Addition of thionucleophiles to nitrocinnamates: Approach toward synthesis of (alkyl/aryl)thio-amino acids

Article abstract of DOI:10.1080/17415993.2015.1107726

The addition of alkyl or aryl thiols to α-nitro or β-nitrocinnamate in the presence of base provided Michael addition products. In the case of β-nitro compounds reaction occurred via the formation of anti-Michael adducts. Selective nitro reduction of α-ni

Full text of DOI:10.1080/17415993.2015.1107726

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Addition of thionucleophiles to nitrocinnamates:
approach toward synthesis of (alkyl/aryl)thio-
amino acids
Elzbieta Lewandowska
To cite this article: Elzbieta Lewandowska (2015): Addition of thionucleophiles to
nitrocinnamates: approach toward synthesis of (alkyl/aryl)thio-amino acids, Journal of Sulfur
Chemistry, DOI: 10.1080/17415993.2015.1107726
To link to this article: http://dx.doi.org/10.1080/17415993.2015.1107726
Published online: 08 Nov 2015.
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Date: 01 December 2015, At: 14:37

JOURNAL OF SULFUR CHEMISTRY, 2015
http://dx.doi.org/10.1080/17415993.2015.1107726
SHORT COMMUNICATION
Addition of thionucleophiles to nitrocinnamates: approach
toward synthesis of (alkyl/aryl)thio-amino acids
Elzbieta Lewandowska
Department of Chemistry, University of Live Sciences, Poznan 60-625, Poland
ABSTRACT
ARTICLE HISTORY
Received 11 August 2015
Accepted 10 October 2015
The addition of alkyl or aryl thiols to α-nitro or β-nitrocinnamate in
the presence of base provided Michael addition products. In the case
of β-nitro compounds reaction occurred via the formation of anti-
Michael adducts. Selective nitro reduction of α-nitroadducts gives
access to β-thio-α-amino acid derivatives.
KEYWORDS
Michael addition;
sulfur-amino acids; α- or
β-Nitrocinnamates;
anti-Michael addition
1. Introduction
The thia-Michael reaction is widely recognized as one of the most important C–S bond-
forming reactions in organic synthesis.[1–4] This reaction is reliable with a variety of
substrates with biological applications such as antibiotic, antimicrobial, anticancer [5,6]
or in non-natural amino acid synthesis.[7,8] The thia-Michael addition is also applicable
providing further synthetic utility in organic chemistry, for example, for the protection of
olefinic double bond in unsaturated carbonyl compounds [9] as well as for the synthesis of
medications such as a calcium channel blocker Diltiazem.[10] Thiols are known as good
donors in addition to Michael acceptors,[11–15] but in the case of the α,β-unsaturated
ester of carboxylic acid the activation of the double bond is often insufficient.[16,17] The
electrophilicity of an unsaturated ester can be enhanced by attaching an electron with-
drawing, for example, a nitro group. This group may be attached at the α carbon of the
unsaturated ester providing the α-nitro Michael acceptor A (Scheme 1). With these accep-
tors the addition of the sulfur nucleophiles occurs at the β-position to form a type B
β-adduct. However, the regioselectivity of the addition to the double bond can be reversed
by attaching at the β carbon the nitro group, which is known to have more powerful
electron-withdrawing properties than the ester group.[18–20] With such acceptors the
CONTACT Elzbieta Lewandowska
elalew@up.poznan.pl
© 2015 Taylor & Francis

2
E. LEWANDOWSKA
Scheme 1. The β-addition vs. α-addition of the nucleophiles to Michael acceptors.
nucleophile addition should lead to the formation of the type C α-adduct as a result of
conjugate reaction via an anti-Michael manner.
We have decided to investigate the addition of sulfur nucleophiles to β-nitrocinnamates
as α-Michael acceptors and α-nitrocinnamates as the conjugate Michael acceptors. The
expected α-nitro-β-thio or β-nitro-α-thio adducts after subsequent reduction of the nitro
group would facilitate the formation of new non-natural derivatives of amino acids. Sulfur
containing amino acids and small peptides are constituents of several natural products and
biologically active molecules and are of particular interest, because of a variety of cellular
function (e.g. redox cycling, detoxification, antioxidant properties, etc.).[21–25] Consid-
ering the potential of these classes of amino acids, developing of the new methodologies
for the synthesis of nitro-cinnamates and to investigate their reactions with aryl and alkyl
thiols have been undertaken. In this paper we report studies on the nucleophilic addition
of S-nucleophiles to α- and β-nitrocinnamate Michael acceptors as a new approach toward
the synthesis of 2-amino-3-thiopropanoate derivatives.
2. Results and discussion
The 2-nitrocinnamic esters 1a–1b required for our studies were prepared by the reac-
tion of the corresponding cinnamic ester with NaNO2-ceric ammonium nitrate (CAN)
as reported (Scheme 2).[26,27] The 3-nitrocinnamic ester 8 (Scheme 3) was obtained by
the nitroaldol (Henry) reaction between the appropriate nitrotoluene and ethyl glyoxalate
as described.[28] The nitrocinnamates 1a–1b, 8 were prepared as mixtures of E and Z
isomers.

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 2. Addition of thionucleophiles to α-nitrocinnamates.
Scheme 3. Addition of thionucleophiles to β-nitrocinnamates.
Initially, we investigated the conjugate Michael addition of sulfur nucleophiles such as
propanethiol, benzylthiol and aromatic thiophenol to α-nitrocinnamates 1a–1b. From a
synthetic point of view benzyl mercaptan is an attractive Michael donor because the ben-
zyl group can be cleaved easily to provide thiols.[29] In order to optimize the addition of
thiols to Michael acceptors, we tested different reaction conditions, such different bases
and various ratios of the nucleophiles to substrates.
The best yields were obtained when four equivalents of thiols were used in the presence
of Amberlyst A21 as a heterogeneous catalyst. Thus, treatment of 1a with propanethiol
in THF and in the presence of Amberlyst A21 at ambient temperature for 12 h led to the
formation of conjugated addition product 2a with a 84% yield as a mixture (1:1) of two
diastereoisomers (Table 1, Entry 1). Analogous conjugated β-addition products 2b–4b
were obtained when appropriate ethyl 2-nitrocinnamates 1a–1b were treated with alkyl,
benzyl and aryl thiols (Table 1, Entries 2–6).
Using the same reaction conditions, the α-addition products 9–11 were obtained as
a result of anti-Michael addition of the appropriate thiols to ethyl 3-nitrocinnamate 8
(Table 1, Entries 7–9). In the case of 11, the isolated yield was only 45%, probably due
to the subsequent elimination of HNO2 from the anti-Michael addition product to form
an unsaturated derivative as previously reported.[30]

4
E. LEWANDOWSKA
Table 1. Reaction parameters for addition of thiolate nucleophiles to nitro-cinnamates.
Entry
Substrate
Nucleophile
Product
Yield(%)c
Isomers ratiod
1
2
3
4
5
6
7
8
9
1aE/Z (2:1)
1bE/Z (5:2)
PrSH
PrSH
BzSH
BzSH
PhSH
PhSH
PrSH
BzSH
PhSH
2aa
2ba
3aa
3ba
4aa
4ba
9b
84
82
92
71
80
72
78
86
45
1:1
1:1
1:1
1:1
2:1
1:1
2:1
1:1
1:0.7
1a
1b
1a
1b
8E/Z (3:1)
8
8
10b
11b
aSee scheme 2.
bSee scheme 3.
cIsolated yield.
dEstimated from the 1H-NMR.
In the next step, we examined the possibility of the reduction of the nitro group into
the amino group. Bearing in mind that we have a sulfur functionality, various different
hydrogenation condition have been explored in order to find conditions, under which the
nitro group may be reduced chemoselectively. As previously reported,[31] the nitro group
may be easily reduced with hydrogen over Raney Ni, but desulfurization also occurred
under these conditions. We tested several reducing agents [32] and found that Zn in
the presence of diluted HCl efficiently reduced the nitro group to the amino group in
α-nitro-β-aryl/alkylthio esters. Thus, treatment of the β-adduct 2a with Zn (20 equiv.)
in HCl/i-PrOH at an ambient temperature for 0.5 h led to the formation of α-amino-β-
propylthioester 5a as a 1:1mixture of the separable diastereoisomers at a 76% yield. The
1H NMR spectrum of 5a shows that two sets of signals corresponding to the hydrogens
at C2 and C3 are shifted upfield than that of the nitro-adduct 2a with the smaller cou-
pling constant (J = 6.8 Hz). An analogous treatment of 2b, 3a–3b provided good yields
of α-amino-β-thio-adducts 5b, 6a–6b as an unseparated mixture of two diastereoisomers.
Reduction of α-nitro-β-phenylthio adduct 4a yielded a more complex mixture of products,
from which the α-amino-β-phenylthio derivative 7a was isolated at a 46% yield.
With these results at hand we then turned our attention for the reduction of β-nitro-α-
thio-adducts 9 or 10. However, we obtained the corresponding β-amino-α-thio products
12 and 13 at low yields of about 22% and 28%, respectively. These β-amino-α-thio esters
are relatively unstable and decomposed during storage. We were able to obtain only NMR
1
spectra of β-amino-α-thio-derivatives. The H NMR spectra confirm reduction of the
nitro group because as in α-amino-β-thio-compounds two sets of doublets related to
the hydrogens at C2 and C3 are shifted upfield than that of the nitro substrates with the
coupling constants of 8–9 Hz.
3. Conclusions
In summary, we have demonstrated that the addition of the alkyl or aryl thionucleophiles to
the α-nitrocinnamic esters 1a–1b in THF in the presence of Amberlyst A21 as a base yields
products 2a–4b resulting from the conjugated Michael addition of thiols. Conversely, an
analogous addition of thiols to the β-nitrocinnamic ester 8 proceeds via the anti-Michael
addition providing products 9–11. The subsequent reduction of the conjugated addition

JOURNAL OF SULFUR CHEMISTRY
5
products 2a or 3a gives convenient access to the β-thio-phenylalanine. Our attempts to pre-
pare the β-thio- tyrosine derivative using our approach were unsuccessful mainly because
efforts to prepare the 2-nitro-p-hydroxycinnamic ester using the CAN protocol [26] failed.
In conclusion, the approach presented here provides a convenient method for the synthesis
of aromatic β-thio-α-amino acids. This protocol offers a useful access to new non-natural
amino acids and possibly peptides. Entry to the asymmetric synthesis of these sulfur
containing amino acids using the Michael β-addition approach is currently in progress.
4. Experimental
4.1. General methods
1
The H (400 MHz) and 13C (100 MHz) NMR spectra were determined in CDCl3. Mass
spectra (HRMS) were obtained with electron impact (EI, 20 eV). Elemental analyses were
determined at Microanalytical Laboratory at Life Science University at Poznan, Poznan,
Poland. 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.
THF was distilled from sodium benzophenone under nitrogen.
4.2. General procedure for the synthesis of 2-nitro-3-thiocinnamic ester (2–4) and
3-nitro-2-thiocinnamic ester (9–11)
To a stirred solution of 1a–1b or 8 (0.20 mmol) in THF (2 mL) at an ambient tempera-
ture were added thiol (0.80 mmol) and Amberlyst A21 (200 mg). After 12 h, the Amberlyst
A21 was removed by filtration (washing with THF) and the filtrate was evaporated to
dryness under vacuum. The oily residue was column chromatographed (hexane → 5%
EtOAc/hexane).
4.2.1. Ethyl 2-nitro-3-phenyl-3-propylthiopropanoate (2a)
=
Mixture of two diastereoisomers (1:1); yield 84%; yellow oil. IR (CHCl3): 1752 (C O),
1568 (NO2) cm−1. One isomer had. 1H NMR δ: 0.80 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.1 Hz,
3H), 1.6 (sexd, J = 7.3, 2.8 Hz, 2H), 2.30–238 (m, 2H), 3.90 (q, J = 7.1 Hz, 2H), 4.56 (d,
J = 11.5 Hz, 1H), 5.39 (d, J = 11.5 Hz, 1H), 7.18–7.27 (m, 5H). 13C NMR δ: 13.2, 13.4,
1
22.3, 33.9, 48.5, 63.0, 91.3, 128.0, 128.5, 128.8, 136.3, 162.2. The second isomer had. H
NMR δ: 0.80 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.62 (sexd, J = 7.3, 2.8 Hz,
2H), 2.30–238 (m, 2H), 4.27 (qd, J = 7.1, 2.7 Hz, 2H), 4.57 (d, J = 10.7 Hz, 1H), 5.34 (d,
J = 10.7 Hz, 1H), 7.18–7.27(m, 5H). 13C NMR δ: 13.23, 13.91, 22.44, 34.43, 49.76, 63.43,
92.03, 128.42, 128.51, 128.93, 136.86, 162.66. HRMS (EI) m/z calcd for C14H19NO4S (M+)
297.1035 found 297.1032.
4.2.2. Ethyl 3-(4-methoxyphenyl)-2-nitro-3-propylthiopropanoate (2b)
−1
=
Mixture of two isomers (1:1); yield 82%; oil. IR (CHCl3): 1752 (C O), 1569 (NO2) cm
;
One isomer had. 1H NMR δ: 0.91 (t, J = 7.3 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H), 1.52–1.55
(m, 2H), 2.36–2.44 (m, 2H), 3.79 (s, 3H), 4.03 (m, 2H), 4.62 (d, J = 11.4 Hz, 1H), 5.42 (d,
J = 11.3 Hz, 1H), 6.86–6.89 (m, 2H), 7.27–7.30 (m, 2H). 13C NMR δ: 13.32, 13.64, 22.47,
33.85, 48.16, 55.23, 63.05, 91.62, 114.24, 127.91, 129.26, 159.62, 162.34. The second isomer

6
E. LEWANDOWSKA
1
had. H NMR δ: 0.91 (t, J = 7.3 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.52–1.55 (m, 2H),
2.36–2.44 (m, 2H), 3.81 (s, 3H), 4.37 (qd, J = 7.1, 2.4 Hz, 2H), 4.64 (d, J = 10.5 Hz, 1H),
5.39 (d, J = 10.3 Hz, 1H), 6.86–6.89 (m, 2H), 7.27–7.30 (m, 2H). 13C NMR δ: 13.24, 13.93,
22.49, 34.23, 49.12, 55.46, 63.42, 92.26, 114.30, 128.52, 129.71, 159.67, 162.71. HRMS (EI)
m/z calcd for C15H21NO5S (M+) 327,1140 found 327,1138.
4.2.3. Ethyl 3-benzylthio-2-nitro-3-phenylpropanoate (3a)
Mixture of two isomers (2:1); yield 92%; solidifying oil. Crystallization (EtOH) yielded
white crystals (m.p. 128–130°C). IR (CHCl3): 1750 (C O), 1560 (NO2) cm−1. The
major isomer had. H NMR δ: 0.91 (t, J = 7.1 Hz, 3H), 3.51 (d, J = 13.2 Hz, 1H) 369
=
1
(d, J = 13.2 Hz, 1H) 3.84–4.05 (m, 2H), 4.52 (d, J = 10.3 Hz, 1H), 5.41 (d, J = 10.3 Hz,
1H), 7.18–7.25 (m, 4H), 7.27–7.33 (m, 6H). 13C NMR δ: 13.43, 36.39, 48.73, 63.04, 91.68,
1
127.42, 128.09, 128.61, 128.83, 129.07, 136.41, 162.12. The minor isomer had. H NMR
δ: 1.34 (t, J = 7.1 Hz, 3H), 3.54 (d, J = 13.2 Hz, 1H) 3.68 (d, J = 13.2 Hz, 1H) 4.30–4.38
(m, 2H), 4.56 (d, J = 11.2 Hz, 1H), 5.49 (d, J = 11.2 Hz, 1H), 7.18–7.25 (m, 4H), 7.27–7.33
(m, 6H). 13C NMR δ: 13.86, 36.10, 47.84, 63.43, 91.09, 127.51, 128.14, 128.5, 128.90, 129.12,
136.33, 162.52. Anal. calcd. for C18H19NO4S: C, 62.59%; H, 5.54%; N, 4.06%; S, 9.28%.
Found: C, 62.84%; H, 5.62%; N, 4.07%; S, 9.24%.
4.2.4. Ethyl 3-benzylthio-3-(4-methoxyphenyl)-2-nitro-propanoate (3b)
Column chromatography (EtOAc/hexane 2% → 12%) mixture of two isomers (1:1); yield
71%; oil. IR (CHCl3): 1751 (C O), 1564 (NO2) cm−1. One isomer had. 1H NMR δ: 0.99
=
(t, J = 7.1 Hz, 3H), 3.53 (d, J = 13.0 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.79 (s, 3H),
3.92–4.05 (m, 2H), 4.48 (d, J = 10.3 Hz, 1H), 5.37 (d, J = 10.3 Hz, 1H), 6.82–6.86 (m,
2H), 7.15–7.18 (m, 2H), 7.19–7.22 (m, 2H); 7.27–7.32 (m, 3H). 13C NMR δ: 13.51, 36.24,
47.46, 55.23, 63.45, 91.32, 114.17, 127.43, 127.94, 128.49, 129.02, 129.45, 129.78, 159.52,
162.16. Second isomer had. 1H NMR δ: 1.33 (t, J = 7.1 Hz, 3H), 3.53 (d, J = 13.0 Hz, 1H),
3.67 (d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 4.28–4.36 (m, 2H), 4.52 (d, J = 11.4 Hz, 1H), 5.41
(d, J = 11.4 Hz, 1H), 6.82–6.86 (m, 2H), 7.15–7.18 (m, 2H), 7.19–7.22 (m, 2H), 7.25–7.31
(m, 3H). 13C NMR δ: 13.76, 36.02, 48.12, 55.35, 63.02, 91.81, 114.38, 127.36, 127.45,
128.55, 129.03, 129.44, 129.78, 159.61, 162.52. HRMS (EI) m/z calcd for C19H21NO5S
(M+) 375,1140 found 375,1138.
4.2.5. Ethyl 2-nitro-3-phenyl-3-phenylthio-propanoate (4a)
−1
=
Mixture of two isomers (1:1); yield 80%; oil. IR (CHCl3): 1752 (C O), 1566 (NO2) cm
.
1
One isomer had. H NMR δ: 0.90 (t, J = 7.1 Hz, 3H), 3.89–3.96 (m, 2H), 4.84 (d,
J = 10.6 Hz, 1H), 5.46 (d, J = 10.6 Hz, 1H), 6.99–7.05 (m, 2H), 7.15–7.21(m, 8H). 13C
NMR δ: 13.42, 52.18, 63.13, 90.52, 127.79, 128.42, 128.63, 128.87, 129.13, 130.57, 134.81,
1
135.74, 162.09. Second isomer had. H NMR δ: 1.29 (t, J = 7.1 Hz, 3H), 4.22–4.27 (m,
2H), 4.87 (d, J = 11.5 Hz, 1H), 5.49 (d, J = 11.5 Hz, 1H), 6.99–7.05 (m, 2H), 7.15–7.21
(m, 8H). 13C NMR δ: 13.91, 53.68, 63.52, 91.34, 128.39, 128.53, 128.71, 129.04, 129.19,
131.53, 135.15, 135.78, 162.61. HRMS (EI) m/z calcd for C17H17NO4S (M+) 331,0878
found 331,0889.

JOURNAL OF SULFUR CHEMISTRY
7
4.2.6. Ethyl 3-(4-methoxyphenyl)-2-nitro-3-phenylthio-propanoate (4b)
−1
=
Mixture of two isomers (1:1); yield 72%; oil. IR (CHCl3): 1752 (C O), 1569 (NO2) cm
.
1
One isomer had. H NMR δ: 1.04 (t, J = 7.1 Hz, 3H), 3.78 (s, 3H), 4.03–4.06 (m, 2H),
4.92 (d, J = 10.5 Hz, 1H), 5.52 (d, J = 10.5 Hz, 1H), 6.77–6.81 (m, 2H), 7.02–7.07 (m,
2H), 7.26–7.27 (m, 4H), 7.29–7.32 (m, 1H) . 13C NMR δ 13.52, 51.88, 55.33, 63.12, 90.68,
114.02 127.48, 128.92, 129.04, 130.81, 132.18, 134.68, 159.62, 162.18. Second isomer had.
1H NMR δ: 1.38 (t, J = 7.1 Hz, 3H), 3.82 (s, 3H), 4.26–4.35 (m, 2H), 4.94 (d, J = 11.4 Hz,
1H), 5.53 (d, J = 11.4 Hz, 1H), 6.77–6.81 (m, 2H), 7.02–7.07 (m, 2H), 7.26–7.27 (m, 4H),
7.29–7.32 (m, 1H). 13C NMR δ: 13.91, 53.13, 55.49, 63.54, 91.40, 114.08, 127.72, 129.11,
129.62, 131.64, 132.58, 135.13, 159.64, 162.58. HRMS (EI) m/z calcd for C18H19NO5S
(M+) 361,0984 found 361,1004.
4.2.7. Ethyl 3-nitro-3-phenyl-2-propylthio-propanoate (9)
−1
=
Mixture of two isomers (2:1); yield 78%; oil. IR (CHCl3): 1752 (C O), 1569 (NO2) cm
;
One isomer had. 1H NMR δ: 0.82 (t, J = 7.4 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.39–1.51
(m, 2H), 2.36–2.44 (m, 2H), 4.14 (d, J = 11.9 Hz, 1H), 4.29 (q J = 7.2 Hz, 2H), 5.75 (d,
J = 11.9 Hz, 1H), 7.37–7.56 (m, 5H). 13C NMR δ: 13.71, 13.88, 22.23, 33.91, 48.28, 62.11,
1
89.93, 128.09, 129.11, 130.42, 132.09, 169.82. Second isomer had. H NMR δ: 1.01 (t,
J = 7.4 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H), 1.68 (sex, J = 7.4 Hz, 2H), 2.71–2.81(m, 2H),
3.95–4.02 (m, 2H), 4.28 (d, J = 11.9 Hz, 1H), 5.71 (d, J = 11.9 Hz, 1H), 7.37–7.56 (m, 5H).
13C NMR δ: 13.02, 13.23, 22.58, 34.71, 49.43, 61.58, 91.03, 128.21, 129.04, 130.60, 132.18,
169.84. HRMS (EI) m/z calcd for C14H19NO4S (M+) 297.1035 found 297.1036.[30]
4.2.8. Ethyl 2-benzylthio-3-nitro-3-phenyl-propanoate (10)
−1
=
Mixture of two isomers (1:0.7); yield 86%; oil. IR (CHCl3): 1750 (C O), 1560 (NO2) cm
.
1
One isomer had. H NMR δ: 1.33 (t, J = 7.1 Hz, 3H), 3.60 (d, J = 13.5 Hz, 1H), 3.72
(d, J = 13.5 Hz, 1H), 4.15 (d, J = 11.7 Hz, 1H), 4.20–4.30 (m, 2H), 5.65 (d, J = 11.7 Hz,
1H), 7.11–7.15 (m, 2H), 7.27–7.46(m, 8H). 13C NMR δ: 14.02, 36.18, 48.71, 62.14, 89.19,
1
127.62, 128.13, 128.64, 128.88, 129.21, 130.53, 131.87, 169.82. Second isomer had. H
NMR δ: 0.99 (t, J = 7.1 Hz, 3H), 3.92 (q, J = 7.1 Hz, 2H), 3.94 (d, J = 13.2 Hz, 1H), 3.96
(d, J = 13.2 Hz, 1H), 4.24 (d, J = 11.7 Hz, 1H), 5.73 (d, J = 11.7 Hz, 1H), 7.11–7.15 (m,
2H), 7.27–7.46 (m, 8H). 13C NMR δ: 13.83, 36.81, 48.28, 61.72, 90.64, 127.88, 128.02,
128.61, 129.04, 129.32, 130.13, 131.69, 167.90. HRMS (EI) m/z calcd for C18H19NO4S
(M+) 345,1035 found 345,1036.
4.2.9. Ethyl 3-nitro-3-phenyl-2-phenylthio-propanoate (11)
−1
=
Mixture of two isomers (1:1); yield 45%; oil. IR (CHCl3): 1754 (C O), 1567 (NO2) cm
.
1
One isomer had. H NMR δ: 0.90 (t, J = 7.1 Hz, 3H), 3.89–3.96 (m, 2H), 4.47 (d,
J = 11.8 Hz, 1H), 5.62 (d, J = 11.8 Hz, 1H), 7.13–7.50 (m, 10H). 13C NMR δ: 13.48, 53.61,
61.68, 90.62, 128.11, 128.58, 129.02, 129.13, 129.33, 130.62, 131.92, 135.34, 167.52. Sec-
1
ond isomer had. H NMR δ: 1.19 (t, J = 7.1 Hz, 3H), 4.15 (q, J = 7.1 Hz, 2H), 4.00 (d,
J = 11.7 Hz, 1H), 5.57 (d, J = 11.7 Hz, 1H), 7.13–7.50 (m, 10H). 13C NMR δ: 13.91, 52.54,
62.18, 89.71, 128.14, 129.48, 129.81, 130.41, 130.48, 130.59, 131.81, 134.78, 169.32. HRMS
(EI) m/z calcd for C17H17NO4S (M+) 331,0878 found 331,0887.

8
E. LEWANDOWSKA
4.3. General procedure for the synthesis of 2-amino-3-thiocinnamic ester (5–7) and
3-amino-2-thiocinnamic ester (12–13)
To a stirred solution of 2–4 or 9–10 (0.15 mmol) in i-PrOH (2 mL) at an ambient tem-
perature was added Zn powder as received (3.0 mmol) followed by aqueous HCl solution
(1 M, 1.5 mmol). After 0.5 h, the resulting mixture was filtered through Celite and saturated
aqueous NaHCO3 was added. The organic layer was extracted tree times with CH2Cl2,
dried over Na2SO4, evaporated to dryness under vacuum and the oily residue was column
chromatographed (5% →20% EtOAc/hexane).
4.3.1. Ethyl 2-amino-3-phenyl-3-propylthio-propanoate (5a)
=
Mixture of 2 diastereoisomers; yield76%; yellow oil. IR (CHCl3): 1731 (C O), 2968,
3019 (NH2) cm−1. Less polar fraction (1:0.2) major isomer had. H NMR δ: 0.89 (t,
1
J = 7.4 Hz, 3H), 1. 24 (t, J = 7.2 Hz, 3H), 1.46–1.56 (m, 2H), 1.68 (br.s, 2H, NH2),
2.26–2.39 (m, 2H),), 3.74 (d, J = 6.8 Hz, 1H), 4.03 (q, J = 7.2 Hz, 2H), 4.15 (d, J = 6.8 Hz,
1H), 7.30–7.42 (m, 5H). 13C NMR δ: 13.61, 13.88, 22.63, 33.51, 55.38, 60.42, 61.09, 127.51,
128.39, 128.52, 139.82, 172.33. More polar fraction (0.2:1) major isomer had. 1H NMR δ:
0.94 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.50–1.55 (m, 2H), 1.56 (br.s 2H, NH2),
2.31–2.40 (m, 2H), 3.84 (d, J = 6.6 Hz, 1H), 4.13 (d, J = 6.6 Hz, 1H), 4.15 (q, J = 7.2 Hz,
2H), 7.27–7.34 (m, 5H). 13C NMR δ: 13.42, 14.31, 22.48, 33.73, 53.78, 59.32, 61.06, 127.81,
128.50, 128.71, 138.28, 173.04. HRMS (EI) m/z calcd for C14H21NO2S (M+) 267,1293
found 267,1291.
4.3.2. Ethyl 2-amino-3-(4-methoxyphenyl)-3-propylthio-propanoate (5b)
Column chromatographed 15%→30% EtOAc/hexan; mixture of two isomers (1:1.5); yield
71%; oil. IR (CHCl3): 1732 (C O), 2970, 3010 (NH2) cm−1. One isomer had. 1H NMR δ:
=
0.91 (t, J = 7.4 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.47–1.57 (m, 2H), 1.62 (br.s 2H, NH2),
2.27–2.41 (m, 2H), 3.71 (d, J = 6.7 Hz, 1H), 3.79 (s, 3H), 4.11 (d, J = 6.7 Hz, 1H), 4.16 (q,
J = 7.2 Hz, 2H), 6.83–6.87 (m, 2H), 7.24–7.27 (m, 2H). 13C NMR δ: 13.31, 14.22, 22.58,
33.60, 53.03, 55.18, 59.21, 61.12, 113.79, 129.72, 130.04, 158.89, 173.01. Second isomer had.
1H NMR δ: 0.89 (t, J = 7.4 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H), 1.47–1.57 (m, 2H), 1.62 (br.s
2H, NH2), 2.27–2.41 (m, 2H), 3.78 (d, J = 6.4 Hz, 1H), 3.80 (s, 3H), 4.05 (q, J = 7.2 Hz,
2H), 4.12 (d, J = 6.4 Hz, 1H), 6.83–6.87 (m, 2H), 7.31–7.35 (m, 2H). 13C NMR δ: 13.41,
13.93, 22.52, 33.41, 54.58, 55.22, 60.51, 61.04, 113.72, 129.53, 131.61, 159.04, 173.04. HRMS
(EI) m/z calcd for C15H23NO3S (M+) 297,1399 found 297,1414.
4.3.3. Ethyl 2-amino-3-benzylthio-3-phenyl-propanoate (6a)
=
Mixture of two isomers (1:0.8); yield 61%; oil. IR (CHCl3): 1734 (C O), 2978,
3009 (NH2) cm−1. One isomer had. 1H NMR δ: 1.21 (t, J = 7.2 Hz, 3H), 1.60 (br.s 2H,
NH2), 3.46 (d, J = 13.4 Hz, 1H), 3.62 (d, J = 13.4 Hz, 1H), 3.80 (d, J = 6.6 Hz, 1H), 4.03
(d, J = 6.6 Hz, 1H), 4.12 (q, J = 7.2, Hz, 2H), 7.15–7.41(m, 10H). 13C NMR δ: 14.12, 35.72,
52.89, 59.01, 61.03, 127.02, 127.88, 128.42, 128.51,128.69, 128.89, 137.61, 137.82, 172.69.
1
Second isomer had. H NMR δ: 1.01 (t, J = 7.2 Hz, 3H), 1.60 (br.s 2H, NH2), 3.40 (d,
J = 13.6 Hz, 1H), 3.60 (d, J = 13.6 Hz, 1H), 3.71 (d, J = 6.4 Hz, 1H), 3.90–4.02 (m, 2H),
4.00 (d, J = 6.4 Hz, 1H), 7.15–7.41(m, 10H). 13C NMR δ: 13.81, 35.24, 54.32, 60.12, 61.09,

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127.12, 127.68, 128.32, 128.41, 128.78, 128.91, 137.52, 139.14, 172.62. HRMS (EI) m/z calcd
for C18H21NO2S (M+) 315,1293 found 315,1291.
4.3.4. Ethyl 2-amino-3-benzylthio-3-(4-methoxyphenyl)-propanoate (6b)
Column chromatographed 15%→30% EtOAc/hexane; mixture of two isomers (1:0.2);
yield 46%; oil. IR (CHCl3): 1735 (C O), 2958, 2998 (NH2) cm−1. One isomer had. 1H
=
NMR δ: 1.04 (t, J = 7.2 Hz, 3H), 1.62 (br.s 2H, NH2), 3.38 (d, J = 13.4 Hz, 1H), 3.58 (d,
J = 13.4 Hz, 1H), 3.67 (d, J = 6.6 Hz, 1H), 3.82 (s, 3H), 3.96 (d, J = 6.6 Hz, 1H), 3.90–4.04
(m, 2H), 6.82–6.85 (m, 2H) 7.16–7.32 (m, 7H). 13C NMR δ: 13.91, 35.23, 53.68, 55.32,
60.21, 61.04, 113.79, 127.02, 128.29, 128.89, 129.71, 130.89, 137.91, 159.03, 172.91. Second
isomer had. 1H NMR δ: 1.22 (t, J = 7.2 Hz, 3H), 1.62 (br.s 2H, NH2), 3.47 (d, J = 13.4 Hz,
1H), 3.60 (d, J = 13.4 Hz, 1H), 3.76 (d, J = 6.3 Hz, 1H), 3.81 (s, 3H), 4.00 (d, J = 6.3 Hz,
1H), 4.12 (q, J = 7.2 Hz, 2H), 6.82–6.85 (m, 2H) 7.16–7.32 (m, 7H). 13C NMR δ: 14.11,
35.72, 52.29, 55.22, 59.13, 61.12, 113.89, 127.04, 128.39, 128.91, 129.92, 130.93, 137.63,
159.21, 172.83. HRMS (EI) m/z calcd for C19H23NO3S (M+) 345,1399 found 345,1391.
4.3.5. Ethyl 2-amino-3-phenyl-3-phenylthio-propanoate (7a)
Column chromatographed 10%→25% EtOAc/hexane; mixture of two isomers (3:2); yield
46%; oil. IR (CHCl3): 1730 (C O), 2968, 3019 (NH2) cm−1. One isomer had. 1H NMR
=
δ: 1.24 (t, J = 7.1 Hz, 3H), 1.67 (br.s 2H, NH2) 3.90 (d, J = 5.8 Hz, 1H), 4.12 (dq, J = 1.7,
7.1 Hz, 2H), 4.58 (d, J = 5.8 Hz, 1H), 7.16–7.30 (m, 8H), 7.32–7.34(m, 2H). 13C NMR δ:
13.91, 58.68, 59.21, 61.23, 127.40, 127.88, 128.29, 128.48, 128.71, 128.82, 132.22, 132.79,
1
172.51. Second isomer had. H NMR δ: 1.24 (t, J = 7.1 Hz, 3H), 1.68 (br.s 2H, NH2)
3.87 (d, J = 6.0 Hz, 1H), 3.93–4.01 (m, 2H), 4.56 (d, J = 6.0 Hz, 1H), 7.16–7.30 (m, 8H),
7.37–7.39 (m, 2H). 13C NMR δ 14.11, 57.03, 60.14, 61.12, 127.23, 127.64, 128.31, 128.52,
128.64, 128.91, 132.12, 132.71, 172.78. HRMS (EI) m/z calcd for C17H19NO2S (M+)
301,1137 found 301,1171.
4.3.6. Ethyl 3-amino-3-phenyl-2-propylthio-propanoate (12)
After column we were able to separate one fraction; yield 22% and get only 1H NMR δ: 0.98
(t, J = 7.3 Hz, 3H), 1.04 (t, J = 7.3 Hz, 3H), 1.57–1.66 (m, 2H), 1.79 (br.s 2H, NH2), 2.64
(t, J = 7.3 Hz, 2H), 3.41 (d, J = 9.2 Hz, 1H), 3.98 (q, J = 7.3 Hz, 2H), 4.25 (d, J = 9.2 Hz,
1H), 7.26–7.27 (m, 1H); 7.29–7.32 (m, 2H), 7.38–7.39 (m, 2H) and 13C NMR δ: 13.38,
13.89, 22.84, 33.84, 55.98, 56.06, 60.81, 127.34, 127.87, 128.41, 141.92, 171.32.
4.3.7. Ethyl 3-amino-2-benzylthio-3-phenyl-propanoate (13)
After column we were able to separate one fraction; yield 28% and get only 1H NMR δ:
1.06 (t, J = 7.2 Hz, 3H), 1.75 (br.s 2H, NH2), 3.37 (d, J = 8.5 Hz, 1H), 3.82 (d, J = 13.5 Hz,
2H), 3.97 (q, J = 7.2 Hz, 2H), 4.26 (d, J = 8.5 Hz, 1H), 7.23–7.31(m, 10H) and 13C NMR
δ: 13.91, 36.05, 55.27, 55.69, 60.90, 127.21, 127.26, 127.77, 128.35,128.52, 129.05, 137.31,
141.81, 171.26.
Disclosure statement
No potential conflict of interest was reported by the author.

10
E. LEWANDOWSKA
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