β-nitroacrylates as precursors of tetrasubstituted furans in a one-pot process and under acidic solvent-free conditions

Article abstract of DOI:10.1055/s-0030-1258031

The reaction of -functionalized carbonyl derivatives with -nitroacrylates, catalyzed by acidic alumina and in the absence of solvent, allows the one-pot synthesis of tetrasubstituted furan derivatives, in which at least two powerful functionalities are present in the 3- and 4-positions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258031

2468
LETTER
b-Nitroacrylates as Precursors of Tetrasubstituted Furans in a One-Pot
Process and under Acidic Solvent-Free Conditions
b-Nitroacrylates
o
b
of
T
etrasub
e
rans to Ballini, Serena Gabrielli, Alessandro Palmieri*
Green Chemistry Group, School of Science and Technology, Chemistry Division, Via S. Agostino 1, 62032 Camerino, Italy
Fax +39(0737)402297; E-mail: alessandro.palmieri@unicam.it
Received 2 July 2010
O
Abstract: The reaction of a-functionalized carbonyl derivatives
R2
O
O
OR3
EWG
acidic Al2O3
with b-nitroacrylates, catalyzed by acidic alumina and in the ab-
sence of solvent, allows the one-pot synthesis of tetrasubstituted fu-
ran derivatives, in which at least two powerful functionalities are
present in the 3- and 4-positions.
+
EWG
R1
O2N
OR3
neat, r.t. to 60 °C
48–77%
R1
R2
O
1
2
3
EWG = keto, ester, nitro, cyano
Key words: heterocycles, heterogeneous catalysis, furans, b-nitro-
acrylates, domino reaction
Scheme 1
aromatic heterocycles,10 a,b-unsaturated esters11 and a- or
b-keto esters.11a,12
Highly substituted furans are found as key structural ele-
ments in many bioactive natural products and important
pharmaceuticals.1 They also represent versatile building
blocks for the synthesis of more elaborate heterocyclic
compounds.2 On this basis, a large number of synthetic
methods to approach substituted furans have been
developed3 and, among them, the Paal–Knorr (from 1,4-
dicarbonyl derivatives)4 and the Feist–Benary syntheses5
are the most popular.
Based on our experience, and due to the ready enolization
of substrates 1, we began the optimization studies of the
reaction under acidic conditions. Furthermore, in order to
avoid the presence of any solvent, we focused our atten-
tion on solid acids. Thus, we investigated a range of solid
promoters (acidic alumina, Montmorillonite K-10, and
zeolite HSZ-320), under neat conditions, using the reac-
tion of 1a with 2a as model, and we found acidic alumina
to be the most effective. Subsequently, we tested a variety
of substrate/promoter ratios (r.t. for 3 h than heating at
60 °C for 3 h) and, as shown in Table 1, the optimal result
was obtained using an alumina/substrate ratio of 1.2 g/
mmol.
Although these methods have proved to be very useful for
the synthesis of furan derivatives, there are some limita-
tions, including the difficulty to access furans with sensi-
tive functional groups, as well as limitations in flexibility
regarding their substitution pattern. Furan derivatives
have been prepared from b-nitroalkenes by initial Michael
addition reaction with 1,3-dicarbonyl compounds, under
Table 1 Synthesis of 3aa with a Variety of Substrate/Promoter
basic conditions.6 Even though this approach permits the Ratios
access to polysubstituted furans, it requires problematic
O
O
solvents (xylene, 1,2-dimethoxyethane, or dimethyl sul-
Et
O
OEt
O
O
acidic Al2O3
foxide) and seems to be constrained to a restricted variety
of substrates. Recently, the usefulness of conjugated ni-
troalkenes as co-reactants with 1,3-dicarbonyl derivatives
+
O2N
OEt
neat,
r.t. (3 h)
60 °C (3 h)
Et
O
3aa
1a
2a
has been highlighted in the synthesis of specific arylben-
zofurans under homogeneous conditions.7,8
Ratio of acidic Al2O3/substrate
3.0 g/mmol
Yield (%)a of 3aa
In this context, in a development of our earlier studies to
Michael addition of substrates containing active methyl-
ene groups to nitroalkenes,9 we have investigated the re-
activity of b-nitroacrylates with a-functionalized carbonyl
derivatives in order to obtain new classes of polyfunction-
alized furans under mild conditions (Scheme 1).
68
70
77
66
1.5 g/mmol
1.2 g/mmol
1.0 g/mmol
a Yield of pure isolated product.
b-Nitroacrylates are a highly reactive class of doubly ac-
tivated olefins having two electron-withdrawing groups in
both a- and b-positions, and this particular molecular
framework makes them useful starting materials for the
synthesis of important targets, such as both aliphatic and
Encouraged by these results, and in order to assess the
generality of our method, a number of different a-func-
tionalized carbonyl derivatives 1 and b-nitroacrylates 2
was tested. As shown in Table 2, the reactions proceeded
in satisfactory to good overall yields (48–77%).
SYNLETT 2010, No. 16, pp 2468–2470
x
x
.x
x
.2
0
1
0
It is important to note that tetrasubstituted furans 3 ob-
tained by this protocol possess at least two functionalities,
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258031; Art ID: D17510ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
b-Nitroacrylates as Precursors of Tetrasubstituted Furans
2469
Table 2 Synthesis of Compounds 313
O
OR3
R2
EWG
R1
R2
O
O
acidic Al2O3
+
EWG
R1
O2N
OR3
neat,
r.t. (t1)
60 °C (t2)
O
3
1
2
Ketone
b-Nitroacrylate
Product
Yield
(%)a
Time (h)
1
R1
EWG
2
R2
R3
Et
Et
Et
Et
Et
Et
Et
Bu
Et
Et
Et
Et
3
t1 + t2
3 + 3
1a
1a
1a
1b
1c
1d
1d
1e
1e
1f
Me
Me
Me
Me
Pr
C(O)Me
C(O)Me
C(O)Me
CO2Et
2a
2b
2c
2a
2d
2e
2f
Et
3aa
3ab
3ac
3ba
3cd
3de
3df
3eg
3ec
3fa
77
70
72
56
48
75
76
58
57
49
50
49
Me2CH(CH2)2
Me(CH2)4
Et
3 + 3
3 + 3
4 + 15
4 + 24
3 + 3
CO2Et
Ph(CH2)2
Me
-(CH2)3C(O)-
-(CH2)3C(O)-
Bu
3 + 3
Et
Et
Ph
C(O)Et
C(O)Et
NO2
2g
2c
2a
2h
2c
Me(CH2)4
Me(CH2)4
Et
3.5 + 6
3.5 + 8
3 + 3
1g
1h
-CH2C(Me)2CH2C(O)-
Ph CN
MeO2C(CH2)4
Me(CH2)4
3gh
3hc
3.5 + 5
3 + 3
a Yield of pure isolated product.
such as keto, ester, nitro, and cyano groups in the 3- and without the need for any quenching or extraction as the re-
4-positions. Such functionalities, whilst very useful for action mixture can be directly charged into a chromatog-
subsequent transformations, are difficult to introduce by raphy column for immediate purification, our method can
other approaches. In addition, by the appropriate choice of be considered to be simple, mild, and possessing general-
the alkyl groups (R1 and R2) in the starting material 1 and ity.
2, it is possible to introduce a variety of substituents at the
2- and 5-positions.
Acknowledgment
Regarding the regioselectivity of the procedure; by using
nonsymmetrical ketones, we tested the reaction of 1h with
2e (Scheme 2) and, although the reaction works with good
overall yield (76%), the regioselectivity is moderate, and
we isolated the regioisomeric products 3he and 3he¢ in
65:35 ratio.
The authors thank the University of Camerino and MIUR-Italy
(FIRB National Project ‘Metodologie di nuova generazione nella
formazione di legami carbonio-carbonio e carbonio-eteroatomo in
condizioni eco-sostenibili’) for financial support.
References and Notes
In conclusion, considering that this procedure works well
in the absence of any solvent and affords compounds 3
(1) (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo,
T. H.; Tong, S. Y. T.; Wong, H. N. C. Tetrahedron 1998, 54,
1955. (b) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209.
(c) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in
Heterocyclic Chemistry, Vol. 14; Grimble, G. W.; Gilchrist,
T. L., Eds.; Pergamon: Oxford, 2002, 139.
O
O
Ph
OEt
(2) (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry, Vol. 5; Katrizky, A. R.; Rees, C. W., Eds.;
Pergamon: New York, 1984, 313. (b) Heaney, H. In
Natural Products Chemistry; Nakanishi, K., Ed.; Kodansha:
Tokyo, 1974, 297. (c) Lipshutz, B. H. Chem. Rev. 1986, 86,
795. (d) Shipman, M. Contemporary Org. Synth. 1995, 2, 1.
(3) (a) Brown, R. C. D. Angew. Chem. Int. Ed. 2005, 44, 850.
(b) Cacchi, S. J. Organomet. Chem. 1999, 576, 42.
(c) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209.
O
3he
+
O
O
O
acidic Al2O3
+
neat
r.t. (3 h)
60 °C (4 h)
76%
Ph
O2N
OEt
O
O
1h
2e
OEt
Ph
3he/3he' = 65:35
O
3he'
Scheme 2
Synlett 2010, No. 16, 2468–2470 © Thieme Stuttgart · New York

2470
R. Ballini et al.
LETTER
(224.25): C, 64.27; H, 7.19. Found: C, 64.34; H, 7.23.
(4) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J.
Org. Chem. 2005, 5277.
Compound 3ba: clear oil. IR (neat): n = 1097, 1210, 1589,
1719 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.21 (t, 3 H,
J = 7.7 Hz), 1.31 (t, 6 H, J = 7.3 Hz), 2.43 (s, 3 H), 2.80 (q,
2 H, J = 7.7 Hz), 4.27 (q, 4 H, J = 7.3 Hz). 13C NMR (100
MHz, CDCl3): d = 12.6, 13.3, 14.3, 14.4, 20.8, 60.7, 60.8,
113.1, 113.8, 155.7, 160.2, 163.9. MS (EI, 70eV): m/z = 254
[M+], 208 (100), 180, 152, 108, 43. Anal. Calcd for C13H18O4
(254.28): C, 61.40; H, 7.14. Found: C, 61.51; H, 7.19.
Compound 3de: clear oil. IR (neat): n = 1046, 1190, 1582,
1687, 1735 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.36 (t, 3
H, J = 7.3 Hz), 2.08–2.17 (m, 2 H), 2.46–2.51 (m, 2 H), 2.48
(s, 3 H), 2.82 (t, 2 H, J = 6.4 Hz), 4.32 (q, 2 H, J = 7.3 Hz).
13C NMR (100 MHz, CDCl3): d = 13.5, 14.4, 22.4, 23.6,
38.8, 60.9, 111.9, 119.6, 158.5, 163.6, 165.8, 192.2. MS (EI,
70 eV): m/z = 222 [M+], 194, 176 (100), 166, 138, 78, 43.
Anal. Calcd for C12H14O4 (222.24): C, 64.85; H, 6.35.
Found: C, 64.94; H, 6.41.
Compound 3gh: clear oil. IR (neat): n = 1223, 1583, 1689,
1736 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.11 (s, 6 H),
1.35 (t, 3 H, J = 7.3 Hz), 1.60–1.74 (m, 4 H), 2.32 (t, 2 H,
J = 6.8 Hz), 2.38 (s, 2 H), 2.69 (s, 2 H), 2.89 (t, 2 H, J = 6.8
Hz), 3.64 (s, 3 H), 4.31 (q, 2 H, J = 7.3 Hz). 13C NMR (100
MHz, CDCl3): d = 14.3, 24.5, 27.1, 27.6, 28.6, 33.8, 35.1,
37.5, 53.3, 61.0, 111.7, 118.4, 162.1, 163.5, 165.0, 174.0,
191.9. MS (EI, 70eV): m/z = 350 [M+], 319, 304, 272, 244,
231, 217 (100), 55, 29. Anal. Calcd for C19H26O6 (350.41):
C, 65.13; H, 7.48. Found: C, 65.22; H, 7.56.
Compound 3hc: clear oil. IR (neat): n = 691, 1112, 1492,
1586, 1603, 1721, 2232, 3062 cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.90 (t, 3 H, J = 6.8 Hz), 1.31–1.39 (m, 4 H),
1.41 (t, 3 H, J = 7.3 Hz), 1.68–1.79 (m, 2 H), 3.05 (t, 2 H,
J = 7.7 Hz), 4.38 (q, 2 H, J = 7.3 Hz), 7.40–7.50 (m, 3 H),
7.98 (d, 2 H, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3):
d = 14.1, 14.2, 22.4, 27.6, 27.7, 31.4, 61.3, 92.1, 114.2,
114.5, 125.7, 127.7, 129.2, 130.5, 158.7, 161.8, 163.3. MS
(EI, 70eV): m/z = 311 [M+], 282, 254, 226 (100), 105, 77, 29.
Anal. Calcd for C19H21NO3 (311.37): C, 73.29; H, 6.80; N,
4.50. Found: C, 73.33; H, 6.85; N, 4.46.
(5) (a) Calter, M. A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002,
4, 209. (b) Holtz, E.; Langer, P. Synlett 2004, 1805.
(6) Yanami, T.; Ballatore, A.; Miyashita, M.; Kato, M.;
Yoshikoshi, A. J. Chem. Soc., Perkin Trans. 1 1978, 1144.
(7) Ishikawa, T.; Miyahara, T.; Asakura, M.; Higuchi, S. Org.
Lett. 2005, 7, 1211.
(8) Song, L.; Li, X.; Xing, C.; Li, D.; Zhu, S.; Deng, H.; Shao,
M. Synlett 2010, 830.
(9) Ballini, R.; Maggi, R.; Palmieri, A.; Sartori, G. Synthesis
2007, 3017.
(10) See, for example: (a) Ballini, R.; Gabrielli, S.; Palmieri, A.
Synlett 2009, 965. (b) Ballini, R.; Bosica, G.; Palmieri, A.;
Bakhtiari, K. Synlett 2009, 268. (c) Ballini, R.; Bosica, G.;
Gabrielli, S.; Palmieri, A. Tetrahedron 2009, 65, 2916.
(11) (a) Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett.
2004, 45, 7027. (b) Ballini, R.; Fiorini, D.; Palmieri, A.
Tetrahedron Lett. 2005, 46, 1245.
(12) Palmieri, A.; Ley, S. V.; Polyzos, A.; Ladlow, M.;
Baxendale, I. R. Beilstein J. Org. Chem. 2009, 5, 23.
(13) Typical Procedure for the Synthesis of Compounds 3
To a stirred mixture of the active methylene derivative 1 (1
mmol) and b-nitroacrylate 2 (1 mmol), acidic alumina (1.2
g) was added. The resulting heterogeneous mixture was
initially stirred at r.t., then heated at 60 °C, and stirred for the
appropriate time (see Table 2; reaction progress was
monitored by TLC). After completion of the reaction the
cooled heterogeneous system was directly charged onto a
silica gel column (eluting with hexanes–EtOAc) to give the
pure product 3.
Spectroscopic Data for Representative Compounds.
Compound 3aa: clear oil. IR (neat): n = 1050, 1189, 1301,
1577, 1684, 1716 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.21 (t, 3 H, J = 7.7 Hz), 1.32 (t, 3 H, J = 7.3 Hz), 2.35
(s, 3 H), 2.40 (s, 3 H), 2.86 (q, 2 H, J = 7.7 Hz), 4.29 (q, 2 H,
J = 7.3 Hz). 13C NMR (100 MHz, CDCl3): d = 12.6, 13.2,
14.4, 21.2, 31.2, 60.9, 112.1, 123.0, 153.7, 161.8, 163.8,
197.3. MS (EI, 70 eV): m/z = 224 [M+], 181, 178 (100), 163,
135, 122, 108, 57, 43, 29. Anal. Calcd for C12H16O4
Synlett 2010, No. 16, 2468–2470 © Thieme Stuttgart · New York