An interesting sidetrack in the tofisopam synthesis: lithium variant of a stereospecific Oppenauer oxidation

In the course of the elaboration of a new manufacturing process of anxiolytic drug tofisopam, a stereospecific lithium-catalyzed Oppenauer-type oxidation was observed. Bromine-lithium exchange on the ethylene ketal of 3-(2-bromo-4,5-dimethoxyphenyl)pentan-2-one followed by quenching with 1 equivalent of 3,4-dimethoxybenzaldahyde gave the corresponding alcohols as a mixture of two diastereomeric racemates. On the other hand, when 2.5 equivalents of the aldehyde were applied, only one of the two alcohol diastereomers could be isolated. The lithium alkoxide precursor of the other diastereomeric alcohol, due to the presence of the excess of benzaldehyde as the oxidant, underwent an Oppenauer-type oxidation to give the corresponding ketone.


Introduction
Tofisopam (1, marketed under brand names Grandaxin ® and Emandaxin ® ) is a 2,3benzodiazepine type anxiolytic drug.Its psychopharmacological and clinical profile differ from the widely used 1,4-benzodiazepines, since in contrast to those, tofisopam does not bind to the distinct benzodiazepine binding site of the GABA A (γ-aminobutyric acid) receptor.It is an anxiolytic agent without addiction potential, [2][3][4] and without the sedative-hypnotic, muscle relaxant and anticonvulsive side effects generally associated with the use of 1,4-benzodiazepines.

Results and Discussion
In the course of our efforts aiming at the elaboration of new manufacturing processes for the synthesis of tofisopam (1), we decided to study a similar route starting from bromo-ketal 7 using lithiation chemistry.Quenching of the lithio species, obtained from bromo-ketal 7 by treatment with butyllithium at -78 °C with 1 equivalent of 3,4-dimethoxybenzaldehyde gave, via diastereomeric lithium alkoxides 13A and 13B, a crude product containing diastereomeric racemates 12A and 12B in a ratio of 1:1.1 (Scheme 3, route A).After chromatographic work-up, 12A and 12B were obtained in 38% and 42% yields, respectively.Since the absolute configuration of the diastereomers is not known, they are characterized by the 1 H NMR chemical shift of the methyl group marked on Scheme 3.

Scheme 3
In the course of the optimization of the excess of 3,4-dimethoxybenzaldehyde to be used in the reaction, we observed the formation of ketone 8 in addition to the alcohols 12 (Scheme 3, route B).Obviously, the excess of benzaldehyde oxidizes the primarily formed lithium alkoxide to ketone 8 in an Oppenauer oxidation process. 16,17In the classical Oppenauer oxidation, aluminum isopropoxide is used as the catalyst and acetone as the oxidant.Later on, metal ions other than aluminum and various aldehydes and ketones as oxidants have also been reported.Nevertheless, the only lithium-catalyzed process was disclosed by Capilla et al: lithiation of bromo derivative 14 followed by reaction with ca. 4 equivalent of 3,4,5-trimethoxybenzaldehyde gave benzophenone 15 in 71% yield (Scheme 4). 18The authors remarked that attempts to isolate alcohol 16 failed due to the fast oxidation of the lithium salt of 16 to ketone 15, however, they did not comment on the mechanism of this unique lithium-catalyzed Oppenauer oxidation.

Scheme 4
The magnesium variant of the Oppenauer oxidation was studied in detail (Scheme 5). 19nterestingly, the presence of LiCl in the reaction mixture considerably accelerated the oxidation reaction.It was suggested that the role of LiCl was both to solubilise the primarily formed magnesium chloride alkoxide and to activate the carbonyl function of benzaldehyde as a Lewis acid.Our attempts to achieve full conversion of alcohols 12 to ketone 8, by using a large excess of 3,4-dimethoxybenzaldehyde for quenching the lithium derivative, failed.Finally we realized that under these conditions only one of the diastereomeric alcohols 12 could be oxidized to ketone 8 by the excess of the benzaldehyde.When adding 2.5 equivalents of 3,4-dimethoxybenzaldehyde to the lithiated derivative of bromo-ketal 7, in addition to ketone 8 (43%), pure unchanged alcohol 12B was also isolated in 35% yield.Thus, we are facing a stereospecific Oppenauer oxidation in this case.
The stereochemistry of the Meerwein-Ponndorf-Verley reductions of ketones and complementary Oppenauer oxidations (MPVO reactions) using optically active alcohols as chiral sources has been extensively studied. 20High stereoselectivities have been mostly observed in intramolecular MPVO reactions, 21 as illustrated by an example in Scheme 6. 22

O
A stereospecific Oppenauer oxidation, similar to our case, was observed when a practically equimolar mixture of cis-and trans-4-tert-butylcyclohexanol was treated with acetone as the oxidant in the presence of zeolite beta polymorph A (BEA) catalyst.Only the cis isomer was converted to the corresponding ketone, the trans isomer remained unchanged (Scheme 7). 23It appears that the required six-membered transition state, involving a Lewis acid aluminum site in the walls of the micropores of the catalyst, can be formed substantially easier with the cis-alcohol than with the trans one (transition state selectivity).

Scheme 7
The explanation of our observation may also lay in the strict steric requirements of the Oppenauer oxidation.From the diastereomeric lithium salt 13A, which leads to 12A in the absence of excess aldehyde, an oxidation occurs with the excess aldehyde to give ketone 8 via the six-membered transition state coordinated by the lithium ion (

Scheme 8
We suppose that in the lithium salt 13B, leading to diastereomer 12B, the required sixmembered ring transition state can not be formed, probably because the Li + primarily attached to the alkoxide is intramolecularly "captured" by the oxygen atoms of the ketal moiety, 24  Although lithium alkoxide 13B can not be oxidized to ketone 8 with excess 3,4dimethoxybenzaldehyde under the Oppenauer conditions, the oxidation of the corresponding alcohol 12B with PDC proceeds in high yield (89%) in dichloromethane.The analogous PDC oxidations starting from the other diastereomer racemate (12A) or from the mixture of 12A and 12B (ratio: 1:1.1) have also been carried out affording tofisopam intermediate 8 in high yields (85 and 88%, respectively).Keto-ketal 8 can be transformed to tofisopam (1) as described in our earlier publication. 14omputational studies for the explanation of the stereospecific character of the Oppenauer oxidation discussed above, together with efforts to assign the absolute configuration of diastereomers 12A and 12B are in progress.

Conclusions
A new manufacturing process of anxiolytic drug tofisopam was elaborated.Bromine-lithium exchange on ethylene ketal of 3-(2-bromo-4,5-dimethoxyphenyl)pentan-2-one (7) followed by reaction with 1 equivalent of 3,4-dimethoxybenzaldahyde gave a mixture of diastereomeric alcohols (12A and 12B racemates), which can be oxidized with pyridinium dichromate to the known keto-ketal key intermediate 8 of tofisopam (1).This approach also uses an environmentally hazardous chromium reagent, although in much smaller quantity than the widely applied process based on the CrO 3 oxidation of diisohomoeugenol.
On the other hand, when 2.5 equivalents of the aldehyde were applied in the reaction with the lithium derivative of compound 7, only one of the two alcohol diastereomers could be isolated.The lithium alkoxide precursor of the other diastereomeric alcohol, due to the presence of the excess of benzaldehyde as the oxidant, underwent a fully stereospecific Oppenauer-type oxidation to give the corresponding keto-ketal 8. Similar lithium-catalyzed Oppenauer oxidations are very scarcely investigated in the literature.

Experimental Section
General.All melting points were determined on a Büchi 535 capillary melting point apparatus.IR spectra were obtained on a Bruker ALPHA-T FT spectrometer as neat. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance III 400 spectrometer (400 and 100 MHz for 1 H and 13 C NMR nuclei, respectively).DMSO-d 6 was used as solvent and tetramethylsilane (TMS) as internal standard.Chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively.Elemental analyses were performed on a Perkin-Elmer 2400 analyzer.The reactions were followed by analytical thin layer chromatography on silica gel 60 F 254 .All unspecified reagents were purchased from commercial sources.7) and subsequent reaction with 3,4-dimethoxybenzaldehyde. Procedure A (utilizing 1 equivalent of 3,4-dimethoxybenzaldehyde): The solution of 2-[1-(2-bromo-4,5-dimethoxyphenyl)propyl]-2methyl-1,3-dioxolane (7, 17.26 g, 50.00 mmol) in anhydrous tetrahydrofuran (170 mL) was cooled to -78 °C, then butyllithium (2.5 M solution in hexanes, 24 mL, 60 mmol) was added under stirring over a period of 45 min.The mixture was stirred at -78 °C for further 1 h, then 3,4-dimethoxybenzaldehyde (8.31 g, 50.0 mmol) was added.The stirring was continued for 20 min at -78 °C, then the temperature of the reaction mixture was allowed to rise to 0 °C.A saturated NH 4 Cl solution (150 mL) was added.After stirring for 10 min at 0 °C the mixture was extracted with ethyl acetate (2×200 mL).The organic layer was washed with brine, dried over MgSO 4 , filtered and evaporated.The residue was purified by column chromatography using hexane-ethyl acetate (7:3) as the eluent.