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Article

Desulfurative Acetoxylation of Alkyl Benzyl Phenyl Sulfides

by
Daniele Canestrari
,
Umamaheswara Rao Boddu
,
Gangaram Pallikonda
and
Mauro F. A. Adamo
*
Centre for Synthesis and Chemical Biology (CSCB), Department of Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland
*
Author to whom correspondence should be addressed.
Chemistry 2025, 7(4), 131; https://doi.org/10.3390/chemistry7040131
Submission received: 25 June 2025 / Revised: 29 July 2025 / Accepted: 15 August 2025 / Published: 18 August 2025
(This article belongs to the Special Issue Organic Chalcogen Chemistry: Recent Advances)
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Abstract

The reaction of thiophenylsulfides with diacetoxyiodobenzene, iodine and light produced corresponding acetoxylated products, allowing the formation of new C-O bonds from starting materials other than carbonyls in high yields. Hence, under these conditions, thiophenylsulfide underwent displacement/substitution by an acetate. 1H-NMR studies of the reaction carried out with exclusion of each single reactant pointed at two operative pathways and to the involvement of an intermediate that was assigned as an acetoxy sulfonium (IV) species.

1. Introduction

The introduction of an acetoxy substituent on an organic framework is a general methodology to form carbon–oxygen bonds, which are ubiquitous in pharmaceuticals, agrochemicals and natural products [1]. Secondary acetoxy esters could be prepared from parent ketones via transition metal-catalyzed hydrogenation [2,3] or enzymatic reduction [3,4], followed by reaction of the resulting alcohol with an opportune acetyl halide. Acetoxy groups could be also introduced in a single step via palladium-catalyzed C–H activation [5,6,7]. To avoid using expensive transition-metal catalysts, alternative methodologies have been developed. For example, the stereoselective acetoxylation of chiral-substituted phenylacetic esters with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [8] has been reported alongside the preparation of benzylic-acetoxylated compounds via radical pathways [9]. Suarez [10] and, later on, Minakata [11] described a hypervalent iodine(III)-mediated decarboxylative acetoxylation of tertiary and benzylic carboxylic acids. The displacement of a sulfur-containing group to achieve the formation of an alkyl acetate was reported by Baldwin, in which a thio-tolyl group, present on an α-aminoacid, was replaced by an acetoxy group [12]. This reaction, reported in the context of the preparation of natural antibiotic A-32390A, involved the elimination of thiolate to form a transient imine, which underwent subsequent addition of acetate using stochiometric Hg(OAc)2. Tanaka reported the substitution of a thiophenyl group from an anomeric position of a sugar by an acetate under the catalysis of Hg(AcO)2; this transformation progressed via thiolate elimination to form an oxonium ion which subsequently reacted with an acetate [13]. In light of our previously published desulfurative halogenations [14,15,16,17], we reasoned that C-O bonds could also be installed via a desulfurative acetoxylation, where a thiophenyl alkyl sulfide is first oxidized to a sulfonium (IV) species, which then undergoes nucleophilic substitution by an acetate nucleophile. In planning the synthesis of acetates, this reaction provides an entry from starting materials different from ketones, and it would avoid the use of transition metal catalysis and hydrides. A literature survey revealed that formation of acetates from alkyl aryl sulfides was first reported by Kwart as a side product of chlorinolysis in acetic acid. Treatment of alkyl aryl sulfides with chlorine gas in acetic acid provided the product of desulfurative chlorination, i.e., an alkyl chloride, in 85% yield, alongside 15% of acetate obtained as the side product, which was formed via competitive nucleophilic substitution by the excess acetate [18]. Similarly, Mori reported the desulfurative acetoxylation of one alkyl aryl sulfide when using bromine and excess acetate [19]. This result was interpreted as arising from a preliminary desulfurative bromination to generate a transient alkyl bromide, which was then reacted in a subsequent nucleophilic substitution with the large excess of acetate present in the reaction media [19]. Herein, we report a new procedure to prepare alkyl acetates 2 or 4 from phenyl sulfides 1 or 3 (Scheme 1 and Scheme 2) that entails reacting sulfides with hypervalent PhI(OAc)2, I2 with the aid of visible LED blue light.

2. Materials and Methods

2.1. General Experimental

1H and 13C NMR spectra were recorded on a Bruker 400 spectrometer. Chemical shifts (δ) are reported in ppm relative to residual solvent signals for 1H and 13C NMR (1H NMR: 7.26 ppm for CDCl3; 13C NMR: 77.00 ppm for CDCl3). 13C NMR spectra were acquired with 1H broad band decoupled mode. Coupling constants (J) are in Hz. High-resolution mass spectra were obtained on a Waters Micromass GCT Premier MS spectrometer. Optical rotations were measured on a Perkin-Elmer 343 polarimeter. The enantiomeric excess (ee) was determined by chiral stationary phase HPLC using a Shimadzu SIL-20AHT HPLC instrument (Shimadzu, Dublin, Ireland).

2.2. Materials

Analytical-grade solvents and commercially available reagents were used as received. Dry CH2Cl2 was purchased from commercial sources. Reactions were monitored by TLC analysis (Merck, silica gel 60 F254, Darmstadt, Germany). Flash column chromatography was performed using silica gel 60 (0.040–0.063 mm, 230–400 mesh). Racemic sulfides were prepared according to published procedure and references therein [14,15]. Chiral sulfides were prepared according to the published procedure [20].

2.3. General Procedures for Desulfurative Acetoxylation of Alkyl Phenyl Sulfides (GP1)

To an oven-dried 10 mL Schlenk tube containing a stirred solution of sulfide 1 (0.2 mmol) and PhI(OAc)2 (0.4 mmol, 2.0 equiv) in dry CH2Cl2/AcOH (1.0 mL, v/v = 1:1), I2 (0.1 mmol, 0.5 equiv) was added under a N2 atmosphere, which resulted in a color change to dark red. The reaction mixture was immediately placed (2.5 cm light-glassware distance) into a blue LED photoreactor (7 W) made with a serpentine of LED strips. After 1 h at rt, the reaction was quenched with sat. aq. soln of Na2S2O3 (ca. 2 mL), which led to an immediate fading of the dark red color, and stirred for a further 2 min. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL) and the combined organic phases were washed with H2O, brine, dried over Na2SO4. The solvent was removed in vacuo and the crude material was purified by flash column chromatography on silica gel to afford the corresponding acetoxylated compound 2.
Chemistry 07 00131 sch001
Scheme 1. Desulfurative acetoxylation of alkyl phenyl sulfides 1.
Scheme 1. Desulfurative acetoxylation of alkyl phenyl sulfides 1.
Chemistry 07 00131 sch001

2.4. General Procedures for Desulfurative Acetoxylation of Alkyl Phenyl Sulfides (GP2)

To an oven-dried 10 mL Schlenk tube containing a stirred solution of sulfide 3a–h (0.2 mmol) and PhI(OAc)2 (0.4 mmol, 2.0 equiv) in dry CH2Cl2/AcOH (1.0 mL, v/v = 1:1) was added I2 (0.1 mmol, 0.5 equiv) under N2 atmosphere, which resulted in a color change to dark red. The reaction mixture was immediately placed (2.5 cm light-glassware distance) into a blue LED photoreactor (7 W) made with a serpentine of LED strips. After 16 h at rt, the reaction was quenched with sat. aq. soln of Na2S2O3 (ca. 2 mL), which led to an immediate fading of the dark red color, and stirred for a further 2 min. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL) and the combined organic phases were washed with H2O, brine, dried over Na2SO4. The solvent was removed in vacuo and the crude material was purified by flash column chromatography on silica gel to afford the corresponding acetoxylated compound 4a–h.
Chemistry 07 00131 sch002
Scheme 2. Desulfurative acetoxylation of alkyl phenyl sulfides 4a–h.
Scheme 2. Desulfurative acetoxylation of alkyl phenyl sulfides 4a–h.
Chemistry 07 00131 sch002

2.5. Analytical Data of Compounds Obtained

2.5.1. 1-Acetoxyadamantane 2a

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 97:3) as a pale-yellow oil (36 mg, 93% yield).
1H NMR (400 MHz, CDCl3) δ 2.15–2.14 (m, 3H), 2.10 (s, 6H), 1.97 (s, 3H), 1.69–1.62 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 170.3, 80.3, 41.3, 36.2, 30.8, 22.7. All analytical data are consistent with those reported in the literature [21].

2.5.2. (4-Chlorophenyl)(phenyl)methyl Acetate 2b

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a colorless oil (51 mg, 98% yield).
1H NMR (400 MHz, CDCl3) δ 7.36–7.28 (m, 9H), 6.84 (s, 1H), 2.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 139.7, 138.7, 133.8, 128.7, 128.6, 128.5, 128.1, 127.0, 76.2, 21.2. All analytical data are consistent with those reported in the literature [22].

2.5.3. (4-Bromophenyl)(phenyl)methyl Acetate 2c

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 97:3) as a colorless oil (58 mg, 95% yield).
1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 4.0, 2H), 7.37 (d, J = 4.0, 1H), 7.25–7.21 (m, 3H), 7.13 (d, J = 4.0, 1H), 7.03–6.99 9m, 2H), 5.94 (s, 1H), 2.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 139.6, 139.3, 131.6, 128.8, 128.6, 128.1, 127.2, 121.9, 21.2. All analytical data are consistent with those reported in the literature [23].

2.5.4. 1-(Naphthalen-2-yl)ethyl Acetate 2d

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a colorless oil (39 mg, 91% yield).
1H NMR (400 MHz, CDCl3) δ 7.84–7.80 (m, 4H), 7.48–7.46 (m, 3H), 6.05 (q, J = 8.2, 1H), 2.09 (s, 3H), 1.61 (d, J = 8.2, 3H); 13C NMR (101 MHz, CDCl3) δ 170.4, 139.0, 133.2, 133.0, 128.3, 128.0, 127.6, 126.2, 126.0, 125.0, 124.1, 72.4, 22.2, 21.4. All analytical data are consistent with those reported in the literature [24].

2.5.5. 1-Phenylbutyl Acetate 2e

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 97:3) as a colorless oil (30 mg, 78% yield).
1H NMR (400 MHz, CDCl3) δ 7.37–7.27 (m, 5H), 5.74 (app t, J = 8.5, 1H), 7.27–1.72 (m, 2H), 1.46–1.25 (m, 2H), 0.92 (t, J = 12.2, 1H); 13C NMR (101 MHz, CDCl3) δ 170.4, 140.8, 128.4, 127.8, 126.5, 75.9, 38.4, 21.3, 18.8, 13.8. All analytical data are consistent with those reported in the literature [23].

2.5.6. 3-Chloro-1-phenylpropyl Acetate 2f

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 97:3) as a colorless oil (17 mg, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 5.93 (dd, J = 8.2, 7.0, 1H), 3.59–3.53 (m, 1H), 3.47–3.41 (m, 1H), 2.44–2.35 (m, 1H), 2.24–2.14 (m, 1H), 2.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.0, 139.5, 128.6, 128.3, 128.4, 73.2, 40.6, 39.0, 21.1. All analytical data are consistent with those reported in the literature [25].

2.5.7. Methyl 3-Acetoxy-3-phenylpropanoate 4a

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a pale-yellow oil (38 mg, 88% yield).
1H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 6.17 (dd, J = 12.2, 4.0, 1H), 3.68 (s, 3H), 2.98 (dd, J = 12.2, 8.5, 1H), 2.76 (dd, J = 12.2, 4.0, 1H), 2.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.2, 169.8, 139.2, 128.6, 128.4, 126.4, 72.08, 51.9, 41.2, 21.1. All analytical data are consistent with those reported in the literature [26].

2.5.8. Ethyl 3-Acetoxy-3-phenylpropanoate 4b

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a colorless oil (42 mg, 89% yield).
1H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 6.17 (dd, J = 12, J = 4, 1H), 4.21 (q, J = 7, 2H), 2.96 (dd, J = 12.0, 8.4, 1H), 2.75 (dd, J = 12.0, 4.2, 1H), 2.06 (s, 3H), 1.22 (t, J = 7.0, 3H); 13C NMR (101 MHz, CDCl3) δ 168.8, 168.7, 139.2, 128.6, 128.4, 126.5, 72.1, 60.8, 41.5, 21.1, 14.1. All analytical data are consistent with those reported in the literature [27].

2.5.9. Methyl 3-Acetoxy-3-(4-chlorophenyl)propanoate 4c

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a pale-yellow oil (42 mg, 82% yield).
1H NMR (400 MHz, CDCl3) δ 7.34–7.29 (m, 4H), 6.12 (dd, J = 8.5, 7.0, 1H), 3.67 (s, 3H), 2.96 (dd, J = 12.2, 8.5, 1H), 2.75 (dd, J = 12.2, 7.0, 1H), 2.05 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.0, 169.7, 137.7, 134.2, 128.9, 128.0, 71.4, 52.0, 41.0, 21.0. All analytical data are consistent with those reported in the literature [28].

2.5.10. Ethyl 3-Acetoxy-3-(4-chlorophenyl)propanoate 4d

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a yellow oil (46 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.35–7.29 (m, 4H), 6.13 (dd, J = 8.0, 4.5, 1H), 4.13 (q, J = 7.5, 2H), 2.94 (dd, J = 16.0, 8.0) 2.73 (dd, J = 16.0, 4.0), 1.23 (t, J = 7.5, 3H); 13C NMR (101 MHz, CDCl3) δ 169.7, 169.5, 137.7, 134.2, 128.8, 128.0, 71.5, 60.9, 41.3, 21.0, 14.1. All analytical data are consistent with those reported in the literature [29,30].

2.5.11. 1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl Acetate 4e

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a white solid (39 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.0, 1H), 7.57 (d, J = 7.0, 1H), 7.47 (t, J = 7.2, 1H), 7.41 (dd, J = 8.5, 5.2 Hz, 1H), 7.04 (t, J = 8.0, 1H), 6.37 (dd, J = 7.9, 5.4 Hz, 1H), 3.71 (dd, J = 14.2, 8.0, 1H), 3.32 (dd, J = 14.2, 5.4, 1H), 2.03 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 195.9, 169.8, 136.5, 133.4, 128.7, 128.5, 128.4, 128.1, 115.6, 115.4, 71.2. HRMS (EI): C17H15FO3: [M−H]+ calculated: 285.2231, found: 285.2227.

2.5.12. Methyl-3-acetoxy-3-(o-tolyl)propanoate 4f

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 97:3) as a colorless oil (42 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.37–7.12 (m, 4H), 6.36 (dd, J = 9.2, 4.2, 1H), 3.68 (s, 1H), 2.91 (dd, J = 14.0, 9.2 Hz, 1H), 2.71 (dd, J = 14.0, 4.0 Hz, 1H), 2.45 (s, 1H), 2.05 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 170.4, 169.8, 137.7, 135.2, 130.6, 128.1, 126.4, 125.6, 69.1, 51.2, 40.6, 21.0, 19.1. HRMS (EI): C13H17O4 [M+H]+ calculated: 237.2721, found: 237.2725

2.5.13. 1-(4-Chlorophenyl)-3-oxobutyl Acetate 4g

Prepared according to GP2. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 95:5) as a white solid (43 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 6.14 (m, 1H), 3.11 (dd, J = 14.2, 8.5 Hz, 1H), 2.82 (dd, J = 14.2, 4.5 Hz, 1H), 2.16 (s, 3H), 2.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 204.3, 169.8, 138.2, 134.1, 128.8, 128.0, 70.9, 49.6, 30.5, 21.1. All analytical data are consistent with those reported in the literature [31].

2.5.14. 1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl Acetate 4h

Prepared according to GP1. The title compound was isolated by flash column chromatography (silica gel; petroleum ether/EtOAc 9:1) as a white solid (52 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.5, 1H), 7.58 (t, J = 7.5, 1H), 7.46 (t, J = 7.0, 1H), 7.42 (dd, J = 14.0, 7.2 Hz, 1H), 7.04 (t, J = 8.0, 1H), 6.37 (t, J = 7.2, 1H), 3.71 (dd, J = 14.2, 8.1, 1H), 3.32 (dd, J = 14.0, 4.2, 1H), 2.02 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 195.9, 169.8, 136.5, 133.4, 128.7, 128.5, 128.4, 128.1, 115.6, 115.4, 71.3, 44.9. HRMS (EI): C17H15ClO3 [M−H]+ calculated: 302.0751, found: 302.0753.

3. Results and Discussion

Following the studies of Minakata on the decarboxylative acetoxylation of benzylic and tertiary carbons [11], we ran a preliminary experiment in which 1-(phenylthio)adamantane 1a, PhI(OAc)2 (PIDA) and I2 were reacted in a methylene chloride (CH2Cl2) solution (Table 1, entry 1). After the addition of PIDA and I2, the resulting dark red solution was immediately placed in a simple photoreactor made by blue LED strips (7 W) and kept at room temperature. After 1 h, the reaction was quenched by addition of a sat solution of Na2S2O3 and the product distribution was determined via 1H NMR carried out on the crude mixture. This experiment showed a 60% conversion of 1a and the formation of acetoxylated 2a as the sole product of reaction. Notably, this experiment showed that indeed the reaction was viable but also that the acetate in 2a came from PIDA.
Next, we showed that the addition of acetic acid improved the reaction yield, presumably by rendering the acetoxy nucleophile more available or via H-bond catalysis as we have noted in related reactions [16]. Hence, reaction of 1a and PIDA/I2 in CH2Cl2 acetic acid (1:1) (Table 1, entry 2) provided full conversion of 1a after just 60 min to give 2a quantitatively. It was also noted that when the blue light source (Table 1, entry 3) or iodine (Table 1, entry 4) were removed, the reaction proceeded at slower rate, with conversion to 2a limited to 50–60%. The acceleration of this reaction via application of blue-led light has been repeatedly noted and pointed (vide infra).
As with previously reported acetoxylation protocols [10,11,32], it was noted that I2 was also an essential reagent to obtain full conversion. This data showed that (i) PIDA was fundamental for the proceeding of this transformation, as its removal (Table 1, entry 5) resulted in starting material being completely recovered; (ii) exclusion of I2 or blue LED light (Table 1, entries 3 and 4) produced a remarkable decrease in conversion. In conclusion, this study confirmed that desulfurative acetoxylation of alkyl tertiary sulfides such as 1a proceeded at its best when 2.0 equivalents of PIDA and 0.5 equivalents of I2 were employed in methylene chloride/acetic acid (1:1) and in the presence of a blue-light source (Table 1, entry 2).
With an optimized set of conditions in-hand, we then studied a wider range of sulfide substrates (Scheme 3). Reaction conditions used in these experiments involved reacting a sulfide 1 (0.2 mmol) and PhI(OAc)2 (0.4 mmol), I2 (0.1 mmol), solvent (1 mL, 0.2 M), blue LED strip (7 W) photoreactor. The yields reported (Scheme 3) are isolated yield after SiO2 chromatography. When the desulfurative acetoxylation protocol was applied on tertiary and secondary substrates 1a–f, corresponding compounds 2a–f were formed as the sole products, as indicated by the 1H NMR analysis of the crude of reaction. Therefore, this transformation provided remarkable selectivity, i.e., no electrophilic halogenation was noted. Compounds 2a–e were isolated in excellent yields after chromatography on silica gel. Compound 2f was equally obtained in high NMR purity after work up; however, elimination occurred during chromatographic purification, hence limiting the isolated yield to 40%. The reaction carried out on non-activated secondary or tertiary alkyl phenyl sulfides 1g,h showed a complete conversion of the starting materials; but a complex mixture of products were observed.
Having shown the feasibility of desulfurative acetoxylation on activated secondary phenyl sulfides, we directed our interest on easily accessible sulfa-Michael derived sulfides 3a–h [33]. Hence, when compounds 3a–h (Scheme 4) were reacted under the optimized conditions, benzylic acetates 4a–h were obtained in high yields. It was observed that although starting materials 3a–h disappeared within an hour from the onset of the reaction, the reaction time should be extended to 16 h to achieve good yields of 4a–h. A 1H-NMR run on crude reaction mixtures indicated that two intermediates were rapidly formed, which were persistent and required extended time to evolve to products 4a–h (vide infra). The reactions yield was independent from the presence of electron withdrawing or electron donating groups on the benzylic aromatic ring, with yields mostly depending on the stability of the resulting product and ease of isolation.
We have previously reported two enantiospecific desulfurative processes in which a thiophenyl was converted to an alkyl halide [14,15,16]. In these procedures, the sulfonium ions generated during the reaction underwent a stereo-invertive nucleophilic substitution. The SN2 mechanism of these halogenations was demonstrated by confirmation of configuration at the C-SPh and at resulting C-X (X = Cl or Br) bonds, when enantiopure sulfides were employed. Hence, to investigate the SN1 vs. SN2 mechanisms operating in the acetoxylation procedure herein discussed, we have prepared substrates (S)-3a and (S)-3c (Table 2) using the methodology reported by Wang [20], which were obtained in 97% ee. Subsequently, compounds (S)-3a and (S)-3c were subjected to reaction with 2.0 equivalents of PIDA, 0.5 equivalents of I2 and light, to give (R)-4a and (R)-4c in 18% ee (Table 2, entry 1) and 28% ee (Table 2, entry 1), respectively. This data demonstrates that at least under the currently employed conditions, a competitive SN1 mechanism is operative, with an SN2 leading to the observed inversion of configuration, being minority. The predominant presence of them (R) enantiomer in 4a–4c has been devised from the measurement of their α[D], which was (+) [33].
In order to address the role of PIDA, I2 and light in the reaction, we subjected 3a to acetoxylation under four different sets of conditions, which included the optimized one, i.e., PIDA, I2, blue-led light and acetate, and others where reactants, i.e., PIDA, blue-led light, I2, were excluded (Table 3). Each reaction was stopped at the given time, the solvent evaporated at low temperature, a crude aliquot was then dissolved in CDCl3 and the 1H NMR immediately recorded. The reaction run with PIDA, I2 and blue-led light (Table 3, Entry 1) showed that starting material 3a was completely consumed after 1 h to give ca 37% of product 4a. The 1H NMR spectrum (Table 3, Entry 1, in purple) showed the presence of a ca 43%, of a species which was identified as diastereoisomeric intermediates 6 (see Figure S16).
In a second experiment, we reacted 3a and PIDA, without I2 and with exclusion of any source of light, (Table 3, Entry 2, in cyan). This experiment indicated that PIDA only is not able to provide conversion, with only some alkene 5 been formed, presumably because of the acidic reaction media. It could not be excluded that a proportion of compound 6 could also be formed during work up. In a next experiment, we reacted 3a and PIDA (Table 3, Entry 3, in green) but allowing laboratory ambient light on the reaction. This experiment demonstrated that a small amount of 4a and sulfoniums 6 were formed, although starting material 3a was the main compound present. Finally, the reaction of 3a and PIDA was run with complete exclusion of internal ambient and blue-led light, but in the presence of 0.5 eq. of I2 (Table 3, Entry 4, in red). This latter experiment showed complete conversion of 3a just after 2 h, with 58% of 4a being formed and 21% of intermediates 6 still being present. This latter experiment highlighted also the presence of ca 7% of methyl 3-hydroxy-3-phenylpropanoate (dd at 5.12 ppm) [34] which may form during work up from intermediates 6.
In summary, this set of experiments demonstrated that the reaction does not require light or irradiation when I2 is present, demonstrating the importance of AcOI 8 (Scheme 5) as the oxidant for the sulfide. In this context, Minakata showed that reaction of PIDA and I2 generates AcOI, which we propose as the primary oxidant for the sulfide in this reaction [11]. However, it should be noted that sulfide 4a can undergo desulfurative acetoxylation in the presence of light even when I2 was not present, although at a much slower rate. Based on this observation, we have formulated the proposed mechanism (Scheme 5), highlighted below.
Initially, reaction of PhI(OAc)2 and I2 generates, independently of hv, AcOI 7 [11], which is described as a fast reaction. Subsequent reaction of 7 and sulfides 8 provided sulfonium species 9. Reaction of 9 with excess acetate led to compound 10. Considering the data collated and discussed in Table 3, a second pathway must be operative that involves PhI(OAc)2 and light. This slower process, which is well documented [35], involves the homolytic cleavage of the PhI-OAc bond in PIDA, leading to iodobenzene 11 and radicals 12. Reaction of 12 with sulfide 8 will lead to sulfonium 14, leading finally to product 10. We have tried the reaction in the presence of 1 to 10 equiv of TEMPO; however, in these experiments, no notable difference has been noted in the conversion vs. time and in the product distribution.

4. Conclusions

In conclusion, we have reported a novel procedure for the acetoxylation of alkyl phenyl sulfides. This reaction provides a new disconnection to form C-O bonds. The methodology is mild and tolerates functional groups including ketones, esters and does not lead to aromatic substitution. NMR studies have led to the identification of sulfonium species which showed remarkable stability and that will be used for the development of enantiospecific procedures, which are currently under development. We believe this study will be of interest for those who are concerned with the generation of libraries of compounds for medicinal chemistry screening [36] both in academia and industry.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry7040131/s1: Figure S1: 1H-NMR and 13C-NMR of 2a; Figure S2: 1H-NMR and 13C-NMR of 2b; Figure S3: 1H-NMR and 13C-NMR of 2c; Figure S4: 1H-NMR and 13C-NMR of 2d; Figure S5: 1H-NMR and 13C-NMR of 2e; Figure S6: 1H-NMR and 13C-NMR of 2f; Figure S7: 1H-NMR and 13C-NMR of 5a; Figure S8: 1H-NMR and 13C-NMR of 5b; Figure S9: 1H-NMR and 13C-NMR of 5c; Figure S10: 1H-NMR and 13C-NMR of 5d; Figure S11: 1H-NMR and 13C-NMR of 5e; Figure S12: 1H-NMR and 13C-NMR of 5f; Figure S13: 1H-NMR and 13C-NMR of 5g; Figure S14: 1H-NMR and 13C-NMR of 5h; Figure S15: characterization of intermediate 6; Figure S16: 1H-1H-COSY NMR of intermediate 6; Figure S17: HPLC traces of (±)-5a and (+)-(R)-5a; Figure S18: HPLC traces of (±)-5c and (+)-(R)-5c; Copies of 1H-NMR and 13C-NMR for compounds 2a–f and 5a–h; Experimental data concerning the characterisation of intermediates 7; procedure for the Enantiospecific desulfurative acetoxylation; HPLC traces of optically active compounds 5a and 5c.

Author Contributions

Conceptualization, M.F.A.A.; methodology and investigation D.C., G.P. and U.R.B.; M.; resources, M.F.A.A.; writing—original draft preparation, M.F.A.A.; funding acquisition, M.F.A.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Irish Research Council (IRC), grant number GOIPG/2015/3942 and Enterprise Ireland, grant number CF-2018-0980-P.

Conflicts of Interest

The authors declare no conflicts of interest.

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Chemistry 07 00131 sch003
Scheme 3. Acetoxylation of alkyl phenyl sulfides.
Scheme 3. Acetoxylation of alkyl phenyl sulfides.
Chemistry 07 00131 sch003
Chemistry 07 00131 sch004
Scheme 4. Acetoxylation of sulfa-Michael-derived sulfides.
Scheme 4. Acetoxylation of sulfa-Michael-derived sulfides.
Chemistry 07 00131 sch004
Chemistry 07 00131 sch005
Scheme 5. Proposed mechanism for the desulfurative acetoxylation.
Scheme 5. Proposed mechanism for the desulfurative acetoxylation.
Chemistry 07 00131 sch005
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Chemistry 07 00131 i001
Entry Oxidant Solvent 1a:2a:3a b
1 PIDA CH2Cl2 40:60:0
2 PIDA CH2Cl2/AcOH (1:1) 0:100:0
3 c PIDA CH2Cl2/AcOH (1:1) 50:50:0
4 d PIDA CH2Cl2/AcOH (1:1) 40:60:0
5 – CH2Cl2/AcOH (1:1) 100:0:0
a Reaction conditions unless stated: 1a (0.2 mmol), PhI(OAc)2 (0.4 mmol), I2 (0.1 mmol), solvent (1 mL, 0.2 M), blue LED strip (7W) photoreactor. b Conversion of 1a and relative ratios of product 2a was determined by 1H NMR spectroscopy of the crude mixture after sat. aq. Na2S2O3 quench (ca. 2 mL). c Reaction performed in the dark. d Reaction performed without I2.
Table 2. Acetoxylation of chiral alkyl phenyl sulfides (R)-4a and (R)-4c a.
Table 2. Acetoxylation of chiral alkyl phenyl sulfides (R)-4a and (R)-4c a.
Chemistry 07 00131 i002
Entry Substrate Conversion of 3 ee of 4 ber
1 (S) -3a 100 18% 59:41
2 (S) -3c 100 28% 64:36
a Reaction conditions unless stated: 3 (0.2 mmol), PhI(OAc)2 (0.4 mmol), I2 (0.1 mmol), solvent (1 mL, 0.2 M), blue LED strip (7 W) photoreactor. b Desired 4 was isolated by column chromatography on silica gel (PE:EtOAc = 95:5) and ees were determined by HPLC analysis on chiral stationary phase.
Table 3. Acetoxylation of sulfide 3a under different conditions.
Table 3. Acetoxylation of sulfide 3a under different conditions.
Chemistry 07 00131 i003
Entry PIDA I2 Light Time 3a 4a 5 6
1 Yes Yes Yes 1 h 0% 37% 6% 43%
2 Yes No No 4 h 88% 0% 12% 0%
3 Yes No Yes 4 h 63% 4% 21% 12%
4 Yes Yes No 2 h 0% 58% 15% 21%
Chemistry 07 00131 i004
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MDPI and ACS Style

Canestrari, D.; Boddu, U.R.; Pallikonda, G.; Adamo, M.F.A. Desulfurative Acetoxylation of Alkyl Benzyl Phenyl Sulfides. Chemistry 2025, 7, 131. https://doi.org/10.3390/chemistry7040131

AMA Style

Canestrari D, Boddu UR, Pallikonda G, Adamo MFA. Desulfurative Acetoxylation of Alkyl Benzyl Phenyl Sulfides. Chemistry. 2025; 7(4):131. https://doi.org/10.3390/chemistry7040131

Chicago/Turabian Style

Canestrari, Daniele, Umamaheswara Rao Boddu, Gangaram Pallikonda, and Mauro F. A. Adamo. 2025. "Desulfurative Acetoxylation of Alkyl Benzyl Phenyl Sulfides" Chemistry 7, no. 4: 131. https://doi.org/10.3390/chemistry7040131

APA Style

Canestrari, D., Boddu, U. R., Pallikonda, G., & Adamo, M. F. A. (2025). Desulfurative Acetoxylation of Alkyl Benzyl Phenyl Sulfides. Chemistry, 7(4), 131. https://doi.org/10.3390/chemistry7040131

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