A Convenient Synthesis of Esters of β-Phenylglutamic Acid Under Aqueous Conditions

Article abstract of DOI:10.1081/SCC-120025174

Several esters of β-phenylglutamic acid (3, 4) are prepared by Michael reaction of glycine ester Schiff bases 1 and 2 under aqueous conditions.

Full text of DOI:10.1081/SCC-120025174

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A Convenient Synthesis of Esters of β-Phenylglutamic
Acid Under Aqueous Conditions
D. Tasheva a , N. Petkova a & V. Dryanska a
a Department of Chemistry , University of Sofia , Sofia, Bulgaria
Published online: 16 Aug 2006.
To cite this article: D. Tasheva , N. Petkova & V. Dryanska (2003) A Convenient Synthesis of Esters of β-Phenylglutamic Acid
Under Aqueous Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:21, 3661-3670, DOI: 10.1081/SCC-120025174
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3661–3670, 2003
A Convenient Synthesis of Esters of
b-Phenylglutamic Acid Under Aqueous Conditions
*
D. Tasheva, N. Petkova, and V. Dryanska
Department of Chemistry, University of Sofia,
Sofia, Bulgaria
ABSTRACT
Several esters of b-phenylglutamic acid (3, 4) are prepared by
Michael reaction of glycine ester Schiff bases 1 and 2 under aqueous
conditions.
b-Phenylglutamic acid has long been known[1] and procedures for its
preparation are of current interest because of the important activities of
glutamic acid derivatives on glutamic acid receptors in the central
nervous system.[2–4] Among the various approaches to the preparation
of b-phenylglutamic acid,[1,5–9] the conjugate addition of Schiff bases
derived from glycine to cinnamic acid derivatives is the most direct
one.[10–16] Thus, the Michael reaction of methyl cinnamate and
*Correspondence: V. Dryanska, Department of Chemistry, University of Sofia,
1 James Bourchior Avenue, 1126 Sofia, Bulgaria; E-mail: vdryanska@
chem.uni-sofia.bg.
3661
DOI: 10.1081/SCC-120025174
Copyright & 2003 by Marcel Dekker, Inc.
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3662
Tasheva, Petkova, and Dryanska
nickel (II) complex of chiral Schiff base of glycine,[10] respectively the
reaction of lithium enolate of ethyl N-(diphenylmethylene)glycinate
with alkoxyalkenylcarbene complexes of chromium,[11] afforded the
corresponding Michael adducts with high diastereoselectivity,[10,11] and
in some cases, enantioselectivity.[11] In recent years it has been reported
that addition of methyl ester of p-nitrocinnamic acid and various Michael
acceptors to the resin-bound benzophenone imine of glycine resulted in
variety of glutamic acid derivatives in high yields and purity.[12]
The conjugate addition of glycine Schiff bases to a,b-unsaturated
compounds under phase-transfer catalysis (PTC) has received little
attention.[13,14] Methyl and tert-butyl N-[bis(methylthio)methylene]
glycinates have been found to react with cinnamates under solid-liquid
phase-transfer catalysis to give the corresponding glutamic acid deriva-
tives.[15] b-Phenylglutamic acid derivatives have also been prepared in an
aq. NaOH/Bu4NBr/CH2Cl2 system.[16] However, the data given in the
reported in Chemical Abstracts symposium document are scarce. Now
we report a convenient procedure for the preparation of esters of
b-phenylglutamic acid by reaction of methyl and ethyl N-(diphenyl-
methylene)glycinate (1, 2) and several esters of cinnamic acid (3) under
aqueous conditions (Sch. 1).
Preliminary experiments for optimization of the reactions of methyl
cinnamate with both 1 and 2 revealed that better stereoselectivity and yield
for the adducts 4a and 5a were obtained by performing the reactions in
acetonitrile solution at 0ꢀC, using 50% aqueous sodium hydroxide without
any phase-transfer catalyst. The presence of TEBA did not effect any
improvment of either yield or selectivity. Thus, HPLC monitoring of
the reaction of 1 and 3a under PTC conditions (50% NaOH, TEBA,
0ꢀC, 30 min) showed diastereoisomeric ratio 89:11, and repeated recrys-
tallization of the isolated crude product (86% yield) did not result
in pure diastereoisomer. On the other hand, ratio 97.2:2.8 (HPLC),
respectively 97:3 (1H NMR) was observed for the crude 4a, obtained
in a yield of 85% from 1 and 3a in the absence of TEBA. One fold
recrystallization of this product produced 4a in a yield of 76% as a
single diastereoisomer.
Under these conditions (50% NaOH, CH3CN, 30 min at 0ꢀC) the
ester Schiff bases 1 and 2 were reacted with the cinnamates 3 to give
the protected glutamic esters 4 and 5. They were isolated as single
diastereoisomers in moderate to good yields by recrystallization or
column chromatography (4c, 5c) of the crude products (Table 1).
The diphenylmethylene protection is known to be easily removed
under acidic conditions.[17–19] For instance, refluxing of the ester 5a
with 6N HCl and subsequent ion-exchange chromatography afforded

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b-Phenylglutamic Acid Under Aqueous Conditions
3663
Scheme 1.
Scheme 2.
b-phenylglutamic acid (6) in 63% yield, while cleavage of the azomethine
bond only was observed by treatment of both 4a and 5a with hydroxyl-
amine hydrochloride (Sch. 2).
Compounds 4a–e, 5a–e, 7, and 8, which are unknown to the best of
our knowlege, were characterized by elemental analysis, IR and 1H NMR
spectra (Tables 1 and 2), TLC and HPLC.

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3664
Tasheva, Petkova, and Dryanska
Table 1. Compounds 4, 5, 7, and 8 prepared.
Found/calculated (%)
Yielda
(%)
M.p.
(ꢀC)
Molecule
formula
Compound
C
H
N
4a
76
72
63
62
47
82
78
68
48
41
53
50
119–121 C26H25NO4
(415.5)
75.42
75.16
75.55
75.50
78.05
78.19
75.93
75.82
76.16
76.12
75.74
75.50
75.80
75.82
78.14
78.39
76.19
76.12
76.44
76.41
54.31
54.26
56.09
55.72
5.81
6.06
6.63
6.34
6.10
5.95
6.56
6.59
6.75
6.83
6.10
6.34
6.29
6.59
6.44
6.18
6.61
6.83
7.37
7.05
5.44
5.31
6.21
6.35
3.42
3.37
3.37
3.26
2.88
2.85
3.28
3.16
3.20
3.06
3.20
3.26
3.20
3.16
2.56
2.77
3.23
3.06
3.29
2.97
4.76
4.87
4.79
4.64
4b
4c
4d
4e
5a
5b
5c
5d
5e
7
98–100 C27H27NO4
(429.5)
Oil
C32H29NO4
(491.6)
114–115 C28H29NO4
(443.5)
117–119 C29H31NO4
(457.6)
120–122 C27H27NO4
(429.5)
99–101 C28H29NO4
(443.5)
Oil
C33H31NO4
(505.6)
84–86
C29H31NO4
(457.6)
103–104 C30H33NO4
(471.6)
127–129 C13H18ClNO4
(287.7)
8
113–115 C14H20ClNO4
(301.8)
aYield of pure diastereoisomer obtained after recrystallization (MeOH and EtOH
(5b, 5d, 5e) or column chromatography (4c, 5c).
In conclusion, this procedure represents a simple and efficient way for
the preparation of glutamic esters 4 and 5 by Michael addition of the ready
available glycine ester Schiff bases 1 and 2 to esters of cinnamic acid.
EXPERIMENTAL
Melting points were determined on a Boetius micro melting point
apparatus and are uncorrected. The IR spectra were recorded on a
Zeiss-Jena Specord 71. The 1H NMR spectra were obtained on an
AVANCE DRX- 250 (250 MHz) and BRUKER ARX 300 (300 MHz)

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b-Phenylglutamic Acid Under Aqueous Conditions
3665
spectrometer using TMS as an internal standard. TLC analysis was per-
formed on silica gel precoated plates ‘‘Silufol UV 254’’ using hexane and
acetone (6:1) as eluent. Column chromatography was perfopmed by SiO2
(0.063–0.200 mm) with the same solvents as eluent. The HPLC analyses
were performed by a modular HPLC system, consisting of reciprocating
pump Waters 510, injector (Waters) U6K, automated gradient controller
Waters 680, UV-VIS Detector SHIMADZU SPD-10AV VP, Eurosphere
C18 column (250 ꢁ 4 mm i.d.), 5 mm and isocratic elution with 57%
CH3CN, 43% H2O (10 mM DBA þ H3PO4, pH 6.5), flow rate
1.2 mL/min, temperature 33ꢀC, detection- 245 and 280 nm. The ester
Schiff bases 1 and 2,[18] isopropyl cinnamate and tert-butyl cinnamate[21]
were prepared according to literature procedures.
5-Alkyl-1-methyl-N-(diphenylmethylidene)-3-phenylglutamates (4)
and 5-alkyl-1-ethyl-N-(diphenylmethylidene)-3-phenylglutamates (5)
General Procedure
To a cooled to 0ꢀC (ice bath) stirred solution of methyl N-(diphenyl-
methylene)glycinate (1, 1.27 g, 5 mmol) or ethyl N-(diphenylmethylene)-
glycinate (2, 1.34 g, 5 mmol), the corresponding alkyl cinnamate (3,
5 mmol) in CH3CN (2.5 mL), was added aqueous sodium hydroxide
(50%, 1.5 mL). The reaction mixture was stirred at 0ꢀC until crystalliza-
tion began, or 30 min (4c, 5c–e). Water (100 mL) was added and the solid
was collected, washed with water until neutral and recrystallyzed from
methanol or ethanol (5b) to give 4 and 5 as white crystals. In the cases of
compounds 4c, 5c, 5d–e, the mixtures were extracted with methylene
chloride (3 ꢁ 25 mL), and the residues obtained after removing of the
solvent were treated with ethanol to give 5d and 5e as white crystals, or
purified by column chromatography (hexane/acetone 18:1 (4c) and 25:1
(5c)) to give 4c and 5c as colorless oils (Tables 1 and 2).
b-Phenylglutamic Acid (6)
A mixture of 0.83 g (2 mmol) of 5a and 6N hydrochloric acid (16 mL)
was refluxed for 6 h. After cooling the separated benzophenone was
removed with ether (3 ꢁ 10 mL), and then water was evaporated under
reduced pressure until dryness. Distilled water (50 mL) was added to the
residue and the mixture was stirred overnight with a strongly acidic
cation exchange resin (Amberlite IR 120-Hþ, 10 mL). The resin was
collectedc on a Buchner funnel, washed with water until the filtrate

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b-Phenylglutamic Acid Under Aqueous Conditions
3667

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3668
Tasheva, Petkova, and Dryanska
showed a negative test of chloride ion (silver nitrate) and stirred
overnight with 6N ammonium hydroxide (75 mL). Then the resin was
filtered and water was removed in vacuo to give 0.28 g (63%) of pure 6.
M.p. 228–231ꢀC (dec.). Lit. M.p. 168–178ꢀC dec.[7] 186–188ꢀC dec.[20]
IR (nujol). 3300ꢂ2500, 1710, 1650, 1600, 1550 cmꢂ1
.
1H NMR (300 MHz, D2O): 2.78, 2.82 (A þ B part of an ABX system,
2H, JAB ¼ 15.4 Hz, JAX ¼ 5.1 Hz, JBX ¼ 10.3 Hz, CH2COOH), 3.55–3.62
(m, 1H, PhCH), 3.95 (d, 1 H, J ¼ 5.2 Hz, CHCOO-), 7.29–7.39 (m, 5H,
arom.)
Anal. calcd. for C11H13NO4: C 59.19, H 5.87, N 6.27. Found C 60.28,
H 6.67, N 6.79.
Dimethyl 3-Phenylglutamate Hydrochloride[7]
A mixture of 0.58 g (1.4 mmol) of 4a and 0.10 g (1.4 mmol) hydroxyl-
amine hydrochloride in anhydrous methanol (20 mL) was refluxed at
60ꢀC for 3 h. After removing of 15 mL of methanol, anhydrous ether
(15 mL) was added and the mixture was left to cool overnight in refrig-
erator. The separated crystal product was collected and recrystallized
from a mixture of anhydrous methanol and anhydrous ether to give
0.21 g (53%) of 7 (Tables 1 and 2).
1-Ethyl-5-methyl-3-phenylglutamate Hydrochloride[8]
Following the above procedure, 0.20 g (50%) of 8 was prepared
starting from 0.60 g (1.4 mmol) of 5a and 0.10 g (1.4 mmol) hydroxylamine
hydrochloride (Tables 1 and 2).
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Received in the UK December 3, 2001