One-pot process to Z-α-benzoylamino-acrylic acid methyl esters via potassium phosphate-catalyzed Erlenmeyer reaction

Article abstract of DOI:10.1016/j.tetlet.2009.11.081

A practical and efficient two reaction sequence one-pot process for the synthesis of Z-α-benzoylamino-acrylic acid methyl esters was developed. The process involves a potassium phosphate-catalyzed Erlenmeyer reaction of aromatic aldehydes with hippuric acid followed by an oxazolone ring-opening methanolysis. This process afforded a good overall yield and an excellent product quality via a simple workup.

Full text of DOI:10.1016/j.tetlet.2009.11.081

Tetrahedron Letters 51 (2010) 625–628
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Tetrahedron Letters
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One-pot process to Z-a-benzoylamino-acrylic acid methyl esters via potassium
phosphate-catalyzed Erlenmeyer reaction
*
Thomas Cleary, Jodie Brice, Nicole Kennedy, Flavio Chavez
Pharmaceutical Technical Development Actives (PTDA-FL), Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506-9330, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient two reaction sequence one-pot process for the synthesis of Z-a-benzoylamino-
Received 7 October 2009
Revised 16 November 2009
Accepted 17 November 2009
Available online 29 November 2009
acrylic acid methyl esters was developed. The process involves a potassium phosphate-catalyzed
Erlenmeyer reaction of aromatic aldehydes with hippuric acid followed by an oxazolone ring-opening
methanolysis. This process afforded a good overall yield and an excellent product quality via a simple
workup.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Erlenmeyer reaction
Acrylic acids
Oxazolones
The synthesis of chiral building blocks has become important in
the development of new drugs. Amino acids are essential
components found in the chemical structures of enzymes,
hormones, antibiotics, and other biologically active compounds.1
base in this reaction. Compared to sodium acetate, K3PO4 is a
cheaper commercially available material which affords good
oxazolone conversion reactions using less than 1 equiv. In this
approach, the relative reaction rate depended on the aromatic
aldehyde substituents in accord with a previously reported study.6
The electron-withdrawing groups (EWGs) increased the reaction
rate, and the opposite was true for the electron-donating groups
(EDGs). Due to this aldehyde substituent effect, Erlenmeyer
reactions with EWG-aldehydes were easily performed using
5–10 mol % potassium phosphate; however, with the more
Moreover,
a,b-dehydro-amino acids are precursors for saturated
amino acids. In effect, these precursors could be synthesized by
Horner–Emmons, Heck, or Erlenmeyer–Plöchl reactions2 followed
by a complementary asymmetric hydrogenation reaction. The
asymmetric hydrogenation is well established due to the
availability of chiral ligands3 that facilitate the preparation of
enantiomerically pure compounds.
Therefore,
a-amidoacrylates can be accessed via a practical
synthetic process. The Erlenmeyer–Plöchl4 reaction is a well-known
approach to these key intermediates because the condensation of
hippuric acid with an aromatic aldehyde provides the Z-oxazolone
isomer as the main product5 (Scheme 1).
O
O
O
O
OH
CH3CO2Na/ Ac2O
N
H
N
+
O
We extended this methodology to develop a one-pot process for
the synthesis of a-amidoacrylates via two sequential reactions: an
R
R
1
2
3
Erlenmeyer reaction followed by an oxazolone ring opening. The
Erlenmeyer reaction was performed using potassium phosphate
as the base to catalyze the condensation of hippuric acid 1 with
an aromatic aldehyde 2 in the presence of acetic anhydride as
the dehydrating agent. Next, methanolysis was carried out in situ
to produce the respective acrylic acid methyl ester 4 as shown in
Scheme 2.
Scheme 1. General Erlenmeyer–Plöchl reaction.
O
O
O
O
O
O
a
b
OH
Potassium phosphate was evaluated as a catalyst for the
Erlenmeyer reaction instead of sodium acetate which is the typical
ArCHO
N
N
H
+
Ph
Ph
N
Ph
H
O
Ar
Ar
1
2
3
4
* Corresponding author. Tel.: +1 843 629 4108; fax: +1 843 629 4128.
E-mail address: flavio.chavez_lopez@roche.com (F. Chavez).
Scheme 2. General synthesis of Z-
Reagents: (a) K3PO4, Ac2O; and (b) MeONa, MeOH.
a-benzoylamino acrylic acid methyl esters.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.081

626
T. Cleary et al. / Tetrahedron Letters 51 (2010) 625–628
Table 1
isolated oxazolones, and melting point comparisons for product
identity confirmation.
Isolated oxazolones from the K3PO4-catalyzed Erlenmeyer reaction
Once the reaction conditions for the Erlenmeyer reaction were
established, the oxazolone ring-opening methanolysis was
performed in situ by adding methanol to the oxazolone reaction
mixture. Next, the pH was adjusted to 7–8 with sodium methox-
ide/methanol solution, and the mixture was heated at reflux.
Upon reaction completion, a simple workup and isolation was
performed by the addition of water to produce the respective
O
O
O
K3PO4 / Ac2O
OH
ArCHO
N
H
N
+
Ph
Ph
O
Ar
1
2
3
a-amidoacrylates in acceptable yield and excellent quality
Entry 2, Ar=
Oxazolonea Reaction Yielde Mp found Mp lit.
timeb (h) (%)
(°C)
(°C)
(Table 2). Compound 4i showed slow methanolysis reaction but
adding a catalytic amount of DBU speeded up the reaction and drove
it to completion (Table 2, entry 6).
1
2
3
4
5
6
7
8
9
C6H4–
3a
3b
3c
3d
3e
3f
2
83
93
88
81
91
93
87
84
86
86
80
166
239
175
162
196
204
144
159
214
183
194
1677
2417
1757
1618
1977
19611
1437
1577
2137
1859
19912
4-NO2C6H4–
3-NO2C6H4–
2-Cl–C6H4–
4-Cl–C6H4–
4-BrC6H4–
4-MeC6H4–
4-MeOC6H4–
4-(CH3)2NC6H4– 3i
0.5c
0.5
1
A unique example in this series of aromatic aldehydes was
vanillin, containing a reactive 4-hydroxyl group (Table 2, entry
7). This hydroxyl functionality was initially acylated in the pres-
ence of acetic anhydride/K3PO4, and then the addition of hippuric
acid and acetic anhydride completed the condensation reaction.
1
3
3g
3h
3d
3d
3
As compared to the reported reaction conditions,12
a faster
10
11
4-FC6H4–
3-MeO-4-OH–
3j
3k
3
3
reaction and better conversion to oxazolone 3k were observed.
Methanolysis was complete after approximately one hour, but
12
13
3l
3
90
89
169
176
1709
O
S
3m
6.5
17910
O
O
O
a
b
c
O
DCE used for improving mixing-compounds 3b–j.
10 mol % K3PO4 catalyst.
5 mol % K3PO4 catalyst.
a
b
N
d
e
50 mol % K3PO4 catalyst.
Isolated yield.
OH
OAc
OAc
c
O
sluggish EDG-aldehydes, and fluorosubstituted aldehyde the
conversion was improved by adding acetic anhydride in portions
(3 equiv total) and, in some cases, increasing the catalyst loading
up to 50 mol % (Table 1, entries 7–10). The Erlenmeyer reaction
was performed by mixing hippuric acid, aldehyde, and acetic anhy-
dride followed by the addition of potassium phosphate and heating
the mixture to 80 °C. After the exotherm13 subsided, heavy slurry
was observed, and, if required, 1,2-dichloroethane (DCE) was
charged to improve reaction mixing (Table 1, entries 2–10). The
data provided in Table 1 include the reaction times, yields of
O
O
N
H
4e
Scheme 3. General synthesis of Z-
OH
-benzoylamino-3-(4-hydroxyphenyl)-acrylic
acid methyl esters. Reagents: (a) K3PO4, Ac2O; (b) hippuric acid, Ac2O; and (c)
MeONa/MeOH, 4e was isolated from methylene chloride/toluene.
a
Table 2
One-pot process for
a-amidoacrylates representative examples
O
O
O
O
O
O
K3PO4 / Ac2O
MeONa / MeOH
OH
ArCHO
N
H
+
Ph
N
N
H
Ph
Ph
O
Ar
Ar
1
2
4
3
Entry
Compound
Ar=
Reaction timea (h)
Overall yieldb (%)
Mp found (°C)
Mp lit. (°C)
1
2
3
4
5
6
7
4b
4e
4f
4g
4h
4i
4-NO2C6H4–
4-Cl–C6H4–
4-BrC6H4–
4-MeC6H4–
4-MeOC6H4–
4-(CH3)2NC6H4–
3-MeO-4-OH–
2
1
1
1
89
82
90
90
83
83
82e
192
138
138
111
154
183
158
19314
13814
—
10717
15314
18414
15715
1
5c
24d
4k
8
4l
1
75
140
13916
O
a
Methanolysis reaction only.
Isolated yield.
MeONa–DBU.
Transesterification reaction time included.
Crystallization from toluene.
b
c
d
e

T. Cleary et al. / Tetrahedron Letters 51 (2010) 625–628
627
Figure 1. Crystal structure of Z-a-benzoylamino acrylic acid methyl esters 4i and 4l respectively.
4. (a) Plöchl, J. Ber. 1893, 16, 2815. Ber. 1884, 17, 1616; (b) Erlenmeyer, E. Ann
1893, 275; Li, J. J. Name Reactions in Heterocyclic Chemistry; John Wiley & Sons:
New Jersey, 2005. pp 229–233.
5. (a) Rao, Y. S. J. Org. Chem. 1976, 41, 722–725; (b) Rao, Y. S.; Filler, R. Synthesis
1975, 749–764.
6. Kennedy, N.; Cleary, T.; Rawalpally, T.; Chavez, F. Substituent Effect on the
Erlenmeyer Plochl Reaction; Understanding an Observed Process Reaction Time; in
press.
the transesterification reaction to remove the acetyl group
required extended time (Scheme 3). In addition, compound 4k
was isolated from methylene chloride and crystallized from tolu-
ene because 4k was soluble in methanol.
X-ray analysis for representative compounds (4i and 4l) showed
the C@C as expected with the Z-configuration (Fig. 1).
7. Karade, N. N.; Shirodkar, S. G.; Dhoot, B. M.; Waghmare, P. B. J. Chem. Res. 2005,
46–47.
8. Yu, C.; Zhou, B.; Su, W.; Xu, Z. Synth. Commun. 2006, 36, 3447–3453.
9. Päsha, M. A.; Jayäshankara, V. P.; Venugopala, K. N.; Rao, G. K. J. Pharmacol.
Toxicol. 2007, 2, 264–270.
10. Tikdari, A. M.; Fozooni, S.; Hamidian, H. Molecules 2008, 13, 3246–3252.
11. Heravi, M. R. J. Univ. Chem. Technol. Metall. 2009, 44, 86–90.
12. Fennoy, L. V. J. Org. Chem. 1961, 26, 4696–4698.
13. The enthalpy of reaction for oxazolone 3l (Table 1, entry 12) was measured on
a RC1 classic equipment and scaled to g/moles of hippuric acid. Observed
Thus, a practical and efficient method has been developed and
demonstrated for the preparation of Z-a-amido-acrylic acid methyl
esters via two sequential reactions in a one-pot process.18 The
initial Erlenmeyer reaction is catalyzed by the inexpensive and
commercially available potassium phosphate, which is used in
the range of 5–50 mol % depending on the aldehyde substrate.
The subsequent ring-opening methanolysis reaction is carried out
with methanol/sodium methoxide. In most cases, isolation simply
involves the addition of water. Because this one-pot process gener-
ates an exceptional overall yield and excellent isolated product
quality,19 tedious chromatography purification techniques are
avoided.
values
D
Hrxn = À40.6 kJ/g moles;
DTaddition-rise = 41.7 °C
14. Krause, H. W.; Taudien, S.; Schinkowski, K. Tetrahedron: Asymmetry 1993, 4,
73–84.
15. Selke, R.; Facklam, C.; Heller, D. Tetrahedron: Asymmetry 1993, 4, 369–382.
16. Krause, H. W.; Wilcke, F. W.; Kreuzfeld, H. J.; Döbler, CH. Chirality 1992, 4, 110–
115.
17. Arenal, I.; Bernabe, M.; Alvarez, E. An. Quim. 1981, 77, 56.
18. One-pot process for Z-a-benzoylamino-4-chlorophenyl-acrylic acid methyl ester
Acknowledgments
4e: To a mixture of hippuric acid (2.5 g, 14 mmol), 4-chlorobenzaldehyde
(1.63 g, 11.6 mmol), and acetic anhydride (3.14 g, 31 mmol) at room
temperature under nitrogen was added potassium phosphate (0.3 g,
1.4 mmol). The resulting slurry was stirred in a pre-heated 70 °C aluminum
block until the exotherm subsided. The reaction mixture was then heated to
80 °C and stirred under nitrogen, and, after observing a heavy yellow slurry,
1,2-dichloroethane was added (2 mL). The slurry was held for one hour at
80 °C, and the reaction was monitored for completion by HPLC. Then, the slurry
was cooled to approximately 40 °C followed by the dropwise addition of
methanol (12–15 mL). After 30 min, sodium methoxide 25 wt % in methanol
(6.5 mL) was added and the mixture was refluxed under nitrogen for one hour.
Upon reaction completion, confirmed by HPLC, the mixture was cooled to room
temperature, and water was added dropwise (12–15 mL). The slurry was
stirred for 30 min and then cooled overnight (10 °C). The N-benzoylamino-2-
(4-chlorophenyl) acrylic acid methyl ester 4e was collected by vacuum
filtration and washed with precooled 1:1 methanol/water (À15 °C) followed
by water. After drying at 60 °C under vacuum for 24 h, the product was
characterized by HPLC, 1H NMR, 13C NMR, and melting point for purity.
19. Melting points and 1H NMR/13C NMR data for N-benzoylamino acrylic acids methyl
esters. N-Benzoylamino-3-(4-nitrophenyl) acrylic acid methyl ester (4b): Mp
192 °C; 1H NMR (500 MHz, DMSO): d 10.30 (s, 1H), 8.26 (d, J = 8.9 Hz, 2H), 7.99
(d, J = 7.4 Hz, 2H), 7.91 (d, J = 8.9 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.54 (t,
J = 7.6 Hz, 2H), 7.45 (s, 1H), 3.78 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d
166.25, 165.15, 147.04, 140.36, 132.95, 132.11, 130.65, 129.86, 129.42, 128.52,
127.82, 123.65, 52.50.
The authors wish to thank Dr. Mark D. Smith for the structure
determination by X-ray crystallography (The University of South
Carolina) and Dr. Shan-Ming for his valuable help. Dr. Ashish Shan-
kar and Maethonia Thompson for the RC1 data.
Supplementary data
Supplementary data (1H NMR data of oxazolones 3 and (1H
NMR/13C NMR for Z-
a-benzoylamino-acrylic acid methyl esters 4
products) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.11.081.
References and notes
1. Aguado, G. P.; Monglioni, A. G.; Ortuño, R. M. Tetrahedron: Asymmetry 2003, 14,
217–223.
2. Marino, S. T.; Stachurska-Buczek, D.; Huggins, B. M.; Krywult, B. M.; Sheehan, C.
S.; Nguyen, T.; Choi, N.; Parson, J. G.; Griffiths, P. G.; James, I. W.; Bray, A. M.;
White, J. M.; Boyce, R. S. Molecules 2004, 9, 405–426.
3. Zhang, F. Y.; Kwok, W. H.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 2337–
2342.
N-Benzoylamino-3-(4-chlorophenyl) acrylic acid methyl ester (4e): Mp 138 °C; 1H
NMR (500 MHz, DMSO-d6): d 10.12 (s, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.70 (d,
J = 8.6 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.48 (d, J = 8.6 Hz,
2H), 7.42 (s, 1H), 3.75 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d 166.14, 165.35,

628
T. Cleary et al. / Tetrahedron Letters 51 (2010) 625–628
133.95, 133.13, 132.40, 131.97, 131.48, 131.45, 128.68, 128.50, 127.72, 127.20,
N-Benzoylamino-3-(4-dimethylaminophenyl) acrylic acid methyl ester (4i): Mp
183 °C; 1H NMR (500 MHz, DMSO-d6): d 9.87 (s, 1H), 8.04 (d, J = 7.3 Hz, 2H),
7.60 (dd, J = 7.7, 15.0 Hz, 2H), 7.55 (m, 3H), 7.43 (s, 1H), 6.69 (d, J = 9.0 Hz, 2H),
3.71 (s, 3H), 2.93 (s, 6H); 13C NMR (125 MHz, DMSO-d6): d 165.89, 165.79,
151.07, 135.28, 133.66, 131.80, 131.67, 128.45, 127.61, 120.98, 120.58, 111.56,
51.86, 39.56.
52.31.
N-Benzoylamino-3-(4-bromophenyl) acrylic acid methyl ester (4f): Mp 138 °C; 1H
NMR (500 MHz, DMSO-d6): d 10.12 (s, 1H), 7.99 (d, J = 7.5 Hz, 2H) 7.61 (d,
J = 9.4 Hz, 5H), 7.54 (t, J = 7.6 Hz, 2H), 7.40 (s, 1H), 3.75 (s, 3H); 13C NMR
(125 MHz, DMSO-d6): d 166.12, 165.36, 133.15, 132.76, 131.95, 131.64, 131.60,
131.55, 128.49, 127.72, 127.34, 122.72, 52,31.
N-Benzoylamino-3-(3-methoxy-4-hydroxyphenyl) acrylic acid methyl ester (4k):
Mp 158 °C; 1H NMR (500 MHz, DMSO-d6): d 9.99 (s, 1H), 9.63 (s, 1H), 8.04 (d,
J = 7.3 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.45 (s, 1H), 7.37
(d, J = 1.8 Hz, 1H), 7.18 (dd, J = 1.8, 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.73 (s,
3H), 3.62 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d 165.94, 165.76, 148.63,
147.35, 134.68, 133.43, 131.86, 128.50, 127.60, 124.70, 124.66, 123.19, 115.33,
113.57, 55.26, 52.07.
N-Benzoylamino-3-(4-methylphenyl) acrylic acid methyl ester (4g): Mp 111 °C;
1H NMR (500 MHz, DMSO-d6): d 10.06 (s, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.61 (dd,
J = 7.7, 15.1 Hz, 3H), 7.54 (t, J = 7.5 Hz, 2H), 7.44 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H),
3.74 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d 166.03, 165.56,
139.47, 133.51, 133.33, 131.86, 130.65, 129.89, 129.23, 128.48, 125.68, 52.17,
20.93.
N-Benzoylamino-3-(4-methoxyphenyl) acrylic acid methyl ester (4h): Mp 154 °C;
1H NMR (500 MHz, DMSO-d6): d 10.01 (s, 1H), 8.03 (d, J = 7.4 Hz, 2H), 7.68 (d,
J = 8.8 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.46 (s, 1H), 6.98
(d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d
166.02, 165.66, 160.34, 133.69, 133.41, 131.83, 131.80, 128.49, 127.67, 125.90,
114.16, 55.25, 52.10.
N-Benzoylamino-3-(furan-2-yl) acrylic acid methyl ester (4m): Mp 140 °C; 1H
NMR (500 MHz, DMSO-d6): d 9.99 (s, 1H), 8.03 (d, J = 7.3 Hz, 2H), 7.86 (m, 1H),
7.61 (m, 1H), 7.54 (dd, J = 4.7, 10.4 Hz, 2H), 7.31 (s, 1H), 6.90 (d, J = 3.5 Hz, 1H),
6.63 (dd, J = 1.8, 3.4 Hz, 1H), 3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6): d
165.62, 165.07, 149.16, 145.61, 133.42, 131,83, 128.47, 127.68, 123.31, 120.84,
116.04, 112.54, 52.20.