Synthesis of ( R )-Modafinil via Organocatalyzed and non-Heme Iron Catalyzed Sulfoxidation Using H 2 O 2 as Environmentally Benign Oxidant

1 General Information ................................................................................................................ 2 2 Experimental Procedures, Analytical and Spectroscopic Data................................................ 2 2.1 General Procedure for the Sulfoxidation towards Thioanisole ............................................ 2 2.2 General Procedure for the Sulfoxidation towards (R)-Modafinil using BINOL-phosphate Catalyst V ..................................................................................................................................... 3 2.3 Procedure for the Sulfoxidation towards (R)-Modafinil using Shi’s N-Substituted Oxazolidinone Ketone VIII........................................................................................................... 3 2.4 Procedure for the Sulfoxidation towards (R)-Modafinil using TADOOH .......................... 4 2.5 Procedure for the Sulfoxidation towards (R)-Modafinil using the Fe(III) and Dipeptide Based Chiral Ligand System ......................................................................................................... 4 3 Spectral Data ........................................................................................................................... 5 3.1 1H-NMR (300 MHz, CDCl3) of (Methylsulfinyl)benzene (1a) ........................................... 5 3.2 1H-NMR (300 MHz, CDCl3) of 1-(Methylsulfinyl)-4-nitrobenzene (1b) ........................... 6 3.3 1H-NMR (300 MHz, CDCl3) of 2-(Benzhydrylsulfinyl)acetamide (2) ............................... 6 4 HPLC data ............................................................................................................................... 7


Introduction
Sulfoxides demonstrate versatile properties and are ubiquitous in bioactive compounds and drugs [1].Being of medicinal interest, chiral sulfoxides serve as building blocks for the generation of biologically active compounds [2].With the discovery of their presence in naturally chiral sulfoxide metabolites [3], such as cysteine sulfoxide derivatives, the demand for new synthetic routes was steadily growing, especially since the pioneering work of Kagan and Modena [4][5][6].
Optically active sulfoxides are important representatives of therapeutically used drugs.There are several examples that playing an important role in medicinal and pharmaceutical chemistry [2], including Esomeprazole [7,8], which acts as proton-pump inhibitor; the selective NK 2 antagonist ZD7944 [9]; and the anti-cancer agent Sulindac ® (Figure 1) [10].

Introduction
Sulfoxides demonstrate versatile properties and are ubiquitous in bioactive compounds and drugs [1].Being of medicinal interest, chiral sulfoxides serve as building blocks for the generation of biologically active compounds [2].With the discovery of their presence in naturally chiral sulfoxide metabolites [3], such as cysteine sulfoxide derivatives, the demand for new synthetic routes was steadily growing, especially since the pioneering work of Kagan and Modena [4][5][6].
The fact that there is a continued demand for novel synthetic methods to attain modafinil is further demonstrated by a recently published one-pot parallel synthetic approach [29] as well as another strategy, established by Cibulka and co-workers, employing electron-deficient heteroarenium salts for the activation of hydrogen peroxide [30].
The quantitative potency of the two enantiomers of modafinil, however, is indeed influenced by the stereogenic sulfoxide group.(R)-modafinil has a longer half-life in the human body compared to (S)-modafinil [31], which is metabolized three times faster [32].
An ester, amide, or carboxylic acid moiety close to the sulfide function, however, can adversely affect enantioselectivity [33].Given that no directing group is available adjacent to the sulfur atom, compared, for instance, to omeprazole [7], most known procedures aim to circumvent an enantioselective oxidation.As an alternative, racemic resolution of diastereomers [34,35], preferential crystallization or chiral chromatography can be applied [36].Thus, the variety of enantioselective synthetic approaches is limited to a small selection, namely, a microbial sulfoxidation [37], an advanced Kagan method patented by Cephalon [33], and an oxygen-transfer by a chiral oxaziridine in ionic liquid [38].
These methods, however, suffer from the need for hazardous oxidizing agents, expensive solvents, and metal catalysts.Apart from a vanadium-based catalytic system, developed in our group, which was able to provide (R)-modafinil in excellent yield and moderate enantiomeric excess within a very short reaction time [39], all other attempts making use of convenient metal complexes generally resulted in a drastically decreased performance of the catalyst [38].
For the pharmaceutical industry it is a permanent issue to free biologically active compounds from metal traces.Thus, the development of a metal-free sulfoxidation process is in high demand.
Wang, Tao and co-workers [52] were the first to develop a sulfoxidation reaction catalyzed by BINOL-phosphates, and List et al. [53,54] impressively demonstrated the potential of a new family of chiral phosphoric acids with results analogous to the best obtained with metal catalysts.Having already shown a very good performance in a patented, efficient, and direct route towards Sulindac ® (Figure 1) [53,54], BINOL-derived phosphoric acids have surprisingly never been applied for the enantioselective synthesis of modafinil.
The fact that there is a continued demand for novel synthetic methods to attain modafinil is further demonstrated by a recently published one-pot parallel synthetic approach [29] as well as another strategy, established by Cibulka and co-workers, employing electron-deficient heteroarenium salts for the activation of hydrogen peroxide [30].
The quantitative potency of the two enantiomers of modafinil, however, is indeed influenced by the stereogenic sulfoxide group.(R)-modafinil has a longer half-life in the human body compared to (S)-modafinil [31], which is metabolized three times faster [32].
An ester, amide, or carboxylic acid moiety close to the sulfide function, however, can adversely affect enantioselectivity [33].Given that no directing group is available adjacent to the sulfur atom, compared, for instance, to omeprazole [7], most known procedures aim to circumvent an enantioselective oxidation.As an alternative, racemic resolution of diastereomers [34,35], preferential crystallization or chiral chromatography can be applied [36].Thus, the variety of enantioselective synthetic approaches is limited to a small selection, namely, a microbial sulfoxidation [37], an advanced Kagan method patented by Cephalon [33], and an oxygen-transfer by a chiral oxaziridine in ionic liquid [38].
These methods, however, suffer from the need for hazardous oxidizing agents, expensive solvents, and metal catalysts.Apart from a vanadium-based catalytic system, developed in our group, which was able to provide (R)-modafinil in excellent yield and moderate enantiomeric excess within a very short reaction time [39], all other attempts making use of convenient metal complexes generally resulted in a drastically decreased performance of the catalyst [38].
For the pharmaceutical industry it is a permanent issue to free biologically active compounds from metal traces.Thus, the development of a metal-free sulfoxidation process is in high demand.
Wang, Tao and co-workers [52] were the first to develop a sulfoxidation reaction catalyzed by BINOL-phosphates, and List et al. [53,54] impressively demonstrated the potential of a new family of chiral phosphoric acids with results analogous to the best obtained with metal catalysts.Having already shown a very good performance in a patented, efficient, and direct route towards Sulindac ® (Figure 1) [53,54], BINOL-derived phosphoric acids have surprisingly never been applied for the enantioselective synthesis of modafinil.
Following our previous successes in applying Lewis base/Brønsted acid catalysts for various organic transformations [55][56][57], we decided to test BINOL-phosphates (chiral bifunctional organocatalysts, Scheme 1) and additional catalytic systems.To the best of our knowledge, we present herein the first organocatalyzed synthesis of enantiomerically enriched modafinil via sulfoxidation.
Scheme 1. Proposed Lewis base/Brønsted acid catalysis-BINOL-phosphates as bifunctional organocatalysts in the oxidation of sulfide with hydrogen peroxide as an oxidant.

Materials and Methods
Solvents were purified by standard procedures and distilled prior to use.Reagents obtained from commercial sources were used without further purification.Thin layer chromatography (TLC) chromatography was performed on pre-coated aluminum silica gel ALUGRAM SIL G/UV254 plates (Macherey, Nagel & Co., Düren, Germany).Flash chromatography was performed using silica gel ACROS 60 Å , (particle size 0.035-0.070mm, Thermofischer ACROS Organics, Janssen-Pharmaceuticalaan 3a, 2440 Geel, Belgium).Proton nuclear magnetic resonance spectroscopy ( 1 H-NMR) spectra were recorded in CDCl3 with Bruker Avance 300 or 400 (Bruker, Billerica, MA, USA).Enantioselectivities were determined by chiral high pressure liquid chromatography (HPLC) analysis in comparison with authentic racemic material.

Materials and Methods
Solvents were purified by standard procedures and distilled prior to use.Reagents obtained from commercial sources were used without further purification.Thin layer chromatography (TLC) chromatography was performed on pre-coated aluminum silica gel ALUGRAM SIL G/UV254 plates (Macherey, Nagel & Co., Düren, Germany).Flash chromatography was performed using silica gel ACROS 60 Å, (particle size 0.035-0.070mm, Thermofischer ACROS Organics, Janssen-Pharmaceuticalaan 3a, 2440 Geel, Belgium).Proton nuclear magnetic resonance spectroscopy ( 1 H-NMR) spectra were recorded in CDCl 3 with Bruker Avance 300 or 400 (Bruker, Billerica, MA, USA).Enantioselectivities were determined by chiral high pressure liquid chromatography (HPLC) analysis in comparison with authentic racemic material.

Results and Discussion
Our initial work started with the screening of different BINOL-phosphates for the sulfoxidation of thioanisole as a model reaction.The required organocatalysts I-VII for the reaction were prepared by conventional means [58].
Initially, the reaction was performed in dichloromethane using 20 mol % of the organocatalyst at −10 • C within 24 h.In case of BINOL-phosphate II, only moderate yield was observed (44% yield, entry 1, Table 1) and the enantiomeric excess was rather low (10% ee).A further reduction of the amount of catalyst from 20 mol % to 10 mol % resulted in a decreased yield, but the enantiomeric ratio remained constant (26% yield, 10% ee, entry 2, Table 1).Surprisingly, BINOL-phosphate III provided the corresponding sulfoxide in high yield (98%) with an enantiomeric excess of 20% (entry 3, Table 1) and we continued to investigate catalyst I. To our delight, the enantiomeric excess increased to 36% ee, but the yield was lowered to 68% (entry 4, Table 1).In the case of BINOL-phosphate with a more sterically hindered moiety, a complete loss of activity was the consequence (entry 5, Table 1).With catalyst V, on the other hand, the product could be isolated with 73% yield and an enantiomeric excess of 30% (entry 6, Table 1).Furthermore, carrying out one reaction without an external catalyst, we could preclude a background reaction (entry 7, Table 1).

Results and Discussion
Our initial work started with the screening of different BINOL-phosphates for the synthesis of thioanisole via sulfoxidation as a model reaction.The required organocatalysts I-VII for the reaction were prepared by conventional means [58].
Initially, the reaction was performed in dichloromethane using 20 mol % of the organocatalyst at −10 °C within 24 h.In case of BINOL-phosphate II, only moderate yield was observed (44% yield, entry 1, Table 1) and the enantiomeric excess was rather low (10% ee).A further reduction of the amount of catalyst from 20 mol % to 10 mol % resulted in a decreased yield, but the enantiomeric ratio remained constant (26% yield, 10% ee, entry 2, Table 1).Surprisingly, BINOL-phosphate III provided the corresponding sulfoxide in high yield (98%) with an enantiomeric excess of 20% (entry 3, Table 1) and we continued to investigate catalyst I. To our delight, the enantiomeric excess increased to 36% ee, but the yield was lowered to 68% (entry 4, Table 1).In the case of BINOLphosphate with a more sterically hindered moiety, a complete loss of activity was the consequence (entry 5, Table 1).With catalyst V, on the other hand, the product could be isolated with 73% yield and an enantiomeric excess of 30% (entry 6, Table 1).Furthermore, carrying out one reaction without an external catalyst, we could preclude a background reaction (entry 7, Table 1).
We investigated the oxidation of a thioanisole derivative bearing a nitro moiety in 4-position (entries 8-11, Table 1).We applied BINOL-phosphate VI, and found that the product could be isolated with a low yield of 11% and a moderate enantiomeric excess of 33% (entry 8, Table 1).Carrying out the reaction with a lower amount of hydrogen peroxide (0.27 equivalent) under otherwise identical conditions, the isolated product had a significantly higher enantiomeric excess of 59% (entry 9, Table 1).With catalyst VII, bearing an electron withdrawing substituent on the phenyl moiety in para position, the desired product was generated only in traces (entry 10, Table 1).We investigated the oxidation of a thioanisole derivative bearing a nitro moiety in 4-position (entries 8-11, Table 1).We applied BINOL-phosphate VI, and found that the product could be isolated with a low yield of 11% and a moderate enantiomeric excess of 33% (entry 8, Table 1).Carrying out the reaction with a lower amount of hydrogen peroxide (0.27 equivalent) under otherwise identical conditions, the isolated product had a significantly higher enantiomeric excess of 59% (entry 9, Table 1).With catalyst VII, bearing an electron withdrawing substituent on the phenyl moiety in para position, the desired product was generated only in traces (entry 10, Table 1).
Subsequently, we studied the sulfoxidation of the prochiral sulfide in the presence of 20 mol % of BINOL-phosphate V, which had previously performed best.The reaction proceeded at −10 • C, in CH 2 Cl 2 as a solvent (Table 2).Initially, we applied the optimized reaction conditions, and the product could be isolated after 24 h in quantitative yield with an enantiomeric excess of 10% (entry 1, Table 2) In order to examine the temperature effect on the reaction, we carried out the sulfoxidation at 0 • C. The product was obtained quantitatively but with a slightly lower ee value of 7% (entry 2, Table 2).A shorter reaction time of 12 h resulted in a lower yield of 61%, and no enantioselectivity could be detected (entry 3, Table 2).A higher initial concentration of the sulfide had a positive influence on the stereoselectivity of the oxidation.Thus, following the previous trend concerning the oxidation of thioanisole (entry 9, Table 1), we observed this supporting effect on the reaction outcome for modafinil as well.Due to an accelerated reaction, the desired compound could be isolated in quantitative yield already after 12 h and the ee value slightly increased to 13% (entry 4, Table 2).Subsequently, we studied the sulfoxidation of the prochiral sulfide in the presence of 20 mol % of BINOL-phosphate V, which had previously performed best.The reaction proceeded at −10 °C, in CH2Cl2 as a solvent (Table 2).Initially, we applied the optimized reaction conditions, and the product could be isolated after 24 h in quantitative yield with an enantiomeric excess of 10% (entry 1, Table 2) In order to examine the temperature effect on the reaction, we carried out the sulfoxidation at 0 °C.The product was obtained quantitatively but with a slightly lower ee value of 7% (entry 2, Table 2).A shorter reaction time of 12 h resulted in a lower yield of 61%, and no enantioselectivity could be detected (entry 3, Table 2).A higher initial concentration of the sulfide had a positive influence on the stereoselectivity of the oxidation.Thus, following the previous trend concerning the oxidation of thioanisole (entry 9, Table 1), we observed this supporting effect on the reaction outcome for modafinil as well.Due to an accelerated reaction, the desired compound could be isolated in quantitative yield already after 12 h and the ee value slightly increased to 13% (entry 4, Table 2).
The Shi's N-substituted oxazolidinone ketone VIII belongs to the attractive class of fructosederived asymmetric organocatalysts, generally employed for the epoxidation of unfunctionalized terminal alkenes [59,60].Having successfully applied it to the one-pot, two-step synthesis of βadrenergic blockers via epoxidation as a key enantioselective step [60], we decided to evaluate its activity for the sulfoxidation reaction as well.Modafinil was generated with a yield of 38% and an enantioselectivity of 26% ee (entry 5, Table 2).a Yield of isolated product; b determined by chiral HPLC (AS, n-hexanes/iPrOH (60:40), flow 0.9 mL/min, 25 °C, 31 bar); c T = 0 °C; d c (sulfide) = 0.8 mol/l; e without H2O2, 1.5 equiv of IX, T = −30 o C > room temperature (RT), tetrahydrofuran (THF).For details of the reaction procedures and product characterizations, see Supplementary Information.
In order to minimize the number of reactants, we next intended to combine the oxidizing agent and the chiral source.Therefore, we applied the synthesized chiral hydroperoxide TADOOH IX, which is generally known for its high efficiency for sulfoxidation reactions [61].A striking feature of this method is that no further external catalyst is needed.With an amount of 1.5 equivalent of the oxidant in tetrahydrofuran (THF), the product was generated in 66% yield with an enantioselectivity of 16% (entry 6, Table 2).The Shi's N-substituted oxazolidinone ketone VIII belongs to the attractive class of fructose-derived asymmetric organocatalysts, generally employed for the epoxidation of unfunctionalized terminal alkenes [59,60].Having successfully applied it to the one-pot, two-step synthesis of β-adrenergic blockers via epoxidation as a key enantioselective step [60], we decided to evaluate its activity for the sulfoxidation reaction as well.Modafinil was generated with a yield of 38% and an enantioselectivity of 26% ee (entry 5, Table 2).
In order to minimize the number of reactants, we next intended to combine the oxidizing agent and the chiral source.Therefore, we applied the synthesized chiral hydroperoxide TADOOH IX, which

Scheme 1 .
Scheme 1. Proposed Lewis base/Brønsted acid catalysis-BINOL-phosphates as bifunctional organocatalysts in the oxidation of sulfide with hydrogen peroxide as an oxidant.