K₂CO₃-Catalyzed Rapid Conversion of N-Sulfonylhydrazones to Sulfinates

Abstract

N-Sulfonylhydrazones derived from alkyl, aryl, and heteroaryl aldehydes and ketones undergo rapid conversion into the corresponding sulfinates when heated with 10 mol % K₂CO₃ in N,N′-dimethylethylene urea (DMEU) at elevated temperature. The reaction conditions are amenable to several functional groups and suitable for gram-scale synthesis. Under these base-catalyzed conditions, N-tosylhydrazones derived from O-allylated and O-propargylated 2-hydroxyarylaldehydes do not undergo the well-established intramolecular [3 + 2]-cycloaddition reactions and generate corresponding sulfinates in good yields. The base-catalyzed transformation proceeds via crucial rapid intermolecular protonation of the diazo intermediate 11 to generate diazonium ion 12, which upon nucleophilic displacement by the sulfonyl ion 10 provides the desired sulfinate selectively.

Introduction

Sulfinates are a class of sulfur-containing molecular entities that are important in terms of their biological activities as well as from the synthetic point of view.¹ A few sulfinates have been reported to exhibit cytotoxic activity against leukemia cell lines in humans.² Sulfinates also act as bioluminescent sensors for the detection of thiols in living cells.³ Synthetically, sulfinates have acquired considerable importance owing to their elegant dual reactivity as electrophiles or as nucleophiles under suitable reaction conditions.⁴ Chiral sulfinates are often utilized as convenient building blocks in the asymmetric synthesis of sulfur-containing compounds such as sulfoxides and sulfonamides.⁵ Due to these widespread applications, a great deal of attention has been paid by the synthetic community across the globe for the development of suitable methods for the synthesis of sulfinates using commercially/readily available starting materials.

Scheme 1 outlines the summary of recent important methods reported in the literature for the synthesis of achiral sulfinates. Electrochemical⁶ as well as transition-metal⁷-catalyzed oxidation of thiols in the presence of suitable alcohols under aerobic conditions has been employed to generate corresponding sulfinates in good yields (Scheme 1a). Interestingly, thiols have also been converted into tert-butylsulfinates by treating with a TBHP/TBAI mixture.⁸ Under an oxygen atmosphere, Cu(OTf)₂ catalyzes the conversion of arylsulfonylhydrazides to arylsulfinyl radicals, which couple with suitable alcohols to generate sulfinates (Scheme 1b).⁹tert-Butyl sulfoxides could also be converted into sulfinates by treating with alcohols in the presence of NBS-AcOH in dichloromethane (Scheme 1c).¹⁰ In the presence of a stoichiometric amount of suitable activators such as BF₃·OEt₂,^11a TMSCl,^11b and H₂SO₄,^11c alcohols undergo condensation with sodium sulfinate to generate various sulfinates in good yields (Scheme 1d). Recently, p-toluenesulfonylmethyl isocyanide (TosMIC) in combination with a wide variety of alcohols has been utilized to generate sulfinate under BiBr₃-catalyzed mild acidic conditions (Scheme 1e).² Intriguingly, TosMIC has also been found to be a suitable reagent for the conversion of alcohols to sulfinates under Mitsunobu conditions (Scheme 1f).¹²

Scheme 1. Recent Methods for Achiral Sulfinate Synthesis.

In the past decade, N-tosylhydrazones, owing to their easy availability and stability toward bench-storage and distinctive modes of reactivity, have emerged as an important counterpart in transition-metal-catalyzed¹³ as well as transition-metal-free cross-coupling¹⁴ reactions. In the presence of a suitable base, N-tosylhydrazones undergo decomposition via the Bamford–Stevens reaction.¹⁵ To this end, an extensive study of solvent-dependent base-mediated decomposition of N-tosylhydrazones has been reported by Wei et al.^16a When treated with a suitable base, N-tosylhydrazones yield dialkylidenehydrazines and oximes in appropriate solvents.^16a The sulfonyl anion, evolved during the base-promoted decomposition of N-tosylhydrazones, couples with the metallocarbene generated in the presence of transition metals (Cu, Fe, and Rh) under suitable conditions to furnish synthetically important sulfones (Scheme 2a).¹⁷ On the contrary, N-tosylhydrazones give corresponding sulfinates when heated with a stoichiometric amount of stabilized Wittig ylide in N,N′-dimethylpropylene urea (DMPU) at elevated temperature under transition-metal-free conditions (Scheme 2b).¹⁸ Adding to this development, in a very recent report, Wu et al. have demonstrated that sulfinates could also be obtained selectively when N-tosylhydrazones are heated with a stoichiometric amount of diisopropylethyl amine in nitromethane at 90 °C (Scheme 2c).¹⁹ Nonetheless, it is worth noting that, as per mechanism, the conversion of N-tosylhydrazone to the corresponding sulfinate should be catalytic with a base. However, unfortunately, the previous methods fail to give a complete conversion with a catalytic amount of base/promoter.^18,19 A catalytic process would reduce the operational cost and waste generation and render practicality to this relatively new transformation. Herein, we report the development of a K₂CO₃-catalyzed rapid conversion of N-tosylhydrazones to sulfinates in N,N′-dimethylethylene urea (DMEU) at elevated temperature.²⁰

Scheme 2. Conversion of N-Tosylhydrazone to Sulfone and Sulfinate.

Results and Discussion

In our recent investigation, we observed that the reaction of N-tosylhydrazone 1j in the presence of 2.5 equiv of K₂CO₃ in N,N-dimethyl formamide (DMF) at 110 °C did not undergo the hypothesized²¹ intramolecular C–C bond-forming reaction to produce the anticipated ethyl-2,3-dihydrobenzofuran-2-carboxylate 2 but gave 66% yield of sulfinate 3j and a small amount of sulfone 4j (Scheme 3). Also, similar results were obtained when 1.0 equiv of K₂CO₃ was used for the transformation. Close inspection of the reaction mixture revealed that most of the insoluble K₂CO₃ remained unreacted during the course of the reaction. This prompted us to carry out the reaction with a catalytic amount of base. To our delight, a complete conversion of N-tosylhydrazone was also observed using 10 mol % K₂CO₃ to give sulfinate 3j and sulfone 4j in 70 and 8% yields, respectively (entry b, Table 1). Smooth decomposition of N-tosylhydrazone 1j in N-methylpyrrolidinone (NMP) as the solvent also provided sulfinate 3j in 76% yield and a small amount of sulfone 4j (entry c, Table 1). When DMPU was used as a solvent, 78% yield of sulfinate 3j and only a trace amount of sulfone 4j were obtained (entry d, Table 1). Selective formation of sulfinate in high yield (80%) was also obtained in DMEU with 10 mol % K₂CO₃ at 110 °C (entry e, Table 1). Other alkali metal carbonates (Li₂CO₃, Na₂CO₃, and Cs₂CO₃) were also tested for the reaction in DMEU; however, inferior results were obtained when compared to K₂CO₃ (entries f–h, Table 1). This suggests that the countercations of alkali metal carbonates play an important role in the overall outcome of the reaction. The reaction with Li₂CO₃, which is weakly basic, provided slow transformation, and only about 75% conversion (60% yield) occurred after 1 h. Na₂CO₃ showed comparable reactivity with K₂CO₃ but gave a slightly lower yield (70%) of sulfinate 3j. The reaction with Cs₂CO₃ was quick, but low yield (65%) was observed due to partial decomposition to unidentified polar compounds. Importantly, no reaction was observed when KHCO₃ was used as the base in DMEU at 110 °C (entry i, Table 1).

Scheme 3. Initial Results.

Table 1. Optimization of Reaction Conditions for Sulfinate Synthesis.

			yield (%)
entry	base (equiv)	conditionsa	3j	4j
a	K2CO3 (1.0)	DMF, 110 °C, 10 min	67	10
b	K2CO3 (0.1)	DMF, 110 °C, 10 min	70	8
c	K2CO3 (0.1)	NMP, 110 °C, 10 min	76	5
d	K2CO3 (0.1)	DMPU, 110 °C, 10 min	78	trace
e	K2CO3 (0.1)	DMEU, 110 °C, 10 min	80	trace
f	Li2CO3 (0.1)	DMEU, 110 °C, 1 hb	60	trace
g	Na2CO3 (0.1)	DMEU, 110 °C, 30 min	70	trace
h	Cs2CO3 (0.1)	DMEU, 110 °C, 10 min	65	trace
i	KHCO3 (0.1)	DMEU, 110 °C, 10 min	NR

^aAll reactions were carried out in 0.20 mmol scale in anhydrous solvent under an inert atmosphere.

^b75% conversion after 1 h; DMF = N,N-dimethyl formamide; NMP = N-methylpyrrolidinone; NR = no reaction.

With the encouraging results in hand, we sought to evaluate the scope of the base-catalyzed transformation. A variety of N-tosylhydrazones derived from known carbonyl compounds were treated with 10 mol % K₂CO₃ in DMEU at 110 °C to convert into the corresponding sulfinates, and the results are presented in Scheme 4. The reaction conditions are amenable to N-tosylhydrazones obtained from aryl aldehydes containing electron-withdrawing (Br and NO₂) as well as electron-releasing (via inductive and resonance effect) groups (Me, ^tBu, OMe, and SPh). N-Tosylhydrazones derived from benzaldehyde gave sulfinate 3a in 72% yield. N-Tosylhydrazones generated from 2-methoxybenzaldehyde and 2-(phenylthio)benzaldehyde showed excellent reactivity and furnished sulfinates 3b and 3c in 82 and 84% yields, respectively. Electron-rich 3,4,5-trimethoxybenzaldehyde-derived N-tosylhydrazone showed good reactivity and provided sulfinate 3d in 70% yield in a short reaction time (15 min). N-Tosylhydrazones derived from aromatic and aliphatic ketones showed much lower reactivity compared to those derived from aryl aldehydes toward the base-catalyzed sulfinate synthesis. N-Tosylhydrazone obtained from fluorenone underwent a slow reaction to furnish sulfinate 3e in 56% yield after 1 h. Cyclopentanone-derived N-tosylhydrazone showed no reaction at 110 °C possibly due to a higher pK_a value of the N–H proton. However, sulfinate 3f could be obtained in moderate yield (52%) when heated at higher temperature (150 °C) for 2 h. It is noteworthy that, in the previous reports,^18,19N-tosylhydrazones derived from aliphatic carbonyl compounds could not be converted into corresponding sulfinates. Thus, the current condition further expands the substrate scope of this important transformation. A few heteroaryl aldehyde-derived N-tosylhydrazones were also subjected to the base-catalyzed reaction conditions. N-Tosylhydrazone obtained from furfuryl-2-carboxaldehyde produced sulfinate 3g in 72% yield in a short reaction time. Pyridine-3-carboxaldehyde-derived N-tosylhydrazone also gave sulfinate 3h in good yield (68%). Next, a fairly good number of N-tosylhydrazones derived from O-alkylated (alkylated with alkyl 2-bromoacetates and benzyl chloride) 2-hydroxyarylaldehydes bearing important functional groups were investigated. Whereas no reaction was observed with N-tosylhydrazone derived from salicylaldehyde^18,19 due to the presence of the acidic phenolic hydroxyl group, N-tosylhydrazones derived from O-alkylated 2-hydroxyarylaldehyedes incurred excellent reactivity and provided corresponding sulfinates (3i–q) in high yields. Further, it is worth noting that, in the presence of a stoichiometric amount of suitable base such as LiO^tBu,^22a KOH,^22b K₂CO₃,^22c etc., N-tosylhydrazones derived from O-allylated and O-propargylated 2-hydroxybenzaldehydes undergo the intramolecular [3 + 2]-cycloaddition reaction to generate dihydropyrazoles and pyrazoles exclusively. In contrast, under the present catalytic conditions, no recognizable intramolecular [3 + 2]-cycloaddition reaction occurred for these substrates and sulfinates 3r and 3s were obtained in 74 and 78% yields, respectively. Similarly, with a catalytic amount of K₂CO₃ in DMEU, no intramolecular [3 + 2]-cycloaddition²³ reaction took place in the case of N-tosylhydrazone derived from 2-(2-formylphenoxy)acetonitrile and sulfinate 3t was obtained in 68% yield in a rapid conversion (Scheme 5). A point to be noted is that sulfinate 3s incorporates an internal alkyne and thus poised for exploration of novel intra- and intermolecular reactions.

Scheme 4. Synthesis of Sulfinates from N-Tosylhydrazones.

All reactions were carried out in 0.20 mmol scale using 10 mol % K₂CO₃ in DMEU (0.5 M) at 110 °C.

Reaction was carried out at 150 °C.

Scheme 5. Synthesis of Sulfinate 3t.

Seeking to evaluate the effect of the aryl/heteroaryl groups attached to the S-atom, a few N-sulfonylhydrazones were synthesized from aryl/heteroaryl hydrazides readily obtained following the reported experimental procedure.^18,24 Salicylaldehyde, O-alkylated with tert-butyl 2-bromoacetate, was chosen as the aryl aldehyde for the excellent reactivity of the N-tosylhydrazone derived thereof (3k, Scheme 4). Choice of the tert-butyl group provided clarity in ¹H NMR spectra in the 4.0–5.5 ppm region where the diastereotopic sulfinate protons appear. As depicted in Scheme 6, the K₂CO₃-catalyzed reaction was found to be effective on N-sulfonylhydrazones derived from various aryl/heteroarylsulfonyl hydrazides. For example, sulfinates 6a and 6b having phenyl and 2,4,6-trimethylphenyl groups on the S-atom were obtained in 80 and 76% yields, respectively. Sulfinate 6c containing a 1-naphthyl group on the S-atom was obtained in 68% yield. Similarly, sulfinate 6d, containing a 4-bromophenyl group, and sulfinate 6e, having a 3-(trifluoromethyl)phenyl group on the S-atom, were obtained in 70 and 66% yields, respectively, under the optimized reaction conditions. Under this base-catalyzed reaction conditions, sulfinate 6f having a 5-bromothiophenyl group on the S-atom could also be obtained in moderate yield (60%). To demonstrate the utility in large-scale synthesis, N-tosylhydrazone derived from 2-(phenylthio)benzaldehyde was subjected to a gram-scale reaction. Gratifyingly, no significant loss in yield and/or reactivity was observed in the 1.0 gram scale reaction of N-toslhydrazone 1c, showcasing the practicality and robustness of this base-catalyzed method (Scheme 7).

Scheme 6. Sulfinates from Various N-Sulfonylhydrazones.

All reactions were carried out in 0.20 mmol scale using 10 mol % K₂CO₃ in DMEU at 110 °C

Scheme 7. Gram-Scale Reaction.

The conversion of N-sulfonylhydrazone to sulfinate proceeds intermolecularly, which was demonstrated by cross-over experiments in previous reports.^18,19 The proposed mechanism of the K₂CO₃-catalyzed conversion is depicted in Scheme 8. The decomposition of N-sulfonylhydrazone 7 is triggered by the abstraction of N–H proton by K₂CO₃, generating deprotonated N-sulfonylhydrazone 8 and mild base KHCO₃ (inert under the reaction conditions). Intermediate ion 8 releases the ambient sulfonyl ion 9, leading to diazo intermediate 11. The diazo intermediate 11 gets converted into intermediate 12 via rapid intermolecular protonation, a crucial step for the success of the catalytic conditions. Nucleophilic displacement of the diazo group in the intermediate 12 by the sulfonyl anion 10 that bears negative charge on the O-atom generates sulfinate 13. At high temperature and in a polar aprotic solvent such as DMEU, the negatively charged O-center of the ambient sulfonyl anion 10 is the favored nucleophile over the negatively charged S-center in 9. Deprotonated N-sulfonylhydrazone 8 enters into the decomposition cycle to generate a sulfinate molecule along with a new entity of the deprotonated N-sulfonylhydrazone 8. The counter cation of the anionic species 8 influences the ionic nature and thus reactivity of the ion pair in a nonsolvating highly polar aprotic solvent, thereby affecting the overall outcome of the reaction. An inspection of the reaction mechanism reveals that substitution of the diazonium ion intermediate 12 with an external ionic nucleophile that can outcompete the sulfonyl ion 9 toward nucleophilic displacement of 12 could be possible. We will examine this in our continued study toward the development of novel reactions of N-sulfonylhydrazones.

Scheme 8. Mechanism of the K₂CO₃-Catalyzed Sulfinate Synthesis.

Conclusions

In summary, a practical, robust, and general method for the conversion of N-sulfonylhydrazones to the corresponding sulfinates using a catalytic amount of K₂CO₃ in DMEU has been developed. The current reaction conditions are compatible with several functional groups. N-Tosylhydrazones derived from O-alkylated 2-hydroxyarylaldehydes show remarkable reactivity. These catalytic conditions permit the synthesis of sulfinates from N-tosylhydrazones derived from O-allylated and O-propargylated 2-hydrobenzaldehydes, which commonly undergo the intramolecular [3 + 2]-cycloaddition reaction in the presence of a stoichiometric amount of base. Sulfinates 3r–t contain important functional groups that readily react with electrophiles and thus could be exploited toward the development of new chemistry of sulfinates.

Experimental Section

General Experimental Details

Unless otherwise mentioned, all chemicals received from commercial sources were used without purification. All commercial-grade solvents were used without any purification. Anhydrous solvents used in the reactions were obtained following standard procedures. Column chromatography was performed on 60–120 mesh silica gel using gradient mixture of ethyl acetate in hexanes as eluent. HRMS spectra were recorded on a SCIEX G2-SQ TOF (U.S.) mass spectrometer. ¹H and ¹³C NMR spectra were recorded on a Jeol JNM-ECS spectrometer at operating frequencies of 400/500 MHz (¹H) or 100/125 MHz (¹³C) as indicated in the individual spectrum using TMS as an internal standard. Thin layer chromatography was performed on aluminum plates (silica gel 60 PF₂₅₄, 0.25 mm) purchased from Merck. Melting points were recorded in open capillary and are uncorrected. The multiplicity in ¹H NMR spectra is presented as s for singlet, d for doublet, dd for doublet of doublet, t for triplet, apt for apparently triplet, q for quartet, ABq for AB-type quartet, and m for multiplet.

N-Sulfonylhydrazones were synthesized from known carbonyl compounds following the previously reported procedure.¹⁸N-Arylsulfonylhydrazides used for the synthesis N-arylsulfonylhydrazones were obtained following the reported^18,24 procedure from commercially available sulfonyl chlorides and hydrazine hydrate. The 2-hydroxyarylaldehydes were O-alkylated with alkyl 2-bromoacetate, benzyl chloride, allyl bromide, propargyl bromide, and 2-bromoacetonitrile following the reported procedure.^22,23,25 Unless otherwise mentioned, all sulfinates were synthesized following the experimental procedure mentioned below.

General Experimental Procedure for the Synthesis of Sulfinates

N-Tosylhydrazone 1b (60.8 mg, 0.20 mmol) and dry DMEU (0.40 mL) were charged into a 10 mL vial fitted with a magnetic stir bar and nitrogen inlet. The mixture was then heated in a preheated oil bath at 110 °C to obtain a clear solution. Anhydrous K₂CO₃ (2.6 mg, 0.02 mmol) was then added to the clear solution, and stirring was continued at 110 °C for 10 min.The reaction mixture was then cooled to rt, diluted with ethyl acetate (25 mL), washed with water (3 × 10 mL) and brine (1 × 10 mL), dried over Na₂SO₄, and evaporated. The crude product was purified by short silica gel column chromatography using a 10 → 20% gradient mixture of ethyl acetate in hexanes as eluent to obtain sulfinate 3b (45.2 mg, 82% yield) as a colorless oil.

Analytical Data for the Synthesized Sulfinates

Benzyl 4-Methylbenzenesulfinate (3a)^11a

35.5 mg, 72% yield; light yellow solid; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 7.61 (d, J = 8.4 Hz, 2H), 7.35–7.27 (m, 5H), 7.27–7.23 (m, 2H), 5.02 (d, J = 11.2 Hz, 1H), 4.55 (d, J = 11.2 Hz, 1H), 2.43 (s, 3H).

2-Methoxybenzyl 4-Methylbenzenesulfinate (3b)

45.2 mg, 82% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.63 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.33–7.21 (m, 3H), 6.92 (apt, J = 7.5 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.11 (d, J = 11.5 Hz, 1H), 4.71 (d, J = 11.5 Hz, 1H), 3.79 (s, 3H), 2.42 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 157.5, 142.5, 141.9, 130.0, 129.9, 129.6, 125.4, 124.0, 120.5, 110.4, 61.9, 55.3, 21.5; HRMS (ESI) calculated for C₁₅H₁₇O₃S [M + H]: 277.0898 found 277.0893.

2-(Phenylthio)benzyl 4-Methylbenzenesulfinate (3c)

59.7 mg, 84% yield; light yellow oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.59 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.33–7.18 (m, 8H), 7.15 (d, J = 7.5 Hz, 2H), 5.19 (d, J = 11.5 Hz, 1H), 4.79 (d, J = 11.5 Hz, 1H), 2.41 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 142.7, 141.5, 137.1, 135.8, 134.3, 133.5, 130.0, 129.9, 129.6, 129.2, 129.1, 128.1, 126.7, 125.3, 64.1, 21.5; HRMS (ESI) calculated for C₂₀H₁₉O₂S₂ [M + H]: 355.0826 found 355.0802.

3,4,5-Trimethoxybenzyl 4-Methylbenzenesulfinate (3d)¹⁸

49.2 mg, 70% yield; light brown oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 7.65 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.47 (s, 2H), 4.94 (d, J = 11.3 Hz, 1H), 4.47 (d, J = 11.3 Hz, 1H), 3.83 (s, 9H), 2.44 (s, 3H).

9H-Fluoren-9-yl 4-Methylbenzenesulfinate (3e)²⁶

35.9 mg, 56% yield; light yellow oil; purified using a 5 → 10% ethyl acetate in petroleum ether as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 7.81–7.73 (m, 3H), 7.66–7.57 (m, 2H), 7.45–7.11 (m, 7H), 6.15 (s, 1H), 2.45 (s, 3H).

Cyclopentyl 4-Methylbenzenesulfinate (3f)

23.4 mg, 52% yield; colorless oil; purified using a 1 → 5% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.58 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.58–4.78 (m, 1H), 2.42 (s, 3H), 1.95 (m, 2H), 1.79–1.99 (m, 4H), 1.62–1.48 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ 142.7, 142.4, 129.6, 125.1, 80.7, 34.1, 33.8, 23.3, 21.5; HRMS (ESI) calculated for C₁₂H₁₇O₂S [M + H]: 225.0949 found 225.0927.

Furan-2-ylmethyl 4-Methylbenzenesulfinate (3g)¹⁸

34.2 mg, 72% yield; brown oil; purified using a 1 → 5% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 7.61 (d, J = 8.5 Hz, 2H), 7.41–7.39 (m, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 4.97 (d, J = 12.5 Hz, 1H), 4.57 (d, J = 12.5 Hz, 1H), 2.41 (s, 3H).

Pyridin-3-ylmethyl 4-Methylbenzenesulfinate (3h)¹⁸

33.7 mg, 68% yield; white solid, mp 120–121 °C; purified using a 20 → 30% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 8.61–8.53 (m, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 5.0, 7.8 Hz, 1H), 5.01 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 2.42 (s, 3H).

Methyl 2-(2-(((p-Tolylsulfinyl)oxy)methyl)phenoxy)acetate (3i)

52.2 mg, 78% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.57 (d, J = 7.5 Hz, 2H), 7.27–7.16 (m, 4H), 6.90 (apt, J = 8.0 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.11 (d, J = 12.5 Hz, 1H), 4.73 (d, J = 12.5 Hz, 1H), 4.56 (s, 2H), 3.70 (s, 3H), 2.34 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 169.1, 155.8, 142.6, 141.9, 130.5, 129.8, 129.6, 125.4, 124.8, 121.7, 111.6, 65.6, 61.8, 52.2, 21.5; HRMS (ESI) calculated for C₁₇H₁₉O₅S [M + H]: 335.0953 found 335.0965.

Ethyl 2-(2-(((p-Tolylsulfinyl)oxy)methyl)phenoxy)acetate (3j)

52.9 mg, 76% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.58 (d, J = 8.2 Hz, 2H), 7.28–7.22 (m, 3H), 7.18 (apt, J = 7.5 Hz, 1H), 6.90 (apt, J = 8.2 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.12 (d, J = 12.5 Hz, 1H), 4.74 (d, J = 12.5 Hz, 1H), 4.54 (s, 2H), 4.17 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.19 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 168.6, 155.9, 142.6, 141.9, 130.5, 129.7, 129.6, 125.4, 124.8, 121.7, 111.6, 65.7, 61.9, 61.3, 21.5, 14.1; HRMS (ESI) calculated for C₁₈H₂₁O₅S [M + H]: 349.1109 found 349.1121;

tert-Butyl 2-(2-(((p-Tolylsulfinyl)oxy)methyl)phenoxy)acetate (3k)

58.7 mg, 78% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.65 (d, J = 8.0 Hz, 2H), 7.36–7.22 (m, 4H), 6.95 (apt, J = 7.5 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.19 (d, J = 11.5 Hz, 1H), 4.81 (d, J = 11.5 Hz, 1H), 4.51 (s, 2H), 2.41 (s, 3H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.7, 155.9, 142.5, 142.0, 130.4, 129.6, 129.5, 125.4, 124.7, 121.4, 111.4, 82.3, 66.0, 62.0, 28.0, 21.5; HRMS (ESI) calculated for C₂₀H₂₅O₅S [M + H]: 377.1422 found 377.1409.

tert-Butyl 2-(4-Methyl-2-(((p-tolylsulfinyl)oxy)methyl)phenoxy)acetate (3l)

62.5 mg, 80% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.65 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 7.5 Hz, 2H), 7.07 (d, J = 1.2 Hz, 1H), 7.04 (dd, J = 1.2, 7.5 Hz, 1H), 5.14 (d, J = 11.5 Hz, 1H), 4.77 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 2.41 (s, 3H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.9, 154.0, 142.5, 142.0, 131.2, 130.8, 130.0, 129.6, 125.4, 124.3, 111.5, 82.2, 66.2, 61.9, 28.0, 21.5, 20.4; HRMS (ESI) calculated for C₂₁H₂₇O₅S [M + H]: 391.1579 found 391.1588.

tert-Butyl 2-(4-Bromo-2-(((p-tolylsulfinyl)oxy)methyl)phenoxy)acetate (3m)

72.6 mg, 80% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.64 (d, J = 8.0 Hz, 2H), 7.36–7.30 (m, 4H), 6.57 (d, J = 8.5 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 2.42 (s, 3H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.3, 154.8, 142.8, 141.6, 132.6, 132.0, 129.7, 127.1, 125.3, 113.7, 82.6, 66.0, 60.4, 28.0, 21.5; HRMS (ESI) calculated for C₂₀H₂₄BrO₅S [M + H]: 451.0528 found 451.0530.

Ethyl 2-(4-Nitro-2-(((p-tolylsulfinyl)oxy)methyl)phenoxy)acetate (3n)

59.1 mg, 70% yield; light yellow oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 8.17–8.13 (m, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 9.5 Hz, 1H), 5.16 (d, J = 12.5 Hz, 1H), 4.74 (d, J = 12.5 Hz, 1H), 4.72 (s, 2H), 4.25 (q, J = 6.5 Hz, 2H), 2.42 (s, 3H), 1.28 (t, J = 6.5 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.4, 159.9, 143.2, 141.9, 141.2, 129.8, 126.4, 125.4, 125.3, 110.9, 65.6, 61.8, 59.6, 21.5, 14.1; HRMS (ESI) calculated for C₁₈H₂₀NO₇S [M + H]: 394.0960 found 394.0976.

Methyl 2-(2,4-Di-tert-butyl-6-(((p-tolylsulfinyl)oxy)methyl)phenoxy)acetate (3o)¹⁸

white solid; 62.5 mg, 70% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (d, J = 8.2 Hz, 2H), 7.33–7.31 (m, 3H), 7.04 (d, J = 2.4 Hz, 1H), 5.05 (d, J = 11.2 Hz, 1H), 4.55 (d, J = 11.2 Hz, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 2.43 (s, 3H), 1.36 (s, 9H), 1.27 (s, 9H).

Ethyl 2-((1-(((p-Tolylsulfinyl)oxy)methyl)naphthalen-2-yl)oxy)acetate (3p)

60.5 mg, 76% yield; light brown oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.98 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.52 (apt, J = 7.5 Hz, 1H), 7.39 (apt, J = 7.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 7.10 (d, J = 9.0 Hz, 1H), 5.71 (d, J = 11.0 Hz, 1H), 5.14 (d, J = 11.0 Hz, 1H), 4.71 (ABq, J = 16.0 Hz, 2H), 4.25 (q, J = 6.5 Hz, 2H), 2.41 (s, 3H), 1.28 (t, J = 6.5 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 168.8, 154.6, 142.5, 141.9, 133.3, 131.4, 129.6, 128.3, 127.4, 125.4, 124.3, 123.4, 117.4, 114.1, 66.9, 61.4, 56.9, 21.5, 14.1; HRMS (ESI) calculated for C₂₂H₂₃O₅S [M + H]: 399.1266 found 399.1273.

(2-(Benzyloxy)naphthalen-1-yl)methyl 4-Methylbenzenesulfinate (3q)

64.4 mg, 80% yield; light yellow oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.90 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.46–7.42 (m, 1H), 7.34–7.24 (m, 6H), 7.20–7.13 (m, 3H), 5.59 (d, J = 10.5 Hz, 1H), 5.10 (s, 2H), 5.08 (d, J =10.5 Hz, 1H), 2.30 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 155.1, 144.0, 136.7, 136.5, 133.4, 131.1, 129.1, 128.5(2), 128.3, 128.0, 127.2, 127.1, 123.9(2), 113.1, 110.3, 70.7, 53.5, 21.5; HRMS (ESI) calculated for C₂₅H₂₃O₃S [M + H]: 403.1368 found 403.1376.

2-(Allyloxy)benzyl 4-Methylbenzenesulfinate (3r)¹⁸

44.7 mg, 74% yield; light yellow oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 400 MHz) δ 7.62 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.28–7.22 (m, 2H), 6.95–6.88 (m, 1H), 6.85–6.80 (m, 1H), 6.07–5.93 (m, 1H), 5.37 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 5.14 (d, J = 11.3 Hz, 1H), 4.74 (d, J = 11.3 Hz, 1H), 4.55–4.49 (m, 2H), 2.41 (s, 3H).

5-Bromo-2-((3-phenylprop-2-yn-1-yl)oxy)benzyl 4-Methylbenzenesulfinate (3s)

70.8 mg, 78% yield; light brown oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.64 (d, J = 8.5 Hz, 1H), 7.44–7.27 (m, 9H), 6.95 (d, J = 8.5 Hz, 1H), 5.07 (d, J = 11.5 Hz, 1H), 4.88 (s, 2H), 4.68 (d, J = 11.5 Hz, 1H), 2.40 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 154.8, 142.9, 141.5, 132.7, 132.1, 131.8, 129.7, 128.9, 128.3, 127.0, 125.4, 121.9, 113.9, 113.6, 87.7, 83.1, 60.5, 57.1, 21.5; HRMS (ESI) calculated for C₂₃H₂₀BrO₃S [M + H]: 455.0316 found 455.0321.

2-(Cyanomethoxy)benzyl 4-Methylbenzenesulfinate (3t)

41.1 mg, 68% yield; light brown oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.63 (d, J = 9.5 Hz, 2H), 7.38–7.29 (m, 4H), 7.07 (apt, J = 7.5 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 11.5 Hz, 1H), 4.75 (s, 2H), 4.67 (d, J = 11.5 Hz, 1H), 2.43 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 154.5, 142.9, 141.5, 131.1, 130.1, 129.7, 129.4, 128.6, 125.3, 123.1, 112.0, 60.8, 53.8, 21.5; HRMS (ESI) calculated for C₁₆H₁₆NO₃S [M + H]: 302.0851 found 302.0842.

tert-Butyl 2-(2-(((Phenylsulfinyl)oxy)methyl)phenoxy)acetate (6a)

57.9 mg, 80% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.69 (dd, J = 2.0, 8.5 Hz, 2H), 7.49–7.41 (m, 3H), 7.25–7.15 (s, 2H), 6.88 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.13 (d, J = 11.5 Hz, 1H), 4.77 (d, J = 11.5 Hz, 1H), 4.44 (s, 2H), 1.38 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.7, 155.9, 144.9, 131.9, 130.5, 129.7, 128.9, 125.4, 124.5, 121.4, 111.4, 82.3, 65.9, 62.3, 28.0; HRMS (ESI) calculated for C₁₉H₂₃O₅S [M + H]: 363.1266 found 363.1276.

tert-Butyl 2-(2-(((Mesitylsulfinyl)oxy)methyl)phenoxy)acetate (6b)

61.5 mg, 76% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (d, J = 7.5 Hz, 1H), 7.28–7.20 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.81 (s, 2H), 6.71 (d, J = 7.5 Hz, 2H), 5.26 (d, J = 11.5 Hz, 1H), 5.17 (d, J = 11.5 Hz, 1H), 4.50 (s, 2H), 2.55 (s, 6H), 2.25 (s, 3H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.7, 155.7, 141.7, 138.4, 137.7, 130.5, 129.9, 129.5, 125.2, 121.4, 111.4, 82.3, 66.0, 65.4, 28.0, 21.1, 19.0; HRMS (ESI) calculated for C₂₂H₂₉O₅S [M + H]: 405.1735 found 405.1755.

tert-Butyl 2-(2-(((Naphthalen-1-ylsulfinyl)oxy)methyl)phenoxy)acetate (6c)

56.1 mg, 68% yield; light yellow oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 8.21 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 2.0, 7.0 Hz, 1H), 7.56 (apt, J = 7.5 Hz, 1H), 7.50–7.43 (m, 2H), 7.15–7.08 (m, 2H), 6.83–6.77 (m, 1H), 6.56 (d, J = 8.5 Hz, 1H), 5.18 (d, J = 11.5 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.27 (ABq, J = 16.0 Hz, 2H), 1.34 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.7, 155.9, 139.4, 133.7, 132.8, 130.6, 129.7, 129.4, 128.6, 127.2, 126.6, 124.8, 124.4, 122.7, 121.3, 11.3, 82.3, 65.8, 62.0, 27.9; HRMS (ESI) calculated for C₂₃H₂₅O₅S [M + H]: 413.1422 found 413.1409.

tert-Butyl 2-(2-((((4-Bromophenyl)sulfinyl)oxy)methyl)phenoxy)acetate (6d)

61.6 mg, 70% yield; colorless oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.68 (m, 4H), 7.29 (d, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 5.19 (d, J = 11.5 Hz, 1H), 4.85 (d, J = 11.5 Hz, 1H), 4.51 (s, 2H), 1.46 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.6, 156.0, 144.0, 132.2, 130.7, 130.0, 127.2, 126.8, 124.2, 121.5, 111.4, 82.4, 65.9, 62.7, 28.0; HRMS (ESI) calculated for C₁₉H₂₂BrO₅S [M + H]: 441.0371 found 441.0389.

tert-Butyl 2-(2-((((3-(Trifluoromethyl)phenyl)sulfinyl)oxy)methyl)phenoxy)acetate (6e)

56.8 mg, 66% yield; light brown oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.95 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.58 (apt, J = 7.5 Hz, 1H), 7.25–7.16 (m, 2H), 6.89 (apt, J = 7.5 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 5.17 (d, J = 8.5 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.45 (s, 2H), 1.38 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.5, 156.1, 146.4, 131.6, 131.6 (q, J = 132 Hz), 130.9, 130.2, 129.6, 129.0, 128.6 (2), 124.0, 122.8, 122.7 (q, J = 17.0 Hz), 121.5, 111.5, 82.4, 65.8, 63.5, 28.0; HRMS (ESI) calculated for C₂₀H₂₂F₃O₅S [M + H]: 431.1140 found 431.1128.

tert-Butyl 2-(2-((((5-Bromothiophen-2-yl)sulfinyl)oxy)methyl)phenoxy)acetate (6f)

53.6 mg, 60% yield; brown oil; purified using a 5 → 10% gradient mixture of ethyl acetate in hexanes as eluent; ¹H NMR (CDCl₃, 500 MHz) δ 7.28–7.18 (m, 3H), 7.03 (d, J = 4.0 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.20 (d, J = 11.5 Hz, 1H), 4.94 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 1.39 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.6, 156.0, 148.9, 130.7, 130.6, 130.2, 130.0, 124.1, 121.5, 119.4, 111.5, 82.4, 65.9, 62.4, 28.0; HRMS (ESI) calculated for C₁₇H₂₀BrO₅S₂ [M + H]: 446.9935 found 446.9942.

Experimental Procedure for Gram-Scale Reaction

N-Tosylhydrazone 1c (1.0 g, 2.61 mmol) and dry DMEU (5.3 mL) were charged into a 10 mL vial fitted with a magnetic stir bar and nitrogen inlet. The mixture was then placed in a preheated oil bath at 110 °C to obtain a clear solution. Anhydrous K₂CO₃ (36 mg, 0.26 mmol) was then added to the clear solution, and stirring was continued at 110 °C for 15 min. The reaction mixture was then cooled to rt, diluted with ethyl acetate (50 mL), washed with water (3 × 20 mL) and brine (1 × 15 mL), dried over Na₂SO₄, and evaporated. The crude product was purified by short silica gel column chromatography using a 10 → 20% gradient mixture of ethyl acetate in hexanes as eluent to obtain sulfinate 3c (820 mg, 82% yield) as a light yellow oil.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c02616.

• ¹H and ¹³C NMR spectra of all new compounds; crude ¹H NMR of a reaction of 1k carried out in DMSO-d₆; ¹H NMR of compound 1k in DMSO-d₆ (Figure S1); ¹H NMR of the crude reaction mixture 1k in DMSO-d₆ (Figure S2) (PDF)

The authors declare no competing financial interest.