Efficient two-step sequence for the synthesis of 2,5-disubstituted furan derivatives from functionalized nitroalkanes: Successive Amberlyst A21- and Amberlyst 15-catalyzed processes

Article abstract of DOI:10.1039/c0cc01097a

The nitroaldol reaction of ketal-functionalized nitroalkanes with α-oxoaldehydes, promoted by Amberlyst A21, followed by acidic treatment (Amberlyst 15) of the obtained nitroalkanol, leads to the formation of 2,5-disubstituted furans in good yields. The p

Full text of DOI:10.1039/c0cc01097a

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Efficient two-step sequence for the synthesis of 2,5-disubstituted furan
derivatives from functionalized nitroalkanes: successive Amberlyst
A21- and Amberlyst 15-catalyzed processesw
Alessandro Palmieri, Serena Gabrielli and Roberto Ballini*
Received 23rd April 2010, Accepted 30th June 2010
DOI: 10.1039/c0cc01097a
The nitroaldol reaction of ketal-functionalized nitroalkanes with
a-oxoaldehydes, promoted by Amberlyst A21, followed by acidic
treatment (Amberlyst 15) of the obtained nitroalkanol, leads to
the formation of 2,5-disubstituted furans in good yields.
The procedure was successfully applied to the total synthesis
of 1-benzyl-3-(50-hydroxymethyl-20-furyl)-indazole (YC-1), an
important pharmaceutical target.
Functionalized furans are found as key structural moieties
Scheme 1 General pathway to the synthesis of furan derivatives.
in many bioactive natural products and important
pharmaceuticals,1 moreover, they are also useful intermediates
in organic synthesis by virtue of their specific chemistry and
latent functionality.2 Although these properties have
motivated the development of several methods for the
synthesis of furans,3 there is still a great need for new furan
derivatives and de novo routes for their preparation. Thus, the
availability of uncomplicated synthetic procedures that enable
the preparation of polysubstituted furans is an important task
for organic and medicinal chemists. These facts, combined
with our previous experience in the synthesis of heterocycles
from aliphatic nitrocompounds,4 have led us to explore a new
approach for the synthesis of functionalized 2,5-substituted
furans.
ethyl acetate, as an eco-friendly solvent.9 As reported in
Table 1, the best result of the first step was obtained using
0.5 g of Amberlyst A21 per mmol of substrate at room
temperature, while the best performance of the second step,
needs 0.7 g of Amberlyst 15 per mmol of substrate, at 55 1C.
Because both the steps gave good results under heterogeneous
conditions, we modified our initial procedure in order to
combine the two reaction steps and with the aim to produce
directly, the target compound 4aa, avoiding any isolation and
purification of the intermediate 3aa and increasing the
eco-sustainability of the process.10 The new revised procedure,
consists of the nitroaldol reaction of 1a with 2a in ethyl acetate
and at room temperature, promoted by Amberlyst A21,
followed by filtration of the catalyst and successive addition
of Amberlyst 15 to the percolate, containing the crude
nitroalkanol 3aa, and heating at 55 1C for the appropriate
length of time (4–6 h). Thus, the direct formation of the furans
4aa takes place in good overall yield (78%).
In recent years, there has been a growing interest in the use
of nitroalkanes as key starting chemicals in the synthesis of
various heterocycles.5 Thus, as a development of our research,
herein we present an innovative, mild and efficient method, for
the synthesis of a series of 2,5-disubstituted furans 4 starting
from functionalized nitroalkanes of type 1.6 As reported in
Scheme 1, the synthetic strategy was initially planned as two
independent steps, starting from the nitroaldol (Henry) reaction
of 1 with the aldehyde 2,7 under basic conditions, followed by
acid treatment of the obtained b-nitroalcohol 3.
Table 1 Screening of different amounts of the two promoters
Based on the high reactivity that nitro compounds showed
recently under solid heterogeneous catalysis,8 and with the
scope to optimize the process, we investigated both the steps
under different amounts of Amberlyst A21 (anionic macro-
molecular ion-exchange resin) and Amberlyst 15 (cationic
macromolecular ion-exchange resin), respectively. We have
chosen, as a model, the reaction of an equimolar ratio of 1a
(R = Me) with 2a (R1 = OBu) in the minimum amount of
g of Amberlyst A21
per mmol of 1a
Yield (%)a of 3aa
0.3
0.5
0.7
73
81
80
g of Amberlyst A15
per mmol of 3aa
Yield (%)a of 4aa starting
from 3aa (temperature 1C)
0.5
0.5
0.7
0.9
Traces (rt)
72 (55)
81 (55)
Green Chemistry Group, School of Science and Technology,
`
Chemistry Division, Universita di Camerino, Via S. Agostino 1,
I-62032, Camerino, Italy. E-mail: roberto.ballini@unicam.it;
Fax: +39 0737 402297; Tel: +39 0737 402270
80 (55)
a
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc01097a
Yield of pure isolated product.
c
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Chem. Commun., 2010, 46, 6165–6167 6165

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Table 2 Preparation by two-step route of the furan derivatives 4
R
1
R1
2
Reaction time of 3/h
Reaction time of 4/h
Overall yield (%)a of 4
Me
Me
n-C5H11
Ph
p-PhC6H4
Et
Et
Ph(CH2)2
Ph(CH2)2
2-Naphthyl
a
a
b
c
d
e
e
f
OBu
Phb
a
b
a
c
c
d
e
c
b
b
3aa (3)
3ab (7)
3ba (3)
3cc (3)
3dc (3)
3ed (4)
3ee (3)
3fc (8)
3fd (7)
3gb (6)
4aa (4.5)
4ab (4.5)
4ba (4.5)
4cc (4)
4dc (4.5)
4ed (4.5)
4ee (4)
4fc (4.5)
4fd (4.5)
4gb (6)
78
65
61
80
60
56
69
84
61
68
OBu
OEtc
OEtc
p-MeC6H4
OBn
OEtc
Phb
f
g
Phb
a
b
Yield of pure isolated product. Phenylglyoxal monohydrate was used. Ethyl glyoxalate solution 50% in toluene was used.
c
In order to verify the generality of our procedure, we
extended the methodology to a variety of nitroalkanes 1 and
aldehydes 2. As reported in Table 2, all the products were
isolated in good overall yields (56–84%), independently from
the nature of both (i) the alkyl or aryl groups (R) in the
nitroalkanes 1 and (ii) the a-oxoaldehyde derivatives 2.
A plausible mechanism for the one-pot conversion of the
nitroalcohols 3 into the furans 4 is reported in Scheme 2, in
which the formed nitroalkanol 3 is protonated at the oxygen
with the formation of the intermediate A. The latter, leads to
the opening of 1,3-dioxolane ring with the formation of B,
which proceeds to the hetero-cyclization by the attack of the
hydroxyl group to the oxonium cation, affording the
intermediate C. Then, the process undergoes an acid–base
equilibrium (D) followed by the elimination of a mole of
ethylene glycol, with the formation of the structure E which
is converted, after deprotonation (F) and elimination of
nitrous acid, into the target furan system 4. Thus, by the
appropriate choice of the nitroalkane 1 it is possible to
introduce the needed alkyl (or aryl) group at 5-position of
the target furan 4.
group, allowing the generation of a new C,C bond (1 + 2 to 3),
then as good leaving group favoring the generation of a
new C,C double bond (F to 4) by elimination of nitrous acid.
As a practical application of our procedure we report here
the total synthesis of 1-benzyl-3-(50-hydroxymethyl-20-furyl)-
indazole (YC-1) (Scheme 3), a very important pharmaceutical
target that exhibits significant inhibitory effects against thrombin-,
AA-, collagen-, and PAF-induced platelet aggregation.11
The synthesis starts from the commercially available
indazole-3-carboxylic acid 5, which was converted into the
corresponding methyl ester 6, by methanol and in the presence
of sulfuric acid.12 Then, 6 was benzylated by CsF-Celite, with
MeCN as solvent and under reflux for 48 hours, affording the
derivative 7.13 The latter was initially reduced, by DIBAL-H,
to the corresponding primary alcohol, which was then
Moreover, it is important to note the key role of the nitro
functionality that firstly acts as good electron-withdrawing
Scheme 2 Proposed reaction mechanism for the formation of furan
derivatives 4.
Scheme 3 Synthetic pathway of biologically active compound 12
(YC-1).
c
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submitted to oxidation, by activated MnO2 in DCM, affording
the aldehyde 8.12 The compound 8, was then alkylated with
vinylmagnesium chloride in diethyl ether at ꢀ10 1C, affording
the corresponding allylic alcohol, which was directly converted
into the a,b-unsaturated ketone 9, under MnO2 and DCM
oxidation. Then, the enone 9 was nitrated using NaNO2, in the
presence of AcOH and in THF, and the formed crude b-nitro
ketone was protected by ethylene glycol, under refluxing
benzene and using the Dean Stark apparatus.6 Finally, 10
was reacted with ethyl glyoxalate following our procedure
(Amberlyst A21 and Amberlyst 15) affording the furan
derivative 11, which was reduced by DIBAL-H into the target
product 12 (YC-1) and in 25% overall yield.
3 (a) T. Yao, X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2004,
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A. Palmieri, Synlett, 2004, 2618; (b) R. Ballini, G. Bosica,
D. Fiorini and A. Palmieri, Green Chem., 2005, 7, 825;
(c) R. Ballini, S. Gabrielli and A. Palmieri, Synlett, 2007, 2430;
(d) R. Ballini, A. Palmieri, M. A. Talaq and S. Gabrielli,
Adv. Synth. Catal., 2009, 351, 2611.
Although, the overall yield of our approach is comparable
to the main already reported procedures,14 differently to them,
our approach involves for the first time, to the best of our
knowledge, the formation of furan ring during the synthetic
process. This peculiarity could offer an easy access to a library
of analogs of the compound 11, having similar activity to the
target 12,14d,15 by the appropriate selection of the aldehyde 2.
In conclusion, our method represents an unprecedented,
simple and regiodefined synthesis of functionalized 2,5-di-
substituted furan derivatives, avoiding any isolation and
purification of the intermediates. In addition, the good overall
yields obtained and the practical applicability of our
procedure have been successfully engaged for the total
synthesis of a very important pharmaceutical target such as
1-benzyl-3-(50-hydroxymethyl-20-furyl)-indazole (YC-1).
The authors thank the University of Camerino and
MIUR-Italy (National Project ‘Sintesi organiche ecosostenibili
mediate da nuovi sistemi catalitici’) for the financial support.
5 (a) R. Ballini, in Studies in Natural Products Chemistry, ed.
Atta-ur-Rahman, Elsevier, Amsterdam, 1997, vol. 2, p. 321;
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6 For the general synthetic pathway of compounds
1 see:
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7 For the synthetic pathway and characterization of compounds 2a
and 2e see: (a) Y.-L. Zhong and T. K. M. Shing, J. Org. Chem.,
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8 See, for example: (a) R. Ballini, G. Bosica, D. Fiorini and
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D. Fiorini, G. Giarlo and A. Palmieri, Green Chem., 2005, 7,
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L. Vaccaro, Green Chem., 2008, 10, 541; (f) R. Ballini,
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L. Vaccari, Adv. Synth. Catal., 2008, 350, 1218.
9 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings,
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c
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Chem. Commun., 2010, 46, 6165–6167 6167