New Methodology for the Synthesis of Thiobarbiturates Mediated by Manganese(III) Acetate

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.

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.

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 Mn 3+ -enolate complex. Mn 3+ is reduced in Mn 2+ , generating a carbon centered radical between carbonyl groups. This radical reacts with terminal alkene, generating a carbon-carbon bond.

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 a B-540 Büchi melting point apparatus. 1 H-NMR (200 MHz) and 13 C-NMR (50 MHz) spectra were recorded on a Bruker ARX 200 spectrometer in CDCl 3 or D 2 O at the Service interuniversitaire de RMN de la Faculté de Pharmacie de Marseille. The 1 H-NMR chemical shifts are reported as parts per million downfield from tetramethylsilane (Me 4 Si), and the 13 C-NMR chemical shifts were referenced to the solvent peaks: CDCl 3 (76.9 ppm) or DMSO-d 6 (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 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.

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 NaHCO 3 (3 × 50 mL) and brine (3 × 50 mL), dried over MgSO 4 , 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.

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.

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.