Mechanosynthesis of γ-nitro dicarbonyl compounds via CaCl 2-catalyzed Michael addition

Article abstract of DOI:10.1016/j.tet.2013.06.089

An efficient strategy for the mechanosynthesis of γ-nitro dicarbonyl esters has been developed. A CaCl₂-catalyzed Michael reaction, conducted at room temperature, afforded nitroalkenes from malonates in a short reaction time and in high yields.

Full text of DOI:10.1016/j.tet.2013.06.089

Tetrahedron 69 (2013) 7320e7324
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Mechanosynthesis of
g
-nitro dicarbonyl compounds via
CaCl2-catalyzed Michael addition
,
,
b
,
a
Chunman Jia a b, Da Chen a, Chunyan Zhang a, Qi Zhang a , Bennan Cao ,
*
Zhendong Zhao a
a Hainan Provincial Key Laboratory of Fine Chemials, Hainan Univerity, Haikou 570228, People’s Republic of China
b Key Study Center of the National Ministry of Education for Tropical Resources Utilization, Hainan University, Haikou 570228,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient strategy for the mechanosynthesis of g-nitro dicarbonyl esters has been developed. A CaCl2-
Received 13 February 2013
Received in revised form 12 June 2013
Accepted 21 June 2013
catalyzed Michael reaction, conducted at room temperature, afforded nitroalkenes from malonates in
a short reaction time and in high yields. In most cases, polymerized side-reactions are eliminated or
minimized.
Available online 2 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Mechanosynthesis
Ball-milling
g-Nitro carbonyl esters
Michael addition
1. Introduction
of 1,3-dicarbonyl compound was required for g-nitro dicarbonyl
compound formation. Notably, the 1,3-dicarbonyl compounds
readily dissolve in nitroalkenes and the reactions were performed
in the liquid phase, with the excess 1,3-dicarbonyl compound
remaining unreacted. When we conducted the reaction using
1.0 equiv of 1,3-dicarbonyl compound, the yield of desired product
was substantially reduced, due, no doubt, to the presence of
a strong electron-withdrawing group. This fact, in combination
with high reagent concentration, appears to allow for facile poly-
merization of the nitroalkene under basic condition.26 It therefore
occurred to us to determine whether these reactions can be
successfully performed with a 1:1 ratio of nitroalkene and 1,3-
dicarbonyl compound equivalents using mechanosynthesis
employing the Michael addition reaction as our model. The results
show that the choice of catalyst and base dramatically affects the
reaction outcome.
Over the past few decades, mechanosynthesis has evolved into
a powerful and environmentally friendly methodology that brings
about a reduction of toxic waste products. In the field of inorganic
chemistry, this technique is typicallyapplied to produce alloys,1 metal
oxides,2 and other inorganic materials.3e5 In addition, mechanosyn-
thesis has found numerous applications in organic chemistry6 in-
cluding CeC bond formations,7e13 amine condensations,14 syntheses
of heterocycles,15e18 and fullerene modifications.19e21
Mechanosynthesis has been applied to the Michael addition
reaction, one of the most useful methods for the mild formation of
CeC bonds. In 2004, Wang and co-workers22,23 reported the first
mechanochemical Michael reaction of 1,3-dicarbonyl compounds
for the preparation of a,b-unsaturated ketones. Furthermore, this
group has presented the reaction of aldehydes with 1,3-dicarbonyl
compounds promoted by iodine and DMAP under mechanical ball-
milling conditions.24 More recently, Xu et al. achieved the first
successful asymmetric Michael reaction of esters to nitroalkenes
under ball-milling conditions.25 In the latter example, the reactions
were carried out using a nitroalkene substrate, an excess of 1,3-
dicarbonyl compound (2.0 equiv), and a chiral catalyst. The excess
2. Results and discussion
At the outset of our studies (Scheme 1), the ball-milling reaction
of nitroalkene (2a) with diethyl malonate (1a) was investigated in
the presence of various bases (Table 1, entries 1e7). Varying the
substrate loading, the reaction time and the ball-milling frequency
resulted in a low isolated yield (30e40%) of the desired product
(3a)da consequence of polymerization of 2a and subsequent for-
mation of black by-products.
* Corresponding author. Tel./fax: þ86 (0)898 6625 7271; e-mail address: hnfi-
nechem@163.com (Q. Zhang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.089

C. Jia et al. / Tetrahedron 69 (2013) 7320e7324
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Table 2
Synthesis of substituted g-nitro diethyl esters
Scheme 1. Mechanosynthesis of diethyl 2-(2-nitro-1-phenylethyl)-malonate.
Entrya
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
p-FePh
3b
3c
3d
3e
3f
3g
3h
3i
86
77
95
96
88
86
88
82
71
94
88
87
51
45
45
52
80
95
86
82
10
Table 1
Optimization studies of test reaction
p-NO2ePh
p-MeePh
p-OMeePh
p-BrePh
o-FePh
o-ClePh
Entrya Base
Catalyst
Equiv ratiob (1a/2a/base/cat.) Yielde (%)
1c
Et3N
DABCO
DBU
DMAP
Na2HPO4
NaHCO3
K2CO3
1.0:1.1:1.0:0
1.0:1.1:1.0:0
1.0:1.1:1.0:0
1.0:1.1:1.0:0
1.0:1.1:1.0:0
1.0:1.1:1.0:0
1.0:1.1:1.0:0
1.0:1.1:0:1.0
1:1.1:1.0:1.0
1:1.1:1.0:1.0
1:1.1:1.0:1.0
1:1.1:1.0:1.0
1:1.1:1.0:1.0
1.0:1.1:1.0:1.0
1.0:1.1:1.0:1.0
40
36
32
35
35
28
30
0
40
35
42
48
34
92
82
87
48
46
53
81
76
84
2c
3c
o-BrePh
4c
9
o-NO2ePh
o-MeOePh
m-MeePh
m-MeOePh
m-ClePh
m-FePh
m-NO2ePh
m-BrePh
2,4-Cl,ClePh
6-F-2-ClePh
2-Naphthyl
2-Furanyl
Bn
3j
3k
3l
5c
10
11
12
13
14
15
16
17
18
19
20
21
6c
7c
3m
3n
3o
3p
3q
3r
3s
3t
8c
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
CaBr2
9c
DABCO
K2CO3
DBU
DMAP
NaOH
Et3N
Et3N
Et3N
Et3N
Et3N
10c
11c
12c
13c
14c
15c
16c
17c
18c
19c
20c
21c
22d
3u
3v
Ca(NO3)2$4H2O 1.0:1.1:1.0:1.0
Ca(OAc)2
MgSO4
1.0:1.1:1.0:1.0
1.0:1.1:1.0:1.0
a
All reactions were performed in a Retsch GmbH MM400 Mixer Mill at room
temperature for 30 min. The amounts of 1a, 2b-2v, CaCl2, and Et3N were 0.33 mmol,
0.30 mmol, 0.30 mmol and 0.30 mmol, respectively.
Et3N
Et3N
Et3N
Et3N
Mn(OAc)2$4H2O 1.0:1.1:1.0:1.0
CaCl2
CaCl2
CaCl2
1.0:1.1:1.0:0.5
1.0:1.1:0.5:1.0
1.0:1.1:1.0:1.0
b
Isolated yields after column chromatography.
a
All reactions were performed in Retsch GmbH MM400 Mixer Mill at room
temperature for 30 min.
In order to further demonstrate the usefulness of this trans-
formation, we also investigated other 1,3-dicarbonyl compounds as
nucleophiles under the same conditions (Table 3). We found that
nitroalkenes reacted smoothly with either methyl malonate or
isopropyl malonate, affording the desired products in high yields
b
1.0 equiv refers to 0.30 mmol.
Frequency of ball-milling of 20 Hz.
Frequency of ball-milling of 30 Hz.
c
d
e
Isolated yields after column chromatography.
(Table 3, entries 1 and 2). Reactions involving
afforded the desired products 3y and 3z in 86% and 79% yields,
respectively (Table 3, entries 3 and 4). However, -diketones, such
as 1-phenylbutane-1,3-dione, could not be transformed to the
corresponding adducts under the same reaction conditions.
b-ketoesters also,
Encouraged by Kobayashi’s recent work,27 we introduced metal
salts into the reaction mixture, which can potentially serve as
reaction catalysts. Several calcium salts (CaCl2, CaBr2, Ca(N-
O3)2$4H2O), together with Et3N as the base, afforded the desired
products (Table 1, entries 14e16) after 30 min. Other bases together
with CaCl2, such as DABCO, K2CO3, DBU, DMAP, and NaOH,
also afforded the desired products, albeit in low yields (Table 1,
entries 9e13). Other metal salts, such as Ca(OAc)2, MgSO4, and
Mn(OAc)2$4H2O, were ineffective as catalysts (Table 1, entries
17e19). Because CaCl2 is very affordable and possesses low toxicity
compared to the other calcium salts, it was selected as the best
catalyst for this reaction. No product formation was observed
without base, demonstrating the importance of Et3N in this re-
action (Table 1, entry 8). Further optimization of the reaction pa-
rameters, such as the frequency of ball-milling (Table 1, entry 22),
catalyst loading (Table 1, entry 20), and base loading (Table 1, entry
21) led to the optimal reaction conditions (Table 1, entry 14), which
consist of a ball-milling frequency of 20 Hz and a substrate ratio
(1a/2a/Et3N/CaCl2) of 1:1.1:1.0:1.0 at room temperature.
After achieving optimal reaction conditions, several substituted
nitroalkenes bearing aryl and heteroaryl groups were tested (Table
2). Most of the nitrostyrene derivatives with different substitution
patterns on the aromatic ring furnished the corresponding prod-
ucts in high yields (3be3m, Table 2, entries 1e12, 17, and 18). In
the case of meta-substituted nitrostyrenes bearing electron-
withdrawing groups, moderate yields were obtained (3ne3q,
Table 2, entries 13e16). The nitroalkene bearing a 2-furanyl het-
erocycle was also well tolerated (3u, Table 2, entry 20).
b
Table 3
Synthesis of other substituted g-nitro dicarbonyl esters
Entrya
R1
R2
Product
Yieldb (%)
1
2
3
4
OMe
OiPr
Me
OMe
OiPr
OEt
3w
3x
3y
3z
87
95
86
79
Ph
OEt
a
All reactions were performed in a Retsch GmbH MM400 Mixer Mill at room
temperature for 30 min.
b
Isolated yields after column chromatography.
Based on our experimental results, as well as those reported by
Kobayashi,26 a plausible mechanism is outlined in Scheme 2. The
catalytic cycle is initiated by the CaCl2-aided deprotonation of the
a
-position of malonate 1a to give calcium enolate 1a0. The activated
species then undergoes nucleophilic addition to nitroalkene 2a to

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C. Jia et al. / Tetrahedron 69 (2013) 7320e7324
4.2.1. Diethyl 2-(2-nitro-1-phenylethyl)malonate (3a).28 1H NMR
(400 MHz, CDCl3)
d
7.26e7.14 (m, 5H), 4.85 (dd, J¼13.1, 4.9 Hz, 1H),
4.79 (dd, J¼13.1, 9.1 Hz, 1H), 4.22e4.09 (m, 3H), 3.93 (q, J¼7.1 Hz,
2H), 3.75 (d, J¼9.3 Hz, 1H), 1.19 (t, J¼7.1 Hz, 3H), 0.97 (t, J¼7.1 Hz,
3H); 13C NMR (101 MHz)
d 167.39, 166.75, 136.19, 128.86, 128.27,
127.95, 77.58, 62.07, 61.80, 54.93, 42.90, 13.88, 13.65; HRMS (ESI)
calcd for C15H19NO6 [MþNa]þ 332.1110, found: 332.1085.
4.2.2. Diethyl 2-(1-(4-fluorophenyl)-2-nitroethyl)malonate (3b).28
1H NMR (400 MHz, CDCl3)
d 7.26e7.20 (m, 2H), 7.03e6.96 (m, 2H),
4.90 (dd, J¼13.1, 4.8 Hz, 1H), 4.81 (dd, J¼13.1, 9.3 Hz, 1H), 4.27e4.16
(m, 3H), 4.02 (q, J¼7.1 Hz, 2H), 3.77 (d, J¼9.3 Hz, 1H), 1.26 (t,
J¼7.2 Hz, 3H), 1.07 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz)
d 167.18,
166.58, 163.62, 161.16, 131.89, 131.85, 129.73, 129.65, 115.91, 115.70,
77.52, 62.11, 61.85, 54.82, 42.16, 13.83, 13.65; HRMS (ESI) calcd for
C
15H18FNO6 [MþNa]þ 350.1016, found: 350.0971.
4.2.3. Diethyl 2-(2-nitro-1-(4-nitrophenyl)ethyl)malonate (3c). 1H
NMR (400 MHz, CDCl3)
d
8.23 (d, J¼8.6 Hz, 2H), 7.50 (d, J¼8.7 Hz,
2H), 5.00 (dd, J¼13.5, 4.9 Hz, 1H), 4.94 (dd, J¼13.5, 9.2 Hz, 1H),
4.43e4.22 (m, 3H), 4.09 (q, J¼7.1 Hz, 2H), 3.86 (d, J¼9.0 Hz, 1H), 1.30
(t, J¼7.1 Hz, 3H), 1.14 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
Scheme 2. Proposed mechanism for the preparation of diethyl 2-(2-nitro-1-
phenylethyl)malonate under ball-milling conditions.
d
166.81, 166.26, 147.78, 143.64, 129.16, 124.02, 76.80, 62.43, 62.22,
54.34, 42.46, 13.87, 13.72; HRMS (ESI) calcd for C15H18N2O8
give adduct 2a0. Subsequent protonation by Et3NþH affords the
corresponding Michael product (3a) and regenerates the catalyst.
Thus, the use of a base with sufficient Brønsted basicity, such as
Et3N, and a catalyst with suitable Lewis acidity, such as CaCl2, is
vital for this reaction to occur efficiently. Although this reaction is
not totally ‘solvent free’, the reduced amount of required solvent
does result in a positive environmental impact.
[MþNa]þ 377.0961, found: 377.0940.
4.2.4. Diethyl 2-(2-nitro-1-(p-tolyl)ethyl)malonate (3d).29 1H NMR
(400 MHz, CDCl3)
d
7.10 (s, 4H), 4.89 (dd, J¼13.0, 5.0 Hz, 1H), 4.82
(dd, J¼13.0, 9.1 Hz, 1H), 4.27e4.13 (m, 3H), 4.01 (q, J¼7.1 Hz, 2H),
3.79 (d, J¼9.3 Hz, 1H), 2.29 (s, 3H), 1.25 (t, J¼7.1 Hz, 3H), 1.06 (t,
J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 167.41, 166.74, 137.96,
133.02, 129.48, 127.71, 77.66, 61.97, 61.72, 54.95, 42.51, 20.92, 13.84,
13.63; HRMS (ESI) calcd for C16H21NO6 [MþNa]þ 346.1267, found:
346.1268.
3. Conclusion
In summary, we have demonstrated a mechanosynthesis-aided
Michael addition catalyzed by CaCl2 for the preparation of g-nitro
4.2.5. Diethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl)malonate (3e).29
dicarbonyl compounds. The main advantages associated with this
protocol are the mild conditions and the short reaction time,
resulting in satisfactory yields. Further applications of mechano-
chemistry are currently under investigation in our laboratory.
1H NMR (400 MHz, CDCl3)
d 7.20e7.13 (m, 2H), 6.89e6.79 (m, 2H),
4.90 (dd, J¼12.9, 4.9 Hz, 1H), 4.82 (dd, J¼12.9, 9.2 Hz, 1H), 4.29e4.13
(m, 3H), 4.03 (q, J¼7.1 Hz, 2H), 3.80 (s, 1H), 3.78 (s, 3H), 1.28 (t,
J¼7.1 Hz, 3H), 1.08 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
167.42, 166.77, 159.35, 129.04, 127.94, 114.20, 77.80, 62.00, 61.74,
4. Experimental section
4.1. General
55.12, 55.03, 42.22, 13.87, 13.69; HRMS (ESI) calcd for C16H21NO7
[MþNa]þ 362.1216, found: 362.1192.
4.2.6. Diethyl 2-(1-(4-bromophenyl)-2-nitroethyl)malonate (3f). 1H
Reagents and solvents were obtained from commercial sup-
pliers and were used without further purification. 1H, 13C were
recorded on Bruker AV 400 instruments at 400 MHz (1H NMR) and
101 MHz (13C NMR). Chemical shifts were reported in parts per
million (ppm) down field from internal Me4Si. HRMS were recor-
ded on a Shimadzu LCMS-IT-TOF spectrometer with the ESI
resource.
NMR (400 MHz, CDCl3)
d
7.53e7.40 (m, 2H), 7.16 (dd, J¼6.4, 4.6 Hz,
2H), 4.92 (dd, J¼13.2, 4.8 Hz, 1H), 4.85 (dd, J¼13.2, 9.3 Hz, 1H),
4.33e4.16 (m, 3H), 4.06 (q, J¼7.1 Hz, 2H), 3.79 (d, J¼9.2 Hz, 1H), 1.28
(t, J¼7.2 Hz, 3H), 1.11 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
167.13, 166.53, 135.23, 132.04, 129.67, 122.38, 77.24, 62.20, 61.97,
54.62, 42.32, 13.87, 13.69; HRMS (ESI) calcd for C15H18BrNO6
[MþNa]þ 410.0215, found: 410.0169.
4.2. Typical procedure for the preparation of
carbonyl ester
g
-nitro di-
4.2.7. Diethyl 2-(1-(2-fluorophenyl)-2-nitroethyl)malonate (3g). 1H
NMR (400 MHz, CDCl3)
d
7.36e7.27 (m, 2H), 7.13 (dt, J¼11.0, 8.0 Hz,
2H), 4.98 (d, J¼7.1 Hz, 2H), 4.55e4.45 (m,1H), 4.29 (qd, J¼7.1, 3.9 Hz,
2H), 4.10e3.98 (m, 3H), 1.33 (t, J¼7.1 Hz, 3H), 1.10 (t, J¼7.1 Hz, 3H);
A stainless-steel jar (10 mL) was charged with nitrostyrene 2a
(0.33 mmol), diethyl malonate 1a (0.30 mmol), Et3N (0.30 mmol),
CaCl2 (0.30 mmol), and a stainless-steel ball (D¼10 mm) succes-
sively. Stirring was started in a grinding bowl using the ball mill
(Retsch MM400 Mixer Mill, Retsch GmbH, Haan, Germany) with
a vibration rate of 20 Hz for 30 min. The crude product was washed
off the reaction vessel with CH2Cl2, and the combined organic
fractions were filtered and concentrated in vacuo. Purification by
flash chromatography on silica gel (EtOAc/hexanes¼1:20) afforded
the pure product 3a.
13C NMR (101 MHz, CDCl3)
d 167.26, 166.65, 162.21, 159.75, 130.65,
130.15, 124.50, 124.46, 123.00, 116.12, 115.90, 76.23, 62.18, 61.85,
53.21, 38.56, 13.89, 13.63; HRMS (ESI) calcd for C15H18FNO6
[MþNa]þ 350.1016, found: 350.0980.
4.2.8. Diethyl 2-(1-(2-chlorophenyl)-2-nitroethyl)malonate (3h).29
1H NMR (400 MHz, CDCl3)
d 7.47e7.42 (m, 1H), 7.31e7.25 (m, 3H),
5.14 (dd, J¼13.5, 8.5 Hz, 1H), 4.98 (dd, J¼13.5, 4.4 Hz, 1H), 4.78 (td,
J¼8.6, 4.4 Hz, 1H), 4.25 (qd, J¼7.1, 3.6 Hz, 2H), 4.11 (dd, J¼14.2,

C. Jia et al. / Tetrahedron 69 (2013) 7320e7324
7323
7.3 Hz, 3H), 1.28 (t, J¼7.1 Hz, 3H), 1.15 (t, J¼7.1 Hz, 3H); 13C NMR
166.54, 163.96, 161.50, 138.74, 138.67, 130.43, 123.65, 115.43, 115.27,
115.22, 115.04, 77.22, 62.19, 61.96, 54.67, 42.51, 29.61, 13.85, 13.66;
HRMS (ESI) calcd for C15H18FNO6 [MþNa]þ 350.1016, found:
350.0991.
(101 MHz, CDCl3)
d 167.33, 166.74, 134.07, 133.70, 130.39, 129.39,
128.83, 127.17, 75.63, 62.06, 61.95, 53.07, 39.37, 13.86, 13.67; HRMS
(ESI) calcd for C15H18ClNO6 [MþNa]þ 366.0720, found: 366.0677.
4.2.9. Diethyl 2-(1-(2-bromophenyl)-2-nitroethyl)malonate (3i). 1H
4.2.16. Diethyl 2-(2-nitro-1-(3-nitrophenyl)ethyl)malonate (3p). 1H
NMR (400 MHz, CDCl3)
d
7.64 (dd, J¼8.0, 0.8 Hz, 1H), 7.32e7.16 (m,
NMR (400 MHz, CDCl3)
d
8.20 (d, J¼6.4 Hz, 2H), 7.60 (dt, J¼13.0,
3H), 5.15 (dd, J¼13.6, 8.3 Hz, 1H), 4.98 (dd, J¼13.6, 4.4 Hz, 1H), 4.79
(td, J¼8.3, 4.4 Hz, 1H), 4.29e4.18 (m, 2H), 4.13 (dt, J¼7.1, 5.1 Hz, 3H),
1.27 (t, J¼7.1 Hz, 3H), 1.16 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz,
7.9 Hz, 2H), 5.02 (dd, J¼13.6, 4.8 Hz, 1H), 4.95 (dd, J¼13.5, 9.4 Hz,
1H), 4.46e4.20 (m, 3H), 4.09 (q, J¼7.1 Hz, 2H), 3.87 (d, J¼8.9 Hz,
1H), 1.33e1.26 (m, 3H), 1.13 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3)
d
167.31, 166.76, 135.36, 133.76, 129.64, 128.45, 127.80,
CDCl3) d 166.85, 166.31, 148.38, 138.52, 134.49, 129.94, 123.37,
124.75, 75.67, 62.04, 62.00, 53.22, 41.44, 13.87, 13.71; LRMS (ESI)
122.95, 76.86, 62.44, 62.20, 54.42, 42.37, 29.60, 13.86, 13.70;
HRMS (ESI) calcd for C15H18N2O8 [MþNa]þ 377.0961, found:
377.0931.
calcd for C15H18BrNO6 [MþNa]þ 410.0215, found: 410.0189.
4.2.10. Diethyl 2-(2-nitro-1-(2-nitrophenyl)ethyl)malonate (3j). 1H
NMR (400 MHz, CDCl3)
d
7.98e7.95 (m, 1H), 7.63 (t, J¼7.6 Hz, 1H),
4.2.17. Diethyl 2-(1-(3-bromophenyl)-2-nitroethyl)malonate (3q).
7.49 (dd, J¼12.1, 7.9 Hz, 2H), 5.19 (dd, J¼13.8, 7.9 Hz, 1H), 5.09 (dd,
J¼13.8, 4.3 Hz, 1H), 4.79 (td, J¼8.1, 4.3 Hz, 1H), 4.30e4.20 (m, 3H),
4.14e4.07 (m, 2H), 1.29 (t, J¼7.1 Hz, 3H), 1.14 (t, J¼7.1 Hz, 3H); 13C
1H NMR (400 MHz, CDCl3)
d
7.48e7.41 (m, 2H), 7.23 (dd, J¼7.8,
5.8 Hz, 2H), 4.95 (dd, J¼13.4, 4.8 Hz, 1H), 4.87 (dd, J¼13.4, 9.2 Hz,
1H), 4.30e4.19 (m, 3H), 4.08 (q, J¼7.1 Hz, 2H), 3.81 (d, J¼9.0 Hz, 1H),
1.29 (t, J¼7.1 Hz, 3H), 1.12 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz,
NMR (101 MHz, CDCl3)
d 167.22, 166.57, 149.91, 133.22, 131.28,
129.20, 125.37, 76.20, 62.26, 62.18, 53.60, 37.65, 33.77, 13.86, 13.65;
HRMS (ESI) calcd for C15H18N2O8 [MþNa]þ 377.0961, found:
377.0946.
CDCl3) d 167.11, 166.50, 138.54, 131.48, 131.14, 130.40, 126.64, 122.81,
77.09, 62.22, 62.01, 54.66, 42.41, 13.88, 13.69; HRMS (ESI) calcd for
C
15H18BrNO6 [MþNa]þ 410.0215, found: 410.0190.
4.2.11. Diethyl 2-(1-(2-methoxyphenyl)-2-nitroethyl)malonate (3k).
4.2.18. Diethyl 2-(1-(2,4-dichlorophenyl)-2-nitroethyl)malonate (3r).
1H NMR (400 MHz, CDCl3)
7.50 (s, 1H), 7.34e7.26 (m, 2H), 5.14 (dd,
1H NMR (400 MHz, CDCl3)
d
7.24 (td, J¼8.2, 1.7 Hz, 1H), 7.14 (dd,
d
J¼7.7, 1.5 Hz, 1H), 6.90e6.81 (m, 2H), 5.01 (dd, J¼12.9, 9.1 Hz, 1H),
4.86 (dd, J¼12.9, 4.5 Hz, 1H), 4.37 (td, J¼9.6, 4.5 Hz, 1H), 4.27e4.10
(m, 3H), 3.94 (q, J¼7.1 Hz, 2H), 3.86 (s, 3H),1.25 (t, J¼7.1 Hz, 3H),1.00
J¼13.6, 8.6 Hz, 1H), 4.99 (dd, J¼13.6, 4.3 Hz, 1H), 4.79e4.72 (m, 1H),
4.33e4.22 (m, 2H), 4.16 (q, J¼7.1 Hz, 2H), 4.10 (d, J¼8.7 Hz, 1H), 1.32
(t, J¼7.1 Hz, 3H), 1.21 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
(t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
167.81, 167.07, 157.31,
d 167.16, 166.59, 134.86, 134.76, 132.41, 130.23, 129.71, 127.53, 75.45,
130.75, 129.49, 123.65, 120.66, 110.97, 76.09, 61.83, 61.43, 55.29,
52.63, 40.36, 13.86, 13.61; LRMS (ESI) calcd for C16H21NO7 [MþNa]þ
362.1216, found: 362.1197.
62.22, 62.14, 52.94, 38.94, 13.89, 13.74; HRMS (ESI) calcd for
C
15H17Cl2NO6 [MþNa]þ 400.0331, found: 400.0287.
4.2.19. Diethyl 2-(1-(2-chloro-6-fluorophenyl)-2-nitroethyl)-malo-
nate (3s). 1H NMR (400 MHz, CDCl3)
7.30e7.20 (m, 2H), 7.07e6.97
4.2.12. Diethyl 2-(2-nitro-1-(m-tolyl)ethyl)malonate (3l). 1H NMR
d
(400 MHz, CDCl3)
d
7.24 (dd, J¼22.1, 14.2 Hz, 1H), 7.08 (dd, J¼20.7,
(m, 1H), 5.10e4.88 (m, 3H), 4.36e4.23 (m, 2H), 4.13e3.91 (m, 3H),
1.32 (t, J¼7.1 Hz, 3H), 1.06 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz,
7.1 Hz, 3H), 4.94 (dd, J¼13.1, 5.0 Hz,1H), 4.88 (dd, J¼13.1, 9.0 Hz,1H),
4.31e4.16 (m, 3H), 4.05 (q, J¼7.1 Hz, 2H), 3.83 (d, J¼9.2 Hz, 1H), 2.34
(s, 3H), 1.29 (t, J¼7.1 Hz, 3H), 1.09 (t, J¼7.1 Hz, 3H); 13C NMR
CDCl3) d 167.10,166.22,130.24,130.14,126.23,122.34,122.18,114.93,
114.69, 75.61, 62.30, 61.85, 52.38, 13.87, 13.53; HRMS (ESI) calcd for
(101 MHz, CDCl3)
d
167.44, 166.78, 138.48, 136.11, 128.99, 128.69,
C
15H17ClFNO6 [MþNa]þ 384.0626, found: 384.0601.
124.80, 77.57, 62.01, 61.75, 54.96, 42.81, 21.27, 13.87, 13.64; HRMS
(ESI) calcd for C16H21NO6 [MþNa]þ 346.1267, found: 346.1263.
4.2.20. Diethyl 2-(1-(naphthalen-2-yl)-2-nitroethyl)malonate (3t).
1H NMR (400 MHz, CDCl3)
d
8.19 (d, J¼8.6 Hz, 1H), 7.86 (d, J¼7.5 Hz,
4.2.13. Diethyl 2-(1-(3-methoxyphenyl)-2-nitroethyl)malonate (3m).
1H), 7.79 (d, J¼9.3 Hz, 1H), 7.61 (ddd, J¼8.4, 6.9, 1.3 Hz, 1H), 7.52 (t,
J¼7.1 Hz, 1H), 7.45e7.38 (m, 2H), 5.25e5.18 (m, 1H), 5.14 (dd, J¼13.1,
8.1 Hz, 1H), 5.05 (dd, J¼13.1, 4.8 Hz, 1H), 4.25e4.14 (m, 2H), 4.07 (d,
J¼8.2 Hz, 1H), 3.99e3.91 (m, 2H), 1.22 (t, J¼7.1 Hz, 3H), 0.94 (t,
1H NMR (400 MHz, CDCl3)
d
7.26 (dd, J¼15.1, 7.2 Hz, 1H), 6.85e6.78
(m, 3H), 4.93 (dd, J¼13.1, 5.1 Hz, 1H), 4.87 (dd, J¼13.1, 8.9 Hz, 1H),
4.31e4.17 (m, 3H), 4.06 (q, J¼7.1 Hz, 2H), 3.83 (d, J¼9.2 Hz, 1H), 1.29
(t, J¼7.2 Hz, 3H), 1.10 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
J¼7.1 Hz, 3H); 13C NMR (101 MHz)
d 167.53, 166.88, 134.04, 132.32,
d
167.38, 166.73, 159.77, 137.74, 129.88, 119.94, 113.96, 113.53, 77.48,
131.02, 129.06, 128.82, 126.86, 125.95, 124.97, 122.26, 77.09, 61.97,
61.84, 54.70, 13.81, 13.49; HRMS (ESI) calcd for C19H21NO6 [MþNa]þ
382.1267, found: 382.1256.
62.05, 61.82, 55.14, 54.88, 42.84, 13.87, 13.68; HRMS (ESI) calcd for
C
16H21NO7 [MþNa]þ 362.1216, found: 362.1216.
4.2.14. Diethyl 2-(1-(3-chlorophenyl)-2-nitroethyl)malonate (3n).
1H NMR (400 MHz, CDCl3)
4.2.21. Diethyl 2-(1-(furan-2-yl)-2-nitroethyl)malonate (3u).29 1H
d
7.29 (d, J¼5.5 Hz, 3H), H), 7.20e7.15 (m,
NMR (400 MHz, CDCl3)
d
7.37 (d, J¼1.4 Hz, 1H), 6.35e6.28 (m, 1H),
1H), 4.95 (dd, J¼13.3, 4.7 Hz, 1H), 4.87 (dd, J¼13.3, 9.3 Hz, 1H),
4.30e4.20 (m, 3H), 4.07 (q, J¼7.1 Hz, 2H), 3.82 (d, J¼9.1 Hz, 1H), 1.28
(d, J¼7.1 Hz, 3H), 1.11 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
6.24 (d, J¼3.3 Hz,1H), 4.98e4.86 (m, 2H), 4.40 (td, J¼7.9, 5.3 Hz,1H),
4.24 (q, J¼7.1 Hz, 2H), 4.17 (q, J¼7.1 Hz, 2H), 3.92 (d, J¼7.9 Hz, 1H),
1.27 (d, J¼7.1 Hz, 3H), 1.22 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz,
d
167.13, 166.53, 138.30, 134.66, 130.14, 128.53, 128.26, 126.19, 77.13,
CDCl3) d 167.04, 166.74, 149.53, 142.62, 110.44, 108.34, 75.35, 62.04,
62.22, 61.99, 54.64, 42.46, 13.86, 13.67; HRMS (ESI) calcd for
C
52.94, 36.75, 29.60, 13.85, 13.79; HRMS (ESI) calcd for C13H17NO7
15H18ClNO6 [MþNa]þ 366.0720, found: 366.0706.
[MþNa]þ 322.0903, found: 322.0865.
4.2.15. Diethyl 2-(1-(3-fluorophenyl)-2-nitroethyl)malonate (3o). 1H
NMR (400 MHz, CDCl3) 7.36e7.29 (m, 1H), 7.10e6.97 (m, 3H), 4.95
4.2.22. Dimethyl 2-(2-nitro-1-phenylethyl)malonate (3w).29 1H
NMR (400 MHz, CDCl3) d 7.25e7.17 (m, 3H), 7.16e7.12 (m, 2H), 4.84
d
(dd, J¼13.3, 4.8 Hz, 1H), 4.88 (dd, J¼13.3, 9.2 Hz, 1H), 4.31e4.20 (m,
(dd, J¼13.2, 5.2 Hz, 1H), 4.78 (dd, J¼13.2, 8.9 Hz, 1H), 4.15 (td, J¼9.0,
3H), 4.08 (q, J¼7.1 Hz, 2H), 3.82 (d, J¼9.1 Hz, 1H), 1.29 (t, J¼7.1 Hz,
5.2 Hz, 1H), 3.78 (d, J¼9.1 Hz, 1H), 3.66 (s, 3H), 3.46 (s, 3H); 13C NMR
3H), 1.12 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
167.15,
(101 MHz, CDCl3) d 167.65, 167.05, 135.95, 128.82, 128.22, 127.67,

7324
C. Jia et al. / Tetrahedron 69 (2013) 7320e7324
77.19, 76.87, 76.55, 54.54, 52.80, 52.61, 42.74; HRMS (ESI) calcd for
C
Corporation Project of Tianjin University/Hainan University, and
Hainan University (grant no. qnjj1169) for financial support. We
also thank Dr. Limin Yang (Hangzhou Normal University) for her
helpful suggestions.
13H15NO6 [MþNa]þ 304.0797, found: 304.0797.
4.2.23. Diisopropyl 2-(2-nitro-1-phenylethyl)malonate (3x).29 1H
NMR (400 MHz, CDCl3)
d
7.08 (ddd, J¼13.4, 10.9, 6.6 Hz, 5H), 4.88
(dd, J¼12.5, 6.3 Hz, 1H), 4.73 (dd, J¼12.9, 4.6 Hz, 1H), 4.68e4.60 (m,
2H), 4.01 (td, J¼9.4, 4.6 Hz, 1H), 3.57 (d, J¼9.6 Hz, 1H), 1.06 (s, 6H),
0.88 (d, J¼6.3 Hz, 3H), 0.82 (d, J¼6.3 Hz, 3H); 13C NMR (101 MHz,
References and notes
1. Trudeau, M. L.; Schulz, R.; Dussault, D.; Van Neste, A. Phys. Rev. Lett. 1990, 64,
99e102.
CDCl3)
d 166.82, 166.10, 136.11, 128.60, 128.02, 127.92, 77.70, 76.54,
2. Sepelak, V.; Begin-Colin, S.; Le Caer, G. Dalton Trans. 2012, 41, 11927e11948.
ꢀꢀ ꢁ
69.66, 69.27, 54.92, 42.71, 29.46, 21.32, 21.19, 21.02, 21.00; HRMS
3. Yuan, W.; Friscic, T.; Apperley, D.; James, S. L. Angew. Chem., Int. Ed. 2010, 49,
(ESI) calcd for C17H23NO6 [MþNa]þ 360.1423, found: 360.141.
3916e3919.
4. Garay, A. L.; Pichon, A.; James, S. L. Chem. Soc. Rev. 2007, 36, 846e855.
5. Pichon, A.; James, S. L. CrystEngComm 2008, 10, 1839e1847.
6. Wang, G.-W. Chem. Soc. Rev. 2013, http://dx.doi.org/10.1039/C3CS35526H
7. Cave, G. W.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159e2169.
8. Rodríguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C. Adv. Synth. Catal. 2007, 349,
2213e2233.
9. Rodríguez, B.; Rantanen, T.; Bolm, C. Angew. Chem., Int. Ed. 2006, 45,
6924e6926.
10. Raston, C. L.; Scott, J. L. Green Chem. 2000, 2, 49e52.
11. Fulmer, D. A.; Shearouse, W. C.; Medonza, S. T.; Mack, J. Green Chem. 2009, 11,
1821e1825.
4.2.24. Ethyl 2-acetyl-4-nitro-3-phenylbutanoate (3y).29 1H NMR
(400MHz,DMSO)
d
7.29 (dd, J¼14.4,9.0Hz,10H),7.20(t,J¼6.8Hz, 5H),
4.95 (dd, J¼21.5, 3.1 Hz, 2H), 4.81 (d, J¼7.5 Hz, 1H), 4.33 (dd, J¼10.7,
7.6 Hz, 1H), 4.17 (dd, J¼14.2, 7.1 Hz, 1H), 4.06e3.89 (m, 6H), 3.81 (q,
J¼7.1 Hz, 1H), 2.50 (s, 6H), 2.40 (s, 3H), 1.01 (t, J¼7.1 Hz, 5H), 0.84 (t,
J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 201.18, 200.92, 167.30,
166.59, 136.37, 136.29, 129.05, 128.89, 128.41, 128.20, 128.05, 127.83,
77.61, 77.52, 61.95, 61.70, 61.50, 42.30, 42.07, 29.78, 29.41,13.69,13.40.
HRMS (ESI) calcd for C14H17NO5 [MþNa]þ 302.1004, found: 302.1019.
12. Mack, J.; Shumba, M. Green Chem. 2007, 9, 328e330.
ꢁ
ꢁꢀ
ꢁ
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13. Veverkova, E.; Polackova, V.; Liptakova, L.; Kazmerova, E.; Meciarova, M.; Toma,
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S.; Sebesta, R. ChemCatChem 2012, 4, 1013e1018.
14. Metro, T.-X.; Bonnamour, J.; Reidon, T.; Sarpoulet, J.; Martinez, J.; Lamaty, F.
4.2.25. Ethyl 2-benzoyl-4-nitro-3-phenylbutanoate (3z).29 1H NMR
Chem. Commun. 2012, 11781e11783.
15. Thorwirth, R.; Stolle, A.; Ondruschka, B.; Wild, A.; Schubert, U. S. Chem. Com-
mun. 2011, 4370e4372.
16. Cook, T. L.; Walker, J. A.; Mack, J. Green Chem. 2013, 15, 617e619.
17. Wang, G.-W.; Dong, Y.-W.; Wu, P.; Yuan, T.-T.; Shen, Y.-B. J. Org. Chem. 2008, 73,
7088e7095.
18. Dong, Y.-W.; Wang, G.-W.; Wang, L. Tetrahedron 2008, 64, 10148e10154.
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Komatsu, K. Tetrahedron Lett. 2003, 44, 4407e4409.
(400 MHz, CDCl3)
d
8.01 (d, J¼7.9 Hz, 2H), 7.81 (d, J¼7.9 Hz, 1H), 7.53
(dt, J¼26.8, 7.4 Hz, 2H), 7.40 (dt, J¼29.8, 7.7 Hz, 4H), 7.29e7.21 (m,
5H), 7.18e7.11 (m, 3H), 4.98e4.85 (m, 3H), 4.80e4.68 (m, 2H),
4.49e4.44 (m, 1H), 4.44e4.38 (m, 1H), 4.13 (q, J¼7.1 Hz, 2H), 3.81
(qd, J¼7.0,1.9 Hz, 2H),1.12 (t, J¼7.1 Hz, 2H), 0.84 (t, J¼7.1 Hz, 3H); 13
C
NMR (101 MHz, CDCl3)
d 192.66, 167.59, 166.86, 136.68, 136.20,
20. Zhu, S.-E.; Li, F.; Wang, G.-W. Chem. Soc. Rev. 2013, http://dx.doi.org/10.1039/
135.95,135.75, 134.08, 133.67, 128.79, 128.75, 128.59, 128.42, 128.18,
127.95, 127.87, 77.86, 77.29, 76.97, 76.65, 62.07, 61.78, 56.94, 56.25,
43.02, 13.72, 13.42; HRMS (ESI) calcd for C19H19NO5 [MþNa]þ
364.1161, found: 364.1148.
C3CS35494F
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Acknowledgements
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We are grateful to the National Natural Science Foundation of
China (grant no. 21166008, 21261008), the Natural Science Foun-
dation of Hainan Province (grant no. 213014), the Innovation Fund