Chapter 4shodhganga.inflibnet.ac.in/bitstream/10603/35843/12... · ), tertiary butyl hydrogen peroxide (TBHP) and Cumene hydroperoxide (CHP). Besides these, aluminum [43, 44], copper

Chapter 4

Highly Enantioselective sulfide

oxidation with chiral iron complex

using aqueous hydrogen peroxide as

terminal oxidant

Chapter 4

102

4.1. Introduction

Chiral sulfoxides are valuable compounds for their application as chiral auxiliaries

[1], ligands [2], organo-catalysts [3, 4] and in pharmaceutical industries [5-7]. The direct

and most efficient synthetic route to synthesize chiral sulfoxides was simultaneously

developed by Kagan et al. [8] and Modena et al. [9] by using modified Sharpless

epoxidation catalytic system. Since then there was spurt of activity in this area of research

and the last two decades have seen important piece of works [10, 11]. Some of the

frequently used metal ions in asymmetric sulfoxidation include titanium [12-16], vanadium

[17-20], manganese [21, 22] and iron [23-42] with various oxidant such as aqueous

hydrogen peroxide (H2O2), tertiary butyl hydrogen peroxide (TBHP) and Cumene

hydroperoxide (CHP). Besides these, aluminum [43, 44], copper [45] polyoxometalate [46,

47] based metal complexes were also explored. Alternatively organo catalysts [48, 49] have

also shown their worth, however, their tedious multistep synthesis and expense of

production restricts them in large scale synthesis. Though metal based catalysts are

efficiently promoted the asymmetric sulfoxidation reaction, but the contamination of toxic

metal in the product is a serious issue especially for the synthesis of biologically active

intermediates and products. In this context iron based catalysts seek utmost attention [50,

51] as it is less toxic, inexpensive, most abundant and environment friendly. Recently,

Benjamin List et al. reported asymmetric counter-anion directed catalysis (ACDC) [42] in

asymmetric sulfoxidation using iron complex containing a chiral phosphate counter ion.

This catalytic protocol provided excellent enantioselectivity for few substrates using PhIO

as an oxidant. Among the asymmetric sulfoxidation protocol utilizing iron based catalysts,

use of hydrogen peroxide as terminal oxidant looks more attractive due to environmental

and economic reasons, although this combination has inherent problem, as most of the first

row transition metals have high activity for the decomposition of H2O2, thereby cause

catalyst destruction via hydroxyl radical generation [40]. Nevertheless, dinuclear iron-(–)-

4,5-pinene-2,2᾿-bipyridine complex by Fontecave and co-workers [31-33] and iron-amino

alcohol derived Schiff base complexes by Blom et al. [34] set the stage for the iron-H2O2

combination. Unfortunately the product yield and enantioselectivity remained in low to

moderate domain. However, this complex showed a quantum improvement in its catalytic

performance when a catalytic amount Li/Na salt of 4-methoxy benzoic acid was used as an

additive [35, 36], but still show moderate enantioselectivity for the ortho substituted aryl

methyl sulfides. Later on Katsuki et al. reported iron-salan complex catalyzed asymmetric

Chapter 4

103

sulfoxidation with H2O2 [38] in water medium giving the desired product in high yield and

enantioselectivity. Still Fe-H2O2 combination is under represented for this reaction, except

for couple of reports by Simonneaux et al. in 2011 [40] where iron-porphyrin catalyst was

used giving moderate to high enantioselectivity of sulfoxide (highest ee being 87%) and by

Tsogoeva et al. [41] in 2012 using in situ generated iron complex of primary amine-derived

non-symmetrical Schiff base (with FeCl3 as iron source) but with lower enantioselectivity

(highest ee being 36%). Our conviction for Fe-H2O2 based catalytic system is that it may

provide excellent results if we hit upon right combination of ligand design and iron source.

This chapter of the thesis demonstrates the synthesis of a series ONONO type ligands

8’-11’ and their in situ generated iron complexes as catalysts in enantioselective

sulfoxidation of prochiral sulfides. Among these ligand 8’ with Fe(acac)3 as iron source

provided high enantioselectivity (highest ee being 98%), selectivity and good yield of the

desired product under very mild reaction condition.

4.2. Experimental Scetion

4.2.1. General methods and materials

As mentioned earlier, all the substrates (sulfides) were purchased from TCI

chemicals (Japan), Acros organics and Sigma Aldrich (USA) and were used without further

purification. Starting materials for the synthesis of ligands viz. (S)-(+)-tert-leucinol, (S)-

(+)-valinol, (S)-(‒)-phenylalaninol, (1R,2S)-(+)-cis-1-amino-2-indanol, 4-tert-butyl-2,6-

diformylphenol and iron salts such as iron(III) 2,4-pentanedionate, Iron(III) 1,3-diphenyl-

1,3-propanedionate and iron(III) chloride for the synthesis of chiral complexes were

purchase from Sigma Aldrich (USA). Urea hydrogen peroxide (UHP) and tert-butyl

hydrogen peroxide (TBHP) were purchased from Merck, 30% aqueous H2O2 was from

Rankem (India) and all required solvents were from Spectrochem (India). All reagents were

used as received but the solvents were dried and stored over activated molecular sieve

under nitrogen atmosphere. 1H NMR and 13C NMR spectra of ligands were obtained from

Bruker-Avance-DPX-200 (200 MHz) or 500 MHz spectrometer at ambient temperature

using TMS as internal standard. Electronic spectra were recorded in chloroform on a Varian

Cary 500 Scan UV–vis.–NIR spectrophotometer and TOFF mass of the catalysts and

intermediates were determined on a Micromass Q-TOF-micro instrument. The

enantiomeric excess of sulfoxides were determined by chiral Shimadzu-HPLC with SPD-

M10A-VP and SPD-M20A UV detector and PDR-Chiral Lnc. advanced Laser Polarimeter

(PDR-CLALP), using chiral Daicel Chiralcel columns with 2-propanol/hexane mixture as

Chapter 4

104

eluent of the crude products. Absolute configurations of chiral sulfoxides were determined

by comparing the sign of optical rotation (obtained from PDR-CLALP) and elution order

with the literature. The conversion and selectivity were determined by integrating the

methyl proton signal of sulfide, sulfoxide and sulfone in 1H NMR spectra of the crude

reaction mixture, but for phenyl ethyl sulfoxide and phenyl benzyl sulfoxide products were

isolated.

4.2.2. Synthesis of amino alcohol derived Schiff base ligands 8’-11’

Chiral ligands were synthesized by the condensation reaction of readily available 4-

tert-butyl-2,6-diformylphenol with chiral 2-aminoethanol derivatives by the modified

procedure. The solvent for the condensation was taken depending on the solubility of the

product.

4.2.2.1. Procedure for the synthesis of ligand 8’

To a stirring solution of 4-tert-butyl-2,6-diformylphenol (E) (1 mmol) in dry toluene

(10 ml) under nitrogen atmosphere, was added (S)-(+)-tert-leucinol (2.2 mmol) solution in

2 ml dry toluene at room temperature under N2 atm. (Scheme 4.1). After the addition of

(S)-(+)-tert-leucinol, yellow precipitate of the ligand started to form. The reaction mixture

was then heated to 70 oC and allowed to stir for 36 h. After the complete consumption of

the bis-aldehyde (checked on TLC), yellow precipitate was filtered and washed three times

with cold toluene to remove the excess L-tert-leucinol and dried under vacuum. The final

compound was isolated as yellow solid; yield: 88 %; m.p.: 247-249 oC; 1H NMR (500 MHz,

DMSO-d6): δ = 14.65 (s, 1H), 8.53 (s, 2H), 7.80 (s, 2H), 4.49 (s, 2H), 3.78 (d, 2H, J = 10.5

Hz), 2.86, (d, 2H, J = 8.5 Hz), 1.29 (s, 9H), 0.92 (s, 18H) ppm; 13C NMR (50 MHz, DMSO-

d6): δ = 159.15, 139.73, 128.11, 120.64, 80.51, 60.45, 33.65, 32.76, 31.07 ppm; Anal.

Calcd. for C24H40N2O3 C, 71.25; H, 9.97; N, 6.92; Found C, 71.31; H, 9.89; N, 6.97; TOF-

MS (ESI+): m/z Calcd. for [C24H40N2O3] 404.30, Found 405.27 [M+H]+.

Scheme 4.1 Synthesis of chiral ligand 8’

Chapter 4

105


To a stirring solution of 4-tert-butyl-2,6-diformylphenol (E) (1 mmol) in dry

methanol (5 ml), was added (S)-(+)-valinol (2.2 mmol) in methanol (1 ml) (Scheme 4.2).

After the addition of amino alcohol the color of the reaction mixture changes to from light

yellow to deep yellow. The reaction mixture was then allowed to stir for 24 h. After the

complete consumption of 4-tert-butyl-2,6-diformylphenol (checked in TLC), reaction

mixture was concentrated and kept at RT for crystallization. Yellow crystals were filtered

off and washed with little amount of cold methanol. Yield: 85 %; m.p.: 197-199 oC; 1H

NMR (500 MHz, DMSO-d6): δ = 14.57 (s, 1H), 8.56 (s, 2H), 7.77 (s, 2H), 4.66 (s, 2H),

3.65 (d, 2H, J = 10 Hz), 3.00 (s, 2H), 1.90 (m, 2H), 1.27, (s, 9H), 0.86, (d, 12H, J = 7 Hz)

ppm; 13C NMR (125 MHz, DMSO-d6): δ = 159.48, 139.64, 128.42, 120.67, 76.96, 62.74,

33.67, 31.09, 29.21, 19.89, 18.00 ppm; Anal. Calcd. for C22H36N2O3 C, 70.18; H, 9.64; N,

7.44; Found C, 70.24; H, 9.59; N, 7.48; TOF-MS (ESI+): m/z Calcd. for [C22H36N2O3]

376.27, Found 377.44 [M+H]+ and 378.49 [M+2H] +.




methanol (4 ml), was added solid (S)-(‒)-phenylalaninol (2.2 mmol) (Scheme 4.3). After

15 min. yellow precipitate of the product started to form. The reaction mixture was then

allowed to stir for 24 h. at RT. After the complete consumption of the bis-aldehyde

(checked in TLC), yellow precipitate was filtered and washed two times with little amount

of ice-cold methanol to remove the excess amino alcohol and dried under vacuum. The

final compound obtained as yellow solid; yield: 75 %; m.p.: 136-138 oC; 1H NMR (500

MHz, DMSO-d6): δ = 14.25 (s, 1H), 8.38 (s, 2H), 7.68 (s, 2H), 7.26-7.23 (m, 4H), 7.19-

7.14 (m, 6H), 4.83 (s, 2H), 3.61 (m, 2H), 3.48 (d, 2H, J = 3.5 Hz), 2.97 (dd, 2H, J = 13.5

Chapter 4

106

Hz, J = 3.5 Hz), 2.79 (dd, 2H, J = 13.5 Hz, J = 8 Hz), 1.25 (s, 9H) ppm; 13C NMR (125

MHz, DMSO-d6): δ = 159.19, 139.84, 138.90, 129.35, 128.13, 125.96, 120.45, 73.01,

64.24, 38.47, 33.74, 31.13 ppm; Anal. Calcd. for C30H36N2O3: C, 76.24; H, 7.68; N, 5.93;

Found C, 76.19; H, 7.74; N, 5.87; TOF-MS (ESI+): m/z Calcd. for [C30H36N2O3] 472.27,

Found 473.48 [M+H] + and 474.54 [M+2H] +.




methanol (4 ml), was added solid (1R,2S)-(+)-cis-1-amino-2-indanol (2.2 mmol). After 15

min. yellow precipitate of the product started to form (Scheme 4.4). The reaction mixture

was then allowed to stir for 24 h. at RT. After the complete consumption of the bis-aldehyde

(checked in TLC), yellow precipitate was filtered and washed two times with little amount

of ice-cold methanol to remove the excess amino alcohol and dried under vacuum. The

final compound obtained as yellow solid; yield: 78 %; m.p.: 195-197 oC; 1H NMR (500

MHz, DMSO-d6): δ = 14.18 (br, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 7.82 (s, 1H), 7.53 (d, 1H,

J = 2.5 Hz), 7.43 (d, 1H, J = 2.5 Hz), 7.35-7.34 (m, 1H), 7.31-7.27 (m, 2H), 7.23-7.21 (m,

3H), 7.14-7.12 (m, 1H), 5.04 (br, 2H), 4.77-4.70 (m, 2H), 4.53 (q, 2H, J = 5 Hz), 3.17-307

(m, 2H), 2.99-2.89 (m, 2H), 1.27 (s, 9H) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 166.43,

161.38, 158.84, 142.39, 142.07, 141.81, 141.63, 141.17, 140.98, 139.17, 139.06, 128.52,

128.48, 127.99, 127.78, 126.69, 126.57, 126.46, 125.58, 124.99, 124.62, 124.62, 124.55,

124.43, 117.35, 87.28, 78.48, 74.05, 73.77, 73.20, 68.35, 33.72, 31.12 ppm; Anal. Calcd.

for C30H32N2O3 C, 76.90; H, 6.88; N, 5.98; Found C, 76.84; H, 6.93; N, 6.07; TOF-MS

(ESI+): m/z Calcd. for [C30H32N2O3] 468.24, Found 469.51 [M+H] +.

Chapter 4

107


4.2.3. General procedure for asymmetric sulfoxidation

The mixture of 8’-11’ (0.0075 mmol) and Fe(acac)3 (0.005 mmol) in dry DCM (1

ml), was stirred for 3 h at room temperature. After the formation of complex p-

OMeC6H4COOH (0.005 mmol) was added to the reaction mixture and continued stirring

for 20 min. There after the addition of appropriate sulfide (0.25 mmol), the reaction mixture

was allowed to stir for another 20 min. Finally 1.2 equiv. of aqueous hydrogen peroxide

(30%; 34 μl, 0.3 mmol) was added in 6 fraction over 40 min. and the reaction mixture was

allowed to stir for 12 h. Then the reaction was quenched by washing the organic layer was

washed three times with water (1 ml 3), sample of the crude reaction mixture was taken

for the HPLC to check the enantioselectivity of the product and 1H NMR analysis to

determined, conversion and selectivity.

4.3. Results and Discussion

In the beginning of study we have synthesized a series of ONONO donor ligands (8’-

11’) by the simple condensation of commercially available 4-tert-butyl-2,6-diformylphenol

with different chiral amino alcohols (Scheme 4.5). There after these ligands were stirred

with iron salt to generate the corresponding iron complexes in situ in DCM for

sulfoxidation reaction.

To evaluate the catalytic efficiency towards the sulfide oxidation using aqueous H2O2

as a stoichiometric oxidant, these complexes were used as catalyst for the asymmetric

oxidation of methyl phenyl sulfide in DCM at RT.

Since free metal itself can catalyze the oxidation of sulfide in non-chiral pathway, to

insure the complete complexation of iron, 1.5 equiv. of ligand with respect to iron salt was

taken for the ligand screening experiments (Table 4.1). The selectivity for the desired

product is excellent for all the ligands and the yield is moderate to high, but in terms of

Chapter 4

108

enantioselectivity the ligand 8’, derived from tert-leucinol provided quite high ee (73%)

for the initial experiment. Rest of the ligands except 9’ (40% ee) showed very poor

enantioselectivity (Table 4.1, entries 3-5).

Scheme 4.5 Synthesis and structure of the synthesized ligands

Table 4.1 Screening of ligands for asymmetric sulfoxidation of methyl phenyl sulfide.a

Entry Ligand Conversion (%)b Selectivity (%)b ee (%)c

1 8’ 82 95 73

2 9’ 75 90 40

3 10’ 67 98 18

4 11’ 55 98 20

a Reaction condition: methyl phenyl sulfide (0.25 mmol), Fe(acac)3 (2 mol%), Ligand

(3 mol%), aquous H2O2 (30%, 1.2 equiv.), in DCM (1 ml) at RT for 12 h. b Conversion and selectivity were calculated by 1H NMR analysis. c Enantiomeric excess were determined by HPLC analysis on a chiral phase Daicel

Chiralcel OD column.

Chapter 4

109

After the optimization of the ligands, next we tested Fe(1,3-di-Ph acac)3 and FeCl3

as alternative sources of iron for the in situ generation of catalyst, considering the effect of

counter ion on the catalytic activity (Figure 4.1). The selectivity of these metal sources

were comparable but both provided very poor enantioselectivity and conversion.

Figure 4.1 Screening of iron source for the enantioselective oxidation of methyl phenyl

sulfide using 8’ as ligand and aqueous H2O2 as oxidant at RT.

So based on these experiments 8’ was selected as ligand and Fe(acac)3 as metal

source for the optimization of catalyst loading and metal to ligand ratio (Table 4.2). We

observed a considerable decrease in the enantioselectivity when the catalyst loading was

decreased to 1 mol% (conversion 70%, ee 59%) from 2 mol% (conversion 82%, ee 73%)

with minor decrease in the conversion and on increasing the catalyst loading to 4 mol%

(conversion 93%, ee 72%) the yield increased slightly without any improvement in the ee

value, but a significant drop in selectivity (95% to 85%) was noted at higher catalyst

loading (Table 4.2, entries 1-3). Considering the structure and the number of the donor

centre in the catalyst we could not denied the binding of two iron atom with one ligand, so

next the metal to ligand (8’) ratio was optimized by keeping the amount of metal source

fixed. With the metal to ligand ratio 1:0.5, a significant drop in both conversion and

enantioselectivity (conversion 67%, ee 55%) was observed, with 1:1 ratio conversion was

almost comparable (conversion 73%, ee 64%) but the ee value still little less than obtained

with 1:1.5 ratio. Further increase in the metal to ligand ratio 1:2 (conversion 76%, ee 68%)

caused only marginal decrease in the enantioselectivity. The obtained results (Table 4.2,

0

20

40

60

80

100

73

27

5

82

29

22

95 99 99

ee

yield

selectivity(%)

Chapter 4

110

entries 4-6) suggest the binding of one iron atom with one ligand to generate the active

catalyst in situ. Furthermore we found that at once addition of the oxidant caused a

substantial drop in enantioselectivity (Table 4.2, entry 7).

Table 4.2 Optimization of catalyst loading and metal to ligand ratio with 8’/Fe(acac)3.a

Entry Catalyst

loading

(mol%)

Metal:Ligand Conversion

(%)b

Selectivity

(%)b

ee

(%)c

1 1 1:1.5 70 94 59

2 2 1:1.5 82 95 73

3 4 1:1.5 93 85 72

4 2 1:0.5 67 94 55

5 2 1:1 73 96 64

6 2 1:2 76 96 68

7d 2 1:1.5 81 95 65

a Reaction condition: methyl phenyl sulfide (0.25 mmol), Fe(acac)3, 8’, aqueous H2O2

(30%, 1.2 equiv.), in DCM (1 ml) at RT for 12 h. b Conversion and selectivity were calculated by 1H NMR analysis. c Enantiomeric excess were determined by HPLC analysis on a chiral phase Daicel

Chiralcel OD column. d H2O2 was added at once.

Considering the structure and the number of the donor atoms in the ligand, the

formation of bimetallic complex cannot be ruled out (Scheme 4.6). To examine this we

have analyzed the UV-vis. (Figure 4.2) and ESI-MS (Figure 4.3 and 4.4) spectroscopy of

the in situ generated complexes obtained from the 1:1 and 1:0.5 ratio of iron source and

ligand. The characteristic peaks in UV-vis. spectra for metal to ligand ratio of 1:1 were

observed at 332, 340 and 430 nm, while for 1:0.5 ratio these peaks lie at 359, 388 and 432

nm, which clearly indicate the formation of different predominant complexes at different

ratio of Fe and 8’. ESI-MS spectra for 1:1 ratio indicate the formation of monometallic (8’-

Fe, 558 [8’-Fe+H]+) complex as predominant species (Figure 4.3) with some trace of

bimetallic (8’-Fe2, 711 [(8’-Fe2)-acac]+) whereas, in 1:0.5 ratio significant amount of

bimetallic complex was observed along with monometallic complex (Figure 4.4).

Interestingly, the saturated solution of the complex (formed with 8’ and Fe(acac)3 in 1:1

ratio) in CH2Cl2 or CHCl3 on aging (>2 days) partially crystallize out 8’, and what remains

in solution correspond to mixture of bimetallic 8’-Fe2 and monometallic complexes as

Chapter 4

111

evidenced by UV-viz and ESI-MS. Due to this behavior it was prudent to optimize the

ligand (8’) to metal ratio. With the metal to ligand ratio 1:0.5, a significant drop in both

conversion and enantioselectivity (conversion 67%, ee 55%) was observed, with 1:1 ratio

conversion was almost comparable (conversion 73%, ee 64%) but the ee value still little

less than what was obtained with 1:1.5 ratio. An increase in the metal to ligand ratio beyond

1:1.5 like in the case of 1:2 (conversion 76%, ee 68%) provided be counterproductive.

These experimental results (Table 2, entries 4-6) and spectral studies as discussed above

clearly indicate that the monomeric complex (8’-Fe) is more reactive and enantioselective

then the dimeric complex (8’-Fe2). Notwithstanding these observations, it is worth noting

that a drop-wise addition of oxidant required for getting best results, as addition of the

oxidant, all at once caused a substantial drop in enantioselectivity (Table 2, entry 7).

Continuing along the process of optimization of reaction parameter, urea hydrogen

peroxide (UHP) and tert-butyl hydrogen peroxide (TBHP) were also tested as

stoichiometric oxidant (Figure 4.5). The conversion and enantioselectivity obtained for

UHP were moderate, where as those were very poor for TBHP as oxidant. However, the

catalyst retained the high selectivity for the desired product with both UHP and TBHP.

Scheme 4.6 Plausible structures of the in situ generated monomeric (8’-Fe) and dimeric

(8’-Fe2) complex.

Chapter 4

112

300 400 500 600 700

0.0

0.5

1.0

Ab

sorb

ance

Wavelength nm.

8'-Fe

8'-Fe2

Figure 4.2 UV-vis. spectra of in situ generated complex with metal to ligand ratio of 1:1

and 1:0.5.

Figure 4.3 ESI-MS spectra of the in situ generated complex with 1:1 metal to ligand ratio.

L1-Fe

L1-Fe2

m/z500 510 520 530 540 550 560 570 580 590 600 610 620 630 640 650 660 670 680 690 700 710 720 730 740 750 760 770 780 790 800

%

0

100

T-FE-A-OX 1 (0.019) 1: TOF MS ES+ 224558.39

556.38

539.19

523.16502.50

503.55

540.20

554.39

559.41

560.37

633.52

588.42581.35

561.37607.24

589.43

619.44

664.46

634.52

658.43

711.41665.48

686.53681.43 710.44

763.58729.31

713.36 740.26 761.68 764.63792.25

766.47786.54 793.42

8’-Fe

8’-Fe2

Chapter 4

113

Figure 4.4 ESI-MS spectra of the in situ generated complex with 1:0.5 metal to ligand

ratio.

Thereafter we found that the strength of H2O2 is having prominent effect on the

activity, chemo and enantioselectivity of the reaction (Figure 4.6). The use of 15% aqueous

H2O2 caused little decrease in both conversion (70%) and enantioselectivity (67% ee) and

when the strength was increased to 50%, we observed a sharp decrease in the

enantioselectivity (55% ee) with more or less similar level of conversion (78%).

Concerning the selectivity, a gradual decrease was noted with the increasing strength of

H2O2.

Figure 4.5 Effect of oxidant on the enantioselective oxidation of methyl phenyl sulfide

catalyzed by in situ generated Fe-8’ complex at RT.

m/z500 510 520 530 540 550 560 570 580 590 600 610 620 630 640 650 660 670 680 690 700 710 720 730 740 750 760 770 780 790 800

%

0

100

FE T REF 1 (0.017) 1: TOF MS ES+ 531558.78

556.78

527.83

525.54

524.55502.87

528.83

539.55556.43

711.90

559.80

643.82

560.81580.80

561.80581.80

641.81624.74

593.66619.75

709.92

644.82

680.91645.82661.71 697.88

712.91

713.91

764.15728.97742.78 798.01786.14767.03

L1-Fe

L1-Fe2

73

38

17

82

57

20

95 97 99

0

20

40

60

80

100

120

ee

yield

selectivity(%)

H2O2 UHP TBHP

8’-Fe

8’-Fe2

Chapter 4

114

Figure 4.6 Effect of the concentration of H2O2 on the enantioselective oxidation of methyl

phenyl sulfide, catalyzed by in situ generated 8’-Fe complex at RT.

Next the catalytic activity in various solvents was screened to find the best catalytic

system in terms of conversion and enantioselectivity. Here we found the similar level of

activity and enantioselectivity for both CH2Cl2 and CHCl3 (Table 4.3, entries 1 and 2). In

rest of the solvents used, low to moderate ee were obtained (Table 4.3, entries 3-5). A trial

to replace the chlorinated solvent with green solvent DMC and DEC (Table 4.3, entries 6-

7) was failed as in these solvents the catalyst gave very poor conversion and ee compare to

the CH2Cl2 and CHCl3. Furthermore, we observed a little increase in the enantioselectivity

with decreasing reaction temperature to 15 oC, but further decrease did not improve ee,

rather it caused lowering of conversion (Table 4.3, entries 8 and 9).

Table 4.3 Variation of solvents for the asymmetric oxidation of methyl phenyl sulfide with

8’/Fe(acac)3 system.a

Entry Solvent Conversion

(%)b

Selectivity (%)b ee (%)c

1 DCM 82 95 73

2 CHCl3 75 96 70

3 MeOH 67 98 14

4 THF 60 98 55

5 PhCH3 85 96 40

6 DMC 20 97 10

6773

50

70

8278

98 9590

0

20

40

60

80

100

120

ee

conversion

selectivity

15% H2O230% H2O2 50% H2O2

(%)

Chapter 4

115

7 DEC 25 96 26

8d DCM 79 95 80

8e DCM 71 98 81

a Reaction condition: methyl phenyl sulfide (0.25 mmol), Fe(acac)3 (2 mol%), 8’ (3

mol%), aqueous H2O2 (30%, 1.2 equiv.), in organic solvent (1 ml) at RT for 12 h. b Conversion and selectivity were calculated by 1H NMR analysis. c Enantiomeric excess were determined by HPLC analysis on a chiral phase Daicel

Chiralcel columns. d The reaction was carried out at 15 oC. e The reaction was carried out at 5 oC.

Taking the example of Blom et al.’s report [35, 36], we further tried to increase the

enantioselectivity using sub stoichiometric amount of electron rich benzoic acid derivatives

as an additive. Initial study with p-OMeC6H4COOH (Figure 4.7) as an additive revealed

that 2 mol% of additive is beneficial in terms of yield and enantioselectivity (conversion

91%, ee 88%). Further increase in additive amount caused to decrease the

enantioselectivity significantly. Thereafter the aid of several electron rich benzoic acid

derivatives and sodium salt of p-OMeC6H4COOH were checked in the final optimization

experiment (Table 4.4). Here we observed same output for p-NH2C6H4COOH and p-

OMeC6H4COONa as obtained with p-OMeC6H4COOH as additive. But with p-

OHC6H4COOH and o-OMeC6H4COOH no improvement and with p-MeC6H4COOH, we

observed slight negative effect on the enantioselectivity.

Figure 4.7 Effect of the concentration of p-OMeC6H4COOH on enantioselective oxidation

of methyl phenyl sulfide catalyzed by in situ generated 8’-Fe complex at 15 oC.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7

ee yield

mol% of p-OMeC6H4COOH

Chapter 4

116

Table 4.4 Screening of benzoic acid derivatives as additive for the enantioselective

oxidation of methyl phenyl sulfide with 8’/Fe(acac)3 system.a

Entry Additive Conversion (%)b Selectivity (%)b ee (%)c

1 p-OHC6H4COOH 89 95 83

2 p-OMeC6H4COOH 91 95 88

3 p-MeC6H4COOH 87 96 74

4 o-OMeC6H4COOH 87 95 81

5 p-NH2C6H4COOH 90 94 87

6 p-OMeC6H4COONa 90 94 88

a Reaction condition: methyl phenyl sulfide (0.25 mmol), Fe(acac)3 (2 mol%), 8’ (3

mol%), additive (2 mol%), aqueous H2O2 (30%, 1.2 equiv.), in organic solvent (1 ml)

at 15 oC for 12 h. b Conversion and selectivity were calculated by 1H NMR analysis. c Enantiomeric excess were determined by HPLC analysis on a chiral phase Daicel


Finally taking 2 mol% of Fe(acac)3, 3 mol% 8’, 2 mol% p-OMeC6H4COOH as

additive and 1.2 equiv. of aqueous H2O2 as terminal oxidant in DCM at 15 oC as optimum

reaction conditions, we applied this catalytic protocol for the asymmetric oxidation of

various prochiral aryl alkyl sulfides (Table 4.5). For the electron withdrawing para

substituted phenyl methyl sulfides (Table 4.5, entries 2-5) such as F (conversion 78%, ee

95%), Cl (conversion 82%, ee 95%), Br (conversion 81%, ee 94%) and NO2 (conversion

72%, ee 96%) we obtained high enantioselectivity, excellent selectivity for the desired

product but with low conversion compare to the phenyl methyl sulfides. The same trend

was followed by the electron withdrawing Cl (conversion 80%, ee 91%) and Br (conversion

78%, ee 90%) substituent at ortho position as well as Cl (conversion 79%, ee 96%) and Br

(conversion 80%, ee 94%) substituent at the meta position of the phenyl ring (Table 4.5,

entries 8-11). Replacement of electron withdrawing substituent at the para position with

donating Me and OMe group (Table 4.5, entries 6 and 7) almost retained both conversion

and ee as obtained for representative substrate, but we noticed a little lowering of selectivity

for the most electron rich substituent p-OMe Phenyl methyl sulfide (93%). Finally we have

used phenyl ethyl sulfide (Table 4.5, entries 12) and phenyl benzyl sulfide (Table 4.5,

entries 13) as variant for the methyl group and obtained good result in terms of conversion

Chapter 4

117

and enantioselectivity for phenyl benzyl sulfide (conversion 89%, ee 85%) having bulkier

ethyl group compare to methyl group. In case of phenyl benzyl sulfide (conversion 88%,

ee 75%) a significant drop in enantioselectivity was observed probably due to the steric

effect of the benzyl group.

Table 4.5 Enantioselective oxidation of various prochiral sulfides with in situ generated

8’-Fe(acac)3 complex.a

Entry Sulfide Conversion

(%)b

Selectivity (%)b eec

1

91 95 88

2

78 98 95

3

82 98 95

4

81 97 94

5

72 96 96

6

90 96 87

7

92 93 85

8

79 98 96

9

80 97 94

10

80 95 91

Chapter 4

118

11

78 94 90

12

89 98 85

13

88 97 75

a Reaction condition: Sulfide (0.25 mmol), Fe(acac)3 (2 mol%), 8’ (3 mol%), p-

OMeC6H4COOH (2 mol%), additive (1 mol%), aqueous H2O2 (30%, 1.2 equiv.), in

DCM (1 ml) at 15 oC for 12 h. b Conversion and selectivity were calculated by 1H NMR analysis. c Enantiomeric excess were determined by HPLC analysis on a chiral phase Daicel


4.4. Probable catalytic route of the reaction

The sulfoxidation reaction mechanism with biomimetic non-heme iron (II)/(III)

complexes has been studied over the last two decades and the involvement of Fe (IV)-oxo

species has been established as an active oxidant [52]. In parallel, a debate is going on in

favor [53, 54] and against [55, 56] the involvement of iron(III)-hydroperoxo species as

active oxidant. Compare to these other iron based catalytic systems involving salen and

aminoalcohols derived Schiff base ligands were not studied adequately to find out the

actual oxidant. Based on spectroscopic techniques, kinetic measurement and

electrochemical properties analysis Sivasubramanian et al. [57] and Rajagopal et al. [58]

identified Fe(IV)-oxo salen species as active oxidant, but Fujii et al. [59, 60] demonstrated

Fe(III)-monophenoxyl radical as the active oxidizing species for sterically hindered Fe-

salen complex at very low temperature (193 K). Possibility of Fe(III)-monophenoxyl

radical as the active oxidizing species can be cancelled as our reaction temperature is very

close to RT. The UV-vis. and ESI-MS spectroscopic analysis suggest the formation of

unstable [Fe(III)-OH] +• after the addition of H2O2, which is then converted to the

[Fe(IV)=O] +• species. Our assumption supported by the study of Costas et al. [61], which

has shown that the formation Fe(V)=O of species passes through the Fe(IV)-OH

intermediate.

The present ligand shows two characteristic peaks at 343 nm and 445 nm. After the

addition of Fe(acac)3 the color of the reaction mixture changes from deep red to brown and

Chapter 4

119

we observed red shift of the peak at 445 nm to 430 nm with hyperchroism due to ligand to

metal charge transfer (LMCT) transition (Figure 4.7) confirms the formation of complex

8’-Fe (Scheme 4.8).

400 500 600 700

0.0

0.2

0.4

0.6

0.8

Abs

orba

nce

Wavelength nm.

8'

8'-Fe

8'-Fe+OX-5 min.

8'-Fe+OX-10 min.

8'-Fe+OX+Sub-20 min.




Figure 4.7 The UV-vis. spectra obtained on the sequential addition of Fe(acac)3 (1 equiv.),

oxidant (5 equiv.) and substrate (1 equiv.) to the solution of 8’ in CHCl3.

Scheme 4.8 Preparation of 8’-Fe complex in situ.

The absorbance of LMCT initially increased [57] then decreased with red shift of 6

nm (424 nm) at 523 nm on the addition of H2O2 [57, 58] and we observed an increase in

absorbance in the region 520-650 nm [58] with an isobestic point at 523 nm due to the

formation of a new species, most probably the active oxidizing species. The pattern of

spectral changes is very similar to the observation of Sivasubramanian et al. [57] and

Rajagopal et al. [58] for Fe(III) salen system. Thus the Fe(V)=O species is likely to be the

active oxidant in our catalytic system as well. To further probe into this matter, we

performed ESI-MS spectroscopic analysis of the reaction mixture after 3 min of the

addition of H2O2 at RT which showed molecular mass peaks equivalent to [Fe(III)-OH]

(X1) and [Fe(III)-OOH] (X2) species (Figure 4.9) in the reaction mixture after 3 min. of

the addition of H2O2 at RT.

Chapter 4

120

Figure 4.9 ESI-MS spectra after (3 min.) the addition of 50 equiv. of H2O2 to the solution

of 8’-Fe complex in methanol.

After 10 min. peaks corresponding to [8’-Fe(III)-OH] (X1) and X2 species

disappeared and a new peak equivalent to mass [8’-Fe(IV)=O] (Y) appeared (Figure 4.10).

Based on the above study we proposed a catalytic cycle (Scheme 4.8) including Y species

as an active oxidant generated from 8’-Fe complex in the presence of H2O2 as an oxidant.

UV-vis study too corroborates our proposed mechanism where a decrease in the LMCT

peak after the addition of substrate to the in situ generated [8’-Fe(IV)=O] intermediate (Y)

was observed, suggesting thereby the binding of the substrate to form intermediate Z.

Finally intramolecular oxygen transfer takes place to form sulfoxide and regenerate the 8’-

Fe complex.

m/z586 588 590 592 594 596 598 600 602 604 606 608 610 612 614 616 618 620 622 624 626 628 630

%

0

100

ST-MEOH-A 3 1 (0.019) 1: TOF MS ES+ 17.6593.15

591.21

588.20586.21 590.81

592.17

607.17

594.14

605.23595.18

597.28

596.13

598.23

599.48 602.34

601.29

603.51

624.22

608.15

609.13

622.27610.27

615.36611.21

614.30 620.48618.35616.22

623.91

625.25

626.28

629.49626.65

[X2+CH3OH+H]+

[X1+CH3OH+H]+

[X1+H2O+H]+

m/z450 460 470 480 490 500 510 520 530 540 550 560 570 580 590 600 610 620 630

%

0

100

T-FE-OX-2 1 (0.019) 1: TOF MS ES+ 140459.21

447.24

457.20

455.05

448.20

475.20

460.22

461.13

463.17

471.17

523.08

476.21

483.07

496.26

496.15489.23

521.10497.19 505.22

514.17

575.09

524.09

556.27

525.12

546.17541.29

530.18

558.29

572.33

560.25

617.20

576.17

597.22590.24581.23 612.28600.26

628.18618.22

620.21629.22

[Y1+CH3OH+H2O] +•

[(L1-Fe)‒acac+2H] +

[Y2+H]+

[Y2+acac+H]+

[(8’-Fe)‒acac+2H]+

Chapter 4

121

Figure 4.10 ESI-MS spectra at 10 min. after the addition of 50 equiv. of H2O2 to the

solution of 8’-Fe complex in methanol.

Scheme 4.8 Plausible catalytic route for catalytic sulfide oxidation with 8’-Fe/H2O2

system.

4.5. Conclusion

In conclusion, a new iron based catalytic protocol was developed for asymmetric

sulfoxidation using environment benign oxidant H2O2 as terminal oxidant. The simplicity

of the procedure and reaction condition makes it attractive over other metal catalyzed

catalytic systems. Catalyst not only showed high enantioselectivity (up to 96%) for

sterically and electronically diverse type of sulfides, it provided excellent chemo selectivity

(up to 98%) and good conversion (up to 92%). Substrates containing electron withdrawing

substituent are seems to be less reactive as those gave comparatively low conversion, but

provided slightly higher enantioselectivity and chemo selectivity even for ortho substituted

sulfides as well. Besides this based on the UV-vis and ESI-MS analysis we have detected

the probable active oxidizing agent and proposed a plausible path for the catalytic oxidation

of prochiral sulfides.

Chapter 4

122

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Documents

Chapter 4shodhganga.inflibnet.ac.in/bitstream/10603/35843/12... · ), tertiary butyl hydrogen peroxide (TBHP) and Cumene hydroperoxide (CHP). Besides these, aluminum [43, 44], copper