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Full PaperReceived: 21 September 2010 Revised: 4 November 2010 Accepted: 10 November 2010 Published online in Wiley Online Library: 9 February 2011

(wileyonlinelibrary.com) DOI 10.1002/aoc.1762

Asymmetric oxidation of sulfides with H2O2catalyzed by titanium complexes of Schiffbases bearing a dicumenyl salicylidenyl unitYing Wanga, Mei Wanga∗, Lin Wanga, Yu Wanga, Xiuna Wanga

and Licheng Suna,b∗ ∗

The sterically hindered Schiff bases (L3 –L5), prepared from 3,5-dicumenyl salicylaldehyde and chiral amino alcohols, wereused in combination with Ti(OiPr)4 for asymmetric oxidation of aryl methyl sulfides with H2O2 as terminal oxidant. Amongthe ligands L3 –L5, L4 with a tert-butyl group in the chiral carbon of the amino alcohol moiety gave the best result with 89%yield and 73% ee for the sulfoxidation of thioanisole under optimal conditions [with 1 mol% of Ti(OiPr)4 in a molar ratioof 100 : 1 : 1.2 : 120 for sulfide : Ti(OiPr)4 : ligand : H2O2 in CH2Cl2 at 0 ◦C for 3 h]. The reaction afforded good yield (84%) witha moderate enantioselectivity (62% ee) even with a lower catalyst loading from 1.0 to 0.5 mol%. The oxidations of methyl4-bromophenyl sulfide and methyl 4-methoxyphenyl sulfide with H2O2 catalyzed by the Ti(OiPr)4 –L4 system gave 79–84%yields and 54–59% ee of the corresponding sulfoxides in CH2Cl2 at 20 ◦C. The chiral induction capability of the cumenyl-modifiedsterically hindered Schiff bases for sulfoxidation was compared with the conventional Schiff bases bearing tert-butyl groups atthe 3,5-positions of the salicylidenyl unit. Copyright c© 2011 John Wiley & Sons, Ltd.

Supporting information may be found in the online version of this article.

Keywords: asymmetric catalysis; chiral sulfoxides; dicumenyl salicylaldehyde; Schiff bases; titanium

Introduction

Enantiopure sulfoxides are useful auxiliaries and synthons in asym-metric synthesis.[1] In recent years, chiral sulfoxides are findingincreasing use as bioactive ingredients in the pharmaceutical in-dustry because of the special biological property of the chiral drugscontaining a sulfinyl group with a defined configuration.[2] Themost challenging approach to enantiopure sulfoxides is transitionmetal-catalyzed asymmetric oxidation of sulfides. In 1984, Kaganand Modena independently discovered that prochiral sulfidescould be effectively oxidized to chiral sulfoxides with good-to-high enantioselectivity by modified Sharpless catalytic systemscomprising Ti(OiPr)4 –chiral tartrate–alkyl hydroperoxide.[3] Thismethod has been successfully used in preparation of the drug es-omeprazole, the active ingredient in AstraZeneca’s antiulcer drugNexium.[4] The disadvantages of this method are the sensitivityof the titanium-based catalyst system to moisture, low turnovernumbers (4–16 mol% of the catalyst required), low chemoselec-tivity, and the use of expensive and toxic aryl hydroperoxides suchas cumene hydroperoxide (CHP) as oxidants.[5] Development ofmore active, highly chemo- and enantioselective, robust, cheapand environmentally benign catalyst systems has been one of theattractive topics in the field of asymmetric catalysis in the pasttwo decades. Various catalyst systems for asymmetric oxidation ofsulfides have been reported, such as Ti-BINOL,[6] -salen,[7] -salan,[8]-C2-symmetric diol[9] and -Schiff base,[10] Zr-trialkanol amine,[11]

Mn-salen,[12] V-[13] and Fe-Schiff base,[14] Al-salan[15] and organiccatalysts.[16] In recent years, the research in this field has mainlyfocused on the titanium- and vanadium-based catalyst systems.

Bolm’s catalyst systems of VO(acac)2-Schiff bases have beenextensively studied since 1995 because of the advantages of

the systems: (1) good-to-high enantioselectivity; (2) the simplicity,convenient preparation and easy modification of chiral Schiff baseligands; (3) the utilization of cheap and environmentally benignterminal oxidant (H2O2); and (4) the facile reaction conditionsand easy workup.[13a] However, vanadium-based catalysts are notdesirable from the environmental point of view. Catalyst systemsbased on nontoxic metals such as titanium and iron with ‘green’oxidant H2O2 are of particular interest. Bolm and co-workersreported that the iron-based catalyst system of Fe(acac)3-Schiffbases could catalyze the oxidation of sulfides using H2O2 asoxidant in the presence of certain acids or carboxylates, givingsulfoxides in 36–78% yields and 66–96% ee.[14c] The other iron-based catalyst is an Fe(salan) complex bearing additional chiralcenters in aromatic rings, which displayed enantioselectivity up to96% ee with 72–90% yields for sulfoxidation of sulfides with H2O2

in water. Synthesis of such salan ligands with additional elements

∗ Correspondence to: Mei Wang, State Key Laboratory of Fine Chemicals, DUT-KTH Joint Education and Research Center on Molecular Devices, DalianUniversity of Technology (DUT), Dalian 116012, P. R. China.E-mail: symbueno@dlut.edu.cn

∗∗ Licheng Sun, State Key Laboratory of Fine Chemicals, Dalian University ofTechnology, Zhongshan Road 158-46, Dalian 116012, P. R. China.E-mail: lichengs@kth.se

a State Key Laboratory of Fine Chemicals, DUT-KTH Joint Education and ResearchCenter on Molecular Devices, Dalian University of Technology (DUT), Dalian116012, P. R. China

b Department of Chemistry, Royal Institute of Technology (KTH), 10044Stockholm, Sweden

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Figure 1. Efficient iodo-functionalized chiral Schiff bases used in Bolm’scatalyst systems.

chirality is difficult.[17a] With easily prepared salen ligands, theenantioselectivity of the iron-based catalyst systems decreased to64% ee.[17b]

Conventional titanium-based catalyst systems need alkyl oraryl hydroperoxides as terminal oxidants to form sulfoxides inhigh enantioselectivity. The first example of the titanium-basedsystems using H2O2 as oxidant for asymmetric oxidation of sulfideswas reported by Pasini in 1986, which gave a low enantioselectivity(<20% ee).[7a] Similarly, low enantioselectivity (10% ee) wasobtained even with a mononuclear titanium salen complexbearing additional elements of chirality in the salen ligand,while the corresponding di-µ-oxo binuclear titanium complex incombination with a complicated salen ligand containing additionalchiral elements displayed good-to-high enantioselectivity (up to99% ee) and 78–92% yields of chiral sulfoxides for the oxidationof aryl methyl sulfides with H2O2.[7b] Furthermore, Ti(OiPr)4

in combination with the N-salicylidene-L-aminoalcohol-derivedSchiff bases, which were usually adopted in vanadium-basedBolm’s catalyst systems, proved to be highly active for oxidationof sulfides with H2O2.[10] These titanium-based catalyst systemsdisplayed good chemoselectivity (up to 97%) but only low-to-moderate enantioselectivities, up to 60% ee for oxidation ofbenzyl phenyl sulfide and 42% ee for aryl methyl sulfide. Althoughit was found that the catalyst systems comprising VO(acac)2

and iodo-functionalized chiral Schiff bases (L1 and L2, Fig. 1)displayed considerably improved enantioselectivity in asymmetricoxidation of sulfides as compared with other analogous Schiffbases,[18] the racemic sulfoxides were obtained from the oxidationsof thioanisole (this work) and methyl 4-nitrophenyl sulfide[10]

catalyzed by Ti(OiPr)4 –L1 and–L2 systems with H2O2 as oxidant.The results indicate that introduction of halogen atoms withsome stereoelectric effect to the aromatic ring of Schiff bases,the strategy used for enhancement of the enantioselectivityof vanadium-based catalysts, does not work for the Ti(OiPr)4-tridentate Schiff base systems.

To find Schiff base ligands with good enantioselectivityfor titanium-catalyzed sulfoxidations with H2O2, we preparedthree sterically hindered chiral Schiff bases L3 –L5 (Fig. 2) fromcondensation reactions of 3,5-dicumenylsalicylaldehyde withchiral amino alcohols. Except for L4,[19] L3 and L5 have notbeen reported in the literature. These Schiff bases were usedfor the asymmetric oxidation of prochiral sulfides for the firsttime. We found that the enantioselectivity of sulfide oxidationswith Ti(OiPr)4-Schiff base systems could be improved by usingthese sterically hindered chiral Schiff bases. We screened thecatalytic behaviors of L3 –L5 in combination with Ti(OiPr)4 forasymmetric oxidation of aryl methyl sulfides and explored theinfluences of terminal oxidants, solvents, temperature, the ratioof Ti(OiPr)4 to Schiff base ligands and the loading amount of

Figure 2. The structures of the Schiff base ligands L3 –L7 .

Table 1. Titanium-catalyzed oxidation of thioanisole with differentoxidantsa

PhS

CH3 PhS

CH3

O

..

oxidant, CH2Cl2, 20 °C

[Ti(Oi-Pr)4]/L4

Entry Oxidant Time (h) Yield (%)b Ee (%)c,d Configuration

1 H2O2 2 89 66 S

2 tBuOOH 10 89 −3 R

3 mCPBA 1 84 21 S

4 PhIO 24 – –

a Reaction conditions: Ti(OiPr)4 (0.01 mmol), L4 (0.012 mmol),thioanisole (1.0 mmol), oxidant (1.2 mmol), CH2Cl2 (2 ml), 20 ◦C.b Isolated yield, calculated based on the adding amount of thesulfide. c Determined by HPLC with Daicel Chiralcel OD-H column,V(hexane)–V(iPrOH) = 9:1.d The absolute configuration was assigned by comparing opticalrotations and HPLC elution orders with literature data.

Ti(OiPr)4 on the asymmetric oxidation of sulfides. Preliminaryresults show that the catalyst systems of Ti(OiPr)4 and Schiff basesbearing cumenyl substituents with H2O2 as oxidant displayed highactivity [using 0.5–1 mol% Ti(OiPr)4] for oxidation of thioanisolewith enantioselectivity up to 73% ee under optimal conditions.The enantioselectivity of sulfoxides comes dominantly from thesulfide oxidation instead of the kinetic resolution in sulfoxideoveroxidation, resulting in high chemoselectivity. The asymmetricinduction effect of Schiff bases L3 –L5 was compared with that ofthe widely used Schiff bases L6 and L7 (Fig. 2).

Results and Discussion

We first explored the performance of the Ti(OiPr)4 –L4 catalystsystem for asymmetric oxidation of thioanisole using differentoxidants in a molar ratio of 1 : 1.2 : 100 : 120 for Ti(OiPr)4 –Schiffbase ligand–thioanisole–oxidant in CH2Cl2 at 20 ◦C. The catalyticresults are given in Table 1. Each catalytic reaction was repeatedat least twice. Thioanisole cannot be oxidized by PhIO in theTi(OiPr)4 –L4 system. With tBuOOH as oxidant, methyl phenylsulfoxide was obtained in good yield after 10 h reaction, but itis nearly racemic. The Ti(OiPr)4 –L4 system displayed a relativelyhigh activity with mCPBA as oxidant. The oxidation of thioanisolecompleted at 20 ◦C in 1 h, giving the corresponding sulfoxide in84% yield with a low enantioselectivity (21% ee). Aqueous H2O2

(30%) emerges as a good performing oxidant for the titanium-catalyzed asymmetric oxidation of thioanisole, which affordedmethyl phenyl sulfoxide in 89% yield and 66% ee (Table 1, entry1). The dominant enantiomer is in S configuration. Aqueous H2O2

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Table 2. Influence of temperature on the titanium-catalyzed asym-metric oxidation of thioanisolea

PhS

CH3 PhS

CH3

O

..

H2O2, CH2Cl2

[Ti(Oi-Pr)4]/L4

Entry Temperature (◦C) Time (h) Yield (%)b ee (%)c,d

1 20 2 89 66

2 0 3 89 73

3 −10 3 88 70

a Reaction conditions: Ti(OiPr)4 (0.01 mmol), L4 (0.012 mmol),thioanisole (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), CH2Cl2 (2 ml).b Isolated yield. c See footnote c in Table 1.d The major enantiomers obtained from all entries are in the Sconfiguration.

(30%) was used as terminal oxidant in the following catalyticreactions.

Table 2 shows the influence of temperature on the oxidationof thioanisole catalyzed by the Ti(OiPr)4 –L4 system with H2O2 inCH2Cl2. The GC analysis showed that the oxidation of thioanisolewas close to the end in 1 h at room temperature and in 3 h at 0 ◦C(Figs S1 and S2, see Supporting Information). When the reactiontemperature was decreased from room temperature to 0 ◦C, theenantioselectivity of the sulfoxide was increased from 66 to 73%ee (entry 1 vs 2). Further decrease in the temperature to −10 ◦Cdid not apparently affect the yield and the enantioselectivity ofthe sulfoxide (entry 2 vs 3).

The GC analysis of the resulting solution from entry 2 in Table 2shows that the reaction reaches equilibrium at 0 ◦C after 3 hand a small amount (ca 10%) of thioanisole is still left in thesolution (Figs S2 and S4). Methyl phenyl sulfoxide is the dominantproduct detected by GC analysis. The peak at 10–11 min in theGC spectrum Fig. S3 for methyl phenyl sulfone, formed from thesulfoxidation of thioanisole catalyzed by VO(acac)2 –Schiff baseligand, is hardly observed in Fig. S4. Further studies on the kineticresolution of racemic methyl phenyl sulfoxide show that methylphenyl sulfoxide can be oxidized to the corresponding sulfoneby the Ti(OiPr)4 –L4 system with H2O2 in CH2Cl2 at 20 ◦C, butthe reaction has no enantioselectivity. The results indicate thatthis titanium-based catalyst system has high chemoselectivity andthat the good enantioselectivity of the Ti(OiPr)4 –L4 system directlycomes from the asymmetric oxidation of thioanisole instead ofthe kinetic resolution by overoxidation of the initially formedsulfoxide.

Next, the influence of solvents on the asymmetric oxidationof thioanisole catalyzed by the Ti(OiPr)4 –L4 system was exploredwith H2O2 as oxidant at 0 ◦C for 3 h (Table 3). Compared with theless hydrophilic solvents such as toluene, CCl4, CHCl3 and CH2Cl2,the solvents with strong polarity and miscible with water such asTHF, CH3CN and CH3OH gave better yields (87–95%) but lowerenantioselectivity (41–47% ee). We also found that slow addition ofH2O2 to the THF or CH3OH solution could apparently improve theenantioselectivity (entry 11 vs 10, 64 vs 39% ee in THF; entry 13 vs12, 47 vs 31% ee in CH3OH), but the yields were decreased by 10% orso. In contrast, slow addition of H2O2 to the solvents hardly misciblewith water, such as CH2Cl2, did not influence the ee value and theyield of methyl phenyl sulfoxide (entry 9 vs 8). Presumably, thebetter solubility of aqueous H2O2 in THF, CH3CN and CH3OH could

Table 3. Influence of solvents on the titanium-catalyzed asymmetricoxidation of thioanisolea

PhS

CH3 PhS

CH3

O

..

H2O2, solvent

[Ti(Oi-Pr)4]/L4

Entry Solvent Temperature (◦C) Time (h) Yield (%)b ee (%)c,d

1 CH2Cl2 0 3 89 73

2 CHCl3 0 3 75 57

3 CCl4 0 3 37 57

4 Toluene 0 3 64 58

5 THF 0 3 88 41

6 CH3CN 0 3 87 47

7 CH3OH 0 3 95 44

8 CH2Cl2 20 2 89 66

9e CH2Cl2 20 2 87 63

10 THF 20 2 85 39

11e THF 20 2 71 64

12 CH3OH 20 2 96 31

13e CH3OH 20 2 87 47

a Reaction conditions: Ti(OiPr)4 (0.01 mmol), L4 (0.012 mmol),thioanisole (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), solvent (2 ml).b Isolated yield. c See footnote c in Table 1. d See footnote d in Table 2.e Slow addition of H2O2 (1.2 mmol for 30 min).

facilitate the formation of an oxidized active titanium species by thesimple reaction of Ti(OiPr)4 with H2O2 without participation of thechiral ligand,[13b,20] leading to a decrease in the enantioselectivityof sulfoxide. Indeed, in the absence of Schiff bases, Ti(OiPr)4 cancatalyze the oxidation of thioanisole with H2O2 in CH2Cl2 at 0 ◦Cto the corresponding racemic sulfoxide. Slow addition of H2O2

may depress the formation of the active achiral titanium species inwater-miscible solvents. Considering both enantioselectivity andyield, dichloromethane is the best solvent among all the testedsolvents for the titanium-catalyzed asymmetric oxidation of arylmethyl sulfides. The oxidation of thioanisole with H2O2 in CH2Cl2at 0 ◦C affords 89% yield of methyl phenyl sulfoxide with 73% ee.

The influence of the molar ratio of Ti(OiPr)4 to the Schiff baseligand was also explored for asymmetric oxidation of thioanisole.When the molar ratio of ligand to Ti(OiPr)4 was changed from 1 : 1to 1.2 : 1, the yield of the sulfoxide was raised from 82 to 89% andthe enantioselectivity from 70 to 73% ee (entry 2 vs 1 in Table 4).Further increase in the ratio of ligand to Ti(OiPr)4 to 1.5 : 1 and 2 : 1led to a decrease in the yield and enantioselectivity of the sulfoxide(entries 3 and 4). These results are identical with the previousreport that titanium species containing more than one ligand pertitanium can hardly be responsible for asymmetric oxidations andtherefore, increasing the ratio of ligand to Ti(OiPr)4 (over 1.25) leadsto lower conversions and enantioselectivity.[10] With a low loadingof Ti(OiPr)4 (0.5 mol%), the oxidation of thioanisole still gave a goodyield and enantioselectivity of methyl phenyl sulfoxide (entry 5,84% yield and 62% ee) in the optimal molar ratio of 1.2 : 1 for ligandto Ti(OiPr)4 with H2O2 as oxidant in CH2Cl2 at 0 ◦C for 3 h. Theresult shows that this titanium-based catalyst system has a highactivity as compared with the conventional titanium-based systemof Ti(OiPr)4 –chiral tartrate–alkyl hydroperoxide, which requires4–16 mol% catalyst loading for effective oxidation of sulfides.[3 – 5]

Increase of the Ti(OiPr)4 loading to 2.0 mol% could not give better

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Table 4. Influences of the molar ratio of Ti(OiPr)4 –L4 and the loadingamount of the catalyst on the asymmetric oxidation of thioanisolea

PhS

CH3 PhS

CH3

O

..

H2O2, CH2Cl2, 0 °C, 3 h

[Ti(Oi-Pr)4]/L4

Entry Ti(OiPr)4 (mol%)Ti(OiPr)4 –L4

(molar ratio) Yield (%)b ee (%)c,d

1 1 1 : 1 82 70

2 1 1 : 1.2 89 73

3 1 1 : 1.5 82 69

4 1 1 : 2 79 68

5 0.5 1 : 1.2 84 62

6 2 1 : 1.2 85 64

a Reaction conditions: Ti(OiPr)4 (0.01 mmol) except for entries 5 and6, L4 , thioanisole (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), CH2Cl2(2 ml), 0 ◦C, 3 h. b Isolated yield. c See footnote c in Table 1.d Seefootnote d in Table 2.

yield and ee value of the sulfoxide (entry 6). On the basis ofthe results obtained from all catalytic experiments, the optimalconditions for the titanium-catalyzed asymmetric oxidation ofsulfides with H2O2 are in the molar ratio of 100 : 1 : 1.2 : 120 forsulfide–Ti(OiPr)4 –ligand–H2O2 with a 1 mol% loading of Ti(OiPr)4

in CH2Cl2 at 0 ◦C.It was found that the iodo and bromo substituents at the 3,

5-positions of the salicylidenyl moiety of the Schiff base displayedquite different effects on the vanadium- and titanium-catalyzedasymmetric oxidations of sulfides. Ligands L1 and L2 containingthe iodo substituent(s) gave high enantioselectivities (90–97% ee)for the vanadium-catalyzed oxidation of thioanisole with H2O2

in CH2Cl2 or CHCl3,[18] while racemic methyl phenyl sulfoxidewas obtained from the same reaction under similar conditionscatalyzed by Ti(OiPr)4 –L1 and–L2 (entries 1 and 2 in Table 5). Theeffect of the bulky cumenyl groups in the Schiff base ligands onthe titanium-catalyzed asymmetric oxidation of sulfides can beillustrated by comparing the catalytic results of the two subsets(L3 vs L6 and L4 vs L7) with the same R group in the chiralamino alcohol moiety. The oxidation of thioanisole using titaniumcatalysts in combination with the Schiff bases L3 and L4 containingtwo cumenyl groups at the 3,5-positions of the salicylidenyl unitgave high yields (89–91%) with 57% and 73% ee (entries 3 and4), respectively, which are apparently higher than those (40% and48% ee) obtained from the titanium catalyst systems with ligandsL6 and L7 bearing two tert-butyl groups (entries 6 and 7). Forthe Schiff bases L3, L4 and L5, with different R groups in thechiral carbon of the amino alcohol moiety, the enantioselectivityof the sulfoxide considerably reduced with decrease in the sizeof the R group (entries 3–5): L4 (R = tert-butyl, 73% ee) >L3

(R = isopropyl, 57% ee) >L5 (R = benzyl, 46% ee). The resultsshow that the large steric effect of the bulky substituents, bothat the 3,5-positions of the salicylidenyl unit and in the chiralcarbon of the amino alcohol moiety, can apparently improve theenantioselectivity of the titanium-catalyzed sulfide oxidation withH2O2 as oxidant.

Asymmetric oxidations of other aryl methyl sulfides werealso explored using the Ti(OiPr)4 –L4 system with H2O2 asterminal oxidant in CH2Cl2 at 0 ◦C. Good yields with moderateenantioselectivities (54–59% ee) were obtained for oxidations

Table 5. Effects of Schiff base ligands on the titanium-catalyzedasymmetric oxidation of aryl methyl sulfidesa

ArS

CH3 ArS

CH3

O

..

H2O2, CH2Cl2, 0 °C

[Ti(Oi-Pr)4]/L

Entry Ligand Ar Yield (%)b ee (%)c,d

1 L1 4-NO2C6H4 43 (3 h) Racemice

2 L2 Ph 66 (24 h) Racemic

3 L3 Ph 91 57

4 L4 Ph 89 73

5 L5 Ph 83 46

6 L6 Ph 71 40

7 L7 Ph 90 48

8f L4 4-BrC6H4 84 54g

9f L4 4-CH3OC6H4 79 59g

a Reaction conditions: Ti(OiPr)4 (0.01 mmol), ligand (0.012 mmol), arylmethyl sulfide (1.0 mmol), aqueous H2O2 (30%, 1.2 mmol), CH2Cl2(2 ml), 0 ◦C, 3 h. b Isolated yield. c See footnote c in Table 1. d Seefootnote d in Table 2. e Bryliakov and Talsi.[10] f At 20 ◦C. g Determinedby HPLC with Daicel Chiralcel OB-H column, V(hexane)–V(iPrOH) = 8:2for entry 8 and 5 : 5 for entry 9.

of methyl 4-bromophenyl sulfide and methyl 4-methoxylphenylsulfide (entries 8 and 9). Compared with the enantioselectivities(29–42% ee) obtained by Ti(OiPr)4 –L1 and–L2 systems forthe asymmetric oxidation of methyl 4-bromophenyl sulfidereported in the literature,[10] the Schiff base L4 containing twocumenyl substituents has a better asymmetric induction effect forasymmetric oxidation of aryl methyl sulfides.

Conclusions

In conclusion, Schiff bases L3 –L5, easily prepared from 3,5-dicumenyl salicylaldehyde and chiral amino alcohols, areeffective ligands for the titanium-catalyzed asymmetric oxidationof aryl methyl sulfides using H2O2 as terminal oxidant. TheTi(OiPr)4 –L (L=L3, L4 and L5) systems exhibited high activitywith low loading of the titanium catalyst (0.5–1.0 mol%) and alsohigh chemoselectivity to sulfoxides (up to 91% isolated yield).Compared with the widely used Schiff bases L1 and L2 derivedfrom 3,5-di-tert-butyl salicylaldehyde and chiral amino alcohols, L3

and L4 in combination with Ti(OiPr)4 displayed apparently higherenantioselectivity [up to 73% ee for (S)-methyl phenyl sulfoxide],which results dominantly from the direct asymmetric oxidation ofsulfides.

Experimental

Materials and Instruments

All aryl methyl sulfides were purchased from Aldrich and chiralamino acids (S)-tert-leucine, (S)-valine and (S)-phenylalanine fromAldrich and GL Biochem (Shanghai) Ltd. 2,4-Dicumenylphenolwas purchased from Aladdin and Ti(OiPr)4 from Alfa Aesar.Other starting compounds of reagent grade were obtained fromlocal suppliers and used as received. Chiral amino alcohols wereprepared by reduction of corresponding amino acids according tothe literature procedures.[21]

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Scheme 1. Synthetic route for Schiff bases L3 –L5 .

The 1H NMR spectra were obtained on an Unity Inova 400NMRspectrometer with TMS as internal standard. Mass spectra wereperformed by electrospray ionization (ESI) on an HP 1100 MSDinstrument. IR spectra were performed on a Jasco FT/IR 430infrared spectrometer. Optical rotations at 589 nm were measuredwith a Jasco P-1010 digital polarimeter.

Synthesis of Schiff Bases

Ligands L6 and L7 were prepared according to literatureprocedures.[10] Schiff bases L3 –L5 were prepared in two steps:formylation of 2,4-dicumenylphenol and condensation of 3,5-dicumenylsalicylaldehyde with chiral amino alcohols, as shownin Scheme 1.

Preparation of 3,5-Dicumenylsalicylaldehyde[22]

2,4-Dicumenylphenol (13.2 g, 0.04 mol) was added to the solutionof Mg(OCH3)2 (2.6 g, 0.03 mol) in methanol (30 ml) under anN2 atmosphere. The mixture was heated to reflux and half ofthe methanol was distilled out. After the resulting solution wascooled to room temperature, 30 ml of toluene was added to thesolution and the low-boiling fractions were removed by distillation.Paraformaldehyde (4.32 g, 0.14 mol) was added portion wise in 1 hat 95 ◦C. The mixture was stirred at 95 ◦C for 2 h and the solutionturned to orange. Dilute sulfuric acid (45 ml, 10%) was slowlyadded to the solution after it was cooled to room temperature.The mixture was stirred at 35 ◦C for 2 h, and then poured to aseparatory funnel and stand overnight. The aqueous layer wasextracted with toluene (3 × 30 ml) and the collected organiclayer was washed with brine and dried over anhydrous MgSO4.Solvents were removed under reduced pressure. The product waspurified by flash chromatography on silica gel with petroleumether–CH2Cl2 (1 : 1, v/v) as eluent. The oily product (yield: 65%)was used directly in the next step synthesis.

General Procedure for the Preparation of L3 –L5

3,5-Dicumenylsalicylaldehyde (1.0 mmol) and a chiral aminoalcohol (1.2 mmol) were dissolved in dry methanol (20–50 ml)under nitrogen atmosphere. The solution was refluxed for 4 h.Afterwards solvent was removed under reduced pressure to givea crude product, which was purified by flash chromatographyon silica gel with ether–CH2Cl2 (4 : 1, v/v) and then CH2Cl2 aseluents.

(S)-2-[N-{3,5-Bis(α,α-dimethylbenzyl)salicylidene}amino]-3-methyl-1-butanol (L3)

Yellow solid, 37% yield, m.p.: 45–46 ◦C, [α]23589 = −21.3◦ (c = 0.05,

CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.83 [d, J = 6.0 Hz, 3H,HC(CH3)2], 0.90 [d, J = 6.0 Hz, 3H, HC(CH3)2], 1.64, 1.70 [2s, 12H,PhC(CH3)2], 1.78–1.85 [m, 1H, HC(CH3)2], 2.88–2.92 (m, 1H, C N-CH), 3.68 (m, 1H, CHHOH), 3.77 (m, 1H, CHHOH), 7.05 (d, J = 2.4 Hz,1H, ArH), 7.13 (t, J = 6.8 Hz, 1H, ArH), 7.18–7.24 (m, 5H, ArH),7.28–7.29 (m, 4H, ArH), 7.33 (d, J = 2.4 Hz, 1H, ArH), 8.25 (s,1H, HC N), 13.06 (s, 1H, ArOH) ppm. 13C NMR (100 MHz, CDCl3):δ = 19.2, 19.3 [2C, HC(CH3)2], 28.8, 30.1, 30.3, 30.9 [4C, PhC(CH3)2],31.1 [HC(CH3)2], 42.3, 42.5 [2C, PhC(CH3)2], 64.5 (CH2OH), 78.2(C N–CH), 125.2, 125.5, 126.8, 127.9, 129.5, 129.6, 136.2, 139.8,150.7, 150.8 (17C, C6H5, C6H2), 157.9 (CPh –OH), 166.7 (HC N)ppm. IR (KBr): ν = 3420, 2964, 2931, 2872, 1630, 1599, 1493, 1462,1442, 1382, 1362, 1278, 764, 699 cm−1. ESI-MS: m/z = 444.2 [M +H]+ .

(S)-2-[N-{3,5-Bis(α,α-dimethylbenzyl)salicylidene}amino]-3,3-dimethyl-1-butanol (L4)

Yellow solid, 35% yield, mp: 53–54 ◦C, [α]23589 = −23.2◦ (c = 0.05,

CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.88 [s, 9H, C(CH3)3],1.62, 1.69 [2s, 12H, PhC(CH3)2], 2.84 (m, 1H, C N-CH), 3.64 (m,1H, CHHOH), 3.82 (m, 1H, CHHOH), 7.05 (d, J = 2.4 Hz, 1H, ArH),7.13 (t, J = 7.0 Hz, 1H, ArH), 7.18–7.23 (m, 5H, ArH), 7.28–7.30(m, 4H, ArH), 7.33 (d, J = 2.4 Hz, 1H, ArH), 8.24 (s, 1H, HC N),13.05 (s, 1H, ArOH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2 [3C,C(CH3)3], 30.3, 30.6, 31.0, 31.2 [4C, PhC(CH3)2], 33.3 [C(CH3)3], 42.3,42.5 [2C, PhC(CH3)2], 62.5 (CH2OH), 81.7 (C N–CH), 125.2, 125.9,126.9, 127.9, 128.2, 129.5, 136.1, 139.8, 150.6, 150.7 (17C, C6H5,C6H2), 157.9 (CPh –OH), 166.9 (HC N) ppm. IR (KBr): ν = 3436,2965, 2870, 1630, 1599, 1493, 1460, 1441, 1396, 1382, 1362, 764,699 cm−1. ESI-MS: m/z = 458.3 [M + H]+ .

(S)-2-[N-{3,5-Bis(α,α-dimethylbenzyl)salicylidene}amino]-3-phenyl-1-propanol (L5)

Yellow solid, 39% yield, mp: 64–65 ◦C, [α]23589 = −128.9◦ (c = 0.05,

CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.66, 1.68 [2s, 12H,PhC(CH3)2], 2.78 (m, 1H, CHHPh), 2.84 (m, 1H, CHHPh), 3.40 (m,1H, C N-CH), 3.68 (m, 2H, CH2OH), 6.93 (s, 1H, ArH), 7.05 (d,J = 7.6 Hz, 2H, ArH), 7.14–7.20 (m, 7H, ArH), 7.24–7.31 (m, 6H,ArH), 7.35 (d, J = 2.4 Hz, 1H, ArH), 8.06 (s, 1H, HC N), 13.07 (s,1H, ArOH) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.3, 29.5, 29.8,31.0 [4C, PhC(CH3)2], 39.1 (PhCH2), 42.2, 42.5 [2C, PhC(CH3)2], 65.6(CH2OH), 73.3 (C N–CH), 125.2, 125.7, 125.8, 126.4, 126.8, 128.0,128.1, 128.2, 128.5, 129.3, 129.5, 136.1, 138.0, 139.8, 150.7 (23C,C6H5, C6H2), 157.7 (CPh –OH), 166.8 (HC N). IR (KBr): ν = 3440,2964, 2927, 2870, 1629, 1493, 1441, 1382, 1361, 764, 699 cm−1.ESI-MS: m/z = 492.3 [M + H]+ .

General Procedure for the Asymmetric Oxidation of ArylMethyl Sulfides

Compound Ti(OiPr)4 (2.8 mg, 0.01 mmol) and a Schiff base ligand(0.012 mmol) were dissolved in solvent (1 ml). The mixture turnedfrom pale yellow to brilliant yellow and stirred at room temperaturefor 30 min. A solution of the sulfide (1.0 mmol) in the selectedsolvent (1 ml) was added with stirring, followed by addition ofan aqueous H2O2 (30%, 1.2 mmol) at 0 ◦C. After the mixture wasstirred at 0 ◦C for 3 h, the resulting solution was extracted with

Appl. Organometal. Chem. 2011, 25, 325–330 Copyright c© 2011 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/aoc

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Y. Wang et al.

CH2Cl2. The organic layer was washed with brine and dried overNa2SO4. Filtration and evaporation gave a residue, which waspurified by flash chromatography on silica gel with petroleumether–ethyl acetate (3 : 2, v/v) and then ethyl acetate as eluents.The pure sulfoxide was obtained after removal of solvent byrotary evaporation. Enantiomeric excesses (ee) of sulfoxides weredetermined by HPLC analysis using chiral columns (Daicel ChiracelOD-H, 25×0.46 cm i.d. and Daicel Chiracel OB-H, 25×0.46 cm i.d.).

Acknowledgments

We are grateful to the National Natural Science Foundation ofChina (grant no. 20973032), the Program for Changjiang Scholarsand Innovative Research Team in University (IRT0711) and the K&AWallenberg Foundation of Sweden for financial support of thiswork.

Supporting information

Supporting information may be found in the online version of thisarticle.

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