General, Practical and Selective Oxidation Protocol for CF3S into CF3S(O) Group

A simple and efficient protocol for the oxidation of trifluoromethyl, mono- and difluoromethyl sulfides to the corresponding sulfoxides without over-oxidation to sulfones, using TFPAA prepared in situ from trifluoroacetic acid and 15% H2O2 aqueous solution was developed. The methodology is suitable for a wide range of aromatic and aliphatic substrates in milligram and multigram scales.


Introduction
The synthesis of trifluoromethylsulfinyl containing compounds is a recent trend in current organic chemistry due to the practical significance of such compounds [1].In particular, their biological activity is promising.They are also key intermediates for trifluoromethyl-containing sulfoximine synthesis and are excellent chiral auxiliaries [2][3][4][5].Synthetic approaches dedicated to trifluoromethyl sulfoxides include (1) trifluoromethylation of the corresponding sulfinyl halides or sulfinic esters using TMSCF 3 [6][7][8], (2) reaction of aromatic compounds with triflinate salts [9], (3) rearrangement of aryl triflinates in the presence of AlCl 3 [10], (4) trifluoromethanesulfinilation using Langlois' system (CF 3 SO 2 Na/POCl 3 ) [11] or with 1-(trifluoromethylsulfinyl)-pyrrolidine-2,5-dione [12].However, the most important and common method for the synthesis of trifluoromethylsulfoxides is the oxidation of the corresponding trifluoromethylsulfides using various oxidants, mainly peroxyacids, e.g.mCPBA [1].It is noteworthy to mention that oxidation with mCPBA is sensitive to temperature.As a result, over-oxidation frequently occurs and non-negligible amounts of trifluoromethylsulfone are formed [13].Furthermore, this reagent converts into m-chlorobenzoic acid, which is sometimes not easy to separate from the sulfoxide.Oxidation of an aliphatic sulfide was also described with Oxone ® as oxidant [14].Waste by-products formed during the oxidation reaction as well as the necessity to use silica as a component of reaction medium cause difficulties in scaling up.Trifluoroperacetic acid (TFPAA) was shown to be a convenient reagent for the oxidation of sulfides to sulfoxides, as it reacts more rapidly at low temperature than other peroxy acids [15].To the best of our knowledge, TFPAA has not been widely applied to the oxidation of perfluoroalkyl sulfides and only a few articles [14,[16][17][18][19][20][21] and patents [22][23][24][25][26][27] documented this procedure.TFPAA solution can be prepared from 30% H 2 O 2 and trifluoroacetic acid or 80-90% H 2 O 2 and trifluoroacetic anhydride [28,29].On the basis of literature data and our experience in oxidation reactions of trifluoromethyl sulfides, the use of TFPAA, obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF 3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H 2 O 2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions (Table 1, Entry 4,10).
Molecules 2019, 24, x 2 of 13 obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions ( obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions ( obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions (   obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions (   obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions (   obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions (   obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions (   obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions ( obtained by both methods, has one common limitation as for mCPBA: over-oxidation readily occurs to form difficult-to-separate mixtures of trifluoromethyl sulfide, trifluoromethyl sulfoxide, and trifluoromethyl sulfone [17][18][19].On the other hand, regarding the advantages of this method (easy to prepare and a cheap reagent, trifluoroacetic acid as side product), we believed there was an urgent need to exploit it.The description of a general and selective method of oxidation is especially important in the context of an exponential growth of molecules bearing a SCF3 group [1].
Herein we propose an easy-to-handle and high-yielding procedure for the oxidation of alkyl and aryl perfluoroalkyl sulfides to the corresponding sulfoxides without over-oxidation thanks to the reappraisal of oxidation by TFPAA.

Results and Discussion
We postulated that a decrease in concentration, associated with a rigorous measurement of the latter, could dramatically reduce the formation of unwanted sulfone.Indeed, the use of TFPAA obtained in situ from trifluoroacetic acid and 15% H2O2 aqueous solution proved to be successful (see experimental part).This method was firstly applied to aryl trifluoromethyl sulfides 1 bearing both electrons donating and electron-withdrawing substituents in various positions on the aromatic ring (Scheme 1, Table 1).Corresponding aryl trifluoromethyl sulfoxides 2 were obtained in high yields whatever the nature of the substituents on the aromatic ring.In all experiments, the crude product contained less than 7% of non-reacted trifluoromethyl sulfide; at the same time, trifluoromethyl sulfone was detected in negligible amounts in only two reactions ( In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation.In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data;2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation.In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation.In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation. 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation.0 100 0 -87 1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Mixture of 2i and corresponding phenol in 85:15 molar ratio (according to 19 F NMR data).
In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
Oxidation of aliphatic sulfides also proved successful (Scheme 2, Table 2).In most cases the crude product needs no further purification.If needed, compounds 2 were easily separated from impurities by standard methods (see experimental part for details).It should be noted that during the oxidation of acylated phenol 1i partial hydrolysis occurred and the crude product contained ~15% of o-trifluoromethylsulfinyl phenol, which we failed to separate from 2i by column chromatography.
The thioether 3a was oxidized by TFPAA in high yield (83%) in 24h.This simple procedure can be favorably compared to our previous method which employed Oxone® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation.The thioether 3a was oxidized by TFPAA in high yield (83%) in 24 h.This simple procedure can be favorably compared to our previous method which employed Oxone ® [14].Compound 4b was isolated in low yield, most probably due to the high solubility of the product in water.Attempts to separate 4b from 3b by distillation failed.Use of an acyl protective group (Table 2, Entry 3) led to a higher yield of sulfoxide 4c.In this case, as well as in the previous one, a small amount (<3%) of trifluoromethyl sulfone was detected in the reaction mixture and the crude product.As in the experiment with acylated phenol 1i (Table 1, Entry 9), product 4c contains ~15% of the corresponding alcohol (Table 2, Entry 3), which we failed to separate from the ester by distillation.Oxidation of sulfide 3d by 15% H 2 O 2 solution in TFA proceeded with 90% conversion.The use of H 2 O 2 in excess (1.1 equiv.)led to the same results and the sulfone was not observed in this reaction mixture.Two other examples demonstrated the efficiency of this transformation (entries 6-7).  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.  1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H2O2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.
1 Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification; 3 Contains ~11 % of starting sulfide 3b; 4 Mixture of 4c and corresponding alcohol 4b in 85:15 molar ratio (according to 19 F NMR data); 5 Use of 10% excess of H 2 O 2 lead to the same results.

Scheme 3. Oxidation of fluoromethyl and difluoromethyl sulfides 5.
As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 °C for 6 h, with further stirring at ~10 °C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.As it is evident from Table 3, all compounds 6a-f were obtained in high yields and the crude products were pure enough to be used without further purification.The oxidation of 5a was strongly exothermic and the reaction was complete within 4 h at room temperature yielding pure sulfoxide 6a, which contained neither difluoromethyl sulfide 5a nor difluoromethyl sulfone.If this reaction was performed at −15 • C for 6 h, with further stirring at ~10 • C for 20 h, the crude product contained ~2% of unreacted sulfide 5a.It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1 H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300  It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1   It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1  It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.It should be emphasized that the oxidation reactions of sulfides 1, 3, and 5 could be performed on a 0.05 to 50 g scale.
The application of this method to heterocyclic thioethers is highly challenging, as demonstrated by the two following preliminary results.Thus, 2-trifluoromethylsulfenyl-5-acetylamino-pyridine 7 was oxidized to sulfoxide 8 with low conversion after seven days stirring, and we failed to separate the product from the starting sulfide (Scheme 4).A study devoted to the oxidation of heterocyclic substrates is needed but falls outside the scope of the present study.Scheme 4. Oxidation of heterocyclic trifluoromethyl sulfides.

General Information.
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1 H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300

General Information
The purification of products by column chromatography (CC) was performed on Silica gel, 70-230 mesh 60A (Aldrich, Saint Louis, MI, USA) or by preparative TLC chromatography. 1 H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300 MHz with Bruker AC-200 or AC-300, or at 400 MHz with Varian UNITY-Plus 400 spectrometer. 19F NMR spectra were recorded on Varian UNITY-Plus 400 spectrometer at 376.5 MHz or at 470 MHz with Bruker AVANCE DRX 500 instrument or at 188 MHz with Bruker AC-200 (Bruker, Billerica, MA, USA).Chemical shifts are given in ppm relative to Me 4 Si and CCl 3 F, respectively, as internal or external standards. 13C NMR-spectra (proton decoupled) were recorded on a Bruker AVANCE DRX 500 instrument at 125.7 MHz, or on Varian UNITY-Plus 400 spectrometer at 100.6 MHz, or at 75 or 50 MHz with Bruker AC-300 or AC-200.IR spectra were recorded with a Vertex 70 (Bruker) instrument (in KBr tablet).Melting points were determined in open capillaries using SMP3 instrument (Stuart Scientific Bibby Sterlin Ltd, Stone, Staffordshire, UK).Elemental analysis was performed in the Analytical Laboratory of the Institute of Organic Chemistry, NAS of Ukraine, Kyiv.

Important Information
It is critical to know the exact concentration of H 2 O 2 used in order to avoid over dosage of reagent that led to over oxidation.A solution of 15% H 2 O 2 (mass concentration) was prepared from commercial ~30-35% H 2 O 2 solution by dilution with water ~1:1 w/w.The concentration of H 2 O 2 solution was measured using densimetry or titration (see Supplementary Materials).

General Procedure for Oxidation of Polyfluoroalkyl Sulfides to Polyfluoroalkyl Sulfoxides
To the solution of sulfide 1, 3, or 5 (10 mmol) in CF 3 COOH (15-20 mL) 15 mass% aqueous solution of H 2 O 2 (containing 10 mmol of H 2 O 2 ) was added dropwise very slowly (during 40-90 min) at room temperature.Reaction is strongly exothermic; H 2 O 2 was added at such a rate that the temperature was kept in the range 25-28 • C inside the flask (20 • C for compounds 1k, 3f,g, and 0 • C for compounds 5e,f).Reaction mixture was stirred overnight at r.t.(for compound 3d − 96 h, for 7-7 days), poured into water, neutralized with solid NaHCO 3 to pH=6-7, then extracted with ether or ethyl acetate (4 × 30 mL).Compounds 2k, 4f,g, and 6e,f were extracted with dichloromethane before neutralizing the TFA with NaHCO 3 .The organic phase was washed with water (4 × 20 mL), dried with MgSO 4 or Na 2 SO 4 .Solvent was removed at atmospheric pressure for low-boiling liquids or on a rotary evaporator for solids or high-boiling liquids.Crude product was analyzed by NMR and purified if necessary.

Conclusions
In summary, a simple, convenient, and high-yielding procedure for the oxidation of fluoroalkyl sulfides to fluoroalkyl sulfoxides was developed.It was shown that the new protocol is suitable for a wide range of aliphatic and aromatic substrates on a milligram and multigram scales.In almost all cases, over-oxidation did not occur, and the crude products contained only a small quantity of starting sulfides.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300

Supplementary Materials:
The following are available online: titration of H 2 O 2 solution, NMRs and IRs of the new synthesized compounds.Author Contributions: Y.L.Y. conceived idea of the article; L.V.S., R.K.O., A.F., B.P., P.D. performed the experiments; L.V.S. wrote the paper, Y.L.Y. and E.M. reviewed and edited the manuscript.All authors read and approved the final manuscript.
1Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
1Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
1Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
1Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
1Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
1Composition of crude product on the basis of 19 F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300

Table 3 .
Oxidation of fluoromethyl and difluoromethyl sulfides 5. Composition of crude product on the basis of19F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300

Table 3 .
Oxidation of fluoromethyl and difluoromethyl sulfides 5. Composition of crude product on the basis of19F NMR data; 2 Crude yield is the isolated yield of product after removing the solvent before further purification;3Reaction time 4 h.
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300
H NMR spectra were recorded at 500 MHz with Bruker AVANCE DRX 500 instrument, or at 200 MHz or 300