Novel approach to the synthesis of aliphatic and aromatic α-keto acids

Article abstract of DOI:10.1016/j.tet.2012.06.078

A new practical and efficient synthesis of α-keto acids was accomplished starting from the synthon 1,4-diacetylpiperazine-2,5-dione. The synthesis encompasses both aromatic and aliphatic substrates proving to be versatile and innovative with excellent carbon economy and recycling of the glycine by-product.

Full text of DOI:10.1016/j.tet.2012.06.078

Tetrahedron 68 (2012) 7374e7379
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journal homepage: www.elsevier.com/locate/tet
Novel approach to the synthesis of aliphatic and aromatic a-keto acids
*
€
Daniele Balducci, Philip A. Conway, Giulia Sapuppo, Helge Muller-Bunz, Francesca Paradisi
Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new practical and efficient synthesis of
a
-keto acids was accomplished starting from the synthon 1,4-
Received 24 March 2012
Received in revised form 5 June 2012
Accepted 20 June 2012
diacetylpiperazine-2,5-dione. The synthesis encompasses both aromatic and aliphatic substrates proving
to be versatile and innovative with excellent carbon economy and recycling of the glycine by-product.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 29 June 2012
Keywords:
a
-Keto acids
Aromatic
Aliphatic
Aldol reaction
1. Introduction
O
O
O
O
COOH
NH
NH
NAc
iii
i
ii
R
a-Keto acids are of major importance in biological processes.
HN
AcN
R
AcN
O
4(a-q)
This class of compounds plays a key role both in the biosynthesis
and metabolism of amino acids and provides interesting in-
termediates for chemical synthesis.1,2 The successful and efficient
production of keto acids is an appealing synthetic objective as they
can be, for example, employed in the synthesis of chiral amino acids
when appropriate biocatalysts are applied.3e5 The development of
O
1
O
2
3(a-t)
+
COOH
+
NH3
suitable methods for the synthesis of a-keto acids has been of in-
5
terest for more than a century since the synthesis of pyruvic acid
was achieved by Berzelius in 1835.6 A variety of preparative
methods for aliphatic7e14 and aromatic14e17 substrates have been
Scheme 1. Synthesis of a-keto acids. (i) Ac2O/DMF, (ii) tBuOK/tBuOH/CH2Cl2 (or THF)/
RCHO, (iii) 6 M HCl, reflux. R: (a) phenyl, (b) 2-methylphenyl, (c) 3-methylphenyl, (d)
2-methoxyphenyl, (e) 3-methoxyphenyl, (f) 2-thiophenyl, (g) 1-naphtyl, (h) 2-naphtyl,
(i) 2,3-difluorophenyl, (j) 2,4-difluorophenyl, (k) 2,5-difluorophenyl, (l) phenyl-ethyl,
(m) cyclohexyl, (n) 2-propenyl, (o) ethyl, (p) 3-cyclohexenyl, (q) tert-Butyl, (r)
2-furanyl, (s) 2-N-methylpyrrolyl, (t) N-Boc-3-indole.
previously reported in the literature for
a-keto compounds, al-
though these methods are somewhat limited to either aliphatic or
aromatic substrates.
We have now developed a simple and reliable synthetic route,
which is applicable to both aliphatic and aromatic substrates,
generating a-keto acids in very good yields.
The 3-arylalkylidene-2,5-piperazine-diones 3 were prepared
following the Gonzalez protocol where the reaction between 2 and
an aromatic aldehyde was performed in a t-BuOH/CH2Cl2 mixture
with t-BuOK as a base.18 For the aliphatic derivatives the synthesis
was accomplished by a modified procedure, which employed THF
as a solvent and a stoichiometric ratio of aldehyde.19 In both cases
the reaction was performed at room temperature and was pro-
moted by the anchimeric assistance of the vicinal N-acetyl group as
described by Gallina and co-workers.20 The reaction displays total
diastereoselectivity in favour of the Z-isomer justified via the
ZimmermaneTraxler21 model (Fig. 1).
2. Results and discussion
Aiming at minimising waste and sustainability of the overall
process, we started from a diketopiperazine synthon 2, which is
easily obtained from the commercially available glycine anhydride
1. The synthesis allows for the recycling of the glycine by-product
resulting in excellent carbon economy (Scheme 1).
We believe that the reaction proceeds through the transition
state a, in which interactions between the acetyl group and the R
substituent on the aldehyde are minimised. This transition state
* Corresponding author. Tel.: þ353 (0) 1 716 2967; fax: þ353 (0) 1 716 2501;
e-mail address: francesca.paradisi@ucd.ie (F. Paradisi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.078

D. Balducci et al. / Tetrahedron 68 (2012) 7374e7379
7375
Ac
R
O
Ac
O
N
b
N
O
H
R
K
HO
K
NH
O
O
i
fast
O
O
O
N
N
AcN
HOOC
O
O
H
a
Favoured
Ac
Ac
O
6
4n
Disfavoured
3n
Scheme 2. Intramolecular cyclization in the formation of 6 (i) 6 M aqueous HCl, reflux.
Fig. 1. ZimmermaneTraxler model.
generates the aldol intermediate, which leads to the formation of
the Z-isomer. The configuration of the double bond has been con-
firmed by NMR18,19 spectroscopy and where possible, by X-ray
analysis as for compounds 3q and 3b (Fig. 2).
In the case of the heteroaromatic DKP, similar product de-
composition was observed but no compounds were identified.
None of the 2-furan 3r, N-methylpyrrole 3s or 3-indole 3t diketo-
piperazines yielded a product. An exception was the 2-thiophene 3f
diketopiperazine for which the hydrolysis step yielded the desired
O
O
O
O
2-thiophene a-keto acid 4f.
Compounds 3 could undergo a further condensation reaction to
generate a symmetric product the hydrolysis of which would yield
2 equiv of 4 without a glycine by-product. Unfortunately, while the
second condensation can be easily achieved, the hydrolysis of such
compounds failed even under extremely harsh conditions.
NH
NH
AcN
AcN
3. Conclusions
In conclusion a new, practical and efficient synthesis of aromatic
and aliphatic keto acids has been accomplished through the use of
a diketopiperazine synthon, which is easily obtained from com-
mercially available glycine anhydride 1. The condensation step re-
sults in excellent yields both with the use of aromatic aldehydes
with a variety of substituents on the aromatic ring, and with the use
of aliphatic aldehydes. Compounds 4g and 4h were also syn-
thesised following previously reported protocols (via azlactone3
and hydantoin24) with much lower isolated yields for the azlac-
tone (17% and 35%, respectively) and for the hydantoin (24% and
20%, respectively).25 These results were in line with what was
previously reported in the literature. Furthermore, these methods
were unsuccessful when applied to the synthesis of aliphatic keto
acids, as the harsh reaction conditions required for the condensa-
tion step were responsible for self-condensation of the aldehydes.
In contrast, our procedure is versatile and innovative, yielding up to
93% of the condensation product and 96% of the desired keto acid
upon hydrolysis, with excellent atom economy that allows for ef-
fective recycling of the glycine by-product.
Fig. 2. X-ray analysis for compounds 3q and 3b.22
The intermediates 3 were hydrolysed by heating at reflux in
a 6 M aqueous HCl solution for 2 h generating the corresponding
keto acid and glycine by-product in good yield. The glycine by-
product was easily recovered from the aqueous phase in quanti-
tative yield, and a protocol to recycle it to glycine anhydride 1 in
two steps is reported in the literature.23 Results are summarised in
Table 1.
Table 1
% Yields of condensation and hydrolysed products
Aldehyde R group (RCHO) Diketopiperazine Yield (%) Keto acid Yield (%)
Phenyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
87
93
89
92
85
79
73
93
93
92
68
88
75
82
78
90
87
81
67
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
d
95
91
95
83
80
48
95
92
91
91
90
85
88
d
2-Methylphenyl
3-Methylphenyl
2-Methoxyphenyl
3-Methoxyphenyl
2-Thiophenyl
1-Naphtyl
2-Naphtyl
4. Experimental
4.1. General
2,3-Difluorophenyl
2,4-Difluorophenyl
2,5-Difluorophenyl
Phenyl-ethyl
Cyclohexyl
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
All chemicals were purchased from Aldrich except where stated.
All reactions were performed under an atmosphere of nitrogen
using oven dried glassware. Oxygen-free nitrogen was obtained
from BOC gases and used without further drying. Proton and carbon
nuclear magnetic resonance spectra (1H and 13C NMR, respectively)
were recorded on 300 MHz, 400 MHz and 500 MHz FT spectrom-
eters. Tetramethylsilane was used as an internal reference in the
2-Propenyl
Ethyl
89
d
3-Cyclohexenyl
tert-Butyl
96
d
2-Furanyl
2-N-Methylpyrrolyl
N-Boc-3-indole
d
d
d
d
deuterated chloroform (CDCl3) (
d
¼0.00 ppm) for 1H NMR spectra.
Under hydrolytic conditions, which have been previously dis-
cussed, unsaturated aliphatic (3n and 3p) and heteroaromatic
(3ret) diketopiperazines do not yield the corresponding keto acids.
In the case of compound 3p the reaction products found were
a mixture of unidentified compounds, while for compound 3n the
product 6 was identified. The presence of 6 indicates that rapid
addition of water to the double bond had occurred, subsequently
followed by an intramolecular cyclization (Scheme 2).
The middle CDCl3 solvent peak was referenced to 77.0 for 13C NMR
spectra. The coupling constants (J) are in hertz and the chemical
shifts (d) are given in parts per million (ppm). High resolution mass
spectra were obtained on a Waters/Micromass instrument. Melting
points were determined using a Gallenkamp melting point appa-
ratus. Melting points are uncorrected. Elemental analyses were
performed by Mr. Adam Coburn and Ms. Ann Connolly, School of
Chemistry and Chemical Biology, University College Dublin.

7376
D. Balducci et al. / Tetrahedron 68 (2012) 7374e7379
4.2. 1,4-Diacetyl-piperazine-2,5-dione (2)26
3.6), 7.34 (s, 1H), 7.54 (d, 1ArH, J 5.1), 7.88 (br s, 1H, NH); dC
(126 MHz, CDCl3) 27.0, 46.0, 113.3, 123.4, 128.5, 128.9, 131.0, 135.4,
160.2, 162.8, 172.3; nmax 3232 (NH), 1689 (COCH3), 1658 (C]O),
1625 (C]C); Elemental analysis found: C, 52.72; H, 4.04; N, 11.21.
C11H10N2O3S requires C, 52.79; H, 4.03; N, 11.19.
A mixture of glycine anhydride (11.4 g, 100 mmol) in acetic an-
hydride was stirred under reflux for 7 h. The solvent was removed
under reduced pressure. The residue was crystallized from ethyl
acetate/ether to yield 2 (17.2 g, 87%) as a brown solid. Mp 99 ꢀC. dH
(500 MHz, CDCl3) 2.60 (s, 6H), 4.66 (s, 4H).
4.2.7. (Z)-1-Acetyl-3-(naphthalene-1-yl-methylene)-piperazine-2,5-
dione (3g). Prepared as described for 3a using 1-Naphthaldehyde
(7.8 mL, 50 mmol) to give the title compound 3g (11.6 g, 79%) as
a yellow solid. Mp 162 ꢀC (dec). dH (500 MHz, DMSO) 2.55 (s, 3H,
eNCOCH3), 4.37 (s, 2H), 7.43 (d, 1ArH, J 6.3), 7.52e7.59 (m,
2ArHþ1H), 7.65 (d, 1ArH, J 7.1), 7.94 (d, 2ArH, J 7.5), 7.96e8.00 (m,
1ArH), 10.17 (br s, 1H, NH); dC (126 MHz, CDCl3) 27.3, 45.5, 110.0,
119.9, 124.7, 126.1, 126.6, 127.1, 127.6, 129.0, 129.1, 130.5, 131.6, 133.8,
161.3, 164.1, 172.5; nmax 3196 (NH), 1690 (COCH3), 1652 (C]O), 1632
(C]C); Elemental analysis found: C, 69.39; H, 4.92; N, 9.51.
C17H14N2O3 requires C, 69.38; H, 4.79; N, 9.52.
4.2.1. (Z)-1-Acetyl-3-benzylidenepiperazine-2,5-dione
(3a).18 1,4-
Diacetyl-piperazine-2,5-dione 2 (11.7 g, 50 mmol) was dissolved
in dry CH2Cl2 (50 mL) under N2 atmosphere. Benzaldehyde (5 mL,
50 mmol) and potassium tert-butoxide (5.61 g, 50 mmol), dissolved
in a minimum amount of tert-butanol (w25 mL), were added to this
solution. The reaction mixture was stirred for 3 h, then a saturated
aqueous solution of NH4Cl (100 mL) was added to quench the re-
action and the mixture was extracted with ethyl acetate (100 mL).
The organic phase was dried over anhydrous sodium sulfate, and
concentrated in vacuo. The product 3a (11.2 g, 92%) was obtained as
a white solid. Mp 199e200 ꢀC. dH (500 MHz, CDCl3) 2.67 (s, 3H),
4.53 (s, 2H), 7.19 (s, 1H), 7.35e7.42 (m, 3ArH), 7.45e7.52 (m, 2ArH),
7.97 (br s, 1H, NH).
4.2.8. (Z)-1-Acetyl-3-(naphthalene-2-yl-methylene)-piperazine-2,5-
dione (3h). Prepared as described for 3a using 2-Naphthaldehyde
(4.8 mL, 50 mmol) to give the title compound 3h (10.7 g, 73%) as
a yellow solid. Mp 229e231 ꢀC. dH (500 MHz, DMSO) 2.51 (s, 3H,
eNCOCH3), 4.39 (s, 2H), 7.10 (s, 1H), 7.50e7.58 (m, 2ArH), 7.68 (d,
1ArH, J 8.2), 7.93 (d, 3ArH, J 8.1), 8.14 (s, 1ArH), 10.17 (br s, 1H, NH);
dC (126 MHz, DMSO) 27.2, 46.2, 110.0, 119.2, 126.9, 127.3, 127.4,
128.0, 128.4, 128.7, 130.0, 131.2, 133.1, 133.3, 162.1, 164.7, 172.3; nmax
3194 (NH), 1688 (COCH3), 1675 (C]O), 1621 (C]C); Elemental
analysis found: C, 69.45; H, 4.83; N, 9.75. C17H14N2O3 requires C,
69.38; H, 4.79; N, 9.52.
4.2.2. (Z)-1-Acetyl-3-(2-methyl-benzylidene)-piperazine-2,5-dione
(3b). Prepared as described for 3a using 2-methylbenzaldehyde
(5.78 mL, 50 mmol) to give the title compound 3b (11.2 g, 87%) as
awhite solid. Mp173e174 ꢀC. dH (500 MHz, CDCl3) 2.32(s, 3H), 2.67 (s,
3H, eNCOCH3), 4.49 (s, 2H), 7.22e7.38 (m, 4ArHþ1H), 7.84 (br s, 1H,
NH); dC (126 MHz, CDCl3) 19.9, 27.3, 46.2, 119.2, 126.1, 126.7, 127.4,
129.4, 131.2, 131.3, 137.6, 159.6, 162.5, 172.5; nmax 3260 (NH), 1708
(COCH3), 1668 (C]O), 1612 (C]C); Elemental analysis found: C,
65.40; H, 5.44;N,10.80. C14H14N2O3 requiresC, 65.11;H, 5.46; N,10.85.
4.2.9. (Z)-1-Acetyl-3-(2,3-difluorobenzylidene)-piperazine-2,5-dione
(3i). Prepared as described for 3a using 2,3-difluorobenzaldehyde
(5.5 mL, 50 mmol) to give the title compound 3i (13 g, 93%) as
a white solid. Mp 195e196 ꢀC. dH (500 MHz, DMSO) 2.51 (s, 3H,
eNCOCH3), 4.35 (s, 2H), 6.86 (s, 1H), 7.16e7.31 (m, 1ArH), 7.34e7.43
(m, 2ArH), 10.46 (br s, 1H, NH); nmax 3221 (NH), 1691 (COCH3), 1648
(C]O), 1618 (C]C); dC (126 MHz, DMSO) 27.3, 46.4, 109.3, 117.6,
123.8, 125.2, 126.2, 130.3, 148.1, 150.5, 160.1, 164.2, 172.4; Elemental
analysis found: C, 55.61; H, 3.50; N, 10.00; F, 13.56. C13H10F2N2O3
requires C, 55.72; H, 3.60; N, 10.00; F, 13.56.
4.2.3. (Z)-1-Acetyl-3-(3-methyl-benzylidene)-piperazine-2,5-dione
(3c). Prepared as described for 3a using 3-methylbenzaldehyde
(5.89 mL, 50 mmol) to give the title compound 3c (12 g, 93%) as
a white solid. Mp 187e188 ꢀC (dec). dH (300 MHz, CDCl3) 2.39 (s,
3H), 2.65 (s, 3H, eNCOCH3), 4.49 (s, 2H), 7.15e7.46 (m, 4ArHþ1H),
8.12 (br s, 1H, NH); dC (101 MHz, CDCl3) 21.4, 27.1, 46.0, 120.2, 125.5,
125.6, 129.1, 129.4, 130.2, 132.4, 139.4, 160.0, 162.8, 172.5; nmax 3248
(NH), 1679 (COCH3), 1627 (C]O), 1618 (C]C); Elemental analysis
found: C, 64.80; H, 5.45; N, 10.80. C14H14N2O3 requires C, 65.11; H,
5.46; N, 10.85.
4.2.10. (Z)-1-Acetyl-3-(2,4-difluorobenzylidene)-piperazine-2,5-
dione (3j). Prepared as described for 3a using 2,4-
difluorobenzaldehyde (5.5 mL, 50 mmol) to give the title compound
3j (13 g, 93%) as a white solid. Mp 157e158 ꢀC. dH (500 MHz, DMSO)
2.50 (s, 3H, eNCOCH3), 4.34 (s, 2H), 6.84 (s, 1H), 7.09e7.20 (m, 1ArH),
7.28e7.36 (m, 1ArH), 7.59e7.69 (m, 1ArH), 10.42 (br s, 1H, NH); nmax
3218 (NH), 1711 (COCH3), 1686 (C]O), 1611 (C]C); dC (126 MHz,
DMSO) 27.4, 46.3, 104.8, 109.9, 112.3, 118.1, 129.3, 132.3, 160.6, 161.2,
162.7,164.3,172.4;Elementalanalysis found:C, 55.60;H, 3.73;N,9.82;
F, 13.81. C13H10F2N2O3 requires C, 55.72; H, 3.60; N, 10.00; F, 13.56.
4.2.4. (Z)-1-Acetyl-3-(2-methoxy-benzylidene)-piperazine-2,5-dione
(3d). Prepared as described for 3a using 2-methoxybenzaldehyde
(5.9 mL, 50 mmol) to give the title compound 3d (12.2 g, 89%) as
a white wax. Mp 183e184 ꢀC. dH (500 MHz, CDCl3) 2.67 (s, 3H,
eNCOCH3), 3.96 (s, 3H), 4.49 (s, 2H), 6.98e7.09 (m, 2ArH), 7.18 (s,
1H), 7.25e7.42 (m, 2ArH), 8.45 (br s, 1H, NH); dC (126 MHz, CDCl3)
27.1, 46.1, 56.0, 112.0, 117.2, 121.6, 121.7, 125.7, 131.0, 156.3, 160.3,
162.5, 172.5; nmax 3192 (NH), 1721 (COCH3), 1677 (C]O), 1628 (C]
C), 1280 (OeMe); Elemental analysis found: C, 61.60; H, 5.13; N,
10.20. C14H14N2O4 requires C, 61.31; H, 5.14; N, 10.21.
4.2.11. (Z)-1-Acetyl-3-(2,5-difluorobenzylidene)-piperazine-2,5-
dione (3k). Prepared as described for 3a using 2,5-
difluorobenzaldehyde (5.5 mL, 50 mmol) to give the title com-
pound 3k (12.9 g, 92%) as a white solid. Mp 186e187 ꢀC. dH
(500 MHz, DMSO) 2.50 (s, 3H, eNCOCH3), 4.35 (s, 2H), 6.84 (s, 1H),
7.21e7.26 (m, 1ArH), 7.28e7.33 (m, 1ArH), 7.41e7.45 (m, 1ArH),
10.54 (br s, 1H, NH); nmax 3186 (NH), 1722 (COCH3), 1695 (C]O),
1615(C]C); dC (126 MHz, DMSO) 27.3, 46.3, 109.3, 117.3, 122.8,
130.1, 156.6, 158.3, 161.0, 164.4, 172.3; Elemental analysis found: C,
55.63; H, 3.84; N, 9.72; F, 13.57. C13H10F2N2O3 requires C, 55.72; H,
3.60; N, 10.00; F, 13.56.
4.2.5. (Z)-1-Acetyl-3-(3-methoxy-benzylidene)-piperazine-2,5-dione
(3e).27 Prepared as described for 3a using 3-methoxybenzaldehyde
(6.09 mL, 50 mmol) to give the title compound 3e (12.6 g, 92%) as
a white solid. Mp 199e200 ꢀC. dH (500 MHz, CDCl3) 2.65 (s, 3H,
eNCOCH3), 3.81 (s, 3H), 4.50 (s, 2H), 6.91e6.97 (m, 3ArH), 7.14 (s,
1H), 7.32e7.41 (m, 1ArH), 8.05 (br s, 1H, NH).
4.2.6. (Z)-1-Acetyl-3-thiophen-2yl-methylene-piperazine-2,5-dione
(3f). Prepared as described for 3a using thiophene-2-carbaldehyde
(4.67 mL, 50 mmol) to give the title compound 3f (10.6 g, 85%) as
a yellow solid. Mp 174e175 ꢀC. dH (500 MHz, CDCl3) 2.65 (s, 3H,
eNCOCH3), 4.54 (s, 2H), 7.18 (dd, 1ArH, J 5.1, 3.6), 7.32 (d, 1ArH, J
4.2.12. (Z)-1-Acetyl-3-(2-Phenyl-propiliden)-piperazine-2,5-dione
(3l). Prepared as described for 3a using 2-Phenyl-propionaldehyde

D. Balducci et al. / Tetrahedron 68 (2012) 7374e7379
7377
(6.7 mL, 50 mmol) to give the title compound 3l (9.3 g, 68%) as
a white solid. Mp 161e162 ꢀC. dH (300 MHz, CDCl3) 1.47 (d, 3H, J
6.6), 2.60 (s, 3H, eNCOCH3), 3.72e3.85 (m, 1H), 4.41 (s, 2H), 6.49 (d,
1H, J 9.3), 7.24e7.35 (m, 5ArH), 8.54 (br s, 1H, NH); dC (126 MHz,
DMSO) 22.2, 27.1, 36.5, 45.9, 125.0, 126.9, 127.1, 128.4, 129.0, 143.2,
159.9, 164.1, 172.6; nmax 3280 (NH), 1723 (COCH3), 1681 (C]O), 1615
(C]C); Elemental analysis found: C, 66.40; H, 5.90; N, 10.25.
C15H16N2O3 requires C, 66.16; H, 5.92; N, 10.29.
160.3, 162.7, 172.5; nmax 3252 (NH), 1718 (COCH3), 1668 (C]O), 1642
(C]C); Elemental analysis found: C, 58.99; H, 7.20; N, 12.45.
C11H16N2O3 requires C, 58.91; H, 7.19; N, 12.49.
4.2.18. (Z)-1-Acetyl-3-(furan-2-ylmethylene)piperazine-2,5-dione
(3r). Prepared as described for 3a using 2-furaldehyde (4.2 mL,
50 mmol) to give the title compound 3r (10.2 g, 87%) as a yellow
solid. Mp 192e194 ꢀC. dH (500 MHz, DMSO) 2.64 (s, 3H, eNCOCH3),
4.51 (s, 2H), 6.56 (dd, J 3.5, 1.9, 1ArH), 6.66 (d, J 3.5, 1ArH), 6.89 (s,
1H), 7.61 (d, J 1.8, 1ArH), 9.11 (s, 1H, NH); dC (126 MHz, DMSO) 27.2,
107.6, 110.2, 110.5, 119.3, 142.5, 154.1, 162.2, 164.6, 172.5; nmax 3248
(NH), 1701 (COCH3), 1687 (C]O), 1622 (C]C); HRMS (ESþ): calcd
for C11H11N2Oþ4 (MþH)þ: 235.0719; found: 235.0718.
4.2.13. (Z)-1-Acetyl-3-cyclohexylmethylene-piperazine-2,5-dione
(3m). 1,4-Diacetyl-piperazine-2,5-dione 2 (11.7 g, 0.05 mol) was
dissolved in dry THF (50 mL) under N2 atmosphere. Cyclo-
hexanecarbaldehyde (6.1 mL, 50 mmol) and potassium tert-but-
oxide (5.61 g, 50 mmol), dissolved in a minimum amount of tert-
butanol (25 mL), were added to this solution. The reaction mixture
was stirred for 3 h, then an aqueous solution of NH4Cl (100 mL) was
added to quench the reaction and the mixture was extracted with
ethyl acetate (100 mL). The organic phase was dried over anhy-
drous sodium sulfate, and concentrated in vacuo. The product 3m
(11 g, 88%) was obtained as a white solid. Mp 198e200 ꢀC. dH
(300 MHz, CDCl3) 1.17e1.42 (m, 5H), 1.64e1.82 (m, 5H), 2.22e2.41
(m, 1H), 2.61 (s, 3H, eNCOCH3), 4.44 (s, 2H), 6.19 (d, 1H, J 9.9), 8.26
(br s, 1H, NH); dC (126 MHz, CDCl3) 25.3, 25.6, 27.1, 31.8, 35.5, 46.0,
124.7, 129.7, 160.1, 163.8, 172.7; nmax 3197 (NH), 1710 (COCH3), 1678
(C]O), 1624 (C]C); Elemental analysis found: C, 62.09; H, 7.22; N,
11.24. C13H18N2O3 requires C, 62.38; H, 7.25; N, 11.19.
4.2.19. (Z)-1-Acetyl-3-((1-methyl-1H-pyrrol-2-yl)methylene) pipera-
zine-2,5-dione (3s). Prepared as described for 3a using N-methyl-
pyrrole-2-carboxaldehyde (5.1 mL, 50 mmol) to give the title
compound 3s (10 g, 81%) as a yellow solid. Mp 187e189 ꢀC. dH
(400 MHz, DMSO) 2.54 (s, 3H, eNCOCH3), 3.67 (s, 3H), 4.48 (s, 2H),
6.02e6.16 (m, 1ArH), 6.11e6.23 (m, 1ArH), 6.52e6.67 (m, 1ArH), 6.81
(s, 1H), 9.80 (s, 1H, NH); dC (126 MHz, DMSO) 27.2, 33.7, 56.6, 106.7,
108.8, 110.2, 119.2, 123.5, 131.9, 162.2, 164.6, 172.5; nmax 3235 (NH),
1700 (COCH3), 1691 (C]O),1652 (C]C); Elemental analysis found: C,
58.31;H, 5.29; N,16.97. C12H13N3O3 requiresC, 58.29; H, 5.30;N,16.99.
4.2.20. (Z)-tert-Butyl
3-((4-acetyl-3,6-dioxopiperazin-2-ylidene)
methyl)-1H-indole-1-carboxylate (3t). Prepared as described for 3a
using a Boc protected indole-3-carboxaldehyde28 (12.3 g, 50 mmol)
to give the title compound 3t (12.8 g, 67%) as a beige solid. Mp
234 ꢀC (dec). dH (300 MHz, CDCl3) 1.70 (s, 9H), 2.58 (s, 3H,
eNCOCH3), 4.52 (s, 2H), 7.43e7.32 (m, 2ArH), 7.66 (d, J 7.6, 1ArH),
7.91 (s, 1H), 8.14 (d, J 8.2, 1ArH), 8.31 (s, 1H); dC (101 MHz, CDCl3)
27.2, 28.3, 46.1, 85.4, 110.1, 115.3, 119.5, 121.5, 122.2, 124.8, 126.1,
126.3, 135.8, 136.64, 149.8, 162.2, 164.5, 172.4; nmax 3180 (NH), 1721
(COCH3), 1679 (C]O), 1644 (C]C), 1154 (CeO); HRMS (ESþ): calcd
for C11H11N2Oþ4 (MꢁH)þ: 384.1559; found: 384.1563.
4.2.14. (3Z,20E)-1-Acetyl-3-but-2-enylidene-piperazine-2,5-dione
(3n). Prepared as described for 3m using trans-crotonaldehyde
(4.1 mL, 50 mmol) to give the title compound 3n (7.8 g, 75%) as
a yellow solid. Mp 217e218 ꢀC (dec). dH (500 MHz, CDCl3) 1.94 (d,
3H, J 6.0), 2.62 (s, 3H, eNCOCH3), 4.47 (s, 2H), 6.21e6.32 (m, 1H),
6.33e6.44 (m, 1H), 6.77 (d, 1H, J 11.7), 8.92 (br s, 1H, NH); dC
(126 MHz, CDCl3) 19.3, 27.1, 46.0, 121.8, 122.2, 123.1, 140.8, 160.3,
164.0, 172.6; nmax 3281 (NH), 1718 (COCH3), 1682 (C]O), 1656 (C]
C), 1624 (C]C); Elemental analysis found: C, 57.39; H, 5.84; N,
13.50. C10H12N2O3 requires C, 57.68; H, 5.81; N, 13.45.
4.2.21. (Z)-2-Hydroxy-3-phenyl-acrylic acid (4a).26 (Z)-1-Acetyl-3-
benzylidenepiperazine-2,5-dione 3a (5 g, 20 mmol) was dissolved
in 6 N aqueous HCl (25 mL) and heated to reflux for 4 h. The re-
action was then cooled to room temperature and extracted with
CH2Cl2 (150 mL). The organic phase was dried over anhydrous so-
dium sulfate, and concentrated in vacuo. The product 4a (3.2 g,
95%) was obtained as a white solid. Mp 151e153 ꢀC. dH (300 MHz,
DMSO) 6.38 (s, 1H), 7.17e7.28 (m, 1ArH), 7.31e7.39 (m, 2ArH), 7.74
(d, 2ArH, J 7.8), 9.22 (br s, 1H), 13.20 (br s, 1H).
4.2.15. (Z)-1-Acetyl-3-propylidene-piperazine-2,5-dione (3o). Prepared
as described for 3m using propionaldehyde (3.6 mL, 50 mmol) to
give the title compound 3o (8 g, 82%) as a white solid. Mp
158e159 ꢀC. dH (300 MHz, CDCl3) 1.15 (t, 3H, J 6.9), 2.16e2.26 (m,
2H), 2.61 (s, 3H, eNCOCH3), 4.44 (s, 2H), 6.30 (t, 1H, J 7.5), 8.21 (br s,
1H, NH); dC (126 MHz, CDCl3) 12.9, 19.5, 27.1, 45.9, 125.8, 126.5,
160.0,164.2,172.6; nmax 3383 (NH),1715 (COCH3), 1693 (C]O),1643
(C]C); Elemental analysis found: C, 55.35; H, 5.99; N, 14.10.
C9H12N2O3 requires C, 55.09; H, 6.16; N, 14.28.
4.2.22. 2-Oxo-3-o-tolyl-propanoic acid (4b). Prepared as described
for 4a using 3b (5 g, 19 mmol) to give the title compound 4b (3.1 g,
91%) as a white solid. Mp 138.4e139.2 ꢀC. dH (300 MHz, CDCl3) 2.19
(s, 3H), 4.17 (s, 2H), 7.08e7.19 (m, 4ArH); dC (101 MHz, CDCl3) 19.6,
42.2, 126.3, 128.0, 130.1, 130.6, 137.2, 138.2, 160.9, 192.5; nmax 3462
(OH), 1742 (C]O), 1618 (C]O), 1584 (C]C); HRMS (ESꢁ): calcd for
C10H9Oꢁ3 (MꢁH)ꢁ: 177.0552; found: 177.0549.
4.2.16. (Z)-1-Acetyl-3-cyclohex-3enyl-methylene-piperazine-2,5-
dione (3p). Prepared as described for 3m using cyclohex-3-
enecarbaldehyde (5.85 mL, 50 mmol) to give the title compound
3p (9.7 g, 78%) as a white solid. Mp 175e176 ꢀC. dH (300 MHz,
CDCl3) 1.54e1.61 (m, 2H), 1.76e1.84 (m, 1H), 1.92e2.02 (m, 1H),
2.12e2.21 (m, 2H), 2.54e2.66 (m, 1H), 2.62 (s, 3H, eNCOCH3), 4.44
(s, 2H), 5.67e5.75 (m, 2H), 6.27 (d, 1H, J 9.9), 8.37 (br s, 1H, NH); dC
(126 MHz, CDCl3) 23.9, 27.1, 27.6, 30.3, 31.4, 46.0, 124.8, 125.3, 127.1,
129.0, 160.1, 164.0, 172.6; nmax 3341 (NH), 1708 (COCH3), 1678 (C]
O), 1666 (C]C), 1618 (C]C); Elemental analysis found: C, 62.60; H,
6.52; N, 11.31. C13H16N2O3 requires C, 62.89; H, 6.50; N, 11.28.
4.2.23. (Z)-2-Hydroxy-3-m-tolyl-acrylic acid (4c). Prepared as de-
scribed for 4a using 3c (5 g, 19 mmol) to give the title compound 4c
(3.2 g, 95%) as a white solid. Mp 141e142 ꢀC. dH (300 MHz, CDCl3)
2.37 (s, 3H), 6.69 (s, 1H), 7.11e7.21 (m, 1ArH), 7.24e7.32 (m, 1ArH),
7.56e7.68 (m, 2ArH); dC (101 MHz, CDCl3) 21.4, 114.0, 127.5, 128.5,
129.5, 130.9, 133.6, 138.1, 170.4; nmax 3389 (OH), 1734 (C]O), 1690
(C]O), 1590 (C]C); HRMS (ESꢁ): calcd for C10H9O3ꢁ (MꢁH)ꢁ:
177.0552; found: 177.0566.
4.2.17. (Z)-1-Acetyl-3-(2,2-dimethyl-propylidene)-piperazine-2,5-
dione (3q). Prepared as described for 3m using 2,2-Dimethyl-pro-
pionaldehyde (5.5 mL, 50 mmol) to give the title compound 3q
(10.1 g, 90%) as a white solid. Mp 161e162 ꢀC. dH (300 MHz, CDCl3)
1.26 (s, 9H), 2.60 (s, 3H, eNCOCH3), 4.43 (s, 2H), 6.27 (s, 1H), 7.62 (br
s, 1H, NH); dC (126 MHz, CDCl3) 27.1, 29.8, 32.5, 45.6, 128.2, 132.5,
4.2.24. (Z)-2-Hydroxy-3-(2-methoxy-phenyl)-acrylic acid (4d).26 Prep-
ared as described for 4a using 3d (5 g, 18 mmol) to give the title

7378
D. Balducci et al. / Tetrahedron 68 (2012) 7374e7379
compound 4d (2.9 g, 83%) as an orange wax. dH (300 MHz, DMSO)
3.80 (s, 3H), 6.78 (s, 1H), 6.91e7.02 (m, 2ArH), 7.16e7.24 (m, 1ArH),
8.15 (d, 1ArH, J 7.0), 9.03 (br s, 1H).
1H, J 6.9, 17.1), 3.33 (dd, 1H, J 6.9, 17.1), 3.36e3.42 (m, 1H), 7.18e7.40
(m, 5ArH); dC (101 MHz, CDCl3) 22.1, 35.2, 45.3, 126.7, 128.7, 144.9,
159.2, 194.8; nmax 3474 (OH), 1756 (C]O), 1634 (C]O); HRMS
(ESꢁ): calcd for C11H11Oꢁ3 (MꢁH)ꢁ: 191.0708; found 191.0703.
4.2.25. 3-(3-Methoxy-phenyl)-2-oxopropionic acid (4e).26 Prepared
as described for 4a using 3e (5 g, 18 mmol) to give the title com-
pound 4e (2.8 g, 80%) as a white solid. Mp 151e152 ꢀC. dH (300 MHz,
CDCl3) 3.79 (s, 3H), 4.18 (s, 2H), 6.77e6.87 (m, 3ArH), 7.21e7.30 (m,
1ArH).
4.2.33. 3-Cyclohexyl-2-oxo-propionic acid (4m).3 Prepared as de-
scribed for 4a using 3m (5 g, 20 mmol) to give the title compound
4m (3 g, 88%) as a pale wax. dH (300 MHz, CDCl3) 0.88e1.31 (m, 5H),
1.66e1.72 (m, 5H), 1.93e2.01 (m, 1H), 2.80 (d, 2H, J 7.1).
4.2.26. (Z)-2-Hydroxy-3-thiophen-2-yl-acrylic acid (4f).3 Prepared
as described for 4a using 3f (5 g, 20 mmol) to give the title com-
pound 4f (1.6 g, 48%) as a yellow solid. Mp 165e166 ꢀC. dH
(300 MHz, DMSO) 6.74 (s, 1H), 6.98e7.06 (m, 1ArH), 7.22 (d, 1ArH, J
3.5), 7.50 (d, 1ArH, J 5.7), 9.24 (br s, 1H), 12.6 (br s, 1H).
4.2.34. 2-Oxo-pentanoic acid (4o).26 Prepared as described for 4a
using 3o (5 g, 25 mmol) to give the title compound 4o (2.6 g, 89%)
as a colourless oil. dH (300 MHz, CDCl3) 0.99 (t, 3H, J 7.5), 1.68e1.75
(m, 2H), 2.94 (t, 2H, J 7.2).
4.2.35. 4,4-Dimethyl-2-oxo-pentanoic acid (4q).26 Prepared as de-
scribed for 4a using 3q (5 g, 22 mmol) to give the title compound 4q
(3.1 g, 96%) as a yellow solid. Mp 55e57 ꢀC. dH (300 MHz, CDCl3)
1.05 (s, 9H), 2.85 (s, 2H), 8.93 (br s, 1H), dC (126 MHz, DMSO) 29.6,
31.2, 50.2, 164.0, 197.1.
4.2.27. (Z)-2-Hydroxy-3-(naphthalen-1-yl)-acrylic acid (4g). Prepared
as described for 4a using 3g (5 g, 17 mmol) to give the title
compound 4g (3.5 g, 95%) as a yellow solid. Mp 149 ꢀC (dec). dH
(500 MHz, CD3OD) 7.26 (s, 1H), 7.48 (t, 2ArH J 7.7), 7.53 (t, 1ArH, J
7.5), 7.77 (d, 1ArH, J 8.2), 7.86 (d, 1ArH, J 8.0), 8.15 (d, 1ArH, J 8.4),
8.32 (d, 1ArH, J 7.3); dC (126 MHz, CD3OD) 105.3, 122.9, 125.9,
125.2, 125.8, 127.5, 127.6, 128.3, 130.5, 131.5, 133.8, 144.9, 166.9;
HRMS (ESꢁ): calcd for C13H9Oꢁ3 (MꢁH)ꢁ: 213.0552; found
213.0545.
4.3. 4-Ethyl-2-hydroxy-cyclopenten-2-one (6)29
dH (300 MHz, DMSO) 0.85 (t, 3H, J 7.0), 1.52e1.82 (m, 2H), 4.86
(m, 1H), 6.24 (s, 1H), 10.26 (br s, 1H).
4.2.28. (Z)-2-Hydroxy-3-(naphthalen-2-yl)-acrylic acid (4h). Prepared
as described for 4a using 3h (5 g, 17 mmol) to give the title
compound 4h (3.4 g, 92%) as a yellow solid. Mp 155 (dec). dH
(500 MHz, CD3OD) 6.66 (s, 1H), 7.40e7.49 (m, 2ArH), 7.76e7.86 (m,
3ArH), 7.92 (d, 1ArH, J 8.6), 8.26 (s, 1ArH); dC (126 MHz, CD3OD)
110.2, 125.7, 127.1, 127.2, 127.8, 128.5, 132.6, 132.7, 133.6, 141.3,
166.9; HRMS (ESꢁ): calcd for C13H9O3ꢁ (MꢁH)ꢁ: 213.0552; found
213.0546.
Acknowledgements
This work was supported by PRTLI cycle 3 and Science Foun-
dation Ireland. We wish to thank the Erasmus Placement Pro-
gramme and the University of Bologna (Italy) for sponsoring Ms.
Sapuppo for a 6 month internship in Dr. Paradisi’s lab and Dr. Mi-
chael Sharkey for proofreading the manuscript.
4.2.29. (Z)-3-(2,3-Difluorophenyl)-2-hydroxyacrylic acid (4i). Prepared
as described for 4a using 3i (5 g, 18 mmol) to give the title com-
pound 4i (3.2 g, 91%) as a pale yellow solid. Mp 119e120 ꢀC (dec). dH
(500 MHz, DMSO) 6.48 (s, 1H), 7.12e7.31 (m, 2ArH), 7.98e8.04 (m,
1ArH), 9.88 (br s, 1H); dC (126 MHz, DMSO) 98.6, 116.0, 125.0, 125.4,
125.7, 144.9, 147.1, 150.0, 166.0; nmax 3471 (OH), 1760 (C]O), 1734
(C]O), 1668 (C]C); HRMS (ESꢁ): calcd for C9H5F2O3ꢁ (MꢁH)ꢁ:
199.0207; found: 199.0206.
References and notes
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Mol. Catal. B: Enzym. 1998, 5, 1e11.
4.2.30. (Z)-3-(2,4-Difluorophenyl)-2-hydroxyacrylic acid (4j). Prepared
as described for 4a using 3j (5 g, 18 mmol) to give the title com-
pound 4j (3.2 g, 91%) as a pale brown solid. Mp 117e118 ꢀC (dec). dH
(500 MHz, DMSO) 6.45 (s, 1H), 7.08e7.27 (m, 2ArH), 8.21e8.29 (m,
1ArH), 9.67 (br s, 1H); dC (126 MHz, DMSO) 99.1, 104.1, 112.0, 119.7,
131.7, 143.6, 159.6, 161.4, 166.2; nmax 3462 (OH), 1722 (C]O), 1698
(C]O), 1642 (C]C); HRMS (ESꢁ): calcd for C9H5F2O3ꢁ (MꢁH)ꢁ:
199.0207; found: 199.0205.
6. Berzelius, J. J. Ann. Phys. 1835, 36, 1e29.
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4.2.31. (Z)-3-(2,5-Difluorophenyl)-2-hydroxyacrylic acid (4k). Prepared
as described for 4a using 3k (5 g, 18 mmol) to give the title
compound 4k (3.1 g, 90%) as a pale yellow solid. Mp 116e117 ꢀC
(dec). dH (500 MHz, DMSO) 6.46 (s, 1H), 7.06e7.12 (m, 1ArH),
7.19e7.25 (m, 1ArH), 7.90e8.03 (m, 1ArH), 9.98 (br s, 1H); dC
(126 MHz, DMSO) 98.9, 115.4, 116.2, 116.7, 124.5, 145.0, 155.7, 158.4,
165.9; nmax 3456 (OH), 1702 (C]O), 1622 (C]O), 1591 (C]C);
HRMS (ESꢁ): calcd for C9H5F2Oꢁ3 (MꢁH)ꢁ: 199.0207; found:
199.0198.
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CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail:deposit@ccdc.cam.ac.Uk).
4.2.32. 2-Oxo-4-phenylpentanoic acid (4l). Prepared as described
for 4a using 3l (5 g, 18 mmol) to give the title compound 4l (3 g,
85%) as a pale wax. dH (300 MHz, CDCl3) 1.34 (d, 3H, J 6.9), 3.18 (dd,

D. Balducci et al. / Tetrahedron 68 (2012) 7374e7379
7379
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