Ruthenium-catalyzed selective hydrogenation of bis-arylidene tetramic acids. Application to the synthesis of novel structurally diverse pyrrolidine-2,4-diones

Article abstract of DOI:10.3390/molecules16076116

Catalytic hydrogenation of 3,5-bis-arylidenetetramic acids, known for their biological activity, has been developed. The chemoselective ruthenium-catalyzed reduction of the exocyclic carbon-carbon double bonds on pyrrolidine-2,4-dione ring system, containing other reducible functions, has been investigated. Depending on the substrate the yield of the hydrogenation process can reach up to 95%. The structural elucidation has been established using NMR and HRMS spectral data.

Full text of DOI:10.3390/molecules16076116

Molecules 2011, 16, 6116-6128; doi:10.3390/molecules16076116
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Ruthenium-Catalyzed Selective Hydrogenation of bis-Arylidene
Tetramic Acids. Application to the Synthesis of Novel
Structurally Diverse Pyrrolidine-2,4-diones
Christos S. Karaiskos 1, Dimitris Matiadis 1, John Markopoulos 2,* and
Olga Igglessi-Markopoulou 1,*
1
Laboratory of Organic Chemistry, Department of Chemical Engineering, National Technical
University of Athens, Zografos Campus, Athens 15773, Greece;
E-Mails: chriskarsp@gmail.com (C.S.K.); matiadis@mail.ntua.gr (D.M.)
2
Laboratory of Inorganic Chemistry, Department of Chemistry, University of Athens, Panepistimio-
polis, Athens 15771, Greece; E-Mail: jmmarko@chem.uoa.gr
* Author to whom correspondence should be addressed; E-Mail: ojmark@chemeng.ntua.gr;
Tel.: +30-210-772-3079; Fax: +30-210-772-3072.
Received: 1 April 2011; in revised form: 5 July 2011 / Accepted: 11 July 2011 /
Published: 20 July 2011
Abstract: Catalytic hydrogenation of 3,5-bis-arylidenetetramic acids, known for their
biological activity, has been developed. The chemoselective ruthenium-catalyzed reduction
of the exocyclic carbon-carbon double bonds on pyrrolidine-2,4-dione ring system,
containing other reducible functions, has been investigated. Depending on the substrate the
yield of the hydrogenation process can reach up to 95%. The structural elucidation has
been established using NMR and HRMS spectral data.
Keywords: hydrogenation; homogeneous catalysis; ruthenium catalysts; BINAP;
arylidenetetramic acid
1. Introduction
Tetramic acids (TAs) containing the pyrrolidine-2,4-dione ring system are a group of naturally
occurring products which possess a broad spectrum of biological and pharmaceutical activities,
including antibiotic, antiviral, cytotoxic and anti-HIV agents [1]. Representative examples of tetramic

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acids and derivatives are tenuazonic acid [2], melophlins [3], reutericyclin [4], pachydermin [5] and
dihydromaltophilin (HSAF) [6] (Figure 1). Recently, it was discovered that the Gram-negative
bacterium Pseudomonas aeruginosa produces the antibiotic C12-TA from one of its “quorum sensing”
molecules, which may also serve as a lead compound for the development of antimicrobial
therapeutics [7]. Additionally, complete activities of the enzymes polyketide synthases (PKSs) and non
ribosomal peptide synthases (NRPSs) have been reconstituted through the biosynthesis of the
functionalized 3-acyl tetramic acid named praespyridone [8]. Moreover, tetramic acids bearing an
arylidene or alkylidene group at C-5 of the heterocyclic ring have been reported as antagonists at the
glycine site on N-methyl-D-aspartate (NMDA) receptor [9]. Consequently, multifunctionalized
pyrrolidine-2,4-diones are considered as “privileged scaffolds” for the construction of a variety of
biologically active nitrogen heterocycles.
Figure 1. Naturally occurring tetramic acids.
Our research group has been involved to the synthesis and structure elucidation of substituted
tetramic acids with appropriate functionalities at C-3 and C-5 positions [10,11]. In this work, we
are interested in the chemoselective homogeneous catalytic hydrogenation of the olefinic bond of
3-arylidene group on the pyrrolidine-2, 4-dione nucleus, over other present reducible functions, using a
ruthenium-catalyst.
Homogeneous hydrogenation constitutes an important synthetic procedure and is one of the most
extensively studied reactions in homogeneous catalysis. The impressive development of coordination
and organometallic chemistry has allowed the preparation of a wide variety of soluble metal
complexes active as homogeneous hydrogenation catalysts under mild conditions [12,13].

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The selective reduction of carbon-carbon double bonds is a very important transformation in
synthetic organic chemistry. Additionally, the enantioselective hydrogenation of prochiral substances
bearing an activated group, such as an ester, an acid or an amide has been developed for a wide range
of transformations from the laboratory to the preparation of fine chemicals and pharmaceuticals in the
industry production [14-16].
Early advances in chemoselective olefin hydrogenation were dominated by the introduction of
homogeneous transition metal complexes [17-19]. Many of them allow the preferential reduction of
carbon-carbon double bonds over a coexisting C=O functionality [20-25].
Herein, we present a new protocol for the synthesis of 3, 5-arylidene-pyrrolidine-2,4-diones, and the
chemoselective ruthenium-catalyzed hydrogenation of exocyclic substituted C=C bonds. The focus
of this work will be on selective catalytic hydrogenation of double-double carbon bonds in substrates
containing other reducible functions.
2. Results and Discussion
The proposed methodology allows the construction of the 5-arylidene-pyrrolidine-2,4-dione motif
in three stages (Scheme 1): (i) The synthesis of the N-substituted tetramic acids 1,2, which can be
achieved in a one-pot reaction, starting from N-acetylglycine [26], (ii) the production of 5-arylidene-3-
alkoxycarbonyl tetramic acids 3,4 [27] and (iii) the elimination of the 3-alkoxycarbonyl group
(Scheme 1) [28]. All these stages occur with high yield and excellent purity. Also, the 3, 5-bisarylidene
tetramic acids 7,8 can be derived in one stage, starting from the 3-alkoxycarbonyltetramic acids by
treating with a substituted benzaldehyde bearing an electron donor group.
Scheme 1. Synthesis of hydrogenation substrates.
Reagents and conditions: (i) a. THF, NHS, DCC, b. NaH; (ii) MeOH/HCl (8% w./w.), 4-NO2-
benzaldehyde, 5 h, MeOH; (iii) AcOEt, water (2% v./v.), reflux, 1 h; (iv) MeOH/HCl (8% w./w.),
reflux, 6 h; (v) MeOH/HCl (8% w./w.), 4-X-benzaldehyde, 24 h

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Comparison of the NMR spectral data of the novel 5-arylidenetetramic acids with the natural
products mentioned in Figure 2 [5] verifies that they also possess the Z-configuration of the exocyclic
double bond.
Figure 2. Z-configuration of the exocyclic double bond.
Catalytic hydrogenation processes using ruthenium complexes in homogeneous phase have been
widely investigated [29-31]. Catalysts based on Ru complexes can activate the hydrogenation of both
carbonyl and olefin double bonds [14,31]. The chemoselectivity depends on the Ru complex ligands,
the substrate and the reaction conditions. For the investigation of these parameters we employed: (i)
different structure substrates, (ii) wide range of reaction conditions, 40–100 °C, 20–60 bar, with a ratio
of substrate / catalyst of 100:1, and (iii) a catalyst structured with four Ru cores, the Η4Ru4(CO)9[μ3-
(S)-BINAP] complex 14 (Figure 3). This catalyst, prepared by Professor Sergey Tunik [32] proved to
be efficient on chemoselective reduction of C=C bond over a coexisting C=O group.
Figure 3. Ruthenium catalyst 14.

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The solvents employed in the proposed strategy can be divided in two categories:
(1). Polar solvents (methanol, ethanol) and
(2). Non-polar solvents (tetrahydrofuran, dichloromethane)
These experimental results are summarized in Table 1. It is known that the pyrrolidine-2,4-dione
nucleus ring is stable, and further stabilization occurs by the introduction of an extended conjugated
double bond system (e.g. benzaldehyde, Scheme 1), It is, therefore, expected that the hydrogenation
reaction conditions should be more intense than those of non conjugated systems reported in the
literature [33].
Table 1. Hydrogenation results for compound 7 to give 9 and 12.
Temp Press Time Conversion% a
Entry
S/C
Solvent/DCM
(°C)
100
100
60
(bar)
60
60
(h)
20
19
20
20
9
4.7
94.0
78.8
94.4
12
94.2
5.9
21.1
5.5
1
2
3
4
250
500
250
493
MeOH (24:1)
EtOH (24:1)
MeOH (24:1)
THF (20:1)
60
100
60
The hydrogenation of 3,5-bisarylidene tetramic acids 7 and 8 occurs in two stages in high yields
(Scheme 2, Tables 1 and 2, entries 1–14). It is noteworthy that the hydrogenated products at the 3-
position, 9 and 10, do not exhibit a chiral center at C-3. The best outcome may be attributed to the
racemization of the chiral carbon center C-3 through enolization [34] (Figure 4), and the prevalence of
the enol tautomers. This is a well established phenomenon on the structure elucidation of
functionalized pyrrolidine-2, 4-diones, on the basis of experimental and theoretical research.
Table 2. Hydrogenation results for compound 8 to give 10 and 13, based on the reaction scheme 2.
Temp Press Time Conversion% a
Entry S/C Solvent/DCM
(°C)
100
100
100
80
(bar)
60
60
60
60
(h)
20
20
41
20
20
20
20
20
20
20
10
13
5
6
120 MeOH (24:1)
405 MeOH (24:1)
405 MeOH (24:1)
429 MeOH (24:1)
429 MeOH (24:1)
227 MeOH (24:1)
405 MeOH (24:1)
405 MeOH (24:1)
24.8
44.0
28.8
13.8
93.3
86.2
34.0
53.2
95.0
25.4
73.9
51.6
47.5
84.4
2.9
7 b
8
9
60
60
10
11
12
13
14
40
60
3.7
80
80
80
40
20
60
64.7
45.7
5.0
405
700
EtOH (24:1)
THF (20:1)
100
60
8.9
a Calculated by HPLC, using a Chiralpak AS column (4.6 × 250 mm); b Compound 11 was isolated
in 23.7% conversion (see Experimental).

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Figure 4. Keto-enol tautomerism of compounds 9 and 10.
Scheme 2. Hydrogenation of compounds 7 and 8.
1
This statement has been verified by comparison of the H NMR and MS spectral data for these
products. Only the “enolic tautomers” of the products 9, 10, 12 and 13 were isolated. In the same
solvent the optimal yields of compounds 10 (entry 9) and 13 (entry 8) were achieved at 60 °C and
80 °C, respectively.
The variation of the applied hydrogen pressure is less effective compared to the temperature, with
respect to the yield of 10 and 13, when the temperature is constant, for the same solvent (entries 11,
12). However, higher pressure favors the formation of 13.
The purification of the solvents is important in order to maintain neutral conditions during the
hydrogenation reactions. The Ru cluster is very sensitive to water and oxygen. For this reason the
solvents are dried and sonicated prior to their use. The solvent has the greatest impact, among all the
reaction parameters, on the hydrogenation result. Further examination of the solvent effect revealed
that methanol favors the formation of compounds 12 and 13 and ethanol predominantly leads to the
formation of compounds 9 and 10 (entries 2, 13, Table). Tetrahydrofuran gives good results only in the

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case of substrates 7 and 8 (entries 4 and 14, respectively). Dichloromethane is employed for the
introduction of the Ru complex in the reaction mixture, and used in small amounts, in every case.
Using only dichloromethane as the reaction solvent for the hydrogenation of compound 10, we cannot
obtain product 13. The novel substrates and hydrogenation products were characterized by micro
analysis, HRMS, 1H- and 13C-NMR spectroscopy [35-38].
3. Experimental
3.1. Preparation of solvents and substrates
Purification of methanol, ethanol and dichloromethane solvents included distillation from CaH2
under a nitrogen atmosphere. Tetrahydrofuran was distilled from Na/Ph2CO, in an argon atmoshpere.
All manipulations were performed using standard Schlenk techniques. Prior to the reaction all
solutions were sonicated for 20 min to remove oxygen and other gases, at room temperature and under
an argon atmosphere. Flash column chromatography was carried out on Macherey–Nagel 0.063–
0.2 mm/70–230 mesh silica gel.
The hydrogenation reaction took place in an Autoclave Engineers’ 300 mL batch reactor. The
reactor was equipped with a glass liner, two thermocouples (for the measurement of the process and
the heater temperature), a pressure gauge, and a PID control tower (CT-1000). The stainless steel
mechanical stirrer, that can go up to 2,500 rpm, was insulated with Teflon. The autoclave has a wide
operational range, from −50 °C to 250 °C, and from 1 bar to 200 bar.
The NMR spectra were recorded on a Varian Gemini 2000 300 MHz spectrometer. MS spectra
were recorded on a Micromass LCT Mass Spectrometer (Chemistry Department, University of
Liverpool, Liverpool, UK). Melting points were determined on a Gallenkamp MFB-595 melting point
apparatus and are uncorrected.
3.2. Synthesis of 5-arylidenetetramic acids
5-Arylidene(4'-nitro)tetramic acid (5) [39]: A mixture of 3-ethoxycarbonyl-5-arylidene(4'-nitro)
tetramic acid (2.0 mmol) and ethyl acetate (60 mL) in water (1.2 mL), was heated under reflux for 1 h.
After cooling to room temperature the solution was dried over anhydrous Na2SO4, and filtered off. The
filtrate was evaporated under reduced pressure and dried in vacuo to afford the compound 5. The solid
was washed several times with dry diethyl ether. Yellow solid (from ethyl acetate), yield 74%; mp
238–239 °C (decomposed); 1H-NMR (DMSO-d6): δ 3.24/5.06 (2s, 2H/1H, 3-H), 6.26/6.32 (2s, 1H/1H,
6-H), 7.78/7.83 (2d, 2H/2H, b- and c-H, J = 8.7 Hz), 8.16/8.18 (2d, 2H/2H, d- and e-H, J = 8.7 Hz),
9.73/11.28 (2s, 1H/1H, NH), 12.03 ppm (s, 1H, OH); 13C-NMR (DMSO-d6): δ 93.0 (C-3), 101.7/102.4
(C-6), 123.7 (C-d, C-e), 129.8/130.1 (C-b, C-c), 136.6/136.9 (C-5), 140.4/141.3 (C-a), 145.6/146.0 (C-
f), 165.7/172.1 (C-2), 173.0/195.5 ppm (C-4); HRMS calcd. for [C11H8N2O4+23Na]+: 255.0382,
found: 255.0397.
5-Arylidene(4'-nitro)-4-methoxytetramic acid (6): 5-Arylidene(4'-nitro)tetramic acid (1.5 mmol) was
refluxed for 6 h in a solution of 8% hydrochloric acid in methanol (prepared by addition of acetyl
chloride (2 mL) in anhydrous methanol (15 mL) until it was dissolved), and then the reaction mixture

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was stirred overnight at room temperature. The resulting solid was filtered off and washed several
1
times with diethyl ether. Dark yellow solid (from methanol), yield 82%; mp 275–276 °C; H-NMR
(DMSO-d6): δ 3.91 (s, 3H, 7-H), 5.45 (s, 1H, 3-H), 6.29 (s, 1H, 6-H), 7.80 (d, 2H, b- and c-H,
13
J = 8.7 Hz), 8.17 (d, 2H, d- and e-H, J = 8.4 Hz), 10.02 ppm (s, 1H, NH); C-NMR (DMSO-d6): δ
58.8 (C-7), 93.2 (C-3), 102.9 (C-6), 123.7 (C-d, C-e), 130.0 (C-b, C-c), 135.1 (C-5), 140.9 (C-a), 145.8
(C-f), 167.2 (C-2), 172.0 ppm (C-4); HRMS calcd. for [C12H10N2O4+23Na]+: 269.0538, found
269.0548.
3, 5-Bis(benzylidene)tetramic acid (7) [40]: 3-Ethoxycarbonyltetramic acid (1.0 mmol) was stirred in a
solution of 8% hydrochloric acid in methanol, prepared from the addition of acetyl chloride (1 mL) in
anhydrous methanol (7 mL) until it was dissolved. Benzaldehyde (3.0 mmol) was added in the solution
and the reaction mixture was refluxed for 24 h, and then left under stirring overnight. The precipitated
was filtered off, washed several times with diethyl ether and dried in vacuo for 5 h, to afford the
corresponding product, as a purple solid, yield 63%; mp 213–214 °C; 1H-NMR (DMSO-d6): δ 6.47 (s,
1H, 6-H), 7.30–7.44 (m, 3H, j-, k- and l-H), 7.56–7.68 (m, 5H, h-, i-, d-, e- and f-H), 7.88/7.91 (2s,
both, 1H, 7-H), 8.52–8.59 (m, 2H, b- and c-H), 11.17 ppm (s, 1H, NH); 13C-NMR (DMSO-d6): δ 106.6
(C-6), 122.4 (C-3), 128.2 (C-f, C-l), 128.7 (C-b, C-c), 128.8 (C-h, C-i), 129.5 (C-j, C-k), 129.6 (C-d,
C-e), 133.2 (C-5), 133.5 (C-a), 133.7 (C-g), 148.1 (C-7), 166.9 (C-2), 184.1 ppm (C-4); HRMS calcd.
for [C18H13NO2+23Na]+: 298.0844, found: 298.0846 and calcd. for [C18H13NO2+23Na+MeOH]+:
330.1106, found: 330.1102.
3, 5-Bis[arylidene(4'-methoxy)]tetramic acid (8) [39]: 3-Ethoxycarbonyltetramic acid (1.0 mmol) was
stirred in a solution of 8% hydrochloric acid in methanol, prepared from the addition of acetyl chloride
(2 mL) in anhydrous methanol (15 mL) until it dissolved. p-Methoxybenzaldehyde (3.0 mmol) was
then added in the solution, the reaction mixture was refluxed for 24 h and then left under stirring
overnight. The precipitated was filtered off, washed several times with diethyl ether and then dried in
1
vacuo for 5 h, to afford the corresponding product as a purple solid, yield 66%; mp 239–240 °C; H-
NMR (DMSO-d6): δ 3.80 (s, 3H, OCH3 (C-f)), 3.89/3.90 (2s, both, 3H, OCH3 (C-l)), 6.44 (s, 1H, 6-H),
6.97 (d, 2H, d- and e-H, J = 8.4 Hz), 7.14 (d, 2H, j- and k-H, J = 9.0 Hz), 7.63 (d, 2H, b- and c-H,
J = 8.7 Hz), 7.80 (s, 1H, 7-H), 8.64 (d, 2H, h- and i-H, J = 9.0 Hz), 10.90 ppm (s, 1H, NH); 13C-NMR
(DMSO-d6): δ 55.2 (OCH3 [C-f]), 55.8 (OCH3 [C-l]), 106.7 (C-6), 114.3 (C-d, C-e), 114.5 (C-j, C-k),
125.8 (C-3), 126.2 (C-5), 130.9 (C-b, C-c), 131.2 (C-h, C-i), 136.7 (C-g), 137.7 (C-a), 147.9 (C-7),
159.3 (C-f), 164.1 (C-l), 167.5 (C-2), 184.0 ppm (C-4); HRMS calcd. for [C20H17NO4+23Na]+:
358.1055, found: 358.1065.
3.3. Procedure for the hydrogenation reaction
The autoclave was sealed and was flushed three times with nitrogen. The substrate was dissolved in
the proper solvent (methanol, ethanol or THF), and the catalyst was dissolved in DCM, both under
argon atmosphere. The solutions were mixed under argon atmosphere and were sonicated for 20 min.
Then the autoclave was loaded with the reaction mixture from a designated reactant inlet, under
nitrogen current. The inlet was then sealed, the autoclave was flushed several times with hydrogen

Molecules 2011, 16
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(pressurized with 10 bar H2 each time), and then pressurized to the desired pressure with hydrogen.
Finally, the stirrer speed was adjusted and the temperature was set to the desired value. After the
completion of the hydrogenation process the reaction vessel was cooled to room temperature and the
pressure was relieved. Next the solvent was evaporated under reduced pressure to give a solid product
that was washed several times with diethyl ether and was purified by silica gel chromatography
(CH2Cl2/MeOH 95:5–92:8).
3.4. Synthesis of hydrogenation products
3-Benzyl-5-benzylidene-4-hydroxy-3-pyrroline-2-one (9) [28,40]: It was derived as a pale yellow solid
(from methanol), mp 188–189 °C; 1H-NMR (DMSO-d6): 3.58 (s, 2H, 7-H), 6.25 (s, 1H, 6-H), 7.22 (m,
13
6H), 7.35 (t, 2H), 7.55 (d, 2H, J = 7.2 Hz), 9.48 (s, 1H, NH), 11.04 ppm (s, 1H, (4)-OH). C-NMR
(DMSO-d6): 26.2 (C-7), 104.1 (C-3), 104.9 (C-6), 125.5 (C-l), 127.1 (C-f), 127.6/128.0/128.5/128.8
(C-b, C-c, C-d, C-e, C-h, C-I, C-j, C-k), 132.5 (C-5), 134.2 (C-a), 140.0 (C-g), 159.4 (C-4), 172.7 ppm
(C-2). HRMS calcd. for [C18H15NO2+23Na]+: 300.1000, found: 300.0999.
3-p-Methoxybenzyl-5-p-methoxybenzylidene-4-hydroxy-3-pyrroline-2-one (10): It was derived as a
1
pale yellow solid (from methanol), mp 189–190 °C; H-NMR (DMSO-d6): 3.49 (s, 2H, 7-H), 3.70 (s,
3H, OCH3 [C-l]), 3.77 (s, 3H, OCH3 [C-f]), 6.19 (s, 1H, 6-H), 6.82 (d, 2H, j- and k-H, J = 7.5 Hz),
6.92 (d, 2H, d- and e-H, J = 8.1 Hz), 7.14 (d, 2H, h- and i-H, J = 8.1 Hz), 7.49 (d, 2H, b- and c-H,
13
J = 8.7 Hz), 9.37 (s, 1H, NH), 10.85 ppm (s, 1H, (4)-OH); C-NMR (DMSO-d6): 25.5 (C-7), 55.0
(OCH3 [C-l]), 55.2 (OCH3 [C-f]), 104.4 (C-3), 105.1 (C-6), 113.6 (C-j, C-k), 114.2 (C-d, C-e), 127.0
(C-a), 129.1 (C-b, C-c), 130.5 (C-h, C-i), 130.9 (C-g), 132.3 (C-5), 157.4 (C-4), 158.6 (C-l), 159.2 (C-
f), 172.9 ppm (C-2). HRMS calcd. for [C20H19NO4+23Na]+: 360.1212, found: 360.1221.
3-p-Methoxybenzyl-5-p-methoxybenzylidene-4-methoxy-3-pyrroline-2-one (11): It was derived as a
1
pale yellow solid (from methanol), mp 184–185 °C; H-NMR (DMSO-d6): 3.71 (s, 3H, OCH3 [C-l]),
3.73 (s, 2H, 7-H), 3.78 (s, 3H, OCH3 [C-f]), 3.98 (s, 3H, OCH3 [C-4]), 6.13 (s, 1H, 6-H), 6.86 (d, 2H,
j- and k-H, J = 7.5 Hz), 6.92 (d, 2H, d- and e-H, J = 8.1 Hz), 7.11 (d, 2H, h- and i-H, J = 8.1 Hz), 7.51
(d, 2H, b- and c-H, J = 8.7 Hz), 9.78 ppm (s, 1H, NH); 13C-NMR (DMSO-d6): 26.4 (C-7), 55.0 (OCH3
[C-l]), 55.2 (OCH3 [C-f]), 59.0 (OCH3 [C-4]), 105.7 (C-3), 105.9 (C-6), 113.9 (C-j, C-k), 114.2 (C-d,
C-e), 126.7 (C-a), 128.7 (C-b, C-c), 130.1 (C-g), 130.7 (C-h, C-i), 132.6 (C-5), 157.5 (C-4), 158.7 (C-
l), 159.7 (C-f), 172.6 ppm (C-2). HRMS calcd. for [C21H21NO4+23Na]+: 374.1368, found: 374.1367.
3, 5-Dibenzyl-4-hydroxy-3-pyrroline-2-one (12): It was derived as a pale yellow solid (from methanol),
1
mp 72–73 °C; H-NMR (DMSO-d6): 2.87–3.05 (dd, 2H, 6-H), 3.16/3.22 (2s, 2H, 7-H), 4.17 (br, 1H,
5-H), 6.75 (d, 2H, J = 6.9 Hz), 7.08 (d, 3H, J = 6.6 Hz), 7.21 (m, 5H), 7.34 (s, 1H, NH), 10.81 ppm (s,
1H, (4)-OH). 13C-NMR (DMSO-d6): 26.2 (C-7), 36.5 (C-6), 56.0 (C-5), 104.6 (C-3), 125.1 (C-l), 126.2
(C-f), 127.7 (C-d, C-e, C-j, C-k), 128.1 (C-4), 128.6 (C-i), 129.1 (C-h), 129.7 (C-b, C-c), 136.2 (C-a),
140.1 (C-g), 168.6 ppm (C-2). HRMS calcd. for [C18H17NO2+23Na]+: 302.1157, found: 302.1199.

Molecules 2011, 16
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3, 5-di-p-Methoxybenzyl-4-hydroxy-3-pyrroline-2-one (13): It was derived as a pale yellow solid (from
1
methanol), mp 81–82 °C; H-NMR (DMSO-d6): 2.82–3.96 (dd, 2H, 6-H, J = 9.9 Hz), 3.07/3.12/3.17/
3.23 (4s, 2H, 7-H), 3.67 (s, 3H, OCH3 [C-l]), 3.73 (s, 3H, OCH3 [C-f]), 4.11 (br, 1H, 5-H), 6.61 (s,
4H), 6.77 (d, 2H, J = 8.4 Hz), 7.09 (d, 2H, J = 8.4 Hz), 7.30 (s, 1H, NH), 10.68 ppm (s, 1H, (4)-ΟH).
13C-NMR (DMSO-d6): 25.2 (C-7), 35.4 (C-6), 54.8 (OCH3 [C-l]), 55.0/55.1 (OCH3 [C-f]), 56.0 (C-5),
105.1 (C-3), 113.0/113.1 (C-d, C-e, C-j, C-k), 127.8 (C-a), 128.6 (C-b, C-c), 130.7 (C-h, C-i), 132.0
(C-g), 156.9 (C-l), 157.7 (C-f), 168.3 (C-4), 173.8 ppm (C-2). HRMS calcd. for [C20H21NO4+23Na]+:
362.1368, found: 362.1364.
4. Conclusions
A high efficient ruthenium-catalyzed reduction of the carbon-carbon double bonds of biologically
active arylidene-pyrrolidine-2, 4-diones has been developed. The availability of the substrates and their
remarkable biological evaluation should make this method attractive to synthetic chemists. The
proposed methodology, therefore, represents an efficient and novel catalytic approach to prepare novel
pharmaceutically and biologically valuable specifically functionalized tetramic acids. Further
investigation into related processes and the enantioselective identification are under investigation by
our group.
Acknowledgments
The authors are grateful to Sergey Tunik, Department of Chemistry, St. Petersburg University,
Russia, for providing the ruthenium catalyst. C.K. and D.M. gratefully acknowledge the Committee of
Reasearch of the National Technical University of Athens for a doctoral assistantship. J. M. would like
to thank the National and Kapodistrian University of Athens for financial support (special account for
research grant No. 70 /4/3337).
Conflict of Interest
The authors declare no conflict of interest.
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