Rapid Photoracemization of Chiral Alkyl Aryl Sulfoxides

Abstract

The photoracemization of chiral alkyl aryl sulfoxides with a photosensitizer has not been sufficiently investigated thus far. Therefore, in this study, a rapid photoracemization reaction of enantiopure alkyl aryl sulfoxides using 1 mol % 2,4,6-triphenylpyrylium tetrafluoroborate (TPT⁺) was developed. Various substitution patterns were tolerated and every racemization reaction proceeded extremely fast (k₂ = 1.77 × 10⁴–6.08 × 10¹ M^–1 s^–1, t_1/2 = 0.4–114 s). Some chiral sulfoxides with easily oxidizable functional groups are not appropriate for this photoisomerization. The electrochemical potentials of the functional groups, determined via cyclic voltammetry, are useful for predicting the reactive or nonreactive groups in this photoracemization reaction. A theoretical study was conducted to clarify the sp²-like nature of S of the sulfoxide cation radical, which makes photoracemization easier.

Introduction

Chiral sulfoxides are important bioactive compounds and intermediates in chemical reactions.¹ The thermal stability of chiral sulfoxides is one of their characteristic properties. It has been elucidated that the pyramidal inversion of a sulfur center requires 159.1–171.7 kJ/mol, which entails substantially extreme conditions (temperatures of around 200 °C).² However, the racemization of chiral sulfoxides by photoirradiation is also possible.³ The envisaged reaction mechanism is the inversion of the pyramidal center of sulfur or α-cleavage and recombination of the radical fragments.⁴ Since the initial reports by Mislow et al.,⁵ the pyramidal inversion of some alkyl aryl sulfoxides in the presence of a photosensitizer has been investigated.⁶ In that case, it was concluded that racemization occurs in an exciplex between the photosensitizer and sulfoxide.⁷ Recently, Lanzalunga’s group has reported that the use of N-methyl quinolinium tetrafluoroborate (NMQ⁺) enabled partial racemization up to 33% ee via 5 min of irradiation⁸ (k₂ = 3.60 × 10^–1 M^–1 s^–1, t_1/2 = 24.5 min);⁹ they showed electron transfer processes involving the reversible formation of sulfoxide radical cations. These results prompted us to investigate the photoracemization reaction in the presence of a photosensitizer. We anticipated that quick racemization of sulfoxides should be applicable to technology, such as the dynamic kinetic resolution.¹⁰ Herein, we report the high-speed photoracemization of chiral alkyl aryl sulfoxides using a photosensitizer 2,4,6-triphenylpyrylium tetrafluoroborate (TPT⁺). Some sulfoxides with specific functional groups resist photoracemization, and this is appropriately assessed based on cyclic voltammograms.

Results and Discussion

Preparation of Alkyl Aryl Sulfoxides

For the preparation of alkyl aryl sulfoxides 1, the corresponding alkyl aryl sulfides 2 were oxidized. Although most of sulfides 2 were purchased, sulfide 2w was prepared from commercially available alkyl chloride 3 using Williamson etherification (Scheme 1).

Scheme 1. Preparation of 2w from 3.

As shown in Scheme 2, except for commercially available 1a,¹¹⁻¹³1b,¹¹⁻¹⁴1k,^11,15 and 1t,¹⁵ oxidation of sulfides 2c–2j, 2l–2q, 2s, 2u, and 2w proceeds smoothly to provide corresponding sulfoxides 1 as racemates (34–92%).

Scheme 2. Preparation of 1 from 2.

Furthermore, sulfoxides with the functionalized alkyl moiety 1r(16) and 1v were synthesized from sulfoxides 1n and 1t, respectively (Scheme 3).

Scheme 3. Preparation of 1r and 1v.

Each chiral sulfoxide (+)-1a–w was obtained by chiral high-performance liquid chromatography (HPLC) separation of the corresponding racemates 1a–w (see the Supporting Information).

Photoracemization of Alkyl Aryl Sulfoxides

First, we evaluated catalysts (A–H) for the photoisomerization of enantiopure methyl p-tolyl sulfoxide{(+)-1a} (>98% ee) in MeCN (Table 1). The enantiomeric ratio was determined by chiral HPLC. Upon irradiation of a 10 mM solution of (+)-1a using an 18 W blue light-emitting diode (LED) (λ = 425 nm) for 10 min, no reaction was observed without the photosensitizer (entry 1). The widely used photosensitizers perylene diimide (A), 9-cyano anthracene (B), thioxanthone (C), and fluorescein (D) were ineffective at the maximum absorption wavelength of the photosensitizer (entries 2–5). However, the addition of Mes-Acr-Me⁺ (E), DDQ (F), or 6-MeO-NMQ⁺ (G) at 1 mol % induced racemization at the optimal wavelength (entries 6–8). HPLC and ¹H NMR analyses confirmed that no residual product, except for the racemate of 1a, was obtained. Notably, TPT⁺ (H) gave the most desirable results (entries 9 and 10). Upon irradiation with 365 nm light, racemization occurred very quickly (k₂ = 1.36 × 10³ M^–1 s^–1, t_1/2 = 5 s) (entry 9).

Table 1. Screening of Reaction Conditions for Racemization of 1a¹¹⁻¹³.

entry	catalyst	wavelength (nm)	t1/2 (s)	k2 (M–1 s–1)
1		425
2	A	525–530
3	B	365
4	C	380
5	D	450–455
6	E	425	106	6.57 × 101
7	F	380	71	9.82 × 101
8	G	365	30	2.28 × 102
9	H	365	5	1.36 × 103
10	H	425	2	3.19 × 103

Furthermore, irradiation with 425 nm light induced the most rapid interconversion of the sulfoxides (k₂ = 3.19 × 10³ M^–1 s^–1, t_1/2 = 2 s) (entry 10). The reaction rates of racemization were examined, and the reactions were shown to follow first-order kinetics. Thus, the second-order rate constants, k₂, were calculated based on the pseudo-first-order rate constants, k_obs (see the Supporting Information). Having determined the optimized conditions, we investigated the substrate scope (Scheme 4).

Scheme 4. Substrate Scope of Racemization of Sulfoxides.

In addition to methyl phenyl sulfoxide (1b),¹¹⁻¹⁴ aromatic moieties containing various functional groups were tolerated (1c,¹¹⁻¹³1d,¹⁷1e,^11,12,141f,^11,121g,¹²1h,¹²1i,¹²1j,¹²). Additionally, alkyl groups attached to the sulfur atom (1k,^11,151l¹⁴) and functionalized alkyl (1m,¹¹1n,¹²1o,¹⁸1p,¹⁷1q,¹⁹1r,¹⁶), tolyl (1s²⁰), and vinyl (1t¹⁵) groups were also rapidly racemized. Investigation of the reaction scope revealed that various substitution patterns were tolerated and every racemization reaction proceeded extremely fast (k₂ = 1.77 × 10⁴–6.08 × 10¹ M^–1 s^–1, t_1/2 = 0.4–114 s). Although most functional groups were tolerated, no photoracemization was observed in several sulfoxides (1u–w). HPLC and ¹H NMR analyses confirmed quantitatively that the starting chiral materials were recovered after 10 min of irradiation. Certain functional groups (dimethylamino, pyrrolidyl, anisyloxy) appeared to hinder photoracemization. The observed drastic effect of the functional groups on the reactivity prompted us to examine the electrochemical potentials of sulfoxides via cyclic voltammetry.

Cyclic Voltammograms of Alkyl Aryl Sulfoxides

All alkyl aryl sulfoxides exhibited irreversible cyclic voltammograms (see the Supporting Information). It was found that the cyclic voltammograms of 1a–t were similar, whereas those of 1u–w were different.

The cyclic voltammograms of 1a are shown in Figure 1. In 1a–t, the highest peak (E_pa1) was observed around +1.94 to +2.25 V against the saturated calomel electrode (SCE). This common peak (E_pa1) was attributed to the sulfoxide. By contrast, 1v and 1w exhibited additional peaks at lower potentials. In the cyclic voltammograms of 1v, the peak observed at a lower potential (E_pa2 = +1.05 V vs SCE) was comparable to that of the pyrrolidinyl group. Similarly, in the cyclic voltammograms of 1w, the peak observed at a lower potential (E_pa2 = +1.51 V vs SCE) was comparable to that of the 4-methoxyphenoxyl group. For a rough analysis of the electrochemical potential of each functional group above, the data reported by Nicewicz’s group²¹ were used as a reference. It should be noted that the additional oxidation occurring at other functional groups is observed at a lower potential (E_pa2) compared with that of the sulfoxide group (E_pa1). Hence, they were more susceptible to oxidation. In accordance with this interpretation, when the photoreaction was performed in the alkyl aryl sulfoxides 1u–w, the more easily oxidized groups should be oxidized first. Therefore, the sulfoxide that is less susceptible to oxidation might evade photoracemization. To confirm this hypothesis, the photoracemization of (+)-1b was examined in the presence of the additives 4 (N,N-dimethylaniline), 5 (1-methyl pyrrolidine), and 6 (1,4-dimethoxybenzene), which are contained in 1u–w as functional groups (Scheme 5). When 1 equivalent of compound 4 was added to the MeCN solution of chiral methyl phenyl sulfoxide (+)-1b, irradiation (425 nm, 18 W, 1 mol % TPT⁺) for 10 min caused no reaction, and (+)-1b was recovered.²² The addition of compounds 5 and 6 produced the same results.

Figure 1.

Cyclic voltammograms of 1a, 1v, and 1w in MeCN.

Scheme 5. Photoreaction of (+)-1b in the Presence of Compounds 4–6.

In the cyclic voltammograms of compounds 4–6, a lower peak (E_pa) than that of sulfoxide was observed (compound 4: +0.88 V vs SCE, compound 5: +1.01 V vs SCE, compound 6: +1.46 V vs SCE) (see the Supporting Information). It was clarified that the presence of easily oxidizable compounds inhibited photoracemization of chiral sulfoxide intermolecularly. Therefore, compounds 1u–w, in which compounds 4–6 were contained as functional groups, have correspondingly lower potential peaks (E_pa2) in cyclic voltammograms. Thus, it was elucidated that chiral alkyl aryl sulfoxides with easily oxidizable functional groups are not appropriate for such photoisomerization. It was also suggested that the electrochemical potentials of the functional groups, determined via cyclic voltammetry, are useful for predicting the reactive or nonreactive groups in this photoracemization reaction.

Calculation Study

We hypothesized a reaction mechanism based on the proposal of Lanzalunga’s group;⁸ the oxidation of chiral sulfoxide (+)-1a by excited TPT (*TPT⁺) would form a sulfoxide radical cation, which is a key intermediate in the racemization process. Thus, the geometry of the sulfoxide radical cation of 1a was optimized by density functional theory (DFT) calculations. Computations were performed with Gaussian 16,A.03,²³ and the geometries of (+)-1a* and its 1e-oxidized cation radicals ((+)-1a^•+) were optimized using the M05-2X functional²⁴ with the 6-311+G(3df,2p) basis set.²⁵ The structures and selected bond lengths and angles are depicted in Figures 2–5 and the Supporting Information (Figures S2–S3 and Tables S2–S3). The method and the basis set were chosen according to prior reports of calculations on various sulfoxides that gave reliable structural and thermodynamic parameters.²⁶ Additionally, among the methods and basis sets tested,²⁷ the S–O bond lengths of the optimized structure provided reasonable results with the structural parameters of aryl sulfoxides reported in the CCDC database.²⁸ In the structures of (+)-1a and [(+)-1a]^•+, the sulfur atom constituted a pyramidal geometry, with S–O being nearly coplanar to the Ar ring; ϕ₁: 6.2 and −7.5°, respectively. The defined torsion angle ϕ₂ for (+)-1a was 79.1°, whereas that of the corresponding radical cation was 51.5°, which was significantly lower than that of the neutral one (Figure 2). The structural change indicates that the geometry of S changed from an sp³-like to sp²-like nature (Figures 3 and 4), resulting in a more planar placement of CAr, S, O, and CCH₃ than that of the neutral species. These structural changes should lower the inversion barrier of the R₂S–O group to make the racemization process much easier for the radical cation than for the neutral sulfoxide. Additionally, the increase in positive charges at the S–R fragment in [(+)-1a]^•+ from the parent neutral substrate and the localization of spin densities on the S and O atoms support the CV data, indicating that 1e oxidation occurs at the sulfoxide unit (Figure 5).

Figure 2.

Selected dihedral angles of (a) (+)-1a and (b) (+)-1a^•+.

Figure 5.

Mulliken charges and spin densities (in square brackets) with hydrogens summed into heavy atoms for (a) (+)-1a and (b) (+)-1a^•+.

Figure 3.

Selected bond lengths of (a) (+)-1a and (b) (+)-1a^•+.

Figure 4.

Selected angles of (a) (+)-1a and (b) (+)-1a^•+.

Conclusions

In conclusion, we achieved the rapid photoracemization of chiral alkyl aryl sulfoxides in the presence of 1 mol % TPT⁺. The acceleration effect of TPT⁺ was extremely high, and a wide substrate scope was elucidated. However, some sulfoxides with functional groups (dimethylamino, pyrrolidyl, anisolyloxy) resisted racemization. It was revealed that the electrochemical potentials of these functional groups determined by cyclic voltammograms are lower than those of sulfoxides. The presence of such easily oxidizable functional groups hindered photoracemization of sulfoxides since they should be oxidized in advance of sulfoxides. It is suggested that the electrochemical potentials of the functional groups, determined via cyclic voltammetry, are useful for predicting the reactive or nonreactive nature of this photoracemization reaction. Furthermore, DFT calculations of the geometry of the sulfoxide radical cation were performed to clarify the sp²-like nature of S of the sulfoxide, which supported the reaction mechanism proposed by Lanzalunga’s group. The rapid photoracemization of chiral sulfoxides should be applied to a novel dynamic kinetic resolution to provide the desired optical isomers efficiently, which is now under investigation.

Experimental Section

General Experimental Procedure

All reagents were purchased from commercial suppliers and used as received. Compounds 1a, 1b, 1k, 1t, 4, 5, and 6 are commercially available. Reaction mixtures were stirred magnetically, and the reactions were monitored by thin-layer chromatography (TLC) on precoated silica gel plates. For the reactions that require heating, an oil bath was used. Column chromatography was performed using silica gel (45–60 μm). Extracted solutions were dried over anhydrous MgSO₄ or Na₂SO₄. Solvents were evaporated under reduced pressure. NMR spectra were recorded on a spectrometer at 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR at 296 K unless otherwise stated. Chemical shifts are given in parts per million (ppm) downfield from tetramethylsilane as an internal standard, and coupling constants (J) are reported in hertz (Hz). Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). The high-resolution mass spectra (HRMS) were recorded using an ESI/TOF mass spectrometer. IR spectra were recorded on an FTIR spectrometer equipped with ATR (diamond). Melting points were recorded on a melting point apparatus and were uncorrected. For irradiation with LEDs, an optical irradiation device (EvoluChemTM PhotoRedOx Box) and chemistry screening kits (HepatoChem Inc., Massachusetts) were used. Chiral sulfoxides were irradiated at rt with blue LED light (28 mW/cm²) at a distance of 5 cm from the light source.

General Procedure for Preparation of Chiral Sulfoxides 1a–w

For chiral HPLC charts of 1a–w and their optical properties, see the Supporting Information. The optical purity of each chiral sulfoxide was determined by chiral HPLC analysis. For chiral HPLC charts of the chiral sulfoxides, see the Supporting Information.

General Procedure for Racemization of 1a–w

A piece of vial tube containing a solution of TPT⁺ (0.08 mg, 0.0002 mmol, 1.0 mol %) and (R)-(+)-1a (3.08 mg, 0.02 mmol) in MeCN was irradiated in a photoreactor equipped with blue LEDs (420 nm; 18 W) using PhotoRedOx Box EvoluChem at 25 °C. The extent of racemization was determined by HPLC analysis on a CHIRALPAK IG column using 100% acetonitrile as the mobile phase (flow rate = 0.5 mL/min) (retention times of 15.9 and 18.5 min for (R)-(+)-1a and (S)-(−)-1a, respectively).

Since compounds 1a–u and sulfides except for 2w are known compounds and purchased from commercial suppliers, their ¹ H NMR and ¹³C NMR characterization data are omitted.

General Procedure for the Preparation of 1a–w

To a stirred solution of methyl p-tolyl sulfide (1.0 mL, 7.5 mmol) in CH₂Cl₂ (25 mL) was added mCPBA (8.25 mmol, 1.1 equiv). After the mixture was stirred at rt for 1 h, the residue was diluted with aq. NaHCO₃ and extracted with CH₂Cl₂. The extract was washed with brine, dried, and concentrated in vacuo. The residue was purified by column chromatography to afford rac-1a as a colorless oil (888 mg, 5.75 mmol, 77% yield).

Preparation and Characterization of Sulfoxides 1a–u

4-Methoxyphenyl Methyl Sulfoxide (rac-1c)

The general procedure was followed starting from 4-methoxyphenyl methyl sulfide (0.5 mL, 3.60 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:3) to yield rac-1c as a colorless oil (415 mg, 2.44 mmol, 69% yield).

4-Formylphenyl Methyl Sulfoxide (rac-1d)

The general procedure was followed starting from 4-(methylthio)benzaldehyde (1.30 mL, 10.0 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to yield the desired rac-1d as a white solid (1.15 g, 6.82 mmol, 68% yield, mp 88–90 °C).

4-Nitrophenyl Methyl Sulfoxide (rac-1e)

The general procedure was followed starting from 2-chloroethyl phenyl sulfide (1.69 g, 10 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to yield the desired rac-1e as a white solid (0.64 g, 3.43 mmol, 34% yield, mp 153–155 °C).

4-Chlorophenyl Methyl Sulfoxide (rac-1f)

The general procedure was followed starting from 2-chloroethyl phenyl sulfide (0.50 g, 3.85 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:3) to yield the desired rac-1f as a colorless oil (0.527 g, 3.02 mmol, 78% yield).

4-Fluorophenyl Methyl Sulfoxide (rac-1g)

The general procedure was followed starting from 4-fluorophenyl methyl sulfide (0.50 mL, 4.08 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:3) to yield the desired rac-1g as a colorless oil (376 mg, 2.38 mmol, 58% yield).

3-Fluorophenyl Methyl Sulfoxide (rac-1h)

The general procedure was followed starting from 3-fluorophenyl methyl sulfide²⁹ (1.22 mL, 10 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to yield the desired rac-1h as a colorless oil (1.27 g, 8.03 mmol, 80% yield).

3-Fluorophenyl Methyl Sulfoxide (rac-1i)

The general procedure was followed starting from 3-fluorophenyl methyl sulfide (1.22 g, 10 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to yield the desired rac-1i as a colorless oil (0.95 g, 5.98 mmol, 60% yield).

2-Pyridyl Methyl Sulfoxide (rac-1j)

The general procedure was followed starting from methyl 2-pyridyl sulfide²⁹ (2.23 mL, 20.0 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1) to yield the desired rac-1j as a colorless oil (1.86 g, 13.2 mmol, 66% yield).

Cyclopropyl Phenyl Sulfoxide (rac-1l)

The general procedure was followed starting from cyclopropyl phenyl sulfide (1.0 mL, 7.00 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:3) to yield the desired rac-1l as a colorless oil (1.03 g, 6.21 mmol, 80% yield).

2-Chloroethyl Phenyl Sulfoxide (rac-1m)

The general procedure was followed starting from 2-chloroethyl phenyl sulfide (1.46 mL, 10 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1) to yield the desired rac-1m as a colorless oil (1.65 g, 8.76 mmol, 88% yield).

2-Hydroxyethyl Phenyl Sulfoxide (rac-1n)

The general procedure was followed starting from 2-hydroxyethyl phenyl sulfide (2.68 mL, 20 mmol) to give the crude product, which was purified by column chromatography on silica gel (dichloromethane/methanol 19:1) to yield the desired rac-1n as a colorless oil (1.20 g, 7.05 mmol, 35% yield).

2-Methoxyethyl Phenyl Sulfoxide (rac-1o)

The general procedure was followed starting from 2-methoxyethyl phenyl sulfide (968 mg, 5.75 mmol) to give the crude product, which was purified by column chromatography on silica gel (dichloromethane/methanol 9:1) to yield the desired rac-1o as a colorless oil (893 mg, 4.85 mmol, 84% yield).

Ethyl Phenylsulfinyl Acetate (rac-1p)

The general procedure was followed starting from ethyl (phenylthio)acetate³⁰ (0.97 mL, 5.6 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:2) to yield the desired rac-1p as a colorless oil (1.00 g, 4.71 mmol, 84% yield).

Methyl 3-(Phenylsulfinyl)propanoate (rac-1q)

The general procedure was followed starting from methyl 3-(phenylsulfinyl)propanoate (69.7 mg, 0.355 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:1) to yield the desired rac-1q as a colorless oil (45.8 mg, 0.216 mmol, 61% yield).

1-Acetate 2-(Phenylsulfinyl)-ethanol (rac-1r)

To a stirred solution of 2-hydroxyethyl phenyl sulfoxide 1n (340 mg, 2.0 mmol) in CH₂Cl₂ (5 mL) were added acetic anhydride (0.380 mL, 4.0 mmol, 2.0 equiv) and pyridine (0.40 mL, 5.0 mmol, 2.5 equiv). After the mixture was stirred at rt overnight, the mixture was treated with H₂O and extracted with CH₂Cl₂. The extract was washed with brine, dried, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1:1) to afford 1r (346 mg, 1.63 mmol, 82% yield) as a colorless oil.

4-Methyl Phenyl Sulfoxide (rac-1s)

The general procedure was followed starting from phenyl p-tolyl sulfide³¹ (4.0 mL, 21.7 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1) to yield the desired rac-1s as a white solid (3.07 g, 14.2 mmol, 65% yield, mp 64–66 °C).

N,N-Dimethyl-4-(methylsulfinyl)benzenamine (rac-1u)¹³

The general procedure was followed starting from N,N-dimethyl-4-(methylthio)benzenamine³² (488 mg, 2.92 mmol) to give the crude product, which was purified by column chromatography on silica gel (dichloromethane/methanol 19:1) to yield the desired rac-1u as a white solid (395 mg, 2.16 mmol, 82% yield, mp 65–67 °C).

1-[2-(Phenylsulfinyl)ethyl]-pyrrolidine (rac-1v)

To a stirred solution of pyrrolidine (1.29 mL, 15.6 mmol, 2.0 equiv) in MeOH (7.8 mL) was added phenyl vinyl sulfoxide 1t (1.02 mL, 7.8 mol). After the mixture was stirred at 50 °C for 2 h, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, CH₂Cl₂/MeOH = 20:1) to afford the desired rac-1v (1.44 g, 6.43 mmol, 82% yield) as a colorless oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.61–7.66 (m, 2H), 7.48–7.53 (m, 3H), 2.88–3.05 (m, 3H), 2.59–2.67 (m, 1H), 2.51–2.54 (m, 4H), 1.73–1.82 (m, 4H). ¹³C{¹H} NMR (CDCl₃, 100 MHz) δ 144.2, 131.0, 129.3, 129.3, 124.2, 124.2, 56.9, 54.1, 54.1, 49.0, 23.6, 23.6; IR (ART) 2962, 2788, 1444, 997 cm^–1; HRMS (ESI-TOF) m/z: [M + Na]⁺. Calcd for C₁₂H₁₇NOSNa 246.0923; found 246.0925.

1-Methoxy-4-[2-(phenylsulfinyl)ethoxy]benzene (rac-1w)

The general procedure was followed starting from 1-methoxy-4-[2-(phenylthio)ethoxy]-benzene (871 mg, 3.00 mmol) to give the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:1) to yield the desired rac-1w as a white solid (850 mg, 2.77 mmol, 92% yield, mp 92–95 °C): ¹H NMR (CDCl₃, 400 MHz) δ 7.65–7.69 (m, 2H), 7.52–7.54 (m, 3H), 6.82 (s, 4H), 4.43 (ddd, 1H, J = 5.2, 6.0, 12.8 Hz), 4.17 (ddd, 1H, J = 5.2, 5.2, 10.8 Hz), 3.77 (s, 3H), 3.12–3.24 (m, 2H). ¹³C{¹H} NMR (CDCl₃, 100 MHz) δ 154.4, 152.2, 143.9, 131.2, 131.2, 129.4, 129.4, 124.0, 124.0, 115.9, 115.9, 114.8, 114.8, 61.6, 57.5, 55.8; IR (ART) 1507, 1218, 1034, cm^–1; HRMS (ESI-TOF) m/z: [M + Na]⁺. Calcd for C₁₅H₁₆O₃SNa 299.0712; found 299.0711.

1-Methoxy-4-[2-(phenylthio)ethoxy]-benzene (2w)

To a stirred solution of 4-methoxy phenol (1.66 g, 13.4 mmol, 1.34 equiv) in EtOH (25 mL) and H₂O (10 mL) were added potassium hydroxide (726 mg, 11.0 mmol, 1.1 equiv) and 2-chloroethyl phenyl sulfide (1.46 mL, 10.0 mmol). After the mixture was stirred at reflux overnight, the mixture was filtered and washed with H₂O. The residue was recrystallized with hot hexane to afford 1-methoxy-4-[2-(phenylthio)ethoxy]-benzene 2w as a white solid (2.20 g, 7.59 mmol, 76% yield, mp 82–84 °C): ¹H NMR (CDCl₃, 400 MHz) δ 7.41 (d, 2H, J = 7.2 Hz), 7.30 (t, 2H, J = 7.2 Hz), 7.21 (t, 1H, J = 7.2 Hz), 6.81 (s, 4H), 4.10 (t, 2H, J = 7.6 Hz), 3.76 (s, 3H), 3.27 (t, 2H, J = 7.2 Hz). ¹³C{¹H} NMR (CDCl₃, 100 MHz) δ 154.2, 152.6, 135.6, 129.9, 129.9, 129.1, 129.1, 126.6, 115.8, 115.8, 114.7, 114.7, 67.5, 55.8, 33.0; IR (ART) 1190, 1021, 817, cm^–1; HRMS (ESI) m/z: [M]⁺. Calcd for C₁₅H₁₆O₂S 260.0871; found 260.0870.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c02320.

• Pseudo-first-order rate constants, k_obs, and second-order rate constants, k₂; electrochemical measurements, cyclic voltammograms of 1a–w, 4–6; computational details; chiral HPLC charts of 1a–w and their optical properties; optical purity of (+)-1a–w; ¹H-, ¹³C-, and 2D-NMR spectra of 1v, 2, 1w; and recovery of 1u–w after irradiation for 10 min (PDF)

The authors declare no competing financial interest.