N-Acyl-α-triphenylphosphonioglycinates in the synthesis of α,β-dehydro-α-amino acid derivatives

Article abstract of DOI:10.1007/s00706-003-0167-1

N-Acyl-α-triphenylphosphonioglycinates when treated with triethylamine are transformed to an equilibrium mixture of the corresponding N-acyliminoacetates and N-acyl-α-triphenylphosphoranylideneglycinates. Wittig reaction of the latter ylides with aromatic and aliphatic aldehydes or ketones enables a new easy entry to N-acyl-α,β-dehydro-α-amino acid esters. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-003-0167-1

Monatshefte f€ur Chemie 135, 807–815 (2004)
DOI 10.1007/s00706-003-0167-1
N-Acyl-a-triphenylphosphonioglycinates
in the Synthesis of a,b-Dehydro-a-amino
Acid Derivatives
1
1
Roman Mazurkiewicz1;ꢀ, Anna Kuznik , Mirosława Grymel ,
´
and Nikodem Kuznik
´
2
1
Department of Organic and Bioorganic Chemistry and Biotechnology, Silesian
University of Technology, PL-44100 Gliwice, Poland
2
Department of Analytical and General Chemistry, Silesian University of Technology,
PL-44100 Gliwice, Poland
Received November 24, 2003; accepted (revised) December 5, 2003
Published online April 22, 2004 # Springer-Verlag 2004
Summary. N-Acyl-ꢀ-triphenylphosphonioglycinates when treated with triethylamine are transformed
to an equilibrium mixture of the corresponding N-acyliminoacetates and N-acyl-ꢀ-triphenylphos-
phoranylideneglycinates. Wittig reaction of the latter ylides with aromatic and aliphatic aldehydes or
ketones enables a new easy entry to N-acyl-ꢀ,ꢁ-dehydro-ꢀ-amino acid esters.
Keywords. N-Acyl-ꢀ-triphenylphosphonioglycinates; N-Acyl-ꢀ-triphenylphosphoranylideneglyci-
nates; Ylides derived from glycine; ꢀ,ꢁ-Dehydro-ꢀ-amino acids; Wittig reaction.
Introduction
ꢀ,ꢁ-Dehydro-ꢀ-amino acids are one of the most interesting groups of nonpro-
teinogenic ꢀ-amino acids. They are common components of naturally occurring
peptides of high biological activity, including enzymes, antibiotics, hormones, and
phytotoxins [1, 2]. The synthesis of ꢀ,ꢁ-dehydro-ꢀ-amino acids has become an
area of great importance with the advent of peptide-derived chemotherapeutics
[2, 3]. The substitution of proteinogenic ꢀ-amino acids by ꢀ,ꢁ-dehydro-ꢀ-amino
acid residues usually affects markedly the physiological activity of peptides, chan-
ging their secondary structure and increasing their resistance to protease catalyzed
hydrolysis [4–6]. Apart from that, the hydrogenation of ꢀ,ꢁ-dehydro-ꢀ-amino
acids using Wilkinson-type chiral catalysts is considered to be one of the most
general and useful methods for the enantioselective synthesis of ꢀ-amino acids
[1, 2, 7–10].
ꢀ
Corresponding author. E-mail: romanm@zeus.polsl.gliwice.pl

808
R. Mazurkiewicz et al.
Scheme 1
Recently, we have developed a new convenient and effective synthesis of
N-acyl-ꢀ-triphenylphosphonioglycinates 1, starting from 4-phosphoranylidene-
5(4H)-oxazolones [11]. N-Acyl-ꢀ-triphenylphosphonioglycinates are a stable,
crystalline, hardly known class of phosphonium salts derived from glycine
[11]. They were obtained for the first time by Kober and Steglich in 1983 by the
photochemical bromination of N-benzoylglycinates with bromine or NBS to ꢀ-
bromoglycinates, followed by the displacement of the bromide anion by
triphenylphosphine [12]. We have also proved that N-acyl-ꢀ-triphenylphosphonio-
glycinates, when treated with an organic base, are transformed to an equilibrium
mixture of the corresponding N-acyliminoacetates 3 and phosphonium ylides
derived from glycine 2 (Scheme 1) [13].
In this contribution, we report a novel synthesis of ꢀ,ꢁ-dehydro-ꢀ-amino acid
derivatives 4 in the Wittig reaction, starting from easily accessible N-acyl-ꢀ-triphe-
nylphosphonioglycinates 1 as precursors of ylides 2 (Scheme 1).
Results and Discussion
N-Acyl-ꢀ-triphenylphosphoranylideneglycinates 2, generated in situ from the
phosphonium salts 1 under the influence of triethylamine in acetonitrile, react
easily with aromatic and aliphatic aldehydes in a Wittig reaction to give, as a rule,
a mixture of (Z) and (E) isomers of N-acyl-ꢀ,ꢁ-dehydro-ꢀ-amino acid esters 4,
usually in good or even excellent yields. In a few cases only the (Z) isomer was
isolated from a reaction mixture (Scheme 1, Table 1).
Our attempts to use simple ketones in this reaction failed. However, we were
able to obtain the expected products using a ketone with electron-withdrawing
groups R2 and R3 (methyl trifluoropyruvate). The reactions were carried out in
the presence of some amount of triphenylphosphine, to shift the equilibrium
between the iminoacetic acid derivative 3 and ylide 2 towards the ylide.
In the case of the reaction with phenylacetaldehyde, we have also isolated from
the reaction mixture methyl (E)-2-(N-pivaloylamino)-4-phenyl-3-butenoate (5) as a
product of partial tautomerisation of the primary Wittig reaction product 4g.
The structure of the obtained ꢀ,ꢁ-dehydro-ꢀ-amino acid derivatives was
1
determined based on their spectral data (IR, H and 13C NMR, and HETCOR

Synthesis of ꢀ,ꢁ-Dehydro-ꢀ-amino Acid Derivatives
809
Table 1. Synthesis of N-acyl-ꢀ,ꢁ-dehydro-ꢀ-amino acid esters 4
Product
Reaction conditions
(Z)=(E)
Ratio
R1
R2
R3
Procedure
Time=h
Salt 1:Carbonyl
compound ratio
4a
4b
4c
4d
4e
4f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
H
Ph
A
A
A
A
A
B
A
A
A
A
A
B
A
A
A
24
6
1:3
1:3
1:3
1:3
1:3
1:5
1:3
1:1.5
1:1.5
1:3
1:3
1:5
1:3
1:3
1:3
2.7:1
11.4:1
5.8:1
2.9:1
4.9:1
25:1
H
4-Pyridyl
2-Furyl
2-Pyrroyl
Et
H
6
H
48
6
H
H
Me
6
a
4g
4h
4i
H
PhCH2
COOMe
COOMe
Ph
24
6
–
a, b
CF3
CF3
H
–
a, b
6
–
4j
Ph
48
6
1.6:1
a
–
4k
4l
Ph
H
2-Furyl
Me
Ph
H
24
6
4:1
a
–
4m
4n
4o
Me
H
2-Quinolyl
2-Thienyl
Ph
Me
H
48
24
2.6:1
2.3:1
Me
H
a
Only one isomer has been detected in the reaction mixture; b the configuration of the isomer was not
established
experiments) and satisfactory elemental analyses. In two cases, results of high-
resolution mass spectrometry also confirmed the structures.
In all cases of reactions with aldehydes we discovered the predominance of the
(Z) stereoisomer of N-acyl-ꢀ,ꢁ-dehydro-ꢀ-amino acid esters. The configuration of
stereoisomers was established taking into account the following four criteria: (i)
the proton at the ꢁ position at the double bond of a (Z) isomer is shielded by about
0.2–1 ppm if compared with the respective (E) isomer [14], (ii) the proton at the
nitrogen atom is also shielded in a (Z) isomer in comparison with the (E) isomer
[15], (iii) the changing of the solvent from CDCl3 to the deuterated trifluoroacetic
acid (TFA) causes an upfield shift of the olefinic proton of an (E) isomer and a
downfield shift of the respective proton in the case of the (Z) isomer [14, 16], and
(iv) in the case of N-benzoyl derivatives the protons of the methoxy group are
shielded in an (E) isomer if compared with the (Z) isomer [16]. The configurations
of the (Z) isomer of compound 4m and the (E) isomers of 4a and 4o were also
confirmed by single crystal X-ray analyses.
The reported method for the synthesis of ꢀ,ꢁ-dehydro-ꢀ-amino acid derivatives
might be compared with a similar method described by Schmidt et al. [17–20],
which consists in the condensation of aldehydes with N-acyl-ꢀ-(dialkyloxy-
phosphinyl)glycinates by way of a Wadsworth-Emmons reaction. The reported
method seems to have two important advantages if compared with Schmidt’s
method: the starting N-acyl-ꢀ-triphenylphosphonioglycinates seem to be much
easier accessible than N-acyl-ꢀ-(dialkyloxyphosphinyl)glycinates, and the reported
reaction is carried out in the presence of triethylamine instead of strong bases like
sodium hydride, lithium diisopropylamide, or potassium t-butoxide.

810
R. Mazurkiewicz et al.
In summary, the Wittig reaction starting from N-acyl-ꢀ-triphenylphosphonio-
glycinates as the corresponding ylide precursors enables a new easy entry to N-
acyl-ꢀ,ꢁ-dehydro-ꢀ-amino acid esters.
Experimental
Melting points were determined in capillary tubes. IR spectra were recorded on a Zeiss Specord M 80
spectrophotometer; the measurements were carried out in CHCl3 (0.2M) using cells of 0.075 mm. 1H
and 13C NMR spectra were recorded in CDCl3 or TFA on a Varian Unity Inova-300 spectrometer at
300 and 75.5MHz, respectively, using TMS as an internal standard. High-resolution mass spectra were
recorded on an AMD 604 Spectrometer with EI ionisation. Kieselgel 60 (Merck, 0.063–0.200 mm)
was used for column chromatography. Elemental analyses (C, H, N) proved to be in satisfactory
agreement with the calculated values.
Methyl N-acyl-ꢀ-triphenylphosphonioglycinate tetrafluoroborates 1 (R1 ¼ t-Bu, Ph, and Me) were
synthesized as previously described [11]. Commercial grade acetonitrile, CH2Cl2, benzene, ethyl
˚
acetate, and n-hexane were distilled and dried over molecular sieves 4 A. Triethylamine was purified
according to Sauer [21].
X-Ray Analyses
The measurements of diffraction intensities were performed on a KUMA KM4 four-circle diffrac-
tometer, MoKꢀ radiation, !=2Y scan mode, Y range 2.5–25.0ꢁ; temperature of the measured crystalls:
293 K. Crystallographic data for the structures 4a, 4m, and 4o were deposited with the Cambridge
Crystallographic Data Centre as supplementary publications number CCDC 221902, CCDC 221901,
and CCDC 221900. A complete listing of the atomic coordinates x, y, and z can be obtained free of
charge, on request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: (þint) 44-1223 336 033; e-mail: deposit@ccdc.cam.ac.uk], on quoting
the depository numbers, the names of the authors, and the journal citation.
Syntheses of N-Acyl-ꢀ,ꢁ-dehydro-ꢀ-amino Acid Methyl Esters 4
Procedure A
To a stirred suspension of 1 mmol of methyl N-acyl-ꢀ-triphenylphosphonioglycinate tetrafluoroborate
in 4 cm3 of CH3CN, 0.393 g of triphenylphosphine (1.5mmol), 1.5–3 mmol of the carbonyl compound,
and 0.17 cm3 of triethylamine (1.25 mmol) were added at room temperature. After the reaction was
completed the solvent was evaporated and the reaction product was isolated by column chromatogra-
phy (ethyl acetate:benzene ¼ 1:10 to 1:1). The crude product was recrystallized from a mixture of
benzene and n-hexane.
Procedure B
A mixture of 1 mmol of methyl N-acyl-ꢀ-triphenylphosphonioglycinate tetrafluoroborate, 4 cm3 of
CH3CN, 0.393 g of triphenylphosphine (1.5 mmol), 5 mmol of the carbonyl compound, and 0.17 cm3
of triethylamine (1.25 mmol) was sealed in a glass tube and shaken at room temperature to make the
phosphonium salt dissolved. The reaction mixture was worked up as described above for procedure A.
Methyl (Z)-2-(N-pivaloylamino)-3-phenylpropenoate (Z-4a, C15H19NO3)
Yield 169.7mg (65%); mp 105–106ꢁC (Ref. [22] 101–102ꢁC); 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.44–
7.26 (m, Ph and –CH¼), 7.24 (s, br, NH), 3.84 (s, OMe), 1.29 (s, t-Bu) ppm; 1H NMR (TFA, 300MHz):

Synthesis of ꢀ,ꢁ-Dehydro-ꢀ-amino Acid Derivatives
811
ꢂ ¼ 7.84 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 176.5 (CONH), 165.8 (COOMe), 134.0,
124.6(Cꢀ and C-1), 131.3, 129.2 (Cꢁ and C-4), 52.6(OMe), 39.2 (CMe3), 27.2(CMe3), 129.5, 128.4 (C-2
and C-3) ppm; IR (CHCl3): ꢃꢀ¼ 3430m, 1720s, 1685vs, 1640 m, 1260 vscmꢂ1
.
Methyl (E)-2-(N-pivaloylamino)-3-phenylpropenoate (E-4a, C15H19NO3)
Yield 62.9 mg (24%); mp 122–123ꢁC; 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.96 (s, –CH¼), 7.81 (s, br,
1
NH), 7.36–7.20 (m, Ph), 3.64 (s, OMe), 1.30 (s, t-Bu) ppm; H NMR (TFA, 300MHz): ꢂ ¼ 7.25 (s,
–CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 177.1 (CONH), 165.5 (COOMe), 135.5 (Cꢀ), 125.79
(Cꢁ), 52.2 (OMe), 39.7 (CMe3), 27.4 (CMe3), 128.6, 127.8 (C-2 and C-3), 127.2, 125.83 (C-4, C-1)
ppm; IR (CHCl3): ꢃꢀ¼ 3420m, 1700 s, 1680s, 1650 m, 1220s cmꢂ1
.
Methyl (Z)-2-(N-pivaloylamino)-3-(4-pyridyl)propenoate (Z-4b, C14H18N2O3)
Yield 212.2mg (81%); mp 116–117ꢁC; 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 8.58 (d, J3–2 ¼ 6.3 Hz, H-2),
7.61 (s, br, NH), 7.23 (s, –CH¼), 7.21 (d, J2–3 ¼ 6.0 Hz, H-3), 3.88 (s, OMe), 1.27 (s, t-Bu) ppm; 1H
NMR (TFA, 300 MHz): ꢂ ¼ 7.69 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 175.8 (CONH),
165.3 (COOMe), 127.2 (Cꢀ), 127.0 (Cꢁ), 53.0 (OMe), 39.4 (CMe3), 27.1 (CMe3), 149.8, 142.1, 123.0
(C-2, C-4, C-3) ppm; IR (CHCl3): ꢃꢀ¼ 3410 m, 1690br, 1640 w, 1280s cmꢂ1
.
Methyl (Z)-2-(N-pivaloylamino)-3-(2-furyl)propenoate (Z-4c, C13H17NO4)
1
Yield 192.9 mg (77%); mp 98–100ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.82 (s, br, NH), 7.50 (d,
J5–4 ¼ 1.8 Hz, H-5), 6.92 (s, –CH¼), 6.54 (d, J3–4 ¼ 3.6 Hz, H-3), 6.49 (dd, J4–3 ¼ 3.5 Hz,
J4–5 ¼ 1.6 Hz, H-4), 3.82 (s, OMe), 1.33 (s, t-Bu) ppm; 1H NMR (TFA, 300 MHz): ꢂ ¼ 7.54 (s,
–CH¼) ppm; 13C NMR (CDCl3, 75.5 MHz): ꢂ ¼ 176.8 (CONH), 165.3 (COOMe), 123.6 (Cꢀ),
115.3 (Cꢁ), 52.5 (OMe), 39.1 (CMe3), 27.3 (CMe3), 150.1, 144.0, 114.8, 112.2 (C-2, C-5, C-3,
C-4) ppm; IR (CHCl3): ꢃꢀ¼ 3445m, 1725 s, 1685vs, 1645 m, 1280s cmꢂ1
.
Methyl (E)-2-(N-pivaloylamino)-3-(2-furyl)propenoate (E-4c, C13H17NO4)
1
Yield 33.3 mg (13%); H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.98 (s, –CH¼), 7.80 (s, br, NH), 7.44 (d,
J5–4 ¼ 1.5 Hz, H-5), 6.96 (d, J3–4 ¼ 3.3 Hz, H-3), 6.45 (dd, J4–3 ¼ 3.5 Hz, J4–5 ¼ 1.6 Hz, H-4), 3.90 (s,
OMe), 1.28 (s, t-Bu) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 176.9 (CONH), 164.4 (COOMe), 122.0
(Cꢀ), 114.8, 114.2 (Cꢁ and C-3), 52.4 (OMe), 39.8 (CMe3), 27.4 (CMe3), 149.5, 143.3, 112.1 (C-2, C-
5, C-4) ppm; IR (CHCl3): ꢃꢀ¼ 3410 m, 1690 s, 1675 vs, 1645 w, 1255 m cmꢂ1
.
Methyl (Z)-2-(N-pivaloylamino)-3-(2-pyrroyl)propenoate (Z-4d, C13H18N2O3)
1
Yield 139.6 mg (56%); mp 152–154ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 9.31 (s, br, NHpyr), 7.48
(s, –CH¼), 7.19 (s, br, NH), 6.94–6.92 (m, H-5), 6.54–6.52 (m, H-3), 6.29–6.26 (m, H-4), 3.80 (s,
OMe), 1.36 (s, t-Bu) ppm; 13C NMR (CDCl3, 75.5 MHz): 179.4 (CONH), 166.3 (COOMe), 116.8
(Cꢀ), 125.1 (Cꢁ), 52.4 (OMe), 39.6 (CMe3), 27.5 (CMe3), 126.7, 123.3, 116.7, 110.7 (C-2, C-5, C-3,
C-4) ppm; IR (CHCl3): ꢃꢀ¼ 3470m, 1690 br, 1635 s, 1260vs cmꢂ1
.
Methyl (E)-2-(N-pivaloylamino)-3-(2-pyrroyl)propenoate (E-4d, C13H18N2O3)
Yield 48.1 mg (19%); 1H NMR (CDCl3, 300MHz): ꢂ ¼ 11.68 (s, br, NHpyr), 7.71 (s, –CH¼), 7.35 (s,
br, NH), 7.00–6.98 (m, H-5), 6.55–6.53 (m, H-3), 6.29–6.26 (m, H-4), 3.86 (s, OMe), 1.29 (s, t-Bu)

812
R. Mazurkiewicz et al.
ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 177.1 (CONH), 165.3 (COOMe), 114.9 (Cꢀ), 127.6, 126.3
(Cꢁ and C-2), 52.5 (OMe), 39.5 (CMe3), 27.4 (CMe3), 122.9, 119.6, 110.4 (C-5, C-3, C-4) ppm; IR
(CHCl3): ꢃꢀ¼ 3455 m, 1700m, 1650 br, 1220 vs cmꢂ1
.
Methyl (Z)-2-(N-pivaloylamino)-2-pentenoate (Z-4e, C11H19NO3)
1
Yield 166.5mg (78%); mp 66–67.5ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.01 (s, br, NH), 6.65 (t,
J ¼ 7.2 Hz, –CH¼), 3.77 (s, OMe), 2.14 (dq, J ¼ 7.4, 7.4 Hz, CH2), 1.28 (s, t-Bu), 1.07 (t, J ¼ 7.5 Hz,
Me) ppm; 1H NMR (TFA, 300 MHz): ꢂ ¼ 7.18 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz):
ꢂ ¼ 176.7 (CONH), 165.4 (COOMe), 124.2 (Cꢀ), 139.7 (Cꢁ), 52.3 (OMe), 39.3 (CMe3), 27.5
(CMe3), 22.3 (CH2), 12.7 (Me) ppm; IR (CHCl3): ꢃꢀ¼ 3430m, 1715vs, 1685 vs, 1645m, 1280s
cmꢂ1
.
Methyl (E)-2-(N-pivaloylamino)-2-pentenoate (E-4e, C11H19NO3)
1
Yield 34mg (16%); H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.69 (s, br, NH), 7.15 (t, J ¼ 7.6 Hz, –CH¼),
3.84 (s, OMe), 2.57 (dq, J ¼ 7.5, 7.5 Hz, CH2), 1.25 (s, t-Bu), 1.08 (t, J ¼ 7.5 Hz, Me) ppm; 13C NMR
(CDCl3, 75.5MHz): 177.1 (CONH), 165.3 (COOMe), 124.3 (Cꢀ), 134.6 (Cꢁ), 52.3 (OMe), 39.6
(CMe3), 27.4 (CMe3), 21.9 (CH2), 14.2 (Me) ppm; IR (CH2Cl2): ꢃꢀ¼ 3420m, 1735s, 1675 s,
1250 s cmꢂ1
.
Methyl (Z)-2-(N-pivaloylamino)-2-butenoate (Z-4f, C10H17NO3)
1
Yield 185.8 mg (93%); oil; H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.04 (s, br, NH), 6.79 (q, J ¼ 7.2 Hz,
1
–CH¼), 3.76 (s, OMe), 1.75 (d, J ¼ 7.2 Hz, Me), 1.29 (s, t-Bu) ppm; H NMR (TFA, 300MHz):
ꢂ ¼ 7.29 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 176.6 (CONH), 165.2 (COOMe), 126.0
(Cꢀ), 133.4 (Cꢁ), 52.2 (OMe), 39.3 (CMe3), 27.5 (CMe3), 14.6 (Me) ppm; IR (CHCl3): ꢃꢀ¼ 3430m,
1710 vs, 1680 vs, 1650 m, 1290 vscmꢂ1
.
Methyl (E)-2-(N-pivaloylamino)-2-butenoate (E-4f, C10H17NO3)
1
Yield 7.4 mg (4%); H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.70 (s, br, NH), 7.26 (q, J ¼ 7.7 Hz, –CH¼),
3.85 (s, OMe), 2.08 (d, J ¼ 7.8Hz, Me), 1.25 (s, t-Bu) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 177.1
(CONH), 165.4 (COOMe), 125.6 (Cꢀ), 127.6 (Cꢁ), 52.3 (OMe), 39.7 (CMe3), 27.4 (CMe3), 14.4 (Me)
ppm; IR (CHCl3): ꢃꢀ¼ 3430m, 1700 s, 1665s, 1640 m, 1250vscmꢂ1
.
Methyl (Z)-2-(N-pivaloylamino)-4-phenyl-2-butenoate (Z-4g, C16H21NO3)
Yield 115.7 mg (42%); 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.40–7.19 (m, Ph), 7.14 (s, br, NH), 6.82 (t,
1
J ¼ 7.0 Hz, –CH¼), 3.76 (s, OMe), 3.48 (d, J ¼ 6.9 Hz, CH2), 1.30 (s, t-Bu) ppm; H NMR (TFA,
300 MHz): ꢂ ¼ 7.42–7.18 (m, Ph and –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 176.9 (CONH),
165.2 (COOMe), 125.1 (Cꢀ), 135.8 (Cꢁ), 52.4 (OMe), 39.4 (CMe3), 27.5 (CMe3), 138.8, 128.6, 126.4
(C-1, C-2þ C-3, C-4), 35.2 (CH2) ppm; IR (CHCl3): ꢃꢀ¼ 3440m, 1715s, 1675vs, 1650 s, 1260s
cmꢂ1
.
Methyl (E)-2-(N-pivaloylamino)-4-phenyl-3-butenoate (E-5, C16H21NO3)
Yield 96.4 mg (35%); 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.40–7.19 (m, Ph), 6.62 (dd,
JHꢄ–Hꢁ ¼ 15.6Hz, JHꢄ–Hꢀ ¼ 1.2 Hz, Hꢄ), 6.36 (d, J ¼ 6.9Hz, NH), 6.19 (dd, JHꢁ–Hꢄ ¼ 15.9Hz,
JHꢁ–Hꢀ ¼ 6.6 Hz, Hꢁ), 5.26 (ddd, JHꢀ–Hꢁ ¼ 6.9 Hz, JHꢀ–NH ¼ 6.9 Hz, JHꢀ–Hꢄ ¼ 1.5 Hz, Hꢀ), 3.79 (s,

Synthesis of ꢀ,ꢁ-Dehydro-ꢀ-amino Acid Derivatives
813
OMe), 1.26 (s, t-Bu) ppm; 13C NMR (CDCl3, 75.5 MHz): ꢂ ¼ 177.9 (CONH), 171.4 (COOMe), 54.1
(Cꢀ), 123.4 (Cꢁ), 133.2 (Cꢄ), 52.7 (OMe), 38.7 (CMe3), 27.4 (CMe3), 135.8, 128.2 (C-1, C-4), 128.6,
126.6 (C-2 and C-3) ppm.
2-Pivaloylamino-3-trifluoromethylbutendioic Acid Dimethyl Ester (4h, C12H16F3NO5)
Yield 295.7mg (95%); mp 79–81ꢁC [13].
2-Benzoylamino-3-trifluoromethylbutendioic Acid Dimethyl Ester (4i, C14H12F3NO5)
Yield 152.4mg (46%); mp 101.5–103.5ꢁC [13].
Methyl (Z)-2-(N-benzoylamino)-3-phenylpropenoate (Z-4j, C17H15NO3)
Yield 65.8 mg (23%); mp 140.5–141.5ꢁC (Ref. [14] 131ꢁC, Ref. [23] 142–143ꢁC); 1H NMR (CDCl3,
300 MHz): ꢂ ¼ 7.88–7.82, 7.56–7.41 and 7.34–7.28 (m, 10Har, NH, and –CH¼), 3.83 (s, OMe) ppm;
1H NMR (TFA, 300 MHz): ꢂ ¼ 7.98–7.38 (m, 10Har, and –CH¼) ppm; 13C NMR (CDCl3, 75.5 MHz):
ꢂ ¼ 165.8, 165.6 (CONH and COOMe), 133.8, 133.5 (Cꢀ and PhCO: C-1), 129.4 (Cꢁ), 52.7 (OMe),
132.1, 131.8 (PhCO: C-4 and PhCH¼: C-4), 128.7, 128.6 (PhCO: C-2 and PhCH¼: C-3), 127.4
(PhCO: C-3), 129.6, 124.2 (PhCH¼: C-2, C-1) ppm; IR (CHCl3): ꢃꢀ¼ 3425m, 1715 s, 1680 vs,
1645 m, 1275vscmꢂ1
.
Methyl (E)-2-(N-benzoylamino)-3-phenylpropenoate (E-4j, C17H15NO3)
1
Yield 41.1 mg (15%); mp 132.5–133ꢁC (Ref. [14] 125ꢁC, Ref. [23] 134–135ꢁC); H NMR (CDCl3,
300 MHz): ꢂ ¼ 8.39 (s, br, NH), 8.05 (s, –CH¼), 7.87–7.82 (m, 2Har), 7.57–7.42 (m, 3Har), 7.33–7.24
(m, 5Har), 3.67 (s, OMe) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 165.8, 165.4 (CONH and COOMe),
135.2 (Cꢀ), 126.3 (Cꢁ), 52.4 (OMe), 134.1, 132.0, 127.8, 127.0 (PhCO: C-1, C-4, C-2, C-3), 128.75,
128.72 (PhCH¼: C-2 and C-3), 127.6, 126.0 (PhCH¼: C-4, C-1) ppm; IR (CHCl3): ꢃꢀ¼ 3405m,
1700 s, 1670vs, 1630 m, 1250s cmꢂ1
.
Methyl (Z)-2-(N-benzoylamino)-3-(2-furyl)propenoate (Z-4k, C15H13NO4)
Yield 135.6 mg (50%); mp 136–137ꢁC; 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 8.28 (s, br, NH), 7.95–7.85
(m, 2Har), 7.60–7.46 (m, 3Har and H-5Fur), 7.08 (s, –CH¼), 6.58 (d, J3–4 ¼ 3.6 Hz, H-3Fur), 6.47 (dd,
J4–3 ¼ 3.4 Hz, J4–5 ¼ 1.6Hz, H-4Fur), 3.84 (s, OMe) ppm; 1H NMR (TFA, 300 MHz): ꢂ ¼ 7.68
(s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 165.6, 165.4 (CONH and COOMe), 123.0
(Cꢀ), 116.2, 115.4 (Cꢁ and Furyl: C-3), 52.6 (OMe), 133.5, 132.2 (PhCO: C-1, C-4), 128.7, 127.5
(PhCO: C-2 and C-3), 149.9, 144.4, 112.3 (Furyl: C-2, C-5, C-4) ppm; IR (CHCl3): ꢃꢀ¼ 3425 m,
1720 s, 1675vs, 1645 m, 1285vs cmꢂ1
.
Methyl (Z)-2-(N-benzoylamino)-2-butenoate (Z-4l, C12H13NO3)
Yield 115.8 mg (53%); mp 79–80.5ꢁC (Ref. [14] 78.5ꢁC); 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.90–7.86
(m, 2Har), 7.61 (s, br, NH), 7.58–7.44 (m, 3Har), 6.90 (q, J ¼ 7.2 Hz, –CH¼), 3.79 (s, OMe), 1.85 (d,
J ¼ 7.2 Hz, Me) ppm; 1H NMR (TFA, 300 MHz): ꢂ ¼ 7.40 (s, –CH¼) ppm; 13C NMR (CDCl3,
75.5MHz): ꢂ ¼ 165.4, 165.1 (CONH and COOMe), 126.0 (Cꢀ), 133.7 (Cꢁ), 52.4 (OMe), 133.9,
132.0, 128.6, 127.4 (C-1, C-4, C-2, C-3), 15.0 (Me) ppm; IR (CHCl3): ꢃꢀ¼ 3420m, 1715s , 1675 vs,
1650 m, 1290vscmꢂ1
.

814
R. Mazurkiewicz et al.
Methyl (E)-2-(N-benzoylamino)-2-butenoate (E-4l, C12H13NO3)
1
Yield 28.9 mg (13%); H NMR (CDCl3, 300 MHz): ꢂ ¼ 8.19 (s, br, NH), 7.85–7.80 (m, 2Har), 7.55–
1
7.41 (m, 3Har and –CH¼), 3.89 (s, OMe), 2.16 (d, J ¼ 7.5 Hz, Me) ppm; H NMR (TFA, 300MHz):
ꢂ ¼ 6.95 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 165.8, 165.2 (CONH and COOMe),
125.7 (Cꢀ), 128.2 (Cꢁ), 52.4 (OMe), 134.8, 131.7, 128.7, 126.9 (C-1, C-4, C-2, C-3), 14.5 (Me) ppm;
IR (CHCl3): ꢃꢀ¼ 3410m, 1700 m, 1670 s, 1645 m, 1270s cmꢂ1; MS (EI): calcd. 219.0895, found
219.0890.
Methyl (Z)-2-(N-acetylamino)-3-(2-quinolyl)propenoate (Z-4m, C15H14N2O3)
1
Yield 267.6mg (99%); mp 106–107ꢁC; H NMR (CDCl3, 300MHz): ꢂ ¼ 12.60 (s, br, NH), 8.14 (d,
J4–3 ¼ 8.4 Hz, H-4), 7.94 (d, J5–6 ¼ 8.1 Hz, H-5), 7.80 (d, J8–7 ¼ 8.4 Hz, H-8), 7.78–7.72 (m, H-7),
7.58–7.52 (m, H-6), 7.32 (d, J3–4 ¼ 8.7Hz, H-3), 6.35 (s, –CH¼), 3.91 (s, OMe), 2.30 (s, Me) ppm; 1H
NMR (TFA, 300 MHz): ꢂ ¼ 7.82 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 168.6 (CONH),
165.7 (COOMe), 126.7 (Cꢀ), 112.3 (Cꢁ), 52.7 (OMe), 23.7 (Me), 155.3, 146.6, 136.9, 135.4, 130.2,
128.3, 127.7, 126.8, 123.2 (Quinolyl) ppm; IR (CHCl3): ꢃꢀ¼ 3400 m, 1730 vs, 1690vs, 1640 s,
1285 vscmꢂ1
.
Methyl (Z)-2-(N-acetylamino)-3-(2-thienyl)propenoate (Z-4n, C10H11NO3S)
Yield 136.6mg (61%); mp 119–120ꢁC (Ref. [15] 118–119ꢁC); 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.80
(s, –CH¼), 7.50 (d, J5–4 ¼ 4.8 Hz, H-5), 7.32 (d, J3–4 ¼ 3.6 Hz, H-3), 7.08 (dd, J4–3 ¼ 3.9 Hz,
1
J4–5 ¼ 4.8 Hz, H-4), 6.83 (s, br, NH), 3.82 (s, OMe), 2.23 (s, Me) ppm; H NMR (TFA, 300MHz):
ꢂ ¼ 8.21 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 169.8 (CONH), 165.3 (COOMe), 121.3
(Cꢀ), 129.8 (Cꢁ), 52.5 (OMe), 23.5 (Me), 136.2, 133.4, 130.8, 127.1 (C-2, C-3, C-5, C-4) ppm; IR
(CHCl3): ꢃꢀ¼ 3415 m, 1715s, 1700 s, 1630m, 1265 vscmꢂ1
.
Methyl (E)-2-(N-acetylamino)-3-(2-thienyl)propenoate (E-4n, C10H11NO3S)
Yield 52.6 mg (23%); mp 117–118ꢁC; 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 8.34 (s, –CH¼), 7.52 (s, br,
NH), 7.43 (d, J5–4 ¼ 4.8 Hz, H-5), 7.29 (d, J3–4 ¼ 3.6Hz, H-3), 7.03 (dd, J4–3 ¼ 3.8 Hz, J4–5 ¼ 5.2 Hz,
H-4), 3.92 (s, OMe), 2.15 (s, Me) ppm; 1H NMR (TFA, 300 MHz): ꢂ ¼ 8.31 (s, –CH¼) ppm; 13C NMR
(CDCl3, 75.5MHz): ꢂ ¼ 168.6 (CONH), 164.1 (COOMe), 120.8 (Cꢀ), 122.5 (Cꢁ), 52.3 (OMe), 24.8
(Me), 136.7, 134.5, 130.1, 126.6 (C-2, C-3, C-5, C-4) ppm; IR (CHCl3): ꢃꢀ¼ 3405m, 1700 vs, 1675s,
1630 m, 1270vscmꢂ1
.
Methyl (Z)-2-(N-acetylamino)-3-phenylpropenoate (Z-4o, C12H13NO3)
Yield 132.9mg (61%); mp 121–122ꢁC (Ref. [14] 115ꢁC, Ref. [24] 121–122ꢁC, Ref. [25] 124ꢁC); 1H
NMR (CDCl3, 300 MHz): ꢂ ¼ 7.63–7.21 (m, Ph and –CH¼), 7.12 (s, br, NH), 3.84 (s, OMe), 2.11 (s,
Me) ppm; 1H NMR (TFA, 300 MHz): ꢂ ¼ 7.88 (s, –CH¼) ppm; 13C NMR (CDCl3, 75.5MHz):
ꢂ ¼ 168.8 (CONH), 165.7 (COOMe), 133.7 (Cꢀ), 129.4 (Cꢁ), 52.7 (OMe), 23.3 (Me), 132.3, 124.2
(C-4, C-1), 129.6, 128.6 (C-2 and C-3) ppm; IR (CHCl3): ꢃꢀ¼ 3420 m, 1700 br, 1635 m, 1265 vs cmꢂ1
.
Methyl (E)-2-(N-acetylamino)-3-phenylpropenoate (E-4o, C12H13NO3)
1
Yield 57.8 mg (26%); H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.87 (s, –CH¼), 7.58 (s, br, NH), 7.50–7.19
(m, Ph), 3.63 (s, OMe), 2.14 (s, Me) ppm; 13C NMR (CDCl3, 75.5MHz): ꢂ ¼ 173.9 (CONH), 164.1
(COOMe), 133.7 (Cꢀ), 126.0, 125.7 (Cꢁ and C-1), 52.3 (OMe), 24.5 (Me), 128.7, 127.8 (C-2þ C-3,

Synthesis of ꢀ,ꢁ-Dehydro-ꢀ-amino Acid Derivatives
815
C-4) ppm; IR (CHCl3): ꢃꢀ¼ 3410m, 1710 vs, 1685 vs, 1635 m, 1270s cmꢂ1; MS (EI): calcd. 219.0895,
found 219.0903.
Acknowledgements
The financial help of the Polish State Committee for Scientific Research (Grant No 4 T09A 026 24) is
gratefully acknowledged.
References
~
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~
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25
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