Na 2 CO 3 -promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives

Abstract

A mild, efficient, and transition-metal-free catalytic strategy is developed to construct thioesters via selective N–C bond cleavage of Boc₂-activated primary amides. This strategy is successfully carried out with stoichiometric Na₂CO₃ as the base and provides the corresponding products in moderate to excellent yields.

Keywords

selective N–C bond cleavage thioesters transition-metal-free catalytic strategy

Introduction

The thioester group is a fundamental structural motif which is found widely in polymers, agrochemicals, pharmaceuticals, and natural products (Figure 1).^1–7 This class of compound is usually employed as key intermediates to synthesize some important skeletal units, such as β-lactams,⁸ β-lactones⁹ esters,^10,11 aldehydes,¹² and ketones.^13,14 Thioesters also play important roles in several biological processes.^3,15,16 During the past decades, significant research efforts have focused on the synthesis of thioesters. The condensation reaction between carboxylic acid derivatives and thiols was the initial synthetic strategy toward thioesters (Scheme (1a)).^15,17–20 In 1997, Xiao and Alper²¹ reported the first palladium-catalyzed method for the synthesis of thioesters via carbonylation of aryl iodides and n-BuSNa. Since then, transition-metal-catalyzed thiocarbonylation processes have attracted much attention and various methods have been explored to construct thioester compounds using aryl halides and S-nucleophiles (Scheme (1b)).^22–31 Moreover, oxidative coupling between aldehydes and thiols (or disulfides) has also offered a reliable solution to obtain thioester compounds (Scheme (1c)).^32,33 However, in principle, metal catalysts or stoichiometric oxidants were needed in the above reaction processes. In view of environmental concerns, metal-free and oxidant-free synthetic methods are highly desirable for the preparation of thioesters.

Figure 1.

Examples of pharmaceuticals containing a thioester motif.

Scheme 1.

Synthesis of thioesters.

In recent years, significant breakthroughs have been exploited to construct C–C or C–X bonds via transition-metal-catalyzed amide N–C bond cleavage.^34–38 In 2015, Hie et al.³⁹ reported the first nickel-catalyzed conversion of amides into esters via selective N–C bond cleavage. Soon after, Suzuki,^40–48 Negishi,^49–51 borylation,^52,53 Heck,^53,54–60 Sonogashlira,⁶¹ and other cross-coupling reactions^{54,52,62–73} have been extended by this means.

However, the geometries of typical amide bonds are planar as a result of amidic resonance, which results in amides having very stable chemical bonds (15–20 kcal mol⁻¹).⁴⁰ Many studies have shown that distortion of amide bonds greatly affects the stability and reactivity of amides. In recent work, cross-coupling of twisted amides with arenes,⁶⁷ amines,^74–77 alcohols,^48,58 and phenols⁷⁸ have been successfully explored and the twisted amide bond is considered as a controlling factor in selective amide bond activation.^79–81 Considering the reactivity of twisted amides, herein, we report a synthetic strategy for the preparation of thioesters using twisted amides and thiols without a transition-metal-catalyst.

Results and discussion

Initially, we carried out the reaction with N,N-di-Boc-activated amide^82–85 1a and p-toluenethiol (2a) as substrates (Table 1), and Et₃N (2.0 equiv.) as the base in 1,4-dioxane (2 mL) at 80 °C for 18 h, which resulted in the formation of product 3a in 68% yield (Table 1, entry 1). Other amides 1b–e were also tested under the same reaction conditions, but their reaction efficiencies were poor (Scheme 2). Second, various organic bases (1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) and inorganic bases (Na₂CO₃, K₃PO₄, Cs₂CO₃, ^tBuONa) were evaluated (Table 1, entries 2–7). When Et₃N was replaced with Na₂CO₃, the product 3a was obtained in 95% isolated yield (Table 1, entry 4). Third, screening of the solvent indicated that other solvents (CH₃CN, tetrahydrofuran (THF), 1,2-dichoroethane (DCE), and dimethylformamide (DMF)) resulted in slightly decreased yields (Table 1, entries 8−11). Fourth, the yield of product 3a was obviously lower when the amount of base was decreased to 1.0 equiv. and 0.5 equiv. (Table 1, entries 12 and 13), and the reaction did not work without a base (Table 1, entry 15). In addition, the reaction efficiency was the best at 80 °C, while a poor yield was observed at rt (33%, Table 1, entry 14).

Table 1.

Optimization of the Reaction Conditions.^a


1a	2a		3a
Entry	Base	Solvent	Yield (%)^b
1	Et₃N	1,4-Dioxane	68
2	DABCO	1,4-Dioxane	63
3	DBU	1,4-Dioxane	60
4	Na₂CO₃	1,4-Dioxane	95
5	K₃PO₄	1,4-Dioxane	85
6	Cs₂CO₃	1,4-Dioxane	78
7	tBuONa	1,4-Dioxane	Trace
8	Na₂CO₃	CH₃CN	70
9	Na₂CO₃	THF	63
10	Na₂CO₃	DCE	78
11	Na₂CO₃	DMF	80
12^c	Na₂CO₃	1,4-Dioxane	50
13^d	Na₂CO₃	1,4-Dioxane	80
14^e	Na₂CO₃	1,4-Dioxane	33
15	–	1,4-Dioxane	N.D.

DABCO: 1,4-diazabicyclo[2.2.2]octane; DBU: 1,8-diazabicyclo[5.4.0] undec-7-ene; THF: tetrahydrofuran; DCE: 1,2-dichoroethane; DMF: dimethylformamide; N.D.: not detected.

Reaction conditions: 1a (0.22 mmol, 1.1 equiv.), 2a (0.2 mmol), base (2.0 equiv.), solvent (2.0 mL), 80 °C, 18 h.

Isolated yield.

Base (0.5 equiv.).

Base (1.0 equiv.).

rt.

Scheme 2.

Evaluating different amides.

With optimized reaction conditions in hand, the substrate scope of the amides was evaluated. As shown in Scheme 3, the reactions of electron-rich amides were well-tolerated and afforded the corresponding thioesters 3b,c in 77% and 75% yields. Delightfully, halogen substituents (such as F, Cl, and Br) were tolerated in this transformation and good yields were obtained (3d,e,f), which implied a potential possibility for further functionalization of thioesters. A slightly lower yield was obtained using a 4-trifluoromethyl-substituted amide as the substrate (3g). Other amides, including heterocycles, and polyarenes were also tolerated and afforded products 3h–j in acceptable yields.

Scheme 3.

Substrate scope of amides.

Next, we tested the tolerance of thiols under the optimized conditions (Scheme 4). Both electron-donating and electron-withdrawing substituents on the phenyl afforded the desired products 4a–c,g in good yields. The halogen substituents (F, Cl, and Br) were tolerated under the standard conditions and afforded the desired products in excellent yields (4d–f). Multi-substituted thiophenols, such as 3,4-dimethyl and perfluoro, could be transformed into the corresponding thioesters 4h,i in acceptable yields. 2-Naphthalenethiol afforded the corresponding thioester 4j in 82% yield. Some alkyl-type thiols were also transformed into thioesters 4k–n under standard conditions in 44%–95% yields. Unfortunately, an aliphatic alkyl-type thiol 4o did not react under the optimized conditions. Finally, a one-pot reaction was carried out under the current conditions and product 3a was obtained in a 53% total yield (Scheme 5). This suggests that the synthetic strategy can be achieved with a common primary amide.

Scheme 4.

Substrate scope of thiols.

Scheme 5.

One-pot experiment.

To check the practicality of this transformation, a gram-scale reaction (10 mmol) was carried out (Scheme 6). The reaction afforded product 3a in 88% yield under standard conditions, which demonstrates that this protocol has potential application value in industrial production.

Scheme 6.

Scale-up experiment.

Conclusion

In summary, we have reported a transition-metal-free cross-coupling reaction for the preparation thioester compounds using commercial primary amides and thiols via activated N–C bond cleavage under exceedingly mild conditions. The transformation is accomplished efficiently with the assistance of stoichiometric Na₂CO₃ under an air atmosphere. A high-yielding gram-scale reaction demonstrated the potential value of the synthetic utility of this method.

General procedure

All reagents and solvents were commercially available and used without further purification. Unless otherwise noted, all reactions were run under a nitrogen atmosphere. Purification of all products was carried out by flash chromatography using brand 200–300 mesh silica gel. ¹H, ¹³C, and ¹⁹F NMR spectra were recorded on a Bruker Ascend instrument at 400, 100 and 376 MHz, respectively. Chemical shifts were reported in δ (ppm) referenced to an internal tetramethylsilane (TMS) standard for ¹H NMR (δ 0.00), and CDCl₃ (δ 77.16) for ¹³C NMR. The following abbreviations were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, hept = heptaplet, m = multiplet, and br = broad. High-resolution mass spectra (HRMS) were obtained on an Agilent mass spectrometer using electrospray ionization-time of flight (ESI-TOF). GC-MS spectra were recorded on a Shimdazu-GC-MS 2010QP-Ultra instrument.

Preparation of the starting materials

General procedure for N,N-Boc₂-amide synthesis

A previously published procedure was followed. An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with the primary amide (8.26 mmol, 1.0 equiv.), 4-dimethylaminopyridine (DMAP) (typically, 0.10 equiv.), and dichloromethane (typically, 25 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum.⁸⁴ Di-tert-butyl dicarbonate (typically, 2.0 equiv.) was added portion-wise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was concentrated and unless stated otherwise, purified directly by chromatography on silica gel (hexanes/ethyl acetate) to give analytically pure product. N,N-Boc₂-benzamide (1a). White solid. Yield 85.2%. MS = 321.2.

General procedure for synthesis of N-Boc amides from secondary amides (1b, 1c)

An oven-dried round-bottomed flask (100 mL) was charged with a secondary amide substrate (5.0 mmol, 1.0 equiv.), DMAP (0.1 equiv.), and dichloromethane (typically, 0.20 M).⁸⁶ Di-tert-butyl dicarbonate (1.0 equiv.) was added in one portion, and the reaction mixture was allowed to stir at room temperature for 15 h. After the indicated time, the reaction mixture was quenched with NaHCO₃ (aq, 10 mL), extracted with EtOAc (3 × 20 mL), washed with H₂O (1 × 20 mL), and brine (1 × 20 mL). The organic layer was dried, and concentrated. Unless stated otherwise, purification by flash chromatography (EtOAc/hexanes) afforded the pure product. In our hands, the N-Boc activation of secondary amides typically proceeds in average yields of >80%. tert-Butyl benzoyl(phenyl)carbamate (1b). White solid. Yield 81%. MS = 297.1. tert-Butyl benzoyl(benzyl)carbamate (1c). Colorless oil. Yield 76%. MS = 311.1.

General procedure for N-acyl-glutarimide synthesis (1d)

An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (8.84 mmol, 1.0 equiv.), triethylamine (typically, 2.0 equiv.), DMAP (typically, 0.25 equiv.), and dichloromethane (typically, 50 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum.⁸⁷ Acyl chloride (typically, 1.1 equiv.) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et₂O (20 mL) and filtered. The organic layer was washed with HCl (1.0 N, 30 mL) and brine (30 mL), dried, and concentrated. Unless stated otherwise, the crude product was purified by recrystallization (toluene) to give analytically pure product. Benzoylpiperidine-2,6-dione (1d). White solid. Yield 87%. MS = 217.1.

General procedure for saccharinamide synthesis (1e)

A previously published procedure was followed.⁸⁸ An oven-dried flask (25 mL) equipped with a stir bar was charged with the amine (typically, 3.0 mmol, 1.0 equiv.), triethylamine (typically, 1.0 equiv.), and N,N-dimethylacetamide (DMAc, typically, 0.75 M), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum. The acyl chloride (typically, 1.0 equiv.) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred for 1 h at room temperature. After the indicated time, the reaction mixture was diluted with H₂O (5 mL). The resulting solid was collected by filtration, washed with Et₂O (1 × 10 mL), and dried. The crude product was purified by recrystallization (methanol or toluene) to give analytically pure product. N-Benzoylsaccharin (1e). Yield 85%. MS = 287.0.

General procedure for the synthesis of S-p-tolyl benzothioate (e.g. 3a)

A mixture of 1a (0.22 mmol, 1.1 equiv.), 2a (0.2 mmol, 1.0 equiv.), and Na₂CO₃ (0.4 mmol, 2.0 equiv.) in 1,4-dioxane (2 mL) for 12–18 h at 80 °C. After the disappearance of 2a (detected by TLC), the reaction mixture was washed with ethyl acetate (3 × 5.0 mL), and the combined organic phase was concentrated in vacuo and the residue purified by column chromatography on silica gel (eluted with PE/EtOAc = 50:1) to provide the desired product 3a.

One-pot experiment

To a dry flask was added primary amide 1a (0.22 mmol, 1.1 equiv.), DMAP (typically, 0.10 equiv.), and dichloromethane (typically, 2 mL), and the mixture placed under a positive pressure of nitrogen. Di-tert-butyl dicarbonate (typically, 2.0 equiv.) was added portion wise with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. The combined organic phase was concentrated in vacuo, a mixture of 2a (0.2 mmol, 1.0 equiv.) and Na₂CO₃ (0.4 mmol, 2.0 equiv.) in 1,4-dioxane (2 mL) for 12–18 h at 80 °C. After the disappearance of 2a (detected by TLC), the reaction mixture was washed with ethyl acetate (3 × 5.0 mL), the combined organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE/EtOAc = 50:1) to provide the desired product 3a (53%).

S-(p-tolyl) benzothioate (3a)⁸⁹: A pale white crystalline solid; yield 95% (42.3 mg); m.p. 75–77 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.91 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.5, 139.8, 136.8, 135.1, 133.6, 130.2, 128.8, 127.5, 123.9, 21.4 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₃OS [M + H]⁺: 229.0687; found: 229.0690.

S-(p-tolyl) 4-methylbenzothioate (3b)⁹⁰: A pale white crystalline solid; yield 77% (37.3 mg); m.p. 123.5–124.5 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.91 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.27–7.23 (m, 4H), 2.41 (s, 3H), 2.39 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.2, 144.6, 139.8, 135.2, 134.3, 130.2, 129.5, 127.7, 124.1, 21.8, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₅H₁₅OS [M + H]⁺; 243.0844; found: 243.0840.

S-(p-tolyl) 4-methoxybenzothioate (3c)⁹¹: A pale white crystalline solid; yield 75% (38.7 mg); m.p. 63–65 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 2.39 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.2, 166.1 (d, ¹J_C-F = 255.2 Hz), 140.0, 135.1, 133.1 (d, ⁴J_C-F = 2.6 Hz), 130.3, 130.1 (d, ³J_C-F = 9.3 Hz), 123.6, 116.0 (d, ²J_C-F = 22.1 Hz), 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₅H₁₅O₂SNa [M + Na]⁺: 281.0612; found: 281.0599.

S-(p-tolyl) 4-fluorobenzothioate (3d): A pale white crystalline solid; yield 91% (44.8 mg); m.p. 71–73 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.06–8.02 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.27–7.24 (m, 2H), 7.14 (t, J = 8.4 Hz, 2H), 2.39 (s, 3H) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.26 ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.2, 166.1 (d, J_C-F = 255.2 Hz), 140.0, 135.1, 133.1 (d, J = 2.6_C-F Hz), 130.3, 130.1 (d, J_C-F = 9.3 Hz), 123.6, 116.0 (d, J_C-F = 22.1 Hz), 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₂FOSNa [M + Na]⁺: 269.0412; found: 269.0394.

S-(p-tolyl) 4-chlorobenzothioate (3e): A pale white crystalline solid; yield 88% (46.1 mg); m.p. 84–86 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.30–7.22 (m, 2H), 2.39 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.5, 140.1, 140.0, 135.2, 135.1, 130.3, 129.1, 128.9, 123.5, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₂ClOS [M + H]⁺: 263.0297; found: 263.0309.

S-(p-tolyl) 4-bromobenzothioate (3f): A pale white crystalline solid; yield 87% (53.1 mg); m.p. 93–95 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.24–7.12 (m, 2H), 2.32 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.7, 140.1, 135.6, 135.1, 132.1, 130.3, 129.0, 128.7, 123.4, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₂BrOS [M + H]⁺: 306.9792; found: 306.9780.

S-(p-tolyl) 4-(trifluoromethyl)benzothioate (3g): A pale white crystalline solid; yield 76% (45.1 mg); m.p. 103–105 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.11 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 2.41 (s, 3H) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ −63.09 ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.9, 140.3, 139.7, 135.1, 135.0 (q, ²J_C-F = 32.8 Hz), 130.4, 127.9, 125.9 (q, ³J_C-F = 3.6 Hz), 123.6 (q, ¹J_C-F = 272.7 Hz), 123.1, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₅H₁₂F₃OS [M + H]⁺: 297.0561; found: 297.0542.

S-(p-tolyl) pyridine-3-carbothioate (3h): A pale white crystalline solid; yield 47% (21.5 mg); m.p. 80–82 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.74 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.57–7.52 (m, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 2.40 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 192.4, 151.9, 149.3, 139.7, 137.5, 135.0, 130.2, 128.1, 124.7, 120.9, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₃H₁₂NOSNa [M + Na]⁺: 252.0459; found: 252.0455.

S-(p-tolyl) furan-2-carbothioate (3i): A pale white crystalline solid; yield 80% (34.9 mg); m.p. 74–76 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.60 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.29–7.17 (m, 3H), 6.55 (dd, J = 3.2, 1.6 Hz, 1H), 2.39 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 179.2, 150.5, 146.5, 140.1, 135.2, 130.2, 122.7, 116.2, 112.5, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₂H₁₁O₂S [M + H]⁺: 219.0479; found: 219.0465.

S-(p-tolyl) naphthalene-2-carbothioate (3j): A pale white crystalline solid; yield 81% (45.1 mg); m.p. 119–121 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.59 (s, 1H), 8.01 (dd, J = 8.4, 1.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.4 Hz, 2H), 7.63–7.48 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.6, 139.9, 136.0, 135.2, 134.1, 132.6, 130.2, 129.7, 129.0, 128.70, 128.67, 127.9, 127.1, 124.0, 123.4, 21.5 ppm. HRMS (ESI-TOF) calcd for C₁₈H₁₅OS [M + H]⁺: 279.0844; found: 279.0847.

S-(4-methoxyphenyl) benzothioate (4a)⁹²: A pale white crystalline solid; yield 65% (31.5 mg); m.p. 92–94 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 191.1, 160.9, 136.8, 136.7, 133.7, 128.8, 127.6, 118.0, 115.1, 55.5 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₃O₂SNa [M + Na]⁺: 267.0456; found: 267.0465.

S-(4-(tert-butyl)phenyl) benzothioate (4b): A pale white crystalline solid; yield 71% (38.4 mg); m.p. 77–79 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.46–7.43 (m, 6H), 1.34 (s, 9H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.6, 152.9, 136.9, 134.8, 133.7, 128.8, 127.6, 126.5, 124.0, 34.9, 31.4 ppm. HRMS (ESI-TOF) calcd for C₁₇H₁₉OS [M + H]⁺: 271.1157; found: 271.1157.

S-(o-tolyl) benzothioate (4c): A yellow oily liquid; yield 84% (38.4 mg); ¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 3H), 7.41–7.33 (m, 2H), 7.32–7.20 (m, 1H), 2.40 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.7, 142.8, 136.9, 136.5, 133.7, 130.9, 130.3, 128.8, 127.7, 126.9, 126.8, 20.9 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₃OS [M + H]⁺: 229.0687; found: 229.0685.

S-(4-fluorophenyl) benzothioate (4d)⁹¹: A pale white crystalline solid; yield 87% (40.4 mg); m.p. 51–52 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.51–7.45 (m, 4H), 7.15 (t, J = 8.8 Hz, 2H) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ −111.02 ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.2, 163.8 (d, ¹J_C-F = 250.1 Hz), 137.3 (d, ³J_C-F = 8.5 Hz), 136.6, 133.9, 128.9, 127.6, 122.8 (d, ⁴J_C-F = 3.4 Hz), 116.7 (d, ²J_C-F = 22.1 Hz) ppm. HRMS (ESI-TOF) calcd for C₁₃H₁₀FOS [M + H]⁺: 233.0436; found: 233.0431.

S-(4-chlorophenyl) benzothioate (4e)⁹⁰: A pale white crystalline solid; yield 95% (47.2 mg); m.p. 73–74 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J = 7.2 Hz, 2H), 7.63–7.55 (m, 3H), 7.48 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.5, 136.6, 136.5, 134.0, 132.6, 128.9, 127.6, 126.6, 124.4 ppm. HRMS (ESI-TOF) calcd for C₁₃H₁₀ClOSNa [M + Na]⁺: 270.9960; found: 270.9950.

S-(4-bromophenyl) benzothioate (4f)⁹³: A pale white crystalline solid; yield 96% (56.1 mg); m.p. 68–70 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J = 7.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz,2H), 7.45–7.40 (m, 4H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.7, 136.5, 136.4, 136.1, 134.0, 129.6, 128.9, 127.6, 126.0 ppm. HRMS (ESI-TOF) calcd for C₁₃H₁₀BrOS [M + H]⁺: 292.9636; found: 292.9623.

S-(4-(trifluoromethyl)phenyl) benzothioate (4g)⁹⁴: A pale white crystalline solid; yield 86% (48.5 mg); m.p. 105–106 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J = 7.4 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.65–7.61 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.83 ppm. ¹³C NMR (100 MHz, CDCl₃): δ 189.0, 136.4, 135.3, 134.2, 132.3, 131.6 (q, ²J_C-F = 32.6 Hz), 129.0, 127.7, 126.1 (q, ³J_C-F = 3.7 Hz), 124.0 (q, ¹J_C-F = 272.5 Hz) ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₀F₃OS [M + H]⁺: 283.0404; found: 283.0405.

S-(3,4-dimethylphenyl) benzothioate (4h): A pale white crystalline solid; yield 46% (22.3 mg); m.p. 78–80 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.23–7.20 (m, 3H), 2.294 (s, 3H), 2.286 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.9, 138.7, 137.9, 136.9, 136.2, 133.6, 132.7, 130.7, 128.8, 127.6, 123.9, 19.9, 19.8 ppm. HRMS (ESI-TOF) calcd for C₁₅H₁₅O [M + H]⁺: 243.0843; found: 243.0832.

S-(perfluorophenyl) benzothioate (4i)⁹⁵: A pale white crystalline solid; yield 33% (20.1 mg); m.p. 47–49 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, J = 7.6 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.82 ppm. ¹³C NMR (100 MHz, CDCl₃): δ 185.7, 139.0, 136.2, 135.8, 134.6, 132.7, 129.2, 129.0, 128.0 ppm. HRMS (ESI-TOF) calcd for C₁₃H₆F₅OS [M + H]⁺: 305.0060; found: 305.0047.

S-(naphthalen-2-yl) benzothioate (4j)⁹¹: A pale yellow crystalline solid; yield 82% (42.3 mg); m.p. 116–118 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, J = 7.6 Hz, 3H), 7.91–7.80 (m, 3H), 7.59 (t, J = 7.2 Hz, 1H), 7.56–7.44 (m, 5H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 190.4, 136.8, 135.0, 133.8, 133.7, 133.6, 131.5, 128.9, 128.9, 128.1, 127.9, 127.6, 127.3, 126.7, 124.8 ppm. HRMS (ESI-TOF) calcd for C₁₇H₁₃OS [M + H]⁺: 265.0687; found: 265.0675.

S-cyclopentyl benzothioate (4k): A white oily liquid; yield 50% (20.6 mg); ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 4.00–3.85 (m, 1H), 2.20 (d, J = 5.6 Hz, 2H), 1.85–1.58 (m, 6H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 192.8, 137.5, 133.2, 128.6, 127.3, 42.8, 33.5, 25.0 ppm. HRMS (ESI-TOF) calcd for C₁₂H₁₅OS [M + H]⁺: 207.0844; found: 207.0827.

S-cyclohexyl benzothioate (4l): A white oily liquid; yield 44% (19.4 mg); ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 3.73 (s, 1H), 2.02 (d, J = 9.2 Hz, 2H), 1.77 (s, 2H), 1.69–1.42 (m, 6H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 192.0, 137.6, 133.2, 128.7, 127.3, 42.7, 33.3, 26.2, 25.8 ppm. HRMS (ESI-TOF) calcd for C₁₃H₁₇OS [M + H]⁺: 221.1000; found: 221.0998.

S-benzyl benzothioate (4m)⁹²: A pale white crystalline solid; yield 95% (43.3 mg); m.p. 36–38 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.27–7.21 (m, 1H), 4.31 (s, 2H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 191.4, 137.6, 136.9, 133.5, 129.1, 128.8, 128.7, 127.4, 127.4, 33.5 ppm. HRMS (ESI-TOF) calcd for C₁₄H₁₃OS [M + H]⁺: 229.0687; found: 229.0693.

S-phenethyl benzothioate (4n)⁹²: A white oily liquid; yield 51% (24.7 mg); ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.3 Hz, 2H), 7.33–7.18 (m, 5H), 3.31 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.7 Hz, 2H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 191.9, 140.2, 137.3, 133.4, 128.8, 128.7, 128.7, 127.3, 126.7, 36.1, 30.6 ppm. HRMS (ESI-TOF) calcd for C₁₅H₁₅OS [M + H]⁺: 243.0844; found: 243.0854.

Supplemental Material

supplementary_material – Supplemental material for Na₂CO₃-promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives

Supplemental material, supplementary_material for Na₂CO₃-promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives by Jiasi Tao, Weijie Yu, Jin Luo, Tao Wang, Wanling Ge, Ziwei Zhang, Bingjie Yang and Fei Xiong in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this paper: We gratefully acknowledge the NSFC (21562026, 21762025) and the Natural Science Foundation of Jiangxi Province (20161BAB203085) for financial support.

ORCID iD

Jin Luo

Supplemental material

Supplemental material for this paper is available online.

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Supplementary Material

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Na 2 CO 3 -promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives

Abstract

Keywords

Introduction

Results and discussion

Conclusion

General procedure

Preparation of the starting materials

General procedure for N,N-Boc2-amide synthesis

General procedure for synthesis of N-Boc amides from secondary amides (1b, 1c)

General procedure for N-acyl-glutarimide synthesis (1d)

General procedure for saccharinamide synthesis (1e)

General procedure for the synthesis of S-p-tolyl benzothioate (e.g. 3a)

One-pot experiment

Supplemental Material

supplementary_material – Supplemental material for Na2CO3-promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material

General procedure for N,N-Boc₂-amide synthesis

supplementary_material – Supplemental material for Na₂CO₃-promoted thioesterification via N–C bond cleavage of amides to construct thioester derivatives