Original TDAE strategy using α-halocarbonyl derivatives

Article abstract of DOI:10.1016/j.tet.2009.05.036

We report herein the selective C-C bond formation by the reaction of nitrobenzyl carbanions, formed via the TDAE strategy, with α-haloesters and α-haloamides. This reaction, extended in benzodioxole and dimethoxybenzene series provides new potentially CNS

Full text of DOI:10.1016/j.tet.2009.05.036

Tetrahedron 65 (2009) 6128–6134
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Original TDAE strategy using
a-halocarbonyl derivatives
*
Marc Since, Thierry Terme, Patrice Vanelle
Laboratoire de Pharmaco-Chimie Radicalaire LPCR, UMR CNRS 6264, Universite´ de la Me´diterrane´e, Faculte´ de Pharmacie, 27 Boulevard Jean Moulin,
13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2009
Received in revised form 11 May 2009
Accepted 18 May 2009
Available online 23 May 2009
We report herein the selective C–C bond formation by the reaction of nitrobenzyl carbanions, formed via
the TDAE strategy, with
dimethoxybenzene series provides new potentially CNS active agents.
Ó 2009 Elsevier Ltd. All rights reserved.
a-haloesters and a-haloamides. This reaction, extended in benzodioxole and
1. Introduction
Tetrakis(dimethylamino)ethylene (TDAE) is an organic reducing
agent,6 which reacts with haloalkyl derivatives to generate an anion
under mild conditions via two sequential transfer of one electron.7
According to this strategy, we have recently developed several re-
actions between nitrobenzylic substrates and a series of carbonyl
Benzodioxole and dimethoxybenzene moieties are present in
the structure of a large number of biologically active compounds
acting in various therapeutic domains: oncology with etoposide1
and CNS pharmacology. Thus, paroxetine (Fig. 1) has become
a commonly prescribed antidepressant2 and piribedil is employed
for its dopaminergic action against cognitive pathological deficit.3
Furthermore, they represent protected forms of catechol moiety,
scaffold of catecholamines and also included in the structure of
entacapone.4 This is used in the treatment of Parkinson’s disease, as
adjuvant to levodopa therapy. Otherwise, some 3-(3,4-dimethoxy-
phenyl)propanamide and 3-(benzodioxol-5-yl)propanamide scaf-
folds have recently revealed interesting analgesic and antipyretic
properties.5 Therefore, the development of new synthetic meth-
odologies of benzodioxole and dimethoxybenzene derivatives
appears quite important.
electrophiles such as aldehydes, ketones,
a-ketoesters, a-keto-
lactams and ketomalonates leading to the corresponding alcohol
adducts.8
Since the discovery of the TDAE reducing properties, haloalkyl
derivatives, presenting an adequate reduction potential, have be-
come the most common type of TDAE substrate, to produce a react-
ing carbanion. However, these carbanions are less reactive than the
carbanions formed via the organometallic strategy, due to their
stabilization by the TDAEþþ cation. Me´debielle described the re-
action with bromodifluoroalkyl substrates9 while our team worked
on o- and p-nitrobenzyl chlorides. Nishiyama presented the use of
TDAE in the reductive debromination of 1,2-bis(bromoethyl)arenes
or in the reductive dimerization of a
-bromoesters.10
To explore the TDAE potentiality, we suggest the use of carbon
halide bond-containing derivatives as electrophilic reagents, in
order to realize a nucleophilic substitution. Thus, we have chosen
H
N
O
some a-haloesters and a
-haloamides, which are less reducible11
O
O
O
O
N
than nitrobenzyl chlorides but sufficiently activated, under TDAE
conditions, to undergo a nucleophilic substitution reaction. In ad-
dition, they present some worthwhile functionalized openings.
In continuation of our research program directed towards the
development of original synthetic methods in medicinal chemis-
try8,12 and the preparation of new potentially CNS active com-
pounds,13 we report herein the nucleophilic substitution by the
nitrobenzylic anions (obtained by the TDAE strategy) of the halogen
N
N
II
I
N
F
NO2
HO
HO
CH3
CH3
CN
N
O
III
atom of
a-haloesters and a-haloamides.
Figure 1. Structures of paroxetine (I), piribedil (II) and entacapone (III).
2. Preliminary study
Initially, we tempted a nucleophilic substitution reaction be-
tween the p-nitrobenzylic carbanion and ethyl 2-bromoacetate
* Corresponding author. Tel.: þ33 4 9183 5580; fax: þ33 4 9179 4677.
E-mail address: patrice.vanelle@pharmacie.univ-mrs.fr (P. Vanelle).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.036

M. Since et al. / Tetrahedron 65 (2009) 6128–6134
6129
Table 1
3. Results and discussion
Reaction of p-nitrobenzyl chloride with various a-halocarbonyl derivatives
NO2
3.1. Optimization and limits
NO2
X
R1
R2
In order to explore this reactivity, the o-nitrobenzyl chloride,
a less dimerizing substrate under TDAE conditions,14 was used
under the same reaction conditions. A high yield (92%) of sub-
stitution product 5a was obtained by the reaction of o-nitrobenzyl
chloride (4) with ethyl 2-bromoacetate (2a) in the presence of
TDAE. This reaction was associated with dimer traces. In order to
evaluate the scope and the limits of this reaction, a mechanistic
study was carried out (Table 2).
The influence of the leaving halide atom has been studied. No
reaction was observed with ethyl 2-chloroacetate and N,N-diethyl-
2-chloroacetamide while good yields were obtained using the
bromo and iodo derivatives 2a, 2c and 2c0 (entries 1, 5 and 6).
However, with ethyl iodoacetate (2a0) only a 50% yield was ob-
served. This limited yield could be explained by secondary poly-
merization reactions, due to its lability under radical reaction
conditions. The iodo esters usually produce polymers under radical
reaction conditions.15 These side reactions seem to limit the re-
action yields to 50–55% with 2-iodoester (entries 2 and 4), but do
TDAE
DMF, -20 °C
+
R1
R2
O
Cl
1
O
2a-c'
3a-c
Entrya
a
-Halocarbonyl compounds
X
R1
R2
Yieldb (%)
1
2
3
2a
2b
2c0
Br
Br
I
H
CH3
H
OC2H5
OC2H5
N(C2H5)2
47
Traces
36
c
a
Reaction conditions: 3 equiv of halocarbonyl compounds 2a–c0, 1 equiv of 1 and
1 equiv of TDAE in anhydrous DMF were stirred at ꢁ20 ꢀC for 1 h and then warmed
up to 70 ꢀC for 2 h, except with 2c0, warmed up to rt for 3 h.
b
% All yields refer to the chromatographically isolated pure products and are
relative to chloride 1.
c
Compound 2c0 was prepared by trans-halogenation of N,N-diethyl-2-chloro-
acetamide with NaI (3 equiv, 48 h in acetone).
not affect the a-iodoamides (entry 6), which are likely more stable
under these conditions.
As concerns the influence of the substitution of the carbon–ha-
lide bond, we observed a decrease in yields with the ethyl 2-bro-
mopropionate (34%) and no reaction was observed with ethyl
(2a), ethyl 2-bromopropionate (2b) or N,N-diethyl-2-iodoacet-
amide (2c0) (Table 1). However, a high rate (37–44%) of the
p-nitrobenzyl dimerization was observed explaining the poor to
mild yields in compounds 3a–c. These results are in accordance
with those reported in our previous study.8c
Table 2
Reaction of o-nitrobenzyl chloride with various halocarbonyl derivatives
NO2
NO2
TDAE, DMF
RX
+
1 h -20 °C
Cl
then rt or 70 °C
4
2a-c'
5a-c
R
Entrya
1
a
-Halocarbonyls
Conditions
70 ꢀ
Synthesized compound
Yieldc (%)
92
O
2a
2 equiv
3 equiv
C
2 h
3 h
NO2
Br
OEt
5a
OEt
O
2
3
2a0
rt
50
34
O
I
OEt
H3C
Br
O
2b
5 equiv
rt
48 h
NO2
OEt
5b
OEt
H3C
O
H3C
I
O
b
4
5
2b0
2c
3 equiv
3 equiv
rt
3 h
2 h
55
52
OEt
O
70 ꢀ
C
Br
N Et
NO2
O
Et
Et
N
5c
O
Et
6
2c0
3 equiv
rt
3 h
72
I
N Et
Et
a
All reactions were performed using 1 equiv (2 mmol) of TDAE in anhydrous DMF.
Compounds 2b0 and 2c0 were prepared by trans-halogenation of ethyl 2-bromopropionate and N,N-diethyl-2-chloroacetamide with NaI (3 equiv, 48 h in acetone).
% All yields refer to the chromatographically isolated pure products and are relative to chloride 4.
b
c

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M. Since et al. / Tetrahedron 65 (2009) 6128–6134
Table 3
2-bromoisobutyrate. This difference of reactivity could be explained
by the steric hindrance and electronic effect of alkyl groups. The use
of iodo ester 2b0 improved to a moderate 55% yield of 5b.
Moreover, the influence of the carbon–halide bond position was
studied. No reaction was observed with the ethyl 3-bromopropionate.
Finally to optimize this reactivity, we modified some parameters
Reaction of various o-nitrobenzyl chloride derivatives with compounds 2a–c
NO2
NO2
Cl
10a-c
TDAE, DMF
R1X
R
+
11a-c
12a-c
13a-c
R
1 h -20 °C
then rt or 70 °C
6-9
R1
2a-c'
such as reaction time, temperature and amount of a-halocarbonyl
Entry TDAE
substrate
R
a
-Halocarbonyl
derivatives
Substitution Yieldd (%)
product
derivative. After monitoring by TLC, optimized conditions were
defined for each halocarbonyl derivative: the reaction temperature
of bromo derivatives (2a and 2c) was 70 ꢀC and rt for iodo de-
rivatives (2b0 and 2c0). The optimal conditions were found to be 3 h
and 3 equiv of the halo compound except for 2a (2 h, 2 equiv).
All these experimental data (dimer formation, influence of the
leaving halide atom, .) led us to suggest a nucleophilic sub-
stitution mechanism for the reaction of the nitrobenzyl carbanion,
1
2
3
4
6
4-Cl
5-CH3
4,5-(OCH3)2
4,5-OCH2O
10a
11a
12a
13a
23a
78a
68a
85a
O
7
8
9
2a
Br
OEt
H3C
Br
O
5
6
6
7
4-Cl
5-CH3
10b
11b
Tracesb
46b
2b
OEt
O
formed from TDAE, with a-halocarbonyl derivatives.
H3C
I
7
8
8
9
4,5-(OCH3)2
4,5-OCH2O
12b
13b
50c
53c
2b0
3.2. Generalization to various o-nitrobenzyl chloride
derivatives
OEt
9
6
7
8
9
4-Cl
5-CH3
4,5-(OCH3)2
4,5-OCH2O
O
N
10c
11c
12c
13c
18c
83c
72c
82c
To generalize the TDAE reactivity on a-haloesters and amides,
10
11
12
2c0
using their respective optimized protocol, we conducted a study
using various o-nitrobenzyl chloride derivatives (Table 3) such as 4-
chloro-2-nitrobenzyl chloride (6), 5-methyl-2-nitrobenzyl chloride
(7), 4,5-dimethoxy-2-nitrobenzyl chloride (8) and 6-nitropiperonyl
chloride (9).
I
Et
Et
a
Reaction conditions: 2 equiv of 2a, 1 equiv of 6–9 and 1 equiv of TDAE in an-
hydrous DMF were stirred at ꢁ20 ꢀC for 1 h and then warmed up to 70 ꢀC for 2 h.
b
Reaction conditions: 5 equiv of 2b, 1 equiv of 6–9 and 1 equiv of TDAE in an-
According to our previous study,12f the lowest reactivity was
observed with the 4-chloro-2-nitrobenzyl chloride (6): traces to
23%. This poor reactivity could be explained by the unstability of
the radical intermediate. Other chloride derivatives gave fair to
good yields (46–85%).
hydrous DMF were stirred at ꢁ20 ꢀC for 1 h and then warmed up to rt for 48 h.
c
Reaction conditions: 3 equiv of 2b0 and 2c0, 1 equiv of 6–9 and 1 equiv of TDAE in
anhydrous DMF were stirred at ꢁ20 ꢀC for 1 h and then warmed up to rt for 3 h.
d
% All yields refer to the chromatographically isolated pure products and are
relative to chloride 6–9.
Table 4
Reaction of 4,5-dimethoxy-2-nitrobenzyl chloride and 6-nitropiperonyl chloride with various
a
-bromoacetamide
NO2
R
O
N
NO2
TDAE, DMF
X
+
R
1 h -20 °C
then 70 °C
Cl
N
Br
O
8-9
14-16
17-22
X
Entrya
TDAE substrate
R
a
-Bromoacetamide
X
Substitution product
Yieldb (%)
H3CO
H3CO
NO2
1
8
4,5-(OCH3)2
14
CH2
17
65
N
O
H3CO
H3CO
NO2
2
3
8
8
4,5-(OCH3)2
4,5-(OCH3)2
15
16
O
18
19
62
79
O
N
O
Cl
Cl
Cl
N
Cl
H3CO
H3CO
NO2
N
N
O
NO2
O
O
4
9
4,5-OCH2O
14
CH2
20
42
N
O

M. Since et al. / Tetrahedron 65 (2009) 6128–6134
6131
Table 4 (continued )
Entrya
TDAE substrate
R
a
-Bromoacetamide
X
O
Substitution product
Yieldb (%)
NO2
O
O
O
5
9
4,5-OCH2O
15
21
22
68
N
O
Cl
Cl
Cl
NO2
O
O
6
9
4,5-OCH2O
16
62
N
N
Cl
N
O
a
Reaction conditions: 3 equiv of
a
-bromoacetamides 14–16, 1 equiv of 8–9 and 1 equiv of TDAE in anhydrous DMF were stirred at ꢁ20 ꢀC for 1 h and then warmed up to
70 ꢀC for 2 h.
b
% All yields refer to the chromatographically isolated pure products and are relative to chloride 8–9.
Variations observed are in accordance with optimization results
obtained by a simple methodology16 using the reaction of 2-bro-
(Table 2): good yields with 2a and 2c0 (68–85%) and fair yields with
2b and 2b0 (entries 3 and 4) due to the steric hindrance and elec-
tronic effect of the methyl group.
moacetyl bromide and the corresponding secondary amine solu-
bilized in butan-2-one in the presence of calcium carbonate. The
moderate yields obtained (42–79%) are in accordance with
previously results observed with N,N-diethyl-2-bromoacetamide
(Table 2).
3.3. Extension to a-haloacetamide derivatives in
benzodioxole and dimethoxybenzene series
In addition to this study, we targeted another original a-hal-
oacetamide, 3-iodo-1-phenylpyrrolidinone (23) (Table 5). This
compound was prepared by the trans-halogenation of the corre-
sponding commercially available bromo derivative. We used the
iodo compound because of the negative influence of the steric
hindrance previously observed with 2b and improved with the use
of 2b0 (Table 2, entry 4). The reaction of compounds 8 and 9 with 23,
according to 2c0 reaction conditions, led to expected pyrolidinone
derivatives 24 and 25 in 44–83% yield.
In order to obtain highly functionalized compounds, we ex-
tended this reactivity with more complex
rivatives (Table 4). Due to their stability and their ease availability
compared with -iodoacetamides, three -bromoacetamides were
a-haloacetamide de-
a
a
prepared according to the previous reaction conditions used with
2c (3 equiv, 70 ꢀC, 3 h). The three
a-bromoacetamides 14–16 were
Table 5
4. Conclusion
Reaction of 4,5-dimethoxy-2-nitrobenzyl chloride and 6-nitropiperonyl chloride
with 3-iodo-1-phenylpyrrolidinone
In conclusion, we have demonstrated that a-haloesters and a-
NO2
I
R
haloamides are able to undergo a nucleophilic substitution with
the carbanions obtained from o-nitrobenzyl chloride derivatives
using TDAE. Compared with the classical method using organo-
metallic compounds or transitional metal catalysts,17 the TDAE
strategy is an easy, original and selective method to create car-
NO2
TDAE, DMF
O
R
+
N
1 h -20 °C
O
Cl
then 3 h at rt
N
23
8-9
24-25
bon–carbon bonds from the carbon–halide bond of
a-haloesters
or -haloamides. The pharmacological evaluation of these new 3-
a
phenylpropanoates and 3-phenylpropanamides is under active
investigation.
Entrya
TDAE substrate
R
Substitution product
Yieldb (%)
NO2
H3CO
H3CO
5. Experimental section
5.1. General
24
O
1
8
4,5-(OCH3)2
83
N
Melting points were determined on a Bu¨chi capillary melting
point apparatus and are uncorrected. Element analyses were per-
formed by the centre de Microanalyse of the University of Aix-
Marseille 3. Both 1H and 13C NMR spectra were determined on
a Bruker AC 200 spectrometer. The 1H the 13C chemical shifts are
reported from CDCl3 peaks: 1H (7.26 ppm) and 13C (76.9 ppm).
Absorptions are reported with the following notations: s, singulet;
d, doublet; t, triplet; q, quartet; m, a more complex multiplet or
overlapping multiplets. The following adsorbents were used for
column chromatography: silica gel 60 (Merck, particule size 0.063–
0.200 mm, 70–230 mesh ASTM). TLC was performed on
5 cmꢂ10 cm aluminium plates coated with silice gel 60 F254
(Merck) in an appropriate solvent.
NO2
O
O
2
9
4,5-OCH2O
44
O
25
N
a
Reaction conditions: 3 equiv of 23, 1 equiv of 8–9 and 1 equiv of TDAE in an-
hydrous DMF were stirred at ꢁ20 ꢀC for 1 h and then warmed up to rt for 3 h.
b
% All yields refer to the chromatographically isolated pure products and are
relative to chloride 8–9.

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M. Since et al. / Tetrahedron 65 (2009) 6128–6134
The N,N-diethyl-2-iodoacetamide (2c0) and the ethyl 2-iodo-
34.6, 60.2, 124.8, 127.9, 132.5, 135.6, 144.2, 146.6, 172.1. Anal. Calcd
for C12H15NO4 (237.25): C, 60.75; H, 6.37; N, 5.90. Found: C, 60.33;
H, 6.45; N, 5.82.
propionate (2b0) were prepared in quantitative yields by a simple
trans-halogenation of N,N-diethyl-2-chloroacetamide and ethyl 2-
bromopropionate with NaI (3 equiv, 48 h in acetone) followed by
a silica gel chromatography using petroleum ether/ethyl acetate as
eluent.
5.2.5. Ethyl 2-methyl-3-(5-methyl-2-nitrophenyl)propanoate (11b)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.08 (t, J¼7.1 Hz, 3H,
CH3), 1.16 (d, J¼7.0 Hz, 3H, CH3), 2.32 (s, 3H, CH3), 2.72–2.83 (m, 1H,
CH), 2.95–3.18 (m, 2H, CH2), 3.99 (q, J¼7.1 Hz, 2H, CH2), 7.07–7.11
(m, 2H, 2ꢂCH), 7.81 (d, J¼8.1 Hz, 1H, CH). 13C NMR (50 MHz, CDCl3)
dC 13.9, 17.4, 21.1, 36.7, 40.3, 60.1, 125.0, 128.0, 133.1, 134.6, 143.9,
146.7, 175.4. Anal. Calcd for C13H17NO4 (251.28): C, 62.14; H, 6.82; N,
5.57. Found: C, 62.20; H, 6.92; N, 5.73.
The secondary
a-bromoacetamides, 2-bromo-1-(piperidin-1-
yl)ethanone 14, 2-bromo-1-morpholino ethanone 15, 2-bromo-1-
4-(3,4-dichloropiperzin-1-yl)ethanone 16 were prepared according
to previously described method.11
5.2. Procedure for TDAE reaction
General procedure for the reaction of o- and p-nitrobenzyl de-
5.2.6. N,N-Diethyl-3-(5-methyl-2-nitrophenyl)propanamide (11c)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 0.92 (t, J¼7.0 Hz, 3H,
CH3), 0.94 (t, J¼7.1 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 2.51 (t, J¼7.0 Hz,
2H, CH2), 2.98–3.25 (m, 6H, 3ꢂCH2), 6.98 (d, J¼8.3 Hz, 1H, CH), 7.07
(s, 1H, CH), 7.66 (d, J¼8.3 Hz, 1H, CH). 13C NMR (50 MHz, CDCl3) dC
12.6, 13.8, 20.8, 28.9, 33.4, 39.8, 41.4, 124.4, 127.5, 132.6, 136.2, 143.9,
146.4, 170.2. Anal. Calcd for C14H20N2O3 (264.32): C, 63.62; H, 7.63;
N, 10.60. Found: C, 63.42; H, 7.77; N, 10.41.
rivatives 1, 4, 6–9 and a
-halocarbonyl derivatives 2a–c0, 14–16, 23
using TDAE. Into a two-necked flask equipped with a nitrogen inlet
was added, under nitrogen at ꢁ20 ꢀC, 6 mL of anhydrous DMF so-
lution of o- and p-nitrobenzyl derivative (2 mmol, 1 equiv) and
corresponding a-halocarbonyl derivatives (2a: 2 equiv; 2b: 5 equiv;
2b0, 2c, 2c0, 14–16, 23: 3 equiv). The solution was stirred and
maintained at this temperature for 15 min and then was added
dropwise via a syringe the TDAE (1 equiv). A red to green colour
immediately developed with the formation of a white fine pre-
cipitate. The solution was vigorously stirred for 1 h and warmed up
(2a, 2c, 14–16: 70 ꢀC for 2 h; 2b: rt for 48 h; 2b0, 2c0, 23: rt for 3 h).
After this time, the crude was extracted by dichloromethane
(50 mL), washed with water (3ꢂ100 mL) and dried by Na2SO4.
Evaporation of the solvent left an orange to brown viscous liquid as
crude product. Purification by silica gel chromatography (CH2Cl2/
petroleum ether (5:5) with 2a, 2b, and 2b0, petroleum ether/ethyl
acetate (5:5) with 2c, 2c0, 14–16, CH2Cl2 with 23) gave the corre-
sponding product of substitution.
5.2.7. Ethyl 3-(4,5-dimethoxy-2-nitrophenyl)-2-methyl
propanoate (12b)
Yellow solid, mp 55 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.10 (t,
J¼7.1 Hz, 3H, CH3), 1.20 (d, J¼6.8 Hz, 3H, CH3), 2.78–2.85 (m, 1H,
CH), 3.10 (d, J¼7.2 Hz, 2H, CH2), 3.88 (s, 3H, CH3), 3.89 (s, 3H, CH3),
3.99 (q, J¼7.1 Hz, 2H, CH2), 6.70 (s, 1H, CH), 7.57 (s, 1H, CH). 13C NMR
(50 MHz, CDCl3) dC 14.0, 17.7, 37.3, 40.4, 56.1, 56.2, 60.2, 108.1, 114.0,
129.9, 141.0, 147.3, 152.6, 175.8. Anal. Calcd for C14H19NO6 (297.30):
C, 56.56; H, 6.44; N, 4.71. Found: C, 56.82; H, 6.61; N, 4.59.
The analytical data of the previously synthesized products 3a,
5.2.8. 3-(4,5-Dimethoxy-2-nitrophenyl)-N,N-diethyl
propanamide (12c)
3b, 5a, 5c, 12a are in accordance to the references.18
Yellow solid, mp 105 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.03 (t,
J¼6.4 Hz, 6H, 2ꢂCH3), 2.63 (t, J¼7.1 Hz, 2H, CH2), 3.14–3.35 (m, 6H,
3ꢂCH2), 3.85 (s, 3H, CH3), 3.87 (s, 3H, CH3), 6.83 (s, 1H, CH), 7.51 (s,
1H, CH). 13C NMR (50 MHz, CDCl3) dC 12.9, 14.1, 29.7, 33.7, 40.2, 41.8,
56.1, 56.3, 107.9, 114.0, 131.9, 140.9, 147.2, 153.0, 170.7. Anal. Calcd for
C15H22N2O5 (310.35): C, 58.05; H, 7.15; N, 9.03. Found: C, 58.22; H,
7.36; N, 9.03.
5.2.1. Ethyl 2-methyl-3-(2-nitrophenyl)propanoate (5b)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.12 (t, J¼7.1 Hz, 3H,
CH3), 1.21 (d, J¼7.0 Hz, 3H, CH3), 2.78–2.89 (m, 1H, CH), 3.00–3.26
(m, 2H, CH2), 4.03 (q, J¼7.1 Hz, 2H, CH2), 7.32–7.37 (m, 2H, ArH),
7.46–7.54 (m, 1H, CH), 7.92 (d, J¼8.3 Hz, 1H, CH). 13C NMR (50 MHz,
CDCl3) dC 14.0, 17.6, 36.6, 40.4, 60.4, 124.8, 127.6, 132.7, 132.8, 134.6,
149.3,175.5. Anal. Calcd for C12H15NO4 (237.25): C, 60.75; H, 6.37; N,
5.90. Found: C, 61.12; H, 6.52; N, 6.02.
5.2.9. Ethyl 3-(6-nitrobenzo[d][1,3]dioxol-5-yl)propanoate (13a)
Yellow solid, mp 78 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.22 (t,
J¼7.1 Hz, 3H, CH3), 2.66 (t, J¼7.4 Hz, 2H, CH2), 3.15 (t, J¼7.4 Hz, 2H,
CH2), 4.18 (q, J¼7.1 Hz, 2H, CH2), 6.07 (s, 2H, CH2), 6.78 (s, 1H, CH),
7.47 (s, 1H, CH). 13C NMR (50 MHz, CDCl3) dC 14.1, 29.1, 34.7, 60.5,
102.9, 105.7, 110.8, 132.9, 142.7, 146.6, 151.7, 172.3. Anal. Calcd for
C12H13NO6 (267.23): C, 53.93; H, 4.90; N, 5.24. Found: C, 53.80; H,
4.98; N, 5.18.
5.2.2. Ethyl 3-(4-chloro-2-nitrophenyl)propanoate (10a)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.22 (t, J¼7.1 Hz, 3H,
CH3), 2.69 (t, J¼7.0 Hz, 2H, CH2), 3.19 (t, 2H, CH2), 4.11 (q, J¼7.1 Hz,
2H, CH2), 7.37 (d, J¼8.3 Hz, 1H, CH), 7.51 (dd, J¼8.3, 2.0 Hz, 1H, CH),
7.93 (d, J¼2.0 Hz, 1H, ArH). 13C NMR (50 MHz, CDCl3) dC 14.1, 27.8,
34.5, 60.6, 124.9, 133.1, 133.2, 133.4, 134.1, 149.5, 172.0. Anal. Calcd
for C11H12ClNO4 (257.67): C, 51.27; H, 4.69; N, 5.44. Found: C, 51.32;
H, 4.71; N, 5.69.
5.2.10. Ethyl 2-methyl-3-(6-nitrobenzo[d][1,3]dioxol-5-yl)-
propanoate (13b)
5.2.3. 3-(4-Chloro-2-nitrophenyl)-N,N-diethylpropanamide (10c)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.08 (t, J¼7.0 Hz, 3H,
CH3),1.10 (t, J¼7.0 Hz, 3H, CH3), 2.66 (t, J¼7.3 Hz, 2H, CH2), 3.14–3.40
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.17 (t, J¼7.2 Hz, 3H,
CH3), 1.21 (d, J¼6.7 Hz, 3H, CH3), 2.76–2.87 (m, 1H, CH), 2.99–3.20
(m, 2H, CH2), 4.07 (q, J¼7.2 Hz, 2H, CH2), 6.07 (s, 2H, CH2), 6.73 (s,
1H, CH), 7.50 (s, 1H, CH). 13C NMR (50 MHz, CDCl3) dC 14.1, 17.7, 37.4,
40.6, 60.4, 102.8, 105.8, 111.4, 132.1, 142.9, 146.7, 151.5, 175.7. Anal.
Calcd for C13H15NO6 (281.26): C, 55.51; H, 5.38; N, 4.98. Found: C,
55.71; H, 5.66; N, 4.87.
(m, 6H, 3ꢂCH2), 7.42–7.51 (m, 2H, CH), 7.86–8.00 (m, 1H, CH). 13
C
NMR (50 MHz, CDCl3) dC 13.0, 14.2, 28.5, 33.6, 40.3, 41.9, 124.6,
132.9, 133.1, 134.1, 135.1, 149.5, 170.3. Anal. Calcd for C13H17ClN2O3
(284.74): C, 54.84; H, 6.02; N, 9.84. Found: C, 54.76; H, 6.20; N, 9.44.
5.2.4. Ethyl 3-(5-methyl-2-nitrophenyl)propanoate (11a)
5.2.11. N,N-Diethyl-3-(6-nitrobenzo[d][1,3]dioxol-5-yl)-
propanamide (13c)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.15 (t, J¼7.1 Hz, 3H,
CH3), 2.32 (s, 3H, CH3), 2.61 (t, J¼7.6 Hz, 2H, CH2), 3.12 (t, J¼7.6 Hz,
2H, CH2), 4.04 (q, J¼7.1 Hz, 2H, CH2), 7.06–7.12 (m, 2H, 2ꢂCH), 7.78
(d, J¼8.2 Hz, 1H, CH). 13C NMR (50 MHz, CDCl3) dC 13.9, 21.0, 28.3,
Yellow solid, mp 90 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.06 (t,
J¼7.1 Hz, 3H, CH3), 1.08 (t, J¼7.1 Hz, 3H, CH3), 2.63 (t, J¼7.8 Hz, 2H,
CH2), 3.14 (t, J¼7.8 Hz, 2H, CH2), 3.23 (q, J¼7.1 Hz, 2H, CH2), 3.33 (q,

M. Since et al. / Tetrahedron 65 (2009) 6128–6134
6133
J¼7.1 Hz, 2H, CH2), 6.04 (s, 2H, CH2), 6.83 (s,1H, CH), 7.43 (s,1H, CH).
13C NMR (50 MHz, CDCl3) dC 13.0, 14.1, 29.8, 33.7, 40.1, 41.8, 102.7,
105.4, 111.2, 134.0, 142.6, 146.4, 151.6, 170.5. Anal. Calcd for
C14H18N2O5 (294.30): C, 57.13; H, 6.16; N, 9.52. Found: C, 57.09; H,
6.30; N, 9.50.
151.7, 170.0. HRMS (EI): calcd for C20H19Cl2N3O5 (Mþ) 452.0775,
found 452.0769.
5.2.18. 3-(4,5-Dimethoxy-2-nitrobenzyl)-1-phenyl
pyrrolidin-2-one (24)
Yellow oil, 1H NMR (200 MHz, CDCl3) dH 1.70–7.95 (m, 1H, CH2),
2.15–2.36 (m, 1H, CH2), 2.89–3.10 (m, 1H, CH), 3.21 (dd, J¼6.5 Hz,
JAB¼13.5 Hz, 1H, CH2), 3.54 (dd, J¼6.0 Hz, JAB¼13.5 Hz, 1H, CH2),
3.68 (m, 2H, CH2), 3.89 (s, 6H, 2ꢂCH3), 6.93 (s,1H, CH), 7.06–7.13 (m,
1H, CH), 7.32 (dd, J¼7.6, 8.1 Hz, 2H, 2ꢂCH), 7.55 (s, 1H, CH), 7.58 (d,
J¼7.6 Hz, 2H, 2ꢂCH). 13C NMR (50 MHz, CDCl3) dC 24.2, 33.1, 44.5,
46.5, 56.1, 56.3, 107.8, 114.0, 119.5, 124.3, 128.6, 129.6, 139.3, 141.5,
147.3, 152.8, 174.8. HRMS (EI): calcd for C19H20N2O5 (Mþ) 357.1445,
found 357.1440.
5.2.12. 3-(4,5-Dimethoxy-2-nitrophenyl)-1-(piperidin-1-
yl)propan-1-one (17)
Yellow solid, mp 98 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.30–1.60
(m, 6H, 3ꢂCH2), 2.61 (t, J¼7.9 Hz, 2H, CH2), 3.12 (t, J¼7.9 Hz, 2H,
CH2), 3.29 (t, J¼5.2 Hz, 2H, CH2), 3.44 (t, J¼5.2 Hz, 2H, CH2), 3.82 (s,
3H, CH3), 3.85 (s, 3H, CH3), 6.79 (s, 1H, CH), 7.49 (s, 1H, CH). 13C NMR
(50 MHz, CDCl3) dC 24.2, 25.3, 26.2, 29.8, 33.7, 42.5, 46.3, 56.0, 56.2,
107.7, 113.8, 131.8, 140.7, 147.1, 152.9, 169.8. Anal. Calcd for
C16H22N2O5 (322.36): C, 59.61; H, 6.88; N, 8.69. Found: C, 59.41; H,
6.99; N, 8.55.
5.2.19. 3-[(6-Nitrobenzo[d][1,3]dioxol-5-yl)methyl]-1-
phenylpyrrolidin-2-one (25)
5.2.13. 3-(4,5-Dimethoxy-2-nitrophenyl)-1-morpholino
propan-1-one (18)
Yellow solid, mp 164 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.75–1.94
(m, 1H, CH2), 2.22–2.34 (m, 1H, CH2), 2.95–3.03 (m, 1H, CH), 3.14
(dd, J¼7.0 Hz, JAB¼13.6 Hz,1H, CH2), 3.47 (dd, J¼6.0 Hz, JAB¼13.6 Hz,
1H, CH2), 3.75 (q, J¼4.0 Hz, 2H, CH2), 6.08 (s, 2H, CH2), 6.93 (s, 1H,
CH), 7.09–7.17 (m, 1H, CH), 7.36 (dd, J¼7.3, 8.5 Hz, 2H, 2ꢂCH), 7.49
(s, 1H, CH), 7.61 (d, J¼8.5 Hz, 2H, 2ꢂCH). 13C NMR (50 MHz, CDCl3)
dC 24.7, 33.9, 44.2, 46.5, 102.8, 105.5, 111.3, 119.7, 124.4, 128.7, 131.8,
139.3, 143.2, 146.7, 151.6, 174.6. HRMS (EI): calcd for C18H16N2O5
(Mþ) 341.1132, found 341.1128.
Yellow solid, mp 135 ꢀC, 1H NMR (200 MHz, CDCl3) dH 2.66 (t,
J¼7.2 Hz, 2H, CH2), 3.18 (t, J¼7.2 Hz, 2H, CH2), 3.39–3.57 (m, 8H,
4ꢂCH2), 3.87 (s, 3H, CH3), 3.90 (s, 3H, CH3), 6.82 (s, 1H, CH), 7.54 (s,
1H, CH). 13C NMR (50 MHz, CDCl3) dC 29.8, 33.7, 41.9, 45.8, 56.1, 56.3,
66.5, 66.6,107.9,113.9,131.5,140.8,147.3,153.1,170.4. Anal. Calcd for
C15H20N2O6 (324.33): C, 55.55; H, 6.22; N, 8.64. Found: C, 55.34; H,
6.40; N, 8.36.
5.2.14. 1-[4-(3,4-Dichlorophenyl)piperazin-1-yl]-3-(4,5-
dimethoxy-2-nitrophenyl)propan-1-one (19)
Acknowledgements
Yellow solid, mp 68 ꢀC, 1H NMR (200 MHz, CDCl3) dH 2.73 (t,
J¼8.1 Hz, 2H, CH2), 3.08 (m, 4H, 2ꢂCH2), 3.21 (t, J¼8.1 Hz, 2H, CH2),
3.69–3.74 (m, 4H, 2ꢂCH2), 3.88 (s, 3H, CH3), 3.92 (s, 3H, CH3), 6.72
(dd, J¼2.8, 9.0 Hz, 1H, CH), 6.84 (s, 1H, CH), 6.91 (d, J¼2.8 Hz, 1H,
CH), 7.21 (d, J¼9.0 Hz, 1H, CH), 7.57 (s, 1H, CH). 13C NMR (50 MHz,
CDCl3) dC 30.0, 33.9, 41.1, 45.0, 48.8, 49.0, 56.2, 56.4, 108.0, 113.9,
115.7, 117.7, 123.0, 130.4, 131.5, 132.7, 140.8, 147.4, 149.9, 153.2, 170.3.
HRMS (EI): calcd for C21H23Cl2N3O5 (Mþ) 468.1088, found 468.1079.
This work is supported by the Centre National de la Recherche
Scientifique. We express our thanks to V. Remusat for 1H and 13C
NMR spectra recording. M.S. thanks the Assistance Publique-
ˆ
Hopitaux de Marseille for hospital appointment.
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propan-1-one (20)
Yellow solid, mp 113 ꢀC, 1H NMR (200 MHz, CDCl3) dH 1.57 (m,
6H, 3ꢂCH2), 2.69 (t, J¼7.9 Hz, 2H, CH2), 3.18 (t, J¼7.9 Hz, 2H, CH2),
3.41–3.54 (m, 4H, 2ꢂCH2), 6.08 (s, 2H, CH2), 6.89 (s, 1H, CH), 7.49 (s,
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propan-1-one (21)
Yellow solid, mp 156 ꢀC, 1H NMR (200 MHz, CDCl3) dH 2.70 (t,
J¼7.2 Hz, 2H, CH2), 3.19 (t, J¼7.2 Hz, 2H, CH2), 3.40–3.74 (m, 8H,
4ꢂCH2), 6.09 (s, 2H, CH2), 6.88 (s, 1H, CH), 7.50 (s, 1H, CH). 13C NMR
(50 MHz, CDCl3) dC 29.8, 33.8, 42.0, 45.9, 66.6, 66.8, 102.8, 105.6,
111.3, 133.6, 142.7, 146.7, 151.8, 170.3. Anal. Calcd for C14H16N2O6
(308.29): C, 54.54; H, 5.23; N, 9.09. Found: C, 54.16; H, 5.15; N,
8.85.
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