N-Aminopyridinium Ylide-Directed, Copper-Promoted Chalcogenation of Arene C─H Bonds

Abstract

N-Aminopyridinium ylide-directing group is employed for copper-promoted chalcogenation of sp² C─H bonds with aryl and alkyl disulfides as well as diphenyl diselenide. Reactions proceed in hexafluoroisopropanol (HFIP) solvent at elevated temperatures and are promoted by copper(II) acetate.

Graphical Abstract

1. INTRODUCTION

Thioethers and their derivatives are ubiquitous motifs found in natural products, pharmaceuticals, and functional materials.¹ Consequently, the methodology for formation of thioether functionality has been extensively explored.² The conventional methods for construction of C─S bonds involve transition-metal-catalyzed cross-coupling reactions between thiols and organic halides or their equivalents.³ This approach offers high efficiency and flexibility; however, it heavily depends on prefunctionalized starting materials. In contrast, direct conversion of C─H bonds to C─S functionality may shorten synthetic pathways and minimize waste production.⁴

Regioselective functionalization of a molecule that contains multiple C─H bonds can be achieved by employing an auxiliary directing the metalation step.^2d,5 A wide range of second-row transition metals, such as Ru, Rh, Pd, and Ag, have been employed for auxiliary-directed C─H bond sulfenylation.6 However, these catalysts are scarce, expensive, and reactions sometimes require costly oxidants or additives. Thus, it is advantageous to replace them with abundant, inexpensive, and often less toxic first-row transition-metal catalysts. In 2006, Yu and co-workers disclosed a method for copper-mediated, pyridine-directed arene C─H thiolation (Scheme 1).^7a In 2012, our group reported a general method for copper-promoted sulfenylation of sp² C─H bonds using a removable 8-aminoquinoline directing group.^7b The reactions are quite general, with dialkyl disulfides, diaryl disulfides, and bis-(trifluoromethyl)disulfide affording C─H sulfenylation products in good yields. Subsequently, many groups have reported copper-catalyzed/mediated C─H bond thiolation using bidentate directing groups.^7c-e The first example of diastereoselective, copper-mediated ferrocene C─H bond thiolation directed by a chiral oxazoline auxiliary was recently disclosed by Yu.^7f Other first-row metals, such as cobalt and nickel, have also been used for directed C─S bond formation.⁸ However, first-row transition-metal catalysis usually requires bidentate or nonremovable pyridine-type directing groups for thiolation of sp² C─H bonds. Very few examples report base metal-promoted C─H sulfenylation by employing monodentate directing groups.^9,10 Dai and co-workers have recently disclosed copper-mediated thiolation of arenes using monodentate amide as a weakly coordinating auxiliary.⁹ This method displays an unusual C─H functionalization selectivity whereby sulfenylation occurs at the more hindered position of amides metasubstituted with fluoro and chloro moieties. In 2016, Ackermann reported copper-mediated chalcogenation of 1,2,3-triazoles via monodentate coordination of a bidentate auxiliary.¹⁰ We have reported the use of pyridine ylides as directing groups in sp² and sp³ C─H functionalization under palladium, copper, and cobalt catalysis.^11,12 Similar ylides have been employed for metal-catalyzed C─H arylation of the pyridine moiety.¹³ We report here a method for copper-promoted arene C─H chalcogenation directed by a monodentate 4-tert-butyl-N-aminopyridinium ylide, displaying regioselectivity different from that reported by Dai and coworkers.

Scheme 1.

Thiolation of C─H Bonds

2. RESULTS

We initiated the study by investigating the reaction of unsubstituted N-aminopyridium ylide 1 with diphenyl disulfide (Table 1). Through extensive screening of copper salts and solvents, we found that Cu(OAc)₂ in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) afforded the best result (entry 1). Subsequently, modification of an ylide pyridine moiety was explored. Methoxy and 4-pyrrolidino substituents on the pyridine ring did not substantially improve the product yield (entries 2 and 3). When 4-tert-butyl-substituted ylide was employed, the yield increased to 57% (entry 4). Increasing reaction temperature to 110 °C afforded 63% of the product (entry 5). Further improvement was achieved if potassium persulfate was added, and the product was obtained in 80% NMR and 76% isolated yield (entry 6). The use of sodium and ammonium persulfate salts gave inferior results (entries 7 and 8). A control experiment performed in the absence of Cu(OAc)₂ afforded no product (entry 9).

Table 1.

Reaction Optimization^a

entry	substrate	additive	product, yield (%)
1	1	none	5, 48
2	2	none	6, 48
3	3	none	7, 43
4	4	none	8, 57
5b	4	none	8, 63
6b	4	K2S2O8	8, 80 (76)c
7b	4	Na2S2O2	8, 57
8b	4	(NH4)2S2O8	8, 47
9b,d	4	K2S2O8	no sulfenylation

^aAmide (0.1 mmol, 1 equiv), diphenyl disulfide (0.15 mmol, 1.5 equiv), Cu(OAc)₂ (0.2 mmol, 2 equiv), additive (0.2 mmol, 2.0 equiv), 1,1,1,3,3,3-hexafluoroisopropanol (HFIP, 0.7 mL), 90 °C. Yields were determined by ¹H NMR analysis using 1,1,2-trichloroethane internal standard.

^bTemperature: 110 °C.

^cIsolated yield.

^dNo Cu(OAc)₂.

After identification of optimal reaction conditions, the sulfenylation scope with respect to substitution on the aromatic ring was studied (Table 2). In general, substrates bearing electron-donating groups gave higher yields than ylides decorated with electron-withdrawing groups. Mixtures of di- and monothiolated products were formed in many cases if parasubstituted substrates were employed (entries 2–6). In contrast, metasubstituted ylides delivered monothiolated products at the less sterically hindered position, offering a high level of positional control (entries 7–10). However, benzdioxolane-substituted ylide (entry 15) afforded a mixture of mono- and dithiolated products, with monothiolation occurring at the more hindered position. The orthosubstituted substrates reacted efficiently and gave acceptable yields of products (entries 11 and 12). Satisfyingly, ylides bearing a wide range of functional groups including ether (entries 3, 8, and 15), trifluoromethyl (entry 4), halogen (entries 5, 9, 10, and 12), ester (entry 6), naphthyl (entry 13), and benzothiophene (entry 14) are compatible with reaction conditions and afforded products in good yields. Sulfenylation fails if the substrate contains nitrile functionality. Ylide derived from the 3,5-dimethylbenzoic acid derivative is unreactive as well. Importantly, a more challenging acrylamide substrate gave a stereoisomer mixture of products in an acceptable yield (entry 16).

Table 2.

Reaction Scope with Respect to Ylides^a

Entry	R	Product	Yield (%)
1	4-MeC6H4		76
2	4-tBuC6H4		R = H, 65; R = SPh, 15
3	4-MeOC6H4		R = H 60; R = H 60;b R = SPh, 20b
4	4-F3CC6H4		R = H, 60; R = SPh, 10
5b	4-FC6H4		R = H, 61; R = SPh, 16
6	4-MeO2CC6H4		R = H, 59; R = SPh, 13
7	3-MeC6H4		68
8	3-MeOC6H4		55
9	3-ClC6H4		64
10	3-IC6H4		45
11	2-MeC6H4		61
12	2-FC6H4		52
13	2-Naphthyl		68
14	3-Benzthio-phenyl		75
15	3,4-Benz-dioxolanyl		R = H, 40; R = SPh, 40
16	MeC=CH2		52 (Z:E = 3:1)c

^aAmide (0.5 mmol, 1 equiv), PhSSPh (0.75 mmol, 1.5 equiv), Cu(OAc)₂ (1.0 mmol, 2 equiv), K₂S₂O₈ (1.0 mmol, 2.0 equiv), HFIP (3.5 mL), 110 °C, 20–24 h. Yields are isolated yields. Please see the Experimental Section for details.

^bDiphenyl disulfide (2.5 equiv).

^cIsomer ratio was determined by ¹H NMR analysis, the yield is that of the isomer mixture. Abbreviation: TBPy = 4-tert-butyl-pyridyl.

Subsequently, the scope for disulfide reactions with ylide 4 was examined (Scheme 2). The sulfenylation is well applicable to both aryl and alkyl disulfides. Formation of a mixture of di- and monothiolated adducts was observed when aryl disulfides were employed (9–12). Interestingly, alkyl disulfides selectively afforded monosubstitution products (13–15). However, disulfide bearing a more sterically hindered isopropyl substituent gave a lower 46% yield of 13.

Scheme 2. Disulfide Scope in C─H Sulfenylation^a.

^aAmide (0.5 mmol, 1 equiv), disulfide (0.75 mmol, 1.5 equiv), Cu(OAc)₂ (1.0 mmol, 2 equiv), K₂S₂O₈ (1.0 mmol, 2.0 equiv), HFIP (3.5 mL), 110 °C, 24 h. Yields are isolated yields.

The same reaction conditions can be applied for C─H selenylation (Scheme 3). para-Methyl substituted ylide 4 gave a mixture of mono- and diselenylation products 18 and 19 in 30 and 42% yields, respectively. The selectivity can be increased by lowering the reaction temperature to 90 °C and decreasing the loading of diphenyl diselenide to 1 equiv. Under these conditions, 50% of 18 was formed, along 4% of 19. The reaction proceeds in higher yields for substrates possessing electron-releasing substituents. Thus, selenylation of 16 gives 80% yield of 20. Increasing the reaction scale to 6 mmol affords a comparable 76% yield of 20. Ylide 17 possessing an electron-withdrawing trifluoromethyl group affords 21 in 62% yield.

Scheme 3. Ylide C─H Selenylation^a.

^aAmide (0.5 mmol, 1 equiv), PhSeSePh (0.75 mmol, 1.5 equiv), Cu(OAc)₂ (1.0 mmol, 2 equiv), K₂S₂O₈ (1.0 mmol, 2.0 equiv), HFIP (3.5 mL), 110 °C, 24 h. Yields are isolated yields. ^bTemperature 90 °C, PhSeSePh (1 equiv), yield determined by ¹H NMR analysis. ^cGram-scale reaction: amide 16 (6 mmol), 40 h.

To further demonstrate the applicability of this method to the functionalization of more complex structures, we performed thiolation of an estrone-derived substrate 22 (Scheme 4). The reaction gave monothiolated product 23 in a 50% yield.

Scheme 4.

Thiolation of an Estrone Derivative

Finally, the practical utility of this method was demonstrated by facile removal of the 4-tert-butylpyridinium directing group (Scheme 5). Compound 8 was treated with zinc in acetic acid at 90 °C, affording amide 24 in 82% yield.¹¹ Additionally, the directing group in compound 13 was cleaved through a sequence of N-alkylation followed by base hydrolysis to give carboxylic acid 25 in 70% overall yield.^12a

Scheme 5.

Directing Group Removal

We performed experiments to determine the intermediacy of radical species (Scheme 6). Sulfenylation of ylide 4 in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) afforded product 8 in yields that are essentially the same as those obtained in the absence of a radical trap. Thus, the intermediacy of free radicals in this reaction is unlikely.

Scheme 6.

Radical Trapping Experiment

While interpretation of a single measurement of the deuterium isotope effect may be misleading, appropriate experiments can provide important information about the timing of C─H bond-breaking step and properties of the bond cleavage transition state.¹⁴ We reacted the perdeuterated ylide 26 with di-n-propyl disulfide under the standard reaction conditions (Scheme 7). At ca. 18% conversion to 27a, 78% of unreacted 26 was recovered, with 5% incorporation of hydrogen at the ortho position of the aromatic ring. If disulfide reagent was omitted, 26 was recovered in 30% yield with 12% hydrogen incorporation. Additionally, 40% of ortho-hydroxylated 27b was isolated. These results suggest that the C─H bond cleavage is likely not the rate-determining step.

Scheme 7.

Deuterium Scrambling Experiments

3. CONCLUSIONS

We report here that N-aminopyridium ylides are efficient directing groups for copper-promoted sulfenylation and selenylation of sp² C─H bonds with aryl and alkyl disulfides as well as diphenyl diselenides under ligand-free conditions. The reaction is conducted in hexafluoroisopropanol solvent at elevated temperatures and is promoted by copper(II) acetate. Products are obtained in moderate to good yields. The directing group can be conveniently cleaved by reduction or N-alkylation followed by hydrolysis.

4. EXPERIMENTAL SECTION

4.1. General Information.

The ¹H, ¹³C NMR spectra were recorded on JEOL EC-400, EC-500, and EC-600 spectrometers using the residual solvent peak as a reference. The compounds for high-resolution mass spectrometry (HRMS) were analyzed by positive mode electrospray ionization (CI or ESI) using an Agilent QTOF mass spectrometer in the Mass Spectrometry Facility (MSF) of the Department of Chemistry and Biochemistry, University of Texas—Austin. Column chromatography was performed using 60 Å silica gel. The reagents and starting materials were purchased from commercial vendors and used without further purification unless noted otherwise. 17-Oxoestra-1,3,5(10)-triene-3-carboxylic acid was synthesized according to a known procedure.¹⁵ The ylide starting materials were prepared using literature methods.^11,12 Starting materials in Table 2 (SM02-16) are labeled with the number corresponding to the entry. Compounds 1–4, SM02-06, SM09-10, and SM12-13 are known.^12a

Method A: To a solution of 4-tert-butylpyridine (6 mmol, 1 equiv) in CH₂Cl₂ (10 mL) was added O-mesitylenesulfonyl hydroxyl amine (MSH) (1.6 g, 7.2 mmol, 1.2 equiv) and the resulting solution was stirred for 3 h. The reaction mixture was evaporated and CH₃CN (20 mL) was added. To the solution were added K₂CO₃ (2.1 g, 15 mmol, 2.5 equiv) and acid chloride (1.2 equiv) at 0 °C. The reaction was warmed to room temperature and stirred for 24 h. After completion, the mixture was filtered through a 5 cm pad of Celite in CH₂Cl₂. The filtrate was concentrated under reduced pressure, the residue was mixed with 20% aqueous NaOH solution (40 mL) and stirred for 1 h. The solution was extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over MgSO₄, and after filtration, the solvent was removed under reduced pressure. The residue was purified by recrystallization from dichloromethane and diethyl ether.

4.1.1. (4-(tert-Butyl)pyridin-1-ium-1-yl)(3-methylbenzoyl)amide (Table 2, SM07 and Scheme 3, 16).

Method A was used with 4-tert-butylpyridine (0.88 mL, 6 mmol) and m-toluoyl chloride (0.95 mL, 7.2 mmol, 1.2 equiv). Recrystallization from CH₂Cl₂/Et₂O; yield 50% (0.8 g); pale yellow solid; mp 217–219 °C, ¹H NMR (600 MHz, CDCl₃) δ 8.63 (d, J = 7.2 Hz, 2H), 7.96 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 2.40 (s, 3H), 1.38 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.3, 162.8, 142.8, 137.5, 137.4, 130.9, 128.6, 127.9, 125.2, 123.1, 35.8, 30.4, 21.6; HRMS (ESI) calcd for C₁₇H₂₀N₂O [M + H]⁺ 269.1648, found 269.1648.

4.1.2. (4-(tert-Butyl)pyridin-1-ium-1-yl)(3-methoxybenzoyl)-amide (Table 2, SM08).

Method A was used with 4-tert-butylpyridine (0.88 mL, 6 mmol) and 3-methoxybenzoyl chloride (1.02 mL, 7.2 mmol, 1.2 equiv). Recrystallization from CH₂Cl₂/Et₂O; yield 57% (0.98 g); pale yellow solid; mp 175–176 °C, ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J = 6.8 Hz, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 6.8 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 6.97 (d, J =8.1 Hz, 1H), 3.85 (s, 3H), 1.36 (s, 9H); ¹³C{¹H} (101 MHz, CDCl₃) δ 170.9, 162.9, 159.4, 142.8, 139.0, 128.9, 123.1, 120.5, 116.8, 112.5, 55.4, 35.8, 30.3; HRMS (ESI) calcd for C₁₇H₂₀N₂O₂ [M + H]⁺ 285.1598, found 285.1599.

4.1.3. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-methylbenzoyl)amide (Table 2, SM11).

Method A was used with 4-tert-butylpyridine (0.88 mL, 6 mmol) and o-toluoyl chloride (0.94 mL, 7.2 mmol, 1.2 equiv). Recrystallization from CH₂Cl₂/Et₂O; yield 55% (0.88 g); pale yellow solid; mp 167–169 °C, ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 6.4 Hz, 2H), 7.67 (d, J = 6.6 Hz, 1H), 7.54 (d, J = 6.2 Hz, 2H), 7.32–7.09 (m, 3H), 2.55 (s, 3H), 1.34 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 174.3, 162.8, 142.6, 138.6, 136.5, 130.7, 128.6, 128.3, 125.4, 123.2, 35.7, 30.3, 20.6; HRMS (ESI) calcd for C₁₇H₂₀N₂O [M + H]⁺ 269.1648, found 269.1649.

Method B: A 100 mL round-bottom flask was charged with 4-tert-butylpyridine (0.59 mL, 4 mmol, 1 equiv) and CH₂Cl₂ (20 mL). MSH (1.03 g, 4.8 mmol, 1.2 equiv) was added to the solution, and the mixture was stirred for 3 h. This step prepares 1-amino-4-tert-butylpyridine. Another 100 mL round-bottom flask was charged with carboxylic acid (4 mmol, 1 equiv) and CH₂Cl₂ (20 mL), and the mixture was cooled to 0 °C. Ethyl chloroformate (0.42 mL, 4.4 mmol, 1.1 equiv) was added to the mixture followed by the addition of triethylamine (1.67 mL, 12 mmol, 3 equiv). The mixture was stirred for an hour at room temperature. To this mixture were added dropwise the 1-amino-4-tert-butylpyridine solution prepared above and solid K₂CO₃ (1.66 g, 12 mmol). After stirring the mixture for 24 h, NaOH (50 mL of a 1 N aqueous solution) was poured in and the mixture was extracted with CH₂Cl₂ (3 × 100 mL). The extracts were dried over MgSO₄, and after filtration, the solvent was removed under reduced pressure. The residue was purified by column chromatography.

4.1.4. (Benzo[b]thiophene-3-carbonyl)(4-(tert-butyl)pyridin-1-ium-1-yl)amide (Table 2, SM14).

Method B was used with benzo[b]thiophene-3-carboxylic acid (4 mmol, 0.71 g). Yield 74% (0.92 g); white solid; mp 179–180 °C (EtOAc/MeOH = 10/1); R_f = 0.52 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0 → 10%); ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J = 8.2 Hz, 1H), 8.68 (d, J = 6.5 Hz, 2H), 8.26 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 6.5 Hz, 2H), 7.47–7.37 (m, 1H), 7.38–7.30 (m, 1H), 1.34 (s, 9H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.6, 162.9, 142.8, 140.7, 137.7, 134.6, 130.4, 125.9, 124.4, 124.1, 123.1, 122.4, 35.7, 30.3. HRMS (ESI) calcd for C₁₈H₁₈N₂OS [M + H]⁺ 311.1213, found 311.1214.

4.1.5. (Benzo[d][ 1,3]dioxole-5-carbonyl)(4-(tert-butyl)pyridin-1-ium-1-yl)amide (Table 2, SM15).

Method B was used with piperonylic acid (0.67 g, 4 mmol, 1 equiv). Yield 52% (0.62 g); white solid; mp 206–209 °C (CH₂Cl₂/Et₂O); R_f = 0.36 (CH₂Cl₂/MeOH = 15/1); purification (5–9% MeOH in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J = 6.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J = 6.5 Hz, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.97 (s, 2H), 1.37 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 170.4, 162.7, 149.2, 147.3, 142.8, 131.8, 123.1, 122.6, 108.6, 107.6, 101.2, 35.7, 30.4; HRMS (ESI) calcd for C₁₇H₁₈N₂O₃ [M + H]⁺ 299.1390, found 299.1392.

4.1.6. (4-(tert-Butyl)pyridin-1-ium-1-yl)(methacryloyl)amide (Table 2, SM16).

Method B was used with metacrylic acid (0.34 mL, 4 mmol, 1 equiv). Yield 70% (0.61 g); off-white solid; mp 154–157 °C (CH₂Cl₂/Et₂O); R_f = 0.28 (CH₂Cl₂/MeOH = 15/1); purification (6–11% MeOH in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J = 6.6 Hz, 2H), 7.56 (d, J = 6.7 Hz, 2H), 5.97 (s, 1H), 5.26 (s, 1H), 2.05 (s, 3H), 1.36 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.6, 162.8, 142.8, 142.4, 123.0, 118.6, 35.7, 30.3, 19.4; HRMS (ESI) calcd for C₁₃H₁₈N₂O [M + H]⁺ 219.1492, found 219.1492.

4.1.7. (4-(tert-Butyl)pyridin-1-ium-1-yl)(3-(trifluoromethyl)-benzoyl)amide (Scheme 3, 17).

Method A was used with 4-tert-butylpyridine (0.88 mL, 6 mmol) and 3-(trifluoromethyl) benzoyl chloride (1.09 mL, 7.2 mmol, 1.2 equiv). Recrystallization from CH₂Cl₂/Et₂O; yield 49% (0.94 g); white solid; mp 230–232 °C, ¹H NMR (600 MHz, CDCl₃) δ 8.63 (d, J = 5.9 Hz, 2H), 8.44 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 5.8 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 1.39 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 169.6, 163.3, 142.6, 138.4, 131.4, 130.2 (q, J = 32.8 Hz), 128.4, 126.7 (q, J = 4.0 Hz), 125.0 (q, J = 3.8 Hz), 124.4 (q, J = 272.3 Hz), 123.3, 35.8, 30.3; ¹⁹F NMR (565 MHz, CDCl₃) δ −62.29; HRMS (ESI) calcd for C₁₇H₁₇F₃N₂O [M + H]⁺ 323.1366, found 323.1372.

4.1.8. (4-(tert-Butyl)pyridin-1-ium-1-yl)((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-phenanthrene-3-carbonyl)amide (Scheme 4, 22).

Method B was used with 4-tert-butylpyridine (0.22 mL, 1.5 mmol) and 17-oxoestra-1,3,5(10)-triene-3-carboxylic acid (0.45 g, 1.5 mmol, 1 equiv); yield 63% (0.41 g); light yellow solid; mp 251–253 °C (CH₂Cl₂/Et₂O); R_f = 0.31 (CH₂Cl₂/MeOH = 15/1); purification (6–8% MeOH in CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃) δ 8.61 (d, J = 7.0 Hz, 2H), 7.91 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.33 (d, J = 8.1 Hz, 1H), 3.01–2.94 (m, 2H), 2.54–2.43 (m, 2H), 2.37–2.31 (m, 1H), 2.18–2.10 (m, 1H), 2.10–2.00 (m, 2H), 1.99–1.94 (m, 1H), 1.67–1.43 (m, 6H), 1.39 (s, 9H), 0.91 (s, 3H); ¹³C{¹H} (151 MHz, CDCl₃) δ 221.2, 171.1, 162.9, 142.9, 141.9, 136.0, 134.7, 128.6, 125.5, 125.0, 123.1, 50.7, 48.1, 44.7, 38.2, 36.0, 35.8, 31.7, 30.4, 29.5, 26.6, 25.8, 21.7, 14.0; HRMS (ESI) calcd for C₂₈H₃₄N₂O₂ [M + H]⁺ 431.2693, found 431.2695.

4.1.9. (4-(tert-Butyl)pyridin-1-ium-1-yl)(benzoyl-2,3,4,5,6-d5)-amide (Scheme 7, 26).

Method B was used with benzoic acid-2,3,4,5,6-d₅ (0.383 g, 3 mmol, 1 equiv). Yield 51% (0.4 g); pale yellow solid; R_f = 0.44 (CH₂Cl₂/MeOH = 15/1); purification (5–9% MeOH in CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 6.8 Hz, 2H), 7.61 (d, J = 6.9 Hz, 2H), 1.39 (s, 9H).

4.2. General Procedure for Copper-Mediated C─H Chalcogenation.

A 2-dram vial equipped with a magnetic stir bar was charged with amide (0.5 mmol), phenyl disulfide (1.5–2.5 equiv), Cu(OAc)₂ (182 mg, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), and hexafluoroisopropanol (3.5 mL). The mixture was stirred at room temperature for 5 min, covered with aluminum foil, placed into a heating block preheated to 110 °C, and then stirred for 20–24 h. After completion, the reaction was cooled to room temperature. To the residue was added an aqueous solution of Na₂EDTA (pH = 8, 25 mL), followed by extraction with CH₂Cl₂ (20 mL). The addition/extraction process was repeated three times. The combined organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using an appropriate eluent. After isolation, the product was dried under reduced pressure.

4.2.1. (4-Methyl-2-(phenylthio)benzoyl)(pyridin-1-ium-1-yl)-amide (Table 1, 5).

Amide 1 (106 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), 90 °C for 20 h; purification (2–7% MeOH in CH₂Cl₂); yield 45% (72 mg); R_f = 0.36 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 161–164 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.79 (d, J = 6.2 Hz, 2H), 7.90 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.0 Hz, 2H), 7.51 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.78 (s, 1H), 2.18 (s, 3H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.1, 143.4, 139.6, 137.5, 137.1, 135.7, 134.4, 133.8, 129.6, 129.3, 129.0, 127.7, 126.3, 126.1, 21.5; HRMS (ESI) calcd for C₁₉H₁₆N₂OS [M + H]⁺ 321.1056, found 321.1057.

4.2.2. (4-Methoxypyridin-1-ium-1-yl)(4-methyl-2-(phenylthio)-benzoyl)amide (Table 1, 6).

Amide 2 (121 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), 90 °C for 20 h; purification (2–7% MeOH in CH₂Cl₂); yield 44% (77 mg); R_f = 0.3 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 174–177 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.46 (d, J = 6.7 Hz, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.1 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 6.9 Hz, 2H), 6.93 (d, J = 7.5 Hz, 1H), 6.75 (s, 1H), 3.91 (s, 3H), 2.14 (s, 3H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.7, 166.1, 145.0, 139.2, 137.0, 135.7, 134.8, 133.5, 129.6, 129.2, 127.5, 126.2, 111.3, 56.9, 21.3; HRMS (ESI) calcd for C₂₀H₁₈N₂O₂S [M + H]⁺ 351.1162, found 351.1164.

4.2.3. (4-Methyl-2-(phenylthio)benzoyl)(4-(pyrrolidin-1-yl)-pyridin-1-ium-1-yl)amide (Table 1, 7).

Amide 3 (141 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), 90 °C for 20 h; purification (2–7% MeOH in CH₂Cl₂); yield 41% (80 mg); R_f = 0.3 (CH₂Cl₂/MeOH = 20/1); light yellow solid; mp 249–251 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.09 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.49 (dd, J = 5.1, 3.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 3.7 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.74 (s, 1H), 6.46 (d, J = 7.6 Hz, 2H), 3.40–3.38 (m, 4H), 2.14 (s, 3H), 2.11–2.03 (m, 4H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 173.1, 151.3, 142.6, 138.8, 136.9, 136.3, 135.6, 133.6, 129.6, 129.2, 128.9, 127.4, 126.2, 106.8, 48.1, 25.4, 21.4; HRMS (ESI) calcd for C₂₃H₂₃N₃OS [M + H]⁺ 390.1635, found 390.1636.

4.2.4. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methyl-2-(phenylthio)-benzoyl)amide (Table 1, 8 and Table 2, Entry 1).

Amide 4 (134 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (2–7% MeOH in CH₂Cl₂); 76% (143 mg); R_f = 0.37 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 215–218 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 6.2 Hz, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 6.3 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.35–7.26 (m, 3H), 6.97 (d, J = 7.7 Hz, 1H), 6.79 (s, 1H), 2.18 (s, 3H), 1.37 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.4, 162.9, 142.7, 139.4, 137.3, 136.0, 134.8, 133.7, 129.7, 129.3, 129.0, 127.6, 126.4, 123.2, 35.8, 30.4, 21.4; HRMS (ESI) calcd for C₂₃H₂₄N₂OS [M + H]⁺ 377.1682, found 377.1685.

4.2.5. (4-(tert-Butyl)-2-(phenylthio)benzoyl)(4-(tert-butyl)pyridin-1-ium-1-yl)amide (A, R = H) and (4-(tert-Butyl)-2,6-bis-(phenylthio)benzoyl)(4-(tert-butyl)-pyridin-1-ium-1-yl)-amide (B, R = SPh) (Table 2, Entry 2).

SM02 (156 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), two products were obtained.

Product A: yield 65% (137 mg); R_f = 0.41 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 221–224 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J = 6.2 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 6.2 Hz, 2H), 7.50 (d, J = 7.3 Hz, 2H), 7.38–7.23 (m, 3H), 7.18 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 1.37 (s, 9H), 1.12 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.4, 162.9, 152.4, 142.7, 136.8, 136.2, 134.9, 133.5, 129.2, 128.7, 127.5, 126.8, 123.1, 122.7, 35.8, 34.8, 31.1, 30.4; HRMS (ESI) calcd for C₂₆H₃₀N₂OS [M + H]⁺ 419.2152, found 419.2154.

Product B: yield 15% (40 mg); R_f = 0.46 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 73–76 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.57 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 7.2 Hz, 4H), 7.29 (t, J = 7.6 Hz, 4H), 7.22 (t, J = 7.4 Hz, 2H), 7.07 (s, 2H), 1.36 (s, 9H), 1.04 (s, 9H). ¹³C{¹H} (151 MHz, CDCl₃) δ 171.4, 163.2, 151.8, 142.6, 139.7, 136.5, 134.3, 131.7, 129.0, 127.5, 126.9, 123.3, 35.8, 34.9, 31.0, 30.4; HRMS (ESI) calcd for C₃₂H₃₄N₂OS₂ [M + H]⁺ 527.2185, found 527.2187.

4.2.6. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methoxy-2-(phenylthiol)benzoyl)amide (A, R = H) and (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methoxy-2,6-bis-(phenylthio)benzoyl)amide (B, R = SPh) (Table 2, Entry 3).

SM03 (143 mg, 0.5 mmol), phenyl disulfide (273 mg, 1.25 mmol, 2.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), two products were obtained.

Product A: yield 60% (118 mg); R_f = 0.34 (CH₂Cl₂/MeOH = 30/1); off-white solid; mp 236–238 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.65 (d, J = 7.2 Hz, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 6.8 Hz, 2H), 7.40–7.32 (m, 3H), 6.67 (d, J = 8.6 Hz, 1H), 6.38 (s, 1H), 3.61 (s, 3H), 1.38 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.9, 162.8, 160.5, 142.8, 141.0, 135.0, 134.9, 130.6, 129.5, 128.6, 128.4, 123.1, 113.5, 110.2, 55.2, 35.8, 30.4; HRMS (ESI) calcd for C₂₃H₂₄N₂O₂S [M + H]⁺ 393.1633, found 393.1633.

Product B: yield 20% (50 mg); R_f = 0.41 (CH₂Cl₂/MeOH = 30/1); yellow solid; mp 155–157 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 6.2 Hz, 2H), 7.60 (d, J = 6.3 Hz, 2H), 7.52 (d, J = 7.2 Hz, 4H), 7.35–7.26 (m, 6H), 6.46 (s, 2H), 3.50 (s, 3H), 1.37 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.2, 163.3, 159.3, 142.6, 137.2, 135.3, 133.7, 132.9, 129.3, 127.6, 123.2, 114.1, 55.3, 35.8, 30.4; HRMS (ESI) calcd for C₂₉H₂₈N₂O₂S₂ [M + H]⁺ 501.1665, found 501.1670.

4.2.7. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-(phenylthio)-4-(trifluoromethyl)benzoyl)amide (A, R = H) and (2,6-Bis-(phenylthio)-4-(trifluoromethyl)benzoyl)(4-(tert-butyl)pyridine-1-ium-1-yl)amide (B, R = SPh) (Table 2, Entry 4).

SM04 (162 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), two products were obtained.

Product A: yield 60% (129 mg); R_f = 0.2 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 196–198 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J = 6.3 Hz, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 6.2 Hz, 2H), 7.54 (d, J = 5.9 Hz, 2H), 7.39–7.36 (m, 4H), 7.13 (s, 1H), 1.39 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.2, 163.6, 142.5, 140.0, 139.9, 134.5, 133.9, 131.3 (q, J = 32.3 Hz), 129.7, 129.3, 128.7, 125.0, 123.9 (q, J = 272.8 Hz), 123.3, 121.6, 35.9, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.84; HRMS (ESI) calcd for C₂₃H₂₁F₃N₂OS [M + H]⁺ 431.1399, found 431.1402.

Product B: yield 10% (27 mg); R_f = 0.34 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 173–176 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J = 4.3 Hz, 2H), 7.65 (d, J = 4.6 Hz, 2H), 7.53 (d, J = 6.9 Hz, 4H), 7.36–7.31 (m, 6H), 7.07 (s, 2H), 1.39 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.3, 164.0, 142.7, 142.6, 137.8, 133.9, 133.3, 130.9 (q, J = 32.5 Hz), 129.6, 128.3, 124.8, 123.5, 123.4 (q, J = 272.9 Hz), 35.9, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.83; HRMS (ESI) calcd for C₂₉H₂₅F₃N₂OS₂ [M + H]⁺ 539.1433, found 539.1436.

4.2.8. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-fluoro-2-(phenylthio)-benzoyl)amide (A, R = H) and (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-fluoro-2,6-bis(phenylthio)benzoyl)amide (B, R = SPh) (Table 2, Entry 5).

SM05 (162 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), two products were obtained.

Product A: yield 61% (116 mg); R_f = 0.39 (CH₂Cl₂/MeOH = 20/1); white solid; mp 211–213 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 6.3 Hz, 2H), 7.92 (t, J = 7.3 Hz, 1H), 7.63 (d, J = 6.3 Hz, 2H), 7.56 (d, J = 5.2 Hz, 2H), 7.44–7.34 (m, 3H), 6.79 (t, J = 8.1 Hz, 1H), 6.50 (d, J = 10.4 Hz, 1H), 1.39 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.4, 163.5 (d, J = 248.7 Hz), 163.2, 142.6, 142.4 (d, J = 8.1 Hz), 135.3, 133.9, 131.7 (d, J = 3.7 Hz), 131.0 (d, J = 8.9 Hz), 129.7, 128.8, 123.23, 114.2 (d, J = 25.3 Hz), 111.6 (d, J = 21.8 Hz), 35.8, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −111.47; HRMS (ESI) calcd for C₂₂H₂₁FN₂OS [M + H]⁺ 381.1431, found 381.1435.

Product B: yield 16% (39 mg); R_f = 0.48 (CH₂Cl₂/MeOH = 20/1); light yellow solid; mp 82–85 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.69 (d, J = 5.8 Hz, 2H), 7.65 (d, J = 6.3 Hz, 2H), 7.55 (d, J = 7.1 Hz, 4H), 7.38–7.30 (m, 6H), 6.46 (d, J = 9.3 Hz, 2H), 1.39 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 170.6, 163.7, 162.3 (d, J = 248.9 Hz), 142.6, 139.2 (d, J = 8.9 Hz), 134.7, 134.0, 133.9, 129.6, 128.4, 123.4, 113.7 (d, J = 24.9 Hz), 35.9, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −112.20; HRMS (ESI) calcd for C₂₈H₂₅FN₂OS₂ [M + H]⁺ 489.1465, found 489.1467.

4.2.9. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-(methoxycarbonyl)-2-(phenylthio)benzoyl)amide (A, R = H) and (4-(tert-Butyl)-pyridin-1-ium-1-yl)(4-(methoxycarbonyl)-2,6-bis(phenylthio)-benzoyl)-amide (B, R = SPh) (Table 2, Entry 6).

SM06 (157 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), two products were obtained.

Product A: yield 59% (125 mg); R_f = 0.34 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 184–187 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 5.8 Hz, 2H), 7.89 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.70–7.60 (m, 3H), 7.53 (d, J = 6.8 Hz, 2H), 7.42–7.29 (m, 3H), 3.80 (s, 3H), 1.40 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.7, 166.6, 163.5, 142.5, 141.8, 138.4, 134.7, 133.8, 130.8, 130.3, 129.5, 128.9, 128.2, 126.4, 123.3, 52.2, 35.8, 30.3; HRMS (ESI) calcd for C₂₄H₂₄N₂O₃S [M + H]⁺ 421.1580, found 421.1584.

Product B: yield 13% (35 mg); R_f = 0.63 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 86–89 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 5.9 Hz, 2H), 7.63 (d, J = 7.5 Hz, 4H), 7.51 (d, J = 7.5 Hz, 4H), 7.36–7.25 (m, 6H), 3.73 (s, 3H), 1.38 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 170.7, 166.1, 163.8, 145.2, 142.6, 136.4, 135.0, 132.6, 130.6, 130.2, 129.5, 127.8, 123.5, 52.4, 35.9, 30.4; HRMS (ESI) calcd for C₃₀H₂₈N₂O₃S₂ [M + H]⁺ 529.1614, found 529.1615.

4.2.10. (4-(tert-Butyl)pyridin-1-ium-1-yl)(5-methyl-2-(phenylthio)-benzoyl)amide (Table 2, Entry 7).

SM07 (134 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 68% (128 mg); R_f = 0.35 (CH₂Cl₂/MeOH = 30/1); gray-yellow solid; mp 209–211 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J = 6.0 Hz, 2H), 7.63 (s, 1H), 7.58 (d, J = 6.0 Hz, 2H), 7.46 (d, J = 7.3 Hz, 2H), 7.30–7.21 (m, 3H), 6.99–6.92 (m, 2H), 2.30 (s, 3H), 1.36 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.6, 163.0, 142.7, 138.4, 136.7, 135.7, 133.2, 132.9, 130.3, 129.4, 129.2, 127.2, 123.2, 35.8, 30.4, 21.0; HRMS (ESI) calcd for C₂₃H₂₄N₂OS [M + H]⁺ 377.1682, found 377.1682.

4.2.11. (4-(tert-Butyl)pyridin-1-ium-1-yl)(5-methoxy-2-(phenylthio)benzoyl)amide (Table 2, Entry 8).

SM08 (143 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 55% (108 mg); R_f = 0.26 (CH₂Cl₂/MeOH = 30/1); off-white solid; mp 187–189 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.56 (d, J = 6.7 Hz, 2H), 7.58 (d, J = 6.8 Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H), 7.34 (s, 1H), 7.26 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H), 1.36 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.4, 163.2, 158.6, 142.6, 141.8, 138.0, 133.6, 131.1, 129.0, 126.4, 125.6, 123.2, 116.2, 113.3, 55.5, 35.8, 30.3; HRMS (ESI) calcd for C₂₃H₂₄N₂O₂S [M + H]⁺ 393.1631, found 393.1635.

4.2.12. (4-(tert-Butyl)pyridin-1-ium-1-yl)(5-chloro-2-(phenylthio)-benzoyl)amide (Table 2, Entry 9).

SM09 (145 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 64% (128 mg); R_f = 0.37 (CH₂Cl₂/MeOH = 20/1); green-yellow solid; mp 147–149 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 5.4 Hz, 2H), 7.86 (s, 1H), 7.64 (d, J = 5.6 Hz, 2H), 7.52 (d, J = 7.3 Hz, 2H), 7.39–7.31 (m, 3H), 7.10 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 1.40 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.6, 163.5, 142.6, 138.4, 136.9, 134.9, 134.2, 131.0, 130.1, 129.5, 129.4, 128.9, 128.2, 123.3, 35.8, 30.4; HRMS (ESI) calcd for C₂₂H₂₁ClN₂OS [M + H]⁺ 397.1136, found 397.1135.

4.2.13. (4-(tert-Butyl)pyridin-1-ium-1-yl)(5-iodo-2-(phenylthio)benzoyl)amide (Table 2, Entry 10).

SM10 (145 mg, 0.5 mmol), phenyl disulfide (190 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 45% (110 mg); R_f = 0.29 (CH₂Cl₂/MeOH = 30/1); orange-yellow solid; mp 206–208 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 6.0 Hz, 2H), 8.19 (s, 1H), 7.64 (d, J = 6.1 Hz, 2H), 7.52 (d, J = 6.1 Hz, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.40–7.31 (m, 3H), 6.63 (d, J = 8.5 Hz, 1H), 1.40 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 170.8, 163.4, 142.5, 138.8, 138.7, 138.1, 137.5, 134.4, 130.3, 129.5, 129.1, 128.3, 123.3, 89.7, 35.8, 30.4; HRMS (ESI) calcd for C₂₂H₂₁IN₂OS [M + H]⁺ 489.0492, found 489.0491.

4.2.14. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-methyl-6-(phenylthio)-benzoyl)amide (Table 2, Entry 11).

SM11 (134 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 61% (115 mg); R_f = 0.17 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 174–176 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.65 (d, J = 6.7 Hz, 2H), 7.60 (d, J = 6.9 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.29–7.23 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.10–7.07 (m, 2H), 7.07–7.03 (m, 1H), 2.51 (s, 3H), 1.36 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.5, 163.4, 142.5, 141.4, 137.0, 135.7, 133.3, 131.3, 129.4, 129.0, 128.2, 126.6, 123.3, 35.7, 30.2, 19.6; HRMS (ESI) calcd for C₂₃H₂₄N₂OS [M + H]⁺ 377.1682, found 377.1684.

4.2.15. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-fluoro-6-(phenylthio)-benzoyl)amide (Table 2, Entry 12).

SM12 (137 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 52% (99 mg); R_f = 0.26 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 195–197 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 4.1 Hz, 2H), 7.63 (d, J = 5.2 Hz, 2H), 7.48 (d, J = 7.3 Hz, 2H), 7.35–7.20 (m, 3H), 7.11 (dd, J = 13.5, 7.6 Hz, 1H), 6.93 (t, J = 8.3 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 1.38 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 169.3, 163.8, 159.7 (d, J = 248.2 Hz), 142.7, 142.6, 137.5, 135.0, 132.8, 129.3, 128.9 (d, J = 13.0 Hz), 127.6, 126.0, 123.2, 113.7 (d, J = 22.4 Hz), 35.7, 30.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −115.80; HRMS (ESI) calcd for C₂₂H₂₁FN₂OS [M + H]⁺ 381.1431, found 381.1434.

4.2.16. (4-(tert-Butyl)pyridin-1-ium-1-yl)(3-(phenylthio)-2-naphthoyl)amide (Table 2, Entry 13).

SM13 (153 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 68% (140 mg); R_f = 0.33 (CH₂Cl₂/MeOH = 30/1); brown solid; mp 226–229 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.64 (d, J = 5.0 Hz, 2H), 8.35 (s, 1H), 7.83 (dd, J = 5.8, 3.2 Hz, 1H), 7.62 (d, J =5.1 Hz, 2H), 7.57 (d, J = 7.2 Hz, 2H), 7.52 (dd, J = 5.8, 3.4 Hz, 1H), 7.44–7.35 (m, 5H), 7.35–7.31 (m, 1H), 1.38 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.4, 163.3, 142.7, 136.1, 135.8, 135.3, 133.9, 133.8, 131.4, 129.4, 128.5, 128.3, 127.9, 127.8, 126.9, 126.8, 125.7, 123.2, 35.8, 30.4; HRMS (ESI) calcd for C₂₆H₂₄N₂OS [M + H]⁺ 413.1682, found 413.1686.

4.2.17. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-(phenylthio)benzo[b]-thiophene-3-carbonyl)amide (Table 2, Entry 14).

SM14 (156 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 75% (157 mg); R_f = 0.44 (CH₂Cl₂/MeOH = 30/1); red-brown solid; mp 227–229 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J = 6.5 Hz, 2H), 8.58 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 6.6 Hz, 2H), 7.62 (d, J = 6.6 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.48–7.37 (m, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 1.39 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 169.0, 163.0, 146.4, 142.8, 139.3, 138.7, 134.8, 134.5, 132.4, 130.9, 129.4, 129.3, 128.8, 124.6, 124.5, 123.4, 123.2, 121.0, 35.8, 30.3; HRMS (ESI) calcd for C₂₄H₂₂N₂OS₂ [M + H]⁺ 419.1246, found 419.1248.

4.2.18. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-(phenylthio)benzo[d]-[1,3]dioxole-5-carbonyl)amide (A, R = H) and (4,6-Bis-(phenylthio)-benzo[d][1,3]dioxole-5-carbonyl)(4-(tert-butyl)-pyridin-1-ium-1-yl)-amide (B, R = SPh) (Table 2, Entry 15).

SM15 (150 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), two products were obtained.

Product A: yield 40% (82 mg); R_f = 0.31 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 186–188 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.48 (d, J = 6.5 Hz, 2H), 7.56 (d, J = 6.8 Hz, 2H), 7.30 (d, J = 8.3 Hz, 3H), 7.19 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.88 (s, 2H), 1.35 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.3, 163.1, 149.0, 147.8, 142.5, 137.2, 137.2, 128.7, 128.3, 125.6, 123.2, 122.4, 112.8, 108.4, 101.4, 35.8, 30.3; HRMS (ESI) calcd for C₂₃H₂₂N₂O₃S [M + H]⁺ 407.1424, found 407.1426.

Product B: yield 40% (103 mg); R_f = 0.46 (CH₂Cl₂/MeOH = 20/1); light yellow solid; mp 87–90 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.51 (d, J = 7.1 Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 7.1 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.24–7.18 (m, 3H), 7.12 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H), 5.88 (s, 2H), 1.34 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.2, 163.4, 153.3, 149.2, 147.6, 142.7, 141.2, 137.2, 136.5, 131.0, 129.1, 128.8, 128.7, 126.8, 126.2, 125.9, 123.3, 113.6, 112.1, 101.8, 35.8, 30.3; HRMS (ESI) calcd for C₂₉H₂₆N₂O₃S₂ [M + H]⁺ 515.1458, found 515.1458.

4.2.19. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-methyl-3-(phenylthio)-acryloyl)amide (Table 2, entry 16).

SM16 (110 mg, 0.5 mmol), phenyl disulfide (164 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (103 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); 52% (85 mg); R_f = 0.31 (CH₂Cl₂/MeOH = 20/1); sticky orange solid; mixture of Z and E isomers (Z/E = 3/1); ¹H NMR (600 MHz, CDCl₃) δ 8.54 (d, J = 7.1 Hz, 2H, Z-H5), 8.53 (d, J = 7.4 Hz, 2H, E-H5), 7.58–7.56 (m, 2H of Z-H4 and 2H of E-H4), 7.48 (d, J = 7.2 Hz, 2H, Z-H11), 7.33–7.28 (m, 2H of Z-H12 and 2H of E-H12), 7.27–7.17 (m, 2H of E-H11, 1H of E-H9, 2H of Z- and E-H13), 6.64 (s, 1H, Z-H9), 2.41 (s, 3H, E-H8), 2.08 (s, 3H, Z-H8), 1.35 (s, 9H, Z-H1), 1.34 (s, 9H, E-H1); please see Supporting Information for proton numbering. ¹³C{¹H} NMR (151 MHz, CDCl₃; list of observed signals of isomer mixture) δ 172.2, 163.0, 142.8, 142.6, 139.6, 135.4, 134.9, 134.0, 131.5, 130.6, 130.2, 129.9, 129.0, 128.6, 128.5, 128.2, 126.9, 126.8, 126.4, 125.8, 123.3, 123.0, 35.8, 30.3, 20.8, 20.1; HRMS (ESI) calcd for C₁₉H₂₂N₂OS [M + H]⁺ 327.1526, found 327.1528.

4.2.20. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methyl-2-(p-tolylthio)-benzoyl)amide (Scheme 2, 9) and (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methyl-2,6-bis(p-tolyl-thio)benzoyl)amide (Scheme 2, 10).

Amide 4 (135 mg, 0.5 mmol), p-tolyl disulfide (185 mg, 0.75 mmol, equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (103 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), compounds 9 and 10 were obtained.

Compound 9: yield 65% (127 mg); R_f = 0.36 (CH₂Cl₂/MeOH = 30/1); off-white solid; mp 201–203 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.66 (d, J = 6.6 Hz, 2H), 7.77 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 6.8 Hz, 2H), 7.41 (d, J = 8 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.92 (d, J = 7.5 Hz, 1H), 6.70 (s, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 1.34 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.4, 162.8, 142.7, 139.3, 138.5, 137.9, 134.4, 133.9, 131.7, 130.1, 128.9, 128.7, 125.8, 123.1, 35.7, 30.3, 21.5, 21.4; HRMS (ESI) calcd for C₂₄H₂₆N₂OS [M + H]⁺ 391.1839, found 391.1840.

Compound 10: yield 13% (34 mg); R_f = 0.6 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 181–183 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 6.2 Hz, 2H), 7.59 (d, J = 5.7 Hz, 2H), 7.41 (d, J = 7.8 Hz, 4H), 7.12 (d, J = 7.4 Hz, 4H), 6.72 (s, 2H), 2.33 (s, 6H), 2.05 (s, 3H), 1.37 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.6, 163.2, 142.7, 138.5, 138.2, 137.4, 135.7, 132.9, 132.0, 130.0, 129.0, 123.2, 35.8, 30.4, 21.3; HRMS (ESI) calcd for C₃₁H₃₂N₂OS₂ [M + H]⁺ 513.2029, found 513.2029.

4.2.21. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-((4-methoxyphenyl)-thio)-4-methylbenzoyl)amide (Scheme 2, 11) and (2,6-Bis((4-methoxyphenyl)thio)-4-methylbenzoyl)(4-(tert-butyl)pyridin-1-ium-1-yl)amide (Scheme 2, 12).

Amide 4 (135 mg, 0.5 mmol), bis(4-methoxyphenyl) disulfide (209 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (103 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), compounds 11 and 12 were obtained.

Compound 11: yield 62% (126 mg); R_f = 0.25 (CH₂Cl₂/MeOH = 30/1); off-white solid; mp 185–186 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.70 (d, J = 6.0 Hz, 2H), 7.80 (d, J = 5.0 Hz, 1H), 7.61 (d, J = 5.9 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 3H), 6.60 (s, 1H), 3.84 (s, 3H), 2.16 (s, 3H), 1.39 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.5, 162.9, 160.0, 142.9, 139.7, 139.4, 136.9, 133.0, 128.9, 127.8, 125.4, 123.0, 115.0, 55.4, 35.8, 30.4, 21.6; HRMS (ESI) calcd for C₂₄H₂₆N₂O₂S [M + H]⁺ 407.1788, found 407.1789.

Compound 12: yield 18% (49 mg); R_f = 0.35 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 78–81 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.74 (d, J = 6.9 Hz, 2H), 7.61 (d, J = 6.9 Hz, 2H), 7.48 (d, J = 8.8 Hz, 4H), 6.87 (d, J = 8.8 Hz, 4H), 6.53 (s, 2H), 3.80 (s, 6H), 2.01 (s, 3H), 1.37 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.4, 163.3, 159.6, 142.6, 138.3, 137.0, 135.8, 135.7, 127.1, 125.4, 123.3, 114.9, 55.4, 35.8, 30.4, 21.4; HRMS (ESI) calcd for C₃₁H₃₂N₂O₃S₂ [M + H]⁺ 545.1927, found 545.1927.

4.2.22. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methyl-2-(propylthio)-benzoyl)amide (Scheme 2, 13).

Amide 4 (135 mg, 0.5 mmol), di-n-propyl disulfide (118 μL, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (103 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 71% (122 mg); R_f = 0.37 (CH₂Cl₂/MeOH = 20/1); light yellow solid; mp 169–171 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 7.5 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.10 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 2.94–2.82 (m, 2H), 2.34 (s, 3H), 1.76–1.65 (m, 2H), 1.37 (s, 9H), 1.02 (t, J = 8.4 Hz, 3H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.8, 162.8, 142.7, 139.1, 137.4, 134.8, 128.8, 127.2, 125.2, 123.1, 35.8, 35.2, 30.4, 22.2, 21.6, 14.0; HRMS (ESI) calcd for C₂₀H₂₆N₂OS [M + H]⁺ 343.1839, found 343.1841.

4.2.23. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-(butylthio)-4-methyl-benzoyl)amide (Scheme 2, 14).

Amide 4 (135 mg, 0.5 mmol), dibutyl disulfide (143 μL, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (103 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 63% (113 mg); R_f = 0.44 (CH₂Cl₂/MeOH = 20/1); yellow solid; mp 131–134 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J = 5.9 Hz, 2H), 7.71 (d, J = 7.3 Hz, 1H), 7.60 (d, J = 5.6 Hz, 2H), 7.10 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 2.91 (t, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.72–1.60 (m, 2H), 1.53–1.43 (m, 2H), 1.38 (s, 9H), 0.92 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 169.8, 162.7, 142.7, 139.1, 137.5, 134.6, 128.8, 127.0, 125.1, 123.0, 35.7, 32.7, 31.0, 30.4, 22.4, 21.6, 13.9; HRMS (ESI) calcd for C₂₁H₂₈N₂OS [M + H]⁺ 357.1995, found 357.1995.

4.2.24. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-(isopropylthio)-4-methylbenzoyl)amide (Scheme 2, 15).

Amide 4 (135 mg, 0.5 mmol), di-isopropyl disulfide (120 μL, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 46% (79 mg); R_f = 0.3 (CH₂Cl₂/MeOH = 30/1); yellow solid; mp 168–170 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.64 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.19 (s, 1H), 6.99 (d, J = 6.6 Hz, 1H), 3.59–3.45 (m, 1H), 2.33 (s, 3H), 1.38 (s, 9H), 1.32 (d, J = 6.3 Hz, 6H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 173.1, 162.8, 142.7, 138.8, 136.9, 135.6, 129.9, 128.7, 126.1, 123.1, 36.65, 35.8, 30.4, 23.2, 21.5; HRMS (ESI) calcd for C₂₀H₂₆N₂OS [M + H]⁺ 343.1839, found 343.1840.

4.2.25. (4-(tert-Butyl)pyridin-1-ium-1-yl)(4-methyl-2-(phenylselanyl)benzoyl)amide (Scheme 3, 18) and (4-(tert-Butyl)-pyridin-1-ium-1-yl)(4-methyl-2,6-bis(phenylselanyl)benzoyl)amide (Scheme 3, 19).

Amide 4 (135 mg, 0.5 mmol), diphenyl diselenide (235 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h. After purification (1–7% MeOH in CH₂Cl₂), compounds 18 and 19 were obtained.

Compound 18: yield 30% (64 mg); R_f = 0.32 (CH₂Cl₂/MeOH = 30/1); light yellow solid; mp 239–241 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 4.8 Hz, 2H), 7.98 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 5.7 Hz, 2H), 7.62 (d, J = 5.6 Hz, 2H), 7.40–7.32 (m, 3H), 6.96 (d, J = 6.5 Hz, 1H), 6.73 (s, 1H), 2.14 (s, 3H), 1.39 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.0, 162.9, 142.8, 140.1, 137.0, 137.0, 136.2, 132.7, 131.6, 129.7, 129.4, 129.3, 128.3, 125.9, 123.2, 35.8, 30.4, 21.5; HRMS (ESI) calcd for C₂₃H₂₄N₂OSe [M + H]⁺ 425.1128, found 425.1128.

Compound 19: yield 42% (122 mg); R_f = 0.52 (CH₂Cl₂/MeOH = 30/1); pale yellow solid; mp 188–191 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J = 6.0 Hz, 2H), 7.73–7.51 (m, 6H), 7.32–7.23 (m, 6H), 6.71 (s, 2H), 1.96 (s, 3H), 1.37 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.2, 163.4, 142.5, 139.2, 136.6, 135.5, 133.7, 131.8, 129.9, 129.3, 127.9, 123.4, 35.8, 30.3, 21.2; HRMS (ESI) calcd for C₂₉H₂₈N₂OSe₂ [M + H]⁺ 581.0611, found 581.0611.

4.2.26. (4-(tert-Butyl)pyridin-1-ium-1-yl)(5-methyl-2-(phenylselanyl)benzoyl)amide (Scheme 3, 20).

Amide 16 (SM07) (134 mg, 0.5 mmol), diphenyl diselenide (235 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 80% (170 mg); R_f = 0.34 (CH₂Cl₂/MeOH = 30/1); off-white solid; mp 229–231 °C (CH₂Cl₂/Et₂O); ¹H NMR (600 MHz, CDCl₃) δ 8.67 (d, J = 6.5 Hz, 2H), 7.89 (s, 1H), 7.69 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 6.8 Hz, 2H), 7.39–7.30 (m, 3H), 6.92 (d, J = 6.3 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 2.29 (s, 3H), 1.38 (s, 9H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 172.0, 163.1, 142.7, 136.9, 135.7, 134.7, 132.4, 131.8, 131.0, 129.9, 129.5, 129.4, 128.2, 123.3, 35.8, 30.4, 20.8; HRMS (ESI) calcd for C₂₃H₂₄N₂OSe [M + H]⁺ 425.1128, found 425.1135.

Gram-scale synthesis of 20: A 75 mL pressure vessel equipped with a magnetic stir bar was charged with amide 16 (SM07) (1.61 g, 6 mmol), diphenyl diselenide (2.81 g, 9 mmol, 1.5 equiv), Cu(OAc)₂ (2.18 g, 12 mmol, 2 equiv), K₂S₂O₈ (3.25 g, 12 mmol, 2 equiv), and hexafluoroisopropanol (40 mL). The mixture was stirred at room temperature for 5 min, placed into an oil bath preheated to 110 °C, and stirred for 40 h. After completion, the reaction was cooled to room temperature. To the residue was added an aqueous solution of Na₂EDTA (pH = 8, 100 mL) followed by extraction with CH₂Cl₂ (75 mL). The addition/extraction process was repeated six times. The combined organic layer was dried over Mg₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using MeOH (1–7%) in CH₂Cl₂ as the eluent. After isolation, the product was dried under reduced pressure and obtained as a pale yellow solid (1.93 g, 76%)

4.2.27. (4-(tert-Butyl)pyridin-1-ium-1-yl)(2-(phenylselanyl)-5-(trifluoromethyl)benzoyl)amide (Scheme 3, 21).

Amide 17 (165 mg, 0.5 mmol), diphenyl diselenide (235 mg, 0.75 mmol, 1.5 equiv), Cu(OAc)₂ (182 mg, 1 mmol, 2 equiv), K₂S₂O₈ (271 mg, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 62% (147 mg); R_f = 0.58 (CH₂Cl₂/MeOH = 50/1); light yellow solid; mp 193–195 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J = 6.4 Hz, 2H), 8.39 (s, 1H), 7.71 (d, J = 6.9 Hz, 2H), 7.66 (d, J = 6.1 Hz, 2H), 7.47–7.35 (m, 3H), 7.28 (d, J = 9.7 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 1.40 (s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.7, 163.6, 142.6, 142.2, 137.4, 135.4, 130.7, 129.8, 129.3, 129.0, 126.97 (q, J = 32.6 Hz), 126.31 (q, J = 3.9 Hz), 126.18 (q, J = 3.5 Hz), 124.4 (q, J = 271.8 Hz), 123.4, 35.9, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.11; HRMS (ESI) calcd for C₂₃H₂₁F₃N₂OSe [M + H]⁺ 479.0845, found 479.0853.

4.2.28. (4-(tert-Butyl)pyridin-1-ium-1-yl)((8R,9S,13S,14S)-2-(ethylthio)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-carbonyl)amide (Scheme 4, 23).

Amide 22 (130 mg, 0.3 mmol), diethyl disufide (58 μL, 0.45 mmol, 1.5 equiv), Cu(OAc)₂ (110 mg, 0.6 mmol, 2 equiv), K₂S₂O₈ (163 mg, 0.6 mmol, 2 equiv), 110 °C for 24 h; purification (1–7% MeOH in CH₂Cl₂); yield 50% (74 mg); R_f = 0.36 (CH₂Cl₂/MeOH = 15/1); light brown solid; mp 155–158 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J = 5.6 Hz, 2H), 7.60 (d, J = 5.6 Hz, 2H), 7.51 (s, 1H), 7.25 (s, 1h), 2.99–2.82 (m, 4H), 2.56–2.37 (m, 2H), 2.30 (t, J = 9.3 Hz, 1H), 2.19–1.91 (m, 5H), 1.69–1.44 (m, 5H), 1.37 (s, 9H), 1.31 (t, J = 6.8 Hz, 3H), 0.90 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 221.2, 172.6, 163.2, 142.7, 140.9, 135.6, 133.4, 133.2, 129.3, 124.9, 123.2, 50.6, 48.0, 44.6, 38.1, 36.0, 35.8, 31.6, 30.6, 30.3, 28.8, 27.6, 26.6, 25.8, 21.7, 13.9; HRMS (ESI) calcd for C₃₀H₃₈N₂O₂S [M + H]⁺ 491.2727, found 491.2728.

4.2.29. 4-Methyl-2-(phenylthio)benzamide (Scheme 5, 24).

A literature method was used.¹¹ To a 2-dram vial equipped with a magnetic stir bar was added 8 (57 mg, 0.15 mmol, 1 equiv), followed by acetic acid (0.7 mL) and zinc dust (100 mg, 1.5 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 90 °C for 16 h. After reaction, the mixture was neutralized by NaHCO₃ (saturated aqueous solution) to pH = 7 and extracted with ethyl acetate (10 mL × 3). The solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography on silica gel, eluting with hexanes/EtOAc (1/1–1/5) giving 30 mg of the product as a white solid (82% yield); R_f = 0.66 (hexanes/EtOAc = 1/2); mp 169–170 °C (CH₂Cl₂/Et₂O); ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 7.9 Hz, 1H), 7.37–7.27 (m, 5H), 7.09 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.69 (s, 1H), 6.21 (s, 1H), 2.26 (s, 3H); ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 169.6, 142.1, 134.8, 134.5, 133.2, 132.4, 131.6, 129.9, 129.6, 128.2, 127.8, 21.4; HRMS (ESI) calcd for C₁₄H₁₃NOS [M + Na]⁺: 266.0610; found: 266.0615

4.2.30. 4-Methyl-2-(propylthio)benzoic acid (Scheme 5, 25).

A literature method was used.^12a To a 2-dram vial equipped with a magnetic stir bar were added 13 (103 mg, 0.3 mmol, 1 equiv), acetone (2 mL), and methyl iodide (0.19 mL, 3 mmol, 10 equiv). The mixture was refluxed for 16 h. After cooling, the volatile materials were removed under vacuum. The residue was dissolved in tetrahydrofuran (THF) (1 mL). Subsequently, water (1 mL) and LiOH (72 mg, 3 mmol) were added to the solution. The mixture was refluxed for 5 h. After the mixture was cooled, water (10 mL) and 6 N HCl (0.8 mL of a 6 N aqueous solution) were added and the mixture was extracted with EtOAc (2 × 20 mL). The extracts were dried over MgSO₄, filtered, and evaporated. The crude mixture was purified by flash chromatography on silica gel, eluting with hexanes/EtOAc (3/1–1/1) giving the product (44 mg, 70%) as a white solid; R_f = 0.45 (hexanes/EtOAc = 2/1); mp 125–128 °C (CH₂Cl₂) ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 2.91 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H), 1.85–1.66 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H); carboxylate proton signal was not observed; ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 171.0, 144.0, 142.8, 132.9, 126.8, 125.2, 123.8, 34.5, 22.0, 21.7, 14.0; HRMS (ESI) calcd for C₁₁H₁₄O₂S [M + Na]⁺ 233.0607, found 233.0606.