Efficient one-pot synthetic protocols for iminosugar-bearing imidazo[1,2-a]pyridines from carbohydrates

Article abstract of DOI:10.1016/j.carres.2009.11.016

This letter describes two unprecedented one-pot high yielding synthetic approaches to imidazo[1,2-a]pyridine scaffolds from carbohydrates. The first approach involves microwave-assisted acid-catalyzed domino reactions of unprotected d-glucose/d-xylose with ammonium acetate and benzoin to afford polyhydroxy iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines. In the second approach, polyhydroxy iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyridines were synthesized by using unprotected d-glucose/d-xylose and 1,2-diamines in the presence of 10 mol % of oxalic acid under solvent-free microwave irradiation conditions.

Full text of DOI:10.1016/j.carres.2009.11.016

Carbohydrate Research 345 (2010) 318–323
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Efficient one-pot synthetic protocols for iminosugar-bearing
imidazo[1,2-a]pyridines from carbohydrates
*
Lal Dhar S. Yadav , Chhama Awasthi
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This letter describes two unprecedented one-pot high yielding synthetic approaches to imidazo[1,2-
Received 5 September 2009
Received in revised form 8 November 2009
Accepted 10 November 2009
Available online 13 November 2009
a]pyridine scaffolds from carbohydrates. The first approach involves microwave-assisted acid-catalyzed
domino reactions of unprotected
D-glucose/D-xylose with ammonium acetate and benzoin to afford
polyhydroxy iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines. In the second approach, polyhy-
droxy iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyridines were synthesized by using unpro-
tected
D-glucose/D-xylose and 1,2-diamines in the presence of 10 mol % of oxalic acid under solvent-
Keywords:
free microwave irradiation conditions.
Carbohydrates
Acid-catalyzed
Microwave
Ó 2009 Elsevier Ltd. All rights reserved.
Solvent-free
Imidazo[1,2-a]pyridines
Iminosugars
Iminosugars are arousing a great interest as potential therapeu-
tic agents against HIV infection,1,2 cancer,3,4 diabetes,5,6 and other
genetic and metabolic disorders7 due to their powerful interfer-
ence with glycosyltranferases. Recently published reviews clearly
reveal the significance of iminosugars.8–10 Imidazole- and
pyridine-based structural scaffolds have been established as the
essential part of many natural products. Synthetic compounds hav-
ing these moieties exhibit a wide range of biological activities.
Thus, tremendous efforts have been devoted to the synthesis of
various imidazo[1,2-a]pyridines to explore their therapeutic po-
tential.11–15 Some of their derivatives act on the central nervous
system16,17 and have cardiotonic,18 antiseptic, antiinflamma-
tory,19,20 and analgesic21 effects, and also show activity against
been reported by using Lewis acids as well as protic liquid and so-
lid acids promoters such as scandium triflate,32–34 ZnCl2,35 TsOH,36
HClO4,37 HOAc,38 montmorillonite K-10 clay,39 and silica–sulfuric
acid.40 However, in spite of the potential utility of aforementioned
routes for the synthesis of imidazo[1,2-a]pyridine derivatives,
many of these reactions suffer from limitations such as introduc-
tion of substituents at specific positions and functional group intol-
erance of the conditions required. Many of these methods involve
expensive reagents, long reaction times, low yields, and use of
toxic organic solvents. However, to the best of our knowledge,
there has been no report on the microwave-assisted synthesis of
iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines starting
from D-glucose and D-xylose although they appear to be utilized
HIV infections.22 They are
a
-amyloid formation inhibitors23 and
for exploiting chemical diversity and generating a drug-like library
to screen for potential new leads. Aside from the simple expecta-
tion that the presence of sugar residues with free hydroxyl groups
in these heterocylic systems should increase the water solubility
and bioavailability, other interesting biological properties may
arise owing to the complex machinery of various glycoconjugate
biological activities.41
On the basis of the above-mentioned points and our ongoing
efforts to devise new MW-assisted solvent-free cyclization
processes,42–44 especially using carbohydrates as starting mate-
rial,45–49 we describe herein two synthetic approaches for an
acid-catalyzed unprecedented synthesis of biologically important
iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines 4, 5, 7,
constitute a novel class of orally active nonpeptide bradykinin B2
receptor antagonists.24 Imidazo[1,2-a]pyridine compounds are
presently in clinical use, for example, zolimidine (an antiulcer
drug),25 zolpidem (a hypnotic drug), and alpidem (a non-sedative
anxiolytic drug).26
Among several methods available for the synthesis of imi-
dazo[1,2-a]pyridines,27–40 the most general involves the coupling
of 2-aminopyridines with a
-halocarbonyl compounds.28 However,
this approach does not readily lend itself to a diversity oriented
synthesis. Recently more than a few synthetic methods for prepar-
ing these compounds based on multicomponent reactions have
and 8 using
D-glucose and D-xylose as biorenewable resources un-
* Corresponding author. Tel.: +91 5322500652; fax: +91 5322460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
der solvent-free microwave irradiation conditions (Scheme 1).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.11.016

Lal Dhar S. Yadav, C. Awasthi / Carbohydrate Research 345 (2010) 318–323
319
HO
OH
OH
N
HO
HO
OH
N
N
N
CHO
3, 1,
6,
OH
n
n
= 4
= 3
n
n
= 4
OH
oxalic acid
(10 mol%)
oxalic acid
(10 mol%)
(CHOH)n
Ar2
Ar1
7
4
CH2OH
HO
MW
MW
D-glucose, n =
4
3
OH
OH
N
HO
= 3
D-xylose, n =
HO
OH
Ar2
Ar1
O
2
NH2
NH2
N
3,
N
N
6,
OH
Ar2
Ar1
1,
NH4OAc
8
5
Scheme 1. Formation of iminosugar-bearing imidazo[1,2-a]pyridines 4, 5, 7, and 8.
Advantageously, the present methodology avoids tedious protec-
tion–deprotection operations.
In order to probe the desired products we performed some pre-
liminary experimentations when it was found that the synthesis of
tetrahydroimidazo[1,2-a]pyridines 4 and 5 could be effected by
HO
OH
N
HO
n = 4
N
OH
CHO
CHOH n
NH2
NH2
MW-activated solvent-free reactions of
D-glucose/D-xylose, ben-
MW
7
+
zoin 3, and ammonium acetate mediated by 10 mol % oxalic acid
(Scheme 2).
Inspired by the above-mentioned synthesis we have also
successfully synthesized iminosugar-bearing tetrahydrobenzimi-
dazo[1,2-a]pyridines 7 and 8 in excellent yields by using 1,2-dia-
10 mol%
HO
CH2OH
oxalic acid
OH
N
D
D
-glucose, n = 4
HO
6
-xylose, n = 3
n = 3
N
2
mine and
D-glucose/D-xylose as starting substrates in the
presence of 10 mol % oxalic acid via amine-driven domino reac-
tions (Scheme 3).
8
It was noted that other catalysts’ silica gel, montmorillonite
K-10 clay, acidic, neutral or basic Al2O3, I2, CeSO4ꢀ8H2O, CeCl3ꢀ7H2O
were far less effective (Table 1) resulting in either no reaction (in
case of basic alumina) or relatively very low yields of products
(4a and 7a of Tables 2 and 3, respectively). To optimize catalyst
loading, we carried out the reactions using 5, 10, and 15 mol % of
oxalic acid and the highest yields were obtained with 10 mol %
(Table 1, entry 7). Moreover, when the reaction was performed
at 80 °C using conventional heating, significantly lower yields of
4a and 7a were obtained in relatively longer reaction times
(Table 1).
Scheme 3. Formation of iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyri-
dines 7 and 8.
Table 1
Optimization of reaction conditions for compounds 4a and 7a
Entry Catalyst system
MW
Oil bath
Timea
(min)
Yieldb
(%)
Timea
(h)
Yieldb
(%)
4a
7a
4a
7a
4a
7a
4a
7a
1
2
3
4
5
6
7
8
K-10 clay
10
12
13
14
13
14
12
14
15
13
13
13
14
13
93
92
69
17
17
33
70
73
89
89
62
18
16
30
68
75
6
7
9
10
9
6
7
8
8
10
10
5
38
36
20
11
13
49
50
51
36
32
18
12
12
48
53
48
First approach: The strategy followed for the envisaged synthe-
sis of tetrahydroimidazo[1,2-a]pyridines 4 and 5 consisted of
MW irradiation of a solvent-free intimate mixture of benzoin 3,
CeCl3ꢀ7H2O–NaI
Silica gel
Neutral alumina
Acidic alumina
5 mol % oxalic acid
10 mol % oxalic acid 12
15 mol % oxalic acid 13
ammonium acetate 1, and D-glucose/D-xylose 2 in the presence of
10 mol % oxalic acid, at 80 °C for 9–13 min in a Chemical Labora-
tory Microwave Oven (Model: BP-310/50, 230 V, 50 Hz power in-
put) (Table 2). After isolation and purification by recrystallization
5
6
4
5
a
Time for the completion of the reaction at 80 °C as indicated by TLC.
Yield of isolated and purified products 4a and 7a.
b
OH
HO
= 4
OH
from ethanol multifunctionalized tetrahydroimidazo[1,2-a]pyri-
dines 4 and 5 were obtained in 80–96% yields.
Second approach: In the second synthetic route, iminosugar-
bearing tetrahydrobenzimidazo[1,2-a]pyridines 7 and 8 were syn-
thesized in 79–91% yields by MW irradiation of a solvent-free inti-
N
n
N
OH
Ar2
Ar1
Ar2
O
4
CHO
CHOH
MW
10 mol%
oxalic acid
NH4OAc
+
+
4
n
OH
Ar1 OH
CH2OH
mate mixture of D-glucose/D-xylose 2, 1,2-diamine 6 and 10 mol %
1
HO
OH
D
D
-glucose, n =
oxalic acid, at 80 °C for 8–14 min in a Chemical Laboratory Micro-
wave Oven (Model: BP-310/50, 230 V, 50 Hz power input) (Table
3), which were isolated and purified by recrystallization from
ethanol.
The formation of target compounds 4 and 5 may be tentatively
rationalized by oxalic acid-catalyzed condensation of aldoses
n
= 3
-xylose, n = 3
3
N
N
2
Ar2
Ar1
5
Scheme 2. Formation of iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines 4
and 5.
(D-glucose/D-xylose) 2, 2-hydroxyketone 3 with ammonia (in situ

320
Lal Dhar S. Yadav, C. Awasthi / Carbohydrate Research 345 (2010) 318–323
Table 2
irradiation conditions. The protocols are generally high yielding
and offer an easy access to chemically and pharmaceutically rele-
vant products.
Microwave-assisted synthesis of iminosugar-bearing tetrahydroimidazo[1,2-a]pyri-
dines 4 and 5
Product
Ar1
Ar2
Timea (min)
Yieldb,c (%)
4a
4b
4c
4d
5a
5b
5c
5d
C6H5
C6H5
C6H5
C6H5
p-MeOC6H4
C6H5
C6H5
C6H5
p-MeOC6H4
10
9
11
12
11
9
93
94
88
83
95
96
89
80
1. Experimental
1.1. General
p-ClC6H4
p-MeOC6H4
p-MeOC6H4
C6H5
p-ClC6H4
p-MeOC6H4
p-MeOC6H4
Melting points were determined by open glass capillary meth-
od and are uncorrected. IR spectra in KBr were recorded on a Per-
kin–Elmer 993 IR spectrophotometer. 1H NMR spectra were
recorded on a Bruker WM-40 C (400 MHz) FT spectrometer in
DMSO-d6 using TMS as internal reference. 13C NMR spectra were
recorded on the same instrument at 100 MHz in DMSO-d6 and
TMS was used as an internal reference. Mass (EI) spectra were re-
corded on a JEOL D-300 mass spectrometer. Elemental analyses
were carried out in a Coleman automatic carbon, hydrogen and
nitrogen analyzer. A Chemical Laboratory Microwave Oven (Mod-
el; BP-310/50, 230 V, 50 Hz power input) was used for all experi-
ments. All chemicals used were reagent grade and were used as
received without further purification. Silica Gel-G was used for
TLC.
10
13
a
b
c
Microwave irradiation time at 80 °C.
Yield of isolated and purified products.
All compounds gave C, H, and N analyses within 0.36% and satisfactory spec-
tral (IR, 1H NMR, 13C NMR, and EIMS) data.
Table 3
Microwave-assisted synthesis of iminosugar-annulated tetrahydrobenzimidazo
[1,2-a]pyridines 7 and 8
Product
Diamine 6
Timea (min)
12
Yieldb,c (%)
89
NH2
7a
1.2. (5S,6R,7S,8S)-5,6,7,8-Tetrahydro-5-(hydroxymethyl)-2,3-
disubstituted-imidazo[1,2-a]pyridines-6,7,8-triol (4) and
(6R,7S,8S)-5,6,7,8-tetrahydro-2,3-disubstituted-imidazo[1,2-a
]pyridine-6,7,8-triol (5): general procedure
NH2
NH2
7b
7c
7d
8a
8b
8c
8d
8
9
79
84
82
91
83
87
90
NH2
NH2
An intimate solvent-free mixture of benzoin 3 (1 mmol), ammo-
nium acetate (2 mmol), and aldose 2 (1 mmol) in the presence of
10 mol % of oxalic acid was taken in a 20 mL vial and subjected
to MW irradiation in a Chemical Laboratory Microwave Oven
(Model: BP-310/50, 230 V, 50 Hz power input) at 80 °C for
9–13 min (Table 2). After completion of the reaction as indicated
by TLC, water (10 mL) was added to precipitate the crude product,
which was recrystallized from ethanol to give an analytically pure
sample of 4 and 5 as a yellow solid.
NH2
NH2
NH2
14
11
10
9
NH2
NH2
NH2
NH2
NH2
1.2.1. 5-Hydroxymethyl-2,3-diphenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridine-6,7,8-triol (4a)
Yellow solid; yield 93%, mp 197–199 °C. IR (KBr) mmax 3344,
NH2
3010, 2856, 1606, 1582, 1456 cmꢁ1 1H NMR (400 MHz, DMSO-
.
NH2
NH2
d6): d = 3.58 (dd, 1H, J6H,7H = 9.3 Hz, J5H,6H = 9.4 Hz, 6-H), 3.78
13
0
0
(ddd, 1H, J1 Ha,5H = 3.1 Hz, J1 Hb,5H = 6.7 Hz, J5H,6H = 6.0 Hz, 5-H),
3.85 (dd, 1H, J1 Ha,1 Hb = 12.7 Hz, J1 Ha,5H = 3.1 Hz, 10-Ha), 3.97 (dd,
0
0
0
a
b
c
Microwave irradiation time at 80 °C.
Yield of isolated and purified products.
0
0
1H, J7H,8H = 9.6 Hz, J6H,7H = 9.3 Hz, 7-H), 4.00 (dd, 1H, J1 Ha,1 Hb
=
12.7 Hz, J1 Hb,5H = 6.7 Hz, 10-Hb), 4.88 (d, 1H, J7H,8H = 9.6 Hz, 8-H),
4.89–5.21 (br s, 4H, 4 ꢂ OH, exchangeable with D2O), 7.20–7.54
(m, 10H). 13C NMR (100 MHz, DMSO-d6): d = 42.5, 60.1, 68.3,
69.8, 81.2, 120.1, 122.4, 125.0, 125.7, 126.3, 126.9, 127.6, 128.2,
134.2, 135.0, 152.2. MS-FAB: m/z = 353 [MH+]. Anal. Calcd for
C20H20N2O4: C, 68.22; H, 5.72; N, 7.95. Found: C, 67.98; H, 5.52;
N, 8.26.
0
All compounds gave C, H, and N analyses within 0.36% and satisfactory spec-
tral (IR, 1H NMR, 13C NMR, and EIMS) data.
generated from ammonium acetate) to form 2-aminoketone 12
and imino-derivative 13, respectively. The adduct 14, formed from
12 and 13, underwent intramolecular dehydrative cyclization fol-
lowed by dehydrogenation to afford the intermediate 17 which
cyclodehydrated to give the products 4 and 5 in 80–96% yields
(Scheme 4).
A plausible mechanistic pathway for the formation of products
7 and 8 allowing the second synthetic strategy is depicted in
Scheme 5. The oxalic acid-catalyzed condensation of aldose (
1.2.2. 2-(4-Chloro-phenyl)-5-hydroxymethyl-3-phenyl-5,6,7,8-
tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol (4b)
Yellow solid; yield 94%, mp 183–185 °C. IR (KBr) mmax 3345,
3011, 2858, 1607, 1583, 1456 cmꢁ1 1H NMR (400 MHz, DMSO-
.
D-glu-
d6): d 3.60 (dd, 1H, J6H,7H = 9.2 Hz, J5H,6H = 9.3 Hz, 6-H), 3.79 (ddd,
cose/ -xylose) with 1,2-diamine gives imine 18 which
D
2
6
0
0
1H, J1 Ha,5H = 3.0 Hz, J1 Hb,5H = 6.7 Hz, J5H,6H = 5.9 Hz, 5-H), 3.87 (dd,
undergoes intramolecular cyclization, dehydrogenation, and cyc-
lodehydration cascade to afford products 7 and 8 in 79–91% yields.
In summary, we have developed two routes for an unprece-
dented one-pot synthesis of polyfunctionalized iminosugar-bear-
ing imidazo[1,2-a]pyridine scaffolds using unprotected
and -xylose as biorenewable resources under solvent-free MW
1H, J1 Ha,1 Hb = 12.6 Hz, J1 Ha,5H = 3.0 Hz, 10-Ha), 3.98 (dd, 1H,
0
0
0
0
0
J7H,8H = 9.5 Hz, J6H,7H = 9.2 Hz, 7-H), 4.02 (dd, 1H, J1 Ha,1 Hb = 12.5 Hz,
J1 Hb,5H = 6.7 Hz, 10-Hb), 4.86 (d, 1H, J7H,8H = 9.5 Hz, 8-H), 7.19–8.00
0
(m, 9Harom), 4.92–5.18 (br s, 4H, 4 ꢂ OH, exchangeable with D2O).
D-glucose
13C NMR (100 MHz, DMSO-d6): d 42.8, 60.7, 68.5, 70.0, 82.1,
D

Lal Dhar S. Yadav, C. Awasthi / Carbohydrate Research 345 (2010) 318–323
321
(COOH)2
(10 mol%)
CH
HN
CHO
CHOH
Ar1
Ar2
O
Ar2
Ar1
O
+
OH
Ar1
Ar2
O
NH
CHOH n
(CHOH)n
n
NH4OAc
+
+
CH2OH
MW
CH2OH
N
NH2
D-glucose, n =
4
H2
CH2OH
D-xylose, n =
3
13
14
12
3
2
OH
7
HO
6
OH
8
5
8a
N1
n
= 4
= 3
4N
Ar1
Ar2
3
Ar1
Ar2
Ar1
Ar2
OH
NH
2
OH
Ar2
N
Ar1
N
4
CHOH
n -H2O
CH2OH
-H2O
CHOH n
CH2OH
-H2
CHOH n
CH2OH
N
H
N
H
N
H
OH
7
8
HO
6
OH
n
15
16
17
8a
5
4
N
1
N
3
2
Ar2
Ar1
5
Scheme 4. A plausible mechanism for the formation of iminosugar-bearing tetrahydroimidazo[1,2-a]pyridines 4 and 5.
CHO
CHOH
oxalic acid
(10 mol%)
N
NH2
NH
n
CHOH n
CH2OH
+
NH2
CHOH
CH2OH
MW
NH2
N
H
D-glucose, n =
4
CH2OH
D-xylose, n =
3
6
18
2
HO
7
OH
HO
6
8
8a
5
n
n
= 4
= 3
4 N N1
3
2
OH
N
7
CHOH
CH2OH
n
N
H
-H2
-H2O
HO
7
OH
8
HO
19
6
8a
5
4N N1
3
2
8
Scheme 5. A plausible mechanism for the formation of iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyridines 7 and 8.
120.2, 122.2, 125.7, 126.3, 126.9, 127.6, 128.5, 131.7, 133.0, 135.2,
1.2.4. 5-Hydroxymethyl-2,3-bis-(4-methoxy-phenyl)-5,6,7,8-
tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol (4d)
152.4. MS-FAB: m/z = 388 [MH+]. Anal. Calcd for C20H19ClN2O4: C,
62.22; H, 4.96; N, 7.25. Found: C, 62.56; H, 4.66; N, 7.05.
Yellow solid; yield 83%, mp 161–163 °C. IR (KBr) mmax 3342,
3009, 2982, 2854, 1604, 1583, 1455 cmꢁ1 1H NMR (400 MHz,
DMSO-d6): d 3.58 (dd, 1H, J6H,7H = 9.1 Hz, J5H,6H = 9.2 Hz, 6-H),
.
1.2.3. 5-Hydroxymethyl-2-(4-methoxy-phenyl)-3-phenyl-
5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol (4c)
Yellow solid; yield 88%, mp 176–178 °C. IR (KBr) mmax 3343,
0
0
3.72 (s, 6H, OCH3), 3.79 (ddd, 1H, J1 Ha,5H = 3.0 Hz, J1 Hb,5H = 6.5 Hz,
0
0
0
J5H,6H = 9.2 Hz, 5-H), 3.82 (dd, 1H, J1 Ha,1 Hb = 12.7 Hz, J1 Ha,5H
=
3.0 Hz, 10-Ha), 3.94 (dd, 1H, J7H,8H = 9.5 Hz, J6H,7H = 9.2 Hz, 7-H),
3010, 2984, 2856, 1605, 1584, 1455 cmꢁ1 1H NMR (400 MHz,
.
3.99 (dd, 1H, J1 Ha,1 Hb = 12.7 Hz, J1 Hb,5H = 6.5 Hz, 10-Hb), 4.85 (d,
1H, J7H,8H = 9.5 Hz, 8-H), 4.95–5.12 (br s, 4H, 4 ꢂ OH, exchangeable
with D2O), 6.97–7.52 (m, 8Harom). 13C NMR (100 MHz, DMSO-d6): d
42.8, 53.9, 54.2, 60.8, 68.0, 70.2, 81.7, 111.8, 112.0, 120.0, 122.8,
126.2, 126.8, 127.8, 128.5, 152.0, 161.1, 161.3. MS-FAB: m/z = 413
[MH+]. Anal. Calcd for C22H24N2O6: C, 64.11; H, 5.87; N, 6.79.
Found: C, 63.79; H, 5.66; N, 6.45.
0
0
0
DMSO-d6): d = 3.57 (dd, 1H, J6H,7H = 9.2 Hz, J5H,6H = 9.3 Hz, 6-H),
0
0
3.71 (s, 3H, OCH3), 3.77 (ddd, 1H, J1 Ha,5H = 3.0 Hz, J1 Hb,5H = 6.6 Hz,
0
0
0
J5H,6H = 9.3 Hz, 5-H), 3.85 (dd, 1H, J1 Ha,1 Hb = 12.6 Hz, J1 Ha,5H
=
3.0 Hz, 10-Ha), 3.95 (dd, 1H, J7H,8H = 9.5 Hz, J6H,7H = 9.2 Hz, 7-H),
4.01 (dd, 1H, J1 Ha,1 Hb = 12.6 Hz, J1 Hb,5H = 6.6 Hz, 10-Hb), 4.84 (d,
1H, J7H,8H = 9.5 Hz, 8-H), 4.97–5.17 (br s, 3H, 3 ꢂ OH, exchangeable
with D2O), 6.98–7.85 (m, 9Harom). 13C NMR (100 MHz, DMSO-d6):
d = 43.0, 54.1, 61.1, 67.9, 70.5, 81.8, 111.7, 120.1, 123.0, 125.1,
126.0, 126.9, 127.0, 127.6, 135.0, 152.1, 161.1. MS-FAB: m/z = 383
[MH+]. Anal. Calcd for C21H22N2O5: C, 66.00; H, 5.80; N, 7.33.
Found: C, 65.73; H, 6.34; N, 7.11.
0
0
0
1.2.5. 2,3-Diphenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-
6,7,8-triol (5a)
Yellow solid; yield 95%, mp 180–182 °C. IR (KBr) mmax 3343,
3009, 2852, 1603, 1580, 1455 cmꢁ1 1H NMR (400 MHz, DMSO-
.

322
Lal Dhar S. Yadav, C. Awasthi / Carbohydrate Research 345 (2010) 318–323
d6): d = 3.48 (ddd, 1H, J6H,7H = 9.1 Hz, J5Ha,6H = 9.7 Hz, J5Hb,6H
=
indicated by TLC, water (10 mL) was added to precipitate the crude
product, which was recrystallized from ethanol to give an analyti-
cally pure sample of 7 and 8 as a yellow solid.
3.5 Hz, 6-H), 3.51 (dd, 1H, J5Ha,5Hb = 12.9 Hz, J6Ha,6H = 9.7 Hz,
5-Ha), 3.89 (dd, 1H, J5Ha,5Hb = 12.9 Hz, J5Hb,6H = 3.5 Hz, 5-Hb), 3.94
(dd, 1H, J7H,8H = 9.5 Hz, J6H,7H = 9.1 Hz, 7-H), 4.82 (d, 1H,
J7H,8H = 9.5 Hz, 8-H), 4.97–5.19 (br s, 4H, 4 ꢂ OH, exchangeable
with D2O), 7.18–7.51 (m, 10Harom). 13C NMR (100 MHz, DMSO-
d6): d = 38.3, 68.0, 71.0, 84.2, 120.1, 121.9, 125.0, 125.7, 126.8,
127.2, 127.7, 128.0, 134.3, 134.7, 152.1. MS-FAB: m/z = 323
[MH+]. Anal. Calcd for C19H18N2O3: C, 70.84; H, 5.63; N, 8.7. Found:
C, 70.64; H, 5.51; N, 9.00.
1.3.1. 1-Hydroxymethyl-1,2,3,4-tetrahydrobenzo
[4,5]imidazo[1,2-a]pyridine-2,3,4-triol (7a)
Yellow solid; yield 89%, mp 206–208 °C. IR (KBr) mmax 3343,
3009, 2857, 1603, 1581, 1455 cmꢁ1 1H NMR (400 MHz, DMSO-
.
d6): d = 3.58 (dd, 1H, J6H,7H = 9.2 Hz, J5H,6H = 9.1 Hz, 6-H), 3.66 (dd,
1H, J1 Ha,1 Hb = 12.8 Hz, J1 Ha,5H = 3.2 Hz, 10-Ha), 3.79 (dd, 1H,
0
0
0
J1 Ha,1 Hb = 12.8 Hz, J1 Hb,5H = 6.5 Hz, 10-Hb), 3.91 (ddd, 1H, J1 Ha,5H
=
0
0
0
0
0
1.2.6. 2-(4-Chloro-phenyl)-3-phenyl-5,6,7,8-tetrahydro
imidazo[1,2-a]pyridine-6,7,8-triol (5b)
3.2 Hz, J1 Hb,5H = 6.5 Hz, J5H,6H = 9.1 Hz, 5-H), 3.95 (dd, 1H,
J7H,8H = 9.7 Hz, J6H,7H = 9.2 Hz, 7-H), 4.85 (d, 1H, J7H,8H = 9.7 Hz, 8-
H), 4.88–5.04 (br s, 4H, 4 ꢂ OH, exchangeable with D2O), 7.21–
7.54 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): d = 50.9, 58.6,
68.7, 70.0, 72.1, 114.7, 114.9, 122.6, 122.9, 132.9, 135.8, 159.4.
MS-FAB: m/z = 251 [MH+]. Anal. Calcd for C12H14N2O4: C, 57.62;
H, 5.64; N, 11.20. Found: C, 57.31; H, 5.89; N, 11.49.
Yellow solid; yield 96%, mp 165–167 °C. IR (KBr) mmax 3344,
3011, 2853, 1605, 1581, 1455 cmꢁ1 1H NMR (400 MHz, DMSO-
.
d6): d 3.58 (ddd, 1H, J6H,7H = 9.1 Hz, J5Ha,6H = 9.6 Hz, J5Hb,6H = 3.4 Hz,
6-H), 3.83 (dd, 1H, J5Ha,5Hb = 12.8 Hz, J5Ha,6H = 9.6 Hz, 5-Ha), 3.92
(dd, 1H, J5Ha,5Hb = 12.8 Hz, J5Hb,6H = 3.4 Hz, 5-Hb), 3.95 (dd, 1H,
J7H,8H = 9.4 Hz, J6H,7H = 9.1 Hz, 7-H), 4.83 (d, 1H, J7H,8H = 9.4 Hz,
8-H), 4.99–5.20 (br s, 3H, 3 ꢂ OH, exchangeable with D2O), 7.17–
7.93 (m, 9Harom). 13C NMR (100 MHz, DMSO-d6): d 38.1, 68.5,
71.2, 83.9, 120.4, 121.5, 125.1, 126.1, 126.7, 127.4, 128.2, 130.9,
133.2, 135.0, 151.8. MS-FAB: m/z = 357 [MH+]. Anal. Calcd for
C19H17ClN2O3: C, 64.09; H, 4.80; N, 7.86. Found: C, 64.40; H,
5.08; N, 7.53.
1.3.2. 1-Hydroxymethyl-7,8-dimethyl-1,2,3,4-tetrahydro
benzo[4,5]imidazo[1,2-a]pyridine-2,3,4-triol (7b)
Yellow solid; yield 79%, mp 192–194 °C. IR (KBr) mmax 3341,
3008, 2984, 2856, 1602, 1580, 1454 cmꢁ1 1H NMR (400 MHz,
.
DMSO-d6): d 2.26 (s, 6H, CH3), 3.53 (dd, 1H, J2H,3H = 9.3 Hz,
0
0
0
J1H,2H = 9.0 Hz, 2-H), 3.69 (dd, 1H, J1 Ha,1 Hb = 12.9 Hz, J1 Ha,1H
=
3.3 Hz, 10-Ha), 3.81 (dd, 1H, J1 Ha,1 Hb = 12.9 Hz, J1 Hb,1H = 6.5 Hz,
0
0
0
0
0
1.2.7. 2-(4-Methoxy-phenyl)-3-phenyl-5,6,7,8-tetrahydro
imidazo[1,2-a]pyridine-6,7,8-triol (5c)
10-Hb), 3.93 (ddd, 1H, J1 Ha,1H = 3.3 Hz, J1 Hb,1H = 6.5 Hz, J1H,2H
=
9.0 Hz, 1-H), 3.99 (dd, 1H, J3H,4H = 9.6 Hz, J2H,3H = 9.3 Hz, 3-H),
4.86 (d, 1H, J3H,4H = 9.6 Hz, 4-H), 4.90–5.12 (br s, 4H, 4 ꢂ OH,
exchangeable with D2O), 7.21 (s, 1Harom), 7.29 (s, 1Harom). 13C
NMR (100 MHz, DMSO-d6): d 16.8, 17.1, 51.2, 57.7, 67.6, 69.7,
114.9, 115.2, 127.8, 128.0, 130.9, 134.9, 161.8. MS-FAB: m/z = 279
[MH+]. Anal. Calcd for C14H18N2O4: C, 60.45; H, 6.52; N, 10.08.
Found: C, 60.78; H, 6.16; N, 10.43.
Yellow solid; yield 89%, mp 169–171 °C. IR (KBr) mmax 3341,
3008, 2985, 2855, 1604, 1584, 1455 cmꢁ1 1H NMR (400 MHz,
.
DMSO-d6): d = 3.46 (ddd, 1H, J6H,7H = 9.0 Hz, J5Ha,6H = 9.5 Hz,
J5Hb,6H = 3.4 Hz, 6-H), 3.50 (dd, 1H, J5Ha,5Hb = 12.8 Hz, J5Ha,6H
=
9.5 Hz, 5-Ha), 3.70 (s, 3H, OCH3), 3.85 (dd, 1H, J5Ha,5Hb = 12.8 Hz,
J5Hb,6H = 3.4 Hz, 5-Hb), 3.92 (dd, 1H, J7H,8H = 9.4 Hz, J6H,7H = 9.0 Hz,
7-H), 4.82 (d, 1H, J7H,8H = 9.4 Hz, 8-H), 4.90–5.09 (br s, 3H,
3 ꢂ OH, exchangeable with D2O), 6.95–7.49 (m, 9Harom). 13C NMR
(100 MHz, DMSO-d6): d = 38.4, 54.2, 68.8, 71.0, 83.7, 112.0, 119.9,
122.2, 125.6, 126.2, 126.9, 127.6, 128.4, 135.0, 152.0, 160.8. MS-
FAB: m/z = 353 [MH+]. Anal. Calcd for C20H20N2O4: C, 68.22; H,
5.72; N, 7.95. Found: C, 68.11; H, 5.98; N, 8.26.
1.3.3. 1-Hydroxymethyl-7-methyl-1,2,3,4-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-2,3,4-triol (7c)
Yellow solid; yield 84%, mp 186–188 °C. IR (KBr) mmax 3341,
3008, 2984, 2856, 1602, 1580, 1454 cmꢁ1 1H NMR (400 MHz,
.
DMSO-d6): d = 2.25 (s, 3H, CH3), 3.51 (dd, 1H, J6H,7H = 9.1 Hz,
0
0
0
J5H,6H = 9.0 Hz, 6-H), 3.71 (dd, 1H, J1 Ha,1 Hb = 12.7 Hz, J1 Ha,5H
=
1.2.8. 2,3-Bis-(4-methoxy-phenyl)-5,6,7,8-tetrahydro
imidazo[1,2-a]pyridine-6,7,8-triol (5d)
3.1 Hz, 10-Ha), 3.85 (dd, 1H, J1 Ha,1 Hb = 12.7 Hz, J1 Hb,5H = 6.4 Hz,
0
0
0
10-Hb), 3.92 (dd, 1H, J7H,8H = 9.6 Hz, J6H,7H = 9.1 Hz, 7-H), 3.97
Yellow solid; yield 80%, mp 141–143 °C. IR (KBr) mmax 3342,
0
0
(ddd, 1H, J1 Ha,5H = 3.1 Hz, J1 Hb,5H = 6.4 Hz, J5H,6H = 9.1 Hz, 5-H),
4.87 (d, 1H, J7H,8H = 9.6 Hz, 8-H), 4.93–5.14 (br s, 4H, 4 ꢂ OH,
exchangeable with D2O), 7.25–7.60 (m, 3Harom). 13C NMR
(100 MHz, DMSO-d6): d = 23.0, 50.8, 58.2, 68.1, 69.7, 71.9, 115.0,
115.3, 123.9, 129.9, 130.8, 135.8, 162.4. MS-FAB: m/z = 265
[MH+]. Anal. Calcd for C13H16N2O4: C, 59.12; H, 6.1; N, 10.61.
Found: C, 59.31; H, 6.31; N, 10.97.
3009, 2856, 1604, 1583, 1454 cmꢁ1 1H NMR (400 MHz, DMSO-
.
d6): d 3.45 (ddd, 1H, J6H,7H = 8.9 Hz, J5Ha,6H = 9.4 Hz, J5Hb,6H = 3.3 Hz,
6-H), 3.49 (dd, 1H, J5Ha,5Hb = 12.7 Hz, J5Ha,6H = 9.4 Hz, 5-Ha), 3.71 (s,
6H, OCH3), 3.88 (dd, 1H, J5Hb,6H = 3.3 Hz, J5Ha,5Hb = 12.7 Hz, 5-Hb),
3.91 (dd, 1H, J7H,8H = 9.4 Hz, J6H,7H = 8.9 Hz, 7-H), 4.80 (d, 1H,
J7H,8H = 9.4 Hz, 8-H), 4.96–5.10 (br s, 3H, 3 ꢂ OH, exchangeable
with D2O), 6.95–7.51 (m, 8Harom). 13C NMR (100 MHz, DMSO-d6):
d 39.0, 53.8, 54.6, 68.4, 71.3, 83.9, 111.5, 112.7, 119.0, 122.6,
126.2, 127.2, 127.9, 128.8, 152.3, 161.2, 161.4. MS-FAB: m/z = 383
[MH+]. Anal. Calcd for C21H22N2O5: C, 66.00; H, 5.80; N, 7.33.
Found: C, 66.28; H, 5.47; N, 6.99.
1.3.4. 5-Hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,2-
a]pyridine-6,7,8-triol (7d)
Yellow solid; yield 82%, mp 161–163 °C. IR (KBr) mmax 3343,
3009, 2858 cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 3.28 (dd, 1H,
.
J7H,8H = 9.5 Hz, J6H,7H = 9.1 Hz, 7-H), 3.60 (dd, 1H, J6H,7H = 9.1 Hz,
1.3. (1S,2R,3S,4S)-1-hydroxymethyl-1,2,3,4-tetrahydro
benzimidazo[1,2-a]pyridine-2,3,4-triol (7) and (2R,3S,4S)-
1,2,3,4-tetrahydrobenzimidazo[1,2-a]pyridine-2,3,4-triol (8):
general procedure
0
0
0
J5H,6H = 8.9 Hz, 6-H), 3.72 (dd, 1H, J1 Ha,1 Hb = 12.6 Hz, J1 Ha,5H
=
3.2 Hz, 10-Ha), 3.84 (dd, 1H, J1 Ha,1 Hb = 12.6 Hz, J1 Hb,5H = 6.2 Hz,
0
0
0
10-Hb), 3.98 (ddd, 1H, J1 Ha,5H = 3.2 Hz, J1 Hb,5H = 6.2 Hz, J5H,6H
=
0
0
8.9 Hz, 5-H), 4.87 (d, 1H, J7H,8H = 9.5 Hz, 8-H), 4.96–5.17 (br s, 4H,
4 ꢂ OH, exchangeable with D2O), 6.29 (d, 1H, J2H,3H = 1.2 Hz, 2H),
6.40 (d, 1H, J2H,3H = 1.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d
48.6, 58.1, 68.1, 68.8, 71.2, 117.0, 121.2, 146.1. MS-FAB: m/z =
201 [MH+]. Anal. Calcd for C8H12N2O4: C, 48.03; H, 6.04; N, 14.0.
Found: C, 47.73; H, 5.92; N, 14.22.
An intimate solvent-free mixture of diamine 6 (1 mmol), aldose
2 (1 mmol), and 10 mol % of oxalic acid was taken in a 20 mL vial
and subjected to MW irradiation in a Chemical Laboratory Micro-
wave Oven (Model: BP-310/50, 230 V, 50 Hz power input) at
80 °C for 8–14 min (Table 3). After completion of the reaction as

Lal Dhar S. Yadav, C. Awasthi / Carbohydrate Research 345 (2010) 318–323
323
1.3.5. 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-
References
2,3,4-triol (8a)
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11. Fos, E.; Bosca, F.; Mauleon, D.; Carganico, G. J. Heterocycl. Chem. 1993, 30, 473–
476.
Yellow solid; yield 91%, mp 197–199 °C. IR (KBr) mmax 3342,
3006, 2855, 1605, 1579, 1454 cmꢁ1 1H NMR (400 MHz, DMSO-
.
d6): d = 3.45 (dd, 1H, J5Ha,5Hb = 12.7 Hz, J5Ha,6H = 9.6 Hz, 5-Ha), 3.60
(ddd, 1H, J5Ha,6H = 9.6 Hz, J5Hb,6H = 3.3 Hz, J6H,7H = 9.0 Hz, 6-H),
3.82 (dd, 1H, J5Ha,5Hb = 12.7 Hz, J5Hb,6H = 3.3 Hz, 5-Hb), 3.92 (dd,
1H, J7H,8H = 9.4 Hz, J6H,7H = 9.0 Hz, 7-H), 4.81 (d, 1H, J7H,8H = 9.4 Hz,
8-H), 4.91–5.19 (br s, 3H, 3 ꢂ OH, exchangeable with D2O),
7.19–7.47 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): d = 46.6,
66.0, 69.7, 72.9, 114.3, 114.6, 122.5, 122.7, 132.1, 135.4, 158.8.
MS-FAB: m/z = 221 [MH+]. Anal. Calcd for C11H12N2O3: C, 60.03;
H, 5.49; N, 12.73. Found: C, 60.39; H, 5.28; N, 12.43.
1.3.6. 7,8-Dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-
a]pyridine-2,3,4-triol (8b)
Yellow solid; yield 83%, mp 145–147 °C. IR (KBr) mmax 3340,
3007, 2981, 2853, 1602, 1580, 1454 cmꢁ1 1H NMR (400 MHz,
.
12. Stefanich, G.; Silvestri, R.; Artico, M. J. Heterocycl. Chem. 1993, 30, 529–
532.
DMSO-d6): d 2.24 (s, 6H, CH3), 3.44 (dd, 1H, J5Ha,5Hb = 12.6 Hz,
J5Ha,6H = 9.5 Hz, 5-Ha), 3.50 (ddd, 1H, J5Ha,6H = 9.5 Hz, J5Hb,6H = 3.1
Hz, J6H,7H = 8.9 Hz, 6-H), 3.81 (dd, 1H, J5Ha,5Hb = 12.6 Hz,
J5Hb,6H = 3.1 Hz, 5-Hb), 3.96 (dd, 1H, J7H,8H = 9.4 Hz, J6H,7H = 8.9 Hz,
7-H), 4.83 (d, 1H, J7H,8H = 9.4 Hz, 8-H), 4.98–5.26 (br s, 3H,
3 ꢂ OH, exchangeable with D2O), 7.18 (s, 1Harom), 7.27 (s, 1Harom).
13C NMR (100 MHz, DMSO-d6): d 16.7, 17.0, 46.1, 65.9, 68.1, 73.7,
114.7, 114.9, 127.3, 127.5, 130.5, 134.2, 161.1. MS-FAB: m/z = 249
[MH+]. Anal. Calcd for C13H16N2O3: C, 62.93; H, 6.5; N, 11.29.
Found: C, 62.82; H, 6.70; N, 11.11.
13. Shaweross, A.; Stanforth, S. D. J. Heterocycl. Chem. 1993, 30, 563–565.
14. Lombardino, J. G. J. Org. Chem. 1965, 30, 2403–2407.
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1320.
1.3.7. 7-Methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-
a]pyridine-2,3,4-triol (8c)
Yellow solid; yield 87%, mp 150–152 °C. IR (KBr) mmax 3343,
3007, 2979, 2856, 1604, 1580, 1453 cmꢁ1 1H NMR (400 MHz,
.
DMSO-d6): d = 2.22 (s, 3H, CH3), 3.47 (dd, 1H, J5Ha,5Hb = 12.6 Hz,
J5Ha,6H = 9.5 Hz, 5-Ha), 3.58 (ddd, 1H, J5Ha,6H = 9.5 Hz, J5Hb,6H
=
3.2 Hz, J6H,7H = 9.0 Hz, 6-H), 3.86 (dd, 1H, J5Ha,5Hb = 12.6 Hz,
J5Hb,6H = 3.2 Hz, 5-Hb), 3.97 (dd, 1H, J7H,8H = 9.3 Hz, J6H,7H = 9.0 Hz,
7-H), 4.85 (d, 1H, J7H,8H = 9.3 Hz, 8-H), 4.90–5.21 (br s, 3H,
3 ꢂ OH, exchangeable with D2O), 6.91–7.45 (m, 3Harom). 13C NMR
(100 MHz, DMSO-d6): d = 22.7, 46.8, 66.1, 69.0, 73.9, 114.2, 114.7,
123.8, 129.2, 130.5, 135.3, 161.8. MS-FAB: m/z = 235 [MH+]. Anal.
Calcd for C12H14N2O3: C, 61.57; H, 6.02; N, 11.97. Found: C,
61.80; H, 6.30; N, 11.82.
31. Burkholder, C.; Dolbier, W. R.; Medebielle, M.; Ait-Mohand, S. Tetrahedron Lett.
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33. Blackburn, C. Tetrahedron Lett. 1998, 39, 5469–5472.
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35. Rousseau, A. L.; Matlaba, P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079–
4082.
1.3.8. 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-6,7,8-triol
(8d)
Yellow solid; yield 90%, mp 137–139 °C. IR (KBr) mmax 3343,
3007, 2979, 2856, 1604, 1580, 1453 cmꢁ1 1H NMR (400 MHz,
.
DMSO-d6):
d 3.23 (ddd, 1H, J5Ha,6H = 9.4 Hz, J5Hb,6H = 3.3 Hz,
36. Chen, J. J.; Golebiowski, A.; MeClenaghan, J.; Klopfenstein, S. R.; West, L.
Tetrahedron Lett. 2001, 42, 2269–2271.
J6H,7H = 9.1 Hz, 6-H), 3.27 (dd, 1H, J7H,8H = 9.2 Hz, J6H,7H = 9.1 Hz,
7-H), 3.49 (dd, 1H, J5Ha,5Hb = 12.5 Hz, J5Ha,6H = 9.4 Hz, 5-Ha), 3.86
(dd, 1H, J5Ha,5Hb = 12.5 Hz, J5Hb,6H = 3.3 Hz, 5-Hb), 4.31 (d, 1H,
J7H,8H = 9.2 Hz, 8-H), 4.97–5.20 (br s, 3H, 3 ꢂ OH, exchangeable
with D2O), 6.30 (d, 1H, J2H,3H = 1.3 Hz, 3-H), 6.40 (d, 1H,
J2H,3H = 1.3 Hz, 2-H). 13C NMR (100 MHz, DMSO-d6): d 45.8, 66.2,
68.3, 70.1, 116.3, 120.8, 145.5. MS-FAB: m/z = 171 [MH+]. Anal.
Calcd for C7H10N2O3: C, 49.44; H, 5.92; N, 16.47. Found: C, 49.11;
H, 5.62; N, 16.83.
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We sincerely thank the CSIR, New Delhi, for financial support.
We are also thankful to SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra.
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