Michael reaction of nitroalkanes with β-nitroacrylates under a solid promoter: Advanced regio-and diastereoselective synthesis of nitro-functionalized ββ-unsaturated esters and 1,3-butadiene-2-carboxylates

Article abstract of DOI:10.1002/adsc.201000142

A new class of nitro-functionalized α,β-unsaturated esters has been prepared by a regio-and diastereoselective Michael addition of nitroalkanes to βnitroacrylates, performed at room temperature, under carbonate on polymer as promoter, and in the presence

Full text of DOI:10.1002/adsc.201000142

FULL PAPERS
DOI: 10.1002/adsc.201000142
Michael Reaction of Nitroalkanes with b-Nitroacrylates under
a Solid Promoter: Advanced Regio- and Diastereoselective
Synthesis of Nitro-Functionalized a,b-Unsaturated Esters and
1,3-Butadiene-2-carboxylates
a
a
a,
Alessandro Palmieri, Serena Gabrielli, and Roberto Ballini *
“
a
Green Chemistry Group”, School of Sciences and Technologies, Chemistry Division, University of Camerino,
via S. Agostino 1, 62032 Camerino, Italy
Fax : (+39)-(0)737-402-297; phone: (+39)-(0)737-402-270; e-mail: roberto.ballini@unicam.it
Received: February 23, 2010; Published online: June 8, 2010
Abstract: A new class of nitro-functionalized a,b-un- conditions the method allows the synthesis of 1,3-bu-
saturated esters has been prepared by a regio- and tadiene-2-carboxylates.
diastereoselective Michael addition of nitroalkanes
to b-nitroacrylates, performed at room temperature,
under carbonate on polymer as promoter, and in the Keywords: 1,3-butadiene-2-carboxylates; Michael ad-
presence of ethyl acetate as eco-friendly solvent. dition; b-nitroacrylates; nitroalkanes; solid-support-
Moreover, by the modular choice of the reaction ed promoter; a,b-unsaturated esters
Introduction
saturated esters are usually accessible through (i)
Knovenagel condensation of active methylene esters
[
7]
One of the main issues in todayꢀs world is the devel- with aldehydes, (ii) condensation of alkyl acetates
opment of new eco-sustainable processes and, in par- with aldehydes followed by dehydration, (iii) Refor-
ticular in the field of organic chemistry, this issue is mastsky reaction with aldehydes followed by elimina-
undoubtedly the production of new fine chemicals. In tion of the resultant hydroxy esters, or (iv) Wads-
this context, a very important answer is achieved by worth-Emmons olefination of carbonyl derivatives.
[
8]
[
9]
[10]
the use of solid-supported reagents (SSR) which, However, within this scenario, new efficient proce-
thanks their peculiarity, represent a viable and con- dures for their synthesis and the need for new classes
venient alternative to traditional synthetic processes of a,b-unsaturated esters, particularly for the poly-
[
1]
realized under homogeneous conditions. In addition, functionalized ones, would be welcome, especially
solid promoters are often able to produce a consistent taking into account the advantages offered by the syn-
increase in the reactivity and selectivity of the related theses on solid supports.
processes so that their utilization becomes mandatory
for a successful synthetic procedure. On this basis,
conjugate addition of nucleophiles to electron-poor Results and Discussion
alkenes represents a test benchmark for a considera-
ble number of solid promoters that may work either For many years, we have been investigating the use of
by activating the nucleophilic reagent (basic supports) unconventional reaction media that could replace
[
2]
or the alkene moiety (acidic supports). Among all harmful reaction conditions while maintaining the
[
11]
the electron-poor olefins, nitroalkenes are surely the highest chemical efficiency.
As a continuation of
[
3]
strongest Michael acceptors and, in particular, b-ni- our interest in the chemistry of nitro compounds and
troacrylates show fascinating ability as precursors of a in the use of solid bases, we have investigated the Mi-
[
4]
variety of fine chemicals.
chael addition of nitroalkanes to b-nitroacrylates, for
a,b-Unsaturated esters are useful chemical entities the production of a new class of nitro-functionalized
[
5]
in organic synthesis which can be further functional- a,b-unsaturated esters, promoted by carbonate on
[
12]
ized by Michael or Diels–Alder reactions, giving polymer.
access to important targets of considerable interest, As reported in Table 1, firstly we tested, as a
mainly in the synthesis of natural products. a,b-Un- sample reaction, the conjugate addition of 1-nitropro-
[
6]
Adv. Synth. Catal. 2010, 352, 1485 – 1492
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Alessandro Palmieri et al.
FULL PAPERS
Table 1. Screening of different promoters.
[a]
Promoter
g (mequiv. of base)
Yield [%] of 4a
dr (E/Z)
Carbonate on polymer support
Amberlyst A21
TBD on polymer
0.286 (1)
1 (~2.5)
0.676 (1)
1
81
35
33
traces
traces
96:4
92:8
93:7
Basic Al O3
2
Na CO3
0.106 (1)
2
[
a]
Yield of pure isolated product.
pane 1a to the acrylate 2a under a variety of basic
The reaction was then applied to the conjugate ad-1
solid promoters and in the presence of ethyl acetate dition of nitroalkanes 1 possessing the alkyl group R
[
13]
2
as eco-friendly solvent.
different from the alkyl group R in the b-nitroacry-
The reaction allows, via elimination of nitrous acid late 2, and a mixture of regioisomers 5 and 6 was ob-
from the adduct 3a, the formation of the nitro a,b-un- tained, in which the elimination of nitrous acid de-
saturated ester 4a as a diastereomeric mixture (with rived from the nitro group, bearing to the incoming
high prevalence of the E isomer, >90%) and the best nitroalkane 1, is strongly favoured (5/6>3) (Table 2).
yields (81%) were obtained by using carbonate on
The trend of the reaction can be explained by the
polymer as promoter. It is evident that from 3a two possible mechanism of the conjugate addition of 1 to
different eliminations could be observed, one involv- 2 (Scheme 1), in which the nitronate anion A, gener-
ing the hydrogen a and the nitro group b, the other ated by deprotonation of the nitroalkane 1, reacts
one the elimination of the hydrogen a and the nitro with b-nitroacrylate 2 affording the Michael adduct B,
group b’. However, from this point of view, due to the which allows (path a) an intramolecular substitution
same nature of the alkyl group (R=Et) in the nitroal- (similarly to those described by Gomez-Sanchez
1
4
kane 1a and in the b-nitroacrylate 2a, the adduct 3a et al. for analogous compounds) and formation of
produces the same a,b-unsaturated ester 4a. In order the isoxazole N-oxide C, that after protonation
to verify the generality of our method, we extended (giving D) and intramolecular elimination, affords the
the use of carbonate on polymer to a variety of other nitronate form E which is prone to convert into the
substrates and, as reported in Table 2, good yields regioisomer 5. The formation of regioisomeric prod-
were obtained even with functionalized nitroalkanes, uct 6, can be rationalized by the competitive path b,
so that polyfunctionalized a,b-unsaturated esters can in which the Michael adduct B is involved in an intra-
be synthesized under very mild reaction conditions.
molecular acid-base equilibrium, giving the regioiso-
meric nitronate anion F. This intermediate, as above
reported for the corresponding adduct B, gives the in-
tramolecular substitution with the formation of het-
erocycle H, which affords, similarly as reported for
the intermediate C, the products 6.
Table 2. Michael reaction for the synthesis of unsaturated
esters 4a–f.
The distribution of the products, suggests that the
reaction is under kinetic control, in which the intra-
molecular substitution rate is higher with the respect
to the acid-base thermodynamic equilibrium rate; or
else the distribution of the products 5 and 6 should be
around 1:1. In addition the formation, exclusively, of
the regioisomer 6, starting from secondary nitroal-
kanes, is explained by their incompatibility with the
path b (see structures H–J).
It is important to point out that synthetic potential
of the compounds 4–6 is strongly increased by the
presence of the nitro group, since it can favour the
generation of stabilized carbanions under basic condi-
[a]
Entry R
Yield [%] of 4 Reaction time (h)
a
b
c
d
e
f
Et
n-Bu
n-C H
Ph
MeOCO
AcO(CH )
81
80
80
81
18
17
17
17
18
19
5
11
ACHTUNGTRENNUNG( CH )
2 2
ACHTUNGTRENNUNG( CH ) 70
2 4
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
55
2
3
[
a]
Yield of pure isolated product.
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Adv. Synth. Catal. 2010, 352, 1485 – 1492

Michael Reaction of Nitroalkanes with b-Nitroacrylates under a Solid Promoter
Table 3. Michael reaction for the synthesis of unsaturated esters 5 and 6a–e.
1
2
[a]
[b]
Entry
R
R
R
Yield [%] of 5+6 (ratio)
Reaction time [h]
a
b
c
d
e
Me
H
H
H
H
Me
Et
n-C H
n-C H
Ph ACHTUNTGNERNUG( CH )
n-C H
63 (100:0)
62 (75:25)
76 (80:20)
55 (75:25)
72 (80:20)
48
18
17
17
17
5
11
n-C H
5
11
Et
Me
Me
5
11
5
11
2 2
[
[
a]
b]
Yield of pure isolated product.
Regioisomeric ratio was defined by H NMR studies.
1
Scheme 1. Proposed reaction mechanism.
Table 4. One-pot preparation of conjugate dienes 7a–d.
tions and, consequently, the formation of new C/C
[15]
bonds. Moreover, the nitro group can be converted
[
16]
into a variety of other functionalities.
As a further development of our method, we found
a new procedure for the synthesis of 1,3-butadiene-2-
carboxylates, simply by a small modification of the re-
action conditions. In fact, as reported in Table 4, the
conjugate addition of 1 to 2 under refluxing EtOAc,
and in the presence of an excess (2.5 equivalents) of
carbonate on polymer, allows a double elimination of
nitrous acid with the formation of the dienes 7 in sat-
isfactory to good overall yields (64–76%).
1
[a]
Entry
R
R
Yield [%] of 7 (EE:ZE ratio)
a
b
c
Et
n-C H
n-C H
Ph
Me
n-C H
n-C H
75 (80:20)
76 (80:20)
73 (80:20)
5
11
13
4
9
6
5
11
d
ACHTUNGTNRENUGN( CH ) PhCH2 64 (75:25)
2 2
[a]
Yield of pure isolated product.
Adv. Synth. Catal. 2010, 352, 1485 – 1492
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Alessandro Palmieri et al.
FULL PAPERS
In addition, although the presence of two conjugate
Moreover, our procedure can be applied to a new,
double bonds, in the final compounds 7 could allow efficient preparation of valproic acid (VPA) 9 and its
four different diastereomers, only two of them were main metabolite (E)-2-[(E)-prop-1-enyl]pent-2-enoic
observed. On the basis of NMR and NOE studies on acid 8a (Scheme 2).
the compound 7b the configurations of the diastereo-
mers were defined as E/E and Z/E, with a high pre- ment of epilepsy.
Valproic acid is a widely used drug for the treat-
[26,27]
Metabolism of VPA occurs
dominance for the former. In particular, the configu- mainly in the liver and several complex metabolic
ration of the C-1’/C-2’ double bound was assigned on pathways have been presented and of great interest
[
28–30]
the basis of H-1’,H-2’ coupling constant (15.8 Hz for are a series of diunsaturated metabolites.
Howev-
both the diastereomers), while the configuration of C- er one of these, the compound 8a, is the most fre-
[31]
2
/C-3 double bond was defined by the NOE correla- quently found in patient serum and urine samples
[32,33]
tion between H-4 and protons H-1’ and H-2’ and it possesses anticonvulsant activity in mice.
(
Figure 1).
In order to undertake metabolic and pharmacoki-
netic studies of 8a, methods of syntheses that would
yield significant quantities of this diene, were re-
[
17]
quired.
Thus, our synthetic approach for the synthesis of
compound 9 and its metabolite 8a, consists in a three-
step pathway. The first step involves the reaction of 1-
nitropropane 1a with b-nitroacrylate 2a, allowing the
formation of the corresponding diunsaturated ester 7
Figure 1. Compound 7b.
The stereochemistry was confirmed by comparison [mainly isolated as a pair of diastereomers 7a (EE)
1
of the H NMR spectra of 7a with those reported in and 7a’ (ZE), in 80:20 ratio]. These diastereomers can
[17]
literature.
be separated by flash chromatography, or alternative-
1
,3-Butadiene-2-carboxylates 7 are a very important ly used as mixture to be converted into the corre-
class of molecules since they have been throughly sponding pair of diunsaturated acids (8a and 8a’).
studied in recent years as potential starting materials This step, performed under refluxing 0.5N aqueous
for organic synthesis, in particular for various [4+ solution of NaOH and in the presence of ethanol, af-
2]cycloadditions, and a number of these compounds fords (after four hours) the diastereomeric acids 8a
have proven to be valuable precursors for functional- and 8a’ in 81% yield. It is important to point out that
[
18–22]
ized alkyl 1-cyclohexene-1-carboxylates,
naturally our synthesis shows remarkable advantages with re-
[
23]
[17]
occurring cyclopentanoid terpenic acids, biological- spect to those reported in literature,
where the
and a-alkylidenebutyro- same transformation was realized, after refluxing for
48 h, in 52% yield. The diastereomeric acids 8 can be
[
24]
ly important litsenolides,
[
25]
lactone natural products.
Scheme 2. Synthetic pathway to valproic acid (9) and its metabolite 8a.
1488
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Adv. Synth. Catal. 2010, 352, 1485 – 1492

Michael Reaction of Nitroalkanes with b-Nitroacrylates under a Solid Promoter
1
3
easily separated by flash chromatography (hexanes- (dd, 1H, J=6.0, 9.0 Hz), 7.14 (t, 1H, J=7.7 Hz); C NMR
100 MHz, CDCl ): d=10.9, 13.0, 14.2, 22.3, 24.5, 61.3, 83.7,
(
1
9
ethyl actetate 80:20) with the isolation of metabolite
a in 65% yield. Alternatively, the mixture can be
subject to catalytic hydrogenation with the formation
of valproic acid 9 in 88% yield.
3
26.7, 151.1, 165.2; EI-MS (70 eV): m/z=186, 169, 141, 123,
5 (100), 81, 67, 55, 41, 29; anal. calcd. for C H NO
8
1
0
17
4
(
6
215.25): C 55.80, H 7.96, N 6.51; found: C 55.99, H 8.03, N
.44.
E)-Ethyl 2-(1-nitropentyl)hept-2-enoate (4b): Colorless
Finally, we focused our investigation on the recov-
(
[
34]
ery and reuse of the promoter, after reactivation, in
ꢀ1
oil. IR (neat): n=1240, 1368, 1552, 1648, 1717 cm ;
the model reaction (1a+2a!4a), with the following
1
H NMR (400 MHz, CDCl ): d=0.83–0.92 (m, 6H), 1.10–
3
st
nd
results: reaction 81%, 1 recycle 76%, 2 recycle
1
.51 (m, 8H), 1.23 (t, 3H, J=7.3 Hz), 1.98–2.11 (m, 1H),
75%.
2.12–2.33 (m, 2H), 2.41–2.55 (m, 1H), 4.15 (q, 2H, J=
7
7
.3 Hz), 5.18 (dd, 1H, J=6.0, 9.0 Hz), 7.10 (t, 1H, J=
1
3
.7 Hz); C NMR (100 MHz, CDCl ): d=14.0, 14.2, 22.6,
3
Conclusions
22.7, 28.6, 28.7, 30.7, 30.9, 61.3, 82.5, 127.4, 149.9, 165.2; EI-
MS (70 eV): m/z=225, 179, 151, 123, 109, 95 (100), 81, 67,
5
9
5, 41, 29; anal. calcd. for C H NO (271.35): C 61.97, H
14 25 4
In conclusion, we have found a new approach for the
regio- and diastereoselective synthesis of nitro-func-
tionalized a,b-unsaturated esters under eco-friendly
conditions (due to the use of eco-compatible solvent,
solid and recycling promoter, and room temperature).
In addition, by the modular choice of the reaction
conditions, even 1,3-butadiene-2-caroboxylates can be
.29, N 5.16; found: C 62.09, H 9.40, N 5.08.
E)-Ethyl 2-(1-nitrohexyl)oct-2-enoate (4c): Colorless oil.
(
ꢀ
1
1
IR (neat): n=1238, 1367, 1552, 1649, 1716 cm ; H NMR
(400 MHz, CDCl ): d=0.81–0.93 (m, 6H), 1.17–1.38 (m,
3
1
(
0H), 1.26 (t, 3H, J=7.3 Hz), 1.42–1.57 (m, 2H), 2.00–2.14
m, 1H), 2.15–2.35 (m, 2H), 2.43–2.56 (m, 1H), 4.19 (q, 2H,
J=7.3 Hz), 5.21 (dd, 1H, J=6.0, 8.6 Hz), 7.14 (t, 1H, J=
1
3
obtained in high diastereoselectivity. Finally, the effi- 7.7 Hz); C NMR (100 MHz, CDCl ): d=14.1, 14.3, 22.5,
3
cient syntheses of both valproic acid and its main me- 22.6, 26.2, 28.3, 29.0, 31.2, 31.6, 31.7, 61.4, 82.5, 127.4, 150.0,
tabolite have been realized as a representative appli- 165.2; EI-MS (70 eV): m/z=253, 207, 179, 137, 123, 109
(
(
6
100), 95, 81, 67, 55, 41, 29; anal. calcd. for C H NO
cation of our results.
16 29 4
299.41): C 64.18, H 9.76, N 4.68; found: C 64.31, H 9.65, N
4.19.
E)-Ethyl
enoate (4d): Colorless oil. IR (neat): n=1246, 1369, 1551,
(
2-(1-nitro-3-phenylpropyl)-5-phenylpent-2-
Experimental Section
ꢀ
1
1
1
603, 1648, 1712, 3028, 3063 cm ; H NMR (400 MHz,
General Remarks
CDCl ): d=1.28 (t, 3H, J=7.3 Hz), 2.18–2.47 (m, 3H), 2.63
3
1
(
4
t, 2H, J=7.3 Hz), 2.66–2.83 (m, 2H), 2.86–2.98 (m, 1H),
.21 (q, 2H, J=7.3 Hz), 5.15 (t, 1H, J=7.3 Hz), 7.09–7.33
General H NMR spectra were recorded at 400 MHz on a
1
3
Varian Mercury Plus 400 in CDCl3 as solvent. C NMR
spectra were recorded at 100 MHz in CDCl3 as solvent.
Micro analyses were performed with a CHNS-O analyzer
Model EA 1108 from Fisons Instruments. IR spectra were
recorded with a Perkin–Elmer Paragon 500 FT-IR. 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.GS-MS analyses were carried out
by means of the EI technique (70 eV).
1
3
(
3
m, 11H); C NMR (100 MHz, CDCl ): d=14.2, 30.5, 32.5,
3
2.8, 34.5, 61.5, 81.4, 126.6, 126.7, 128.0, 128.5, 128.6, 128.8,
128.9, 140.0, 140.2, 148.6, 165.0; EI-MS (70 eV): m/z=320,
231, 185, 117, 105, 91 (100), 77, 65; anal. calcd. for
C H25NO (367.44): C 71.91, H 6.86, N 3.81; found: C 72.03,
H 6.99, N 3.73.
(E)-6-Ethyl 1,11-dimethyl 7-nitroundec-5-ene-1,6,11-tri-
carboxylate (4e): Colorless oil. IR (neat): n=1171, 1369,
1
1
1
6
2
22 4
ꢀ
1
1
552, 1648, 1736 cm ; H NMR (400 MHz, CDCl ): d=
3
.18–1.46 (m, 3H), 1.26 (t, 3H, J=7.3 Hz), 1.48–1.59 (m,
H), 1.60–1.74 (m, 4H), 1.97–2.14 (m, 1H), 2.18–2.39 (m,
H), 2.47–2.69 (m, 1H), 3.65 (s, 3H), 3.66 (s, 3H), 4.18 (q,
H, J=7.3 Hz), 5.20 (dd, 1H, J=6.0, 8.5 Hz), 7.11 (t, 1H,
Typical Procedure for the Synthesis of Compounds 4,
5
and 6
To a stirred solution of the opportune nitroalkane 1
1.1 mmol) and the b-nitroacrylate 2 (1 mmol) in ethyl ace-
tate (2 mL), the carbonate on polymer support (286 mg,
mmol) was added. The resulting heterogeneous mixture
1
3
J=7.7 Hz); C NMR (100 MHz, CDCl ): d=14.2, 24.6, 24.7,
(
3
26.0, 28.0, 28.6, 30.9, 33.7, 33.8, 51.7, 51.8, 61.5, 82.2, 127.7,
149.2, 164.9, 173.8; EI-MS (70 eV): m/z=356, 338, 279, 261,
235, 201, 163 (100), 135, 111, 79, 55, 29; anal. calcd. for
C H29NO (387.42): C 55.80, H 7.54, N 3.62; found: C 55.93,
H 7.66, N 3.55.
(E)-5-(Ethoxycarbonyl)-6-nitronon-4-ene-1,9-diyl diace-
tate (4f): Colorless oil. IR (neat): n=1237, 1365, 1551, 1648,
1735 cm ; H NMR (400 MHz, CDCl ): d=1.27 (t, 3H, J=
1
was stirred at room temperature for the required time (the
reaction progress was monitored by TLC, Table 2), then the
promoter was filtered off, washing with EtOAc. Finally the
filtrate was concentrated under vacuum to give the crude
products 4–6 which were purified by flash chromatography
column (hexane-ethyl acetate).
18 8
ꢀ
1
1
3
(
E)-Ethyl 2-(1-nitropropyl)pent-2-enoate (4a): Colorless
7.3 Hz), 1.51–1.79 (m, 3H), 1.81–1.90 (m, 1H), 2.04 (s, 6H),
2.05–2.21 (m, 1H), 2.26–2.47 (m, 2H), 2.55–2.72 (m, 1H),
4.05–4.13 (m, 4H), 4.19 (q, 2H, J=7.3 Hz), 5.25 (dd, 1H,
ꢀ
1
oil. IR (neat): n=1238, 1365, 1552, 1647, 1719 cm ;
H NMR (400 MHz, CDCl ): d=0.92 (t, 3H, J=7.7 Hz),
.11 (t, 3H, J=7.7 Hz), 1.26 (t, 3H, J=7.3 Hz), 2.04–2.40
1
3
1
3
1
J=6.4, 8.6 Hz), 7.14 (t, 1H, J=7.7 Hz);
C NMR
(
m, 3H), 2.48–2.61 (m, 1H), 4.18 (q, 2H, J=7.3 Hz), 5.14
(100 MHz, CDCl ): d=14.3, 21.0, 21.1, 25.7, 25.8, 27.6, 27.9,
3
Adv. Synth. Catal. 2010, 352, 1485 – 1492
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Alessandro Palmieri et al.
FULL PAPERS
6
1.7, 63.5, 63.6, 81.8, 128.0, 148.6, 164.8, 171.1, 171.2; EI-MS
2.5 mmol) was added. The resulting heterogeneous mixture
was stirred three hours at reflux, then, after cooling at room
temperature, the catalyst was filtered off, washing with
EtOAc. Finally the filtrate was concentrated under vacuum
to give the crude products 7 which were purified by flash
chromatography column (hexane-toluene 7:3).
(
(
7
70 eV): m/z=313, 267, 225, 207, 183, 165, 147, 119, 91, 43
100), 29; anal. calcd. for C H NO (359.37): C 53.47, H
1
6
25
8
.01, N 3.90; found: C 53.59, H 6.90, N 3.98.
Ethyl 3-nitro-2-(propan-2-ylidene)octanoate (5a): Color-
ꢀ
1
less oil. IR (neat): n=1242, 1364, 1553, 1638, 1721 cm ;
1
H NMR (400 MHz, CDCl ): d=0.87 (t, 3H, J=7.3 Hz),
3
(E)-Ethyl 2-[(E)-prop-1-enyl]pent-2-enoate (7a): Color-
ꢀ
1
1
.23–1.34 (m, 9H), 1.88–1.99 (m, 1H), 1.96 (s, 3H), 2.05 (s,
less oil. IR (neat): n=1714, 1651, 1629, 1603, 1234 cm ;
3
7
2
H), 2.29–2.41 (m, 1H), 4.12–4.27 (m, 2H), 5.25 (t, 1H, J=
1
H NMR (400 MHz, CDCl ): d=1.06 (t, 3H, J=7.3 Hz),
3
13
.3 Hz); C NMR (100 MHz, CDCl ): d=14.1, 14.2, 22.2,
3
1.30 (t, 3H, J=7.3 Hz), 1.82 (dd, 3H, J=1.3, 6.4 Hz), 2.25–
2.5, 23.8, 26.0, 31.5, 31.6, 61.0, 85.2, 124.4, 149.6, 166.6; EI-
2
1
7
2
.34 (m, 2H), 4.20 (q, 2H, J=7.3 Hz), 6.02 (dq, 1H, J=6.4,
MS (70 eV): m/z=186, 169, 141, 123, 95 (100), 81, 67, 55, 41,
2
5
5.8 Hz), 6.14 (dd, 1H, J=1.3, 15.8 Hz), 6.55 (t, 1H, J=
9; anal. calcd. for C H NO (257.33): C 60.68, H 9.01, N
13
1
3
23
4
.3 Hz); C NMR (100 MHz, CDCl ): d=13.7, 14.4, 19.3,
3
.44; found: C 60.81, H 9.13, N 5.35.
Mixture of regioisomeric compounds 5b and 6b (75:25):
2.2, 60.7, 123.5, 130.0, 131.1, 143.1, 167.9; EI-MS (70 eV):
+
m/z=168 (M ), 140, 123, 111, 95 (100), 79, 67, 55, 39, 29;
Colorless oil. IR (neat): n=1247, 1365, 1552, 1639,
anal. calcd. for C H O (168.23): C 71.39, H 9.59; found: C
ꢀ
1
1
10 16
2
1
3
1
3
720 cm ; H NMR (400 MHz, CDCl ): d=0.82–0.93 (m,
3
7
1.50, H 9.68.
Z)-Ethyl 2-[(E)-prop-1-enyl]pent-2-enoate (7a’): Color-
H), 0.93 (t, 0.75H, J=7.7 Hz), 1.12 (t, 2.25H, J=7.7 Hz),
.19–1.38 (m, 8.5H), 1.43–1.56 (m, 0.5H), 2.00–2.42 (m,
H), 2.43–2.63 (m, 1H), 4.14–4.24 (m, 2H), 5.14 (dd, 0.25H,
(
ꢀ
1
1
less oil. IR (neat): n=1716, 1648, 1603, 1231 cm ; H NMR
(
400 MHz, CDCl ): d=1.02 (t, 3H, J=7.3 Hz), 1.33 (t, 3H,
3
J=6.0, 8.9 Hz), 5.21 (dd, 0.75H, J=6.0, 8.9 Hz), 7.11 (t,
0
1
3
J=7.3 Hz), 1.75 (dd, 3H, J=1.3, 6.8 Hz), 2.17–2.27 (m, 2H),
.26 (q, 2H, J=7.3 Hz), 5.63–5.77 (m, 2H), 6.01 (dd, 1H,
.75H, J=7.7 Hz), 7.16 (t, 0.25H, J=7.7 Hz); C NMR
4
(100 MHz, CDCl ): d=11.0, 13.1, 14.1, 14.3, 22.4, 22.5, 22.6,
3
13
J=1.3, 15.8 Hz); C NMR (100 MHz, CDCl ): d=14.0, 14.5,
3
2
1
4.6, 26.2, 28.3, 29.0, 31.2, 31.6, 31.7, 61.4, 82.5, 83.8, 127.1,
50.2, 151.0, 165.2, 165.3.
Mixture of regioisomeric compounds 5c and 6c (80:20):
1
8.5, 23.2, 60.8, 126.6, 129.2, 131.1, 137.7, 168.4; EI-MS
+
(
70 eV): m/z=168 (M ), 140, 123, 111, 95 (100), 79, 67, 55,
3
9, 29; anal. calcd. for C H O (168.23): C 71.39, H 9.59;
Colorless oil. IR (neat): n=1246, 1365, 1551, 1639,
10 16 2
ꢀ
1
1
found: C 71.21, H 9.47.
1
3
1
3
719 cm ; H NMR (400 MHz, CDCl ): d=0.83–0.91 (m,
3
(
E)-Ethyl 2-[(E)-pent-1-enyl]hept-2-enoate (7b): Color-
H), 0.93 (t, 2.4H, J=7.7 Hz), 1.12 (t, 0.6H, J=7.7 Hz),
.20–1.37 (m, 7.4H), 1.43–1.55 (m, 1.6H), 2.01–2.39 (m,
H), 2.43–2.61 (m, 1H), 4.13–4.23 (m, 2H), 5.14 (dd, 0.8H,
ꢀ
1
less oil. IR (neat): n=1716, 1650, 1627, 1602, 1232 cm ;
H NMR (400 MHz, CDCl ): d=0.87–0.95 (m, 6H), 1.29 (t,
1
3
3
H, J=7.3 Hz), 1.30–1.49 (m, 6H), 2.12 (q, 2H, J=7.3 Hz),
2.27 (q, 2H, J=7.3 Hz), 4.20 (q, 2H, J=7.3 Hz), 6.00 (dt,
1H, J=6.8, 15.8 Hz), 6.11 (d, 1H, J=15.8 Hz), 6.58 (t, 1H,
J=6.0, 8.9 Hz), 5.21 (dd, 0.2H, J=6.0, 8.9 Hz), 7.11 (t,
0
1
3
.2H, J=7.7 Hz), 7.16 (t, 0.8H, J=7.7 Hz); C NMR
(100 MHz, CDCl ): d=11.0, 13.1, 14.1, 14.3, 22.4, 22.5, 22.6,
3
1
3
2
1
4.6, 26.2, 28.3, 29.0, 31.2, 31.6, 31.7, 61.4, 82.5, 83.8, 127.1,
50.2, 151.0, 165.2, 165.3.
Mixture of regioisomeric compounds 5d and 6d (75:25):
J=7.3 Hz); C NMR (100 MHz, CDCl ): d=13.9, 14.1, 14.5,
3
22.6, 22.7, 28.6, 31.4, 35.9, 60.7, 122.4, 130.6, 136.3, 142.0,
+
168.0; EI-MS (70 eV): m/z=224 (M ), 195, 179, 167, 149,
Colorless oil. IR (neat): n=1242, 1364, 1551, 1638,
139, 121, 111, 95 (100), 79, 67, 55, 41, 29; anal. calcd. for
C H O (224.34): C 74.95, H 10.78, found: C 75.07, H
ꢀ
1
1
1
718 cm ; H NMR (400 MHz, CDCl ): d=0.85–0.92 (m,
3
14 24
2
3
H), 1.20–1.37 (7.5H), 1.43–1.56 (m, 1.5H), 1.77 (d, 2.25H,
10.89.
J=6.9 Hz), 1.92 (d, 0.75H, J=7.3 Hz), 2.02–2.34 (m,
(Z)-Ethyl 2-((E)-pent-1-enyl)hept-2-enoate (7b’): Color-
less oil. IR (neat): n=1714, 1652, 1631, 1600, 1240 cm ;
ꢀ
1
1
0
0
.75H), 2.44–2.56 (m, 0.25H), 4.15–4.22 (m, 2H), 5.24 (dd,
1
.25H, J=6.0, 8.9 Hz), 5.32 (q, 0.75H, J=7.3 Hz), 7.06 (t,
H NMR (400 MHz, CDCl ): d=0.85–0.93 (m, 6H), 1.27–
3
1
3
.75H, J=7.7 Hz), 7.24 (q, 0.25H, J=7.3 Hz); C NMR
1
.46 (m, 6H), 1.33 (t, 3H, J=7.3 Hz), 2.05 (q, 2H, J=
7.3 Hz), 2.21 (q, 2H, J=7.3 Hz), 4.27 (q, 2H, J=7.3 Hz),
.66 (dt, 1H, J=6.8, 15.8 Hz), 5.74 (t, 1H, J=7.3 Hz), 6.00
(
100 MHz, CDCl ): d=14.1, 14.2, 14.8, 17.8, 22.5, 22.6, 26.1,
3
2
1
8.3, 28.8, 31.2, 31.6, 31.7, 61.4, 77.9, 82.2, 128.9, 144.5, 148.6,
65.0, 165.1.
5
(
1
1
1
13
d, 1H, J=15.8 Hz); C NMR (100 MHz, CDCl ): d=14.0,
3
Mixture of regioisomeric compounds 5e and 6e (80:20):
4.1, 14.5, 22.6, 29.6, 31.7, 35.2, 60.7, 128.1, 131.8, 133.8,
Colorless oil. IR (neat): n=1244, 1364, 1551, 1638, 1713,
+
36.4, 168.5; EI-MS (70 eV): m/z=224 (M ), 195, 179, 167,
ꢀ
1
1
3
025, 3061 cm ; H NMR (400 MHz, CDCl ): d=1.24–1.30
3
49, 139, 121, 111, 95 (100), 79, 67, 55, 41, 29; anal. calcd.
(
m, 3H), 1.57 (d, 2.4H, J=7.3 Hz), 1.70 (d, 0.6H, J=
for C H O (224.34): C 74.95, H 10.78; found: C 74.79, H
1
4
24
2
7
1
.3 Hz), 2.32–3.03 (m, 4H), 4.15–4.24 (m, 2H), 5.17–5.25 (m,
1
0.67.
H), 7.11 (t, 0.8H, J=7.7 Hz), 7.14–7.34 (m, 5.2H);
(
E)-Ethyl 2-[(E)-hex-1-enyl]oct-2-enoate (7c): Colorless
1
3
C NMR (100 MHz, CDCl ): d=14.1, 14.2, 14.4, 17.4, 30.8,
ꢀ1
3
oil. IR (neat): n=1718, 1647, 1628, 1605, 1254 cm ;
3
1
2.4, 32.6, 34.5, 61.3, 61.4, 77.8, 81.0, 126.7, 128.5, 128.6,
28.7, 128.8, 128.9, 129.5, 140.0, 140.3, 144.9, 146.9, 164.8.
1
H NMR (400 MHz, CDCl ): d=0.86–0.94 (m, 6H), 1.31 (t,
3
3
7
6
H, J=7.3 Hz), 1.27–1.51 (m, 10H), 2.16 (q, 2H, J=
.3 Hz), 2.28 (q, 2H, J=7.3 Hz), 4.21 (q, 2H, J=7.3 Hz),
.01 (dt, 1H, J=6.4, 16.2 Hz), 6.13 (d, 1H, J=15.8 Hz), 6.59
Typical Procedure for the Synthesis of Compounds 7
13
(
t, 1H, J=7.3 Hz); C NMR (100 MHz, CDCl ): d=14.1,
3
To a stirred solution of the respective nitroalkane 1
14.2, 14.5, 22.4, 22.7, 28.8, 28.9, 31.6, 31.8, 33.5, 60.7, 122.2,
130.6, 136.5, 141.9, 167.9; EI-MS (70 eV): m/z=252 (M ),
+
(
1.1 mmol) and the b-nitroacrylate 2 (1 mmol) in ethyl ace-
tate (4 mL), the carbonate on polymer support (715 mg,
209, 181, 163, 139, 109, 93, 79 (100), 67, 55, 41; anal. calcd.
1490
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1485 – 1492

Michael Reaction of Nitroalkanes with b-Nitroacrylates under a Solid Promoter
for C H O (252.39): C 76.14, H 11.18; found: C 76.36, H Typical Procedure for the Synthesis of Valproic Acid
16
28
2
1
1.31.
(
9)
(
Z)-Ethyl 2-[(E)-hex-1-enyl]oct-2-enoate (7c’): Colorless
ꢀ
1
To a solution of the diastereomeric mixture of the diunsatu-
rated acid 8 (1.36 mmol) in EtOAc (14 mL), 10% Pd/C
oil. IR (neat): n=1716, 1649, 1625, 1601, 1236 cm ;
1
H NMR (400 MHz, CDCl ): d=0.85–0.92 (m, 6H), 1.33 (t,
3
(
200 mg) was added. The suspension was hydrogenated (4
3
6
5
H, J=7.3 Hz), 1.23–1.48 (m, 10H), 2.08 (q, 2H, J=
.8 Hz), 2.20 (q, 2H, J=7.3 Hz), 4.27 (q, 2H, J=7.3 Hz),
.67 (dt, 1H, J=6.8, 16.2 Hz), 5.74 (t, 1H, J=7.7 Hz) 6.00
atm) under stirring at room temperature for 23 h. Then the
catalyst was filtered off through a pad of celite washing with
EtOAc. Finally, after evaporation of the solvent, the pure
product, 2-propylpentanoic acid (9) was obtained; yield:
88%; colorless oil. IR (neat): n=3380–2375 (bs), 1707,
1
7
1
2
1
3
(
d, 1H, J=16.2 Hz); C NMR (100 MHz, CDCl ): d=14.2,
3
1
1
2
4.3, 14.5, 22.5, 22.7, 29.2, 29.8, 31.5, 31.7, 32.8, 60.7, 128.0,
32.0, 133.8, 136.4, 168.5; EI-MS (70 eV): m/z=252 (M ),
+
ꢀ
1
1
254 cm ; H NMR (400 MHz, CDCl ): d=0.91 (t, 6H, J=
.3 Hz), 1.26–1.51 (m, 6H), 1.56–1.68 (m, 2H), 2.33–2.42 (m,
H), 11.85 (bs, 1H); C NMR (100 MHz, CDCl ): d=14.2,
0.8, 34.6, 45.4, 183.5. EI-MS (70 eV) m/z: 115, 102, 73
09, 181, 163, 139, 109, 93, 79 (100), 67, 55, 41, 29; anal.
3
calcd. for C H O (252.39): C 76.14, H 11.18; found: C
16
28
2
1
3
7
5.97, H 10.98.
Diastereomeric mixture of compounds (E)-ethyl 5-
phenyl-2-[(E)-3-phenylprop-1-enyl]pent-2-enoate (7d) and
Z)-ethyl 5-phenyl-2-[(E)-3-phenylprop-1-enyl]pent-2-
enoate (7d’): Colorless oil. IR (neat): n=3062, 3027, 1715,
3
(
100), 55, 41, 29; anal. calcd. for C H O (144.21): C 66.63,
8 16 2
H 11.18; found: C 66.75, H 11.27.
(
ꢀ
1
1
1
1
3
4
602, 1239, 1178 cm ; H NMR (400 MHz, CDCl ): d=
3
.25–1.35 (m,3H), 2.55–2.64 (m, 2H), 2.71–2.79 (m, 2H),
.44 (d, 0.5H, J=6.8 Hz), 3.49 (d, 1.5H, J=5.1 Hz), 4.17–
.29 (m, 2H), 5.82–5.93 (m, 0.5H), 6.02–6.23 (m, 1.75), 6.70
Acknowledgements
1
3
(
t, 0.75H, J=7.7 Hz), 7.11–7.36 (m, 10H);
C NMR
Financial support from the University of Camerino and
MIUR Italy (National Project “Sintesi organiche ecososteni-
bili mediate da nuovi sistemi catalitici”) are gratefully ac-
knowledged.
(100 MHz, CDCl ): d=14.4, 14.5, 30.9, 31.6, 35.3, 35.6, 39.3,
3
4
1
1
0.1, 60.8, 60.9, 123.5, 126.1, 126.2, 126.3, 128.5, 128.6, 128.7,
28.8, 128.9, 129.2, 130.5, 130.9, 133.4, 133.7, 134.9, 136.4,
40.0, 140.1, 141.2, 141.3, 141.4, 167.5, 168.0.
References
Typical Procedure for the Synthesis of Compounds 8
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4
h and concentrated to 1/3 of the volume. Water (100 mL)
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1
HCl, then extracted with EtOAc (5ꢂ20 mL), washed with
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2
4
solvent was removed under reduced pressure and the crude
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ꢀ
1
1
1
7
6
191 cm ; H NMR (400 MHz, CDCl ): d=1.08 (t, 3H, J=
3
.7 Hz), 1.84 (d, 3H, J=5.1 Hz), 2.28–2.38 (m, 2H), 6.02–
.16 (m, 2H), 6.79 (t, 1H, J=7.7 Hz), 12.10 (bs, 1H);
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3
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+
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1
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8
12
2
(
140.18): C 68.54, H 8.63; found: C 68.71, H 8.78.
Z)-2-[(E)-Prop-1-enyl]pent-2-enoic acid (8a’): Colorless
oil. IR (neat): n= 3513–2352 (bs), 1695, 1616, 1252,
(
ꢀ
1
1
1
7
5
196 cm ; H NMR (400 MHz, CDCl ): d=1.05 (t, 3H, J=
3
.7 Hz), 1.77 (dd, 3H, J=1.3, 6.4 Hz), 2.37–2.46 (m, 2H),
.87 (dq, 1H, J=6.4, 15.8 Hz), 5.99 (t, 1H, J=7.7 Hz), 6.08
1
3
(
d, 1H, J=15.8 Hz), 11.69 (bs, 1H); C NMR (100 MHz,
CDCl ): d=14.0, 18.6, 23.4, 127.2, 128.6, 131.0, 142.4, 173.9;
3
+
EI-MS (70 eV): m/z=140 (M , 100), 125, 111, 95, 79, 67, 55,
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63, 3456–3459.
3
9; anal. calcd. for C H O (140.18): C 68.54, H 8.63;
8 12 2
found: C 68.73, H 8.77.
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ꢀ
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