New methodology for the synthesis of thiobarbiturates mediated by manganese(III) acetate

Article abstract of DOI:10.3390/molecules17044313

A three step synthesis of various thiobarbiturate derivatives 17-24 was established. The first step is mediated by Mn(OAc)3, in order to generate a carbon-carbon bond between a terminal alkene and malonate. Derivatives 1-8 were obtained in moderate to good yields under mild conditions. This key step allows synthesis of a wide variety of lipophilic thiobarbiturates, which could be tested for their anticonvulsive or anesthesic potential.

Full text of DOI:10.3390/molecules17044313

Molecules 2012, 17, 4313-4325; doi:10.3390/molecules17044313
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
New Methodology for the Synthesis of Thiobarbiturates
Mediated by Manganese(III) Acetate
Ahlem Bouhlel, Christophe Curti and Patrice Vanelle *
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Institut de Chimie Radicalaire
ICR, UMR 7273, Aix-Marseille Univ, CNRS, 27 Bd Jean Moulin, CS 30064,
13385 Marseille Cedex 05, France
* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univ-amu.fr;
Tel.: +33-491-835-580; Fax: +33-491-794-677.
Received: 15 March 2012; in revised form: 30 March 2012 / Accepted: 31 March 2012 /
Published: 10 April 2012
Abstract: A three step synthesis of various thiobarbiturate derivatives 17–24 was
established. The first step is mediated by Mn(OAc)3, in order to generate a carbon-carbon
bond between a terminal alkene and malonate. Derivatives 1–8 were obtained in
moderate to good yields under mild conditions. This key step allows synthesis of a wide
variety of lipophilic thiobarbiturates, which could be tested for their anticonvulsive or
anesthesic potential.
Keywords: manganese(III) acetate; barbiturates; radical
1. Introduction
Manganese(III) acetate has been extensively explored during the past decades, and it remains an
useful tool for carbon-carbon bond formation [1,2]. Its specificity to carbonyl derivatives allows a
wide variety of radical synthetic applications, as studied on acetoacetate [3], -ketoesters [4],
-ketonitriles [5,6] and -ketosulfones [7–9]. Malonate derivatives, key-step substrates for barbiturates
synthesis [10,11], are also useful substrates for manganese(III) acetate-mediated reactions [12,13].
In continuation of our research program centered on the design and synthesis of original molecules
with pharmacological properties [14–18], we propose herein a manganese(III) acetate-mediated
multistep synthesis of new original barbiturates.

Molecules 2012, 17
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Barbiturate derivatives are a well-known pharmacological class with anticonvulsive, sedative and
anesthetic properties [19]. Original barbiturates were also recently reported as matrix metalloproteinase
inhibitors with potent pharmacological applications against focal cerebral ischemia after acute
stroke [20] and cancer cells invasiveness inhibitors [21]. Barbiturate derivatives also show
antitubercular [22], PPAR- agonist [23–25] and protein kinase C inhibitor [26] activities.
The lipophilicity of barbiturates is an important parameter which enhances anesthetic onset [27]. It
can be improved by replacing oxygen by a sulfur [28], as seen with the very short acting barbiturate
thiopenthal. Substituents on the carbons of the barbituric acid scaffold also have a great influence
on the pharmacological activity [27,29]. Our methodology allows synthesis of a wide variety of
substituted barbiturates, which could be tested for their anticonvulsive or anesthetic potentialities.
2. Results and Discussion
Starting from malonate barbiturate precursors, reproducible methodology for synthesis of various and
highly functionalized derivatives was established. As reported in previously described mechanisms [30],
Mn(OAc)3 and malonates in acetic acid form a Mn3+-enolate complex. Mn3+ is reduced in Mn2+,
generating a carbon centered radical between carbonyl groups. This radical reacts with terminal alkene,
generating a carbon-carbon bond.
Depending on the malonate substituent, several reactions may occur and in order to investigate a
larger variety of barbiturate synthesis possibilities, we have studied three of them. Results are reported
in Scheme 1.
Scheme 1. Mn(OAc)3 reactivity towards various malonate derivatives.
Method A : Mn(OAc)3
O
O
O
O
O
O
Method B : Mn(OAc)3
Cu(OAc)2
H3C
H3C
O
CH3
O
R
O
O
CH3
H3C
O
O
CH3
+
+
R
AcOH
R
R
R
R
R
R
R
2 (10-36%)
4 (11-31%)
1 (11-49%)
3 (17-52%)
R
O
O
Mn(OAc)3
Cu(OAc)2
O
O
O
H3C
O
H3C
O
CH3
+
H3C
O
O
O
O
CH3
AcOH
CH3
R
R
5 (47%)
6 (46%)
O
Mn(OAc)3
Cu(OAc)2
O
O
H3C
CH3
+
H3C
O
O
CH3
AcOH
R
R
7 (26%)
8 (68%)
R = -CH3, -(CH2)3 -
As reported by Citterio and coworkers [31–33], benzylmalonate allowed synthesis of two
derivatives: Tetralines 1,3 from radical aromatic substitution, and elimination products 2,4. We have
previously reported different methods for optimizing yields of these two products [34]. For conditions
favoring spirocyclic tetralin 1,3 formation, we divided up the Mn(OAc)3 to ensure moderate oxidizing
conditions (method A). Tetralins 1,3 were obtained as the major compound (49–52%) and alkenes 2,4
were observed as secondary products (10–11%). Stronger oxidative conditions [Cu(OAc)2 + Mn(OAc)3,

Molecules 2012, 17
4315
method B] afforded an increase in elimination products 2,4 (31–36%), while these conditions
drastically decreased yields of tetralines 1,3 (11–17%).
With methyl malonate, only elimination products 5–6 were obtained with moderate yields (46–47%).
With allyl malonate, cyclization generates a cyclopentane ring [35], and annulation products 7–8 were
synthesized (26–68%). These three different reactivities depend on the malonate substituents, and
allow access to a wide variety of substituted substrates for barbiturate synthesis.
C-Functionalized malonates 1–8 thus obtained reacted with thiourea [36], forming thiobarbituric
scaffolds 9–16 in moderate to good yields (46–90%). Results are summarized in Scheme 2 and Table 1.
Scheme 2. Thiobarbituric acid synthesis from malonates 1–8.
S
S
O
O
DMSO
HN
NH
+
H3C
CH3
O
O
H2N
NH2
tBuOK
O
O
R1
R2
R1
R2
1-8
9-16 (46-90%)
Table 1. Thiobarbituric acids 9–16 synthesis from malonates 1–8.
R1,R2 (malonate) Product Yields
Entry
S
O
O
HN
NH
H3C
H3C
H3C
CH3
O
O
O
O
1
2
53%
46%
H3C
1
9
H3C
S
O
O
HN
NH
H3C
O
O
CH3
O
O
CH3
CH3
CH3
O
2a / 2b
CH3
S
10a / 10b
O
HN
O
NH
H3C
CH3
O
O
O
3
4
5
64%
88%
75%
3
11
S
O
O
HN
NH
H3C
O
O
CH3
O
O
4
12
S
O
O
HN
NH
H3C
O
H3C
O
CH3
O
O
H3C
CH3
CH3
CH3
5a / 5b
CH3
13a /13b

Molecules 2012, 17
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Table 1. Cont.
Entry
R1,R2 (malonate)
Product
Yields
S
O
O
HN
NH
H3C
O
H3C
O
CH3
O
H3C
O
6
7
8
90%
6
14
S
O
O
O
HN
O
NH
H3C
O
CH3
O
70%
54%
CH3
CH3
CH3
O
7
CH3
NH
15
S
O
HN
O
H3C
O
O
CH3
O
8
16
Finally, in order to synthesize intravenous administrable thiobarbiturates, each thiobarbituric acid
was turned into the corresponding salt with potassium hydroxide in isopropanol [37], as reported in
Scheme 3.
Scheme 3. Thiobarbituric acid to thiobarbiturate salt formation.
S
S- K+
KOH
HN
NH
HN
N
Isopropanol
O
O
O
O
R1
R2
R1
R2
9-16
17-24
3. Experimental
3.1. General
Microwave-assisted reactions were performed in a multimode microwave oven (ETHOS Synth Lab
Station, Ethos start, Milestone Inc., Shelton, CT, USA). Melting points were determined with
1
13
a B-540 Büchi melting point apparatus. H-NMR (200 MHz) and C-NMR (50 MHz) spectra were
recorded on a Bruker ARX 200 spectrometer in CDCl3 or D2O at the Service interuniversitaire de
RMN de la Faculté de Pharmacie de Marseille. The 1H-NMR chemical shifts are reported as parts per
13
million downfield from tetramethylsilane (Me4Si), and the C-NMR chemical shifts were referenced
to the solvent peaks: CDCl3 (76.9 ppm) or DMSO-d6 (39.6 ppm). Absorptions are reported with the
following notations: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, a more complex
multiplet or overlapping multiplets. Elemental analysis and mass spectra which were run on
an API-QqToF mass spectrometer were carried out at the Spectropole de la Faculté des Sciences
Saint-Jérôme site. Silica gel 60 (Merck, particle size 0.040–0.063 nm, 70–230 mesh ASTM) was used

Molecules 2012, 17
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for flash column chromatography. TLC were performed on 5 cm × 10 cm aluminium plates coated
with silica gel 60 F-254 (Merck, Gernsteim, Germany) in an appropriate solvent.
3.2. General Procedure for the Synthesis of Substituted Malonates 1–8
Method A: A solution of manganese(III) acetate dihydrate (1.68 mmol, 0.45 g) in glacial acetic acid
(55 mL) was heated under microwave irradiation (200 W, 80 °C) for 15 min, until dissolution. Then,
the reaction mixture was cooled down to 60 °C, and a solution of malonate (3.99 mmol, 1 equiv.) and
alkene (11.97 mmol, 3 equiv.) in glacial acetic acid (5 mL) was added. The mixture was heated under
microwave irradiation (200 W, 80 °C) for 20 min. Then, the reaction mixture was cooled down to 60 °C
once more, and a second portion of manganese(III) acetate dihydrate (1.68 mmol, 0.45 g) was added.
The mixture was heated under microwave irradiation (200 W, 80 °C) for 20 min. The addition of
manganese(III) acetate dihydrate (1.68 mmol, 0.45 g) was repeated three times under the same
conditions every 20 min. successively. The reaction mixture was poured into cold water (100 mL), and
extracted with chloroform (3 × 70 mL). The organic extracts were collected, washed with saturated
aqueous NaHCO3 (3 × 50 mL) and brine (3 × 50 mL), dried over MgSO4, filtrated, and concentrated
under vacuum. The crude product was purified by silica gel chromatography with ethyl
acetate/petroleum ether (0.5/9.5) to give corresponding compounds 1–4.
Method B: A solution of manganese(III) acetate dihydrate (8.38 mmol, 2.24 g, 2.1 equiv.) and
copper(II) acetate monohydrate (3.99 mmol, 0.80 g, 1 equiv.) in glacial acetic acid (55 mL) was heated
under microwave irradiation (200 W, 80 °C) for 15 min, until dissolution. Then, the reaction mixture
was cooled down to 60 °C, and a solution of malonate (3.99 mmol, 1 equiv.) and alkene (7.98 mmol,
3 equiv.) in glacial acetic acid (5 mL) was added. The mixture was heated under microwave irradiation
(200 W, 80 °C) for 60 min. The reaction mixture was poured into cold water (100 mL), and extracted
with chloroform (3 × 70 mL). The organic extracts were collected, washed with saturated aqueous
NaHCO3 (3 × 50 mL) and brine (3 × 50 mL), dried over MgSO4, filtrated, and concentrated under
vacuum. The crude product was purified by silica gel chromatography with ethyl acetate/petroleum
ether (0.5/9.5) to give corresponding compounds 1–8.
Diethyl 4,4-diethyl-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (1). Colorless oil; yields: 49%
1
(method A), 11% (method B); H-NMR (CDCl3) H 0.77 (t, J = 7.3, 6H, 2CH3), 1.22 (t, J = 7.2, 6H,
2CH3), 1.52–1.68 (m, 4H, 2CH2), 2.32 (s, 2H, CH2), 3.17 (s, 2H, CH2), 4.08–4.21 (m, 4H, 2CH2),
7.10–7.18 (m, 4H, 4CH). 13C-NMR (CDCl3) C 8.3 (2CH3), 13.8 (2CH3), 33.1 (CH2), 33.3 (2CH2),
35.4 (CH2), 40.2 (C), 52.5 (C), 61.2 (2CH2), 125.5 (CH), 126.2 (CH), 126.5 (CH), 128.6 (CH), 134.2
(C), 141.5 (C), 172.9 (2C). HMRS (ESI): m/z calcd for C20H28O4 [M+H+]: 333.2060. Found: 333.2061.
Diethyl 2-benzyl-2-(2-ethylbut-2-enyl)malonate (2a/2b) (50:50 inseparable mixture of Z/E isomers).
Colorless oil; yields: 10% (method A), 36% (method B); 1H-NMR (CDCl3) H 0.89–0.99 (m, 3H, CH3),
1.12–1.22 (m, 6H, 2CH3), 1.54–1.64 (m, 3H, CH3), 1.93–2.04 (m, 2H, CH2), 2.63 and 2.80 (s, 2H,
CH2), 3.24 and 3.26 (s, 2H, CH2), 4.03–4.15 (m, 4H, 2CH2), 5.26–5.42 (m, 1H, CH), 7.11–7.36 (m,
13
5H, 5CH). C-NMR (CDCl3) C 12.7 (CH3), 12.8 and 13.2 (CH3), 13.8 and 13.9 (2CH3), 23.3 and
29.6 (CH2), 33.5 and 40.6 (CH2), 39.1 and 39.2 (CH2), 58.9 and 59.0 (C), 61.1 (2CH2), 122.2 and

Molecules 2012, 17
4318
123.0 (CH), 126.7 (CH), 128.0 (2CH), 130.1 (2CH), 130.2 (C), 136.8 and 137.3 (C), 171.5 and 171.6
(2C). HMRS (ESI): m/z calcd for C20H28O4 [M+H+]: 333.2060. Found: 333.2063.
Diethyl 2'H-spiro[cyclohexane-1,1'-naphtalene]-3',3'(4'H)-dicarboxylate (3). [34] Colorless oil;
yields: 52% (method A), 17% (method B); 1H-NMR (CDCl3) H 1.22 (t, J = 7.1, 6H, 2CH3), 1.47–1.80
(m, 10H, 5CH2), 2.46 (s, 2H, CH2), 3.19 (s, 2H, CH2), 4.14 (q, J = 7.1, 2H, CH2), 4.15 (q, J = 7.1, 2H,
CH2), 7.10–7.23 (m, 3H, 3CH), 7.35–7.39 (m, 1H, 1CH). 13C-NMR (CDCl3) C 13.9 (2CH3), 21.9
(2CH2), 25.9 (CH2), 34.9 (CH2), 35.6 (CH2), 36.8 (C), 39.6 (2CH2), 52.4 (C), 61.26 (2CH2), 125.8
(CH), 126.1 (CH), 126.5 (CH), 128.7 (CH), 133.4 (C), 144.0 (C), 171.8 (2C). Anal. Calcd for
C21H28O4: C, 73.23; H, 8.19. Found: C, 73.40; H, 8.50.
Diethyl 2-benzyl-2-(cyclohexenylmethyl)malonate (4). [34] Colorless oil; yields: 11% (method A), 31%
(method B); 1H-NMR (CDCl3) H 1.20 (t, J = 7.1, 6H, 2CH3), 1.55–1.59 (m, 4H, 2CH2), 1.90–2.00 (m,
4H, 2CH2), 2.58 (s, 2H, CH2), 3.26 (s, 2H, CH2), 4.12 (q, J = 7.1, 4H, 2CH2), 5.52 (s, 1H, 1CH),
7.11–7.24 (m, 5H, 5CH). 13C-NMR (CDCl3) C 13.9 (2CH3), 22.1 (CH2), 23.0 (CH2), 25.5 (CH2), 29.2
(CH2), 39.0 (CH2), 41.4 (CH2), 58.7 (C), 61.0 (2CH2), 126.4 (CH), 126.7 (CH), 128.0 (2CH), 130.1
(2CH), 133.1 (C), 136.7 (C), 171.4 (2C). Anal. Calcd for C21H28O4: C, 73.23; H, 8.19. Found: C,
72.95; H, 8.35.
Diethyl 2-(2-ethylbut-2-enyl)-2-methylmalonate (5a/5b) (50:50 inseparable mixture of Z/E isomers).
1
Colorless oil; yields: 47% (method B); H-NMR (CDCl3) H 0.81–0.93 (m, 3H, CH3), 1.14–1.21 (m,
6H, 2CH3), 1.27 (s, 3H, CH3), 1.48–1.53 (m, 3H, CH3), 1.65–1.96 (m, 2H, CH2), 2.57 and 2.71 (s, 2H,
13
CH2), 4.04–4.15 (m; 4H, 2CH2), 5.13 and 5.34 (m, 1H, 1CH). C-NMR (CDCl3) C 12.4 (CH3), 12.6
and 12.9 (CH3), 13.7 and 13.8 (CH3), 19.2 and 19.7 (CH3), 22.9 and 29.7 (CH2), 33.6 and 40.8 (CH2),
53.2 and 53.4 (C), 60.9 and 61.0 (2CH2), 122.4 and 123.4 (CH), 136.6 and 136.8 (C), 172.3 and 172.5
(2C). HMRS (ESI): m/z calcd for C14H24O4 [M+H+]: 257.1747. Found: 257.1743.
Diethyl 2-(cyclohexenylmethyl)-2-methylmalonate (6). Colorless oil; yields: 46% (method B); 1H-NMR
(CDCl3) H 1.23 (t, J = 7.1 Hz, 6H, 2CH3), 1.34 (s, 3H, CH3), 1.44–1.58 (m, 4H, 2CH2), 1.73–2.03 (m,
4H, 2CH2), 2.58 (s, 2H, CH2), 4.15 (q, J = 7.1, 2CH2), 5.43 (s, 1H, 1CH). 13C-NMR (CDCl3) C 14.0
(2CH3), 19.9 (CH3), 22.0 (CH2), 22.9 (CH2), 25.4 (CH2), 29.2 (CH2), 43.7 (CH2), 53.3 (C), 61.1
(2CH2), 126.6 (CH), 132.9 (C), 172.6 (2C). HMRS (ESI): m/z calcd for C15H24O4 [M+H+]: 269.1747.
Found: 269.1754.
Diethyl 3,3-diethyl-4-methylenecyclopentane-1,1-dicarboxylate (7). Colorless oil; yields: 26% (method B);
1H-NMR (CDCl3) H 0.79 (t, J = 7.3, 6H, 2CH3), 1.24 (t, J = 7.1, 6H, 2CH3), 1.33–1.41 (m, 4H,
2CH2), 2.29 (s, 2H, CH2), 2.98–3.00 (m, 2H, CH2), 4.17 (q, J = 7.1, 4H, 2CH2), 4.65 (bs, 1H, CH),
4.95 (bs, 1H, CH). 13C-NMR (CDCl3) C 8.6 (2CH3), 14.0 (2CH3), 29.9 (2CH2), 41.8 (CH2), 43.3
(CH2), 48.5 (C), 57.3 (C), 61.4 (2CH2), 106.0 (CH2), 154.8 (C), 172.3 (2C). HMRS (ESI): m/z calcd
for C16H26O4 [M+H+]: 283.1904. Found: 283.1906.
Diethyl 4-methylenespiro[4.5]decane-2,2-dicarboxylate (8). Colorless oil; yields: 68% (method B);
1H-NMR (CDCl3) H 1.22 (t, J = 7.2, 6H, 2CH3), 1.33–1.66 (m, 10H, 5CH2), 2.33 (s, 2H, CH2), 3.01

Molecules 2012, 17
4319
13
(bs, 2H, CH2), 4.15 (q, J = 7.1, 4H, 2CH2), 4.77 (bs, 1H, CH), 4.87 (bs, 1H, CH). C-NMR (CDCl3)
C 13.9 (2CH3), 23.2 (2CH2), 25.8 (CH2), 38.0 (2CH2), 40.8 (CH2), 42.6 (CH2), 45.6 (C), 57.9 (C),
61.4 (2CH2), 104.6 (CH2), 158.4 (C), 172.1 (2C). HMRS (ESI): m/z calcd for C17H26O4 [M+H+]:
295.1904. Found: 295.1903.
3.3. General Procedure for the Synthesis of Thiobarbituric Acids 9–16
Thiourea (1.25 g, 16.38 mmol, 6 equiv.) was added to a solution of malonate 1–8 (2.73 mmol,
1 equiv.) in dry DMSO (3 mL). Then, a solution 1M of potassium tert-butoxide (0.67 g, 6.0 mmol,
2.2 equiv.) was added dropwise. The solution was stirred for 4 h under inert atmosphere and at rt
(starting from malonates 1, 3, 7, 8) or at 50 °C (starting from malonates 2, 4, 5, 6). The solution was
diluted with ethyl acetate (15 mL) and washed with a solution of 1 N hydrochloric acid. The layers
were separated and the aqueous phase was extracted with ethyl acetate. The collected organic phase
was washed with brine, dried over anhydrous Na2SO4, filtered and the solvent was removed in vacuo.
The residue was purified with column chromatography (CH2Cl2/petroleum ether, 8:2), affording the
corresponding thiobarbituric acids 9–16.
4,4-Diethyl-2'-thioxo-3,4-dihydro-1H,2'H-spiro[naphthalene-2,5'-pyrimidine]-4',6'(1'H,3'H)-dione (9).
White solid; m.p. 151 °C (cyclohexane); yields: 53% 1H-NMR (CDCl3) H 0.76 (t, J = 7.4, 6H, 2CH3),
1.67–1.80 (m, 4H, 2CH2), 2.23 (s, 2H, CH2), 3.28 (s, 2H, CH2), 7.12–7.36 (m, 4H, 4CH), 8.99 (bs,
2H). 13C-NMR (CDCl3) C 8.4 (2CH3), 31.5 (2CH2), 34.3 (CH2), 38.2 (CH2), 52.2 (C), 53.4 (C), 126.0
(CH), 126.2 (CH), 126.8 (CH), 128.5 (CH), 132.4 (C), 140.9 (C), 170.4 (2C), 176.0 (C). HMRS (ESI):
m/z calcd for C17H20N2O2S [M+H+]: 317.1318. Found: 317.1317.
5-Benzyl-5-(2-ethylbut-2-enyl)-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (10a/10b) (50:50 inseparable
1
mixture of Z/E isomers). White solid; m.p. 182 °C (cyclohexane); yields: 46% H-NMR (CDCl3) H
0.90–0.99 (m, 3H, CH3), 1.53–1.66 (m, 3H, CH3), 1.85–2.02 (m, 2H, CH2), 2.87 and 3.00 (s, 2H,
CH2), 3.30 and 3.38 (s, 2H, CH2), 5.19–5.30 and 5.41–5.52 (m, 1H, CH), 7.07–7.24 (m, 5H, 5CH),
13
8.84 (bs, 2H). C-NMR (CDCl3) C 12.6 and 13.0 (CH3), 13.4 and 13.7 (CH3), 23.4 and 29.9 (CH2),
39.1 and 44.9 (CH2), 45.0 and 45.2 (CH2), 58.0 and 59.0 (C), 124.6 and 124.8 (CH), 127.9 (CH), 128.9
(2CH), 129.5 and 129.6 (2CH), 134.2 and 134.3 (C), 134.7 and 135.7 (C), 169.6 (2C), 175.3 (C). m/z
calcd for C17H20N2O2S [M+H+]: 317.1318. Found: 317.1323.
2"-Thioxo-2"H,4'H-dispiro[cyclohexane-1,1'-naphtalene-3',5"-pyrimidine]-4",6"(1"H,3"H)-dione (11).
1
White solid; m.p. 200–202 °C (ethyl alcohol); yields: 64% H-NMR (CDCl3) H 1.49–1.84 (m, 10H,
5CH2), 2.35 (s, 2H, CH2), 3.31 (s, 2H, CH2), 7.12–7.41 (m, 4H, 4CH), 9.33 (bs, 2H, 2NH). 13C-NMR
(CDCl3) C 22.0 (2CH2), 25.7 (CH2), 33.6 (CH2), 37.8 (C), 38.1 (2CH2), 38.3 (CH2), 52.2 (C), 125.1
(CH), 126.1 (CH), 127.2 (CH), 128.5 (CH), 132.1 (C), 143.8 (C), 170.2 (2C), 176.0 (C). HMRS (ESI):
m/z calcd for C18H20N2O2S [M+H+]: 329.1318. Found: 329.1317.
5-Benzyl-5-(cyclohexenylmethyl)-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (12). Colorless oil;
yields: 88% 1H-NMR (CDCl3) H 1.35–2.04 (m, 8H, 4CH2), 2.82 (s, 2H, CH2), 3.31 (s, 2H, CH2), 5.50
13
(s, 1H, 1CH), 7.13–7.26 (m, 5H, 5CH), 8.98 (bs, 2H, 2NH). C-NMR (CDCl3) C 21.9 (CH2), 22.8

Molecules 2012, 17
4320
(CH2), 23.6 (CH2), 29.8 (CH2), 44.5 (CH2), 47.6 (CH2), 58.9 (C), 127.7 (CH), 127.8 (CH), 128.8
(2CH), 129.5 (2CH), 131.5 (C), 134.3 (C), 169.7 (2C), 175.4 (C). HMRS (ESI): m/z calcd for
+
C18H20N2O2S [M+NH4 ]: 346.1584. Found: 346.1579.
5-(2-Ethylbut-2-enyl)-5-methyl-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (13a/13b) (50:50 inseparable
1
mixture of Z/E isomers). Colorless oil; yields: 75% H-NMR (CDCl3) H 0.87–0.97 (m, 3H, CH3),
1.54–1.61 (m, 3H, CH3), 1.57 (s, 3H, CH3), 1.80–2.01 (m, 2H, CH2), 2.70 and 2.82 (s, 2H, CH2), 5.18
and 5.47 (m, 1H, CH), 9.05 (bs, 2H, 2NH). 13C-NMR (CDCl3) C 12.6 and 13.0 (CH3), 13.3 and 13.9
(CH3), 23.1 and 23.3 (CH3), 23.5 and 29.9 (CH2), 40.4 and 46.2 (CH2), 51.0 and 51.9 (C), 124.5 and
125.0 (CH), 134.8 and 135.9 (C), 170.5 and 170.6 (2C), 176.0 (C). Anal. Calcd for C11H16N2O2S: C,
54.98; H, 6.71; N, 11.66. Found: C, 55.15; H, 6.86; N, 11.63.
5-(Cyclohexenylmethyl)-5-methyl-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (14). White solid;
1
m.p. 160–164 °C (ethyl alcohol); yields: 90% H-NMR (CDCl3) H 1.37–1.52 (m, 4H, 2CH2), 1.57
(s, 3H, CH3), 1.76–1.98 (m, 4H, 2CH2), 2.65 (s, 2H, CH2), 5.44 (s, 1H, 1CH), 9.61 (bs, 2H, 2NH).
13C-NMR (CDCl3) C 21.8 (CH2), 22.8 (CH2), 23.0 (CH3), 25.4 (CH2), 29.7 (CH2), 48.5 (CH2), 51.8
(C), 127.5 (CH), 131.6 (C), 170.9 (2C), 176.2 (C). HMRS (ESI): m/z calcd for C12H16N2O2S [M+H+]:
253.1005. Found: 253.1007.
2,2-Diethyl-3-methylene-8-thioxo-7,9-diazaspiro[4.5]decane-6,10-dione (15). White solid; m.p.
1
194–196 °C (cyclohexane); yields: 70% H-NMR (CDCl3) H 0.83 (t, J = 7.4, 6H, 2CH3), 1.43–1.70
(m, 4H, 2CH2), 2.27 (s, 2H, CH2), 3.03 (bs, 2H, CH2), 4.77 (bs, 1H, CH), 5.01 (bs, 1H, CH), 8.96 (bs,
2H, 2NH). 13C-NMR (CDCl3) C 8.7 (2CH3), 29.0 (2CH2), 44.4 (CH2), 47.2 (CH2), 49.9 (C), 54.3 (C),
+
107.4 (CH2), 153.4 (C), 170.7 (2C), 176.1 (C). HMRS (ESI): m/z calcd for C13H18N2O2S [M+NH4 ]:
284.1427. Found: 284.1434.
14-Methylene-3-thioxo-2,4-diazadispiro[5.1.5.2]pentadecane-1,5-dione (16). White solid; m.p. 177 °C
(isopropanol); yields: 54% 1H-NMR (CDCl3) H 1.22–1.47 (m, 6H, 2CH3), 1.66–1.77 (m, 4H, 2CH2),
2.33 (s, 2H, CH2), 3.06 (s, 2H, CH2), 4.89–4.93 (m, 2H, CH2), 9.09 (bs, 2H, 2NH). 13C-NMR (CDCl3)
C 23.2 (2CH2), 25.7 (CH2), 37.5 (2CH2), 44.0 (CH2), 45.2 (CH2), 46.8 (C), 55.0 (C), 105.4 (CH2),
+
157.4 (C), 170.7 (2C), 176.2 (C). HMRS (ESI): m/z calcd for C14H18N2O2S [M+NH4 ]: 296.1427.
Found: 296.1422.
3.4. General Procedure for Salification of Barbituric Acids to Barbiturate Potassium Salts 17–24
A suspension of potassium hydroxide (0.02 g, 0.36 mmol, 1 equiv.) in isopropanol (5 mL) was
stirred under inert atmosphere. The corresponding barbituric acid 9–16 (0.36 mmol, 1 equiv.) was
added, and reaction was monitored by TLC until the barbituric acid disappeared. Isopropanol was
removed in vacuo, and corresponding barbiturates 17–24 were obtained without further purification.
Potassium 4,4-diethyl-4',6'-dioxo-1',3,4,6'-tetrahydro-1H,4'H-spiro[naphthalene-2,5'-pyrimidine]-2'-
1
thiolate (17). White solid; m.p. 161–163 °C (isopropanol); yields: 77%; H-NMR (D2O) H 0.72 (s,
3H, CH3), 0.99 (s, 3H, CH3), 1.42–1.79 (m, 4H, 2CH2), 2.38 (d, J = 15.4, 1H, CH2), 2.53 (d, J = 15.4,
1H, CH2), 3.13 (d, J = 16.4, 1H, CH2), 3.40 (d, J = 16.4, 1H, CH2), 7.35–7.41 (m, 4H, 4CH). 13C-NMR

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(D2O) C 8.4 (CH3), 8.5 (CH3), 32.9 (CH2), 35.1 (CH2), 35.2 (CH2), 35.8 (CH2), 41.2 (C), 57.2 (C),
126.5 (CH), 127.0 (CH), 127.9 (CH), 129.1 (CH), 136.2 (C), 142.8 (C), 177.0 (2C), 178.9 (C). HMRS
(ESI): m/z calcd for C17H19N2O2S− M: 315.1173. Found: 315.1183.
Potassium 5-benzyl-5-[2-ethylbut-2-en-1-yl]-4,6-thioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (18a/ 18b)
(50:50 inseparable mixture of Z/E isomers). White solid; m.p. 142–144 °C (isopropanol); yields: 78%;
1H-NMR (D2O) H 0.98–1.05 (m, 3H, CH3), 1.61–1.73 (m, 3H, CH2), 1.93–2.12 (m, 2H, CH2), 2.89
and 3.01 (s, 2H, CH2), 3.28 and 3.38 (s, 2H, CH2), 5.11 and 5.51 (bs, 1H, 1CH), 7.22–7.39 (m, 5H,
13
5CH). C-NMR (D2O) C 12.6 and 12.7 (CH3), 13.2 and 13.3 (CH3), 23.6 and 29.8 (CH2), 39.3 and
44.8 (CH2), 45.0 and 45.9 (CH2), 57.6 (C), 122.7 and 123.8 (CH), 128.0 (CH), 129.1 (2CH), 129.9
(2CH), 135.9 (C), 138.0 (C), 172.9 (C), 179.6 (2C). HMRS (ESI): m/z calcd for C17H19N2O2S− M:
315.1173. Found: 315.1180.
Potassium 4",6"-dioxo-1",6"-dihydro-4'H,4"H-dispiro[cyclohexane-1,1'-naphtalene-3',5"-pyrimidine]-
2"-thiolate (19). White solid; m.p. 216–218 °C (isopropanol); yields: 70%; 1H-NMR (D2O) H 1.38–2.25
(m, 10H, 5CH2), 2.40 (bs, 1H, CH2), 3.08–3.68 (m, 3H, CH2), 7.40–7.58 (m, 3H, 3CH), 7.72–7.78 (m,
1H, 1CH). 13C-NMR (D2O) C 22.1 (CH2), 22.4 (CH2), 26.0 (CH2), 35.8 (CH2), 37.6 (CH2), 37.7 (C),
38.2 (CH2), 42.0 (CH2), 56.9 (C), 126.8 (CH), 127.2 (CH), 127.3 (CH), 129.3 (CH), 135.3 (C), 144.7
(C), 176.5 (C), 178.8 (C), 181.5 (C). HMRS (ESI): m/z calcd for C18H19N2O2S− M: 327.1173. Found:
327.1184.
Potassium 5-benzyl-5-(cyclohex-1-en-1-ylmethyl)-4,6-dioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (20).
1
White solid; m.p. 143 °C (isopropanol); yields: 84% H-NMR (D2O) H 1.36–1.60 (m, 4H, 2CH2),
1.74–2.00 (m, 4H, 2CH2), 2.70 (s, 2H, CH2), 3.18 (s, 2H, CH2), 5.39 (s, 1H, 1CH), 7.06–7.11 (m, 2H,
13
2CH), 7.26–7.30 (m, 3H, 3CH). C-NMR (D2O) C 22.3 (CH2), 23.3 (CH2), 25.7 (CH2), 29.8 (CH2),
45.5 (CH2), 47.6 (CH2), 57.3 (C), 126.2 (CH), 127.8 (CH), 129.1 (2CH), 129.9 (2CH), 134.0 (C),
136.6 (C), 181.5 (2C), 192.6 (C). HMRS (ESI): m/z calcd for C18H19N2O2S− M: 327.1173. Found:
327.1173.
Potassium 5-[2-ethylbut-2-en-1-yl]-5-methyl-4,6-dioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (21a/ 21b)
(50:50 inseparable mixture of Z/E isomers). White solid; m.p. 174–176 °C (isopropanol); yields: 28%
1H-NMR (D2O) H 0.82–0.98 (m, 3H, CH3), 1.32–1.42 (m, 3H, CH3), 1.49–1.56 (m, 3H, CH3),
13
1.76–2.05 (m, 2H, CH2), 2.54–2.69 (m, 2H, CH2), 5.01 and 5.45 (bs, 1H, 1CH). C-NMR (D2O) C
12.8 and 13.0 (CH3), 13.2 and 14.0 (CH3), 21.0 and 22.7 (CH3), 23.7 and 30.2 (CH2), 38.5 and 44.8
(CH2), 56.7 and 57.0 (C), 123.1 and 123.8 (CH), 138.3 and 139.1 (C), 177.8 and 177.9 (C), 180.0 and
180.1 (C), 181.5 and 181.6 (C). HMRS (ESI): m/z calcd for C11H15N2O2S− M: 239.0860. Found:
239.0857.
Potassium 5-(cyclohex-1-en-1-ylmethyl)-5-methyl-4,6-dioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (22).
1
White solid; m.p. 177 °C (isopropanol); yields: 69% H-NMR (D2O) H 1.47 (s, 3H, CH3),
13
1.45–1.61 (m, 4H, 2CH2), 1.84–2.09 (m, 4H, 2CH2), 2.55 (s, 2H, CH2), 5.41 (s, 1H, 1CH). C-NMR
(D2O) C 22.4 (CH2), 22.5 (CH3), 23.3 (CH2), 25.7 (CH2), 29.6 (CH2), 47.4 (CH2), 56.8 (C), 126.7

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(CH), 134.9 (C), 177.9 (2C), 181.6 (C). HMRS (ESI): m/z calcd for C12H15N2O2S− M: 251.0860.
Found: 251.0859.
Potassium 2,2-diethyl-3-methylene-6,10-dioxo-7,9-diazaspiro[4.5]dec-7-ene-8-thiolate (23). White
1
solid; decomp. 270 °C (isopropanol); yields: 88% H-NMR (D2O) H 0.72–0.83 (m, 6H, 2CH3),
1.14–1.53 (m, 4H, 2CH2), 2.27 (s, 2H, CH2), 2.84 (d, J = 16.3, 1H, CH2), 3.04 (d, J = 16.3, 1H, CH2),
4.72 (bs, 1H, CH), 5.01 (bs, 1H, CH). 13C-NMR (D2O) C 8.6 (CH3), 8.7 (CH3), 30.5 (CH2), 31.0
(CH2), 41.7 (CH2), 45.0 (CH2), 49.1 (C), 62.5 (C), 105.8 (CH2), 157.2 (C), 176.7 (C), 179.1 (C), 182.1
(C). HMRS (ESI): m/z calcd for C13H17N2O2S− M: 265.1016. Found: 265.1025.
Potassium 14-methylene-1,5-dioxo-2,4-diazaspiro[5.1.5.2]pentadec-2-ene-3-thiolate (24). White solid;
1
m.p. 174–176 °C (isopropanol); yields: 53% H-NMR (D2O) H 1.13–1.65 (m, 10H, 5CH2), 2.25 (d,
J = 14.0, 1H, CH2), 2.40 (d, J = 14.0, 1H, CH2), 2.88 (d, J = 16.4, 1H, CH2), 3.04 (d, J = 16.4, 1H,
CH2), 4.86 (bs, CH), 4.96 (bs, CH). 13C-NMR (D2O) C 22.8 (CH2), 22.9 (CH2), 37.6 (CH2), 38.6
(CH2), 40.1 (CH2), 44.0 (CH2), 45.7 (C), 62.3 (C), 104.0 (CH2), 160.7 (C), 175.9 (C), 178.3 (C). 1C
not observed in these conditions. HMRS (ESI): m/z calcd for C14H17N2O2S− M: 277.1016. Found:
277.1009.
4. Conclusions
We have synthesized eight new functionalized thiobarbiturates by a three steps synthesis, thanks
to Mn(OAc)3 radical reactivity. This methodology allows C-functionalization of barbituric acid with
a wide variety of scaffolds, such as aromatic, aliphatic and spirocyclic moieties. Derivatives thus
obtained could be tested for their anesthetic potentialities, but also for targeting anticonvulsive leads.
Acknowledgements
This work was supported by the Centre National de la Recherche Scientifique and Aix-Marseille
University. We would like to express our thanks to V. Remusat for recording the NMR spectra and
V. Monnier for recording the mass spectra.
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Sample Availability: Samples of the compounds 6, 8, 10, 15, 17–24 are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).