Solvent-free, anti-Michael addition of active methylene derivatives to β-nitroacrylates: Eco-friendly, chemoselective synthesis of polyfunctionalized nitroalkanes

Article abstract of DOI:10.1055/s-0028-1087515

The chemoselective, anti-Michael addition of active methylene derivatives to β-nitroacrylates can be easily performed at room temperature, under solvent-free conditions, using a catalytic amount of potassium carbonate as heterogeneous catalyst. Georg Thie

Full text of DOI:10.1055/s-0028-1087515

268
LETTER
Solvent-Free, anti-Michael Addition of Active Methylene Derivatives to
b-Nitroacrylates: Eco-Friendly, Chemoselective Synthesis of Polyfunctionali-
zed Nitroalkanes
S
ynthesis of Poly
o
functionaliz
b
ees rto Ballini,* Giovanna Bosica, Alessandro Palmieri, Khadijeh Bakhtiari
‘Green Chemistry Group’, Dipartimento di Scienze Chimiche dell’Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Fax +39(0737)402297; E-mail: Roberto.ballini@unicam.it
Received 23 October 2008
riety of other powerful functionalities.8 In addition, the
Abstract: The chemoselective, anti-Michael addition of active
need for two equivalents of DBU and a toxic solvent like
methylene derivatives to b-nitroacrylates can be easily performed at
MeCN make this procedure of limited interest from the
room temperature, under solvent-free conditions, using a catalytic
eco-sustainability point of view.
amount of potassium carbonate as heterogeneous catalyst.
Key words: anti-Michael addition, solvent-free, eco-friendly syn-
thesis, chemoselective, polyfunctionalized nitroalkanes
NO2
O
NO2
O
R1
OEt
R3
DBU (2 equiv), MeCN
r.t., 1–10 h
1
R1
R2
OEt
R3
+
Catalytic technologies have played a vital role in the eco-
nomic development of the chemical industry in the 20th
century. In the 21st century, we can expect the drive to-
ward cleaner technologies1 and, in this context, heteroge-
neous systems show great potential since the use of toxic
solvent is drastically reduced, the chemoselectivity and
the atom-efficiency are often improved, the product isola-
tion is simplified, and the volume of waste is significantly
reduced.2
O
O
O
O
R2
3
2
– HNO2
O
R1
R2
OEt
R3
O
O
Aliphatic nitro compounds, an important class of starting
material for the generation of new carbon–carbon bonds,
demonstrate high sensitivity to the catalytic system em-
ployed, in terms of yields, waste production, chemoselec-
tivity, and of atom-efficiency.3 Thus, the right choice of
the catalyst becomes crucial in the reaction of nitro deriv-
atives.
4
Scheme 1
During our studies into the application of heterogeneous
catalysis,3a,9 we have now found that the reaction of 1 with
active methylene compounds 5 can be easily performed
under solvent-free conditions and in the presence of a cat-
alytic amount (0.1 equiv) of potassium carbonate. Under
these mild, solvent-free reaction conditions (Scheme 2) a
variety of polyfunctionalized nitro derivatives 6 is ob-
tained in high yields (75–95%) via an anti-Michael
reaction10 and with complete chemoselectivity since no
elimination of nitrous acid is observed from the adduct
6.11
b-Nitroacrylates are an emerging class of electron-poor
alkenes since they can be converted into other important
‘fine chemicals’4 or employed as Michael acceptors with
indoles,5 amines,6 and b-dicarbonyl derivatives.7 The lat-
ter conjugate addition of active methylene derivatives 2
has been studied using a homogeneous solution of two
equivalents of DBU as organic base, in acetonitrile, giving
the in situ elimination of nitrous acid (Scheme 1) from the
Michael adduct 3.
NO2
O
The nitrous acid elimination is induced both by the pres-
ence of (i) the electron-withdrawing group at the b-posi-
tion to the nitro function in the intermediate 3 and (ii) a
strong base like DBU. However, in spite of the great util-
ity of the unsaturated systems 4 obtained, the elimination
of the nitro group from the Michael adduct 3 represents an
important loss in terms of atom economy and functional-
ity, due to the easy conversion of the nitro group into a va-
K2CO3 (0.1 equiv)
r.t., 1–2 h, 75–95%
COR2
EWG
NO2
O
R1
EWG
OEt
R2
+
OEt
R3
R1
R3
1
5
O
6
Scheme 2
The reaction works well at room temperature and under
very short reaction times (1–2 h) and seems to be indepen-
dent of the bulk of the reactants since hindered nucleo-
philic derivatives (6k–n) furnish comparable results to
SYNLETT 2009, No. 2, pp 0268–0270
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087515; Art ID: D35508ST
x
x.
x
x.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Polyfunctionalized Nitroalkanes
269
Table 1 Synthesis of Compounds 612
(2) (a) McKillop, A.; Young, D. W. Synthesis 1979, 401.
(b) Noritaka, M.; Misono, M. Chem. Rev. 1998, 98, 199.
(c) Maitlis, P. M.; Long, H. C.; Quyoum, R.; Turner, M. L.;
Wang, Z.-Q. Chem. Commun. 1996, 1. (d) Sheldon, R. A.
Chem. Ind. 1997, 12.
Entry
R
R3 R4
EWG
Yield (%)a
of 6
(reaction
time, h)
(3) (a) Ballini, R.; Palmieri, A. Curr. Org. Chem. 2006, 10,
2145. (b) Ballini, R.; Palmieri, A. Adv. Synth. Catal. 2006,
348, 1154. (c) Ballini, R.; Palmieri, A.; Petrini, M.; Shaikh,
R. R. Adv. Synth. Catal. 2008, 350, 129. (d) Ballini, R.;
Bosica, G.; Palmieri, A.; Pizzo, F.; Vaccaro, L. Green Chem.
2008, 10, 541. (e) Ballini, R.; Barboni, L.; Castrica, L.;
Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Adv. Synth.
Catal. 2008, 350, 1218.
(4) Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2004,
45, 7027.
(5) Ballini, R.; Gabrielli, S.; Palmieri, A.; Petrini, M.
Tetrahedron 2008, 64, 5435.
a
b
c
d
e
f
Et
Me
H
H
H
H
H
H
H
H
H
H
COMe 75 (1.5)
COOEt 85 (1)
Me
OEt
Ph
n-Pr
n-Pr
n-Pr
n-C5H11
COPh
80 (2)
OEt
OEt
OEt
COMe 83 (1.5)
CN
CN
CN
CN
CN
CN
CN
CN
95 (1)
87 (1)
83 (1)
92 (1)
84 (2)
94 (1)
84 (1)
95 (1)
95 (1)
86 (1)
(6) Ballini, R.; Bazán, N. A.; Bosica, G.; Palmieri, A.
g
h
i
MeOCO(CH2)4 OEt
Tetrahedron Lett. 2008, 49, 3865.
(7) Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2005,
46, 1245.
Et
OEt
OEt
OEt
Ph
(8) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia
1979, 33, 1. (b) Rosini, G.; Ballini, R. Synthesis 1988, 833.
(c) Ono, N. The Nitro Group in Organic Synthesis; Wiley:
New York, 2001. (d) Ballini, R.; Petrini, M. Tetrahedron
2004, 60, 1017. (e) Ballini, R.; Bosica, G.; Fiorini, D.;
Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
(f) Ballini, R.; Palmieri, A.; Barboni, L. Chem. Commun.
2008, 2975.
(9) (a) Ballini, R.; Fiorini, D.; Gil, M. V.; Palmieri, A. Green
Chem. 2003, 5, 475. (b) Sartori, G.; Ballini, R.; Bigi, F.;
Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004, 104, 199.
(c) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Synthesis
2004, 1938. (d) Ballini, R.; Barboni, L.; Fiorini, D.; Giarlo,
G.; Palmieri, A. Green Chem. 2005, 7, 828. (e) Ballini, R.;
Fiorini, D.; Maggi, R.; Oro, C.; Palmieri, A.; Sartori, G.
Synlett 2006, 1849.
j
Ph(CH2)2
n-Bu
k
l
OEt n-C5H11
OEt n-C5H11
Ph(CH2)2
Et
m
n
OEt Me2CHCH2 CN
OEt Me2CHCH2 CN
n-C5H11
a Yield of pure isolated product.
those obtained from simple active methylenes (6a–j,
Table 1).
(10) Lewandowska, E. Tetrahedron 2007, 63, 2107.
(11) Spectroscopic Data for Representative Compounds
Compound 6a: oil. IR (neat): 1732, 1555, 1369 cm–1. 1H
NMR (400 MHz, CDCl3): d = 0.98 (t, 3 H, J = 7.2 Hz), 1.24
(t, 3 H, J = 7.2 Hz), 1.90–2.00 (m, 1 H), 2.12–2.22 (m, 1 H),
2.34 (s, 3 H), 2.42 (s, 3 H), 3.75 (dd, 0.6 H, J = 3.4, 11.0 Hz),
3.82 (dd, 0.4 H, J = 5.8, 8.9 Hz), 3.92 (d, 0.6 H, J = 11.0 Hz),
4.02 (d, 0.4 H, J = 8.9 Hz), 4.11–4.22 (m, 2 H), 4.48–4.53
(m, 0.4 H), 4.96–5.09 (m, 0.6 H). 13C NMR (100 MHz,
CDCl3): d = 10.8, 14.0, 24.5, 31.0, 46.6, 47.3, 62.3, 62.4,
66.9, 88.5, 89.9, 169.2, 169.6, 200.2, 200.6. Anal. Calcd for
C12H19NO6 (273.283): C, 52.74; H, 7.01; N, 5.13. Found: C,
52.01; H, 6.81; N, 4.98.
By our procedure a new class of useful, polyfunctional-
ized nitro derivatives can be easily prepared in high
yields, at room temperature, and under very short reaction
times with the minimum consumption of energy.
In addition, several other ecological advantages are of-
fered since the amount of catalyst is 0.1 equivalents, and
all the reactions can be performed in the absence of any
solvent and with 100% of atom economy.
Finally, any workup can be avoided because the crude
products can be directly charged onto a chromatographic
column.12
Compound 6b: oil. IR (neat): 1738, 1557, 1370 cm–1. 1H
NMR (400 MHz, CDCl3): d = 1.20–1.30 (m, 9 H), 1.55 (d,
1.35 H, J = 6.8 Hz), 1.65 (d, 1.65 H, J = 6.8 Hz), 3.69 (d,
0.45 H, J = 9.4 Hz), 3.76 (dd, 0.55 H, J = 5.1, 8.1 Hz). 3.88
(d, 0.55 H, J = 7.7 Hz), 3.96 (dd, 0.45 H, J = 5.5, 9.4 Hz),
4.12–4.28 (m, 6 H), 4.74–4.81 (m, 0.45 H), 4.89–4.96 (m,
0.55 H). 13C NMR (100 MHz, CDCl3): d = 14.0, 14.1, 15.2,
17.5, 41.8, 47.8, 51.0, 51.5, 62.2, 62.4, 62.5, 81.0, 81.3,
167.0, 167.4, 169.1. Anal. Calcd for C13H21NO8 (319.308):
C, 48.90; H, 6.63; N, 4.39. Found: C, 49.01; H, 6.61; N, 4.27.
Compound 6c: waxy solid. IR (neat): 1732, 1554, 1370 cm–
1. 1H NMR (400 MHz, CDCl3): d = 0.87 (t, 3 H, J = 7.3 Hz),
1.11–1.41 (m, 5 H), 1.61–2.40 (m, 2 H), 4.05–4.13 (m, 2 H),
4.18–4.30 (m, 1 H), 4.58–4.79 (m, 0.4 H), 4.81–4.87 (m, 0.6
H), 5.8 (d, 0.6 H, J = 8.7 Hz), 6.16 (d, 0.4 H, J = 10.6 Hz),
7.37–7.60 (m, 6 H), 7.85–8.00 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 13.4, 13.6, 13.9, 14.0, 19.6, 19.8, 33.3,
Thus, our method represents an important step in the syn-
thesis of polyfunctionalized nitroalkanes under eco-
friendly reaction conditions.
Acknowledgment
The authors thank the University of Camerino and MUR-Italy
(PRIN 2006, project: Sintesi Organiche Ecosostenibili Mediate da
Nuovi Sistemi Catalitici) for financial support.
References and Notes
(1) (a) Clark, J. H.; Rhodes, C. N. RSC Clean Technology
Monographs; Clark, J. H., Ed.; RSC: Cambridge, 2000.
(b) Clark, J. H. Acc. Chem. Res. 2002, 35, 791.
Synlett 2009, No. 2, 268–270 © Thieme Stuttgart · New York

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R. Ballini et al.
LETTER
34.0, 49.0, 49.2, 56.0, 56.4, 62.2, 62.3, 87.1, 88.0, 128.9,
129.1, 133.6, 134, 3, 136.0, 136.5, 169.2, 169.9, 193.5,
193.6, 193.7, 194.0. Anal. Calcd for C23H25NO6 (411.451):
C, 67.14; H, 6.12; N, 3.40. Found: C, 67.81; H, 7.11; N,
3.87.
were prepared by the standard procedure.4
Typical Procedure for the Conjugate Addition of Active
Methylene 5 to b-Nitroacrylates 1: Nitroacrylate 1 (1
mmol), active methylene derivatives 5 (1 mmol), and K2CO3
(13.8 mg, 0.1 mmol) were mixed by magnetical stirring for
the appropriate time (Table 1, monitored by TLC). Then, the
mixture was directly charged onto a chromatographic
column (cyclohexane–EtOAc) allowing the pure products 6.
(12) The GLC analyses were performed with an SE-54 fused
silica capillary column (25 m, 0.32 mm internal diameter),
FID detector, and nitrogen as carrier gas. b-Nitroacrylates
Synlett 2009, No. 2, 268–270 © Thieme Stuttgart · New York

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