Enantioselective oxidation of thioanisole to metyl phenyl sulfoxide by chiral compounds bearing N-Cl bond

Article abstract of DOI:10.1080/10426507.2015.1012203

Chiral sulfoxides are used in asymmetric synthesis and are present in various biologically active compounds. Asymmetric synthesis of the sulfoxides has been performed by chiral metal complexes and non-metals containing peroxide and oxide moieties. In this study, a new metal free method has been developed to oxidize thioanisole into methyl phenyl sulfoxide with easily accessible chiral compounds carrying N-Cl bond. For this purpose, chiral amine and amide bearing reagents were synthesized and chlorinated by using N-chlorosuccinimide. In oxidation reactions, chiral information has been transferred from N-chloramines to sulfides. With chlorinated chiral reagents, we observed enantioenriched sulfoxide formation. Although the observed results are promising, the best chiral amines are yet to be found. This is the first report on such a reaction, to the best of our knowledge.

Full text of DOI:10.1080/10426507.2015.1012203

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Phosphorus, Sulfur, and Silicon and the Related
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Enantioselective Oxidation of Thioanisole to Methyl
Phenyl Sulfoxide by Chiral Compounds Bearing N-Cl
Bond
Halil İpeka & Akin Akdaga
a Department of Chemistry, Middle East Technical University, TR-06800 Ankara, Turkey
Accepted author version posted online: 11 Feb 2015.
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To cite this article: Halil İpek & Akin Akdag (2015): Enantioselective Oxidation of Thioanisole to Methyl Phenyl
Sulfoxide by Chiral Compounds Bearing N-Cl Bond, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2015.1012203
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ENANTIOSELECTIVE OXIDATION OF THIOANISOLE TO METYL PHENYL
SULFOXIDE BY CHIRAL COMPOUNDS BEARING N-Cl BOND
Halil İpek, Akin Akdag*
Department of Chemistry, Middle East Technical University, TR-06800 Ankara, Turkey.
E-mail: aakdag@metu.edu.tr ; Tel: +903122103236
Abstract
Chiral sulfoxides are used in asymmetric synthesis and are present in various biologically active
compounds. Asymmetric synthesis of the sulfoxides has been performed by chiral metal
complexes and non-metals containing peroxide and oxide moieties. In this study, a new metal
free method has been developed to oxidize thioanisole into methyl phenyl sulfoxide with easily
accessible chiral compounds carrying N-Cl bond. For this purpose, chiral amine and amide
bearing reagents were synthesized and chlorinated by using N-chlorosuccinimide. In oxidation
reactions, chiral information has been transferred from N-chloramines to sulfides. With
chlorinated chiral reagents, we observed enantioenriched sulfoxide formation. Although the
observed results are promising, the best chiral amines are yet to be found. This is the first report
on such a reaction, to the best of our knowledge.
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Keywords: Asymmetric oxidation, Chiral sulfoxides, Chiral N-chloramines, Chiral N-
chloramides
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INTRODUCTION
A description of the first optically active sulfoxide in 1926 shed light on the nature of the bond
between sulfur-oxygen atoms and the geometry of sulfur.1 With this study, the tetrahedral
electron group geometry of the optically active sulfoxide molecule was referred to mentioning
that the sulfur atom is linked to three atoms with three covalency and one electrovalency where
sulfur is the stereogenic center of the chiral compound. For typical sulfoxides, ihe nversion
barrier is in the range of 38–41 kcal/mol depending on substituents. This energy barrier is
difficult to overcome at typical working temperature ranges, hence chiral sulfoxide enantiomers
are easy to isolate. To racemize chiral sulfoxides, it is necessary to raise temperatures above
200oC. 2
Chiral sulfoxides are known as the building blocks in the asymmetric synthesis due to their
stability at room temperature, both enantiomeric forms can be accessed. These could be used as
chiral information carrier for further reactions.3 Two faces of the sulfoxides can be differentiated
by using large alkyl substituents leading to higher stereoselectivity in asymmetric reactions.
Lone pair of electrons on oxygen and sulfur atoms promote sulfoxides to coordinate to Lewis
acids to attain highly ordered transition states.4 The sulfur atom can form covalent bonds, thus
sulfoxides readily interact with other atoms. Hence, chiral sulfoxides are widely used in
asymmetric synthesis, especially, as the chiral ligands (Figure 1).
Chiral sulfoxides show biological activity and they are widely used in the pharmaceutical
industry.5 Numerous sulfoxides find use in pharmaceutical industry as the active ingredients of
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the drugs. For instance, S-omeprazole is used for treatment of ulcers, R-modafinil is used for
treatment of narcolepsy, and S-sulindac is used for treatment of inflammation (Figure 2).
Many methods have been developed to synthesize enantiomerically pure sulfoxides from
corresponding sulfides due to the versatile use of them. These methods include metal catalyzed
and non-metal catalyzed systems. Among metal catalyzed systems, titanium catalyzed systems
are reported as the most efficient asymmetric sulfoxidation systems.6 The use of titanium
complexes in asymmetric sulfoxidation were first reported in 1984 by Kagan et al. (Scheme 1).7
Several research groups employed this system with modifications on the ligand around titanium,
and performed asymmetric sulfoxidations with the complexes. In these studies sulfoxides were
obtained with high enantioselectivity and in good yields.
Vanadium Schiff base complexes8 and manganese salen complexes9 were also employed as
efficient systems for stereoselective oxidation of sulfides to corresponding chiral sulfoxides.
High enantioeselectivities were attained by using numerous derivatives of these vanadium and
manganese complexes.6
Non-metal based systems were also examined for the synthesis of chiral sulfoxides. In these
studies, chiral oxaziridines,10 hypervalent iodine complexes11 and hydroperoxides12 were
employed. However, efficiency of these systems were not as high as metal-catalyzed ones.
As mentioned above chiral sulfoxides are used as the active ingredients of various medicines; it
is important to employ non-metal catalyzed systems to obtain these compounds in order not to
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cause accumulation of the metals in human body.13 In this study, it was aimed to develop a new
non-metal based method to obtain optically active sulfoxides based on N-chloramines.
This idea was conceived from the work of Harville,14 Corey,15 and Worley.16 In all of these
studies halogen was transferred from nitrogen to sulfur atom (vide infra). Harville used N-
chlorosuccinimide to oxidize thioanisole to methylphenyl sulfoxide (Scheme 2). Even though the
research did not intend to get chiral sulfoxides, racemic sulfoxides were obtained in high
yields.14
Corey used N-chlorosuccinimide with dimethylsulfide to oxidize alcohols into corresponding
carbonyl compounds (Scheme 3). They proposed that “Cl” was transferred to sulfides in their
mechanism.15
Worley used N-halamines to detoxificate mustard gas by converting the sulfide into sulfoxides
(Scheme 4).16
With the information given above, we proposed that if N-halamine contains a stereogenic center,
the chlorine transfer will be enantioselective. To test this idea, we synthesized various N-
halamine containing species and treated with thioanisole under different conditions.
RESULTS AND DISCUSSION
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It is known that in the presence of an oxygen source the interaction of the chlorine of the N-
chlorosuccinimide with the sulfur atom of the sulfide, oxidation of sulfide to sulfoxide is
observed. We modified this procedure in order to synthesize enantioenriched sulfoxide by
transferring the chlorine from chiral N-chloramines, hoping whether enantiodifferentiation in
sulfoxidation could be promoted with the use of chlorinated chiral amines and amides instead of
N-chlorosuccinimide.
For this study, the compounds given in Figure 3 were designed in order to be used in the
asymmetric sulfoxidation studies. These compounds contain variety of nitrogens (i.e. amines,
amides, and sultam) which can be chlorinated. Compounds 117, 217, 318 and 419 could be easily
synthesized from L-Phenylalanine. Compound 5 was purchased.
Esterification of L-Phenylalanine was performed by using thionylchloride and methanol. Then,
the ester was converted to corresponding N-methyl amide by using methylamine. Resulting N-
methyl amide was converted to compound 1 by a condensation reaction with acetone in presence
of p-TSA. Compound 2 was obtained by condensation of the N-methyl amide with
trimethylacetaldehyde in presence of ferric chloride (p-TSA did not function as expected). After
esterification step by dissolving ester in aqueous ammonium hydroxide solution, corresponding
amide was obtained, and by condensing this amide with acetone in presence of acetone,
compound 3 was obtained. Finally with the acetylation of the phenyl alanine methyl ester by
using acetic anhydride, compound 4 was obtained.
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Before the enantioselective oxidation reaction, chlorination of the chiral nitrogen containing
compounds were performed by employing N-chlorosuccinimide as the chlorinating agent. N-
chlorosuccinimide was choosen as the chlorinating agent, because chlorine transfer from N-
chlorosuccinimide to our chiral amine and amide derivatives was expected on account of the
knowledge that dissociation constant of the bonds between nitrogen and chlorine atoms in imide-
Cl is larger than that of amine-Cl and amide-Cl.20 Stability order of N-Cl bonds in amine-Cl,
amide-Cl and imide-Cl is determined based on the calculations and the experimental dissociation
constants of the bond between nitrogen and chlorine atoms: dissociation constant in water for N-
Cl in amine is the smallest and N-Cl in imide is the largest. Hence the chlorine transfer for
imide-Cl to an amine is thermodynamically favored (Scheme 5).
Another option was hypochlorous acid to chlorinate the chiral amines. However, amines
decompose upon treatment with hypochlorous acid. This is probably due to dehydrochlorination.
During sulfoxidation, it was expected that the chlorine atom of chlorinated chiral reagent and
sulfur atom of prochiral sulfide would interact. By this way, one face of prochiral sulfide would
be blocked and the opposite face becomes more tendent to nucleophilic attacks due to partial
positive charge on Cl. Therefore, oxygen could attack from the opposite direction from the one
which chlorine blocks. Oxygen from water, attacks sulfur and substitutes chlorine (Scheme 6).
By this way, enantioenriched sulfoxide could be observed.
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In the second part of this study, enantioselective sulfoxidation studies were performed by using
N-chloramines and N-chloramides as the chlorinating agents and water as the oxygen source
(Scheme 7).
In these studies, N-chlorosuccinimide (chlorinating agent) and selected chiral reagent was firstly
stirred in selected solvent for an hour at room temperature for the transfer of chlorine atom to the
chiral reagent. 1.5 equivalent N-chlorosuccinimide was employed for 1.0 equivalent of chiral
reagent for chlorination of compounds 1,2,4 and 5. For the chlorination of compound 3, 2.0
equivalents of chlorinating agent was employed due to the presence of two nitrogen atoms to be
chlorinated. After chlorination of chiral reagents, the mixture was filtered to remove
succinimide. Then, the reaction temperature was adjusted, thioanisole was added to the solution
of chiral N-chloramines. At the selected temperature, mixture was stirred for 2 hours and reaction
was ended upon monitoring with thin layer chromatography. At the end of the sulfoxidation
reaction, one of the end products was methyl phenyl sulfone. The sulfone formation was due to
the overoxidation of the sulfoxide. This occurs after the reaction was worked up by washing the
reaction mixture with water. However, when the reaction work-up is done with sodium sulfite
(Na2SO3) solution, sulfone formation was not observed. The hypochlorous acid formed by
equilibrium was deactivated with sulfite anion.
In the first set of sulfoxidation reactions, toluene was choosen as the reaction solvent to eliminate
solvent interference during the oxidation process, despite the fact that toluene is not a good
solvent for substitution reactions. In the reactions performed in toluene, the oxidation of
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o
thioanisole was examined at 25, 0, -10 and -78 C with all the chiral N-chloramines. Among
these chiral N-chloramines, highest enantioselectivities were obtained in the reactions performed
with compounds 1 and 4. Subsequently, all asymmetric sulfoxidation reactions were performed
o
with compound 1 and 4 at 25, 0, -10 and -78 C in acetonitrile. In these set of oxidation
reactions, acetonitrile was used as the solvent because it is both a polar aprotic solvent and inert
to such reactions. Compound 1 provided us with higher enantioselectivity in both of the solvents.
The highest stereoselectivities were obtained when the oxidation was carried out at 0oC.
Moreover, compound 1 was examined in dichloromethane, dimethylformamide and tert-butanol
o
at 0 C but no improvement on enantiomeric excesses were observed. These oxidation studies
were summarized in Table 1.
o
The highest enantiomeric excesses in this study was observed when reactions are run at 0 C.
The higher temperatures will increase the random collision between thioanisole and the N-Cl
moiety. This, in turn, resulted in the decrease in enantiomeric excesses. The lower temperatures
slowed down the molecular motions which led to random and slow chlorine transfer onto the
sulfur atom. This is most likely the reason the highest ee was observed at 0 oC.
In this study, enantiomeric excesses (ee) up to 23% were obtained which supports the idea that
asymmetric oxidation of sulfides could be afforded by chiral N-halamines.
CONCLUSION
The general goal of the study is to develop a new method for the stereoselective oxidation of
sulfides to the corresponding chiral sulfoxides without using metal complexes. Chiral amine and
amide reagents were designed, synthesized, and chlorinated. To our best knowledge, such an
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asymmetric sulfoxidation method has been presented for the first time. Our aim was to search for
enantioselectivity in this study. More attention was paid over enantiomeric excesses rather than
chemical yields. The chemical yields vary between 10 and 37%. Quest for a better N-chloramine
is still under investigation. The results will be reported in due course. This study will provide an
important role in designing better N-halamines for enantioselective oxidation of prochiral
sulfides.
EXPERIMENTAL SECTION
General:
All commercially available chemicals were used as received from Sigma-Aldrich, unless
otherwise is stated. During reactions, temperature was adjusted to 0 oC with ice, -10 oC with ice-
sodium chloride mixture and -78 oC with dry ice-acetone mixture. NMR spectra were recorded at
400 MHz Bruker Spectrospin Advance DPX NMR spectrometer with using solvents CDCl3, D2O
and d6-DMSO. NMR solvents were purchased from Merck Chemicals. Chemical shifts were
recorded in parts per million (ppm) relative to the internal standard tetramethylsilane. Coupling
constants (J) were reported in Hertz (Hz). IR spectra was recorded with Bruker Platinium ATR-
IR spectrometer. HPLC chromatograms were recorded with Agilent 1100 HPLC and analysis
were performed with OD-H chiral column with the solvent system of n-Hexane:i-propanol
(90:10). Silica gel 60 (0.040-0.063 mm) purchased from Merck was used for the column
chromatography. In thin layer chromatography analysis, UV-lamp and iodine chamber were used
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for visualization of the spots. Figures S 1 – S 32 (Supplemental Materials) contain sample 1H,
13C NMR and IR spectra and HPLC scans for compounds 1 – 4.
Optimized procedure for the enantioenriched sulfoxidation of thioanisole:
Chiral reagent (1.0 mmol) and N-chlorosuccinimide (1.0 mmol) were stirred in acetonitrile (10
mL) at room temperature for an hour. Then, reaction temperature was adjusted and thioanisole
(1.00 mmol) was added to the flask at 0oC. Mixture was stirred at selected temperature for 2
hours and water (0.1 mL, 5.55 mmol) was added at this temperature. Then, reaction mixture was
stirred at selected temperature (Table 1) 1 hour and reaction was ended. After ending the
reaction, mixture was concentrated in vacuo. Then, by performing extraction with
dichloromethane and the saturated aqueous sodium sulfite solution, sulfone and N-succinimde
was separated from the product. Seperated organic layer was dried over MgSO4(s) and
concentrated. After concentrating the organic layer, thin layer chromatography (TLC) was
performed and it was observed that thioanisole and chlorinated chiral reagent residue were also
present in the resulting mixture besides methylphenyl sulfoxide. Therefore, column
chromatography was performed with the solvent system of hexane:ethyl acetate (50:10) in order
1
to separate methylphenyl sulfoxide in 10-37% chemical yield (pale yellow liquid). H NMR
(CDCl3, 400 MHz) δ 7.68-7.46 (m, 5H), 2.73 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 131.0,
123.4, 123.5, 43.9. According to the chiral HPLC analysis up to 23% enantiomeric excess was
recorded. IR: 1033 cm-1 (S=O) stretching.
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ACKNOWLEDGEMENTS
We gratefully acknowledge the support of this study by TUBITAK (112T350) and Middle East
Technical University.
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Table 1. Oxidation of thioanisole under different conditions and the observed enantiomeric
excesses
Compound
Solvent
Temperature
Enantiomeric
Excess (ee%)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25 oC
0 oC
12
18
16
10
2
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
5
-10 oC
-78 oC
25 oC
0 oC
6
-10 oC
-78 oC
25 oC
0 oC
4
2
2
7
-10 oC
-78 oC
25 oC
0 oC
2
4
6
22
19
19
4
-10 oC
-78 oC
25 oC
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Toluene
0 oC
-10 oC
-78 oC
25 oC
0 oC
4
20
8
5
Toluene
5
Toluene
5
Acetonitrile
2
1
Acetonitrile
23
6
1
Acetonitrile
-10 oC
-78 oC
25 oC
0 oC
1
Acetonitrile
6
1
Acetonitrile
10
12
8
4
Acetonitrile
4
Acetonitrile
-10 oC
-78 oC
0 oC
4
Acetonitrile
9
4
Dichloromethane
10
12
14
1
Dimethylformamide
0 oC
1
tert-Butanol
0 oC
1
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Figure 1- Chiral sulfoxides used as chiral ligands
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Figure 2- Chiral sulfoxides used in pharmaceutical industry
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Scheme 1- Kagan’s asymmetric sulfoxidation system
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Scheme 2- Sulfoxidation with N-chlorosuccinimide
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Scheme 3- Interaction between chlorine and sulfur atom in Corey-Kim oxidation
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Scheme 4- Detoxification of mustard simulant with oxidation of sulfide
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Figure 3- Amine and amide derivative chiral reagents
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Scheme 5- Proposed mechanism for chlorine transfer from imide-Cl to amine
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Scheme 6- Proposed enantioselective oxidation mechanism
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Scheme 7- Enantioselective sulfoxidation strategy
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