in AcOH (5.0 mL) was stirred at room temperature in open air.
The reaction was complete in 6 h as indicated by the TLC analysis.
The reaction mixture was triturated with EtOAc to give precipitates,
which were collected by filtration using nylon membrane filter. The
aldo-naphthimidazole products prepared as such was practically pure
for characterization. This protocol is applicable to the reaction of
larger scale, e.g., 2 mmol.
and efficient manner. Our preliminary study indicated that
several aldo-naphthimidazoles derived from pentoses and hex-
oses were resolved by HPLC on reversed-phase columns (Figure
2). The detection limit was around 1 ppm. The analysis of aldo-
naphthimidazoles can be further investigated by using capillary
electrophoresis as a high-resolution and sensitive method.
HPLC Analysis of Aldo-naphthimidazoles. For UV detection,
the detection wavelength is set at 310 nm. For fluorescence
detection, the excitation wavelength is 232 nm and the detection
wavelength is 326 nm. The sample was eluted on a pair of HC-C18
column (250 mm × 4.6 mm; 5 µm porosity) at 30 °C, and the
retention time of sample components was recorded. The mobile
phase is sodium phosphate buffer (100 mM, pH 5.0) containing
28% methanol and 2% acetonitrile at a flow rate of 0.8 mL/min.
(1′S,2′R,3′R,4′R)-1-Acetyl-5,6-dimethyl-2-(1,2,3,4,5-pentaacetoxy)-
pentylbenzimidazole (3b-Ac). According to the general procedure
(method A), D-glucose (180 mg, 1.0 mmol) and 4,5-dimethyl-1,2-
benzenediamine (396 mg, 3.0 mmol) were stirred with iodine in
aqueous AcOH solution for 11 h at room temperature. The crude
product was subsequently treated with Ac2O in pyridine to give
compound 3b-Ac (319 mg, 58% overall yield). C26H32N2O11:
yellowish solid, mp ) 83-85 °C; TLC (EtOAc/hexane, 1:2) Rf )
0.16; [R]25D +63.1 (c 1.2, CHCl3); IR Vmax (NaCl) 3456, 1752, 1367,
Conclusion
Using iodine as an oxidant/promoter, various aldoses react
readily with o-phenylenediamines or 2,3-naphthalenediamine in
acetic acid solution to form the corresponding aldo-benzimi-
dazoles and aldo-naphthimidazoles in high yields. Other func-
tional groups such as hydroxyl, carboxyl, and amido groups
are inert in the mild reaction conditions. Thus, the oxidative
condensation reactions of various aldoses were realized without
protection or modification of other functional groups. The
success of this method relies on the crucial role of iodine and
choice of acetic acid as the solvent. This protocol shows
advantages over the previous methods3,5 by conducting the
oxidative condensation reactions under mild conditions in a one-
pot procedure to give high yields of aldo-imidazole products,
which can be isolated simply by trituration of the crude reaction
mixture with ethyl acetate. No racemization of saccharides or
cleavage of the glycoside bonds occurs in our reaction protocol.
In contrast to the starting materials of fluorescence-insensitive
aldose and 2,3-naphthalenediamine, the aldo-naphthimidazole
is highly fluorescent. Such property of enhanced fluorescence
is potentially useful to the research of glycochemistry and
glycobiology. In a preliminary study, we have demonstrated an
application in carbohydrate composition analysis via the aldo-
naphthimidazole derivatives.
1
1222,1036 cm-1; H NMR (CDCl3, 400 MHz) δ 7.50 (1 H, s),
7.33 (1 H, s), 6.60 (1 H, d, J ) 3.6 Hz), 5.90 (1 H, dd, J ) 5.6, 3.6
Hz), 5.55 (1 H, t, J ) 5.6 Hz), 5.56-5.54 (1 H, m), 4.38 (1 H, dd,
J ) 12.4, 2.4 Hz), 4.26 (1 H, dd, J ) 12.4, 5.6 Hz), 2.82 (3 H, s),
2.39 (3 H, s), 2.34 (3 H, s), 2.20 (3 H, s), 2.10 (3 H, s), 2.08 (3 H,
s), 2.05 (3 H, s), 1.93 (3 H, s); 13C NMR (CDCl3, 100 MHz) δ
169.9, 169.4, 169.2 (2 × ), 169.0, 168.9, 149.3, 140.5, 134.1, 133.1,
129.8, 120.8, 113.6, 69.4, 69.3, 69.2, 69.0, 61.6, 26.9, 21.2, 21.1
(2×), 21.0 (2×), 20.7, 20.3; HRMS (ESI) calcd for C26H33N2O11
549.2079, found m/z 549.2061 [M + H]+.
(1′S,2′R,3′R,4′R)-2-(1,2,3,4,5-Pentahydroxyl)pentyl-1H-naph-
thimidazole (3g). According to the general procedure (method C),
D-glucose (3.6 mg, 0.02 mmol) and 2,3-naphthalenediamine (3.5
mg, 0.022 mmol) were stirred with iodine (0.5 mg, 0.002 mmol)
in 5.0 mL of AcOH for 6 h at room temperature. The crude product
was triturated with EtOAc to give compound 3g (6.2 mg, 98%
yield). C16H18N2O5: brownish solid, mp ) 175-177 °C; 1H NMR
(DMSO-d6, 600 MHz) δ 8.06 (2 H, s), 7.94 (2 H, d, J ) 6.2, 3.2
Hz), 7.46 (2 H, d, J ) 6.2, 3.2 Hz), 5.12 (1 H, d, J ) 5.3 Hz), 4.20
(1 H, dd, J ) 5.3, 1.6 Hz), 3.59 (1 H, dd, J ) 8.6, 1.3 Hz),
3.52-3.48 (2 H, m), 3.35 (1 H, dt, J ) 11.9, 0.9 Hz); 13C NMR
(DMSO-d6, 150 MHz) δ 161.1 (2×), 139.5 (2×), 129.8 (2×), 127.9
(2×), 123.5 (2×), 110.9, 72.2, 71.6, 71.4, 70.4, 63.7; HRMS (ESI)
calcd for C16H19N2O5 319.1294, found m/z 319.1285 [M + H]+.
(1′S,2′R,3′R,4′R)-1-Acetyl-2-[1,2,4,5-tetraacetoxy-3-O-(2,3,4,5-tet-
raacetoxy-ꢀ-D-galactopyranosyl)]pentylbenzimidazole (14a-Ac). Ac-
cording to the general procedure (method B), D-lactose monohydrate
(180 mg, 0.5 mmol) and o-phenylenediamine (108 mg, 1.0 mmol)
were stirred with iodine (127 mg, 0.5 mmol) in aqueous AcOH
buffer solution for 58 h at room temperature. The crude product
was subsequently treated with Ac2O in pyridine to give compound
14a-Ac (359 mg, 88% overall yield) without further purification.
C36H44N2O19: yellowish foam; TLC (EtOAc/hexane, 1:1) Rf ) 0.12;
Experimental Section
General Procedure for Oxidative Condensation of Aldoses with
o-Phenylenediamines or 2,3-Naphthalenediamine. Method A. An
appropriate aldose (1.0 mmol) and o-phenylenediamine (192 mg,
3.0 mmol) were dissolved in a solution containing acetic acid (1
mL) and water (7 mL). The mixture was stirred with a solution of
iodine (254 mg, 1.0 mmol) in MeOH (2 mL) at room temperature
until the aldose was completely consumed as indicated by the TLC
analysis. During the reaction period, the deep brown color of
reaction mixture remained. The reaction was quenched by addition
of Na2S2O3 (2 mL of saturated aqueous solution), and the mixture
was concentrated under reduced pressure to give the crude products
of aldo-benzimidazoles.
The crude aldo-benzimidazole product was treated with acetic
anhydride (2 mL) and pyridine (2 mL) at 0-25 °C for 8 h and
then partitioned between 1 N HCl (30 mL) and CH2Cl2 (50 mL).
The organic phase was washed once with brine (30 mL), concen-
trated under reduced pressure, and purified by silica gel column
chromatography (EtOAc/hexane, 1:2) to afford the desired product
of aldo-benzimidazole peracetatate.
Method B. The oxidative condensation reactions were also
performed in buffer solution. Thus, an appropriate aldose (1.0
mmol) and o-phenylenediamine (2.0 mmol, 132 mg) was dissolved
in acetic acid buffer solution (4 mL, pH 4.38). Iodine (1.0 mmol,
254 mg dissolved in 2 mL of methanol) was added, and the mixture
was stirred at room temperature until the aldose was completely
consumed as indication of the TLC analysis. The reaction mixture
was quenched by Na2S2O3, concentrated, and subjected to per-
acetylation with Ac2O/pyridine to afford the desired product of aldo-
benzimidazole peracetatate.
[R]25 +40.3 (c 2.7, CHCl3); IR Vmax (NaCl) 3443, 1750, 1371,
D
1227, 1047 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.74-7.72 (1 H,
m), 7.66-7.63 (1 H, m), 7.39-7.31 (2 H, m) 6.63 (1 H, dd, J )
2.8, 0.8 Hz), 5.74 (1 H, m), 5.34 (1 H, d, J ) 3.6 Hz), 5.22-5.19
(1 H, m), 5.13 (1 H, dd, J ) 10, 8 Hz), 5.00 (1 H, m), 4.63 (1 H,
m), 4.41 (1 H, t, J ) 5.6 Hz), 4.21 (1 H, dd, J ) 10.8, 7.2 Hz),
4.02-3.92 (2 H, m), 3.84 (1 H, t, 6.8), 2.88 (3 H, s), 2.27 (3 H, s),
2.14 (3 H, s), 2.13 (3 H, s), 2.09 (3 H, s), 2.06 (3 H, s), 2.00 (3 H,
s), 1.98 (3 H, s), 1.93 (3 H, s); 13C NMR (CDCl3, 100 MHz) δ
169.9, 169.8, 169.7 (2×), 169.6 (2×), 169.3, 169.2, 168.8, 151.1,
142.1, 131.7, 125.0, 124.2, 120.5, 113.4, 100.9, 70.7, 70.6, 70.3,
69.4, 69.3, 68.8, 66.6, 61.3, 60.7, 60.1, 26.5, 20.8, 20.7, 20.6 (2×),
Method C. A mixture of aldose (0.02 mmol), 2,3-naphthalene-
diamine (3.5 mg, 0.022 mmol), and iodine (0.5 mg, 0.002 mmol)
3852 J. Org. Chem. Vol. 73, No. 10, 2008
Lin, Chunchi
