Iron(III) chloride in ethanol-water: Highly efficient catalytic system for the synthesis of Garcia Gonzalez polyhydroxyalkyl- and C-glycosylfurans

Article abstract of DOI:10.1055/s-0029-1216865

An efficient method has been developed for the synthesis of Garcia Gonzalez polyhydroxyalkyl- and C-glycosylfurans in excellent yields from unprotected sugar aldoses with β-keto esters by Knoevenagel condensation in the presence of anhydrous iron(III) chl

Full text of DOI:10.1055/s-0029-1216865

2278
PAPER
Iron(III) Chloride in Ethanol–Water: Highly Efficient Catalytic System for
the Synthesis of Garcia Gonzalez Polyhydroxyalkyl- and C-Glycosylfurans
P
olyhydroxyalk
i
yl- and
n
C
-
Glycosylf
g
urans fromU
a
nprotected
i
Sugar
a
A
ldoses h Nagarapu,* Mahankhali Venu Chary, Apuri Satyender, B. Supriya, Rajashaker Bantu
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27193382; E-mail: nagarapu@iict.res.in
Received 13 November 2008; revised 16 March 2009
was first reported by Garcia Gonzalez et al. in the 1950s.9
Abstract: An efficient method has been developed for the synthesis
of Garcia Gonzalez polyhydroxyalkyl- and C-glycosylfurans in ex-
cellent yields from unprotected sugar aldoses with b-keto esters by
Knoevenagel condensation in the presence of anhydrous iron(III)
chloride.
More recently, the syntheses of these furan derivatives
were reported to be carried out by the condensation of un-
protected sugar aldoses with b-dicarbonyl compounds in
the presence of Lewis acids or protic acids involving ace-
tic acid,10 ytterbium(III) trifluoromethanesulfonate,11 ce-
rium(III) chloride heptahydrate,12 phosphoryl chloride,6
silicon dioxide–cerium(III) chloride heptahydrate/sodium
iodide,13 and indium(III) chloride.14 However, these meth-
ods suffer from disadvantages such as low yields, harsh
reaction conditions, long reaction times, and the use of ex-
pensive, toxic, and moisture-sensitive reagents, which
limit their practical utility in organic synthesis. Therefore,
the development of a more practical and economical
method for the one-pot synthesis of polyhydroxyalkyl-
and C-glycosyl furans is highly desirable.
Key words: D-glucose, b-keto esters, Knoevenagel reaction,
furans, carbohydrates
Syntheses of polyhydroxyalkyl- and C-glycosylfuran de-
rivatives occupy an important place in the realm of natural
and synthetic organic chemistry due to the therapeutic and
pharmacological properties of these compounds. They
have emerged as integral backbones of over 100 natural
products isolated from plants and microorganisms.1 The
C-glycosylfuran ring system is also an integral part of
various types of natural products such as palytoxin, bre-
vetoxin, and polyether antibiotics.2 They are also useful
building blocks in heterocyclic chemistry3 and in the syn-
thesis of carbohydrates,4 which, in turn, are of enormous
importance in chemical, biological, and medicinal science
as well as in the preparation of pharmaceuticals and agro-
chemicals.5 Among the various classes of heterocycles,
furan derivatives exhibit a wide spectrum of biological
activities including cytotoxic,6 antifungal, antitrypano-
somal, gastrointestinal motility, and phosphodiesterase
inhibitory activity,7 and, recently, these compounds have
also been used as potential enzyme inhibitors and to con-
struct mimics of peptidoglycans.4c,8 In view of their bio-
logical significance, the synthesis of these heterocycles is
of current importance.
In recent years, iron(III) chloride has emerged as a power-
ful Lewis acid catalyst, and performs many useful organic
transformations under mild reaction conditions. More-
over, iron salts are inexpensive, easy to handle, and envi-
ronmentally friendly.15 In continuation of our program on
the development of novel methodologies in organic syn-
thesis,16 a general and practical method for the synthesis
of Garcia Gonzalez furan derivatives from unprotected
sugar aldoses and b-keto esters in the presence of anhy-
drous iron(III) chloride in an ethanol–water (4:1) solvent
system under mild conditions has been developed and is
reported herein.
Initially, the condensation of D-glucose (1a) with ethyl
acetoacetate (2a) (Scheme 1) was attempted under various
reaction conditions in the presence of different acid cata-
lysts such as K5CoW12O40·3H2O, bismuth(III) chloride,
tin(II) chloride, iodine, silica gel, IR-120 H+, Dowex-50
H+, and iron(III) chloride in water, ethanol, methanol, iso-
propyl alcohol, 1,4-dioxane, or combinations of these. Of
The synthesis of C-glycosylfuran derivatives in about
32% yield by the condensation of unprotected sugars with
b-dicarbonyl compounds in the presence of zinc chloride
in methanol under relatively harsh reaction conditions
O
OEt
HO
O
O
O
FeCl3 (10 mol%)
O
+
HO
OH
O
EtOH–H2O (4:1), 90 °C
OEt
HO
OH
HO
OH
3a
1a
2a
Scheme 1
SYNTHESIS 2009, No. 13, pp 2278–2282
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.06.2009
DOI: 10.1055/s-0029-1216865; Art ID: Z24308SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Polyhydroxyalkyl- and C-Glycosylfurans from Unprotected Sugar Aldoses
2279
all the various permutations, the reaction in ethanol–water tained with an iron(III) chloride/unprotected sugar aldose/
(4:1) in the presence of iron(III) chloride (10%) afforded b-keto ester ratio of 0.1:1:1.2. In a typical experimental
the C-glycosyl 3,4-dihydroxy-2,3,4,5-tetrahydro-2,2¢-bi- procedure, a mixture of ethyl acetoacetate (2a) or ethyl
furan 3a in 95% yield (Scheme 1). All the other tested cat- benzoylacetate (2b) and one of sugar aldoses 1a–f in
alysts afforded only 0–11% yield, and in the absence of ethanol–water (4:1) in the presence of a catalytic amount
catalyst the reaction product 3a could not be isolated, even of iron(III) chloride (10 mol%) was heated at 90 °C
after a long reaction time (72 h) at 90 °C.
(Table 1); after completion of the reaction as indicated by
thin-layer chromatography, the reaction mixture was con-
centrated and purified by flash column chromatography
over silica gel. Under these conditions, D-ribose (1c),
To improve the yields, we performed the reaction with
different quantities of reagents. The best results were ob-
Table 1 Synthesis of Polyhydroxylated Furans 3 Catalyzed by Iron(III) Chloride in Ethanol–Water (4:1)a
Entry
1
Aldose 1
R
2
Furan 3
Time (h) Yieldb (%)
O
HO
HO
O
OEt
1a
Me
2a
3a
5.0
6.0
95
88
OH
O
O
HO
OH
HO
OH
HO
HO
O
O
2
1b
Me
2a
3a
OH
OH
OH
OH
HO
HO
HO
HO
OH
O
HO
HO
HO
HO
OEt
3
4
5
1c
1d
1e
Me
Me
Me
2a
2a
2a
3b
3b
3c
4.5
5.0
6.0
90
82
82
O
OH
HO
OH
O
OH
O
O
HO
OEt
O
OH
HO
OH
O
OEt
Ph
6
1a
Ph
2b
3d
5.0
87
O
O
HO
OH
7
8
1b
1c
1d
1e
Ph
Ph
Ph
Ph
2b
2b
2b
2b
3d
3e
3e
3f
5.5
4.5
5.0
4.5
82
86
80
85
O
HO
OEt
Ph
O
HO
OH
9
O
HO
OEt
Ph
10
O
HO
OH
a Reaction conditions: 1 (1 equiv), 2 (1.2 equiv), EtOH–H2O (4:1), anhyd FeCl3 (10 mol%), 90 °C.
b Isolated yield.
Synthesis 2009, No. 13, 2278–2282 © Thieme Stuttgart · New York

2280
L. Nagarapu et al.
PAPER
O
OEt
HO
HO
HO
O
O
O
O
FeCl3 (10 mol%)
+
R
OH
O
EtOH–H2O (4:1)
90 °C
R
OEt
OH
HO
OH
1f
2a: R = Me
2b: R = Ph
3g: R = Me; α/β = 3:7
3h: R = Ph; α/β = 6:4
Scheme 2
D-arabinose (1d), and D-lyxose (1e) produced furan deriv- Mechanistically, the reaction may proceed by Knoevena-
atives 3b, 3c, 3e, and 3f with polyhydroxyalkyl side gel condensation of, for example, D-glucose (1a) with the
chains (entries 3–5 and 8–10), whereas in the case of D- enolate of, for example, b-keto ester 2a in the presence of
glucose (1a) and D-mannose (1b), further cyclization oc- iron(III) chloride, to form a stable tetraol L via K
curred to furnish b-linked hydroxylated 2,3,4,5-tetrahy- (Scheme 3). Further cyclodehydration of compound L
dro-2,2¢-bifuran derivatives 3a and 3d in excellent yields predominantly follows an SN1 mechanism. That is to say,
(entries 1,2, 6, and 7). The reactions of several combina- the easily formed carbocation at C1¢ is stabilized by the
tions were studied, to investigate the generality of the pro- neighboring trans-hydroxy group of C2¢ to give the inter-
cess, and the novelty of this process for the synthesis of mediate M, which undergoes in-plane attack of the hy-
polyhydroxyalkyl- and C-glycosyl furans is illustrated in droxy group on C4¢ in a stereoselective process to give the
Table 1.
b-isomer of 3,4-dihydroxy-2,3,4,5-tetrahydro-2,2¢-bifu-
ran 3a exclusively and in excellent yield. In contrast, in
the case of D-galactose (1f), the intermediate carbocation
is not stabilized by the neighboring cis-hydroxy group of
C2¢, and the attack of the nucleophile may proceed on ei-
ther side of the plane, thus resulting in a mixture of a- and
b-isomers 3g in a 3:7 ratio.6,17
Many of the pharmacologically relevant substitution pat-
terns on the furan ring could be introduced efficiently with
a variety of b-keto ester compounds, such as ethyl ace-
toacetate and ethyl benzoylacetate, which worked well,
without the formation of any side products. The use of just
ten mol% of iron(III) chloride is sufficient to push the re-
action forward. Larger amounts of iron(III) chloride did In conclusion, a series of (hydroxyalkyl)furans 3b, 3c, 3e,
not improve the results to a great extent. No additive or and 3f and b-linked 3,4-dihydroxy-2,3,4,5-tetrahydro-
protic/Lewis acid is necessary in the procedure, and the 2,2¢-bifurans 3a and 3d were synthesized by one-pot con-
1
products obtained are of high purity (>95% by H NMR densation of one of the unprotected sugar pentoses 1c–e,
spectroscopy).
or hexoses 1a,b, respectively, with one of the b-keto
esters 2a or 2b in the presence of a catalytic amount of
iron(III) chloride (10 mol%) in ethanol–water (4:1) as a
solvent system. The remarkable catalytic activity exhibit-
ed by iron(III) chloride is convincingly superior to the
other recently reported catalytic systems with respect to
reaction time and amount of catalyst used. Due to easy
workup and the use of an inexpensive, readily available
The products obtained from the reactions of D-galactose
(1f) with ethyl acetoacetate (2a) or ethyl benzoylacetate
(2b) were, however, mixtures of the a- and b-linked
2,3,4,5-tetrahydro-2,2¢-bifurans 3g or 3h, respectively, in
a/b ratios of 3:7 and 6:4, respectively (determined by 1H
NMR integration) (Scheme 2).
O
HO
O
OEt
+
HO
OH
O
HO
2a
HO
OH
– H2O
OEt
O
FeCl3
1a
OEt
O
O
H
HO
3a
HO
HO
OH
HO
OH
FeCl3
K
O
OH
OEt
HO
O
OEt
H
Cl3Fe
HO
••
HO
O
+
– H2O
O
OH+
H
HO
1'
2'
4'
3'
••
OH
– FeCl3
– H2O
HO
M
HO
L
Scheme 3
Synthesis 2009, No. 13, 2278–2282 © Thieme Stuttgart · New York

PAPER
Polyhydroxyalkyl- and C-Glycosylfurans from Unprotected Sugar Aldoses
2281
1H NMR (300 MHz, CDCl3): d = 1.40 (t, J = 7.8 Hz, 3 H), 3.35–4.05
(m, 2 H), 4.20–4.50 (m, 4 H), 6.75 (d, J = 6.3 Hz, 1 H), 7.40 (m, 3
H), 8.00 (d, J = 10.3 Hz, 2 H).
catalyst, the procedure is superior to existing methods.
Furthermore, the protocol reported here is readily amena-
ble to parallel synthesis and combinatorial generation of
substituted furan libraries.
MS–FAB: m/z [M + 1] calcd for C16H18O6: 307; found: 307.
Compound 3f (Table 1, Entry 10)
IR (KBr): 3424, 1715 cm–1.
All the commercially obtained reagents and solvents were used
without further purification unless stated otherwise. Melting points
were recorded on a Buchi 535 melting-point apparatus and are un-
corrected. All the reactions were monitored by TLC performed on
precoated silica gel 60F254 plates (Merck). Compounds were visual-
ized with UV light at 254 nm and 365 nm, I2, and heating plates after
dipping the plates in 2% phosphomolybdic acid in 15% aq H2SO4.
IR spectra of samples prepared as KBr pellets were recorded on
Perkin-Elmer 683 or 1310 FT-IR spectrometers. NMR spectra were
recorded on Varian Unity 400 MHz and Bruker AMX 300 spec-
trometers; TMS was used as an internal standard. Mass spectra were
recorded on an LCMSD-Trap mass spectrometer.
1H NMR (300 MHz, CDCl3): d = 1.38 (m, 3 H), 3.38–4.01 (m, 4 H),
4.21–4.45 (m, 2 H), 6.78 (d, J = 6.7 Hz, 1 H), 7.40 (m, 3 H), 7.98
(d, J = 9.3 Hz, 2 H).
MS–FAB: m/z [M + 1] calcd for C16H18O6: 307; found: 307.
Compound 3g (Scheme 2)
Mixture of stereoisomers.
IR (KBr): 3419, 1695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (m, 3 H), 2.52 (2 s, a/b = 3:7,
3 H), 3.66–4.35 (m, 6 H), 4.52 (d, J = 3.9 Hz, 1 H), 6.60 (2 s, a/b =
3:7, 1 H).
3,4-Dihydroxy-2,3,4,5-tetrahydro-2,2¢-bifuran 3a (Table 1,
Entry 1); Typical Procedure
MS–FAB: m/z [M + 1] calcd for C12H16O6: 257; found: 257.
Anhyd FeCl3 (0.162 g, 1 mmol) was added to a stirred soln of D-glu-
cose (1a; 1.80 g, 10 mmol) and ethyl acetoacetate (2a; 2.56 g, 12
mmol) in an EtOH–H2O mixture (4:1; 10 mL). The reaction mixture
was refluxed for 5 h until completion of the reaction (TLC monitor-
ing) and concentrated under reduced pressure, before the residue
was purified by flash column chromatography (silica gel, EtOAc–
PE, 3:7) to afford 3a as a thick syrup.
Compound 3h (Scheme 2)
Mixture of stereoisomers.
IR (KBr): 3416, 1720 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.30 (m, 3 H), 4.10–4.32 (m, 7 H),
6.75 (2 s, a/b = 6:4, 1 H), 7.35 (m, 3 H), 8.00 (m, 2 H).
MS–FAB: m/z [M + 1] calcd for C17H18O6: 319; found: 319.
Yield: 2.432 g (95%).
IR (KBr): 3414, 1711 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H), 2.55 (s,
3 H), 3.81 (dd, J = 4.2, 9.8 Hz, 1 H), 4.11–4.45 (m, 5 H), 4.59 (d,
J = 6.3 Hz, 1 H), 6.59 (s, 1 H).
Acknowledgment
Authors M. V. Chary and A. Satyender thank CSIR, New Delhi for
the financial support in the form of Senior Research Fellowships.
13C NMR (75 MHz, CDCl3): d = 13.81, 29.20, 59.97, 70.60, 72.54,
74.28, 76.45, 109.25, 113.65, 149.58, 159.31, 163.76.
References
MS–FAB: m/z [M + 1] calcd for C12H16O6: 257; found: 257.
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Compound 3b (Table 1, Entry 3)
IR (KBr): 3435, 1714 cm–1.
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Compound 3d (Table 1, Entry 7)
IR (KBr): 3416, 1714 cm–1.
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(m, 5 H), 6.79 (s, 1 H), 7.39 (m, 3 H), 7.90 (d, J = 10.1 Hz, 2 H).
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74.69, 76.58, 111.27, 113.95, 127.68, 128.11, 129.09, 129.18,
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Compound 3e (Table 1, Entry 8)
IR (KBr): 3423, 1716 cm–1.
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Synthesis 2009, No. 13, 2278–2282 © Thieme Stuttgart · New York