Nucleophilic addition to nitroacrylates: application towards the synthesis of 2,3-dehydroamino acids and 2,3-diamino acids

Article abstract of DOI:10.1016/j.tet.2009.11.029

The addition of the N-pronucleophiles to 2- or 3-nitro-2-alkenoates in the presence of base provided Michael addition products. In the case of 3-nitro compounds, reaction occurred via the formation of α-adducts and the subsequent elimination of nitrous ac

Full text of DOI:10.1016/j.tet.2009.11.029

Tetrahedron 66 (2010) 152–156
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nucleophilic addition to nitroacrylates: application towards the
synthesis of 2,3-dehydroamino acids and 2,3-diamino acids
*
Elzbieta Lewandowska , Kinga Wichlacz, Adam J. Sobczak
Department of Chemistry, Poznan University of Life Sciences, 60-625 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 May 2009
Received in revised form 20 October 2009
Accepted 5 November 2009
Available online 10 November 2009
The addition of the N-pronucleophiles to 2- or 3-nitro-2-alkenoates in the presence of base provided
Michael addition products. In the case of 3-nitro compounds, reaction occurred via the formation of
a
-adducts and the subsequent elimination of nitrous acid to produce olefins with high Z stereoselectivity.
3-Phthalimido-2-nitrocinnamate adduct 8a was converted into 2,3-diamino ester 11a.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate addition
anti-Michael addition
Nitroacrylates
1. Introduction
routes to 2,3-diaminocarboxylic acids of variable length, yields and
complexity have been reported.5 However, to the best of our
knowledge, the conjugate addition of nitrogen nucleophiles to ni-
tro-Michael acceptors towards the synthesis of 2,3-diamino acids
has been only reported in a study for a synthesis of an angiotensin II
analogue.8 Herein, we report studies on the nucleophilic addition of
N-pronucleophiles to a- and b-nitroacrylates as Michael acceptors
in a new approach towards the synthesis of 2,3-diamino and N-
protected 2,3-dehydroamino acid derivatives.
The Michael addition between various nucleophiles and a,b-un-
saturated alkenoates in most cases occurs regioselectively at the
position to give the
-adduct.1 The regioselectivity of the Michael
reaction can be reversed by attaching groups with strongly electron-
withdrawing properties at the -carbon, which leads to the formation
of the
-substituted products.2 It was also predicted, based on the
theoretical calculations that methyl 3-nitropropenoate should react
with nucleophiles to give a
-substituted adduct.3 This approach has
been employed in the synthesis of aliphatic
-thioacrylates,4a poly-
functionalized
-unsaturated esters4b and very recently in the
uncatalyzed -addition of amines to
-nitroacrylates.4c We have
decided to investigate the addition of nitrogen nucleophiles to
-nitroacrylates as -Michael acceptors and -nitroacrylates as con-
jugate Michael acceptors. The expected -amino- -nitro or -amino-
-nitroadducts after subsequent reduction of nitro group would lead
to the formation of -diamino acids or to -dehydroamino acids
after -elimination of HNO2.
-Diaminocarboxylic acids5 and
-dehydroamino acids6 are constituents of several natural products
b-
b
b
a
a
a
2. Results and discussion
a,b
a
b
We started with the investigation of anti-Michael addition of
nitrogen pronucleophiles such as imides and carbamates to
b-
b
a
a
nitroacrylates. The 3-nitrocrotonate 1a was prepared by reaction of
a
b
b
the corresponding acrylic ester with NaNO2–ceric ammonium ni-
a
trate (CAN) as reported.9 The 3-nitropentenoate 1b and
b-nitro-
a
,b
a,b
cinnamic esters 1c–d were obtained by the nitroaldol (Henry)
reaction between the appropriate nitroalkanes and ethyl glyoxalate
as described.10,11 The 3-nitroacrylates 1a–b were obtained as single
b
a,b
a,b
and biologically active molecules. Considering the potential of these
classes of amino acids, developing new methodologies for their
synthesis have been undertaken.
Mioskowski and co-workers recently utilized the reaction of
3,3,3-trifluoro-1-nitropropene with N-nucleophiles for the syn-
thesis of vicinal diamines.7 In the past years a number of synthetic
E-isomers while b-nitrocinnamates 1c–d were prepared as mix-
tures of E and Z isomers. Initially, we studied nucleophilic addition
of the anion derived from phthalimide as a source of the amino
group. Thus, treatment of 3-nitrocrotonate (E)-1a with phthalimide
in the presence of DBU (in acetonitrile at ꢀ10 ꢁC) initially produced
the anti-Michael addition product 4a (TLC), which underwent
subsequent in-situ elimination of HNO2 to produce stable 2-N-
phthalimido-2-butenoate 5a as a single Z-isomer (84%; Table 1,
* Corresponding author. Tel.: þ48 61 8487847; fax: þ48 61 8487824.
E-mail address: elalew@au.poznan.pl (E. Lewandowska).
entry 1). Analogous treatment of
b-nitrocinnamate 1c gave
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.029

E. Lewandowska et al. / Tetrahedron 66 (2010) 152–156
153
addition products. Very recently, Buevich et al.10 reported that
a-
Table 1
Addition of nitrogen nucleophiles to ethyl-
b
-nitroacrylates
nitrocinnamic esters can be efficiently prepared by the addition of
a nitro group to cinnamic esters utilizing NaNO2–ceric ammonium
NO2
O
O
NO2
O
nitrate (NaNO2–CAN) method.9 Using this methodology the
a-
a or b
- HNO2
+ RR'NH
OEt
OEt
OEt
R1
R1
R1
NRR'
NRR'
nitrocinnamates 7a–c were prepared as a mixture of E and Z
isomers.
1
2 or 3
4
5 or 6
Series: a R1 = Me; b R1 = Et; c R1 = Ph; d R1 = 4-Me-Ph
Thus, treatment of
(1.2 equiv) in the presence of DBU (1.2 equiv) in acetonitrile, at 0 ꢁC
gave stable -nitro- -phthalimido product 8a in 94% yield as
a mixture of two diastereoisomers (1:2; Table 2, entry 1). Analogous
treatment of the substituted -nitrocinnamates (E/Z)-7b–c also
afforded -adducts 8b–c (entries 2 and 3). Reaction of the -nitro-
cinnamates 7a–c with 2-oxazolidinone (1.2 equiv) in the presence
of DBU (1.2 equiv) in acetonitrile at 0 ꢁC also provided the
-nitro-
a-nitrocinnamate (E/Z)-7a with phthalimide
O
a
b
3 or 6 RR'N =
N
2 or 5 RR'N =
N
O
O
O
a
Reagents and condition: (a) DBU/CH3CN/0oC; (b) BuLi/THF/-20oC
b
a
Entry
Substrate
Nucleophile
Product
Yielda (%)
Condition
a
b-
1
2
3
4
5
6
7
8
1a (E)
1b (E)
1c (E)
1d (E/Z)
1a (E)
1b (E)
1c (E)
2
2
2
2
3
3
3
3
5a
5b
5c
5d
6a
6b
6c
6d
84
81
98
87
58
48
60
64
a
a
a
a
b
b
a
a
oxazolidin-2-yl products 9a–c in 56–72% yields (entries 4–6).
Table 2
Addition of nitrogen nucleophiles to ethyl-
a
-nitroacrylates
NRR' O
NO2
O
DBU
CH3CN
R1
1d (E/Z)
+ RR'NH
OEt
OEt
a
Isolated yield.
NO2
R1
2 or 3
8 or 9
7
Series: a R1 = H; b R1 = MeO; c R1 = Me
a separable mixture of the olefin 5c and the unstable a-addition
product 4c (2:1, estimated by 1H NMR spectroscopy). The 1H NMR
spectrum of 4c showed that the adduct (3:1 mixture of two
O
3 or 9 RR'N =
N
2 or 8 RR'N =
N
diastereoisomers) is derived from
a-addition of phthalimide to
O
b
-nitrocinnnamate 1c. The presence of two sets of doublets (d,
O
O
J¼10.7 Hz for the major isomer, and J¼11.4 Hz for the minor one)
corresponds to the hydrogens at C2 and C3 instead of signals for two
Entry
Substrate
Nucleophile
Product
Yielda (%)
Isomers ratiob
hydrogens at C2. Numerous attempts to prepare exclusively the a-
1
2
3
4
5
6
7a E/Z (2:1)
7b E/Z (5:2)
7c E/Z (2:1)
7a
7b
7c
2
2
2
3
3
3
8a
8b
8c
9a
9b
9c
94
81
84
56
58
72
2:1
1.4:1
1.4:1
3:1
1:1
1:1
addition product 4c failed. On the other hand, we found that re-
action of 1c with 3.6 equiv of phthalimide in the presence of DBU/
MeCN afforded exclusively product (Z)-5c (98%, entry 3). The 1H
NMR spectrum of (Z)-5c reveals that the chemical shift of the b-vinyl
proton signal occurs at 8.11 ppm in agreement with the literature
value.12 Analogous reaction of 3-nitroalkenoates 1b and 1d with
phthalimide produced olefinic products 5b and 5d with good yields
and Z-stereochemistry (entries 2 and 4).
a
Isolated yield.
Estimated from the 1H NMR.
b
These results clearly indicate that the nitro group at the
sition of the Michael acceptor is an important factor contributing to
the stabilization of the -addition product of type 4, in which the
presence of an acidic hydrogen atom at the -position to the ester
group induces the -elimination of nitrous acid to form the
unsaturated product of type 5 or 6 in basic conditions. Therefore
the 3-nitroacrylates 1a–b and -nitrocinnamates 1c–d could serve
as a convenient precursors to N-phthalimido-2,3-dehydroamino
acids16 or enamides of type 6.
-Nitrocinnamates 7a–c, however,
b-po-
We then turned our attention to the anion resulting from 2-
oxazolidinone, which is a moderately basic nitrogen nucleophile,
and can be conveniently cleaved from the addition adducts to
generate an amino group.13 Moreover the 4-phenyl-2-oxazolidi-
none derivative in both enantiomeric forms has been shown to
offer control of diastereoselectivity in the Michael addition to
nitroalkenes14 and fluorinated nitroalkenes.7 However, reaction of
a
a
b
a,b-
b
b
-nitrocinnamate 1c with 2-oxazolidinone (1.2 equiv) in the pres-
ence of DBU (1.2 equiv) in acetonitrile at 0 ꢁC led to the formation of
a
can be converted to 2,3-diamino acids derivatives by reduction of
the nitro group and cleavage of the imide17 or carbamate13 func-
tionalities in the addition products. To illustrate this approach, the
elimination product 6c as a single Z-isomer. The Z-stereochemistry
for 6c was established by comparison of the chemical shift of the b-
vinyl proton signal (7.71 ppm) with the known15 E-isomer
(6.21 ppm). Different reaction conditions (3.6 equiv of 2-oxazoli-
dinone) resulted in the formation of alkenoate 6c in higher yield
Ph
O
Ph
O
O
O
(60%, entry 7) rather than affording
product of type 4. Analogous treatment of 1d with 2-oxazolidinone
gave 6d (64%, entry 8).
Reactions of 2-oxazolidinone with 3-nitroacrylates 1a and 1b in
the presence of DBU/MeCN also afforded the olefins 6a and 6b after
a-oxazolidin-2-yl addition
OEt
OEt
N
N
NH2
NO2
H2/Raney Ni/EtOH
68% yield
O
O
8a
10a
NH2NH2xH2O/
EtOH/AcOH
b
-elimination of HNO2 but in low yield. Various bases, as well as
62% yield
different solvents and temperatures were tested to optimize the
reaction conditions towards the formation these interesting N-
protected 2,3-dehydroamino acids. It was found the BuLi in THF at
ꢀ20 ꢁC produced the olefins 6a–b in better yields (entries 5 and 6).
We have envisioned that addition of N-pronucleophiles to 2-
Ph
O
OEt
H2N
NH2
11a
Scheme 1.
nitroalkenoates could be utilized as efficient route to
b-amino

154
E. Lewandowska et al. / Tetrahedron 66 (2010) 152–156
addition product 8a was transformed into an amino derivative 11a.
Thus, the reduction of nitro group with hydrogen over Raney Ni led
to the formation of a 3-N-protected 2,3-diamino acid derivative
10a. Subsequent deprotection with hydrazine17 afforded 2,3-dia-
mino ester 11a with spectroscopic data consistent with literature18
(Scheme 1).
hexane 35%/40% system as eluent) of 4c and 5c (31:69 based on 1H
NMR spectrum). The mixture of products was separated in 90%
CH2Cl2/hexane as eluent. Compound 4c has 1H NMR (isomers ratio
3:1) major isomer:
(d, J¼10.7 Hz, 1H), 6.43 (d, J¼10.7 Hz, 1H), 7.23–7.29 (m, 3H), 7.39–
7.49 (m, 2H), 7.66–7.70 (m, 2H), 7.73–7.76 (m, 2H); 13C NMR
13.7,
d
1.24 (t, J¼7.1 Hz, 3H), 4.28 (q, J¼7.1 Hz, 2H), 6.14
d
In conclusion, we have demonstrated that the
nucleophiles such as phthalimide or 2-oxazolidinone to
a
-addition of N-
-nitro-
52.0, 63.1, 87.3, and signals for both of diastereomers: 123.8, 124.0,
128.0,128.6,129.1,130.5,130.6,130.8,131.0,134.5,134.7,165.0,166.6,
b
acrylates produced 2-N-phthalimido or 2-oxazolidinyl alkenoate
derivatives with good yields and excellent Z stereoselectivity. Ad-
166.61, 166.8; minor isomer:
d
0.97 (t, J¼7.1 Hz, 3H), 4.01 (dq, J¼3.1,
7.1 Hz, 2H), 5.92 (d, J¼11.4 Hz, 1H), 6.66 (d, J¼11.4 Hz, 1H), 7.23–7.29
dition of such N-nucleophiles to
-addition products, which served as precursors to 2,3-diamino
esters. Access to the asymmetric synthesis of 2,3-diamino acids
using a Michael -addition approach is currently in progress.
a
-nitrocinnamates provided stable
(m, 3H), 7.39–7.49 (m, 2H), 7.78–7.81 (m, 2H), 7.91–7.94 (m, 2H); 13C
b
NMR d 13.6, 53.6, 62.5, 88.0, and signals listed above; FABMS 369
[MþH]þ, 391 [MþNa]þ.
b
3.5. Ethyl 3-phenyl-2-N-phthalimido-2(Z)-propenoate (5c)
3. Experimental
3.1. General
Treatment of 1c (22 mg, 0.10 mmol) with phthalimide (50 mg,
0.34 mmol) and DBU (17
(excess of phthalimide was gel filtered using CH2Cl2) gave 5c12a
(31 mg, 98%): IR (CHCl3) 2927, 1788, 1723 cmꢀ1 1H NMR
1.30 (t,
mL, 17 mg, 0.11 mmol) by procedure A
THF was distilled from sodium/benzophenone and CH3CN was
distilled from CaH2 under an argon atmosphere. 1H (400 or
300 MHz) and 13C (100 or 75 MHz) NMR spectra were determined in
CHCl3. Mass spectra (MS) and HRMS were obtained with electron
impact (EI, 20 eV) unless otherwise noted. Merck Kieselgel 60-F254
sheets were used for TLC and products were detected with 254 nm
light. Merck Kieselgel 60 (230–400 mesh) was used for column
chromatography.
;
d
J¼7.1 Hz, 3H), 4.30 (q, J¼7.1 Hz, 2H), 7.27–7.34 (m, 3H), 7.39–7.43
(m, 2H), 7.75–7.80 (m, 2H), 7.86–7.94 (m, 2H), 8.11 (s, 1H); 13C NMR
d
14.5, 62.4, 120.8, 123.9, 124.3, 129.3, 129.7 130.8, 132.5, 132.8,
133.0, 134.7, 134.8, 143.1, 163.50, 167.2, 168.2.
3.6. Ethyl 3-(4-methylphenyl)-2-N-phthalimido-2(Z)-
propenoate (5d)
3.2. Ethyl 2-N-phthalimido-2(Z)-butenoate (5a)
Treatment of 1d(E/Z) (23 mg, 0.1 mmol) with phthalimide
(53 mg, 0.36 mmol) and DBU (18 mL, 18.5 mg, 0.12 mmol) by pro-
3.2.1. Procedure A. DBU (0.04 mL, 41 mg, 0.27 mmol) was added to
a stirred solution of phthalimide (40 mg, 0.27 mmol) in CH3CN
(6 mL) at 0 ꢁC under an argon atmosphere. After 1 h at 0 ꢁC, the
reaction mixture was cooled to ꢀ10 ꢁC and a solution of 1a (36 mg,
0.23 mmol) in CH3CN (1 mL) was added. The resulting mixture was
stirred for 30 min at which time TLC showed complete disappear-
ance of 1a. The reaction mixture was quenched with saturated
aqueous NH4Cl (3 mL) and after being warmed to room tempera-
ture, the mixture was extracted with EtOAc (2ꢂ8 mL). The com-
bined organic layer was washed with water, brine, dried (Na2SO4)
and evaporated to dryness under vacuum. The oily residue was
column chromatographed (CHCl3) to give 5a as an oil (49 mg, 84%):
cedure A (using 90:100 CH2Cl2/hexane as eluent for column chro-
matography) gave 5d as a solidifying oil (29 mg, 87%): IR (CHCl3)
2926,1794,1723 cmꢀ1; 1H NMR:
d
1.30 (t, J¼7.1 Hz, 3H), 2.30 (s, 3H),
4.29 (q, J¼7.1 Hz, 2H), 7.10 (d, J¼8.1 Hz, 2H), 7.31 (d, J¼8.1 Hz, 2H),
7.76–7.82 (m, 2H), 7.90–7.96 (m, 2H), 8.08 (s, 1H); 13C NMR
14.2,
d
21.5, 61.9, 119.3, 123.9, 129.5, 129.6 129.7, 132.2, 134.4, 141.1, 142.6,
163.5, 166.9; HRMS m/z Calcd for C20H17NO4 (Mþ) 335.1158, found
335.1123.
3.7. Ethyl 2-(2-oxazolidinyl)-2(Z)-butenoate (6a)
3.7.1. Procedure B. BuLi (0.12 mL (1.6 M/hexane), 0.20 mmol) was
added to a stirred solution of 2-oxazolidone (17 mg, 0.20 mmol) in
THF (6 mL) at ꢀ20 ꢁC under an argon atmosphere. After 1 h, the
solution of 1a (32 mg, 0.20 mmol) in THF (1 mL) was added and
resulting mixture was stirred for 30 min at 0 ꢁC than for 12 h at rt at
which time TLC showed complete disappearance of 1a. The reaction
mixture was quenched with saturated aqueous NH4Cl (3 mL) and
resulting mixture was extracted with EtOAc (2ꢂ6 mL). The com-
bined organic layer was washed with water, brine, dried (Na2SO4)
and evaporated to dryness under vacuum. The oily residue was
column chromatographed (EtOAc/hexane 20%/35%) to give 6a as
IR (CHCl3) 2928, 1790, 1740 cmꢀ1
1.83 (d, J¼7.1 Hz, 3H), 4.22 (q, J¼7.1 Hz, 2H), 7.38 (q, J¼7.1 Hz, 1H),
7.74–7.80 (m, 2H), 7.90–7.96 (m, 2H); 13C NMR
14.1, 14.5, 61.7,
;
1H NMR
d
1.25 (t, J¼7.1 Hz, 3H),
d
123.6, 123.8, 132.1, 134.4, 142.9, 162.5, 166.7; HRMS m/z Calcd for
C14H13NO4 (Mþ) 259.0845, found 259.0839.
3.3. Ethyl 2-N-phthalimido-2(Z)-pentenoate (5b)
Treatment of 1b (30 mg, 0.18 mmol) with phthalimide (31 mg,
0.21 mmol) and DBU (31
[column chromatographed (EtOAc/hexane 20%/25%)] gave 5b as
an oil (38 mg, 81%): IR (CHCl3) 2930, 1784, 1740 cmꢀ1 1H NMR
1.11 (t, J¼7.7 Hz, 3H), 1.27 (t, J¼7.1 Hz, 3H), 2.17 (quintet, J¼7.7 Hz,
2H), 4.22 (q, J¼7.1 Hz, 2H), 7.30 (t, J¼7.7 Hz, 1H), 7.74–7.81 (m, 2H),
mL, 32 mg, 0.21 mmol) by procedure A
an oil (29 mg, 58%): IR (CHCl3) 2926, 1750, 1700 cmꢀ1 1H NMR
;
;
d
1.31 (t, J¼7.1 Hz, 3H),1.88 (d, J¼7.1 Hz, 3H), 3.67–3.84 (m, 2H), 4.24
d
(q, J¼7.1 Hz, 2H), 4.44–4.52 (m, 2H), 7.38 (q, J¼7.1 Hz, 1H); 13C NMR
d
13.9, 14.2, 45.9, 61.3, 62.7, 128.0, 140.9, 156.8, 163.1; HRMS m/z
7.90–7.97 (m, 2H); 13C NMR
d
12.5,14.1, 22.2, 61.5,121.6,123.8, 132.1,
Calcd for C9H13NO4 (Mþ) 199.0845, found 199.0839.
134.4, 149.8, 162.8, 167.1; HRMS m/z Calcd for C15H15NO4 (Mþ)
273.1001, found 273.1027.
3.8. Ethyl 2-(2-oxazolidinyl)-2(Z)-pentenoate (6b)
3.4. Ethyl 3-nitro-3-phenyl-2-(N-phthalimido)pro-
panoate (4c)
Treatment of 1b (44 mg, 0.25 mmol) with 2-oxazolidone
(22 mg, 0.25 mmol) and BuLi (0.16 mL (1.6 M/hexane), 0.25 mmol)
by procedure B gave 6b as an oil (26 mg, 48%): IR (CHCl3) 2996,
Treatment of 1c(E) (38 mg, 0.17 mmol) with phthalimide
1757, 1702 cmꢀ1
;
1H NMR
d
1.11 (t, J¼7.7 Hz, 3H), 1.32 (t, J¼7.1 Hz,
(30.5 mg, 0.21 mmol) and DBU (31
mL, 31.5 mg, 0.21 mmol) by pro-
3H), 2.28 (quintet, J¼7.7 Hz, 2H), 3.76–3.82 (m, 2H), 4.25 (q,
cedure A gave a mixture (59 mg, non-separable by using EtOAc/
J¼7.1 Hz, 2H), 4.44–4.49 (m, 2H), 7.00 (t, J¼7.7 Hz, 1H); 13C NMR

E. Lewandowska et al. / Tetrahedron 66 (2010) 152–156
155
d
12.6, 14.2, 21.6, 46.2, 61.4, 62.6, 126.5, 147.2, 156.9, 162.3; HRMS m/
2H), 6.15 (d, J¼11.8 Hz, 1H), 6.78 (d, J¼11.8 Hz, 1H), 6.83–6.89 (m,
z Calcd for C10H15NO4 (Mþ) 213.1001, found 213.0879.
2H), 7.54–7.58 (m, 2H), 7.70–7.74 (m, 2H), 7.81–7.87 (m, 2H); 13C
NMR
d 13.6, 53.1, 55.3, 63.5, 86.0, 114.5, 123.7, 125.6, 130.0, 131.5,
3.9. Ethyl 3-phenyl-2-(2-oxazolidinyl)-2(Z)-propenoate (6c)
Treatment of 1c (42 mg, 0.19 mmol) with 2-oxazolidone (59 mg,
134.5, 160.2, 162.5, 167.4; IR (CHCl3) 2927, 1752, 1720, 1566 cmꢀ1
;
HRMS m/z Calcd for C20H18N2O7 (Mþ) 398.1114, found 398.1087.
0.68 mmol) and DBU (34
(reaction mixture was kept at 6 ꢁC for overnight for complete
consumption of 1c) gave 6c15 (30 mg, 60%): 1H NMR
1.37 (t,
m
L, 35 mg, 0.23 mmol) by procedure A
3.13. Ethyl 3-(4-methylphenyl)-2-nitro-3-(N-phthalimido)-
propanoate (8c)
d
J¼7.1 Hz, 3H), 3.72 (t, J¼7.8 Hz, 2H), 4.33 (q, J¼7.1 Hz, 2H), 4.49 (t,
Treatment of 7c (E/Z, 2:1; 72 mg, 0.31 mmol) with phthalimide
(54 mg, 0.37 mmol) and DBU (55 L, 56 mg, 0.37 mmol) by pro-
cedure C gave 8c (98 mg, 84%) as a mixture of two isomers (1.4: 1)
as an oil. The major isomer had: 1H NMR
J¼7.8 Hz, 2H), 7.39–7.43 (m, 3H), 7.55–7.61 (m, 2H), 7.71 (s, 1H).
m
3.10. Ethyl 3-(4-methylphenyl)-2-(2-oxazolidinyl)-2(Z)-
propenoate (6d)
d
1.05 (t, J¼7.1 Hz, 3H), 2.31
(s, 3H), 4.08 (dq, J¼1.1, 7.1 Hz, 2H), 6.19 (d, J¼11.5 Hz, 1H), 6.83 (d,
J¼11.5 Hz, 1H), 7.15–7.20 (m, 2H), 7.48–7.55 (m, 2H), 7.70–7.74 (m,
Treatment of 1d (43 mg, 0.18 mmol) with 2-oxazolidone (57 mg,
2H), 7.81–7.87 (m, 2H); 13C NMR
d 13.5, 21.2, 54.4, 63.3, 85.9, 123.7,
0.66 mmol) and DBU (32
m
L, 33 mg, 0.22 mmol) by procedure A
129.0, 129.7, 130.5, 131.3, 134.5, 139.5, 161.9, 167.4. The minor isomer
(reaction mixture was kept at 6 ꢁC for overnight for complete
had: 1H NMR
d
1.13 (t, J¼7.1 Hz, 3H), 2.30 (s, 3H), 4.19 (q, J¼7.1 Hz,
consumption of 1d) gave 6d as an oil (32 mg, 64%): IR (CHCl3) 2956,
2H), 6.17 (d, J¼11.8 Hz, 1H), 6.81 (d, J¼11.8 Hz, 1H), 7.15–7.20 (m,
1762, 1714 cmꢀ1; 1H NMR
d
1.35 (t, J¼7.1 Hz, 3H), 2.37 (s, 3H), 3.72
2H), 7.48–7.55 (m, 2H), 7.70–7.74 (m, 2H), 7.81–7.87 (m, 2H); 13C
(t, J¼7.8 Hz, 2H), 4.32 (q, J¼7.1 Hz, 2H), 4.48 (t, J¼7.8 Hz, 2H), 7.21 (d,
NMR d 13.6, 21.2, 53.3, 63.5, 85.7, 123.7, 128.5, 129.8, 131.0, 131.4,
J¼8.0 Hz, 2H), 7.48 (d, J¼8.0 Hz, 2H), 7.67 (s, 1H); 13C NMR
d
14.3,
134.4, 139.4, 162.5, 167.3; IR (CHCl3) 2987, 1752, 1720, 1566 cmꢀ1
;
21.5, 45.4, 61.7, 62.9, 124.8, 129.7, 129.8, 130.0, 139.6, 141.1, 157.6,
164.1; HRMS m/z Calcd for C15H17NO4 (Mþ) 275.1158, found
275.1209.
HRMS m/z Calcd for C20H18N2O6 (Mþ) 382.1165, found 382.1189.
3.14. Ethyl 2-nitro-3-(2-oxazolidinyl)-3-phenylpro
panoate (9a)
3.11. Ethyl 2-nitro-3-phenyl-3-(N-phthalimido)-
propanoate (8a)
Treatment of 7a (E/Z, 2:1; 36 mg, 0.16 mmol) with 2-oxazoli-
done (17 mg, 0.19 mmol) and DBU (30 L, 30 mg, 0.19 mmol) by
m
3.11.1. Procedure C. DBU (35
m
L, 35 mg, 0.23 mmol) was added to
procedure C (reaction mixture was quenched after overnight at rt)
gave 9a (28 mg, 56%) as a mixture of two diastereoisomers (3:1).
Crystallization (EtOH) yielded white crystals (mp 128–130 ꢁC) as
a mixture of diastereoisomers (9:1). The major isomer had: 1H NMR
a stirred solution of phthalimide (34 mg, 0.23 mmol) in CH3CN
(6 mL) at 0 ꢁC under an argon atmosphere. After 1 h, the solution of
7a (E/Z, 2:1; 43 mg, 0.19 mmol) in CH3CN (1 mL) was added and
resulting mixture was stirred for 10 min at which time TLC showed
complete disappearance of 7a. The reaction mixture was then
quenched with saturated aqueous NH4Cl (3 mL) and after being
warmed to rt, the mixture was extracted with EtOAc (2ꢂ8 mL). The
combined organic layer was washed with water, brine, dried
(Na2SO4) and was evaporated to dryness under vacuum. The oily
residue was column chromatographed (EtOAc/hexane 20%/25%)
to give 8a (68 mg, 94%) (2:1) as a mixture of two diastereoisomers.
Crystallization (EtOH) yielded white crystals (mp 147–150 ꢁC) as
a mixture of diastereoisomers (3:1). The minor isomer had: 1H NMR
d
1.01 (t, J¼7.1 Hz, 3H), 3.52–3.56 (m, 1H), 3.58–3.65 (m, 1H), 4.00–
4.10 (m, 2H), 4.25–4.36 (m, 2H), 5.48 (d, J¼11.4 Hz, 1H), 6.38 (d,
J¼11.4 Hz, 1H), 7.38–7.44 (m, 5H); 13C NMR
d 13.5, 43.7, 58.9, 62.3,
63.3, 86.7, 127.8, 128.4, 129.3, 132.7, 157.4, 161.9. The minor isomer
had: 1H NMR
(m, 4H), 5.63 (d, J¼11.5 Hz,1H), 6.16 (d, J¼11.5 Hz,1H), 7.38–7.44 (m,
d
1.35 (t, J¼7.1 Hz, 3H), 3.38–3.64 (m, 2H), 4.24–4.38
5H); 13C NMR
d 13.7, 43.9, 57.4, 62.3, 63.5, 86.4, 127.8, 128.4, 129.3,
132.7, 157.4, 162.7; IR (CHCl3) 2985, 1752, 1567 cmꢀ1; HRMS m/z
Calcd for C14H16N2O6 (Mþ) 308.1008, found 308.1020.
d
1.13 (t, J¼7.1 Hz, 3H), 4.20 (q, J¼7.1 Hz, 2H), 6.21 (d, J¼12.1 Hz, 1H),
6.83 (d, J¼12.1 Hz, 1H), 7.32–7.38 (m, 3H), 7.60–7.65 (m, 2H), 7.71–
7.76 (m, 2H), 7.81–7.87 (m, 2H); 13C NMR
13.5, 54.7, 63.3, 85.9,
123.8, 128.6, 129.1, 129.5, 131.4, 133.6, 134.5, 162.5, 167.4. The major
isomer had: 1H NMR
3.15. Ethyl 3-(4-methoxyphenyl)-2-nitro-3-(2-oxazolidinyl)-
propanoate (9b)
d
Treatment of 7b (E/Z, 5:2; 49 mg, 0.19 mmol) with 2-oxazoli-
d
1.02 (t, J¼7.1 Hz, 3H), 4.08 (dq, J¼1.2, 7.1 Hz,
done (20 mg, 0.23 mmol) and DBU (35
procedure C gave 9b (38 mg, 58%) as a mixture of two di-
astereoisomers (1:1) as an oil. 1H NMR
mL, 36 mg, 0.23 mmol) by
2H), 6.22 (d, J¼11.5 Hz, 1H), 6.85 (d, J¼11.5 Hz, 1H), 7.32–7.38 (m,
3H), 7.60–7.65 (m, 2H), 7.71–7.76 (m, 2H), 7.81–7.87 (m, 2H); 13C
d
1.04 (t, J¼7.1 Hz, 3H), 1.33
NMR
d
13.6, 53.5, 63.6, 85.7, 123.8, 128.6, 129.2, 129.5, 131.4, 134.0,
(t, J¼7.1 Hz, 3H), 3.38–3.66 (m, 2H), 3.40–3.58 (m, 2H), 381 (s, 3H),
3.82 (s, 3H), 4.00–4.12 (m, 2H), 4.23–4.30 (m, 2H), 4.24–4.32 (m,
4H), 5.42 (d, J¼11.5 Hz, 1H), 5.54 (d, J¼11.5 Hz, 1H), 6.12 (d,
J¼11.5 Hz, 1H), 6.32 (d, J¼11.5 Hz, 1H), 6.88–6.93 (m, 4H), 7.31–7.37
134.5, 162.5, 167.4; IR (CHCl3) 2926, 1752, 1720, 1568 cmꢀ1; HRMS
m/z Calcd for C19H16N2O6 (Mþ) 368.1008, found 368.0981.
3.12. Ethyl 3-(4-methoxyphenyl)-2-nitro-3-(N-phthalimido)-
(m, 4H); 13C NMR
d 13.5, 13.8, 42.9, 43.6, 55.3, 57.2, 58.4, 62.3, 62.4,
propanoate (8b)
63.3, 63.7, 86.7, 86.9, 114.5, 114.7, 124.5, 124.9, 129.2, 129.8, 157.4,
160.4, 160.5, 161.9, 162.6; IR (CHCl3) 2926, 1753, 1566 cmꢀ1; HRMS
m/z Calcd for C15H18N2O7 (Mþ) 338.1114, found 338.1146.
Treatment of 7b (E/Z, 5:2; 68 mg, 0.27 mmol) with phthalimide
(48 mg, 0.32 mmol) and DBU (48
cedure C gave 8b (87 mg, 81%) as a mixture of two isomers (1.4:1)
as an oil. The major isomer had: 1H NMR
mL, 49 mg, 0.32 mmol) by pro-
3.16. Ethyl 3-(4-methylphenyl)-2-nitro-3-(2-oxazolidinyl)-
propanoate (9c)
d
1.06 (t, J¼7.1 Hz, 3H), 3.77
(s, 3H), 4.09 (dq, J¼2.6, 7.1 Hz, 2H), 6.18 (d, J¼11.5 Hz, 1H), 6.81 (d,
J¼11.5 Hz, 1H), 6.83–6.89 (m, 2H), 7.54–7.58 (m, 2H), 7.70–7.74 (m,
Treatment of 7c (E/Z, 2:1; 85 mg, 0.36 mmol) with 2-oxazoli-
2H), 7.81–7.87 (m, 2H); 13C NMR
d
13.5, 54.2, 55.3, 63.3, 86.1, 114.4,
done (38 mg, 0.43 mmol) and DBU (65
procedure C gave 9c (84 mg, 72%) as a mixture of two di-
astereoisomers (1:1) as an oil. 1H NMR
1.05 (t, J¼7.1 Hz, 3H), 1.33
mL, 66 mg, 0.43 mmol) by
123.7,126.0,130.6,131.4,134.4,160.3,162.0,167.5. The minor isomer
had: 1H NMR
1.12 (t, J¼7.1 Hz, 3H), 3.78 (s, 3H), 4.19 (q, J¼7.1 Hz,
d
d

156
E. Lewandowska et al. / Tetrahedron 66 (2010) 152–156
(t, J¼7.1 Hz, 3H), 2.35 (s, 6H), 3.35–3.66 (m, 2H), 3.41–3.58 (m, 2H),
4.00–4.15 (m, 2H), 4.22–4.38 (m, 4H), 4.23–4.36 (m, 2H), 5.48 (d,
J¼11.5 Hz, 1H), 5.60 (d, J¼11.5 Hz, 1H), 6.12 (d, J¼11.5 Hz, 1H), 6.33
(d, J¼11.5 Hz, 1H), 7.18–7.21 (m, 4H), 7.27–7.31 (m, 4H); 13C NMR
3H), 1.76 (br s, 4H), 3.61 (d, J¼5.1 Hz, 1H), 4.10 (dq J¼1.3, 7.2 Hz, 2H),
4.25 (d, J¼5.1 Hz, 1H), 7.33–7.37 (m, 5H); 13C NMR
d 14.0, 58.4, 60.9,
61.0, 126.8, 127.4, 128.4, 142.5, 174.0.
d
13.4, 13.7, 21.1, 42.7, 43.4, 57.2, 58.5, 62.2, 62.3, 63.2, 63.8, 86.4,
Acknowledgements
86.8, 127.6, 128.2, 129.5, 129.9, 130.0, 139.7, 157.4, 161.9, 162.6; IR
(CHCl3) 2982, 1752, 1566 cmꢀ1; HRMS m/z Calcd for C15H18N2O6
(Mþ) 322.1165, found 322.1178.
The support by Polish Ministry of Science and Higher Education
grant N20412131/2773 is gratefully acknowledged.
3.17. Ethyl 2-amino-3-phenyl-3-(N-phthalimido)-
propanoate (10a)
References and notes
1. (a) Bergman, E. D.; Gonsburg, D.; Pappo, R. Org. React. 1959, Vol. 10, 179–555; (b)
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, UK, 1991;
Vol. 4; (c) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, UK, 1992.
A suspension of 8a (mixture of diastereoisomers 2:1, 40 mg,
0.11 mmol) and Raney nickel (w5 mg) in EtOH (4 mL) was hydro-
genated over H2 gas under balloon atmosphere for 8 h. The
resulting solution was filtered over Celite, and washed with EtOH
(5 mL). The organic layer was evaporated and purified by column
chromatography (EtOAc/hexane 30%/50%) to afford 10a as a sep-
arable mixture of two diastereoisomers 2:1 (25 mg, 68%) as a so-
2. Lewandowska, E. Tetrahedron 2007, 63, 2107.
3. (a) Chatfield, D. C.; Augsten, A.; D’Cunha, C.; Lewandowska, E.; Wnuk, S. F. Eur. J.
Org. Chem. 2004, 313; (b) Lewandowska, E.; Chatfield, D. C. Eur. J. Org. Chem.
2005, 3297.
4. (a) Lewandowska, E. Tetrahedron 2006, 62, 4879; (b) Ballini, R.; Fiorini, D.;
Palmieri, A. Tetrahedron Lett. 2005, 46, 1245; (c) Ballini, R.; Bazan, N. A.; Bosica,
G.; Palmieri, A. Tetrahedron Lett. 2008, 49, 3865.
5. Viso, A.; Fernandez de la Pradilla, R.; Garcia, A.; Flores, A. Chem. Rev. 2005, 105,
3167.
6. Bonauer, C.; Walenzyk, T.; Konig, B. Synthesis 2006, 1.
7. (a) Turconi, J.; Lebeau, L.; Paris, J.-M.; Mioskowski, C. Tetrahedron Lett. 2006, 47,
121; (b) Turconi, J.; Lebeau, L.; Paris, J.-M.; Mioskowski, C. Tetrahedron 2006, 62,
8109.
lidifying oil. The minor isomer (less polar) had: 1H NMR
d 0.96 (t,
J¼7.2 Hz, 3H), 1.58 (br s, 2H), 4.11–3.98 (m, 2H), 4.98 (d, J¼11.0 Hz,
1H), 5.35 (d, J¼11.0 Hz, 1H), 7.33–7.41 (m, 3H), 7.64–7.73 (m, 4H),
7.80–7.86 (m, 2H); 13C NMR
d 13.8, 53.9, 58.3, 61.3, 123.3, 128.6,
128.9, 129.5, 131.7, 134.1, 136.3, 167.7, 173.0. The major isomer (more
polar) had: 1H NMR
d
0.94 (t, J¼7.2 Hz, 3H), 1.58 (br s, 2H), 3.95 (q,
8. Mohan, R.; Chou, Y.-L.; Bihovsky, R.; Lumma, W. C., Jr.; Erhardt, P. W.; Shaw, K. J.
J. Med. Chem. 1991, 34, 2402.
J¼7.2 Hz, 2H), 4.87 (d, J¼11.0 Hz, 1H), 5.40 (d, J¼11.0 Hz, 1H), 7.27–
9. Jayakanthan, K.; Madhusudanan, K. P.; Vankar, Y. D. Tetrahedron 2004, 60, 397.
10. Buevich, A. V.; Wu, Y.; Chan, T.-M.; Stamford, A. Tetrahedron Lett. 2008, 49, 2132.
11. Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2004, 45, 7027.
12. (a) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595; (b) Barluenga, J.;
Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin Trans. 1 1990, 2193; (c) Easton, C. J.;
Hutton, C. A.; Roselt, P. D.; Tiekink, E. R. T. Tetrahedron 1994, 50, 7320; The
alkene geometry has been confirmed by comparison to the literature for known
compound 5c and remaining examples were assigned by analogy.
13. (a) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3783; (b) Fisher, J. W.;
Dunigan, J. M.; Hatfield, L. D.; Hoying, R. C.; Ray, J. E.; Thomas, K. L. Tetrahedron
Lett. 1993, 34, 4755.
7.34 (m, 3H), 7.57–7.62 (m, 2H), 7.67–7.71 (m, 2H), 7.82–7.84 (m,
2H); 13C NMR
d 13.8, 55.1, 58.8, 60.9, 123.3, 128.4, 128.5, 129.1, 131.8,
134.0, 136.5, 168.5, 173.8; IR (CHCl3) 3420, 1773, 1713 cmꢀ1; HRMS
(LSIMS) m/z Calcd for C19H19N2O4 [MþH]þ 339.1345, found
339.1340.
3.18. Ethyl 2,3-diamino-3-phenylpropanoate (11a)
14. (a) Lucet, D.; Toupet, L.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 1997, 62, 2682;
(b) Lucet, D.; Sabelle, S.; Kostelitz, O.; Le Gall, T.; Mioskowski, C. Eur. J. Org.
Chem. 1999, 2583.
15. Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
16. Chen, J.; Liu, Q.; Zhang, W.; Spinella, S.; Lei, A.; Zhang, X. Org. Lett. 2008, 10,
3033.
17. (a) Ing, H. R.; Manske, H. F. J. Chem. Soc. 1926, 2348; (b) Konosu, T.; Oida, S.
Chem. Pharm. Bull. 1991, 39, 2212.
18. Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789.
Hydrazine monohydrate (0.007 mL, 7 mg, 0.14 mmol) was
added to
a stirred solution of 10a (major isomer) (14 mg,
0.04 mmol) in EtOH (3 mL) at 0 ꢁC. After 1.5 h, AcOH was added
(few drops) and the mixture was stirred for 10 min at 0 ꢁC and then
allowed to warm to rt overnight. Concentration in vacuo and pu-
rification by column chromatography (CH2Cl2/MeOH/NH4OH
100:5:0.5) afforded 11a18 (5.5 mg, 62%): 1H NMR
d
1.15 (t, J¼7.2 Hz,