Direct Synthesis of Various Thioesters from Acyl Fluorides and Thiosilanes through the Assistance of a Si–F Bond Formation

Abstract

Herein it is described that the coupling reactions of aromatic and aliphatic acyl fluorides with phenyl trimethylsilyl sulfide proceeded smoothly under neat conditions to produce thioester derivatives. The addition of a catalytic amount of typical bases, such as triethylamine (Et₃N) and potassium butoxide (KO ^t Bu), effectively activates thiosilanes, which could facilitate the coupling reactions of aroyl fluorides with a variety of aryl/alkyl thiosilanes containing an alkyl group, a halogen, an ester, or a heterocyclic ring to produce a variety of thioesters in practical yields.

Introduction

Thioesters constitute one of the fundamental functional groups in organic chemistry and have also been utilized in polymer science and biochemistry. For example, acyl CoA, which is a type of thioester derivative, is an important component of tricarboxylic acid (TCA) cycle. Moreover, thioesters have been employed as synthetic intermediates. Thioesters react with organometallic reagents in the presence of transition-metal catalysts to afford ketone derivatives, and the reduction of thioesters with hydrosilanes in the presence of palladium on carbon (Pd/C) produces various aldehydes (the Fukuyama reduction). Moreover, thioesters can be easily transformed into esters, sulfides, or sulfinate esters in the presence of various transition metal catalysts.

Thioesters are generally synthesized from carboxylic acids and thiol derivatives. The classical synthetic method involves the coupling of acyl chlorides with thiols in the presence of a base. To promote these transformations, various additives, such as CsF-Celite, , a phase-transfer catalyst, or 1,1,3,3,3-hexafluoroisopropan-2-ol (HFIP), have been added (Scheme a). Condensation between carboxylic acids and thiols with a condensation reagent, such as N,N’-dicyclohexylcarbodiimide (DCC), also induces a reliable preparation of thioesters (Scheme b). In addition to these methods, synthetic methodologies with acyl fluorides, which are generally less reactive and easier to handle than acyl chlorides and have recently attracted a lot of interest in our community, have also been developed (Scheme c). For example, Arisawa and Yamaguchi et al. prepared thioesters from acyl fluorides and disulfides in the presence of a rhodium­(I)-catalyst and triphenylphosphine. Manabe et al. reported the stepwise synthesis of thioesters from acyl fluorides generated in situ from N-formylsaccharin, bromobenzene, and potassium fluoride in the presence of a palladium catalyst and thiols in the presence of triethylamine as a base.

1. Approaches to Thioesters through Carboxylic Acid Derivatives and Thiol Derivatives.

Other facile approaches involving the reactions of acyl chlorides with metal thiolates, such as thallium thiolates, ^b tin thiolates, copper thiolates, germanium thiolates, mercurial thiolates, and zinc thiolates, ^h have also been developed (Scheme a). As a more practical preparation, the coupling reaction of acyl halides with easy-to-handle thiosilanes could enable us to effectively produce a variety of thioester derivatives (Scheme b). Talley reported the synthesis of thioesters through the reaction of acyl chlorides and thiosilanes without any additives. This reaction proceeds without an additive as a reaction promotor. However, the procedure in this reaction requires the heating conditions under the solution to undertake the desired coupling reaction. Ando et al. found that the addition of potassium fluoride (KF)/18-crown-6 to the same reaction mixture promotes the preparation of thioesters. In contrast, the effective and useful synthesis of thioesters through the coupling of acyl fluorides and thiosilanes has not been studied extensively except for one trial, in which Ando et al. examined the coupling reaction of benzoyl fluoride with ethyl trimethylsilyl sulfide, but the expected thioester was not obtained (Scheme c). On the other hand, these methods still need stoichiometric amounts of base and a high temperature to start the desired reaction. In some cases, the employment of metals, such as thallium, tin, and mercury, has an environmental impact. Therefore, the development of an effective and simple approach to produce various thioesters from acyl fluorides and thiosilanes has been in high demand. Recently, as examples utilizing the interaction of a Si–F bond, the photoredox-catalyzed couplings of acyl fluorides with organosilanes in the presence of N-heterocyclic carbene and the reaction of sulfonimidoyl fluorides with silyl-substituted alkynes have been reported. In addition, the synthesis of thioesters through the palladium-catalyzed coupling of in situ generated acyl fluoride intermediates with triisopropylsilyl thioesters was disclosed by Nakada et.al. Until now, as unique synthesis of thioesters, the practical methods involving three-component couplings of a carboxylic acid or an aldehyde, elemental sulfur, and a hydrocarbon, , metal-catalyzed oxidative coupling of a carboxylic acid or an aldehyde with a disulfide, − and an oxidative coupling of a methyl arene with a disulfide, have been achieved.

2. Approaches to Thioesters through Acyl Chlorides and Metal Thiolates or Acyl Fluorides and Thiosilane.

In this context, we demonstrate various molecular transformations using these unique acyl fluorides. During our ongoing study on coupling reactions using acyl fluorides, we found that coupling of various acyl fluorides with trimethyl­(phenylthio)­silane proceeds under neat conditions at room temperature to effectively produce a variety of thioester derivatives (Scheme d). We also found that the catalytic addition of a typical base to reaction systems activated a Si–S bond of thiosilanes to skillfully improve the nucleophilicity of a sulfur atom, which led to facilitating subsequent C–S bond formation of thioesterification. Herein, we report the scope and limitations of this study.

Results and Discussion

The reaction conditions were investigated using 3,5-dimethylbenzoyl fluoride (1a: 0.5 mmol) and trimethyl­(phenylthio)­silane (2a: 0.75 mmol) as the model substrate (Table and Table S1 and S2). Initially, when acyl fluoride 1a and thiosilane 2a, which was prepared from benzoyl chloride and KF, were reacted at 80 °C for 1 h in toluene, the corresponding reaction did not proceed smoothly, forming the desired S-phenyl 3,5-dimethylbenzenecarbothioate 3aa in only 2% yield (entry 1). Therefore, to activate thiosilane 2a, the addition of several bases was examined. When the reaction was performed in the presence of a typical carbonate, such as Li₂CO₃ and K₂CO₃, the desired thioester 3aa was obtained in moderate yields (entries 2 and 3). In contrast, CaCO₃ was ineffective for the coupling reaction (entry 4). These results may depend on the low solubility of inorganic salts. Therefore, when a catalyst (5 mol %) of KF or potassium ethylxanthate (KEX) was added as the base, the yield of 3aa remarkably improved to 89% and 97%, respectively (entries 5 and 6). The addition of triethylamine (Et₃N) slightly decreased the yield of the thioester 3aa (entry 7). In the case of KEX, thioester 3aa was obtained in an acceptable yield, although thiosilane 2a decreased to 1.1 equiv for acyl fluoride 1a (entry 8). Moreover, conducting the coupling reaction at 60 °C, the yield of 3aa did not decrease (entry 9). Surprisingly, the reaction proceeded effectively in the absence of solvents at room temperature to give the desired thioester 3aa in nearly quantitative yield (entries 10 and 11). Moreover, under neat conditions, the reaction did not require the addition of a base to the reaction mixture, and the coupling reaction between 1a and 2a in equimolar amounts was completed within 1 min at room temperature (entries 12 and 13). After the evaporation of the reaction mixture, impurities such as Me₃SiF were nearly absent, eliminating the need for standard purification.

1. Optimization of the Reaction Conditions .

entry	base	X	solvent	temp	GC yield of 3aa
		(equiv)		(°C)	(%)
1		1.5	toluene	80	2
2	Li2CO3	1.5	toluene	80	38
3	K2CO3	1.5	toluene	80	67
4	CaCO3	1.5	toluene	80	4
5	KF	1.5	toluene	80	89
6	KEX	1.5	toluene	80	97
7	Et3N	1.5	toluene	80	86
8	KEX	1.1	toluene	80	91
9	KEX	1.1	toluene	60	90
10	KEX	1.1		60	93
11	KEX	1.1		r.t.	92
12		1.1		r.t.	91
13,		1.0		r.t.	(95)

^a 1a (0.5 mmol), a base (5 mol %), a solvent (0.5 mL), 80 °C, 1 h.

^b1 min.

^cIsolated yield.

The generality of the aromatic acyl fluorides was then examined under the optimal conditions (Scheme ). First, the chemical properties and electronic effects of each substituent on aromatic acyl fluorides were examined. In the case of 1b, which has an unsubstituted group, the desired thioester 3ba was obtained in good yield. When using substrate 1 with either electron-donating or withdrawing groups, such as methyl, phenyl, or fluoro groups, the desired coupling reaction proceeded smoothly to give the corresponding thioesters 3ca, 3da, or 3ea in good yields. Moreover, acyl fluorides 1f having a 2,4,6-trimethyl group did not give the desired thioester 3fa. These results show that the steric hindrance around the benzene ring of acyl fluorides has a significant effect on the approach of thiosilane 2. In contrast, when acyl fluorides 1g and 1h with 2-iodo and 2,6-difluoro groups were used, the expected thioesters 3ga and 3ha were obtained in relatively good yields. Pentafluorobenzoyl fluoride 1i also exhibited robust reactivity in this transformation. The coupling reaction of acyl fluoride 1j with a 1-naphthyl group also proceeded to afford 3ja in 70% yield.

3. Substrate Scope of Aromatic Acyl Fluorides (without Et₃N) .

^a 1 (0.5 mmol), 2a (0.5 mmol), rt, 1 min.

Next, thioesterification was applied to various aliphatic acyl fluorides 1k–p (Scheme ). For example, when heptanoyl fluoride (1k) and acyl fluoride 1l derived from a fatty acid with a 15-carbon chain were used, the desired thioesters 3ka and 3la were obtained in 67% and 42% yields, respectively. For 3la, it seems that there is a steric hindrance between the long carbon chain moiety of 1l and thiosilane 2a. Moreover, when substrates 1m and 1n with secondary or tertiary alkyl groups, such as cyclohexyl and 1-adamantyl groups, were used under optimal conditions, the desired products thioesters 3ma and 3na, respectively, were obtained in good yields. Interestingly, although acyl fluoride 1o with a 1-phenyl-1-cyclopentyl ring significantly decreased the yield of thioester 3oa, acyl fluoride 1p with a 1-phenyl-1-cyclopropyl ring afforded the desired thioester 3pa in high yield. To clarify the difference in the results between 1o and 1p, structural optimization was performed using DFT calculations. Detailed calculation results are provided in the Supporting Information involving the optimal structure of 1o (Figure S1) and 1p (Figure S2) by DFT calculations and Cartesian Coordinates of acyl fluoride 1o (Table S6) and 1p (Table S7). The results strongly implied that the steric congestion between the cyclopropyl ring and the next carbonyl group facilitates a thiosilane approach. This coupling reaction could be applied to acyl fluoride 1q with a conjugate alkene moiety to give thioester 3qa in good yields.

4. Substrate Scope of Aliphatic Acyl Fluorides (without Et₃N) .

^a 1 (0.5 mmol), 2a (0.5 mmol), rt, 1 min.

In the above studies, we found that acyl fluorides, having an electron-donating methoxy group or having an alkyl substituent at the 2- or 6-position led to low yields of the corresponding aromatic thioesters 3ea, 3ga, and 3ia. Thus, we re-examined the reaction conditions and found that the addition of a catalytic amount of Et₃N (5 mol %) drastically improved the product yield (Table S3). Thus, we added a base to the reaction mixture containing acyl fluorides (Scheme ). For instance, when substrates 1r and 1s with 4-methoxy and 3,5-dimethoxy groups, respectively, were reacted in the presence of Et₃N (5 mol %), the desired reactions proceeded cleanly to give thioesters 3ra and 3sa, respectively, in quantitative yields. Similarly, the coupling of acyl fluoride 1f with a mesityl group with thiosilane 2a improved the yield of thioester 3fa. Although when using aliphatic acyl fluoride 1l, thioester 3la was obtained in low yield. For 3la, when the reaction time was extended to 10 min, the yield of 3la was not improved. In contrast, the coupling reaction of 1o with a cyclopentyl ring with 2a produced thioester 3oa in 98% yield.

5. Substrate Scope of Acyl Fluorides and Phenylthiosilanes (with Et₃N) .

^a 1 (0.5 mmol), 2a (0.5 mmol), and Et₃N (5 mol %), rt, 1 min.

^b 1 (0.5 mmol), 2a (0.5 mmol), rt, 1 min.

Next, the substrate scope of the aryl group on the thiosilanes was examined (Scheme ). When the coupling reactions of 1a with various aryl thiosilanes 2a–j that involve substituents on the benzene ring were carried out without a base, the desired aryl thioesters were not obtained in all cases. These results imply that aryl thiosilanes having an electron-donating group, such as a methyl group, involve a stable S–Si bond, the characteristic of which led to a decrease in the reactivity of the coupling between these thiosilanes and acyl fluorides. Therefore, in addition to the results shown in Scheme , when a catalytic amount (5 mol %) of Et₃N was added to each reaction system, as expected, the reactivity of all coupling reactions drastically improved to afford the corresponding thioesters 3ab–3aj in high yields. Regardless of the electronic effect on the group of benzene rings, when aryl thiosilanes with methyl, methoxy, fluoro, and chloro groups at the para-position were used, the desired thioesters 3ab–3ae were obtained in good to high yields. Similarly, the coupling reaction with thiosilanes at the meta-position proceeded smoothly to afford the expected thioesters 3af–3ah in practical yield. Disubstituted aryl thiosilanes with a 3,5-dimethyl group 2i or a 2,4-dimethyl group 2j also gave the desired thioesters 3ai and 3aj in 92% and 79% yields, respectively. Consequently, the position of the group on the benzene ring did not influence the nucleophilic attack on acyl fluoride.

6. Substrate Scope 1a and Aryl Thiosilanes (with Et₃N) .

^a 1a (0.5 mmol), 2 (0.5 mmol), Et₃N (5 mol %), rt, 1 min.

^b 1a (0.5 mmol), 2 (0.5 mmol), rt, 1 min.

Moreover, when the coupling of acyl fluoride 1a with alkyl thiosilane, decyl trimethylsilyl sulfide (2k), was examined in the presence and absence of Et₃N, the desired coupling reactions did not proceed (Table , entries 1 and 2). Therefore, we re-examined the optimal conditions for the coupling reaction using alkyl thiosilanes and found that the addition of a stronger base to the reaction mixture in a THF-aqueous solution led to the desired coupling reaction, producing the corresponding thioester derivative (Tables S4 and S5). For instance, when 5 mol % of the strong base KO ^t Bu was used under neat conditions, the desired thioester 3ak was obtained in only 8% GC yield (entry 3). This result strongly implies that an alkoxide anion contributes to the cleavage of the Si–S bond of thiosilane. To further improve the solubility of KO ^t Bu, water (0.5 mL) was added to the reaction mixture. Although the addition of water alone was ineffective, the coupling in THF increased the GC yield to 67% (entries 4 and 5). Thus, conducting the reaction in a THF-aqueous solution (H₂O/THF = 1/49) significantly increased the yield, giving the desired thioester 3ak in high yield (entry 6). Furthermore, the yield of 3ak did not decrease, although the amount of the base was reduced to 0.01 equiv per thiosilane 2k (entry 7). Conditions without a base did not result in the desired coupling reaction (entry 8).

2. Optimization of the Reaction Conditions for Alkylthiosilane .

entry	base	solvent	GC yield of 3ak
	(mol %)	(mL)	(%)
1			n.d.
2	Et3N (5)		n.d.
3	KO t Bu (5)		8 (trace)
4	KO t Bu (5)	H2O (0.5)	19
5	KO t Bu (5)	THF (0.5)	67
6	KO t Bu (5)	H2O/THF (1:49) (0.05)	97
7	KO t Bu (1)	H2O/THF (1:49) (0.05)	99 (98)
8		H2O/THF (1:49) (0.05)	n.d.

^a 1a (0.5 mmol), 2k (0.5 mmol), 1 min.

The generality of alkyl thiosilanes was examined under the optimal conditions listed in Table (Scheme ). When thiosilane 2l bearing an n-butyl group was used, the desired reaction proceeded to give the desired thioester 3al in 37% yield; however, the reason for the decrease in the yield of 3al was unclear at this stage. To investigate the steric effect of the alkyl group on the alkyl thiosilanes, thiosilane 2m with a t-butyl group was treated under the optimal conditions. As expected, the yield of 3am decreased. Interestingly, the coupling reactions of acyl fluoride 1a with thiosilanes 2n and 2o with an ester group and a furfuryl group afforded the corresponding thioesters 3an and 3ao in quantitative yields. On the other hand, when the reaction of palmitoyl fluoride (1l) with (1-decylthio)­trimethylsilane (2k) was examined under the conditions shown in Scheme , the desired thioester was not obtained.

7. Substrate Scope of Alkyl thiosilanes .

^a 1a (0.5 mmol), 2 (0.5 mmol), KO ^t Bu (1 mol %), H₂O/THF (1:49; 0.05 mL), rt, 1 min.

This reaction could be applied to the gram-scale synthesis of thioester 3aa (Scheme ). When acyl fluoride 1a (5 mmol) was reacted with phenyl thiosilane 2a (5 mmol) under neat conditions, the corresponding coupling reaction was completed within 5 min to afford thioester 3aa in 98% yield (1.19 g) after column chromatography.

8. Gram-Scale Synthesis of Thioester 3aa .

Several control experiments were conducted to determine the reaction mechanisms of these couplings (Scheme ). Initially, the radical scavengers, 2,2,6,6-tetramethylpiperidine 1-oxyl radical (TEMPO) and dibutylhydroxytoluene (BHT), were added to each reaction mixture (Scheme A). In all the coupling reactions, since the yields of thioesters 3aa, 3ad, and 3ak did not decrease significantly, it was implied that the radical process was not involved in the coupling reactions. In addition, to demonstrate the steric effect of the silyl group on thiosilane 1a, coupling reactions of 1a with phenyl­(triisopropyl)­silane (2p) were examined under neat conditions (Scheme B). Regardless of the presence or absence of the base, the coupling reaction did not occur. These results showed that the steric hindrance of the silyl group strongly influenced the approach between thiosilane and acyl fluoride. Moreover, when the coupling of acyl chloride 1a’ with aryl thiosilane 2a was performed under neat conditions, the expected thioester 3aa was obtained in low yield (Scheme C). Similarly, when running acyl fluoride 1a or acyl chloride 1a’ with thiol 2a’, neither coupling produced the desired thioester 3aa (Scheme D). Based on these results, the strong interaction between silicon and fluorine atoms functions as a driving force to promote thioesterification.

9. Control Experiments.

Based on the results of the control experiments and the related mechanism reported in precedent literature, a plausible mechanism for the coupling reaction is illustrated in Scheme . In the case of direct coupling without a base (Scheme A), it is assumed that (i) the nucleophilic sulfur atom of thiosilane 2 adds to the carbonyl carbon of acyl fluoride 1 to generate intermediate A, (ii) the silyl group in intermediate A shifts to form intermediate B, and (iii) the emission of Me₃SiF occurs from intermediate B, facilitated by a strong interaction between the fluorine and a silicon atoms to give thioester 3. The formation of Me₃SiF was confirmed by ¹H-, ¹³C­{¹H}-, and ¹⁹F-NMR spectroscopy (Figures S3 and S4 and S5). In the case of the coupling with a base (Scheme B), it is assumed that (i) a base (Et₃N or KO ^t Bu) functions as an activator of thiosilane 2 to produce thiolate anion C; (ii) in situ generated C nucleophilically adds to acyl fluoride 1 to give intermediate D; (iii) intermediate D liberates a fluoride anion to produce thioester 3; and (vi) the eliminated fluoride anion is incorporated into this catalytic cycle to activate starting thiosilane 2 again.

10. Plausible Reaction Mechanism.

Conclusion

In conclusion, we developed a method for the synthesis of thioesters from aromatic/aliphatic acyl fluorides and a variety of thiosilanes. Remarkably, when phenyl thiosilane was employed, the desired coupling reactions proceeded effectively under neat conditions at room temperature to produce the corresponding thioesters in good to excellent yields, high product purity was obtained by the removal of the sole byproduct, Me₃SiF. Moreover, the coupling reactions of acyl fluorides with various aryl/alkyl thiosilanes proceeded smoothly with the assistance of a catalytic amount of KO ^t Bu in a THF-aqueous solution.

Experimental Section

General Information

All reactions were carried out in air, unless otherwise noted. All the heating reactions were performed in an oil bath. Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. Toluene, THF, Et₂O, and hexane were distilled over sodium benzophenone. CH₃CN and CH₂Cl₂ were dried over CaH₂ and distilled water. CHCl₃ was dried over CaCl₂ and distilled water. Column chromatography was performed using silica and alumina gels. The ¹H NMR spectra were recorded at 500 and 400 MHz using tetramethylsilane as an internal standard (0.00 ppm). ¹³C­{¹H} NMR spectra were recorded at 126 and 100 MHz using the central peak of CDCl₃ (77.0 ppm). Chemical shifts in the ¹⁹F NMR spectra were reported in ppm relative to the external reference, CF₃C₆H₅ (−62.6 ppm). High-resolution mass spectra (HRMS) were obtained in FAB-positive mode using 3-nitrobenzyl alcohol (NBA) as the matrix. The GC analyses were performed using a DB-5 capillary column (30 m × 0.25 mm with a film thickness 0.25 μm). Acyl fluorides 1 and thiosilanes 2 were prepared by the literature method. −

Representative Procedure A for the Synthesis of Acyl Fluoride Derivatives

KF (2.91 g, 50.0 mmol) and CH₃CN (25 mL) were added to a 100 mL round-bottom flask. Then, 3,5-dimethylbenzoyl chloride (4.22 g, 25.0 mmol) was added to the mixture. The mixture was stirred at 50 °C for 115 h under N₂. The resulting mixture was filtered, and the solvent was removed under reduced pressure. The crude material was purified by distillation under reduced pressure to yield 3,5-dimethylbenzoyl fluoride 1a (2.73 g, 72%).

3,5-Dimethylbenzoyl Fluoride (1a)

Transparent solid (2.73 g, 72%); ¹H NMR (400 MHz, CDCl₃) δ 7.64 (s, 2H), 7.31 (s, 1H), 2.37 (s, 6H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 157.7 (d, J _C–F = 343 Hz), 138.8 (d, J _C–F = 10 Hz), 137.0, 129.0 (d, J _C–F = 3.0 Hz), 124.6 (d, J _C–F = 59 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ = 18.4; MS (EI): m/z 152 (M⁺).

Representative Procedure B for the Synthesis of Acyl Fluoride Derivatives

A 100 mL round-bottom flask was charged with KHF₂ (1.56 g, 20.0 mmol) and H₂O (17 mL). The mixture was then stirred at room temperature for 1 h. Subsequently, tetrabutylammonium chloride (0.2 mmol), 2,6-difluorobenzoyl chloride (1.77 g, 10.0 mmol), and CH₂Cl₂ (25 mL) were added to the mixture. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was washed with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄ and filtered, and the filtrate was evaporated under reduced pressure. The crude material was purified via distillation under reduced conditions to give 2,6-difluorobenzoyl fluoride 1l (0.79 g, 25%).

2,6-Difluorobenzoyl Fluoride (1l)

White solid (0.79 g, 25%); ¹H NMR (400 MHz, CDCl₃) δ 7.70–7.63 (m, 1H), 7.10–7.06 (m, 2H); ¹³C­{¹H} NMR (126 MHz, CDCl₃) δ 162.4 (dd, J _C–F = 264.2, 3.8 Hz), 150.7 (d, J _C–F = 343.4 Hz), 136.5 (dd, J _C–F = 11.3 Hz), 112.8 (dd, J _C–F = 21.4, 2.5 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ 47.8 (t, J _F–F = 23.5 Hz), −104.8 (d, J _F–F = 47.1 Hz); MS (EI): m/z 160 (M⁺).

Representative Procedure C for the Synthesis of Acyl Fluoride Derivatives

To a 100 mL round-bottom flask, SOCl₂ (2.38 g, 20.0 mmol), CH₂Cl₂ (10 mL), 3,5-dimethoxybenzoic acid (1.82 g, 10.0 mmol), and DMF (a few drops) were added. The mixture was stirred overnight at room temperature under N₂. The resulting mixture was evaporated under reduced pressure to produce acyl chlorides.

KF (1.16 g, 20.0 mmol) and CH₃CN (10 mL) were added to a 100 mL round-bottom flask. Subsequently, 3,5-dimethoxybenzoyl chloride was added to the crude product. The mixture was stirred for 24 h at 50 °C under N₂. The resulting mixture was filtered, and the solvent was removed under reduced pressure. The crude material was purified via silica gel column chromatography or distilled under reduced pressure to give 3,5-dimethoxybenzoyl fluoride 1f (0.96 g, 52%).

3,5-Dimethoxybenzoyl Fluoride (1f)

White solid (0.96 g, 52%); ¹H NMR (500 MHz, CDCl₃) δ 7.17 (d, J = 2.5 Hz, 2H), 6.76 (t, J = 2.5 Hz, 1H), 3.84 (s, 6H); ¹³C­{¹H} NMR (126 MHz, CDCl₃) δ 161.0, 157.3 (d, J _C–F = 334.7 Hz), 126.5 (d, J _C–F = 60.4 Hz), 108.8 (d, J _C–F = 3.8 Hz), 108.0, 55.7; ¹⁹F NMR (376 MHz, CDCl₃) δ 18.9; MS (EI): m/z 184 (M⁺).

Representative Procedure for the Synthesis of Thiosilane Derivatives

Benzenethiol (11.0 g, 100 mmol), THF (100 mL), and Et₃N (12.1 g, 120 mmol) were added to a 100 mL round-bottom flask. Trimethylsilyl chloride (12.0 g, 110 mmol) was added to the mixture. Subsequently, the mixture was stirred at room temperature for 24 h under N₂. The mixture was evaporated under reduced pressure and filtered, and the solvent was removed under reduced pressure. The crude material was purified via distillation under reduced pressure to yield trimethyl­(phenylthio)­silane 2a (15 g, 82%).

Trimethyl­(phenylthio)­silane (2a)

Colorless oil (15 g, 82%); ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.40 (m, 2H), 7.25–7.23 (m, 3H), 0.27 (s,9 H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 135.1, 131.4, 128.7, 126.8, 0.81; MS (EI): m/z 182 (M⁺).

Representative Procedure for the Synthesis of Thioester Derivatives

3,5-Dimethylbenzoyl fluoride (76.1 mg, 0.500 mmol), and trimethyl­(phenylthio)­silane (91.2 mg, 0.500 mmol) were added to a 10 mL round-bottom flask. The mixture was then stirred at room temperature for 1 min. After the reaction, the crude material was purified by silica gel column chromatography (hexane to hexane/EtOAc = 99:1) to yield S-phenyl 3,5-dimethylbenzothioate 3aa (116.1 mg, 99%).

S-Phenyl 3,5-Dimethylbenzothioate (3aa)

White solid (116.1 mg, 99%); ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 2H), 7.52–7.49 (m, 2H), 7.46–7.43 (m, 3H), 7.23 (s, 1H), 2.38 (s, 6H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.3, 138.4, 136.6, 135.3, 135.0, 129.4, 129.2, 127.6, 125.1, 21.2; MS (FAB-Magnetic sector): m/z calcd for C₁₅H₁₅OS (M⁺ + H): 243.08; found: 243.08.

Representative Procedure for the Synthesis of Thioester Derivatives

To a 10 mL round-bottom flask was charged with 3,5-dimethylbenzoyl fluoride (76.1 mg, 0.500 mmol), Et₃N (2.5 mg, 0.025 mmol), and trimethyl­(4-methylphenylthio)­silane (98.2 mg, 0.500 mmol) were added. The mixture was then stirred at room temperature for 1 min. After the reaction, the crude material was purified by silica gel column chromatography (hexane to hexane/EtOAc = 99:1) to yield S-(4-methylphenyl) 3,5-dimethylbenzothioate 3ab (112.5 mg, 85%).

S-(4-Methylphenyl) 3,5-Dimethylbenzothioate (3ab)

White solid (112.5 mg, 85%); ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 2H), 7.39–7.36 (m, 2H), 7.26–7.24 (m, 2H), 7.21 (s, 1H), 2.39 (s, 3H), 2.37 (s, 6H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.7, 139.6, 138.4, 136.7, 135.2, 135.0, 130.0, 125.1, 124.0, 21.3, 21.2; MS (FAB-Magnetic Sector): m/z calcd for C₁₆H₁₇OS (M⁺ + H): 257.10; found: 257.10.

Representative Procedure for the Synthesis of Thioester Derivatives

To a 10 mL round-bottom flask, 3,5-dimethylbenzoyl fluoride (76.1 mg, 0.500 mmol), KO^tBu (0.56 mg, 0.0050 mmol), THF (49 μL), H₂O (1 μL), and (1-decylthio)­trimethylsilane (123.3 mg, 0.5000 mmol) were added. The mixture was then stirred at room temperature for 1 min. The reaction mixture was then evaporated under reduced pressure. After the reaction, the crude material was purified using silica gel column chromatography (hexane/EtOAc = 99:1) to give S-(1-decyl) 3,5-dimethylbenzothioate 3ak (145.6 mg, 98%).

S-(1-Decyl) 3,5-Dimethylbenzothioate (3ak)

Colorless oil (145.6 mg, 98%); ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 2 H), 7.17 (s, 1H), 3.04 (t, J = 7.2 Hz, 2H), 2.35 (s, 6H), 1.69–1.61 (m, 2H), 1.45–1.23 (m, 14H), 0.88 (t, J = 7.2 Hz, 3 H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 192.4, 138.2, 137.3, 134.8, 124.9, 31.9, 29.6, 29.53, 29.49, 29.3, 29.2, 29.0, 28.9, 22.7, 21.2, 14.1; HRMS (FAB): m/z calcd for C₁₉H₃₁OS (M⁺ + H): 307.2096; found: 307.2095.

The data underlying this study are available in the published article and its online Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c01677.

• General experimental information, synthesis methods of starting materials, and NMR spectra of the prepared products (PDF)

The authors declare no competing financial interest.