Me
i
H
2.1
C-(2,3,4,6-Tetra-O-benzoyl-b-D
-glucopyranosyl)formamide43 (3,
1.0 g, 1.60 mmol) and Et3OꢀBF4 (0.91 g, 4.80 mmol) were dissolved
in anhydrous CH2Cl2 (15 mL), the mixture was stirred at rt under
Ar and monitored by TLC (1:1 EtOAc–hexane). After completion of
the reaction (2 days), the mixture was diluted with CH2Cl2
(30 mL), extracted with satd aq NaHCO3 solution (30 mL) and then
with water (30 mL). The organic phase was dried over MgSO4, fil-
tered and the solvent was evaporated. The crude pale yellow amor-
phous product (1.0 g, 96%) was used without further purification. Rf:
0.55 (1:1 EtOAc–hexane); 1H NMR (CDCl3) d (ppm): 8.06–7.25 (21H,
m, aromatics, NH), 5.99, 5.72, 5.55 (3 ꢂ 1H, 3 pseudo t, J = 10.6,
9.2 Hz in each, H-2, H-3, H-4), 4.70 (1H, dd, J = 11.9, 2.6 Hz, H-6a),
4.52 (1H, dd, J = 11.9, 5.3 Hz, H-6b), 4.25 (1H, ddd, J = 9.2, 5.3,
2.6 Hz, H-5), 4.21 (1H, d, J = 9.2 Hz, H-1), 4.12–3.91 (2H, m, CH2),
0.84 (3H, t, 6.6 Hz, CH3); 13C NMR (CDCl3) d (ppm): 167.5, 166.1,
165.7, 165.1 (2) (CO, CNH), 133.5–128.2 (aromatics), 75.8, 74.6,
73.6, 70.7, 69.1 (C-1–C-5), 62.8, 62.1 (C-6, CH2), 13.4 (CH3).
3. Conclusion
New synthetic pathways were elaborated for the formation of
substituted 2-(b- -glucopyranosyl)-benzimidazoles by heterocyc-
lizations of 2,6-anhydro-aldonic acid derivatives as precursors.
Condensation of O-perbenzoylated C-(b- -glucopyranosyl)formic
acid with 1,2-diaminobenzenes in the presence of P(OPh)3 under
microwave irradiation gave the desired benzimidazoles in moder-
D
D
ate yields. Ring closure of O-perbenzoylated ethyl C-(b-D-glucopyr-
anosyl)formimidate, prepared from the corresponding formamide
by Et3OꢀBF4, with the 1,2-diaminobenzenes afforded a more effi-
cient procedure. With electron depleted aromatic diamines unde-
sirable b-elimination of benzoic acid from the 1,2-positions of
the glucopyranosyl moiety also took place to yield 1-C-benzimi-
dazolyl glucals besides the target compounds. Enzyme kinetic
4.4. Ethyl C-(2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyl)-
thioformimidate (7)
studies with the new 2-(b-D-glucopyranosyl)-benzimidazoles
showed the compounds to inhibit RMGPb in the low micromolar
range. Substitution of the benzimidazole moiety by a methyl
group in the 4-position or further annelation of a benzene ring
provided more efficient inhibitors than the unsubstituted parent
compound.
C-(2,3,4,6-Tetra-O-benzoyl-b-D-glucopyranosyl)thioformamide
(4, 0.2 g, 0.31 mmol) and Et3OꢀBF4 (0.18 g, 0.94 mmol) were dis-
solved in anhydrous CH2Cl2 (4 mL), the mixture was stirred at rt
under Ar and monitored by TLC (1:1 EtOAc–hexane). After comple-
tion of the reaction (2 days), the mixture was diluted with CH2Cl2
(10 mL), extracted with satd aq NaHCO3 solution (15 mL), then
with water (15 mL). The organic phase was dried over MgSO4, fil-
tered and the solvent was evaporated. The crude pale yellow amor-
phous product (0.19 g, 90%) was used without further purification.
Rf: 0.62 (1:1 EtOAc–hexane); 1H NMR (CDCl3) d (ppm): 8.06–7.24
(21H, m, aromatics, NH), 5.95, 5.74, 5.70 (3 ꢂ 1H, 3 pseudo t,
J = 9.8, 9.1 Hz in each, H-2, H-3, H-4), 4.68 (1H, dd, J = 11.9,
2.8 Hz, H-6a), 4.51 (1H, dd, J = 11.9, 4.9 Hz, H-6b), 4.39 (1H, d,
J = 9.1 Hz, H-1), 4.22 (1H, ddd, J = 9.1, 4.9, 2.8 Hz, H-5), 2.88–2.71
(2H, m, CH2), 1.17 (3H, pseudo t, 7.7, 7.0 Hz, CH3); 13C NMR (CDCl3)
d (ppm): 172.7 (CNH), 166.1, 165.7, 165.1, 164.9 (CO), 133.4–128.2
(aromatics), 80.6, 76.1, 73.9, 70.9, 69.1 (C-1–C-5), 62.8 (C-6), 23.1
(CH2), 13.1 (CH3).
4. Experimental
4.1. General methods
Melting points were measured on a Kofler hot-stage and are
uncorrected. Optical rotations were determined with a Perkin–
Elmer 241 polarimeter at rt. NMR spectra were recorded with
Bruker 360 (360/90 MHz for 1H/13C) spectrometer. Chemical shifts
are referenced to Me4Si (1H), or to the residual solvent signals (13C).
Microwave assisted procedures were performed in a CEM-Discover
Focused Microwave Synthesis System (2450 MHz) with a built-in
infrared temperature sensor and a CEM-Explorer computer con-
trolled robotic sampler.
4.5. General procedure I for the synthesis of substituted 2-
TLC was performed on DC-Alurolle Kieselgel 60 F254 (Merck),
and the plates were visualized under UV light and by gentle heat-
ing. For column chromatography Kieselgel 60 (Merck, particle size
0.063–0.200 mm) was used. Dichloromethane was distiled from
P4O10 and stored over 4 Å molecular sieves. 2,3,4,6-Tetra-O-
(20,30,40,60-tetra-O-benzoyl-b-
D
-glucopyranosyl)-benzimidazoles
from O-perbenzoylated C-(b-
D-glucopyranosyl)formic acid (5)
C-(2,3,4,6-Tetra-O-benzoyl-b-
D
-glucopyranosyl)formic
acid44
benzoyl-b-D
-glucopyranosyl cyanide,43 C-(2,3,4,6-tetra-O-benzoyl-
(5, 0.1 g, 0.16 mmol), a 1,2-diaminobenzene (a or f or h, 0.16 mmol,

Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
183
1 equiv) and triphenyl phosphite (50
l
l, 0.19 mmol, 1.2 equiv)
129.3–128.5 (aromatics), 120.0 (d, 3JC-F = 7 Hz, benzimidazole), 112.3
3
2
were dissolved in anhydrous pyridine (2 mL). The closed vial was
irradiated by microwaves for 20 min at 140 °C (maximum pres-
sure: 20 bar, power 220 W). The completion of the reaction was
monitored by TLC (1:1 EtOAc–hexane). The reaction mixture was
concentrated under reduced pressure, traces of pyridine were re-
moved by repeated co-evaporations with toluene. The crude prod-
uct was purified by column chromatography (2:3 EtOAc–hexane).
(d, JC-F = 6 Hz, benzimidazole), 110.9 (d, JC-F = 23 Hz, benzimid-
2
azole), 109.7 (2JC-F = 23 Hz, benzimidazole), 104.5 (d, JC-F = 24 Hz,
2
benzimidazole), 98.0 (d, JC-F = 27 Hz, benzimidazole), 79.1, 74.8,
74.2, 73.4, 71.5, 69.0 (C-10–C-50), 62.8 (C-60). Anal. Calcd for
C41H31FN2O9 (714.69): C, 68.90; H, 4.37; N, 3.92. Found: C, 68.84;
H, 4.29; N, 4.03.
Compound 9b: Yield: 0.032 g (35%), pale yellow syrup; Rf: 0.58
(2:3 EtOAc–hexane); [
a
]
D = ꢃ7 (c 0.5, CHCl3); 1H NMR (CDCl3) d
4.6. General procedure II for the synthesis of substituted 2-
(ppm): 10.41 (1H, br s, benzimidazole NH), 8.02–6.94 (18H, m, aro-
matics), 6.43 (1H, br s, H-20), 5.95–5.92 (2H, m, H-30, H-40), 4.88
(1H, ddd, J = 4.0, <1 Hz, H-50), 4.79 (2H, s, H-60a, H-60b); 13C NMR
(20,30,40,60-tetra-O-benzoyl-b-
D-glucopyranosyl)-benzimidazoles
from O-perbenzoylated ethyl (C-b-D-glycopyranosyl)
formimidate (6)
1
(CDCl3) d (ppm): 166.2, 165.6, 165.0 (CO), 159.8 (d, JC-F = 239 Hz,
benzimidazole C-5), 146.8 (benzimidazole C-2), 145.0 (C-10),
143.1, 139.8 (2 br s, benzimidazole C-3a, C-7a), 133.5–128.4 (aro-
Ethyl C-(2,3,4,6-tetra-O-benzoyl-b-
D
-glycopyranosyl)formimi-
1,2-diaminobenzene (a–i,
2
date (6, 0.1 g, 0.15 mmol) and
a
matics), 120.2 (br s, benzimidazole C-4 or C-7), 111.9 (d, JC-
0.30 mmol, 2 equiv) were dissolved in anhydrous CH2Cl2 (3 mL).
The mixture was refluxed and monitored by TLC (2:3 EtOAc–
hexane). After completion of the reaction the solvent was evapo-
rated, and the residue was purified by column chromatography.
F = 25 Hz, benzimidazole C-6), 104.4 (br s, benzimidazole C-4 or
C-7), 99.4 (C-20), 75.2, 67.9, 67.3 (C-30–C-50), 61.7 (C-60). Analysis:
C34H25FN2O7 (592.57), ESI-MS (positive mode) m/z: 615.157
[M+Na]+, 1207.327 [2 M+Na]+.
4.7. General procedure III for the Zemplén-deacylation
4.10. 5(6)-Chloro-2-(20,30,40,60-tetra-O-benzoyl-b-
D-
glucopyranosyl)-benzimidazole (8c) and 5(6)-chloro-2-(30,40,60-
A benzoylated compound was dissolved in dry MeOH (5 mL/
100 mg, a few drops of CHCl3 were added in case of incomplete dis-
solution) and a catalytic amount of a NaOMe solution (ꢁ1 M in
MeOH) was added. The mixture was kept at rt and monitored by
TLC (7:3 CHCl3–MeOH). When the starting material was consumed
the mixture was neutralised with a cation exchange resin Amberlyst
15 (H+ form), then the resin was filtered off and the solvent
removed. The residue was purified by column chromatography.
tri-O-benzoyl-20-deoxy-
D-arabino-hex-1-enopyranosyl)-
benzimidazole (9c)
From imidate 6 (0.10 g, 0.15 mmol) and 1,2-diamino-4-chloro-
benzene (c, 0.04 g, 0.30 mmol) according to General Procedure II.
Reaction time: 5 h. Purified by column chromatography (2:3
EtOAc–hexane) to give 9c as the first and 8c as the second fraction.
Compound 8c: Yield: 0.085 g (76%), pale yellow solid; Rf: 0.29
(2:3 EtOAc–hexane); mp: 123–125 °C; [
a
]
D = ꢃ61 (c 0.5, CHCl3);
4.8. 2-(20,30,40,60-Tetra-O-benzoyl-b-
benzimidazole (8a)
D
-glucopyranosyl)-
1H NMR (CDCl3) d (ppm): 11.33 (1H, br s, benzimidazole NH),
7.94–6.95 (23H, m, aromatics), 6.21, 6.14, 6.00 (3 ꢂ 1H, 3 pseudo
t, J = 9.4, 9.4 Hz in each, H-20, H-30, H-40), 5.31 (1H, d, J = 9.4 Hz,
H-10), 4.72 (1H, dd, J = 12.3, <1 Hz, H-60a), 4.60 (1H, dd, J = 12.3,
4.4 Hz, H-60b), 4.50 (1H, ddd, J = 9.4, 4.4, <1 Hz, H-50); 13C NMR
(CDCl3) d (ppm): 166.5, 166.0, 165.1 (2) (CO), 149.8 (benzimidazole
C-2), 142.0, 137.8 (2 br s, benzimidazole C-3a, C-7a), 133.3–127.8
(aromatics), 126.9, 123.3, 119.3 (br s), 112.4 (br s) (benzimidazole
C-4–C-7), 77.0, 75.5, 74.1, 71.7, 69.5 (C-10–C-50), 63.4 (C-60). Anal.
Calcd for C41H31ClN2O9 (731.15): C, 67.35; H, 4.27; N, 3.84. Found:
C, 67.47; H, 4.13; N, 3.90.
A: From acid 5 (0.1 g, 0.16 mmol) and o-phenylenediamine (a,
0.02 g, 0.16 mmol) according to General procedure I. Yield: 0.05 g
(45%).
B: From imidate 6 (0.10 g, 0.15 mmol) and o-phenylenediamine
(a, 0.04 g, 0.30 mmol) according to General Procedure II. Reaction
time: 3 h. Purified by column chromatography (2:3 EtOAc–hexane)
to yield 0.09 g (89%) of white solid. Mp: 122–124 °C (Lit.22 mp: 120–
123 °C). 1H and 13C NMR data correspond to the reported spectra.22
Compound 9c: Yield: 0.022 g (24%), pale yellow syrup; Rf: 0.59
4.9. 5(6)-Fluoro-2-(20,30,40,60-tetra-O-benzoyl-b-
D
-
(2:3 EtOAc–hexane); [
a]
D = ꢃ5 (c 0.5, CHCl3); 1H NMR (CDCl3) d
glucopyranosyl)-benzimidazole (8b) and 5(6)-fluoro-2-(30,40,60-
(ppm): 11.40 (1H, br s, benzimidazole NH), 8.00–7.07 (18H, m, aro-
matics), 6.45 (1H, d, J = 4.0 Hz, H-20), 5.98 (1H, pseudo t, J = 6.6,
5.9 Hz, H-30 or H-40), 5.94 (1H, pseudo t, J = 5.9, 4.0 Hz, H-30 or H-
40), 4.81 (1H, ddd, J = 6.6, 4.6, 4.0 Hz, H-50), 4.71–4.70 (2H, m, H-60a,
H-60b); 13C NMR (CDCl3) d (ppm): 166.1, 165.6, 164.9 (CO), 146.8
(brs, benzimidazoleC-2), 145.0(C-10), 144.1, 141.8(2br s, benzimid-
azole C-3a, C-7a), 133.6–133.2 (aromatics), 132.0 (br s, benzimid-
azole C-5), 129.8–128.3 (aromatics), 123.9, 120.3, 119.1, 112.2,
111.3 (br s for each, benzimidazole C-4, C-6, C-7), 99.8 (C-20), 75.2,
68.1, 67.3 (C-30–C-50), 61.7 (C-60). Analysis: C34H25ClN2O7 (609.02),
ESI-MS (positive mode) m/z: 631.123 [M+Na]+, 1239.257 [2M+Na]+.
tri-O-benzoyl-20-deoxy-
D-arabino-hex-1-enopyranosyl)-
benzimidazole (9b)
From imidate 6 (0.10 g, 0.15 mmol) and 1,2-diamino-4-fluoro-
benzene (b, 0.04 g, 0.30 mmol) according to General Procedure II.
Reaction time: 5 h. Purified by column chromatography (1:2, then
2:3 EtOAc–hexane) to give 9b as the first than 8b as the second
fraction.
Compound 8b: Yield: 0.051 g (46%) pale yellow solid; Rf: 0.31
(2:3 EtOAc–hexane); mp: 124–126 °C; [
a
]
D = ꢃ39 (c 0.5, DMSO);
1H NMR (CDCl3) d (ppm): 11.58 (1H, br s, benzimidazole NH),
7.96–6.76 (23H, m, aromatics), 6.30–6.21, 6.02 (3 ꢂ 1H, 3 pseudo
t, J = 9.2, 9.2 Hz in each, H-20, H-30, H-40), 5.36 (1H, d, J = 9.2 Hz,
H-10), 4.69 (1H, dd, J = 12.3, <1 Hz, H-60a), 4.57 (1H, dd, J = 12.3,
5.3 Hz, H-60b), 4.52 (1H, ddd, J = 9.2, 5.3, <1 Hz, H-50); 13C NMR
(DMSO-d6) d (ppm): 165.4, 165.1, 164.8, 164.3 (CO), 158.9 (d,
4.11. 5(6)-Bromo-2-(20,30,40,60-tetra-O-benzoyl-b-
D-
glucopyranosyl)-benzimidazole (8d) and 5(6)-bromo-2-(30,40,60-
tri-O-benzoyl-20-deoxy-
D-arabino-hex-1-enopyranosyl)-
benzimidazole (9d)
1JC-F = 237 Hz, benzimidazole), 158.2 (d, JC-F = 237 Hz, benzimid-
azole), 151.1, 150.3 (benzimidazole), 142.8 (d, JC-F = 9 Hz, benz-
From imidate 6 (0.10 g, 0.15 mmol) and 1,2-diamino-4-bromo-
benzene (d, 0.06 g, 0.30 mmol) according to General Procedure II.
Reaction time: 3 h. Purified by column chromatography (2:3
EtOAc–hexane) to give 9d as the first and 8d as the second fraction.
1
3
3
imidazole), 139.0 (br s, benzimidazole), 134.2 (d, JC-F = 9 Hz,
benzimidazole), 133.7–133.3 (aromatics), 130.9 (br s, benzimidazole),

184
Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
Compound 8d: Yield: 0.064 g (54%) pale yellow solid; Rf: 0.31
(2:3 EtOAc–hexane); mp: 126–128 °C; [
B: From imidate 6 (0.10 g, 0.15 mmol) and 3,4-diaminotoluene
a]
D = ꢃ62 (c 0.5, CHCl3);
(f, 0.04 g, 0.30 mmol) according to General Procedure II. Reaction
time: 2 h. Purified by column chromatography (2:3 EtOAc–hexane)
to yield 0.09 g (83%) of pale yellow syrup. Rf: 0.41 (1:1 EtOAc–
1H NMR (CDCl3) d (ppm): 8.02–6.76 (23H, m, aromatics), 6.42,
6.29, 6.14 (3 ꢂ 1H, 3 pseudo t, J = 9.6, 9.6 Hz in each, H-20, H-30,
H-40), 5.39 (1H, d, J = 9.6 Hz, H-10), 4.72 (1H, dd, J = 12.3, 2.2 Hz,
H-60a), 4.63 (1H, dd, J = 12.3, 4.9 Hz, H-60b), 4.56 (1H, ddd, J = 9.6,
4.9, 2.2 Hz, H-50); 13C NMR (CDCl3) d (ppm): 166.4, 166.0, 165.0
(2) (CO), 149.6 (benzimidazole C-2), 140.9, 138.1 (2 br s, benzimid-
azole C-3a, C-7a), 133.3–127.7 (aromatics), 125.9, 119.0 (br s),
117.3 (br s), 115.9 (benzimidazole C-4, C-5, C-6, C-7), 77.0, 75.5,
74.1, 71.7, 69.4 (C-10–C-50), 63.4 (C-60). Analysis: C41H31BrN2O9
(775.60), ESI-MS (positive mode) m/z: 799.112 [M+Na]+,
1573.242 [2M+Na]+.
hexane); [
a
]
D = ꢃ65 (c 0.5, CHCl3); 1H NMR (CDCl3) d (ppm):
10.73 (1H, br s, benzimidazole NH), 7.92–6.90 (23H, m, aromatics),
6.19, 6.11, 5.96 (3 ꢂ 1H, 3 pseudo t, J = 9.2, 9.2 Hz in each, H-20,
H-30, H-40), 5.32 (1H, d, J = 9.2 Hz, H-10), 4.68 (1H, dd, J = 12.2,
2.6 Hz, H-60a), 4.54 (1H, dd, J = 12.2, 5.3 Hz, H-60b), 4.44 (1H, ddd,
J = 9.2, 5.3, 2.6 Hz, H-50), 2.32 (3H, s, CH3); 13C NMR (CDCl3) d
(ppm): 166.4, 165.9, 165.2 (2) (CO), 148.1 (benzimidazole C-2),
142.4, 138.8 (2 br s, benzimidazole C-3a, C-7a), 133.4–128.0
(aromatics, benzimidazole C-5), 124.4, 118.9, 111.1 (br s for each,
benzimidazole C-4, C-6, C-7), 76.8, (C-10), 75.3, 74.1, 71.5, 69.5 (C-
10–C-50), 63.4 (C-60), 21.5 (CH3). Anal. Calcd for C42H34N2O9
(710.73): C, 70.98; H, 4.82; N, 3.94. Found: C, 70.83; H, 4.96; N, 4.09.
Compound 9d: Yield: 0.029 g (29%) pale yellow syrup; Rf: 0.61
(2:3 EtOAc–hexane); [
a
]
D = ꢃ4 (c 0.25, CHCl3); 1H NMR (CDCl3) d
(ppm): 10.06 (1H, br s, imidazole NH), 8.04–7.33 (18H, m, aromat-
ics), 6.46 (1H, br s, H-20), 5.97–5.93 (2H, m, H-30, H-40), 4.91 (1H,
ddd, J = 4.0, <1 Hz, H-50), 4.81 (2H, s, H-60a, H-60b). Analysis:
C34H25BrN2O7 (653.48), ESI-MS (positive mode) m/z: 677.074
[M+Na]+, 1329.197 [2M+Na]+.
4.14. 4(7)-Methyl-2-(20,30,40,60-tetra-O-benzoyl-b-
D-
glucopyranosyl)-benzimidazole (8g)
From imidate 6 (0.10 g, 0.15 mmol) and 2,3-diaminotoluene (g,
0.04 g, 0.30 mmol) according to General Procedure II. Reaction
time: 5 h. Purified by column chromatography (1:2 EtOAc–hexane)
4.12. 5(6)-Nitro-2-(20,30,40,60-tetra-O-benzoyl-b-
D-
glucopyranosyl)-benzimidazole (8e) and 5(6)-nitro-2-(30,40,60-
tri-O-benzoyl-20-deoxy-
D-arabino-hex-1-enopyranosyl)-
to yield 0.087 g (79%) of yellow solid. Mp: 117–119 °C; [
a
]
D = ꢃ43
benzimidazole (9e)
(c 0.5, CHCl3); 1H NMR (CDCl3) d (ppm): 10.88 (1H, br s, benzimid-
azole NH), 7.96–6.88 (23H, m, aromatics), 6.18, 6.06, 5.92 (3 ꢂ 1H,
3 pseudo t, J = 9.2, 9.2 Hz in each, H-20, H-30, H-40), 5.38 (1H, d,
J = 9.2 Hz, H-10), 4.69 (1H, dd, J = 11.7, <1 Hz, H-60a), 4.51 (1H, dd,
J = 11.7, 5.3 Hz, H-60b), 4.44 (1H, ddd, J = 9.2, 5.3, <1 Hz, H-50),
2.33 (3H, s, CH3); 13C NMR (CDCl3) d (ppm): 166.3, 165.8, 165.3,
165.2 (CO), 147.7 (benzimidazole C-2), 142.1 (br s, benzimidazole
C-3a, C-7a), 133.4–128.0 (aromatics), 123.1, 122.4, 116.8, 108.8
(br s for each, benzimidazole C-4–C-7), 76.8, 75.2, 73.9, 71.4, 69.5
(C-10–C-50), 63.3 (C-60), 16.5 (CH3). Anal. Calcd for C42H34N2O9
(710.73): C, 70.98; H, 4.82; N, 3.94. Found: C, 70.87; H, 4.90; N,
3.85.
From imidate 6 (0.10 g, 0.15 mmol) and 1,2-diamino-4-nitro-
benzene (e, 0.05 g, 0.30 mmol) according to General procedure II.
in anhydrous ethanol. Reaction time: 1 day. Purified by column
chromatography (1:2 EtOAc–hexane) to give 9e as the first and
8e as the second fraction.
Compound 8e: Yield: 0.052 g (46%) yellow solid; Rf: 0.25 (2:3
EtOAc–hexane); mp: 134–136 °C; [
a]
D = ꢃ65 (c 0.5, CHCl3); 1H
NMR (CDCl3) d (ppm): 12.87 (1H, br s, benzimidazole NH), 8.45–
6.96 (23H, m, aromatics), 6.20, 6.12, 6.01 (3 ꢂ 1H, 3 pseudo t,
J = 9.4, 9.4 Hz in each, H-20, H-30, H-40), 5.33 (1H, d, J = 9.4 Hz, H-
10), 4.77 (1H, dd, J = 11.8, <1 Hz, H-60a), 4.63 (1H, dd, J = 11.8,
<1 Hz, H-60b), 4.51 (1H, ddd, J = J = 9.4, <1 Hz, H-50); 13C NMR
(CDCl3) d (ppm): 166.3, 165.8, 165.1, 164.8 (CO), 152.7 (benzimid-
azole C-2), 143.3 (benzimidazole C-5), 141.6, 138.0 (2 br s, benz-
imidazole C-3a, C-7a), 133.5–127.6 (aromatics), 118.9, 116.1,
111.6 (br s for each, benzimidazole C-4, C-6, C-7), 77.1, 75.4,
74.0, 71.7, 69.0 (C-10–C-50), 63.2 (C-60). Anal. Calcd for
4.15. 5,6-Dimethyl-2-(20,30,40,60-tetra-O-benzoyl-b-
D-
glucopyranosyl)-benzimidazole (8h)
A: From acid 5 (0.1 g, 0.16 mmol) and 1,2-diamino-4,5-dimeth-
ylbenzene (h, 0.02 g, 0.16 mmol) according to General procedure I.
Yield: 0.05 g (43%).
C
41H31N3O11 (741.70): C, 66.39; H, 4.21; N, 5.67. Found: C, 66.26;
B: From imidate 6 (0.10 g, 0.15 mmol) and 1,2-diamino-4,5-
dimethylbenzene (h, 0.04 g, 0.30 mmol) according to General pro-
cedure II. Reaction time: 3 h. Purified by column chromatography
(2:3 EtOAc–hexane) to yield 0.09 g (81%) of pale yellow solid.
H, 4.13; N, 5.79.
Compound 9e:Yield: 0.019 g (20%) yellow syrup; Rf: 0.39 (2:3
EtOAc–hexane); [a]
D = +1 (c 0.5, CHCl3); 1H NMR (DMSO-d6) d
(ppm): 13.51 (1H, br s, benzimidazole NH), 8.13–7.48 (18H, m,
aromatics), 6.40 (1H, br s, H-20), 6.02 (1H, pseudo t, J = 5.3,
4.0 Hz, H-30 or H-40), 5.93 (1H, pseudo t, J = 6.6, 5.9 Hz, H-30 or
H-40), 5.23 (1H, ddd, J = 5.9, 5.3, 3.3 Hz, H-50), 4.89 (1H, dd,
J = 12.6, 5.3 Hz, H-60a), 4.78 (1H, dd, J = 12.6, 3.3 Hz, H-60b); 13C
NMR (DMSO-d6) d (ppm): 165.3, 165.0, 164.5 (CO), 150.5 (br s),
149.7 (br s), 147.5 (br s), 145.0, 143.0, 142.3 (br s), 138.7 (br s)
(benzimidazole, C-10), 133.8–128.7 (aromatics), 119.2, 118.5,
117.8, 115.2, 112.3, 108.4 (br s for each, benzimidazole), 100.5
(C-20), 74.6, 67.9, 67.0 (C-30–C-50), 61.5 (C-60). Analysis:
Mp: 207–209 °C; [
a]
D = ꢃ64 (c 0.5, CHCl3); 1H NMR (CDCl3) d
(ppm): 11.00 (1H, br s, benzimidazole NH), 7.98–6.92 (22H, m, aro-
matics), 6.27, 6.21, 6.05 (3 ꢂ 1H, 3 pseudo t, J = 9.2, 9.2 Hz in each,
H-20, H-30, H-40), 5.34 (1H, d, J = 9.2 Hz, H-10), 4.67 (1H, dd, J = 11.9,
2.6 Hz, H-60a), 4.54 (1H, dd, J = 11.9, 5.3 Hz, H-60b), 4.48 (1H, ddd,
J = 9.2, 5.3, 2.6 Hz, H-50), 2.17 (6H, s, CH3); 13C NMR (CDCl3) d
(ppm): 166.3, 165.9, 165.1, 165.0 (CO), 147.5 (benzimidazole C-
2), 141.1 (br s, benzimidazole C-3a, C-7a), 133.2–127.9 (aromatics,
benzimidazole C-5, C-6), 119.5, 111.6 (2 br s, benzimidazole C-4, C-
7), 76.8, 75.6, 74.3, 71.7, 69.5 (C-10–C-50), 63.3 (C-60), 20.2
(2 ꢂ CH3). Anal: Calcd for C43H36N2O9 (724.75): C, 71.26; H, 5.01;
N, 3.87. Found: C, 71.15; H, 4.92; N, 3.99.
C
34H25N3O9 (619.58), ESI-MS (positive mode) m/z: 642.148
[M+Na]+, 1261.309 [2M+Na]+.
4.13. 5(6)-Methyl-2-(20,30,40,60-tetra-O-benzoyl-b-
glucopyranosyl)-benzimidazole (8f)
D-
4.16. 2-(20,30,40,60-Tetra-O-benzoyl-b-
naphtho[2,3-d]imidazole (8i)
D-glucopyranosyl)-
A: From acid 5 (0.1 g, 0.16 mmol) and 3,4-diaminotoluene
(f, 0.02 g, 0.16 mmol) according to General procedure I. Yield:
0.06 g (53%).
From imidate 6 (0.10 g, 0.15 mmol) and 2,3-diamino-naphtha-
lene (i, 0.05 g, 0.30 mmol) according to General procedure II.
Reaction time: 4 h. Purified by column chromatography (4:5

Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
185
EtOAc–hexane) to yield 0.091 g (79%) of pale brown solid. Mp:
Anal. Calcd for C13H15BrN2O5 (359.17): C, 43.47; H, 4.21; N, 7.80.
Found: C, 43.43; H, 4.34; N, 7.93.
184–186 °C;
[a
]
D = ꢃ113 (c 0.25, CHCl3); 1H NMR (CDCl3)
d
(ppm): 10.64 (1H, br s, naphthoimidazole NH), 7.81–6.92 (26H,
m, aromatics), 6.14, 6.05, 5.90 (3 ꢂ 1H, 3 pseudo t, J = 9.6, 9.6 Hz
in each, H-20, H-30, H-40), 5.29 (1H, d, J = 9.6 Hz, H-10), 4.64 (1H,
dd, J = 12.3, <1 Hz, H-60a), 4.49 (1H, dd, J = 12.3, 5.3 Hz, H-60b),
4.39 (1H, ddd, J = 9.6, 5.3, <1 Hz, H-50); 13C NMR (CDCl3) d (ppm):
166.2, 165.9, 165.1 (2) (CO), 152.9 (naphthoimidazole C-2), 142.7
(br s, naphthoimidazole C-3a, C-9a), 133.2–127.8, 123.6 (aromat-
ics), 116.2, 107.8 (2 br s, naphthoimidazole C-4, C-9), 76.9, 75.6,
74.2, 71.7, 69.5 (C-10–C-50), 63.4 (C-60). Analysis: C45H34N2O9
(746.76), ESI-MS (positive mode) m/z: 769.219 [M+Na]+,
1516.457 [2M+Na]+.
4.20. 2-(b-D-Glucopyranosyl)-5(6)-nitro-benzimidazole (10e)
From 8e (0.30 g, 0.40 mmol) according to General procedure III.
Reaction time: 1 day. Purified by column chromatography (85:15
CHCl3–MeOH) to yield 0.07 g (53%) of yellow syrup. Rf: 0.27 (4:1
CHCl3–MeOH); 1H NMR (DMSO-d6) d (ppm): 13.03 (1H, br s, benz-
imidazole NH), 8.44 (1H, d, J = 1.3 Hz, benzimidazole H-4), 8.11
(1H, dd, J = 9.2, 1.3 Hz, benzimidazole H-6), 7.70 (1H, d, J = 9.2 Hz,
benzimidazole H-7), 5.14 (3H, br s, 3 ꢂ OH), 4.60 (1H, br s, OH),
4.42 (1H, d, J = 9.2 Hz, H-10), 3.74 (1H, dd, J = 11.9, <1 Hz, H-60a),
3.63 (1H, pseudo t, J = 9.2, 9.2 Hz, H-20or H-30 or H-40), 3.49 (1H,
dd, J = 11.9, 5.3 Hz, H-60b), 3.39–3.34 (2H, m, H-20 or H-30 or H-40,
H-50), 3.24 (1H, pseudo t, J = 9.2, 9.2 Hz, H-20or H-30 or H-40); 13C
NMR (DMSO-d6) d (ppm): 157.3 (benzimidazole C-2), 142.5 (benz-
imidazole C-5), 141.4, 138.8 (2 br s, benzimidazole C-3a, C-7a),
117.7, 114.3 (br s), 112.6 (br s) (benzimidazole C-4, C-6, C-7),
81.6, 77.7, 76.0, 72.8, 70.0 (C-10–C-50), 61.2 (C-60). Anal. Calcd for
4.17. 5(6)-Fluoro-2-(b-D-glucopyranosyl)-benzimidazole (10b)
From 8b (0.22 g, 0.30 mmol) according to General Procedure III.
Reaction time: 3.5 h. Purified by column chromatography (4:1
CHCl3–MeOH) to yield 0.048 g (54%) of pale yellow syrup. Rf: 0.19
(10:3 CHCl3–MeOH); [a]
D = +9 (c 0.2, DMSO); 1H NMR (CD3OD) d
C13H15N3O7 (325.27): C, 48.00; H, 4.65; N, 12.92. Found: C, 47.87;
(ppm): 7.48 (1H, s, benzimidazole H-4), 7.21 (1H, d, J = 8.7 Hz, benz-
imidazole H-7), 6.97 (1H, t, J = 8.7 Hz, benzimidazole H-6), 4.46 (1H,
d, J = 9.4 Hz, H-10), 3.88 (1H, dd, J = 11.8, <1 Hz, H-60a), 3.73 (1H, dd,
J = 11.8, <1 Hz, H-60b), 3.61 (1H, pseudo t, J = 9.8, 9.8 Hz, H-20 or H-
30or H-40), 3.52–3.47 (3H, m, H-20 and/or H-30 and/or H-40, H-50);
13C NMR (DMSO-d6) d (ppm): 158.3 (d, 1JC-F = 236 Hz, benzimidazole
C-5,), 153.9, 143.2, 138.9, 133.7, 130.6, 119.7, 112.0, 109.7, 104.0,
98.0 (br s for each, benzimidazole), 81.4, 77.8, 75.9, 72.7, 70.0 (C-
10–C-50), 61.3 (C-60). Anal. Calcd for C13H15FN2O5 (298.27): C,
52.35; H, 5.07; N, 9.39. Found: C, 52.26; H, 5.21; N, 9.33.
H, 4.56; N, 12.96.
4.21. 2-(b-D-Glucopyranosyl)-5(6)-methyl-benzimidazole (10f)
From 8e (0.27 g, 0.38 mmol) according to General procedure III.
Reaction time: 3 h. Purified by column chromatography (85:15
CHCl3–MeOH) to yield 0.10 g (87%) of colourless syrup. Rf: 0.42
(7:3 CHCl3–MeOH); [a]
D = +18 (c 0.5, MeOH); 1H NMR (CD3OD) d
(ppm): 7.41 (1H, d, J = 7.9 Hz, benzimidazole H-6 or H-7), 7.32
(1H, s, benzimidazole H-4), 7.03 (1H, d, J = 7.9 Hz, benzimidazole
H-6 or H-7), 4.49 (1H, d, J = 9.2 Hz, H-10), 3.91 (1H, dd, J = 11.9,
<1 Hz, H-60a), 3.76 (1H, dd, J = 11.9, 4.0 Hz, H-60b), 3.66 (1H, pseudo
t, J = 9.2, 9.2 Hz, H-20 or H-30 or H-40), 3.61–3.49 (3H, m, H-20and/or
H-30 and/or H-40, H-50), 2.42 (3H, s, CH3); 13C NMR (CD3OD) d
(ppm): 153.4 (benzimidazole C-2), 139.0, 137.6 (benzimidazole
C-3a, C-7a), 133.6 (benzimidazole C-5), 125.2, 115.9, 115.4 (benz-
imidazole C-4, C-6, C-7), 82.1, 79.3, 77.3, 74.8, 71.2 (C-10–C-50),
62.7 (C-60), 21.7 (CH3). Anal. Calcd for C14H18N2O5 (294.30): C,
57.13; H, 6.16; N, 9.52. Found: C, 57.29; H, 6.07; N, 9.39.
4.18. 5(6)-Chloro-2-(b-D-glucopyranosyl)-benzimidazole (10c)
From 8c (0.24 g, 0.33 mmol) according to general procedure III.
Reaction time: 5 h. Purified by column chromatography (4:1
CHCl3–MeOH) to yield 0.092 g (89%) of colourless syrup. Rf: 0.23
(4:1 CHCl3–MeOH); [a]
D = +23 (c 0.5, DMSO); 1H NMR (CD3OD) d
(ppm): 7.50 (1H, d, J = 1.4 Hz, benzimidazole H-4), 7.45 (1H, d,
J = 8.9 Hz, benzimidazole H-7), 7.15 (1H, dd, J = 8.9, 1.4 Hz, benz-
imidazole H-6), 4.47 (1H, d, J = 8.9 Hz, H-10), 3.88 (1H, dd,
J = 11.6, <1 Hz, H-60a), 3.73 (1H, dd, J = 11.6, 4.8 Hz, H-60b), 3.61
(1H, pseudo t, J = 8.9, 8.9 Hz, H-20or H-30 or H-40), 3.55–3.45 (3H,
m, H-20 and/or H-30 and/or H-40, H-50); 13C NMR (CD3OD) d
(ppm): 155.2 (benzimidazole C-2), 140.3, 138.1 (2 br s, benzimid-
azole C-3a, C-7a), 129.2 (benzimidazole C-5), 124.1, 117.1 (br s),
115.9(br s) (benzimidazole C-4, C-6, C-7), 82.2, 79.2, 77.3, 74.8,
71.2 (C-10–C-50), 62.8 (C-60). Anal. Calcd for C13H15ClN2O5
(314.72): C, 49.61; H, 4.80; N, 8.90. Found: C, 49.72; H, 4.87; N,
8.75.
4.22. 2-(b-D-Glucopyranosyl)-4(7)-methyl-benzimidazole (10g)
From 8g (0.25 g, 0.35 mmol) according to General Procedure III.
Reaction time: 4 h. Purified by column chromatography (4:1
CHCl3–MeOH) to give 0.075 g (73%) of colourless syrup. Rf: 0.20
(4:1 CHCl3–MeOH); [a]
D = +13 (c 0.5, DMSO); 1H NMR (DMSO-d6)
d (ppm): 12.46 (1H, br s, benzimidazole NH), 7.32, 7.04, 6.95
(3 ꢂ 1H, benzimidazole), 5.14 (3H, br s, 3 ꢂ OH), 4.64 (1H, br s,
OH), 4.36 (1H, d, J = 10.2 Hz, H-10), 3.73–3.24 (6H, m, H-20, H-30,
H-40, H-50, H-60a, H-60b), 2.50 (3H, s, CH3); 13C NMR (DMSO-d6) d
(ppm): 151.9 (benzimidazole C-2), 141.8, 133.5, 128.4, 121.6,
115.6, 109.0 (br s for each, benzimidazole C-3a, C-7a, C-4–C-7),
81.3, 77.9, 75.9, 72.7, 70.0 (C-10–C-50), 61.2 (C-60). Anal. Calcd for
4.19. 5(6)-Bromo-2-(b-D-glucopyranosyl)-benzimidazole (10d)
From 8d (0.27 g, 0.35 mmol) according to General procedure III.
Reaction time: 6 h. Purified by column chromatography (8:1
CHCl3–MeOH) to yield 0.073 g (58%) of colourless syrup. Rf: 0.23
C
14H18N2O5 (294.30): C, 57.13; H, 6.16; N, 9.52. Found: C, 57.18;
H, 6.05; N, 9.64.
(10:3 CHCl3–MeOH); [a]
D = +21 (c 0.43, DMSO); 1H NMR (CD3OD)
4.23. 5,6-Dimethyl-2-(b-D-glucopyranosyl)-benzimidazole (10h)
d (ppm): 7.65 (1H, s, benzimidazole H-4), 7.41, 7.29 (2 ꢂ 1H, 2d,
J = 8.4 Hz, benzimidazole H-6, H-7), 4.47 (1H, d, J = 9.4 Hz, H-10),
3.88 (1H, dd, J = 11.8, <1 Hz, H-60a), 3.74 (1H, dd, J = 11.8, <1 Hz,
H-60b), 3.61 (1H, pseudo t, J = 9.4, 8.4 Hz, H-20or H-30 or H-40),
3.53–3.46 (3H, m, H-20 and/or H-30 and/or H-40, H-50); 13C NMR
(DMSO-d6) d (ppm): 153.8 (benzimidazole C-2), 141.5, 134.8 (2
br s, C-3a, C-7a), 124.5, 121.0, 113.9, 113.8 (br s for each, benzimid-
azole C-4–C-7), 81.5, 77.8, 75.9, 72.8, 70.0 (C-10–C-50), 61.3 (C-60).
From 8h (0.27 g, 0.37 mmol) according to General procedure III.
Reaction time: 3 h. Purified by column chromatography (85:15
CHCl3–MeOH) to yield 0.09 g (78%) of colourless syrup. Rf: 0.42
(7:3 CHCl3–MeOH); [a]
D = +24 (c 0.5, MeOH); 1H NMR (CD3OD) d
(ppm): 7.28 (2H, s, benzimidazole H-4, H-7), 4.47 (1H, d,
J = 9.2 Hz, H-10), 3.91 (1H, dd, J = 11.9, <1 Hz, H-60a), 3.76 (1H, dd,
J = 11.9, 5.3 Hz, H-60b), 3.67 (1H, pseudo t, J = 9.2, 9.2 Hz, H-20 or

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Éva Bokor et al. / Carbohydrate Research 381 (2013) 179–186
H-30 or H-40), 3.59–3.49 (3H, m, H-20 and/or H-30 and/or H-40, H-50),
2.31 (6H, s, CH3); 13C NMR (CD3OD) d (ppm): 152.7 (benzimidazole
C-2), 137.6 (benzimidazole C-3a, C-7a), 132.7 (benzimidazole C-5,
C-6), 115.9 (benzimidazole C-4, C-7), 82.1, 79.3, 77.3, 74.7, 71.2
(C-10–C-50), 62.7 (C-60), 20.5 (CH3). Anal. Calcd for C15H20N2O5
(308.34): C, 58.43; H, 6.54; N, 9.09. Found: C, 58.56; H, 6.59; N,
8.95.
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From 8i (0.25 g, 0.33 mmol) according to General Procedure III.
Reaction time: 4 h. Purified by column chromatography (4:1
CHCl3–MeOH) to yield 0.085 g (77%) of colourless syrup. Rf: 0.17
(4:1 CHCl3–MeOH); [a]
D = +10 (c 0.6, DMSO); 1H NMR (DMSO-d6)
d (ppm): 12.47 (1H, br s, naphthoimidazole NH), 8.06–7.99 (4H,
m, aromatics), 7.38–7.36 (2H, m, aromatics), 5.20 (2), 5.11 (3H,
br s, 3 ꢂ OH), 4.59 (1H, br s, OH), 4.46 (1H, d, J = 9.9 Hz, H-10),
3.77 (1H, dd, J = 11.2, <1 Hz, H-60a) 3.71 (1H, pseudo t, J = 9.2,
9.2 Hz, H-20 or H-30 or H-40), 3.51 (1H, dd, J = 11.2, 6.6 Hz, H-60b)
3.46–3.36 (2H, m, H-20 or H-30 or H-40, H-50), 3.26 (1H, pseudo t,
J = 9.2, 9.2 Hz, H-20 or H-30 or H-40); 13C NMR (DMSO-d6) d
(ppm): 157.0 (naphthoimidazole C-2), 138.7 (br s), 129.6, 127.7,
123.3, 110.7 (br s) (naphthoimidazole), 81.6, 77.8, 76.1, 72.8, 70.1
(C-10–C-50), 61.3 (C-60). Anal. Calcd for C17H18N2O5 (330.34): C,
61.81; H, 5.49; N, 8.48. Found: C, 61.74; H, 5.60; N, 8.55.
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Acknowledgements
This work was supported by the Hungarian Scientific Research
Fund (OTKA CK77712, CNK80709) and TÁMOP 4.2.1./B-09/1/
KONV-2010-0007
TÁMOP-4.2.2./B-10/1-2010-0024
projects
implemented through the New Hungary Development Plan, co-fi-
nanced by the European Social Fund, as well as János Bolyai Re-
search Scholarship (to TD) of the Hungarian Academy of Sciences.
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