Molybdenum-Catalyzed Enantioselective Sulfoxidation Controlled by a Nonclassical Hydrogen Bond between Coordinated Chiral Imidazolium-Based Dicarboxylate and Peroxido Ligands

Chiral alkyl aryl sulfoxides were obtained by molybdenum-catalyzed oxidation of alkyl aryl sulfides with hydrogen peroxide as oxidant in mild conditions with high yields and moderate enantioselectivities. The asymmetry is generated by the use of imidazolium-based dicarboxylic compounds, HLR. The in-situ-generated catalyst, a mixture of aqueous [Mo(O)(O2)2(H2O)n] with HLR as chirality inductors, in the presence of [PPh4]Br, was identified as the anionic binuclear complex [PPh4]{[Mo(O)(O2)2(H2O)]2(μ-LR)}, according to spectroscopic data and Density Functional Theory (DFT) calculations. A nonclassical hydrogen bond between one C–H bond of the alkyl R group of coordinated (LR)− and one oxygen atom of the peroxido ligand was identified as the interaction responsible for the asymmetry in the process. Additionally, the step that governs the enantioselectivity was theoretically analyzed by locating the transition states of the oxido-transfer to PhMeS of model complexes [Mo(O)(O2)2(H2O)(κ1-O-LR)]− (R = H, iPr). The ∆∆G≠ is ca. 0 kcal∙mol−1 for R = H, racemic sulfoxide, meanwhile for chiral species the ∆∆G≠ of ca. 2 kcal∙mol−1 favors the formation of (R)-sulfoxide.


Enantioselective Oxidation of Different Sulfides with Aqueous Hydrogen Peroxide Catalyzed by the System [Mo(O)(O2)2(H2O)n]/HL R /[PPh4]Br
The optimization of the reaction conditions were performed with the (S,S)-HL iPr compound, 1c, and methyl phenyl sulfide, and were previously communicated [42]. Chloroform was used as solvent (1 mL) with a 1:1:0.025:2 ratio of methyl phenyl sulfide:H2O2:Mo-complex:[PPh4]Br. Reactions were carried out in a micro-reactor, at 0 °C during 1 h, on 1 mmol scale. A solution of MoO3 (2.5% mmol) in aqueous hydrogen peroxide, namely [Mo(O)(O2)2(H2O)n] (see Materials and Methods), in conjunction with 1c and tetraphenylphosphonium bromide was employed to in-situ generate the catalyst. In these conditions, a 94% of conversion with high selectivity to sulfoxide (95%) and 40% ee to the (R)-sulfoxide was obtained [42]. A number of additional imidazolium-based zwitterionic dicarboxylic acids were also tested as chiral inductors in the enantioselective oxidation of methyl phenyl sulfide (Table 1). They are derived both from natural α-amino acids of general formula (S,S)-HL R (R = Me, 1b; CH2Ph, 1d; i Bu, 1e, (S)-sec-Bu, 1f) or non-natural α-amino acids, such as (R,R)-HL iPr (1c') and (S,S)-HL tBu (1g) (Scheme 1). They were prepared by condensation of 2 equiv. of the corresponding amino acid with glyoxal and p-formaldehyde in water at 90 °C for one hour, following the procedures described in the literature [45,46]. Additionally, the new compounds (S,S)-HL tBu (1g) and (R,R)-HL iPr (1c') were also straightforwardly obtained in an enantiopure form by the same procedure using the corresponding nonproteinogenic amino acids. Compounds 1g and 1c' were characterized by IR, NMR ( 1 H and 13 C{ 1 H}) and mass spectra (see Materials and Methods and Figures S1-S5 in Supplementary Materials). These compounds were employed to investigate the influence of (i) absence of chirality in the ligand (HL H , 1a); (ii) size and branching of alkyl substituents (1c-e,g); (iii) an additional chiral center (1f); and (iv) a chiral center with opposed sense of chirality (1c vs 1c').

Scheme 1.
Enantioselective sulfoxidation with hydrogen peroxide in the presence of chiral inductors HL R . The optimization of the reaction conditions were performed with the (S,S)-HL iPr compound, 1c, and methyl phenyl sulfide, and were previously communicated [42]. Chloroform was used as solvent ( Materials and Methods), in conjunction with 1c and tetraphenylphosphonium bromide was employed to in-situ generate the catalyst. In these conditions, a 94% of conversion with high selectivity to sulfoxide (95%) and 40% ee to the (R)-sulfoxide was obtained [42]. A number of additional imidazolium-based zwitterionic dicarboxylic acids were also tested as chiral inductors in the enantioselective oxidation of methyl phenyl sulfide (Table 1). They are derived both from natural α-amino acids of general formula (S,S)-HL R (R = Me, 1b; CH 2 Ph, 1d; i Bu, 1e, (S)-sec-Bu, 1f) or non-natural α-amino acids, such as (R,R)-HL iPr (1c') and (S,S)-HL tBu (1g) (Scheme 1). They were prepared by condensation of 2 equiv. of the corresponding amino acid with glyoxal and p-formaldehyde in water at 90 • C for one hour, following the procedures described in the literature [45,46]. Additionally, the new compounds (S,S)-HL tBu (1g) and (R,R)-HL iPr (1c') were also straightforwardly obtained in an enantiopure form by the same procedure using the corresponding nonproteinogenic amino acids. Compounds 1g and 1c' were characterized by IR, NMR ( 1 H and 13 C{ 1 H}) and mass spectra (see Materials and Methods and Figures S1-S5 in Supplementary Materials).

Results and Discussion
These compounds were employed to investigate the influence of (i) absence of chirality in the ligand (HL H , 1a); (ii) size and branching of alkyl substituents (1c-e,g); (iii) an additional chiral center (1f); and (iv) a chiral center with opposed sense of chirality (1c vs 1c'). Br system was effective for the sulfoxidation of methyl phenyl sulfide with conversions ranging from 67%, for 1d (entry 5), to 93-95% for reagents 1a-c, 1f and 1g. In all cases, reactions proceeded with chemoselectivity with nearly quantitative sulfoxide yields. The nature of the chiral inductor HL R clearly controls enantioselectivity. The use of the achiral reagent 1a gave the expected racemic mixture (entry 1). When reagents 1b-g were employed, it was observed that an increase in the branching at the C α atom of the R group of the ligand seemed to have a beneficial effect on the enantioselectivity. Specifically, reactions performed with chiral ligands with unbranched alkyl groups, such as 1b and 1d (entries 2 and 5, respectively), gave rise to low ee values of 2% and 5%, respectively. Conversely, the use of ligands with branched alkyl groups, such as 1c, 1f and 1g (entries 3, 7 and 8, respectively), produced ee values higher than 30%. The highest ee was observed with the reagent 1f (47% ee) in which the additional chiral center could have a positive effect in the enantioselectivity. Importantly, the reaction performed with (R,R)-HL iPr (1c') (entry 4) gave an ee result comparable to that of its (S,S)-enantiomer, 1c, only with opposed sense of sulfoxide chirality. The adequate selection of the HL R inductor chirality controls the production of the sulfoxide enantiomer. Finally, the activity of the system was tested with other sulfide substrates using compound 1f as chiral inductor (entries 9-15). In general, good conversions and enantioselectivities close to 50% for the corresponding (R)-sulfoxide were found, with the exception of the sulfide Ph(HOCH 2 CH 2 )S, which showed lower values (29% sulfoxide yield and 43% ee for the (S) enantiomer, entry 13). Conversions obtained with 1f were similar to those found with 1c [42], but enantioselectivity values were slightly superior using 1f than 1c for the same substrates [42].
One equivalent of hydrogen peroxide per substrate was used in all experiments because formation of the corresponding sulfone was observed when two or more equivalents of the oxidant were employed [42,43]. As we previously communicated, the ee can be increased by kinetic resolution and the (R)-sulfoxide PhMeSO was obtained in 83% ee with a 1.6-fold excess of the oxidant [42]. To probe the kinetic resolution process in more detail, we performed the oxidation of racemic PhMeSO sulfoxide, under the same reaction conditions, varying the oxidant-to-substrate ratio ( Figure 1). From the analysis of the variation of the enantiomeric excess with respect to the conversion of sulfoxide, it was possible to determinate a stereoselectivity factor E of 2.8 (E = kS'/kR', see Supplementary Materials for details) [47]. Therefore, one may conclude that the enantiomeric excess of the sulfoxide can be controlled by adjusting the degree of conversion (at the expense of the sulfoxide yield).
probe the kinetic resolution process in more detail, we performed the oxidation of racemic PhMeSO sulfoxide, under the same reaction conditions, varying the oxidant-to-substrate ratio ( Figure 1). From the analysis of the variation of the enantiomeric excess with respect to the conversion of sulfoxide, it was possible to determinate a stereoselectivity factor E of 2.8 (E = kS'/kR', see Supplementary Materials for details) [47]. Therefore, one may conclude that the enantiomeric excess of the sulfoxide can be controlled by adjusting the degree of conversion (at the expense of the sulfoxide yield).     [48].

Nature of the Molybdenum Catalyst and Origin of the Enantioselectivity
In order to support the formulation of the Mo catalyst, the activity of the isolated complex Na{[Mo(O)(O 2 ) 2 (H 2 O)] 2 (µ-L iPr )} was tested in the sulfoxidation reaction of methyl phenyl sulfide, under the optimized reaction conditions. The conversion (93%) and ee (42%) values achieved were completely similar to those observed when the catalytic species was in-situ formed [42], thus proving the nature of the catalyst as a binuclear In order to support the formulation of the Mo catalyst, the activity of the isolated complex Na{[Mo(O)(O2)2(H2O)]2(μ-L iPr )} was tested in the sulfoxidation reaction of methyl phenyl sulfide, under the optimized reaction conditions. The conversion (93%) and ee (42%) values achieved were completely similar to those observed when the catalytic species was in-situ formed [42], thus proving the nature of the catalyst as a binuclear {[Mo(O)(O2)2(H2O)]2(μ-L R )} − oxidodiperoxidomolybdenum(VI) species.  Table 2 and optimized structures in Figure S10 in Supplementary Materials). Compounds {[Mo(O)(O2)2(H2O)]2(μ-L R )} − (R = i Pr, 2c; i Bu, 2e; sec Bu, 2f; and t Bu, 2g) display C-H···O distances within the range 2.50-2.66 Å and C-H···O angles higher than 160° (Table 2), which are typical parameters of nonclassical C-H···O hydrogen bonds (cut-off values of distances <2.8 Å and angles >90°) [52][53][54]. Interestingly, these compounds are those in which an asymmetric process is observed (inductors 1c,e-g in Table 1), while for compounds without the C-H···O interaction, low or null activity is found (inductors 1a,b,d in Table 1).   Table 2 and optimized structures in Figure S10 (Table 2), which are typical parameters of nonclassical C-H···O hydrogen bonds (cut-off values of distances <2.8 Å and angles >90 • ) [52][53][54]. Interestingly, these compounds are those in which an asymmetric process is observed (inductors 1c,e-g in Table 1), while for compounds without the C-H···O interaction, low or null activity is found (inductors 1a,b,d in Table 1). With the aim of confirming that these interactions are responsible of the asymmetry, we have for simplicity only one molybdenum atom, and studied the step that controls the enantioselectivity. This is the oxido-transfer step, which follows a Sharpless-type outer-sphere concerted mechanism according to previous studies [43]. The oxygen atom transfer is produced by the nucleophilic attack of sulfide onto the peroxide ligand that cleaves The calculated ∆∆G = of ca. 2 kcal·mol −1 is well suited for the asymmetric process observed using 1c (entry 3, Table 1). With the aim of confirming that these interactions are responsible of the asymmetry, we have selected the model complexes [Mo(O)(O2)2(H2O)(κ 1 -O-L R )] − (R = H, 3a, and i Pr, 3c), containing for simplicity only one molybdenum atom, and studied the step that controls the enantioselectivity. This is the oxido-transfer step, which follows a Sharpless-type outer-sphere concerted mechanism according to previous studies [43].  Table 1). By contrast, for chiral [Mo(O)(O2)2(H2O)(κ 1 -O-L iPR )] − species, 3c, there are two transition states, those that yield the R sulfoxide TS_c1 and TS_c4, showing lower energies than TS_c2 and TS_c3 that afford the S sulfoxide. The calculated ∆∆G ≠ of ca. 2 kcal•mol −1 is well suited for the asymmetric process observed using 1c (entry 3, Table 1).

General
Synthetic reactions were carried out under aerobic conditions. Chemicals were obtained from commercial sources and used as supplied, while solvents were appropriately purified using standard procedures. Infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrum Two spectrophotometer (pressed KBr pellets). NMR spectra were recorded at the Centro de Investigaciones, Tecnología e Innovación (CITIUS) of the University of Sevilla by using Bruker AMX-300 or Avance III spectrometers with 13 C{ 1 H} and 1 H shifts referenced to the residual solvent signals. All data are reported in ppm downfield from Si(CH3)4. The gas chromatograms (GC) were obtained using a Varian Chromatogram CP-3800 with nitrogen as the carrier gas. The chromatogram used a

General
Synthetic reactions were carried out under aerobic conditions. Chemicals were obtained from commercial sources and used as supplied, while solvents were appropriately purified using standard procedures. Infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrum Two spectrophotometer (pressed KBr pellets). NMR spectra were recorded at the Centro de Investigaciones, Tecnología e Innovación (CITIUS) of the University of Sevilla by using Bruker AMX-300 or Avance III spectrometers with 13 C{ 1 H} and 1 H shifts referenced to the residual solvent signals. All data are reported in ppm downfield from Si(CH 3 ) 4 . The gas chromatograms (GC) were obtained using a Varian Chromatogram CP-3800 with nitrogen as the carrier gas. The chromatogram used a Varian automatic injector, model CP-8410, flame ionization detector (FID), and an Agilent column, model CP-7502. The HPLC chromatograms were performed on an Agilent 1260 Infinity instrument with a Chiralpak IA column at a flow rate of 1.0 mL/min with AcOEt/heptane = 6/4 (v/v) and using a UV detector at 254 nm. For Ph(HOCH 2 CH 2 )SO sulfoxide, a flow rate of 0.5 mL/min with heptane/ i PrOH = 9/1 (v/v) was employed. The absolute configuration (reported in Table 1) was determined by comparing HPLC elution orders and the sign of the specific rotations with the literature data [14,15]. Polarimetry was carried out using a JASCO P-2000 Digital Polarimeter and the measurements were made at ca. 25 • C (concentration of ca. 10 mg/mL). High-resolution mass spectra (HRMS) were carried out by using a Q-Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer from Thermo Scientific at the CITIUS of the University of Sevilla.

Synthesis of Chiral Imidazolium-Based Zwitterionic Dicarboxylic Acids HL R
The syntheses of compounds (S,S)-HL R (1a-f) have been previously described [45,46] and they were identified by comparison of their IR, NMR ( 1 H and 13 C{ 1 H}) and mass spectra with those previously reported (see Figure S6, Supplementary materials).

Preparation and Titration of [Mo(O)(O 2 ) 2 (H 2 O) n ] Solution
Solutions of the aqua complex of oxidodiperoxidomolybdenum in aqueous hydrogen peroxide were prepared as previously described [55]. For the purpose of simplicity the solution is referred to in this work simply as aqueous The resulting aqueous solution of molybdenum complex has an excess of hydrogen peroxide. The addition of the 0.025 mmol of molybdenum species in the catalytic essays includes a supplementary amount of oxidant. In order to avoid the formation of sulfone product, one equivalent of 30% hydrogen peroxide per sulfide substrate should be used.    The reactor was sealed and maintained at the working temperature, with constant stirring (600 rpm) in a thermostatted bath for the duration of the reaction. Upon completion, the reaction mixture was treated with diethyl ether (10 mL) and then filtered with 0.45 µm nylon syringe filter. The resulting solution was analyzed by GC (by adding 50 µL of dodecane as the internal standard). Afterwards the solution was evaporated to dryness by using a rotavap. The resulting residue was then analyzed by HPLC (by adding 20 mL of ethyl acetate).  H, 3a, and i Pr, 3c) were computed using density functional theory at the B3LYP level [56,57]. The Mo atom was described with the LANL2DZ basis set [58,59] while the 6-31G(d,p) basis set was used for the C, N, O, S and H atoms. The transition states of the interaction of PhMeS with 3a and 3c, namely TSa1-4 and TSc1-4, were located at the same level of theory. Geometries of all model complexes were optimized without symmetry constraints. Frequency calculations were carried out at the same level of theory to identify all of the stationary points as transition states (one imaginary frequency) or as minima (zero imaginary frequencies) and to provide the thermal correction to free energies at 298.15 K and 1 atm. The DFT calculations were performed using the Gaussian 09 suite of programs [60]. Coordinates of the optimized compounds are collected in Table S4 (Supplementary Materials).

Conclusions
A simple process for the enantioselective Mo-catalyzed sulfoxidation with aqueous hydrogen peroxide, by using imidazolium-based dicarboxylate compounds HL R , 1b-g, as chiral inductors, has been developed. The advantages of this system are: (i) better reaction times (1 h Figure S7: calculated IR spectrum of 2c, Figures S7 and S8: determination of the stereoselectivity factor, Figures S10 and S11: optimized structures of transition states and compounds 2, Figure S12: selected chiral HPLC diagrams of optical active sulfoxides, Table S1: energies of the transition states for the oxido-transfer, and Table S2: Coordinates of the optimized structures.