Squaramide-Catalyzed Michael Addition as a Key Step for the Direct Synthesis of GABAergic Drugs

Article abstract of DOI:10.1055/s-0035-1560420

Enantioselective organocatalytic Michael additions serve as the key step in syntheses of chiral drugs based on γ-aminobutyric acid. The applicability of various squaramide catalysts for these Michael-type reactions has been assessed. Very good results in

Full text of DOI:10.1055/s-0035-1560420

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
A
paper
Synthesis
E. Veverková et al.
Paper
Squaramide-Catalyzed Michael Addition as a Key Step for the
Direct Synthesis of GABAergic Drugs
O
O
Eva Veverková
Stanislav Bilka
Rastislav Baran
Radovan Šebesta*
N
H
N
H
F3C
NO2
CHO
HN
overall
25%
CF3
MeNO2
CHO
NH2.HCl
CO2H
Cl
Comenius University in Bratislava, Faculty of Natural Sciences,
Department of Organic Chemistry, Mlynska dolina, Ilkovičova
Cl
Cl
6
4%, 92% ee
6, 84215, Bratislava, Slovakia
CH2(CO2Me)2
MeO2C
CO2Me
Cl
baclofen
radovan.sebesta@fns.uniba.sk
NO2
O
O
NO2 overall
6%
5
N
H
N
H
Me2N
F3C
Cl
7
6%, 86% ee
CF3
Received: 26.11.2015
Accepted after revision: 05.02.2016
Published online: 11.03.2016
typical structural motives in this catalysis. The key step in
the organocatalyzed synthesis of GABA derivatives such as
baclofen involves Michael addition of enolizable carbonyl
DOI: 10.1055/s-0035-1560420; Art ID: ss-2015-t0683-op
20,21
compounds to nitroalkenes with thioureas as catalysts.
Abstract Enantioselective organocatalytic Michael additions serve as
the key step in syntheses of chiral drugs based on γ-aminobutyric acid.
The applicability of various squaramide catalysts for these Michael-type
reactions has been assessed. Very good results in terms both activity
and enantioselectivity were obtained in the Michael addition of dimeth-
yl malonate to β-nitrostyrenes. On the other hand, a complementary
approach, the addition of nitromethane to cinnamaldehydes, worked
well with a squaramide catalyst possessing an adjacent pyrrolidine moi-
ety. The corresponding Michael adducts obtained in the best conditions
are suitable chiral intermediates for the synthesis of therapeutically
useful GABA derivatives. Polymer-immobilized squaramides afforded
the Michael adduct in high enantiomeric purity, but yield deterioration
was observed between runs. Two different formal total syntheses of ba-
clofen have also been accomplished.
Interestingly, squaramides often function in a complemen-
tary manner to thiourea catalysts. Therefore, many useful
Michael additions2
2–27
and related domino reactions
28–30
have also been catalyzed by squaramides. Recently, our
group has reported an efficient enantioselective Michael
addition of 1,3-dicarbonyl compounds to an aliphatic ni-
troalkene catalyzed by various squaramides. The Michael
adduct, obtained by a reaction of Meldrum’s acid and (E)-4-
methyl-1-nitropent-1-ene with an enantiomeric purity of
97:3 e.r., was successfully used as a key intermediate in the
total synthesis of pregabalin. Song and Bae recently de-
scribed highly enantioselective Michael additions in the
syntheses of rolipram and pregabalin using squaramide ca-
talysis on water.31 The synthesis of baclofen based on a con-
jugate addition of nitromethane to α,β-unsaturated carbon-
yl compounds catalyzed by chiral pyrrolidines was per-
formed by Zu and co-workers.32 However, the use of chiral
squaramides in Michael additions of nitromethane has only
Key words asymmetric catalysis, organocatalysis, Michael addition,
squaramides, baclofen
3-Substituted derivatives of γ-aminobutyric acid (GA-
BA) are already certified or potentially centrally acting skel-
etal muscle relaxants, and some of them are active ingredi-
1
®
®
33,34
ents in drugs. Baclofen (Lioresal and Baclon ) is used to
treat spasticity caused by spinal cord injury or various neu-
been described a few times.
In this context, we decided to investigate both alterna-
tive Michael additions of malonate to aromatic nitroalkenes
as well as the conjugate addition of nitromethane to the
corresponding α,β-unsaturated aldehyde with the aim to
prepare the chiral intermediates for the synthesis baclofen
and phenibut.
2
rological disorders. Another related GABA-mimetic psy-
chotropic drug phenibut has anxiolytic effects. Because
3
only one enantiomer of both of these compounds exhibits
the required activity, it is important to develop enantiose-
lective strategies for their preparation.
Asymmetric organocatalysis has proved useful in the
synthesis of many biologically relevant compounds.4 Key
intermediates in the enantioselective synthesis of GABA-
ergic drugs are products of asymmetric Michael additions.
From among various activation modes, hydrogen-bonding
catalysts have proved useful for this kind of Michael addi-
As shown in Figure 1, we prepared various squaramide
catalysts including polymer-supported systems. The squar-
–7
35
36
37
22
33
21
amide organocatalysts C1, C2, C3, C4, C5, C6, and
38,39
C7
were synthesized according to literature procedures.
The preparation of squaramides C8 and C9 and polymer-
supported catalysts C10–12 is described in the experimen-
tal section.
8–11
12–16
17–19
tion.
Chiral thioureas
and squaramides
became
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
Synthesis
E. Veverková et al.
Paper
O
O
Table 1 Optimization of the Reaction Conditions for Michael Addition
of Dimethyl Malonate to Alkene 1aa
F3C
O
O
N
H
N
H
F3C
N
H
N
H
MeO2C
CO2Me
MeO2C
CO2Me
NO2
NO2
R2N
F3C
C1 (5 mol%)
N
C2, NR2 = NMe2
C4, NR2 = piperidino
C1, NR2 = NMe2
C3, NR2 = piperidino
Cl
CF3
solvent, r.t., 4 d
1a
Cl
2a
O
O
F3C
O
O
b
e.r.c
Entry
Solvent
CH Cl
Conversion (%) Yield (%)
N
1
2
3
4
5
2
2
2
56d
91
52
84
96
80
46
67
90:10
NH
NH
N
NH
NH
F3C
CH
Cl
2
93:7
F3C
OMe
CF3
THF
100
83
63:37
83:17
85:15
90:10
N
O
C6
C5
N
toluene
MeCN
brine
O
O
O
65
6
–e
N
H
N
H
N
H
N
H
a
F3C
Reaction conditions: trans-4-chloro-β-nitrostyrene (0.55 mmol), dimethyl
malonate (0.5 mmol), C1 (5 mol%, unless otherwise stated), solvent (1 mL),
r.t., 4 d.
Determined by H NMR of the crude reaction mixture.
Determined by chiral HPLC on the purified product.
F3C
HN
HN
O
b
c
1
CF3
CF3
C7
C8
HN
O
O
d
e
1
mol% of catalyst.
O2N
Not determined.
N
N
H
H
N
C9
O
O
O
O
er yields and moderate enantioselectivities in comparison
with catalyst C1 (Table 1, entry 2 vs. Table 2, entries 1–6).
The catalysts C7 and C8, which possess an additional pyrro-
lidine unit, gave very little or no chiral product 2a even if
catalyst loading was increased and the reaction time was
prolonged (Table 2, entries 7–9). Poor results were also ob-
tained with catalyst C9 (Table 2, entries 10 and 11).
Hence, we selected the optimal reaction conditions as
follows: dichloromethane as solvent, 96 hours reaction
time, C1 at 5 mol% catalyst loading. Under these conditions,
the Michael product 2a was obtained in 84% yield and en-
antiomeric purity 86% ee also on a synthetically useful
scale.
We expanded the optimized protocol to trans-β-nitro-
styrene because phenibut has a similar structure to ba-
clofen (only without chlorine atom in the para-position of
the phenyl group. The chiral phenibut intermediate 2b was
prepared in comparable yield and enantioselectivity to ad-
duct 2a (Table 2, entry 12). The substrate bearing an aro-
matic ring with an electron-donating substituent, a meth-
oxy group, 1c participated equally well in the reaction (Ta-
ble 2, entry 13).
N
H
N
H
N
H
N
H
R2N
C10, NR2 = NMe2
C11, NR2 = piperidino
HN
C12
Figure 1 Squaramide catalysts used in this study
With organocatalysts in hand, we started screening the
reaction conditions for the Michael addition of dimethyl
malonate to selected aromatic nitroalkenes.
Firstly, the reaction between dimethyl malonate and
trans-4-chloro-β-nitrostyrene (1a) in the presence of
squaramide C1 was examined. The results are collected in
Table 1. We selected the substrate 1a because the corre-
sponding chiral adduct 2a can be further processed to af-
ford baclofen.
As follows from Table 1, the use of 1 mol% of the catalyst
leads to low conversion of reactants, and, therefore, we in-
creased catalyst loading to 5 mol% (Table 1, entry 1 vs. 2).
The effect of solvent was also investigated, and it can be
concluded that dichloromethane appeared to be the best
solvent to obtain high ee values, other solvents provided
poorer results (Table 1, entry 2 vs. 3–5). Interestingly, also
brine can be used with good effect, but the yield was some-
what lower than in dichloromethane (Table 1, entry 6).
Next, the effect of squaramide catalysts C2–9 on the
course of the reaction was tested (Table 2). The catalysts
C2–6, which worked well in our previous study on the
In a view of potentially more efficient chemical produc-
tion, the design and preparation of immobilized, easily re-
coverable, and reusable catalysts appears as one of the most
promising strategies. Some pyrrolidine derivatives support-
ed on polystyrene resins display high catalytic activity and
enantioselectivity in various Michael additions.40 Several
37
Michael addition to an aliphatic nitroalkene, afforded low-
squaramide catalysts have been immobilized by various
strategies.4
1–44
Polymer-immobilized squaramide catalysts
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E. Veverková et al.
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Table 2 Screening of Squaramide Catalysts for the Michael Reaction
Dimethyl Malonate to β-Nitrostyrenes
First, the resin C10 was tested as a catalyst for the
Michael addition of dimethyl malonate to 4-chloro-β-nitro-
styrene (1a). The reaction was carried out in dichlorometh-
ane. A very good result was achieved in the first run. The
product 2a was obtained in a synthetically valuable yield
(83%) with high enantiomeric purity (96% ee) (Table 3, en-
try 1). The high enantiomeric purity of product 2a re-
mained unchanged in following cycles, but the yield de-
creased dramatically especially in the third cycle (Table 3,
entries 2 and 3). The catalyst C11 was equally as enantiose-
lective as C10, but it was less active in terms of the yield
a
MeO2C
catalyst
solvent, r.t.
CO2Me
MeO2C
CO2Me
NO2
NO2
R
1a–c
R
2a–c
e.r.c
Entry
Alkene, R
Catalyst
Time (d) Yield (%)
(conversion, %)
b
(
mol%)
1
2
3
4
5
6
7
8
9
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1a, Cl
1b, H
1c, OMe
C2 (5)
C3 (5)
C3 (5)
C4 (5)
C5 (5)
C6 (5)
C7 (5)
C7 (10)
C8 (5)
C9 (5)
C9 (10)
C1 (5)
C1 (5)
4
25 (39)
85:15
4
59 (65)
50 (–)d
25 (35)
52 (55)
8 (26)
98:2
97:3
77:23
95:5
–
(Table 2, entries 5–7).
4
In an attempt to improve the yield of the product 2a, we
4
tried to use toluene as the solvent (Table 3, entries 7–9). We
observed that the yield increased markedly in the second
run (Table 3, entry 8). This fact is probably caused by ad-
sorption of the product onto aminopolystyrene in the first
run while the saturated resin does not allow this adsorption
in the second cycle. The activity of the catalyst unfortunate-
ly again decreased in the subsequent third run (Table 3, en-
try 9). We tried to improve the recycling of our immobilized
catalysts by using ultrasound technique, but without visible
progress.
4
4
4
5 (58)
–
14
10
4
6 (64)
–
0 (64)
–
10
11
12
3
17 (34)
9 (63)
82:18
85:15
91:9
95:5
14
4
82 (95)
70 (83)
1
4
Table 3 Addition of Dimethyl Malonate to trans-4-Chloro-β-nitrosty-
a
Reaction conditions: 1 (0.55 mmol), dimethyl malonate (0.5 mmol), cata-
Cl (1 mL), r.t.
Determined by H NMR of the crude reaction mixture.
Determined by chiral HPLC on the purified product.
Not determined.
rene (1a) Using Resins C10 and C11a
lyst C1–9 (5 mol%), CH
2
2
b
c
1
MeO2C
CO2Me
MeO2C
CO2Me
NO2
NO2
d
C10 or C11
Cl
solvent, r.t., 4 d
1a
Cl
2a
have not been used in this transformation. Therefore, we
prepared immobilized catalyst C10 and C11 with the best
effective squaramide units C1 (yield) and C2 (enantioselec-
tivity).
These catalysts were prepared by a route shown in
Scheme 1. Aminomethylpolystyrene was treated with di-
methyl squarate to provide functionalized resin 3. Both cat-
alysts C10 and C11 were prepared from the resin 3 through
functionalization with diamines 4 and 5, respectively.
e.r.c
Entry
Catalyst
Solvent
Cycle
Yield (%)
(conversion, %)b
1
2
3
4
5
6
7
8
C10
C10
C10
C11
C11
C11
C11
C11
C11
CH
CH
CH
CH
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
2
2
1
2
3
1
2
3
83 (100)
61 (73)
11 (24)
55 (100)
48 (69)
15 (19)
59 (100)
82 (94)
41 (46)
98:2
98:2
98:2
95:5
97:3
98:2
94:6
95:5
96:3
CH Cl
2
2
CH Cl
O
O
toluene
toluene
toluene
1
2
3
O
O
MeO
OMe
NH2
N
H
OMe
9
CH2Cl2, 2 d
a
3
Reaction conditions: 1a (0.55 mmol), dimethyl malonate (0.5 mmol),
C10,11 (100 mg), solvent (0.5 mL), 4 d.
b
c
1
Determined by H NMR of the crude reaction mixture.
Determined by chiral HPLC on the purified product.
O
O
H2N
NR2
, NR2 = NMe2
, NR2 = piperidino
N
H
N
H
In the second part of our study, we examined a reversed
4
5
Michael addition, that is the addition of nitromethane to
α,β-unsaturated aldehydes. We envisaged that bifunctional
catalysts C7 and C8 could prove useful here. These catalysts
showed very small or no activity in the above described re-
action of β-nitrostyrene with dimethyl malonate. We pre-
sumed that the pyrrolidine unit in compounds C7 and C8
R2N
C10, NR2 = NMe2
C11, NR2 = piperidino
CH2Cl2, r.t., 3 d
Scheme 1 Synthesis of immobilized catalysts C10 and C11
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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E. Veverková et al.
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could activate the aldehyde via iminium salt formation. On
the other hand, the squaramide moiety can activate nitro-
methane via hydrogen bonding. Another reason for the
choice of this reaction was again that its products could be
used in the syntheses of baclofen or phenibut.
Table 4 Optimization of Conjugate Addition of Nitromethane to trans-
Cinnamaldehydes 6a,ba
NO2
CHO
MeNO2
CHO
catalyst, additive
At first, we tested the addition of nitromethane to cin-
namaldehyde (6a) with a higher amount of catalyst C7 (20
mol%). As follows from Table 4, we achieved very poor re-
sults when dichloromethane or methanol was used as a sol-
vent (entries 1 and 2).
R
solvent, r.t.
6
a, R = H
R
6b, R = Cl
7
a,b
Entry Catalyst
Solvent, additive
Time Yield
(d) (%)
e.r.b
(
mol%)
1
2
3
4
5
6
7
8
9
C7 (20)
C7 (20)
C7 (20)
C8 (20)
C7 (20)
C7 (5)
CH
2
Cl
2
4
4
4
4
2
2
2
2
2
1
0
–
Based on experiences with the Michael addition of ni-
tromethane to cinnamaldehyde (6a) reported by many
groups, an acidic or basic additives are necessary for a suc-
cessful reaction. We decided to perform the reaction simi-
lar conditions as published by Hayashi and co-workers us-
ing benzoic acid (20 mol%) as an acidic additive and metha-
MeOH
17 (7a)
43 (7a)
16 (7a)
81 (7a)
78 (7a)
67 (7a)
16 (7a)
5 (7a)
–
c
MeOH, PhCO H
2
–
Hc
MeOH, PhCO
2
–
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
, MeOH, NaOAcd
, MeOH, NaOAcd
, MeOH, NaOAcd
95:5
97:3
55:45
–
45
nol as the solvent. The catalyst C7 afforded the product 7a
in medium yield and catalyst C8 even displayed markedly
lower activity (Table 4, entries 3 and 4). Therefore we tried
to use a basic additive, and the reaction was realized ac-
cording to a protocol reported by Lombardo et al., using 20
mol% of catalyst and 30 mol% of sodium acetate in a mix-
C8 (5)
C1 (5)
, MeOH, NaOAcd
, MeOH, NaOAcd
D,L-proline (20) CH
C7 (5) CH
rac
96:4
10
, MeOH, NaOAcd
91 (7b)
a
Reaction conditions: 6a,b (0.3 mmol), MeNO
or 0.06 mmol), solvent (0.5 mL).
Determined by chiral HPLC of the purified product.
0 mol% of PhCO
0 mol% of NaOAc was used.
2
(0.9 mmol), catalyst (0.015
46
ture of dichloromethane/methanol (9:1). Pleasingly, a sig-
nificant increase in the yield of up to 81% was achieved
with the catalyst C7. The product 7a was isolated in high
enantiomeric purity (90% ee) (Table 4, entry 5). Decreasing
the catalyst loading from 20 mol% to 5 mol% did not have a
negative effect in terms of the yield and enantioselectivity
b
c
2
3
2
H was used.
d
O
O
H2N
O
O
(
Table 4, entry 6). Catalyst C8 afforded the product 7a in
N
Boc
lower yield and poor enantiomeric purity in comparison to
catalyst C7 (Table 4, entry 7).
8
N
H
OMe
N
H
N
H
CH2Cl2, r.t., 3 d
3
N
Surprisingly, the application of catalyst C1 or racemic
proline afforded the product in much lower yields (Table 4,
entries 8 and 9). These results suggest that combination of
squaramide and pyrrolidine unit (C7) is very useful for con-
jugated Michael addition of nitromethane to cinnamalde-
hyde.
Boc
9
O
O
TFA
N
N
H
H
CH2Cl2, r.t., 1 d
HN
C12
As an extension of the present protocol to the prepara-
tion of baclofen, we applied catalyst C7 in the reaction of p-
chlorocinnamaldehyde (6b) with nitromethane. The chiral
intermediate 7b was obtained in high enantiomeric purity
Scheme 2 Synthesis of immobilized catalyst C12
clofen via the addition of nitromethane to α,β-unsaturated
aldehyde 6b.
(92% ee) and in preparatively significant yield (91%) (Table
4
, entry 10).
To compare the synthetic versatility of both adducts 2a
and 7b, we demonstrate here two different total syntheses
of (R)-baclofen. As there are several baclofen syntheses de-
scribed in the literature, we chose those that utilize chiral
intermediates obtained by the above-mentioned Michael
additions.
Lastly, we prepared immobilized catalyst C12 with the
active part similar to that of catalyst C7 (Scheme 2). The
synthesis of this polystyrene supported catalyst consisted
of functionalization of the resin 3 with amine 8, followed by
removal of the Boc group from the amine.
As follows from Table 5, the application of catalyst C12
led to high yields of product 7b especially in the second and
third cycle but the enantioselectivity was lower in compari-
son with a nonsupported counterpart C7. In this view, the
catalyst C7 is preferable to C12 in the total synthesis of ba-
We started the synthesis by performing the Michael ad-
dition of dimethyl malonate to nitroalkene 1a on a 5-mmol
scale. The adduct 2a allowed the synthesis of baclofen hy-
drochloride (12) via a three-step sequence described by
Takemoto and co-workers in 56% overall yield (Scheme 3,
route A).47
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E. Veverková et al.
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Table 5 Conjugate Addition of Nitromethane to trans-p-Chlorocin-
namaldehyde (6b) Using Resin C12
In terms of the total yield of baclofen, route A seems
preferable to route B, probably for higher stability of adduct
a
2a in comparison to compound 7b. On the other hand,
NO2
MeNO2
route B appears preferable judging by enantioselectivity of
the Michael addition.
CHO
CHO
C12, AcONa
Enantiomerically enriched GABAergic drugs can be syn-
thesized by asymmetric organocatalytic Michael additions
using chiral squaramide organocatalysts. We have tested a
range of structurally diverse squaramide derivatives and
found that squaramide C1 was the most useful for catalyz-
ing the Michael addition of dimethyl malonate to trans-β-
nitrostyrenes. Under optimized reaction conditions, the
products 2a–c were obtained in synthetically important
yields with very good enantiomeric purities. Based on this
strategy, the product 2a can be transformed into the highly
enantioenriched baclofen in 56% overall yield.
CH2Cl2/MeOH, r.t.
Cl
Cl
6
b
7b
Cycle
Conversion (%)
Yield (%)
e.r.b
1
2
100
100
100
71
94
92
85:15
82:18
83:17
3
a
Reaction conditions: 6b (0.3 mmol), MeNO
Cl /MeOH (9:1, 0.5 mL), r.t., 24 h.
Determined by chiral HPLC on the purified product.
2
(0.9 mmol), C12 (100 mg),
NaOAc (0.09 mmol), CH
2
2
b
On the other hand, the squaramide organocatalyst pos-
sessing additional pyrrolidine unit C7 worked very well in
the complementary conjugated addition of nitromethane to
cinnamaldehydes. Under basic reaction conditions, the cor-
responding adduct 7b was prepared in high yield with an
enantiomeric purity of 92% ee. Using this methodology as a
key step, a short synthesis of baclofen can be realized in
MeO2C
CO2Me
MeO2C
CO2Me
NO2
NO2
C1 (5 mol%)
CH2Cl2, r.t.
Cl
1a
2a, 76%
6% ee
9
6 h
Cl
8
O
MeO2C
1. NaOH
NiCl2, NaBH4
NH
EtOH, r.t., 30 min
25% overall yield. Both approaches can be used in the syn-
MeOH, 0 °C to r.t., 8 h
2. toluene, reflux, 6 h
thesis of baclofen. The former route gives higher overall
yield, but the latter is more enantioselective. Polymer-
immobilized squaramides C10 and C11 catalyzed the
Michael addition highly enantioselectively, but yields de-
creased between runs.
Chiral squaramides appear as viable alternatives to
thioureas in catalysis of Michael additions, which are key
steps in the syntheses of chiral GABA derivatives.
Cl
10, 90%
O
NH2·HCl
CO2H
NH
6
M HCl
reflux, 24 h
12, 92%
overall 56%)
Cl
11, 89%
Cl
(
Scheme 3 Synthesis of baclofen hydrochloride (10); route A
The solvents were purified by standard methods.49 NMR spectra were
recorded on Varian NMR System 300 or 600 instrument (300 MHz for
Alternative Michael addition of nitromethane to enal 6b
was performed on a 6-mmol scale. Starting from compound
1
13
H, 151 MHz for C) relative to TMS. Specific optical rotations were
7
b, baclofen hydrochloride (12) was prepared in only two
3
–1
32
measured on Jasco P-2000 instrument and are given in deg cm g
steps, an oxidation according to protocol by Zu et al. and a
reduction published by Camps et al. in 25% overall yield
–1
dm . Column chromatography was performed on Merck silica gel 60.
TLC was performed on Merck TLC-plates silica gel 60, F-254. Enantio-
meric excesses were determined by HPLC using Chiralpak AD-H, AS-
H, or OD-H (Daicel Chemical Industries) columns using n-hexane/
i-PrOH as a mobile phase and detected by UV at 254 nm and 210 nm.
48
(
Scheme 4, route B).
MeNO2
NO2
CHO
C7 (5 mol%)
NaOAc (30 mol%)
35
36
37
22
33
21
CHO
The squaramide organocatalysts C1, C2, C3, C4, C5, C6, and
C7
38,39
were synthesized according to literature procedures.
Cl
CH2Cl2/MeOH (9:1)
r.t., 24 h
Cl
6b
7b, 64%, 92% ee
(S)-N-{(1R,2R)-2-[(2-{[3,5-Bis(trifluoromethyl)benzyl]amino}-3,4-
dioxocyclobut-1-en-1-yl)amino]cyclohexyl}pyrrolidine-2-carbox-
amide (C8)
NO2
NH2·HCl
CO2H
KH2PO4
H2O2, NaClO2
1. H2, Raney-Ni
MeOH
A solution of (S)-Boc-proline (215 mg, 1.0 mmol) and Et N (100 mg,
3
CO H
2
1
.0 mmol) in THF (4 mL) was stirred for 1 h at 0 °C. Then ethyl chloro-
formate (88 μL, 1.0 mmol) was added and the mixture was stirred for
0 min at 0 °C. After this time, 3-{[3,5-bis(trifluoromethyl)ben-
MeCN, 4 h
2. HCl
Cl
Cl
12, 64%
overall 25%)
13, 61%
3
(
zyl]}amino-4-{[(R,R)-2-aminocyclohexyl]amino}cyclobut-3-ene-1,2-
dione (400 mg, 0.9 mmol) was added, the solution was allowed to
Scheme 4 Synthesis of baclofen hydrochloride (10); route B
23
reach r.t. and stirred for a further 12 h. The resulting solid Boc-pro-
tected C8 was obtained by filtration. Deprotection was performed
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
Synthesis
E. Veverková et al.
Paper
with CH Cl /TFA (4:1; 12.5 mL) for 2 h at r.t. After concentration, the
Immobilized Catalyst C10
2
2
oil residue was triturated with MeOH saturated with NH3 (10 mL).
The resin 3 (0.42 g, 0.64 mmol of squaramide unit) was added to a
Catalyst C8 was obtained as a colorless solid; yield: 350 mg (86%); mp
51
solution of diamine 4 (273 mg, 1.92 mmol) in CH Cl (5 mL). The
2
2
25
2
32 °C (decomp.); [α]D +4.1 (c 0.5, MeOH).
mixture was stirred for 3 d at r.t. The suspension was filtered, and the
solid was sequentially washed with Et O (50 mL), EtOAc (2 × 50 mL),
IR: 3195, 3051, 2930, 1647, 1563, 1470, 1435, 1381, 1339, 1274,
2
–1
1172, 1124, 840, 801, 724, 703, 682 cm
.
and MeOH (2 × 50 mL). The resin was dried at r.t. for 1 d to give the
1
immobilized catalyst C10 (0.445 g); Anal. C, 79.73; H, 8.04; N, 4.52.
H NMR (300 MHz, CD OD): δ = 7.98 (s, 2 H), 7.88 (s, 1 H), 4.94 (s, 2
3
–1
The final functionalization (1.46 mmol g ) was calculated from the
difference between reacted and unreacted diamine that was recov-
ered from combined washings after concentration (0.180 g, 1.27
mmol, ca. 2 equiv).
H), 3.89–3.81 (m, 2 H), 3.74–3.66 (m, 1 H), 3.12–3.07 (m, 2 H), 2.26–
2
H), 1.50–1.34 (m, 5 H).
.15 (m, 1 H), 2.12–2.04 (m, 1 H), 1.97–1.92 (m, 1 H), 1.83–1.71 (m, 4
13
C NMR (150 MHz, CD OD): δ = 182.5, 182.1, 170.9, 168.0, 161.8 (q,
3
J = 34.5 Hz), 141.8, 131.6 (q, J = 33.0 Hz), 128.2, 124.2 (q, J = 272 Hz),
Immobilized Catalyst C11
121.1, 117.8 (q, J = 293 Hz), 59.8, 57.3, 53.3, 46.3, 46.1, 33.0, 31.3,
The resin 3 (663 mg, 1.01 mmol of the squaramide unit) was added to
30.0, 24.3, 24.1.
37
a solution of diamine 5 (445 mg, 2.44 mmol) in CH Cl (5 mL). The
2
2
+
HRMS (HESI): m/z [M + H] calcd for C24H27F N O : 533.1982; found:
6
4
3
mixture was stirred for 3 d at r.t. The suspension was filtered, and the
solid was sequentially washed with Et O (50 mL), EtOAc (2 × 50 mL),
533.1992.
2
UV-VIS: λmax = 292 nm.
and MeOH (2 × 50 mL). The filtrate was evaporated, and weight of un-
reacted diamine was 297 mg (1.63 mmol). The resin was dried at r.t.
for 1 d to give the immobilized catalyst C11 (781 mg); Anal. C, 81.99;
H, 8.09; N, 4.27. The final functionalization (1.04 mmol g ) was cal-
culated from the difference between reacted and unreacted diamine
that was recovered from combined washings after concentration
(0.297 g, 1.63 mmol).
3-{[(1R,2R)-2-(Dimethylamino)cyclohexyl]amino}-4-[(4-nitro-
–1
phenyl)amino]cyclobut-3-ene-1,2-dione (C9)
To a solution of (R,R)-1,2-diaminocyclohexane (220 mg, 1.92 mmol)
in CH Cl (8 mL) was added 3-methoxy-4-[(4-nitrophenyl)amino]cy-
2
2
50
clobut-3-ene-1,2-dione (477 mg, 1.92 mmol). The mixture was
stirred for 24 h at r.t. After this time, the resulting mixture was dilut-
ed with H O (50 mL) and the generated precipitate was collected by
Immobilized Catalyst C12
2
filtration. Then, to the precipitate was added aq HCHO (37%, 2 mL)
The resin 3 (0.42 g, 0.64 mmol of squaramide unit) was added to solu-
39
and HCO H (80%, 2 mL) and the mixture was stirred at 65 °C for 24 h.
tion of amine 8 (0.32 g, 1.6 mmol) in CH Cl (2.5 mL). The mixture
2
2 2
The mixture was filtered with the aid of HCO H (2 mL). The filtrate
was stirred for 3 d at r.t. Resin 9 was separated by filtration and
2
was basified by 6 M aq NaOH to pH 12 and extracted with EtOAc. The
combined organic layers were dried (Na SO ) and then concentrated.
washed with CH Cl (2 × 20 mL) (the filtrate was evaporated, and
weight of unreacted diamine was 192 mg, 0.96 mmol, 1.5 equiv). The
2
2
2
4
Recrystallization (MeOH) gave C9 as an orange solid; yield: 110 mg
deprotection was performed with a mixture of TFA (2 mL) in CH Cl2
(10 mL) for 1 d at r.t. Deprotected resin C12 was removed by filtration
2
25
(30%); mp 238 °C (decomp.); [α]D –98.4 (c 0.20, MeOH).
and then suspended in 1% NaHCO solution (50 mL). After 1 h, the res-
in was again filtered and washed with water (2 × 50 mL) and MeOH
IR: 3194, 3144, 2934, 2856, 2780, 1798, 1666, 1620, 1602, 1576,
3
–1
1558, 1509, 1433, 1417, 1335, 1270, 1190, 1110, 848, 748 cm .
(2 × 50 mL). The resin was dried in air at r.t. for 1 d to give C12 (419
1
H NMR (300 MHz, DMSO-d ): δ = 8.20 (d, J = 9.3 Hz, 2 H), 7.56 (d,
6
mg); Anal. C, 75.51; H, 7.04; N, 3.88. The final functionalization (1.53
J = 9.3 Hz, 2 H), 4.00 (m, 1 H), 2.54–2.47 (m, 1 H), 2.32 (s, 6 H), 2.26–
–1
mmol g ) was calculated from the difference between reacted and
unreacted diamine that was recovered from combined washings after
concentration (192 mg, 0.96 mmol).
2.21 (m, 1 H), 1.99–1.76 (m, 3 H), 1.49–1.26 (m, 4 H).
13
C NMR (150 MHz, CD OD): δ = 186.1, 181.9, 171.5, 164.3, 146.6,
3
1
2
43.9, 126.9, 126.5, 119.1, 111.5, 68.5, 56.6, 40.6, 40.4, 36.1, 26.0,
5.8, 22.9.
Enantioselective Michael Addition of Dimethyl Malonate to Sub-
stituted trans-β-Nitrostyrenes; General Procedure
HRMS (HESI): m/z [M + H]+ calcd for C18H23N O : 359.1714; found:
4
4
3
59.1716.
To a solution of trans-β-nitrostyrene 1a–c (0.55 mmol) and dimethyl
malonate (66 mg, 0.50 mmol) in CH Cl (0.5 mL), catalyst C1–9 (0.025
UV-VIS: λmax = 388 nm.
2
2
mmol) was added. The mixture was stirred at r.t. for 96 h. Then, the
mixture was diluted with CH Cl (15 mL), washed with 1 M HCl (10
Immobilized Squaramide 3
2
2
mL), and dried (Na SO ). After evaporation of solvent, the residue was
2
4
Aminomethylpolystyrene (AM-NH , f = 1.4 mmol/g; 1.051 g) was
2
o
purified by column chromatography (silica gel, EtOAc/hexanes 1:5) to
afford desired product 2a–c. Yields and enantiomeric excesses are
summarized in Tables 1 and 2.
added to a solution of dimethyl squarate (1.007 g, 7.09 mmol) in
CH Cl (10 mL) and the mixture was stirred for 2 d at r.t. The suspen-
2
2
sion was filtered, and the resin 3 was sequentially washed with Et O
2
(
50 mL), EtOAc (2 × 50 mL), and MeOH (2 × 50 mL). The resin was
Polymer-Supported Michael Addition of Dimethyl Malonate to
trans-4-Chloro-β-nitrostyrene (1a)
dried at r.t. for 1 d to give 3 (1.321 g); content squaramide unit 1.527
–1
mmol g . The content of squaramide unit was calculated on the basic
weight of unreacted dimethyl squarate that was recovered from com-
bined washings after concentration (0.779 g, 5.48 mmol).
To a solution of trans-β-nitrostyrene 1a (0.55 mmol) and dimethyl
malonate (66 mg, 0.5 mmol) in CH Cl (0.5 mL), catalyst C10 (100 mg,
2
2
0.025 mmol) or C11 (100 mg, 0.025 mmol) was added. The mixture
was stirred at r.t. for 96 h. Then, the mixture was diluted with CH Cl2
2
(
15 mL) and the catalyst was directly filtered off. The solid resin was
washed with Et O (15 mL) followed by EtOAc (15 mL) and reused in
2
the next cycle after drying in air at r.t. for 1 d. The combined filtrates
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
Synthesis
E. Veverková et al.
Paper
were concentrated and the residue was purified by column chroma-
tography (silica gel, EtOAc/hexanes 1:5) to afford desired product 2a.
Yield and enantiomeric excess data for 2a are summarized in Table 3.
mixture was stirred at r.t. for 24 h. The mixture was then diluted
CH Cl (15 mL) and the resin was directly filtered off. The solid resin
2
2
was washed with Et O (15 mL) followed by EtOAc (15 mL) and reused
2
in another cycle after drying in air at r.t. for 1 d. The combined fil-
trates were washed with 1 M HCl (10 mL) and dried (Na SO ). After
Dimethyl 2-[1-(4-Chlorophenyl)-2-nitroethyl]malonate (2a)
2
4
Colorless solid; yield: 132 mg (84%); 86% ee; mp 93 °C (Lit.52 93.1–
concentration, the residue was purified by column chromatography
silica gel, EtOAc/hexanes 1:5) to afford the desired product 7b. Yields
and enantiomeric excesses are summarized in Table 5.
(
94.7 °C).
1
H NMR (300 MHz, CDCl ): δ = 7.31 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4
3
Hz, 2 H), 4.94–4.83 (m, 2 H), 4.26–4.18 (m, 1 H), 3.83 (d, J = 9 Hz, 1 H),
4
-Nitro-3-phenylbutanal (7a)
3
.76 (s, 3 H), 3.59 (s, 3 H).
Colorless oil; yield: 45 mg (78%); 94% ee.
13
C NMR (151 MHz, CDCl ): δ = 167.6, 167.0, 134.6, 134.4, 129.27,
3
1
H NMR (300 MHz, CDCl ): δ = 9.71 (s, 1 H), 7.35–7.22 (m, 5 H), 4.70–
129.26, 77.2, 54.5, 53.1, 53.0, 42.3.
3
4.58 (m, 2 H), 4.11–4.06 (m, 1 H), 2.96 (d, J = 7.2 Hz, 2 H).
Spectral data are consistent with those in the literature.53 Enantio-
meric purity was determined by HPLC [Daicel Chiralpac OD-H, hex-
13
C NMR (151 MHz, CDCl ,): δ = 198.9, 133.6, 130.1, 128.5, 127.4, 79.4,
3
46.4, 37.9.
anes/i-PrOH (70:30), flow rate 1.0 mL/min, λ = 220 nm]: t = 9.96 (mi-
R
nor), 12.42 min (major).
Spectral data are consistent with those in the literature.46 Enantio-
meric purity was determined by HPLC [Daicel Chiralpac OD-H, hex-
ane/i-PrOH (70:30), flow rate 0.70 mL/min, λ = 210 nm]: t = 34.2
Dimethyl 2-[1-(4-Methoxyphenyl)-2-nitroethyl]malonate (2c)
R
(minor), 38.3 min (major).
Colorless oil; yield: 109 mg (70%); 90% ee.
1
H NMR (300 MHz, CDCl ): δ = 7.14 (d, J = 8.7 Hz, 2 H), 6.84 (d, J = 8.7
3
3
-(4-Chlorophenyl)-4-nitrobutanal (7b)
Colorless oil; yield: 62 mg (91%); 92% ee.
1H NMR (300 MHz, CDCl
): δ = 9.70 (s, 1 H), 7.33 (d, J = 8.7 Hz, 2 H),
.18 (d, J = 8.7 Hz, 2 H), 4.71–4.55 (m, 2 H), 4.15–4.01 (m, 1 H), 2.94
Hz, 2 H), 4.90–4.81 (m, 2 H), 4.23–4.15 (m, 1 H), 3.83 (d, J = 9.3 Hz, 1
H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.57 (s, 3 H).
13
3
C NMR (151 MHz, CDCl ,): δ = 170.4, 169.9, 161.8, 131.3, 130.4,
3
7
116.0, 79.8, 56.8, 56.5, 57.1, 53.8, 44.9.
(d, J = 7.2 Hz, 2 H).
Spectral data are consistent with those in literature.53 Enantiomeric
purity was determined by HPLC [Daicel Chiralpac OD-H, hexane/
13
C NMR (151 MHz, CDCl ,): δ = 198.2, 136.7, 129.4, 128.8, 124.3, 79.1,
3
46.3, 37.3.
i-PrOH (70:30), flow rate 1.0 mL/min, λ = 254 nm]: t = 12.38 (minor),
R
14.24 min (major).
Spectral data are consistent with those in the literature.46 Enantio-
meric purity was determined by HPLC [Daicel Chiralpac OD-H, hex-
ane/i-PrOH (70:30), flow rate 0.70 mL/min, λ = 210 nm]: t = 26.0
(minor), 31.9 min (major).
Dimethyl 2-(2-Nitro-1-phenylethyl)malonate (2b)
Colorless solid; yield: 115 mg (82%); 82% ee; mp 63 °C (Lit.54 63 °C).
R
1
H NMR (300 MHz, CDCl ): δ = 7.33–7.28 (m, 3 H), 7.24–7.21 (m, 2 H),
3
Baclofen; Synthesis by Route A
Large-Scale Preparation of 2a
4
.94–4.86 (m, 2 H), 4.28–4.21 (m, 1 H), 3.86 (d, J = 9 Hz, 1 H), 3.76 (s, 3
H), 3.56 (s, 3 H).
13
C NMR (151 MHz, CDCl ,): δ = 168.1, 167.8, 136.3, 129.2, 128.6,
3
To a solution of trans-β-nitrostyrene 1a (1.068 g, 5.82 mmol) and di-
methyl malonate (700 mg, 5.30 mmol) in CH Cl (6 mL), catalyst C1
128.1, 77.4, 55.0, 53.3, 53.0, 43.1.
2
2
Spectral data are consistent with those in the literature.25 Enantio-
meric purity was determined by HPLC [Daicel Chiralpac OD-H, hex-
ane/i-PrOH (80:20), flow rate: 1.0 mL/min, λ = 220 nm]: t = 11.32
(122 mg, 0.265 mmol) was added. The mixture was stirred at room
temperature for 96 h. Then, the reaction mixture was diluted by
CH Cl (50 mL) washed with 1 M HCl (2 × 50 mL) and dried (Na SO ).
R
2
2
2
4
(minor), 19.71 min (major).
After evaporation of solvent, the residue was purified by column
chromatography (SiO , EtOAc/hexanes 1:5) to afford desired product
2a (1.27 g, 76%).
2
Enantioselective Conjugate Addition of Nitromethane to trans-
Cinnamaldehydes; General Procedure
To a solution of cinnamaldehyde 6a,b (0.3 mmol) in CH Cl /MeOH
Methyl (R)-4-(4-Chlorophenyl)-2-oxopyrrolidine-3-carboxylate
(10)
2
2
47
(9:1, 0.5 mL) catalyst C7 or C8 (0.015 mmol), MeNO2 (91 mg, 0.9
mmol), and NaOAc·3H O (12.2 mg, 0.09 mmol) were added. The re-
2
To a solution of 2a (196 mg, 0.62 mmol) in MeOH (3 mL) was added
sulting mixture was stirred at r.t. for the stated time. The mixture was
then diluted with CH Cl (15 mL), washed with 1 M HCl (10 mL), and
NiCl ·6H O (146 mg, 0.62 mmol) and then NaBH (258 mg, 7.44
2
2
4
2
2
mmol) at 0 °C. The resulting mixture was stirred for 8 h at r.t. Then
dried (Na SO ). After concentration, the residue was purified by col-
2
4
sat. NH Cl solution was added and the product was extracted with
4
umn chromatography (silica gel, EtOAc/hexanes 1:5) to afford desired
product 7a,b. Yields and enantiomeric excesses are summarized in
Table 4.
CHCl . The combined organic extracts were dried (MgSO ) and con-
3
4
centrated. Column chromatography (silica gel, CHCl /MeOH 20:1) af-
3
47
forded 10 (142 mg, 90%) as a colorless solid; mp 162–163 °C (Lit.
1
61–162 °C).
Polymer-Supported Conjugate Addition of Nitromethane to trans-
p-Chlorocinnamaldehyde (6b)
1
H NMR (300 MHz, CDCl ): δ = 7.32 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.7
3
Hz, 2 H), 6.42 (br s, 1 H), 4.15–4.06 (q, J = 9 Hz, 1 H), 3.84–3.79 (m, 3
H), 3.52 (d, J = 9.6 Hz, 1 H), 3.40 (t, J = 9 Hz, 1 H).
1H NMR data agree with those in the literature.
To a solution of cinnamaldehyde 6b (50 mg, 0.3 mmol) in CH Cl /
2
2
MeOH (9:1, 0.5 mL), catalyst C12 (100 mg), MeNO (91 mg, 0.9 mmol),
2
and NaOAc·3H O (12.2 mg, 0.09 mmol) were added. The resulting
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
Synthesis
E. Veverková et al.
Paper
(
R)-4-(4-Chlorophenyl)pyrrolidin-2-one (11)47
To a solution of 10 (142 mg, 0.53 mmol) in EtOH (3 mL), 1 M aq NaOH
1 mL) was added and the resulting mixture was stirred for 30 min at
(R)-4-Amino-3-(4-chlorophenyl)butanoic Acid Hydrochloride
48
(12)
(
To a solution of acid 13 (200 mg, 1.65 mmol) in MeOH (30 mL), Raney
r.t. EtOH was evaporated in vacuo; the residue was neutralized with 1
M HCl and extracted with CHCl3 (4 × 20 mL). The combined organic
nickel (500 mg, 50% in H O) was added. The resulting mixture was
2
stirred for 24 h at r.t. under an atmosphere of H (5 atm). The reaction
2
extracts were dried (MgSO ) and concentrated. Solid residue was dis-
solved in boiling toluene (8 mL) and this solution was refluxed for 6 h.
was quenched with 0.1 M aq NaOH (15 mL) and the mixture was fil-
tered through a pad of Celite. The filtrate was concentrated and then
dissolved in 2 M HCl (10 mL). This solution was then washed with
EtOAc (2 × 20 mL). Aqueous phase was concentrated and the residue
dissolved in MeOH (10 mL) and filtered. The solvent was then dis-
tilled off and the solid residue was refluxed in 6 M HCl (5 mL) for 2 h.
The solvent was then again distilled off and the residue dried under
reduced pressure to give 12 (127 mg, 64%).
4
Distillation of the solvent afforded compound 11 (98 mg, 89%) as a
4
7
30
colorless solid; mp 108–111 °C (Lit. 111–112 °C). [α]D –40.0 (c 1.0,
47
30
CHCl ) {Lit. [α]D –39.0 (c 1.0, CHCl )}.
3
3
1
H NMR (300 MHz, CDCl ): δ = 7.32 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4
3
Hz, 2 H), 6.32 (br s, 1 H), 3.78 (t, J = 8.7 Hz, 1 H), 3.68 (m, 1 H), 3.38 (q,
J = 8.7, 7.2 Hz, 1 H), 2.74 (dd, J = 16.8, 8.7 Hz, 1 H), 2.46 (dd, J = 17.1,
8.4 Hz, 1 H).
1H NMR data agree with those in the literature.
Acknowledgment
(
R)-4-Amino-3-(4-chlorophenyl)butanoic Acid Hydrochloride
This publication is the result of the project implementation:
47
(12)
26240120001 supported by the Research & Development Operational
A solution of 11 (80 mg, 0.40 mmol) in 6 M HCl (2.5 mL) was refluxed
for 24 h. Careful evaporation and subsequent drying afforded 12 (94
Programme funded by the European Regional Development Fund.
55
mg, 92%) as a colorless solid; mp 198–200 °C (Lit. 198–199 °C);
25
47
25
[
α]D –1.97 (c 0.6, H O) {Lit. [α]D –2.17 (c 0.6, H O)}.
Supporting Information
2
2
1
H NMR (300 MHz, D O): δ = 7.49–7.36 (m, 4 H), 3.50–3.24 (m, 3 H),
2
Supporting information for this article is available online at
2.94–2.74 (m, 2 H).
http://dx.doi.org/10.1055/s-0035-1560420.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
1
H NMR (300 MHz, DMSO-d ): δ = 12.20 (br s, 1 H), 7.97 (s, 3 H), 7.34–
6
7.25 (m, 4 H), 3.06–3.00 (m, 1 H), 2.92–2.85 (m, 1 H), 2.75 (dd, J = 5.4,
1
6.5 Hz, 1 H), 2.50 (dd, J = 9.3, 16.2 Hz, 1 H).
References
13
C NMR (75 MHz, D O): δ = 175.3, 137.0, 133.3, 129.4, 129.2, 43.6,
2
(1) Leyva-Pérez, A.; García-García, P.; Corma, A. Angew. Chem. Int.
39.4, 38.3.
Ed. 2014, 53, 8687.
NMR data agree with those in the literature.
(2) Bowery, N. G.; Hill, D. R.; Hudson, A. L.; Doble, A.; Middlemiss,
D. N.; Shaw, J.; Turnbull, M. Nature (London) 1980, 283, 92.
Baclofen; Synthesis by Route B
(3) Lapin, I. CNS Drug Rev. 2001, 7, 471.
(
4) Ricci, A. ISRN Org. Chem. 2014, article ID 531695;
http://dx.doi.org/10.1155/2014/531695, http://www.hindawi.com/
journals/isrn/contents/organic.chemistry/.
Large-Scale Preparation of 7b
To a solution of cinnamaldehyde 6b (906 mg, 5.46 mmol) in CH Cl /
2
2
(
5) Aleman, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774.
MeOH (9:1, 6 mL) catalyst C7 (115 mg, 0.273 mmol), MeNO (1.048 g,
2
(
6) Christmann, M. Applications of Aminocatalysis in Target-Ori-
ented Synthesis, In Science of Synthesis: Asymmetric Organocatal-
ysis; Vol. 1; List, B., Ed.; Thieme: Stuttgart, 2012, 439–454.
7) Marcia de Figueiredo, R.; Christmann, M. Eur. J. Org. Chem. 2007,
1
6.4 mmol) and NaOAc·3H O (223 mg, 1.63 mmol) were added. The
2
resulting mixture was stirred at room temperature for 24 h. The reac-
tion mixture was then diluted with CH Cl (100 mL) washed with 1 M
2
2
(
HCl (2 × 50 mL) and dried (Na SO ). After concentration, the residue
2
4
2575.
was purified by column chromatography (SiO , EtOAc/hexanes 1:5) to
2
(8) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
afford desired product 7b (793 mg, 64%).
(9) Žabka, M.; Šebesta, R. Molecules 2015, 20, 15500;
http://www.mdpi.com/journal/molecules.
3
-(4-Chlorophenyl)-4-nitrobutanoic Acid (13)32
(
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633.
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To a solution of 7b (738 mg, 2.21 mmol) in MeCN (17 mL), a solution
2
of KH PO (332 mg, 2.44 mmol) in H O (8 mL) and 30% H O (480 mg,
2
4
2
2
2
(
4.24 mmol) were added at 0 °C. Then a solution of NaClO2 (830 mg,
4
9
.17 mmol, technical grade 80%) in H O (16 mL) was added and the
2
(
(
resulting mixture was stirred for 4 h at r.t The reaction was stopped
by the addition of sat. aq Na S O solution and then acidified with sat.
2
2
3
2013, 11, 7051.
KHSO solution. The crude product was extracted with CH Cl (5 × 50
4
2
2
(
(
(
(
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mL) and the combined extracts were dried (MgSO ). Evaporation of
4
solvents afforded carboxylic acid 13 (480 mg, 61%) as colorless oil, in
25
acceptable purity for the next reaction step; [α] +21.7 (c 0.5, CHCl3)
D
32
20
{
Lit. [α]D +10.4 (c 1.0, CHCl )}.
3
1
H NMR (300 MHz, CDCl ): δ = 7.34–7.31 (m, 2 H), 7.18–7.16 (m, 2 H),
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2011, 17, 6890.
3
4.74–4.56 (m, 2 H), 3.98–3.82 (m, 1 H), 2.82–2.78 (m, 2 H).
1H NMR data agree with those in the literature.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I