A facile one-pot synthesis of biphenyl methyl-C-β-d-glycosides

Article abstract of DOI:10.1016/j.carres.2012.05.001

Facile one-pot synthesis of biphenyl methyl-C-β-d-glycosides was carried out using 4,6-O-protected-C-glycoside, aromatic aldehydes and malononitrile in pyrrolidine as an organocatalyst. Studies reveal that the use of pyrrolidine resulted in a better yield.

Full text of DOI:10.1016/j.carres.2012.05.001

Carbohydrate Research 357 (2012) 139–142
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Note
A facile one-pot synthesis of biphenyl methyl-C-b-D-glycosides
⇑
Ramanathan Rajaganesh, Thangamuthu Mohan Das
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile one-pot synthesis of biphenyl methyl-C-b-D-glycosides was carried out using 4,6-O-protected-C-
glycoside, aromatic aldehydes and malononitrile in pyrrolidine as an organocatalyst. Studies reveal that
the use of pyrrolidine resulted in a better yield.
Received 24 February 2012
Received in revised form 30 April 2012
Accepted 3 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 11 May 2012
Keywords:
Protected sugars
C-Glycosides
Biphenyl derivatives
One-pot reaction
The chemistry of C-glycosides has been extensively developed
due to the diversity of biological and pharmaceutical applica-
tions.1–4 C-Glycosides as subunits occur in a variety of biologically
important natural products and also in synthetic compounds.5
More recently, aryl-C-b-glycosides6,7 have been reported to possess
potent SGLT2 inhibitor activity (Fig. 1). Multicomponent reactions
emerged as a powerful tool for the construction of several novel
and complex molecular structures with diversities of biological
activities and pharmaceutical applications.8 Several biologically
important polysubstituted biphenyl derivatives have been devel-
oped via multicomponent reactions.9–12 Thus a new synthetic
route to C-glycosides could have a major impact on the potential
applications of these useful compounds.
aromatic protons of the resultant products. The appearance of a
broad peak around 7.00 ppm in the 1H NMR spectrum corresponds
to exchange protons (–NH2) which is absent in the substrates. Dis-
appearance of an aldehyde peak in the product and also a peak at
2.13 ppm, which corresponds to the methyl group of –CH2COCH3
of sugar derivative confirms the product formation. In addition,
disappearance of carbonyl and methyl carbons of –CO–CH3 which
appear at 200 and 30 ppm, respectively in the substrates further
confirms the structure of the expected product. Moreover, appear-
ance of a peak at d 115.0 ppm in the 13C NMR spectrum which is
characteristic for two –CN groups ensures the product formation.
Structure of aromatic aldehydes, biphenyl-C-glycosides, reaction
time and product yields is given in Table 1.
4,6-O-Butylidene-
-glycopyranosyl)propan-2-one (3) were synthesized by adopting
procedures reported in the literature.13 Biphenyl methyl-C-b-
glucopyranosides (6a–g) were synthesized in one-step from the
reaction of 1-(4,6-O-butylidene- -glucopyranosyl)propane-2-one
(3), aromatic aldehydes (4a–g) and malononitrile (5) in the pres-
ence of pyrrolidine as an organocatalyst (Scheme 1). Optimization
of reaction condition shows, use of 1 equiv of methyl ketone (3),
1 equiv of aromatic aldehydes (4a–g) and 2 equiv of malononitrile
(5) gives the desired biphenyl derivatives (6a–g) in moderate yield.
Details about the use of different solvents and bases for the optimi-
zation of reaction conditions are given in ESI. The structures of the
resulting biphenyl C-glycoside derivatives (6a–g) were determined
by 1H and 13C NMR spectroscopy and elemental analysis. The mul-
tiplets appearing in the range of 6.80–7.52 ppm correspond to the
D
-glucopyranose and 1-(4,6-O-butylidene-b-
Thus, we have designed and synthesized biphenyl methyl-C-
glycosides having a methylene group that favours flexibilities of
the molecule as is observed with sugar-b-lactam derivatives.14,15
An efficient one-pot synthetic methodology reported in this paper
has the advantages of using wide scope of substrates, under mild
reaction conditions, simple work-up and high yield and it is ex-
pected to provide a way for potential application in the synthesis
of several C-glycosyl natural product derivatives.
D
D
-
D
1. Experimental section
1.1. General methods
D-Glucose, acetylacetone and all substituted aldehydes were
obtained from Sigma–Aldrich Chemicals Pvt. Ltd USA and were of
high purity. Butyraldehyde, organic catalyst (pyrrolidine) and other
bases were obtained from SRL India. Other reagents such as sodium
hydrogen carbonate and solvents (AR Grade) were obtained from
⇑
Corresponding author. Tel.: +91 44 22202814; fax: +91 44 22352494.
E-mail address: tmdas_72@yahoo.com (T. Mohan Das).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.05.001

140
R. Rajaganesh, T. Mohan Das / Carbohydrate Research 357 (2012) 139–142
CH
3
OH
O
O
Cl
O
O
O
H
HO
HO
O
HO
HO
H
O
OH
OH
OCH
3
OH
1
2
Flavone C-glycoside
Sergliflozin
Figure 1. Representative examples of C-glycosides (1) and (2).
CH
3
CH
3
O
R
O
H
H
O
H
O
CN
CN
Pyrrolidene
THF, 65 °C
O
O
+
+
O
HO
CH
3
R
HO
OH
OH
NC
CN
O
NH
2
3
4a-g
5
6 (a-g)
a
R = H
( )
R = 2-Cl
R = 4-Cl
(b)
c
( )
R = 2-Pyridyl (d)
R = 3-Pyridyl (e)
f
R = 4-OCH3 ( )
R =
(g)
O
O
Scheme 1. Synthesis of biphenyl methyl-C-b-D-glycosides (6a–g).
Sd-fine, India of high purity and were used without any further
purification. Column chromatography was performed on silica gel
(100–200 mesh). NMR spectra were recorded on a Brucker DRX
300 MHZ instrument in either CDCl3 or DMSO-d6 (with a few drops
of CDCl3). Chemical shifts are referenced to internal TMS. Elemental
analyses were performed using a Perkin–Elmer 2400 series CHNS/O
analyser. While assigning the spectral data several abbreviations
were used and these include ‘Ar’ for aromatic, ‘Ace’ for acetal,
‘Ano’ for anomeric, ‘Sac’ and H-10–H-60 for saccharide and ‘Ha’ for
methylene protons that connect between the sugar and biphenyl
moieties.
(t, J 4.5 Hz, 2H, Ace-H), 4.09 (t, J 3.3 Hz, 1H, H-40), 3.68–3.76 (m, 2H,
H-1, H-30), 3.58–3.64 (m, 2H, H-50, H-60), 3.40–3.48 (m, 3H, H-20,
Sac-OH), 3.23–3.25 (m, 3H, Ha & Sac-OH), 1.61–1.63 (br, 2H, –
CH2), 1.59 (m, 2H, –CH2), 0.90 (t, J 7.5 Hz, 3H, –CH3). 13C NMR
(CDCl3): dC 152.7 (Ar-C), 149.7 (Ar-C), 148.0 (Ar-C), 137.5 (Ar-C),
129.6 (Ar-C), 128.8 (Ar-C), 128.4 (Ar-2C), 120.8 (Ar-2C), 116.1
(Ar-CN), 115.6 (Ar-CN), 102.5 (Ace-C), 97.07 (Ar-C), 94.4 (Ar-C),
80.3 (C-5), 79.4 (C-3), 75.2 (C-1), 74.2 (C-2), 70.4 (C-4), 68.2 (C-
6), 37.5 (–CH2–Ar), 36.2 (–CH2), 17.5 (–CH2), 13.9 (–CH3). Anal.
Calcd for C25H27N3O5: C, 66.80; H, 6.05; N, 9.35. Found: C, 66.32;
H, 6.28; N, 9.10.
1.2. General procedure for the synthesis of biphenyl-methyl-C-
1.2.2. Physicochemical and spectral data for 2-amino-4-
b-D
-4,6-O-butylidene-D-glucopyranose derivatives (6a–g)
(chlorophenyl-2-yl)-6-[(4,6-O-butylidene-b-D-glucopyranosyl)-
methyl] isophthalonitrile (6b)
To a solution of C-b-glycosidic ketone (3, 1.0 mmol) in 10 mL of
From 1-(4,6-O-butylidene-b-D-glucopyranosyl)propane-2-one
anhydr THF were added pyrrolidine (2.5 mmol) and aromatic alde-
hyde (4a, 1.0 mmol). Reaction mixture was refluxed until comple-
tion of reaction. To the reflux solution malononitrile (5, 2.0 mmol)
was added and the reaction mixture was evaporated under re-
duced pressure. The crude product was slurried with silica gel
and purified by flash chromatography.
(3) (0.270 g, 1.0 mmol), 2-chlorophenylcarboxaldehyde (4b)
(0.140 g, 1.0 mmol), malononitrile (5) (0.132 g, 2.0 mmol). Yellow
solid (0.241 g, 50%); mp 110–112 °C; 1H NMR (CDCl3): dH 7.51–
7.63 (m, 1H, Ar-H), 7.39–7.44 (m, 2H, Ar-H), 7.30–7.36 (m, 2H,
Ar-H), 6.75 (s, 1H, Ano-H), 5.33 (s, 2H, –NH2), 4.53 (t, J 4.8 Hz,
1H, Ace-H), 4.05–4.08 (broad, 1H, H-40), 3.60–3.80 (m, 2H, H-10,
H-30), 3.39–3.43 (m, 3H, H-20, H-50, H-60), 3.22 (d, J 4.8 Hz, 2H,
Sac-OH), 2.29–2.35 (m, 2H, Ha), 1.59–1.63 (m, 2H, –CH2), 1.44 (m,
2H, –CH2), 0.92 (t, J 7.5 Hz, 3H, –CH3). 13C NMR (CDCl3): dC 152.4
(Ar-C), 148.2 (Ar-C), 147.4 (Ar-C), 136.3 (Ar-C), 136.0 (Ar-C),
132.3 (Ar-C), 130.5 (Ar-2C), 130.1 (Ar-2C), 127.1 (Ar-2C), 115.0
(Ar-2ꢀCN), 102.5 (Ace-C), 96.0 (C-5), 80.3 (C-3), 79.0 (C-1), 74.9
(C-2), 70.4 (C-4), 68.2 (C-6), 36.2 (–CH2–Ar), 32.0 (–CH2), 17.5 (–
CH2), 14.0 (–CH3). Anal. Calcd for C25H26ClN3O5: C, 62.05; H, 5.42;
N, 8.68. Found: C, 62.32; H, 5.28; N, 8.40.
1.2.1. Physicochemical and spectral data for 2-amino-4-
(phenyl-1-yl)-6-[(4,6-O-butylidene-b-D-glucopyranosyl)-methyl]
isophthalonitrile (6a)
From 1-(4,6-O-butylidene-b-D-glucopyranosyl)propane-2-one
(3) (0.274 g, 1.0 mmol), 1-phenylcarboxaldehyde (4a) (0.106 g,
1.0 mmol), malononitrile (5) (0.132 g, 2.0 mmol).
Brown solid (0.301 g, 67%); mp 102–104 °C; 1H NMR (CDCl3): dH
7.51–7.52 (m, 4H, Ar-H), 6.80 (s, 1H, Ar-H), 5.23 (s, 2H, –NH2), 4.54

R. Rajaganesh, T. Mohan Das / Carbohydrate Research 357 (2012) 139–142
141
Table 1
One-pot synthesis of biphenyl methyl-C-b-D-glycosides (6a–g)
Entry
Aromatic aldehydes (4a–g)
Biphenyl-methyl-C-b-
D-glycosides (6a–g)
Time (h)
Yield (%)
O
H
H
H
CH3
O
O
O
O
O
O
O
H
O
1
30
67
50
72
57
42
68
47
O
(a)
HO
OH
NC
NC
NC
NC
NC
NC
NC
CN
NH2
O
O
O
CH3
Cl
H
O
Cl
O
2
3
4
5
6
7
37
33
42
40
32
45
(b)
HO
OH
CN
NH2
CH3
H
Cl
O
O
Cl
(c)
HO
OH
CN
NH2
H
N
CH3
H
O
O
(d)
HO
N
OH
CN
NH2
O
H
N
CH3
H
O
O
N
(e)
HO
OH
CN
NH2
O
O
H
CH3
H
OCH3
O
O
OCH3
(f)
HO
OH
CN
NH2
H
CH3
O
O
O
H
O
O
O
(g)
HO
OH
CN
NH2
1.2.3. Physicochemical and spectral data for 2-amino-4-(chloro
phenyl-4-yl)-6-[(4,6-O-butylidene-b-D-glucopyranosyl)-methyl]
isophthalonitrile (6c)
From 1-(4,6-O-butylidene-b-D-glucopyranosyl)propane-2-one
(3) (0.274 g, 1.0 mmol), 4-chlorophenylcarboxaldehyde (4c)
(0.140 g, 1.0 mmol), malononitrile (5) (0.122 g, 2.0 mmol). White
solid (0.348 g, 72%); mp 152–154 °C; 1H NMR (CDCl3): dH 7.40 (s,
2H, Ar-H), 7.20 (s, 2H, Ar-H), 6.67 (s, 1H, Ano-H), 5.27 (s, 2H,
–NH2), 4.45 (t, J 5.1 Hz, 1H, Ace-H), 3.96–4.01 (m, 1H, Ace-H),
3.59–3.64 (m, 1H, H-40), 3.49–3.54 (m, 1H, H-30), 3.28–3.40 (m,
2H, H-10, H-20), 3.11–3.20 (m, 3H, H-50, H-60, Sac-OH), 2.80–2.88
(m, 1H, Sac-OH), 2.70 (s, 2H, Ha), 1.50–1.56 (m, 2H, –CH2),

142
R. Rajaganesh, T. Mohan Das / Carbohydrate Research 357 (2012) 139–142
1.18–1.32 (m, 2H, –CH2), 0.86 (t, J 7.2 Hz, 3H, –CH3). 13C NMR
(CDCl3): dC 152.8 (Ar-C), 148.3 (Ar-C), 135.9 (Ar-C), 135.8 (Ar-C),
129.7 (Ar-C), 129.1 (Ar-C), 127.4 (Ar-C), 120.5 (Ar-2C), 115.8 (Ar-
CN), 115.5 (Ar-CN), 102.5 (Ace-C), 97.2 (Ar-C), 94.1 (Ar-C), 80.3
(Ar-C), 79.4 (C-5), 77.3 (C-3), 75.1 (C-1), 74.3 (C-2), 70.4 (C-4),
68.2 (C-6), 37.6 (–CH2–Ar), 36.2 (–CH2), 17.4 (–CH2), 13.9 (–CH3).
Anal. Calcd for C25H26ClN3O5: C, 62.05; H, 5.42; N, 8.68. Found: C,
62.12; H, 5.20; N, 8.20.
NMR (CDCl3): dC 160.7 (Ar-C), 152.9 (Ar-C), 149.4 (Ar-2C), 147.9
(Ar-C), 129.8 (Ar-2C), 129.7 (Ar-C), 120.1 (Ar-2C), 114.3 (Ar-
2ꢀCN), 102.5 (Ace-C), 96.2 (Ar-C), 94.0 (Ar-C), 80.3 (C-5) 79.5 (C-
3), 77.3 (C-1), 75.0 (C-2), 74.3 (C-4), 70.4 (C-6), 55.3 (-OCH3),
36.2 (–CH2–Ar), 27.0 (–CH2), 17.5 (–CH2), 14.0 (–CH3). Anal. Calcd
for C26H29N3O6: C, 65.12; H, 6.10; N, 8.76. Found: C, 65.50; H,
6.29; N, 8.46.
1.2.7. Physicochemical and spectral data for 2-amino-4-
1.2.4. Physicochemical and spectral data for 2-amino-4-
(benzo[1,3]-dioxol-4-yl)-6-[(4,6-O-butylidene-b-D-
(pyridin-2-yl)-6-[(4,6-O-butylidene-b-
D-glucopyranosyl)-
glucopyranosyl)-methyl] isophthalonitrile (6g)
methyl] isophthalonitrile (6d)
From 1-(4,6-O-butylidene-b-D-glucopyranosyl)propane-2-one
From 1-(4,6-O-butylidene-b-
D
-glucopyranosyl)propane-2-one
(3) (0.274 g, 1.0 mmol), piperanal (4g) (0.150 g, 1.0 mmol), malon-
onitrile (5) (0.122 g, 2.0 mmol). White solid (0.231 g, 47%); mp
161–163 °C; 1H NMR (CDCl3): dH 7.27 (s, 2H, Ar-H), 6.99–7.04 (m,
1H, Ar-H), 6.90–6.93 (m, 1H, Ar-H), 6.74 (s, 1H, Ar-H), 5.96–6.05
(m, 1H, Ar-H), 5.25 (broad, 1H, –NH2), 4.52 (t, J 4.8 Hz, 1H, Ano-
H), 4.06–4.10 (m, 1H, Ace-H), 3.68–3.71 (m, 1H, H-40), 3.56–3.66
(m, 1H, H-30), 3.44–3.47 (m, 2H, H-10, H-20), 3.36–3.43 (m, 3H, H-
50, H-60, Sac-OH), 3.21–3.23 (m, 2H, Sac-OH), 2.88–2.96 (m, 2H,
Ha), 1.35–1.40 (m, 2H, –CH2), 1.25 (m, 2H, –CH2), 0.94 (t, J 7.2 Hz,
3H, –CH3). 13C NMR (CDCl3): dC 152.7 (Ar-C), 149.4 (Ar-2C), 148.1
(Ar-C), 147.8 (Ar-C), 131.4 (Ar-C), 122.7 (Ar-2C), 120.6 (Ar-C),
118.3 (Ar-CN), 118.7 (Ar-CN), 108.7 (Ace-C), 108.6 (Ar-C), 102.5
(Ar-C), 101.6 (Ar-C), 97.0 (C-5), 80.3 (C-3), 79.4 (C-1), 75.2 (C-2),
74.2 (C-4), 70.4 (C-6), 68.2 (Ar-CH2), 37.4 (–CH2–Ar), 36.2 (–CH2),
17.4 (–CH2), 13.9 (–CH3). Anal. Calcd for C26H27N3O7: C, 63.28; H,
5.51; N, 8.51. Found: C, 63.50; H, 5.29; N, 8.16.
(3) (0.274 g, 1.0 mmol), 2-pyridinecarboxaldehyde (4d) (0.107 g,
1.0 mmol), malononitrile (5) (0.122 g, 2.0 mmol). Brown solid
(0.189 g, 42%); mp 122–124 °C; 1H NMR (CDCl3): dH 8.29–8.34
(m, 2H, Ar-H), 7.53 (d, J 7.8 Hz, 1H, Ar-H), 7.08 (t, J 4.8 Hz, 1H,
Ar-H), 6.36 (s, 1H, Ano-H), 5.74 (s, 1H, –NH2), 4.98 (broad 1H, –
NH2), 4.92 (broad 1H, Ace-H), 4.68 (s, 1H, Ace-H), 3.88–3.95 (m,
1H, H-40), 3.60–3.64 (m, 1H, H-30), 3.12–3.18 (m, 4H, H-10, H-20,
H-50, H-60), 2.80–2.89 (m, 3H, Ha & Sac-OH), 2.45–2.52 (m, 1H,
Sac-OH), 1.17–1.18 (m, 2H, –CH2), 0.86–1.01 (m, 2H, –CH2), 0.51
(t, J 7.2 Hz, 3H, –CH3). 13C NMR (CDCl3): dC 158.3 (Ar-C), 154.9
(Ar-C), 153.8 (Ar-C), 153.5 (Ar-C), 150.3 (Ar-C), 140.8 (Ar-C),
138.6 (Ar-C), 128.6 (Ar-C), 128.3 (Ar-C), 124.5 (Ar-C), 120.8 (Ar-
CN), 120.2 (Ar-CN), 106.9 (Ace-C), 102.9 (Ar-C), 98.4 (C-5), 85.3
(C-3), 84.6 (C-1), 79.4 (C-2), 75.3 (C-4), 72.9 (C-6), 42.3 (–CH2–
Ar), 41.0 (–CH2), 22.1 (–CH2), 18.7 (–CH3). Anal. Calcd for
C24H26N4O5: C, 63.99; H, 5.82; N, 12.44. Found: C, 63.50; H, 5.39;
N, 12.32.
Acknowledgements
1.2.5. Physicochemical and spectral data for 2-amino-4-
(pyridin-3-yl)-6-[(4,6-O-butylidene-b-D-glucopyranosyl)-
methyl] isophthalonitrile (6e)
T.M. acknowledges financial support from the SERC-DST, New
Delhi. We also thank DST, New Delhi for 300 MHz NMR spectrom-
eter under FIST scheme to the Department of Organic Chemistry,
University of Madras, Chennai.
From 1-(4,6-O-butylidene-b-D-glucopyranosyl)propane-2-one
(3) (0.274 g, 1.0 mmol), 3-pyridinecarboxaldehyde (4e) (0.107 g,
1.0 mmol), malononitrile (5) (0.132 g, 2.0 mmol). Brown solid
(0.256 g, 57%); mp 142–144 °C; 1H NMR (CDCl3): dH 8.60–8.65
(m, 2H, Ar-H), 7.81–7.84 (m, 1H, Ar-H), 7.37–7.40 (m, 1H, Ar-H),
6.66 (s, 2H, –NH2), 5.96 (s, 1H, Ano-H), 5.06 (broad, 1H, Ace-H),
4.77 (broad 1H, Ace-H), 4.44 (t, J 4.8 Hz, 1H, H-4), 3.92–3.96 (m,
1H, H-30), 3.43–3.52 (m, 2H, H-10, H-20), 3.30–3.35 (m, 2H, H-50,
H-60), 3.09–3.19 (m, 3H, Ha & Sac-OH), 2.81–2.84 (m, 1H, Sac-
OH), 1.47–1.52 (m, 2H, –CH2), 1.28–1.35 (m, 2H, –CH2), 0.80 (t, J
7.2 Hz, 3H, –CH3). 13C NMR (CDCl3): dC 158.2 (Ar-C), 154.9 (Ar-C),
153.8 (Ar-C), 153.6 (Ar-C), 150.3 (Ar-C), 140.7 (Ar-C), 138.5 (Ar-
C), 128.2 (Ar-C), 124.5 (Ar-C), 120.7 (Ar-CN), 120.1 (Ar-CN), 106.9
(Ace-C), 102.9 (Ar-C), 98.5 (Ar-C), 85.3 (C-5), 84.6 (C-3), 79.5 (C-
1), 79.3 (C-2), 75.3 (C-4), 72.9 (C-6), 42.3 (–CH2–Ar), 41.0 (–CH2),
22.1 (–CH2), 18.7 (–CH3). Anal. Calcd for C24H26N4O5: C, 63.99; H,
5.82; N, 12.44. Found: C, 63.32; H, 5.40; N, 12.20.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2012.05.
001.
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D
(3) (0.274 g, 1.0 mmol), 4-methoxyphenylcarboxaldehyde (4f)
(0.136 g, 1.0 mmol), malononitrile (5) (0.132 g, 2.0 mmol). Pale yel-
low solid (0.306 g, 68%); mp 143–145 °C; 1H NMR (CDCl3): dH 7.50–
7.57 (m, 1H, Ar-H), 7.34 (s, 1H, Ar-H), 7.02 (d, J 8.4 Hz, 1H, Ar-H),
6.78–6.89 (m, 2H, –NH2), 5.30 (s, 2H, Ace-H), 4.53 (d, J 4.5 Hz,
1H, Ano-H), 4.06–4.09 (d, J 8.7 Hz, 1H, H-40), 3.81 (s, 2H, H-30, H-
10), 3.74 (s, 5H, H-20, H-50, H-60, Sac-OH), 3.40 (t, J 6.6 Hz, 2H, Ha),
3.23–3.25 (m, 3H, –OCH3), 2.82–2.93 (m, 1H, Sac-OH), 1.70 (m,
2H, –CH2), 1.45 (m, 2H, –CH2), 0.74 (t, J 7.5 Hz, 3H, –CH3). 13C
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