A one-pot synthesis of 3-amino-3-arylpropionic acids

Article abstract of DOI:10.1016/S0040-4020(02)00824-4

3-Aminopropionic acids (β-amino acids) are biologically active compounds of interest in medicinal and pharmaceutical chemistry. Twenty-one 3-amino-3-arylpropionic acids were synthesized via a facile one-pot synthesis. In addition, a series of mechanistic studies have been performed to optimize the production of these β-amino acids. The reaction mechanism of this one-pot synthesis of β-amino acids, as well as the electronic effect of para-substitution and the influence of solvent polarity on the proposed reaction mechanism are discussed.

Full text of DOI:10.1016/S0040-4020(02)00824-4

Tetrahedron 58 (2002) 7449–7461
A one-pot synthesis of 3-amino-3-arylpropionic acids
C. Y. K. Tana and D. F. Weavera,b
,
*
aDepartment of Chemistry, Queen’s University, Kingston, Ont., Canada, K7L 3N6
bDepartment of Medicine (Neurology) and Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4J3
Received 24 September 2001; revised 9 July 2002; accepted 11 July 2002
Abstract—3-Aminopropionic acids (b-amino acids) are biologically active compounds of interest in medicinal and pharmaceutical
chemistry. Twenty-one 3-amino-3-arylpropionic acids were synthesized via a facile one-pot synthesis. In addition, a series of mechanistic
studies have been performed to optimize the production of these b-amino acids. The reaction mechanism of this one-pot synthesis of b-amino
acids, as well as the electronic effect of para-substitution and the influence of solvent polarity on the proposed reaction mechanism are
discussed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
stantive modification of a reaction described by Rodionow
and Postovskaja for the preparation of cinnamic acids.7
The synthesis of 3-aminopropionic acids, also known as
b-amino acids, has recently attracted increasing attention
due to their significant pharmacological properties.1
b-Amino acids are not only components of pharmacologi-
cally relevant natural products,2 but are also of great value
in the synthesis of complex compounds, such as peptides3
and b-lactam antibiotics.4 These properties have resulted in
numerous recent studies pertaining to their syntheses.5
Owing to their importance as potential drugs and drug
intermediates in medicinal chemistry, the search for simple
scaleable syntheses of b-amino acids is of continuing
interest.
In Part I, the synthesis of twenty-one 3-amino-3-aryl-
propionic acids will be described; in Part II, a series of
mechanistic studies was performed. These studies have
three goals: Goal (i) to investigate the reaction mechanism
of this one-pot synthesis of b-amino acids, Goal (ii) to
evaluate the influence of electronic effects of substituents at
the para-position upon the reaction mechanism, and Goal
(iii) to determine the role that solvent polarity plays in the
product distribution.
2. Results and discussion
2.1. Part I
Most recent methods for the synthesis of b-amino acids
require extensive multi-step preparations.5 In addition, over
the years, many works that utilized the condensation of an
aldehyde, malonic acid and an amine to generate other
3-aminopropionic acids have been reported.6 However, in
this paper, we report a facile and efficient one-pot synthesis
of aromatic substituted 3-aminopropionic acids, 3-amino-3-
arylpropionic acids (Part I). In addition, we also studied the
reaction mechanism (Part II) to optimize the yield of these
3-amino-3-arylpropionic acids. This synthesis is a sub-
This synthesis involves a single step in which a benz-
aldehyde derivative was refluxed with 1 equiv. of malonic
acid and 2 equiv. of ammonium acetate in ethanol (Scheme
1) to give the 3-amino-3-arylpropionic acid and its
corresponding cinnamic acid as side product.
The 3-amino-3-arylpropionic acid was then isolated by
Scheme 1. One-pot synthesis of 3-amino-3-arylpropionic acids.
Keywords: 3-amino-3-arylpropionic acids; b-amino acids; one-pot synthesis; reaction mechanism.
*
Corresponding author. Tel.: þ1-902-494-7183; fax: þ1-902-494-1310; e-mail: weaver@chem3.chem.dal.ca
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00824-4

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C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
Table 1. Structures and yields of synthesized 3-amino-3-arylpropionic acids
filtration of the reaction mixture and was subjected to
further work up as described in Section 3. However, there
were preparations in which the 3-amino-3-arylpropionic
acid remained dissolved in the reaction mixture. In these
cases, the corresponding cinnamic acid, which was the
minor side product, precipitated out of solution. The
cinnamic acid was removed by filtration and the filtrate
was evaporated to give the corresponding 3-amino-3-
arylpropionic acid. The crude 3-amino-3-arylpropionic
acid was purified as described in Section 3. Using these
procedures, twenty-one 3-amino-3-arylpropionic acids were
synthesized in yields ranging from 17 to 70% as shown in
Table 1. Among these 3-amino-3-arylpropionic acids,
nineteen are novel compounds.
This one-step reaction was affected by both the steric and

C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
7451
Scheme 2. The proposed reaction mechanism of the synthesis of 3-amino-3-arylpropionic acids.
electronic effects of the substituents on the phenyl ring.
Compounds with a substituent at the ortho-position of
the phenyl ring give lower yields of the 3-amino-3-
arylpropionic acids due to a steric effect. Compounds 2, 8
and 13–15, have yields of less than 30%. An obvious trend
was identified by comparing 2, 3 and 4, as the methyl
substituent was moved from the ortho to the meta and then
to the para-positions, the corresponding yield increased. In
terms of electronic effect, substituents with electronic-
donating groups in the para-position (i.e. 9 and 16) lead
to higher yield than with electron-withdrawing groups
including the non-substituted 1. Further investigation on the
electronic effect is discussed in Part II.
proceeded through a single pathway (pathway A–B, C
and H, Scheme 2). Addition of ammonia to the correspond-
ing benzaldehyde derivative I gave the Schiff base II.
Subsequent addition of malonic acid to II (step B) then
afforded the amino dicarboxylic acid intermediate III.
Hereafter, III could either be decarboxylated (step C)
to produce the corresponding b-amino acid IV or
be deaminated and decarboxylated (step H) to give
the corresponding cinnamic acid VII. He concluded that
the formation of the b-amino acid IV was through the
decarboxylation of the amino dicarboxylic acid III and not
by an addition reaction of ammonia to the double bond of
the corresponding cinnamic acid VII. Hence, the formation
of VII occurred only through the decarboxylation and
deamination of III.
The goal of our synthetic work is to synthesize b-amino
acids to be screened in high throughput assays for biological
activity relevant to neurologic disease. Since this is
preliminary screening work, the syntheses were developed
to rapidly produce inexpensive racemic mixtures. However,
we anticipate that the use of a chiral amine (rather than
ammonium acetate) would impart asymmetry and would
support an asymmetric version of this reaction.
In this study, we found that the reaction mechanism of this
one-pot reaction was more complex, involving more than
just one pathway. In turn, we proposed that the reaction has
two main pathways, A–B, C, H, G (pathway A–B) and
D–E, F, G, H, C (pathway D–E) (Scheme 2), with key
intermediates, III and VI, respectively. In addition, these
key intermediates, III and VI, were interchangeable
between these two main pathways via step G. With these
intermediates, we were then able to show that they could be
further reacted to produce both the corresponding b-amino
acid and cinnamic acid. Our study demonstrated that the
b-amino acid and cinnamic acid could be produced through
both pathways A–B and D–E, rather than only through
pathway A–B as claimed by Rodionow.
2.2. Part II
2.2.1. Background to mechanistic problem. In investi-
gating the mechanism of Knoevenagel’s synthesis of
cinnamic acids, Rodionow7 discovered that in addition to
the desired cinnamic acid derivatives, corresponding
b-amino acids were also produced when benzaldehyde
analogues were allowed to react with malonic acid and
ammonia. He proposed that the reaction mechanism
In pathway D–E, addition of malonic acid to the

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C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
Table 2. Percentage yields of intermediates III–VII in various reactions
No.
1.
Reactions
(Equation, yield %)
R¼CH3
R¼OCH3
R¼NO2
Eq. (1)
Eq. (8)
Eq. (15)
74
85
54
2.
3.
Eq. (2)
Eq. (9)
Eq. (16)
77
67
87
Eq. (3)
67 (66)
25 (25)
5 (5)
Eq. (10)
Eq. (17)
73
19
5
40
53
5
4.
Eq. (4)
63 (65)
29 (27)
7 (6)
N.A.
N.A.
–
–
–
–
–
–
benzaldehyde derivative I afforded the hydroxy dicar-
boxylic acid intermediate V as proposed by Hann and
Lapworth.8 Subsequent dehydration (step E) then produced
the cinnamic dicarboxylic acid intermediate VI. Inter-
mediate VI, could either be decarboxylated (step F) to afford
the corresponding cinnamic acid VII, or converted to the
amino dicarboxylic acid intermediate III (via step G) in the
presence of ammonia. Part of the pathway D–E, conden-
sation of the benzaldehyde and malonic acid to produce
the corresponding cinnamic acid, is an example of a
Knoevenagel condensation.9,13
1 equiv. of malonic acid in ethanol. The reaction was
allowed to stir at room temperature to give the correspond-
ing intermediate III. Intermediate VI was obtained by
stirring the corresponding benzaldehye derivative with
2 equiv. of malonic acid and 0.01 equiv. of ammonium
acetate in ethanol at room temperature. Second, we
subjected these intermediates to various experiments to
study further steps C and F–H. These experiments involved
reaction of intermediates III and VI in ethanol with:
(1) 2 equiv. of ammonium acetate and 1 equiv. of malonic
acid, (2) 2 equiv. of ammonium acetate, (3) refluxing
conditions only (without the presence of ammonium acetate
or malonic acid). A control experiment with the presence of
water to mimic the actual one-pot reaction conditions was
also performed. The results of these experiments are
summarized in Table 2. The mechanism was studied using
three different benzaldehyde derivatives: p-tolualdehyde
(a series), p-anisaldehyde (b series) and p-nitrobenzalde-
hyde (c series). In addition, each reaction was carried out in
2.2.2. Overall approach to mechanistic studies. To study
the reaction mechanism of this one-pot synthesis of b-amino
acids (Goal (i)), we divided the proposed reaction
mechanism into logical parts. First, we synthesized the
reaction intermediates III and VI. Intermediate III was
synthesized in the presence of 1 equiv. of the corresponding
benzaldehye derivative, 2 equiv. of ammonium acetate and

C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
7453
Table 2 (continued)
No.
Reactions
(Equation, yield %)
R¼CH3
R¼OCH3
R¼NO2
5.
Eq. (5)
62 (62)
32 (32)
Eq. (11)
76
19
Eq. (18)
47
47
6.
N.A.
Eq. (12)
Eq. (19)
–
–
–
85
–
13
88
7
3
7.
Eq. (6)
72 (73)
–
Eq. (13)
88
–
Eq. (20)
86
8
27 (25)
11
4
8.
Eq. (7)
93 (94)
Eq. (14)
94
Eq. (21)
93
N.A.: not applicable; values in paranthesis: control experiment with the present of 1 equiv. of H2O.
three different solvents: methanol, ethanol and 2-propanol.
These permitted us to study whether para-substitutions
(electronic effect) on the phenyl ring (Goal (ii)) and the
polarity of the solvents (Goal (iii)) could affect the reaction
mechanism and its yield.
amount of VIa for subsequent investigations, a different
reaction condition was used. In this reaction, ammonium
acetate was added as the catalyst to activate the malonic acid
to produce intermediate Va. Subsequent dehydration then
afforded the more stable intermediate VIa in 77% yield
(Eq. (2) of Table 2). Furthermore, we also employed a
different method in obtaining VIa.10 In this method, we
subjected p-tolualdehyde and malonic acid, in a bed of
alumina, to microwave radiation. After the work up, VIa
was obtained in 61% yield.
2.2.3. Goal (i), investigation of the reaction mechanism.
In the first series (a series) of reactions, in which
p-tolualdehyde was used, intermediate IIIa was produced
in a reasonable yield of 74% (Eq. (1) of Table 2) along with
a trace of VIa. This result suggested that pathway A–B was
the dominant pathway of the reaction. The reaction of VIa
to give product also verified the hypothesis that VIa was an
intermediate in the reaction pathway. To obtain a sufficient
In a study by Corey, he proposed that in general, water
elimination (step E) and decarboxylation (step F) should
occur simultaneously in a Knoevenagel condensation.11

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C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
Moreover, he also proposed that a,b-unsaturated malonic
acids decarboxylate readily only where the a-carbon atom
was not linked by a double bond. In our investigation,
however, we were able to isolate intermediate VI, which
provided evidence that water elimination and decarboxyl-
ation steps do not necessary occur simultaneously. In our
case, water elimination clearly occurred prior to the
decarboxylation, which was in agreement with a study by
Patai.12 In addition, we were able to decarboxylate VI, in
which the a-carbon atom of VI was linked by a double bond
to the corresponding cinnamic acid VII.
In the second series (b series) of reactions, p-anisaldehyde
was employed. As with p-tolualdehyde series, this series of
reactions was also divided into two parts. In the first part, we
investigated steps A, B, D and E via the synthesis of
intermediate IIIb and VIb. Intermediate IIIb was produced
in a higher yield (85%, Eq. (8) of Table 2) for p-anisaldehyde
than for p-tolualdehyde. However, intermediate VIb from
p-anisaldehyde was produced in a much lower yield (67%,
Eq. (9) of Table 2) than for p-tolualdehyde and at a much
slower rate. Both the yield and the rate of reaction of VIb
could be improved by subjecting the reaction to heat. Once
again these results suggested that IIIb and VIb were true
intermediates for the one-pot reaction and that IIIb
underwent pathway A–B, whereas VIb underwent pathway
D–E, similar to p-tolualdehyde series. The possible
explanation for the differences in yields of intermediate
IIIb and VIb will be discussed later.
Next, we subjected IIIa to three different reaction
conditions. The purpose was to examine whether different
reactant(s) would dictate the pathway that intermediate IIIa
was following and thus which product(s) would be formed.
The products that resulted from these three reactions (Eqs.
(3)–(5) of Table 2) were quite similar; in all three different
reactions, the b-amino acid was the predominant product
(60–70%) and the corresponding cinnamic acid was the
side product (25–30%). These results suggested that IIIa
underwent decarboxylation via step C to yield the b-amino
acid more readily than other steps (G–F, and H). In the
presence of ammonium acetate (Eqs. (3) and (4) of Table 2),
intermediate VIa was produced as a minor side product
(5–10%), while there was no evidence of VIa in the absence
of ammonium acetate (Eq. (5) of Table 2). Hence, in the
presence of ammonium acetate, IIIa might have taken either
a two step reaction through step G (deamination) then step F
(decarboxylation) and/or a one step reaction via step H
(deamination and decarboxylation) in producing VIIa in
addition to the decarboxylation of IIIa to give IVa.
However, in the absence of ammonium acetate, IIIa
underwent step H and step C instead. A plausible
explanation of this observation was, in the presence of
excess ammonia, ammonia abstracted the acidic proton
(a carbon) to give intermediate VIa followed by decarboxyl-
ation to give the cinnamic acid VII.
In the second part, intermediates IIIb and VIb were then
subjected to various experimental conditions to study the
subsequent steps of the reaction mechanism. Results from
both reactions (Eqs. (10) and (11) of Table 2) carried out
on IIIb were similar. Both sets of reactions produced
the corresponding b-amino acid (via step C) and cinnamic
acid (via steps G–F and/or step H). In the presence of
ammonium acetate, there was a trace of VIb as well, the
same observation as with the p-tolualdehyde series. These
suggested that IIIb underwent both steps G and H.
As with intermediate VIb, three different experiments were
carried out. Reactions 6 and 7 (Eqs. (12) and (13) of Table 2)
produced both b-amino acid (10–15%) and cinnamic acid
(85–90%). However, in absence of ammonium acetate
(Eq. (14) of Table 2), only cinnamic acid was produced.
These results implied that VIb underwent steps G and F, and
it also helped to explain the higher yield of cinnamic acid
over b-amino acid, similar to the p-tolualdehyde series.
A plausible explanation was that there were two paths that
could produced the cinnamic acid compared to a single two-
step process (steps G–C) in attaining the b-amino acid. In
summary, the results from the p-anisaldehyde series
complemented the p-tolualdehyde series, supporting the
proposed reaction mechanism.
As with IIIa, intermediate VIa was also subjected to two
different experiments. These results suggested that in the
presence of ammonium acetate, intermediate IIIa was
produced via Michael addition of NH3 (step G) followed by
decarboxylation of IIIa (step C) to afford the corresponding
b-amino acid IVa. Concurrently, decarboxylation of VIa
via step F then yielded the cinnamic acid VIIa. In the
absence of ammonium acetate, decarboxylation of VIa then
afforded the corresponding cinnamic acid. In summary,
results from this series of reactions with p-tolualdehyde,
supported the proposed mechanism. Furthermore, the
results also suggested that the synthesis of b-amino acid
was the main pathway of the reaction.
In the third series (c series) of reactions, p-nitrobenzalde-
hyde was used. Again, the investigation was divided into
two parts. In the first part, intermediates IIIc and VIc were
synthesized. Intermediate IIIb was produced in 54%
(Eq. (15) of Table 2) yield, the lowest among the three
series of reactions. Intermediate VIc was however produced
(via step D) in a much higher yield (87%, Eq. (16) of Table
2). As with the previous two series of reactions, once IIIc
and VIc were obtained, different experiments were then
carried out to investigate the subsequent steps of the
reaction mechanism (steps C, F, G and H). First,
intermediate IIIc was subjected to two different sets of
reactions (Eqs. (17) and (18) of Table 2). The percentage
yield of the b-amino acid and the cinnamic acid in both
reactions were similar, about a one to one ratio. This result
suggested that decarboxylation in step C for this series was
slower than the previous two series. This outcome also
provided one of the reasons why the yield of b-amino acid
for this series was much lower than the previous two. Once
In the control experiments, both IIIa and VIa were
subjected to the same varying reaction conditions as
mentioned above except an equal amount of water was
added in each reaction to mimic the actual one-pot
reaction condition. The results of these control experi-
ments (Eqs. (3)–(7) of Table 2) were very close to the
corresponding reactions without added water. (These
results suggest that the presence of a small quantity of
water does not affect the reaction mechanism or the
product distribution.)?

C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
7455
Table 3. Percentage yield and the ratio of the b-amino acid IV over the
cinnamic acid VII in three different solvent systems
polarity for methyl and methoxy substituents. However,
these observations were inverted with the more hydrophobic
functional group (nitro substituent). A plausible explanation
for these observations was that as the polarity of the solvent
decreased, the solubility of intermediate VI (for both methyl
and methoxy functional groups) decreased. Hence, not only
intermediate III precipitated out; intermediate VI also
started to precipitate which ultimately led to larger yields of
cinnamic acid. On the other hand, the solubility of
intermediate VI (nitro functional group) increased with
decreasing polarity of the solvent, due to its less polar
functional group. This caused the equilibrium to shift more
to pathway A–B, whereas intermediate III precipitated out
as the reaction was refluxed.
Methanol
Ethanol
2-propanol
Yield Ratioa Yield Ratioa Yield Ratioa
(%)
(%)
(%)
p-Anisaldehyde
p-tolualdehyde
IV
VII 24
IV 64 1.8
VII 36
76 3.2
70 2.4
30
54 1.2
45
51 1.1
48
51 1.1
48
p-Nitrobenzaldehyde IV
15 0.12
27 0.4
73
33 0.5
66
VII 84
a
Yield ratio of intermediate IV over intermediate VII.
again, as with previous two series of experiments, in the
presence of ammonium acetate, there was a trace of VIc
detected. Intermediate VIc was again subjected to three
different reactions (Eqs. (19)–(21) of Table 2). As with the
previous series of reactions, the results from these three
reactions suggested that VIc, in the presence of ammonium
acetate, underwent Michael addition of ammonia via step G
to give the corresponding b-amino acid along with the
decarboxylation of VIc to yield the corresponding cinnamic
acid. In the absence of ammonium acetate, VIc underwent
decarboxylation (via path F) to afford the corresponding
cinnamic acid only. In summary, the results from this series
of reaction as with two previous series (a and b) supported
the proposed reaction mechanism of this one-pot synthesis
of b-amino acids.
In conclusion, results from these investigations support our
proposed reaction mechanism for this one-pot synthesis of
3-amino-3-arylpropionic acid, as shown in Scheme 2. The
synthesis of 3-amino-3-arylpropionic acid is via the main
pathway. The substituent on the benzene ring does play an
important role in the reaction with the synthesis of 3-amino-
3-arylpropionic acid being favored by substituent(s) with
electron-donating property. Finally, polarity of the solvent
also affects the product distribution. One can influence the
synthesis of 3-amino-3-arylpropionic acid by selecting the
proper solvent for the particular benzaldehyde derivative.
3. Experimental
2.2.4. Goal (ii), evaluate the electronic effect of the para-
substituents upon the reaction mechanism. In Goal (ii),
we determined whether electronic effects play a role in this
reaction. Examining the ratio of the yield of the b-amino
acid to its corresponding cinnamic acid, (Table 3) revealed
that p-anisaldehyde (electron-donating group) has the
largest ratio, followed by p-tolualdehyde (as the control),
then p-nitrobenzaldehyde (electron-withdrawing group).
The same trend was consistent in all three solvent systems.
This observation suggested that this one-pot synthesis of
b-amino acid was more effective with phenyl groups having
an electron-donating group substituted at the para-position.
A plausible reason was that specific stabilization of
canonical forms of the resonance structures facilitated the
addition of the ammonia to the aldehyde functional group.
Thus when R is an electron-donating group, it stabilized
the canonical forms of benzaldehyde derivative. This
explanation was also supported by the result from Reactions
1 and 2 of Table 2, where the yield of intermediate 3
increased with R¼OCH3.CH3.NO2.
Proton (1H) and carbon (13C) nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker ACF-200
(200 MHz) spectrometer with D2O, D2O/K2CO3, CD3OD
or CDCl3 as solvents. Infrared (IR) spectra were recorded on
a Bomem MB-120 spectrophotometer using KBr disks.
Melting points (mp) were determined using a Mel-Temp II
capillary apparatus and are uncorrected. Elemental analyses
were performed by G–C–L Laboratories (Guelph, Canada).
Solvents were purified using standard methods.
3.1. Part I
General Procedure for 4, 6, 20 and 21. 4-Methylbenzalde-
hyde (2.4 g, 20.0 mmol), ammonium acetate (3.1 g,
40.2 mmol), and malonic acid (2.1 g, 20.2 mmol) were
refluxed in EtOH (50 mL) for 7 h. The reaction mixture was
cooled to room temperature and a white solid was collected.
The white solid was then dissolved in 20 mL of 1.0N HCl
followed by evaporation to dryness. Subsequent recrystalli-
zation with EtOH then yielded 4 as white crystals (2.2 g,
54%).
2.2.5. Goal (iii), investigate the solvent effects upon the
product distribution. The final objective of this study was
to determine whether polarity of the solvent system affects
the reaction. To accomplish this, we subjected each
benzaldehyde derivative to three different solvent systems:
methanol, ethanol and 2-propanol. For each benzaldehyde
derivative, all reactions were refluxed in the same oil bath
with the external temperature set to 838C to eliminate any
differences in the reaction conditions. The outcome of this
study (Table 3), showed that the yield of b-amino acid
increased with increasing polarity of the solvent, whereas
the yield of cinnamic acid increased with decreasing
General Procedure for 2, 13, and 15. 2-Methylbenzalde-
hyde (6.94 mL, 60.0 mmol), ammonium acetate (6.4 g,
80.0 mmol), and malonic acid (6.24 g, 60.0 mmol) were
refluxed in EtOH (80 mL) for 16 h. The reaction mixture
was allowed to cool to room temperature and the cinnamic
acid was removed by filtration. The filtrate was evaporated
to give a white solid, which was collected by filtration and
dissolved in a warm (708C) solution of Na2CO3 (4 g) in
50 mL of H2O. The aqueous layer was then acidified to pH 7
with 1.0N HCl added dropwise to give a white solid.

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Subsequent recrystallization of the solid from hot MeOH
afforded 2 as white crystals (2.04 g, 19%).
3.1.7. 3-Amino-3-(4-bromo)phenylpropionic acid (7).
Compound 7 as white crystals was obtained, mp 2348C;
IR (KBr) 3061, 1594 cm21; 1H NMR (D2O/K2CO3) d 7.38–
7.42 (m, 2H), 7.14–7.17 (m, 2H), 4.09 (t, J¼7.25 Hz,
1H), 2.36–2.48 (m, 2H); 13C NMR (D2O/K2CO3) d 171.7,
135.7, 132.5, 129.6, 123.5, 51.6, 37.9. Anal. calcd for
C9H10NO2Br: C, 44.29; H, 4.13; N, 5.74. Found: C, 44.35;
H, 3.93; N, 5.70.
General Procedure for 1, 3, 5, 7–12, 14, 16–19. 2,5-Di-
methoxybenzaldehyde (4.98 g, 30.0 mmol), ammonium
acetate (3.1 g, 40.2 mmol), and malonic acid (3.1 g,
30.2 mmol) were refluxed in EtOH (50 mL) for 6 h. The
reaction mixture was allowed to cool to room temperature
before the white solid was collected by filtration. This white
solid was then recrystallized twice from hot MeOH to afford
14 as white crystals (1.49 g, 22%).
3.1.8. 3-Amino-3-(2-chloro)phenylpropionic acid (8).
White crystals of 8 were obtained, mp 2198C; IR (KBr)
1
3060, 596 cm21; H NMR (D2O/K2CO3) d 7.12–7.38 (m,
3.1.1. 3-Amino-3-phenylpropionic acid (1).
1
was
4H), 5.05 (t, J¼6.4 Hz, 1H), 2.27–2.62 (m, 2H); 13C NMR
(D2O/K2CO3) d 171.6, 133.9, 133.5, 131.0, 130.5, 128.2,
128.1, 48.5, 37.1. Anal. calcd for C9H10NO2Cl: C, 54.15; H,
5.05; N, 7.02. Found: C, 54.34; H, 4.95; N, 7.04.
obtained as white crystals, mp 220–2218C (lit. 220–
2278C,6a 2168C,6d 216–2188C,6j 21–2198C6k); IR (KBr)
3035, 1625 cm21; 1H NMR (D2O/K2CO3) d 7.26–7.33 (m,
5H), 4.50 (t, J¼7.30 Hz, 1H), 2.59–2.82 (m, 2H); 13C NMR
(D2O/K2CO3) d 171.9, 136.5, 129.5, 129.3, 127.5, 52.2,
38.1. Anal. calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.26; H, 6.55; N, 8.42.
3.1.9. 3-Amino-3-(4-methoxy)phenylpropionic acid (9).
Compound 9 was obtained as white crystals, mp 2398C
;
(lit.6d 2328C); IR (KBr) 3046, 1607 cm21 1H NMR
(D2O/K2CO3) d 7.11 (d, J¼8.71 Hz, 2H), 6.77 (d, J¼
8.71 Hz, 2H,), 3.96 (t, J¼7.85 Hz, 1H), 3.61 (s, 3H), 2.31–
2.36 (m, 2H); 13C NMR (D2O/K2CO3) d 182.4, 160.1,
139.4, 129.8, 116.5, 57.9, 55.4, 48.2. Anal. calcd for
C10H13NO3: C, 61.53; H, 6.71; N, 7.17. Found: C, 61.46; H,
6.74; N, 7.20.
3.1.2. 3-Amino-3-(2-methyl)phenylpropionic acid (2).
Compound 2 as white crystals was obtained, mp: 2198C;
IR (KBr) 3160, 1607 cm21; 1H NMR (D2O/K2CO3) d 7.05–
7.30 (m, 4H), 4.39 (t, J¼7.35 Hz, 1H), 2.42 (dd, J¼6.56,
1.93 Hz, 2H), 2.25 (d, J¼5.35 Hz, 3H); 13C NMR
(D2O/K2CO3) d 171.9, 136.8, 134.9, 131.3, 129.3, 127.2,
125.9, 47.8, 38.1, 18.6. Anal. calcd for C10H13NO2: C,
67.02; H, 7.31; N, 7.82. Found: C, 66.90; H, 7.76; N, 7.78.
3.1.10. 3-Amino-3-(4-trifluoromethoxy)phenylpropionic
acid (10). Compound 10 as white crystals was obtained, mp
1
222–2238C; IR (KBr) 3071, 1616 cm21; H NMR (D2O/
3.1.3. 3-Amino-3-(3-methyl)phenylpropionic acid (3).
Compound 3 was obtained as white crystals, mp 226–
2278C; IR (KBr) 2937, 1625 cm21; 1H NMR (D2O/K2CO3)
d 6.91–7.20 (m, 4H), 4.38 (t, J¼7.37 Hz, 1H), 2.31–2.42
(m, 2H), 2.23 (s, 3H); 13C NMR (D2O/K2CO3) d 170.3,
137.4, 134.5, 128.3, 127.4, 126.3, 122.7, 50.4, 36.4, 18.8.
Anal. calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.88; H, 7.60; N, 7.83.
K2CO3) d 7.32 (d, J¼8.71 Hz, 2H), 7.18 (d, J¼8.71 Hz,
2H), 4.15 (t, J¼7.23 Hz, 1H), 2.44 (dd, J¼7.43, 2.91 Hz,
2H); 13C NMR (D2O/K2CO3) d 171.7, 150.0, 135.6, 129.7,
122.5, 121.7, 51.4, 37.9. Anal. calcd for C10H10NO3F3: C,
48.20; H, 4.04; N, 5.62. Found: C, 48.42; H, 4.20; N, 5.48.
3.1.11. Hydrochloride of 3-amino-3-(4-acetamido)phenyl-
propionic acid (11). Compound 11 was obtained as white
1
crystals, mp 221–2228C; IR (KBr) 3038, 1604 cm21; H
3.1.4. Hydrochloride of 3-amino-3-(4-methyl)phenylpro-
pionic acid (4). White crystals of 4 was obtained, mp 208–
2108C; IR (KBr) 3018, 1601 cm21; 1H NMR (D2O) d 7.11–
7.20 (m, 4H), 4.13 (t, J¼7.35 Hz, 1H), 2.40–2.47 (m, 2H),
2.19 (s, 3H); 13C NMR (D2O) d 172.1, 138.4, 135.1, 131.1,
127.5, 52.1, 37.1, 18.7. Anal. calcd for C10H14NO2Cl: C,
55.69; H, 6.54; N, 6.49. Found: C, 55.35; H, 6.04; N, 6.45.
NMR (D2O) d 7.25–7.23 (s, 4H), 4.12 (t, J¼7.4 Hz, 1H),
2.44 (dd, J¼4.9, 2.5 Hz, 2H), 2.02 (s, 3H); 13C NMR (D2O)
d 172.0, 171.0, 140.0, 131.7, 128.1, 120.5, 51.8, 38.0, 23.0.
Anal. calcd for C11H14N2O3·1/2H2O: C, 57.13; H, 6.54; N,
12.11. Found: C, 57.33; H, 6.80; N, 12.07.
3.1.12. 3-Amino-3-(3-methyl-4-methoxy)phenylpropionic
acid (12). Compound 12 as white crystals was obtained,
;
mp 238–2408C; IR (KBr) 3081, 1610 cm21 1H NMR
(D2O/K2CO3) d 7.07–7.10 (m, 2H), 6.82–6.88 (m, 1H),
4.09 (t, J¼7.29 Hz, 1H), 3.71 (s, 1H), 2.39–2.46 (m, 2H),
2.06 (s, 3H); 13C NMR (D2O/K2CO3) d 170.5, 157.3, 127.9,
126.1, 125.9, 124.7, 108.8, 53.3, 50.2, 36.5, 13.7. Anal.
calcd for C11H15NO3·1/2H2O: C, 60.54; H, 7.39; N, 6.42.
Found: C, 60.86; H, 7.17; N, 6.45.
3.1.5. 3-Amino-3-(4-fluoro)phenylpropionic acid (5).
White crystals of 5 were obtained, mp 216–2178C; IR
1
(KBr) 3160, 1606 cm21; H NMR (D2O/K2CO3) d 7.19–
7.28 (m, 2H), 6.91–7.03 (m, 2H), 4.11 (t, J¼7.39 Hz, 1H),
2.34–2.54 (m, 2H); 13C NMR (D2O/K2CO3) d 171.9, 165.2,
132.6, 130.0, 116.3, 51.6, 38.1. Anal. calcd for C9H10NO2F:
C, 59.01; H, 5.50; N, 7.65. Found: C, 58.81; H, 5.41; N,
7.53.
3.1.13. 3-Amino-3-(2-hydroxy-3-methoxy)phenylpropio-
nic acid (13). White crystals of 13 were obtained, mp 200–
2018C; IR (KBr) 2999, 1616 cm21; 1H NMR (D2O/K2CO3)
d 6.66–6.76, 6.49–6.41 (m, 3H), 4.46 (t, J¼7.30 Hz, 1H),
3.62 (s, 3H), 2.51 (d, J¼7.25 Hz, 2H); 13C NMR (D2O/
K2CO3) d 171.6, 156.1, 153.8, 134.0, 130.0, 125.6, 124.9,
55.6, 36.7, 14.0. Anal. calcd for C10H13NO4: C, 56.87; H,
6.20; N, 6.63. Found: C, 57.05; H, 6.41; N, 6.55.
3.1.6. Hydrochloride of 3-amino-3-(4-chloro)phenylpro-
pionic acid (6). Compound 6 as white crystals was obtained,
mp 188–1898C; IR (KBr) 3006, 1597 cm21 1H NMR
;
(D2O) d 7.20–7.31 (m, 4H), 4.13 (t, J¼7.2 Hz, 1H), 2.41–
2.54 (m, 2H); 13C NMR (D2O) d 171.8, 143.9, 135.5, 131.4,
124.7, 51.4, 37.9. Anal. calcd for C9H11NO2Cl2: C, 45.79;
H, 4.70; N, 5.93. Found: C, 45.53; H, 4.54; N, 5.91.

C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
7457
3.1.14. 3-Amino-3-(2,5-dimethoxy)phenylpropionic acid
(14). Compound 14 as white crystals was obtained, mp
38.1. Anal. calcd for C15H14NO3Cl3: C, 49.68; H, 3.89; N,
3.86. Found: C, 49.34; H, 3.87; N, 3.93.
206–2088C; IR (KBr) 2944, 1630 cm21
;
1H NMR
(D2O/K2CO3) d 6.70–6.88 (m, 3H), 4.30 (t, J¼7.89 Hz,
3.1.21. Hydrochloride salt of 3-amino-3-(3,4-dibenzyl-
oxy)phenylpropionic acid (21). White crystals of 21 was
1H), 3.64–3.68 (m, 6H) 2.21–2.54 (m, 2H); 13C NMR
1
(D2O/K2CO3)
d
172.3, 154.2, 151.4, 124.5, 115.2,
obtained, mp 198–2008C; IR (KBr) 3133, 1604 cm21; H
114.95, 112.6, 55.5, 55.3, 48.9, 36.6. Anal. calcd for
C11H15NO4.H2O: C, 54.31; H, 7.04; N, 5.76. Found: C,
54.05; H, 6.85; N, 5.66.
NMR (D2O) d 7.19–7.40 (m, 10H), 6.87–7.08 (m, 3H),
5.06 (s, 4H), 4.43 (t, J¼8.35 Hz, 1H), 2.65–2.85 (m, 2H);
13C NMR (D2O) d 173.6, 149.9, 149.6, 137.5, 129.8, 128.5,
128.1, 128.0, 128.0, 127.6, 120.7, 115.3, 114.4, 71.5, 71.1,
52.3, 38.9. Anal. calcd for C23H24NO4Cl: C, 66.74; H, 5.84;
N, 3.38. Found: C, 66.96; H, 6.00; N, 3.41.
3.1.15. 3-Amino-3-[2-fluoro-3-(trifluoromethyl)]phenyl-
propionic acid (15). Compound 15 was obtained as white
1
crystals, mp 2068C; IR (KBr) 2948, 1625 cm21; H NMR
(D2O/K2CO3) d 7.45–7.58 (m, 2H), 7.20 (t, J¼7.91 Hz, 1H)
4.44 (t, J¼7.30 Hz, 1H,), 2.51 (d, J¼7.38 Hz, 2H); 13C NMR
(D2O/K2CO3) d 171.3, 159.5, 133.5, 128.6, 125.6, 125.4,
124.7, 121.1, 45.4, 36.9. Anal. calcd for C10H9NO2F4: C,
47.82; H, 3.61; N, 5.58. Found: C, 47.90; H, 4.00; N, 5.90.
3.2. Part II
3.2.1. Preparation of ammonium salt of 3-amino-3-(4-
methylphenyl)-2-carboxy-propanoic acid (IIIa). A mix-
ture of p-tolualdehyde Ia (1.0 mL, 8.48 mmol), ammonium
acetate (1.50 g, 19.5 mmol) and malonic acid (0.884 g,
8.49 mmol) in EtOH (20 mL) were stirred at room
temperature for 48 h. A white solid was then collected by
filtration and recrystallised twice from H2O/EtOH (1:4) to
afford IIIa (1.41 g, 74%); mp 195–1978C; IR (KBr) 3411,
3.1.16. 3-Amino-3-(4-phenoxy)phenylpropionic acid
(16). White crystals of 16 were obtained, mp 214–2158C;
IR (KBr) 3066, 1615 cm21; 1H NMR (D2O/K2CO3) d 6.89–
7.33 (m, 9H), 4.12 (t, J¼7.23 Hz, 1H), 2.44 (dd, J¼7.12,
2.39 Hz, 2H); 13C NMR (D2O/K2CO3) d 172.9, 162.4,
160.4, 131.9, 131.1, 130.2, 125.2, 120.5, 119.8, 52.6, 39.0.
Anal. calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.79; H, 5.64; N, 5.38.
3058, 1588, 823 cm21; H NMR (D2O) d 7.08–7.22 (m,
1
4H), 4.49–4.54 (m, 1H), 3.48 (d, J¼9.06 Hz, 1H), 2.19 (s,
3H); 13C NMR (D2O) d 177.5, 177.2, 142.1, 134.5, 132.2,
129.7, 62.3, 57.4, 22.7. Anal. calcd (analytical calculation)
for C11H16N2O4: C, 54.99; H, 6.71; N, 11.66. Found: C,
54.62; H, 6.83; N, 11.26.
3.1.17. 3-Amino-3-(4-phenyl)phenylpropionic acid (17).
Compound 17 was obtained as white crystals, mp 2448C; IR
1
(KBr) 3029, 1615 cm21; H NMR (D2O/K2CO3) d 7.19–
3.2.2. Preparation of 3-(4-methylphenyl)-2-carboxy-2-
propenoic acid (VIa). A mixture of p-tolualdehyde 1a
(1.0 mL, 8.48 mmol), malonic acid (1.76 g, 16.9 mmol) and
ammonium acetate (0.0057 g, 0.0739 mmol) in EtOH
(20 mL) were stirred at room temperature for 48 h. A
white solid was obtained by filtration, followed by
recrystallization from EtOAc to give VIa (1.34 g, 77%);
mp 212–2138C (lit.10 203–2048C); IR (KBr) 3036, 1710,
7.46 (m, 9H), 4.16 (t, J¼6.7 Hz, 1H), 2.41 (d, J¼7.2 Hz,
2H); 13C NMR (D2O/K2CO3) d 171.0, 158.1, 154.3, 135.4,
129.0, 128.0, 127.8, 127.0, 124.2, 52.0, 37.9. Anal. calcd for
C15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.47; H,
6.35; N, 5.80.
3.1.18. 3-Amino-3-[3-(4-methylphenoxy)]phenylpropionic
acid (18). White crystals of 18 were obtained, mp 206–
2088C; IR (KBr) 3030, 1608 cm21; 1H NMR (D2O/K2CO3)
d 6.77–7.28 (m, 8H), 4.08 (t, J¼7.30 Hz, 1H), 2.40 (d, J¼
7.29 Hz, 2H,), 2.19 (s, 3H); 13C NMR (D2O/K2CO3) d
171.8, 159.0, 154.5, 138.4, 133.9, 130.9, 130.6, 121.6, 119.5,
118.8, 117.2, 51.9, 38.1, 19.9. Anal. calcd for C16H17NO3:
C, 70.83; H, 6.32; N, 5.16. Found: C, 70.66; H, 6.10; N, 5.10.
1693, 830, 811 cm21; H NMR (CD3OD) d 7.53 (s, 1H),
1
7.38 (d, J¼8.18 Hz, 2H), 7.14 (d, J¼8.17 Hz, 2H), 2.27 (s,
3H); 13C NMR (CD3OD) d 173.5, 169.9, 145.1, 144.6,
134.0, 133.3, 133.2, 130.0, 24.0. Anal. calcd for C11H10O4:
C, 64.07; H, 4.89. Found: C, 64.22; H, 4.91.
Preparation of 3-(4-methylphenyl)-2-carboxy-2-propenoic
acid (VIa) by microwave.9 p-tolualdehyde Ia (1.0 mL,
8.48 mmol), malonic acid (2.71 g, 26.1 mmol) and aluminum
oxide (basic, activity type I; 4.92 g, 48.2 mmol) was mixed
thoroughly with a vortex mixer. The mixture was then
subjected to microwave (conventional microwave) for 7 min.
Once the reaction mixture was cooled to room temperature, it
was sequentially washed three times (50 mL) with the
following solvents: (i) hexane, (ii) ice cold H2O, (iii)
MeOH. The MeOH washes were combined and evaporated
to dryness to yield a white solid. The resulting white solid was
then recrystallised from EtOAc to afford VIa (1.06 g, 61%).
3.1.19. 3-Amino-3-[3-(4-chlorophenoxy)]phenylpropionic
acid (19). Compound 19 was obtained as white crystals, mp
1
202–2038C; IR (KBr) 3099, 1616 cm21; H NMR (D2O/
K2CO3) d 7.22–7.29, 7.03–7.06, 6.88–6.91 (m, 8H), 4.09
(t, J¼7.29 Hz, 1H), 2.40 (d, J¼7.25 Hz, 2H); 13C NMR
(D2O/K2CO3) d 172.7, 159.0, 156.9, 139.7, 132.1, 131.0,
129.9, 123.4, 121.5, 120.6, 118.8, 52.8, 39.0. Anal. calcd for
C15H14NO3Cl: C, 61.76; H, 4.84; N, 4.80. Found: C, 61.95;
H, 5.02; N, 4.81.
3.1.20. Hydrochloride of 3-amino-3-[3-(3,4-dichloro-
phenoxy)]phenylpropionic acid (20). Compound 20 as
white crystals was obtained, mp 164–1658C; IR (KBr)
3193, 1609 cm21; 1H NMR (D2O) d 6.96–7.31, 6.83, 6.57–
6.62 (m, 7H), 4.03 (t, J¼7.88 Hz, 1H), 2.29–2.41 (m, 2H);
13C NMR (D2O) d 171.8, 157.1, 156.79, 139.0, 133.2,
131.6, 131.3, 126.9, 123.3, 120.6, 120.2, 118.6, 118.6, 51.8,
3.2.3. Reaction of 3-amino-3-(4-methylphenyl)-2-car-
boxy-propanoic acid (IIIa) with ammonium acetate
and malonic acid. Preparation of 3-amino-3-(4-methyl)-
phenylpropanoic acid (IVa), 3-(4-methylphenyl)-2-car-
boxy-2-propenoic acid (VIa) and 4-methylcinnamic acid
(VIIa). IIIa (0.195 g, 0.873 mmol), ammonium acetate

7458
C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
(0.135 g, 1.75 mmol) and malonic acid (0.091 g, 0.87
mmol) were refluxed in EtOH (20 mL) for 24 h. The
reaction mixture was allowed to cool to room temperature
and the resulting white solid was collected by filtration. This
solid was then washed twice with 20 mL of EtOH and then
triturated three times with hot MeOH (20 mL) to give IVa
(0.105 g, 67%); mp 231–2328C (lit. 2268C,6b 2318C6f); IR
acid (IIIa) refluxed in ethanol. Preparation of 3-amino-3-
(4-methyl)phenylpropanoic acid (IVa) and 4-methylcin-
namic acid (VIIa). IIIa (0.196 g, 0.877 mmol) was refluxed
in ethanol (20 mL) for 24 h. The reaction mixture was
allowed to cool to room temperature before a white solid
was collected by filtration. The solid was then washed twice
with 20 mL of EtOH to give IVa (0.0973 g, 62%). The
EtOH filtrate was evaporated to dryness and taken up in
10 mL of 1.0N aqueous NaOH. Subsequently, VIIa
(0.0451 g, 32%) precipitated out of solution following
acidification to pH 3 with 1.0N HCl (added dropwise).
(KBr) 3443, 3013, 1623, 1586, 815 cm21 1H NMR
;
(D2O/K2CO3) d 6.98–7.09 (m, 4H), 4.00 (t, J¼7.45 Hz,
1H), 2.30–2.35 (m, 2H), 2.09 (s, 3H); 13C NMR
(D2O/K2CO3) 172.4, 138.7, 134.5, 131.7, 128.5, 50.1,
38.1, 18.7. Anal. calcd for C11H13NO2: C, 67.02; H, 7.31;
N, 7.82. Found: C, 66.70; H, 7.61; N, 7.75. The MeOH
filtrates were combined and evaporated to dryness to afford
VIa (0.0086 g, 5%). The EtOH filtrate (from the reaction
mixture) was evaporated to dryness and dissolved in 1.0N
aqueous NaOH (10 mL). The aqueous solution was then
acidified to pH 3 with 1.0N HCl added dropwise to obtain
VIIa as a white solid (0.0358 g, 25%); mp 199–2008C (lit.6c
196–1988C); IR 3032, 1681, 988, 813; 1H NMR (CDCl3) d
7.79 (d, J¼16.01 Hz, 1H,), 7.47 (d, J¼8.15 Hz, 2H), 7.22 (d,
J¼8.16 Hz, 2H), 6.42 (d, J¼16.01 Hz, 1H), 2.40 (s, 3H);
13C NMR (CDCl3) d 170.6, 146.4, 142.1, 133.1, 130.7,
129.3, 118.2, 21.5. Anal. calcd for C10H10O2: C, 74.06; H,
6.21. Found: C, 74.01; H, 6.39.
3.2.8. Control experiment: 3-amino-3-(4-methylphenyl)-
2-carboxy-propanoic acid (IIIa) refluxed in ethanol. IIIa
(0.123 g, 0.512 mmol) and water (0.0092 mL, 0.51 mmol)
were refluxed in EtOH (15 mL) for 24 h to give IVa
(0.061 g, 62%) and VIIa (0.027 g, 32%).
3.2.9. Reaction of 3-(4-methylphenyl)-2-carboxy-2-pro-
penoic acid (VIa) with ammonium acetate. Preparation
of 3-amino-3-(4-methyl)phenylpropanoic acid (IVa) and
4-methylcinnamic acid (VIIa). VIa (0.102 g, 0.495 mmol)
and ammonium acetate (0.0763 g, 0.991 mmol) were
refluxed in ethanol (15 mL) for 24 h. The reaction was
then worked up as before to afford IVa (0.0241 g, 27%) and
VIIa (0.0577 g, 72%).
3.2.4. Control experiment: reaction of 3-amino-3-(4-
methylphenyl)-2-carboxy-propanoic acid (IIIa) with
ammonium acetate and malonic acid. IIIa (0.121 g,
0.499 mmol), ammonium acetate (0.077 g, 1.0 mmol),
malonic acid (0.053 g, 0.51 mmol) and water (0.009 mL,
0.5 mmol) were refluxed in EtOH (15 mL) for 24 h to give
IVa (0.063 g, 66%), VIa (0.0051 g, 5%) and VIIa (0.020 g,
25%).
3.2.10. Control experiment: reaction of 3-(4-methylphenyl)-
2-carboxy-2-propenoic acid (VIa) with ammonium acetate.
VIa (0.110 g, 0.533 mmol), ammonium acetate (0.0822 g,
1.067 mmol) and water (0.0096 mL, 0.53 mmol) were
refluxed in ethanol (15 mL) for 24 h to give IVa (0.025 g,
25%) and VIIa (0.063 g, 73%).
3.2.11. 3-(4-methylphenyl)-2-carboxy-2-propenoic acid
(VIa) refluxed in ethanol. Preparation of 4-methylcin-
namic acid (VIIa). VIa (0.0966 g, 0.469 mmol) was
refluxed in EtOH (15 mL) for 24 h. The reaction was then
worked up as before to yield VIIa (0.0708 g, 93%).
3.2.5. Reaction of 3-amino-3-(4-methylphenyl)-2-carb-
oxy-propanoic acid (IIIa) with ammonium acetate.
Preparation of 3-amino-3-(4-methyl)phenylpropanoic
acid (IVa), 3-(4-methylphenyl)-2-carboxy-2-propenoic
acid (VIa) and 4-methylcinnamic acid (VIIa). IIIa
(0.207 g, 0.929 mmol) and ammonium acetate (0.143 g,
1.86 mmol) were refluxed in EtOH (20 mL) for 24 h. The
reaction mixture was allowed to cool to room temperature
and a white solid was then collected by filtration.
Subsequently, the solid was washed twice with 20 mL of
EtOH followed by trituration with hot MeOH (3£20 mL) to
afford IVa as a white solid (0.105 g, 63%). The MeOH
filtrates were combined and evaporated to yield VIa
(0.0138 g, 7%). The EtOH filtrate (from the reaction
mixture) was evaporated to dryness and dissolved in 1.0N
aqueous NaOH (10 mL). The aqueous was then acidified to
pH 3 with 1.0N HCl added dropwise to obtain VIIa as a
white solid (0.0429 g, 29%).
3.2.12. Control experiment: 3-(4-methylphenyl)-2-car-
boxy-2-propenoic acid (VIa) refluxed in ethanol. VIa
(0.108 g, 0.527 mmol) and water (0.0094 mL, 0.52 mmol)
were refluxed in EtOH (15 mL) for 24 h to give VIIa
(0.0799 g, 94%).
3.2.13. Preparation ammonium salt of 3-amino-3-
(4-methoxyphenyl)-2-carboxy-propanoic acid (IIIb).
p-Anisaldehyde Ib (2.0 mL, 16.44 mmol), ammonium
acetate (3.08 g, 40.0 mmol) and malonic acid (1.81 g,
17.4 mmol) in EtOH (25 mL) were stirred at room
temperature for 17 h. A white solid was then collected by
filtration and recrystallised twice from H2O/EtOH (1:4)
to afford IIIb (3.331 g, 85%); mp 158–1598C; IR (KBr)
1
3.2.6. Control experiment: reaction of 3-amino-3-(4-
methylphenyl)-2-carboxy-propanoic acid (IIIa) with
ammonium acetate. IIIa (0.116 g, 0.483 mmol), ammo-
nium acetate (0.074 g, 0.966 mmol) and water (0.0087 mL,
0.48 mmol) were refluxed in EtOH (15 mL) for 24 h to
give IVa (0.060 g, 65%), VIa (0.0060 g, 6%) and VIIa
(0.021 g, 27%).
3459, 1591, 1262, 826 cm21; H NMR (D2O) d 7.29 (d,
J¼6.42 Hz, 2H), 6.93 (d, J¼6.41 Hz, 2H), 4.54–4.59 (m,
1H), 3.74 (s, 3H), 3.52 (d, J¼9.20 Hz, 1H); 13C NMR (D2O)
d 177.6, 177.1, 161.7, 131.3, 130.0, 117.0, 62.3, 57.8, 57.1.
Anal. calcd for C11H16N2O5: C, 51.56; H, 6.29; N, 10.93.
Found: C, 51.60; H, 6.47; N, 10.82.
3.2.14. Preparation of 3-(4-methoxyphenyl)-2-carboxy-
2-propenoic acid (VIb). p-Anisaldehyde Ib (2.0 mL,
3.2.7. 3-Amino-3-(4-methylphenyl)-2-carboxy-propanoic

C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
7459
16.4 mmol), malonic acid (3.50 g, 33.7 mmol) and ammo-
nium acetate (0.0105 g, 0.136 mmol) in EtOH (25 mL) were
stirred at room temperature for 4 d. The reaction mixture
was evaporated to dryness and dissolved in 1.0N aqueous
NaOH (10 mL). The aqueous was then acidified to pH 3
with 1.0N HCl added dropwise to give an ‘off-white’ solid.
Subsequent recrystallization of this solid from EtOAc
then afforded VIb (2.43 g, 67%); mp 204–2058C (lit.10
(IVb) and 4-methoxycinnamic acid (VIIb). VIb (0.262 g,
1.18 mmol) and ammonium acetate (0.204 g, 2.65 mmol)
were refluxed in EtOH (15 mL) for 24 h. The reaction was
then worked up as for VIa to give IVb (0.0248 g, 11%) and
VIIb (0.184 g, 88%).
3.2.19. 3-(4-Methoxyphenyl)-2-carboxy-2-propenoic
acid (VIb) refluxed in ethanol. Preparation of 4-meth-
oxycinnamic acid (VIIb). VIb (0.249 g, 1.12 mmol) was
refluxed in EtOH (20 mL) for 24 h. The reaction was then
worked up as for VIa to yield VIIb (0.198 g, 94%).
1
184–1858C); IR (KBr) 3052, 1719, 1278, 844 cm21; H
NMR (CD3OD) d 7.45 (s, 1H), 7.41 (d, J¼2.08 Hz, 1H),
7.35 (d, J¼1.96 Hz, 1H), 6.82 (d, J¼2.06 Hz, 1H), 6.79
(d, J¼1.95 Hz, 1H), 3.67 (s, 3H); 13C NMR (CD3OD) 171.1,
167.5, 163.2, 141.9, 132.7, 126.5, 125.6, 115.3, 55.9. Anal.
calcd for C11H10O5: C, 59.46; H, 4.54. Found: C, 59.46; H,
4.51.
3.2.20. Preparation of ammonium salt of 3-amino-3-(4-
nitrophenyl)-2-carboxy-propanoic acid (IIIc). p-Nitro-
benzaldehyde Ic (1.53 g, 10.15 mmol), ammonium acetate
(1.63 g, 21.17 mmol) and malonic acid (1.11 g, 10.67
mmol) in EtOH (25 mL) were stirred at room temperature
for 48 h. A yellowish white solid was then collected through
filtration and recrystallised twice from H2O/EtOH (1:4) to
afford IIIc (1.40 g, 54%); mp 270–2718C (dec.); IR (KBr)
3426, 3039, 1650, 1583, 1343, 859 cm21; 1H NMR (D2O) d
8.02 (d, J¼8.86 Hz, 2H), 7.40 (d, J¼8.86 Hz, 2H), 4.28 (d,
J¼9.92 Hz, 1H), 3.23 (d, J¼9.92 Hz, 1H); 13C NMR (D2O)
d 177.0, 176.6, 150.5, 144.9, 131.0, 126.8, 62.6, 57.0. Anal.
calcd for C10H13N3O6: C, 44.28; H, 4.83; N 15.49. Found:
C, 44.45; H, 4.82; N, 15.24.
3.2.15. Reaction of 3-amino-3-(4-methoxyphenyl)-2-car-
boxy-propanoic acid (IIIb) with ammonium acetate and
malonic acid. Preparation of 3-amino-3-(4-methoxy)-
phenylpropanoic acid (IVb), 3-(4-methoxyphenyl)-2-
carboxy-2-propenoic acid (VIb) and 4-methoxycinnamic
acid (VIIb). IIIb (0.135 g, 0.562 mmol), ammonium
acetate (0.114 g, 1.482 mmol) and malonic acid (0.0585 g,
0.562 mmol) were refluxed in EtOH (20 mL) for 24 h. The
work up for this reaction was the same as described for IIIa.
IVb was then obtained as a white solid (0.0803 g, 73%); mp
2398C (lit. 2328C,6d 240–2418C6l); IR (KBr) 3440, 3046,
1
1607, 1591, 823 cm21; H NMR (D2O/K2CO3) 7.11 (dd,
3.2.21. Preparation of 3-(4-nitrophenyl)-2-carboxy-2-
propenoic acid (VIc). p-Nitrobenzaldehyde Ic (2.02 g,
13.37 mmol), malonic acid (2.87 g, 27.57 mmol) and
ammonium acetate (0.0100 g, 0.130 mmol) in EtOH
(25 mL) were stirred at room temperature for 6 d. The
reaction mixture was evaporated to dryness and triturated
with H2O (150 mL) twice to yield VIc (2.75 g, 87%); mp
294–2958C (dec.); IR (KBr) 3055, 1727, 1696, 1524, 1351,
J¼2.58, 8.75 Hz, 2H), 6.77 (dd, J¼2.59, 8.76 Hz, 2H), 3.96
(t, J¼7.85 Hz, 1H), 3.61 (s, 3H), 2.31–2.36 (m, 2H); 13C
NMR (D2O/K2CO3) 172.4, 150.1, 134.4, 129.8, 116.5, 52.9,
50.4, 38.2. Anal. calcd for C10H13NO3: C, 61.53; H, 6.71; N,
7.17. Found: C, 61.46; H, 6.74; N, 7.20 along with VIb
(0.0064 g, 5%) and VIIb (0.0204 g, 20%); mp 172–1738C
(lit.6e,13 169–170, 1718C); IR (KBr) 3030, 1687, 1255,
1
1
936, 826 cm21; H NMR (CDCl3) d 7.61 (d, J¼16.01 Hz,
835 cm21; H NMR (CD3OD) d 8.07 (d, J¼8.92 Hz, 2H,),
1H), 7.53 (d, J¼6.77 Hz, 2H), 6.94 (d, J¼6.76 Hz, 2H),
6.32 (d, J¼16.01 Hz, 1H), 3.72 (s, 3H); 13C NMR (CDCl3)
170.8, 163.1, 146.2, 130.9, 128.4, 116.6, 115.4, 55.8. Anal.
calcd for C10H10O3: C, 67.41; H, 5.66. Found: C, 67.20; H,
5.52.
7.58 (d, J¼8.92 Hz, 2H), 7.55 (s, 1H); 13C NMR (CD3OD)
170.3, 170.1, 149.7, 140.8, 139.2, 132.3, 131.2, 124.8. Anal.
calcd for C10H7NO6: C, 50.64; H, 2.97; N, 5.91. Found: C,
50.64; H, 2.92; N, 5.82.
3.2.22. Reaction of 3-amino-3-(4-nitrophenyl)-2-car-
boxy-propanoic acid (IIIc) with ammonium acetate and
malonic acid. Preparation of 3-amino-3-(4-nitro)phenyl-
propanoic acid (IVc), 3-(4-nitrophenyl)-2-carboxy-2-
propenoic acid (VIc) and 4-nitrocinnamic acid (VIIc).
IIIc (0.198 g, 0.779 mmol), ammonium acetate (0.127 g,
1.65 mmol) and malonic acid (0.100 g, 0.963 mmol) were
refluxed in EtOH (20 mL) for 48 h. The work up for this
reaction was the same as described for IIIa. IVc was then
obtained as light-yellow solid (0.0608 g, 40%); mp 229–
2308C (dec.); IR (KBr) 3477, 3034, 1607, 1598, 1357, 1283,
847 cm21; 1H NMR (D2O/K2CO3) 7.98 (d, J¼8.92 Hz, 2H),
7.37 (d, J¼8.91 Hz, 2H), 4.16 (t, J¼7.35 Hz, 1H), 2.30–
2.51 (m, 2H); 13C NMR (D2O/K2CO3) 172.0, 160.2, 150.4,
129.9, 126.4, 50.8, 39.3. Anal. calcd for C9H10N2O4: C,
51.43; H, 4.80; N, 13.33. Found: C, 51.69; H, 4.68; N, 13.21.
along with VIc (0.0085 g, 5%) and VIIc (0.0873 g, 53%);
mp 293–2948C (dec.) (lit.13 285–2868C, dec.); IR (KBr)
3040, 1696, 1342, 1265, 947, 850 cm21; 1H NMR (CDCl3)
d 7.90 (d, J¼8.90 Hz, 1H), 7.38 (d, J¼8.90 Hz, 2H,), 7.03
(d, J¼16.30 Hz, 2H,), 6.28 (d, J¼16.30 Hz, 1H,); 13C NMR
(CDCl3) 169.2, 149.7, 144.6, 140.1, 131.1, 130.8, 126.4.
3.2.16. 3-Amino-3-(4-methoxyphenyl)-2-carboxy-propa-
noic acid (IIIb) refluxed in ethanol. Preparation of
3-amino-3-(4-methoxy)phenylpropanoic acid (IVb) and
4-methoxycinnamic acid (VIIb). IIIb (0.119 g, 0.495
mmol) was refluxed in EtOH (20 mL) for 24 h. The work
up was the same as for IIIa to yield IVb (0.074 g, 76%) and
VIIb (0.0166 g, 19%).
3.2.17. Reaction of 3-(4-methoxyphenyl)-2-carboxy-2-
propenoic acid (VIb) with ammonium acetate and
malonic acid. Preparation of 3-amino-3-(4-methoxy)-
phenylpropanoic acid (IVb) and 4-methoxycinnamic
acid (VIIb). VIb (0.268 g, 1.20 mmol), ammonium acetate
(0.205 g, 2.66 mmol) and malonic acid (0.128 g, 1.23
mmol) were refluxed in EtOH (15 mL) for 24 h. The
reaction was then worked up as for VIa to afford IVb
(0.0315 g, 13%) and VIIb (0.183 g, 85%).
3.2.18. Reaction of 3-(4-methoxyphenyl)-2-carboxy-2-
propenoic acid (VIb) with ammonium acetate. Prepa-
ration of 3-amino-3-(4-methoxy)phenylpropanoic acid

7460
C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
Anal. calcd for C9H7NO4: C, 55.96; H, 3.65; N, 7.25.
Found: C, 55.80; H, 3.57; N, 7.10.
solution was then acidified to pH 3 with 1.0N HCl added
dropwise to yield VIIa (methanol; 0.497 g, 3.062 mmol,
36%), (ethanol; 0.618 g, 3.808 mmol, 45%) and (2-propanol;
0.656 g, 4.045 mmol, 48%).
3.2.23. 3-Amino-3-(4-nitrophenyl)-2-carboxy-propanoic
acid (IIIc) refluxed in ethanol. Preparation of 3-amino-3-
(4-nitro)phenylpropanoic acid (IVc) and 4-nitrocin-
namic acid (VIIc). IIIc (0.201 g, 0.792 mmol) was refluxed
in EtOH (20 mL) for 48 h. The work up was the same as for
IIIa to yield IVc (0.0787 g, 47%) and VIIc (0.0717 g, 47%).
3.2.28. Preparation of 3-amino-3-(4-methoxy)phenylpro-
panoic acid (IVb) and 4-methoxycinnamic acid (VIIb) in
methanol, ethanol and 2-propanol as solvent systems.
p-Anisaldehyde Ib (1.0 mL, 8.22 mmol), ammonium
acetate (1.30 g, 16.84 mmol) and malonic acid (0.858 g,
8.24 mmol) were refluxed in MeOH (30 mL). p-Anisalde-
hyde Ib (1.0 mL, 8.22 mmol), ammonium acetate (1.277 g,
16.57 mmol) and malonic acid (0.859 g, 8.26 mmol) were
refluxed in EtOH (30 mL). p-Anisaldehyde Ib (1.0 mL,
8.22 mmol), ammonium acetate (1.279 g, 16.59 mmol) and
malonic acid (0.861 g, 8.28 mmol) were refluxed in 2-PrOH
(30 mL). The three reactions were carried out in the same oil
bath set at 838C. These reactions were refluxed for 24 h and
allowed to cool to room temperature before a white solid
was collected (through filtration) from each reaction
mixture. The white solid was then triturated with EtOH
(50 mL) twice to give IVb (methanol; 1.219 g, 76%),
(ethanol; 1.034 g, 70%) and (2-propanol; 0.744 g, 51%).
The filtrate from each reaction mixture was evaporated to
dryness and dissolved in 1.0N NaOH (25 mL). This aqueous
was then acidified to pH 3 with 1.0N HCl added dropwise to
yield VIIb (methanol; 0.352 g, 24%), (ethanol; 0.434 g,
30%) and (2-propanol; 0.700 g, 48%).
3.2.24. Reaction of 3-(4-nitrophenyl)-2-carboxy-2-pro-
penoic acid (VIc) with ammonium acetate and malonic
acid. Preparation of 3-amino-3-(4-nitro)phenylpropa-
noic acid (IVc) and 4-nitrocinnamic acid (VIIc). VIc
(0.207 g, 0.874 mmol), ammonium acetate (0.148 g,
1.923 mmol) and malonic acid (0.0956 g, 0.919 mmol)
were refluxed in EtOH (20 mL) for 48 h. The reaction
mixture was cooled to room temperature before an off white
solid was collected by filtration. The solid was then washed
twice with EtOH (20 mL) followed by trituration with H2O
(20 mL) twice to afford IVc (0.0062 g, 3%). The H2O
filtrates were combined and evaporated to give IIIc
(0.0158 g, 7%). The EtOH filtrate, from the reaction
mixture, was evaporated to dryness and dissolved in 1.0N
NaOH (10 mL). The aqueous was then acidified to pH 3
with 1.0N HCl added dropwise to yield VIIc (0.148 g,
88%).
3.2.25. Reaction of 3-(4-nitrophenyl)-2-carboxy-2-pro-
penoic acid (VIc) with ammonium acetate. Preparation
of 3-amino-3-(4-nitro)phenylpropanoic acid (IVc) and
4-nitrocinnamic acid (VIIc). VIc (0.208 g, 0.879 mmol)
and ammonium acetate (0.146 g, 1.90 mmol) were refluxed
in EtOH (20 mL) for 48 h. The reaction was then worked up
(as the above procedure) to give IVc (0.0070 g, 4%), IIIc
(0.0185 g, 8%) and VIIc (0.146 g, 0.754 mmol, 86%).
3.2.29. Preparation of 3-amino-3-(4-nitro)phenylpropa-
noic acid (IVc) and 4-nitrocinnamic acid (VIIc) in
methanol, ethanol and 2-propanol as solvent systems.
p-Nitrobenzaldehyde Ic (1.007 g, 6.65 mmol), ammonium
acetate (1.091 g, 14.16 mmol) and malonic acid (0.697 g,
6.700 mmol) were refluxed in MeOH (30 mL). p-Nitro-
benzaldehyde Ic (1.007 g, 6.65 mmol), ammonium acetate
(1.049 g, 13.61 mmol) and malonic acid (0.695 g,
6.68 mmol) were refluxed in EtOH (30 mL). p-Nitrobenz-
aldehyde Ic (1.007 g, 6.65 mmol), ammonium acetate
(1.068 g, 13.86 mmol) and malonic acid (0.700 g,
6.72 mmol) were refluxed in 2-PrOH (30 mL). The three
reactions were carried out in the same oil bath set at 838C.
These reactions were refluxed for 24 h and allowed to cool
to room temperature before a white solid was collected
(through filtration) from each reaction mixture. The white
solid was then triturated with EtOH (50 mL) twice to give
IVc (methanol; 0.206 g, 15%), (ethanol; 0.374 g, 27%) and
(2-propanol; 0.455 g, 33%). The filtrate from each reaction
mixture was evaporated to dryness and dissolved in 1.0N
NaOH (25 mL). This aqueous was then acidified to pH 3
with 1.0N HCl added dropwise to yield VIIc (methanol;
1.081 g, 84%), (ethanol; 0.932 g, 73%) and (2-propanol;
0.851 g, 66%).
3.2.26. 3-(4-Nitrophenyl)-2-carboxy-2-propenoic acid
(VIc) refluxed in ethanol. Preparation of 4-nitrocin-
namic acid (VIIc). VIc (0.208 g, 0.876 mmol) was refluxed
in EtOH (20 mL) for 48 h. The reaction was then worked up
as for VIa to yield VIIc (0.157 g, 0.812 mmol, 93%).
3.2.27. Preparation of 3-amino-3-(4-methyl)phenylpro-
panoic acid (IVa) and 4-methylcinnamic acid (VIIa) in
methanol, ethanol and 2-propanol as solvent systems.
p-Tolualdehyde Ia (1.0 mL, 8.48 mmol), ammonium acet-
ate (1.511 g, 19.60 mmol) and malonic acid (0.892 g,
8.57 mmol) were refluxed in MeOH (30 mL). p-Tolualde-
hyde Ia (1.0 mL, 8.48 mmol), ammonium acetate (1.511 g,
19.60 mmol) and malonic acid (0.896 g, 8.610 mmol) were
refluxed in EtOH (30 mL). p-Tolualdehyde Ia (1.0 mL,
8.48 mmol), ammonium acetate (1.519 g, 19.71 mmol) and
malonic acid (0.893 g, 8.54 mmol) were refluxed in 2-PrOH
(30 mL). The three reactions were carried out in the same oil
bath set at 838C. These reactions were refluxed for 24 h and
allowed to cool to room temperature before a white solid
was collected (through filtration) from each reaction
mixture. The white solid was then triturated with EtOH
(50 mL) twice to give IVa (methanol; 0.971 g, 64%),
(ethanol; 0.822 g, 54%) and (2-propanol; 0.772 g, 51%).
The filtrate from each reaction mixture was evaporated to
dryness and dissolved in 1.0N NaOH (20 mL). This aqueous
Acknowledgments
C. Y. K. T. acknowledges a Natural Sciences and
Engineering Research Council (NSERC) of Canada
Scholarship. D. F. W. acknowledges operating grants
from NSERC and Medical Research Council of Canada
(MRC).

C. Y. K. Tan, D. F. Weaver / Tetrahedron 58 (2002) 7449–7461
7461
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