Practical preparation of Z-α-(N-acetylamino)- and Z-α-(N-benzoylamino)-α,β-unsaturated acids

Article abstract of DOI:10.1080/00397910701265895

An efficient two-step synthetic procedure for the preparation of numerous variations of N-protected α,β-unsaturated α-amino acids and their corresponding esters from N-protected glycine and either aliphatic or aromatic aldehydes was developed. The reaction involved cyclization of the N-protected glycine into oxazolone, condensation with the aldehyde, and ring opening with a base. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701265895

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Practical Preparation of Z‐α‐(N‐Acetylamino)‐
and Z‐α‐(N‐Benzoylamino)‐α,β‐unsaturated
Acids
Branko S. Jursic a , Sarada Sagiraju a , Dustin K. Ancalade a , Traneil Clark a
& Edwin D. Stevens a
a Department of Chemistry, University of New Orleans, New Orleans,
Louisiana
Version of record first published: 22 May 2007.
To cite this article: Branko S. Jursic , Sarada Sagiraju , Dustin K. Ancalade , Traneil Clark & Edwin D. Stevens
(2007): Practical Preparation of Z‐α‐(N‐Acetylamino)‐ and Z‐α‐(N‐Benzoylamino)‐α,β‐unsaturated Acids,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:10, 1709-1714
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Synthetic Communicationsw, 37: 1709–1714, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701265895
Practical Preparation of Z-a-(N-
Acetylamino)- and Z-a-(N-Benzoylamino)-
a,b-unsaturated Acids
Branko S. Jursic, Sarada Sagiraju, Dustin K. Ancalade,
Traneil Clark, and Edwin D. Stevens
Department of Chemistry, University of New Orleans, New Orleans,
Louisiana
Abstract: An efficient two-step synthetic procedure for the preparation of numerous
variations of N-protected a,b-unsaturated a-amino acids and their corresponding
esters from N-protected glycine and either aliphatic or aromatic aldehydes was
developed. The reaction involved cyclization of the N-protected glycine into
oxazolone, condensation with the aldehyde, and ring opening with a base.
Keywords: acylaminocinnamic acid, azlactone condensation, azlactone ring opening,
azalactones, oxazolones
Amino acid derivatives are compounds of high commercial importance.[1]
A variety of asymmetric synthetic methods for amino acid preparation have
been developed. One method of importance involves hydrogenation of an
enamide using chiral transition-metal catalysts. Perhaps one of the best
examples using enamides as a starting material[2] is enantioselective synthesis
of [(S)-2-amino-3-(3,4-dihyroxyphenyl)propanoic acid] (L-DOPA),[3] which
involves a rhodium hydrogenation catalyst containing a chiral phosphorus
ligand reacting with an enamide.
Unfortunately, large-scale manufacturing of a,b-unsaturated amino acids
has proven to be problematic. Theoretically, amino acids are ideal starting
Received in the USA August 21, 2006
Address correspondence to Branko S. Jursic, Department of Chemistry, University
of New Orleans, New Orleans, LA 70148. E-mail: bjursic1@uno.edu
1709

1710
B. S. Jursic et al.
materials in the preparation of these compounds. For instance, L-threonine
methyl ester is an excellent starting material in the preparation of Z-2-(N-
acetylamino) butenoate.[4] However, there is no general synthetic procedure
using amino acids as precursors. Here we present a general synthetic
procedure for the preparation of large quantities of a-acetylamino- and a-
benzoylamido-a,b-unsaturated acids.
N-Protected glycine and the corresponding aldehydes were chosen as
the optimal starting reagents for these reactions. To fully understand and
demonstrate the scope of this condensation, the reaction progression
between N-acetylglycine (1) and 1,4-benzenedicarbaldehyde (3) was
followed by NMR spectroscopy (Fig. 1). The first step is the formation
of 2-methyl-4H-oxazol-5-one (2), which readily condenses with 3 to
form the monocondensation product 4. The reaction continues, and
the final double condensation product 5 is formed. According to
our NMR studies, the conversion appears to be nearly quantitative.
Similar reaction conditions were used for the preparation of oxazolones 7
(Table 1).
The oxazolone ring is exceptionally easy to open with either hydroxy or
alcoxy ions, which produces the corresponding acids or esters, respectively.
This approach was used for quantitative preparations of esters 8 or acids 9
(Table 1).
To determine the stereochemistry of the double bond generated in the
course of the condensation reaction, X-ray structural analysis was performed
with 7g (Fig. 2). X-ray analysis proved that this isomer was the major isomer
(more than 95%) of the condensation reaction. Our X-ray crystallographic
study confirms that the stereochemistry of the major isomer formed during
condensations of 2 with aldehyde has Z-configuration of the newly formed
double bond of 7. Therefore, in preparation of both esters 8 and acids 9,
which are prepared by ring opening of 7, stereochemistry of the double
bond must be preserved.
We developed a successful method for the preparation of Z-2-acetamido
and Z-2-benzamido-2,3-unsaturated acids and their methyl esters starting
from N-protected glycine. The starting materials are inexpensive, and the
reaction procedures are very simple, therefore it is applicable to large-scale
(industrial) preparation of these valuable intermediates for use in the pharma-
ceutical industry.

Preparation of a-(N-Acylamino)-a,b-unsaturated acids
1711
Figure 1. NMR data of reaction following experiment for preparation of 5.
Figure 2. Ortep drawing of the X-ray determined structure of 7g.
EXPERIMENTAL
All NMR reactions following experiments were performed on 500-MHz
Unity500 Varian NMR instrument by taking samples from the reaction
Table 1. Isolated yields
R1
R2
7
Yield of 7
8
Yield of 8
9
Yield of 9
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
C6H5
n-C8H17
C6H5
7a
7b
70
90
92
93
80
90
95
87
90
80
90
84
92
8a
8b
8c
8d
8e
8f
70
90
82
90
80
89
90
87
90
80
90
87
91
9a
9b
9c
9d
9e
9f
87
93
96
88
92
96
91
98
96
93
91
92
89
3,4,5-(MeO)3C6H4 7c
4-(Me2N)C6H4
1-naphthyl
2-furyl
7d
7e
7f
CH3
n-C8H17
Ph
7g
7h
7i
8g
8h
8i
9g
9h
9i
C6H5 3,4,5-(MeO)3C6H4 7j
8j
9j
C6H5
C6H5
C6H5
4-(Me2N)C6H4
1-naphthyl
2-furyl
7k
7l
8k
8l
9k
9l
7m
8m
9m

1712
B. S. Jursic et al.
mixture containing 0.02 mol of N-acetylglycine, 20 mL of acetic anhydride,
3 g of sodium acetate, and 0.01 mol of 1,4-benzenedicarbaldehyde. The
NMR sample was prepared as DMSO-d6 solution. All DMSO-d6 samples
were clear solutions. Elemental analysis was performed by Atlantic
Microlab, Inc. X-ray structure determination was performed on Bruker
Smart 1KCCD automated diffractometer. Crystals of compound 7g were
obtained by slow crystallization from a diluted methanol solution of 7g. The
monocrystal needle of 7g for X-ray study was tricilinic with P-1 symmetry
˚
space group. Dimensions of 7g crystal were a ¼ 3.8583(10) A,
˚
˚
b ¼ 10.957(3) A, c ¼ 11.692(3) A, a ¼ 68.628(9)8, b ¼ 80.577(7)8,
g ¼ 82.749(7)8. Cell formula unit is Z ¼ 2. Computation of X-ray data collec-
tion and the cell refinement were performed by Bruker Smart. Computation of
X-ray data reduction was performed by Bruker Saint. Computation of
structure solution and structure refinement from X-ray data were performed
1
by SHELXL-97. Our H NMR spectroscopic data for compounds 7b, 7i,
7k, and 7m are in agreement with previously reported NMR data.[5]
General Procedure for Preparation of Oxazolone 7: Preparation of
2-Methyl-4-(3,4,5-trimethoxybenzylidene)-4H-oxazol-5-one (7c)
A suspension of N-acetylglycine (5.9 g; 0.05 mol), sodium acetate (4.1 g;
0.05 mol), and acetic anhydride (30 mL) was stirred at room temperature
for 30 min. Into the white suspension, 3,4,5-trimethoxybenzaldehyde (8.3 g;
0.05 mol) was added. The resulting suspension was stirred at room tempera-
ture for 1 h and then at 608C for 5 h. The reaction mixture became a brown
solution that upon cooling to room temperature again became a suspension.
This suspension was mixed with water (1 L) and stirred at room temperature
for a half an hour. The insoluble material was separated by filtration, washed
with water (3 Â 30 mL), and recrystallized from methanol (ꢀ250 mL) to
afford 12.8 g (92%) of product. Mp 153–1558C. 1H NMR (CDCl3,
300 MHz) d 7.33 (2H, s), 6.94 (1H, s), 3.87 (3H, s), 3.86 (6H, s), and
2.33 ppm (3H, s). 13C NMR (CDCl3) d 167.8, 165.7. 153.1, 141.0, 131.7,
131.2, 128.6, 109.6, 61.0, 56.1, and 15.7 ppm. Anal. calcd. for C14H15NO5
(MW 277.27): C, 60.64; H, 5.45; N, 5.05. Found: C, 60.58; H 5.53, N 4.96.
General Procedure for Preparation of 8: Preparation of Methyl (Z)-
2-Benzoylaminobut-2-enoate (8g)
The methanol (20 mL) solution of 7g (1.87 g; 0.01 mol) and sodium
methoxide in methanol (2 mL of 25% CH3ONa in CH3OH) was stirred at
room temperature for 15 min. Solvent was evaporated, and the residue was
partitioned between 10% aqueous ammonium chloride (100 mL) and
methylene chloride (150 mL). The organic layer was washed with water
(3 Â 100 mL), dried over anhydrous sodium sulfate, and evaporated to an

Preparation of a-(N-Acylamino)-a,b-unsaturated acids
1713
oily residue. The oily residue was dissolved in hot petroleum ether (500 mL)
from which white needles of product crystallized. The yield of the product was
1
1.97 g (90%). Mp 70–728C. H NMR (CDCl3, 400 MHz) d 7.87 (2H, d,
J ¼ 7.2 Hz), 7.63 (1H, broad s), 7.54 (1H, t, J ¼ 7.2 Hz), 7.46 (2H, t,
J ¼ 7.2 Hz), 6.89 (1H, q, J ¼ 7.6 Hz), 3.78 (3H, s), and 1.84 ppm (2H, d,
J ¼ 7.6 Hz). 13C NMR (CDCl3,) d 165.4, 165.1 (two carbonyls), 133.9,
133.8, 132.0, 128.6, 127.4, 126.0 (six alkene carbons), 52.4 (CH3 carbon),
and 15.0 ppm (CH2 carbon). Anal. calcd. for C12H13NO3 (MW 219.24): C,
65.74; H, 5.98; N, 6.39. Found: C, 65.57; H 6.05, N 6.26.
General Procedure for Preparation of 9: Preparation of
2-Acetylamino-3-phenylacrylic Acid (9b)
Into aqueous (200 mL) sodium hydroxide (4.0 g; 0.1 mol), a solution of
methanol (200 mL) and 4-benzylidene-2-methyl-4H-oxazol-5-one (18.7g;
0.1 mol) was added. The reaction mixture was stirred at room temperature
for 30 min, followed by methanol evaporation at reduced pressure. The
remaining clear water solution was acidified with 10% hydrochloric acid to
pH ꢀ3 and left at room temperature overnight. The formed crystalline
product was separated by filtration, washed with cold water (3 Â 50 mL)
and dried at 1108C for 30 min to afford pure product. The yield of the
reaction was 19.1 g (93%). Mp 188–1908C. 1H NMR (DMSO-d6, 300
MHz) d 9.5 (1Hm s, NH), 7.62 (2H, d, J ¼ 7.2 Hz), 7.41 (2H, t,
J ¼ 6.0 Hz), 7.35 (1H, t, J ¼ 7.2 Hz). 7.24 (1H, s, CH), and 1.91 ppm (3H, s,
CH3); 13C NMR (DMSO-d6) d 169.4 and 166.5, 133.8, 131.2, 129.8, 129.2.
128.6, 127.5, and 22.6 ppm. Anal. calcd. for C11H11NO3 (MW 205.21): C,
64.38; H, 5.40; N, 6.83. Found: C, 64.26; H, 5.49; N, 6.89.
ACKNOWLEDGMENT
We express our appreciation to the Louisiana Board of Regents (LEQSF(2001-
04)-RD-B-12) and the National Science Foundation (DMR-0243977 and EPS-
0092001) for partial support of this work.
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