C-H Halogenation of Pyridyl Sulfides Avoiding the Sulfur Oxidation: A Direct Catalytic Access to Sulfanyl Polyhalides and Polyaromatics.

Palladium-catalyzed oxidative C-H halogenation and acetoxylation reactions of S-unprotected sulfides, selectively directed by pyridinyl groups, allows the formation of C-X bonds (X = I, Br, Cl, OAc) by using simple halosuccinimide or phenyliodine diacetate (PIDA) oxidants. The undesired formation of sulfoxides and/or sulfones, which are usually observed under oxidative conditions, is fully obviated. Under the solvent-dependent conditions that we proposed, sulfide C-H functionalization is achieved in less than 1 h without any direct electrophilic halogenation at the pyridine moiety. N-Directed ortho-C-H activation of aryl also facilitates dibromination reactions which are hardly accessible with sulfone and sulfoxide counterparts because of their higher structural rigidity. This general method gives a straightforward access to polyhalide sulfides, without an organosulfur reduction step or protection-deprotection sequence. Polyhalide sulfides are valuable synthons that give a practical entry to new constrained polyaromatic and biphenyl sulfides, including synthetically challenging unsymmetrical examples.

Introduction

C–H functionalization is a powerful synthetic tool that enforces more sustainable conditions for modern organic synthesis. This general approach avoids the lengthy synthetic installation of more reactive and expensive functional groups and as such prevents the stoichiometric formation of undesired, sometimes toxic, byproducts.[1−6] Palladium-catalyzed pyridyl-directed C–H functionalizations have become very useful because they avoid synthetic steps and circumvent regioselectivity issues. Despite significant progress, the oxidizing reaction conditions that are generally reported remain poorly suitable for substrates bearing functions that are highly sensitive to oxidation, such as well-known sulfanyl groups.[7−9] The use of sulfides in palladium C–H oxidation is delicate because of the potential poisoning of transition metal catalysts by strong coordination to the sulfur atoms and due to the sulfur instability to oxidation. Thus, under the standard oxidative C–H activation reactions most organosulfur C–H functionalization studies have been conducted from more robust S-protected sulfones and sulfoxides (Scheme a)[10,11] or other highly oxidized sulfur derivatives.

Scheme 1

Pyridyl-Directed C–H Functionalization of Organosulfurs (a) and Halogenation of Unprotected Aryl Sulfides (b)

Very recently, the Ananikov group described a single example of palladium-catalyzed ligand-directed C–H vinylation of a pyridyl aryl sulfanyl, in which K2S2O8 was used as a mild oxidant and the sulfur atom was preserved from oxidation.[8b] A mixture of mono- and difunctionalized vinyl aryl sulfanyl was obtained, for which the NMR yields were estimated at 35% and 7%, respectively. Additionally, the reduction of sulfoxides[12] either under stoichiometric or catalytic conditions requires reagents such as phosphines, hydrosilanes, hydroboranes, or thiols, sometimes in the presence of a transition metal. The reduction of sulfones is even more challenging because of the high thermal stability of sulfonyl groups.[12a] Thus, synthetic protocols using sulfides which allow circumventing reduction of sulfoxides or sulfones is desirable, and we developed such an approach herein for palladium-catalyzed oxidative C–H halogenation.

Results and Discussion

Direct C–H halogenation reactions are very attractive since organohalides are pivotal synthons in current organic synthesis.[13] As a part of our program directed toward methodology for C–H fluorination and halogenation reactions, we reported that substrates such as tetrazines,[14a,14b] pyrazoles,[14c] and sulfones[11b] are amenable to C–H oxidation with simple electrophilic succinimide halogen sources. We envisioned that selective C–H oxidative functionalization in the presence of oxidation-sensitive sulfides (Scheme b) would be useful for further applications in late-stage C–H functionalization of bioactive organosulfur compounds (Scheme ).[15,16] We thus investigated the challenging formation of o-C–H-functionalized aryl sulfanyles as an ideal precursor for further direct formation of polyaromatic and biphenyl sulfides.

Scheme 2

Ortho-Brominated Aryl Pyridyl Sulfides Patented for Plant, Animal, and Human Health Applications[16]

Pyridyl Sulfide o-C–H Bromination Conditions Screening

Palladium salts in polar solvents promote the o-C–H halogenation of 2-pyridyl sulfoxides[11a] and 2-pyridyl sulfones[11b] by using halosuccinimides. We reasoned that with the more challenging oxidation-sensitive pyridyl aryl sulfides a suitable combination of catalyst and a well-controlled amount of halogen oxidant might favor C–H oxidation over sulfur oxidation. We first explored C–H bromination of (pyridyl)-o-chloroaryl sulfanyl 1 by using 2.5 equiv of N-bromosuccinimide (NBS) as the oxidant and bromination agent. The use of undried solvents led to the formation of large amounts of sulfoxide and brominated derivative (see Figure S1, illustrating the case of chlorobenzene). In the presence of 10 mol % of Pd(acac)2 using various solvents under strictly anhydrous conditions (CH3NO2, toluene, PhCF3, and PhCl, Table , entries 1–4), we observed a complete chemoselectivity for the formation of C–H brominated aryl sulfanyl 1a within 1 h reaction time at 120 °C, without any trace of sulfur oxidation. However, the conversion was limited to 36% maximum by using chlorobenzene as solvent (entry 4).[11a,17] We then explored the best conditions to reach in short time reactions a complete conversion. Since chlorobenzene gave by far the best conversion and yield, it was conserved for exploring the palladium catalyst source and amount (entries 6–9). In the absence of palladium, little reaction occurred (entry 5), while 20 mol % of Pd(acac)2 was effective for a quantitative conversion of 1 into 1a (entry 8). The conversion rate was shown to be fast from 1H NMR time-resolved monitoring (Figures S2a and S2b), with >85% conversion after 40 min. While the use of 10 mol % of Pd limited the conversion at 36%, further palladium content optimization lengthened reaction time for full conversion to several hours. We assumed to conserve fast reaction rates against metal minimization, and this also was to reduce the residence time of sulfide in solution and the risks of S-oxidation. Conversely, the amount of NBS was reduced to 2.0 equiv without a decrease of 1a yield, while 1.5 equiv of NBS limited the conversion to 55%. We used these conditions for C–H bromination of functionalized pyridyl aryl sulfanyl substrates. Because of the high reactivity and fast conversion observed, we first explored oxidative C–H halogenation with o-functionalized pyridyl sulfide to specifically achieve monofunctionalization.

Table 1

Screening of C–H Monobromination of Pyridyl Aryl Sulfanyl (1)a

entry	[PdII]	Pd mol %	solvent	conv. (%)b	1a (%)b
1	Pd(acac)2	10	CH3NO2	12	12 (6)
2	Pd(acac)2	10	toluene	14	14 (7)
3	Pd(acac)2	10	PhCF3	0	0
4	Pd(acac)2	10	PhCl	36	29 (16)
5	/	/	PhCl	9	9
6	Pd(OAc)2	10	PhCl	25	25 (14)
7	[Pd2(dba)3]	10	PhCl	38	38 (27)
8	Pd(acac)2	20	PhCl	100	99 (65)
9	[Pd2(dba)3]	20	PhCl	35	35

Conditions: 2-(4-methylphenylthio)-3-methyl-pyridine (1.0 equiv), NBS (2.5 equiv), [Pd], dry solvent (0.125 M), 120 °C, 1 h, under argon.

1H NMR yield based on 2-(4-methylphenylthio)-3-methyl-pyridine using triphenylmethane as internal standard.

o-C–H Halogenation of o-Functionalized Pyridyl Sulfide

We studied the o-bromination of aryl sulfides 1–8 in which the o-position at C6 was functionalized with various electron-withdrawing and electron-donating groups (Scheme ). From 3-methylated pyridyl aryl sulfides 1–5, a full conversion into brominated products 1a–5a (99%, 1H NMR) was achieved, which tolerates the presence of o-chloro, o-fluoro, o-trifluoromethyl, o-methoxyl, and o-methyl groups, respectively. As we previously noted for other haloarenes,[14,11b] workup procedures to remove excess NBS by crystallization, followed by chlorobenzene evaporation (bp 132 °C) and chromatography, reduced the isolated yield (see workup details in SI and Figure S3). However, in our hands it remains the best protocol to isolate pure halogenated compounds since several successive chromatographies were even more detrimental for final yields.

Scheme 3

Palladium-Catalyzed o-C–H Halogenation of Pyridyl Aryl Sulfides

2 h.

NXS (3 equiv), 17 h. Conversion to Xn (isolated yield).

In the replacement of the electron-donating 3-methyl group on the pyridyl moieties by hydrogens, the conversions into 6a–8a remained excellent but slightly lowered. The formation of the presumed catalytically competent palladacycle from nitrogen coordination to palladium (Figure S2c)[14b,14c] is even less favored in those cases, but still no oxidation of the sulfur atoms occurred. Notably, this halogenation reaction is an example for a directed C–H oxidative functionalization proceeding through a six-membered metallacycle, which is much less common than reactions proceeding through five-membered metallacycles.[6]

Pleasingly, our protocol successfully extends to C–H iodination reactions by using N-iodosuccinimide (NIS) in oxidative anhydrous conditions (Scheme , 1b, 3b–5b), again with fast reaction rates ranging from 1 to 2 h. In the absence of other halogen functions, iodide aryl sulfides were in general more easy to isolate in yields above 75%. Chlorination was also achieved, albeit by using N-chlorosuccinimide (NCS) under more drastic conditions (3 equiv of NCS, 17 h, giving 1c, 3c, and 5c). C–H fluorination conducted by using N-fluorobenzenesulfonimide (NFSI),[14] which is fully compatible with redox-sensitive aryl tetrazines,[14] resulted in the expected C–H fluorination together with the undesired oxidation of a sulfur atom (Figures S4).[2c]

Facile o-C–H Dihalogenation of Pyridyl Sulfides

The fast C–H halogenation rate associated with pyridyl aryl sulfide substrates prevented, in our hands, the selective monofunctionalization of o-unsubstituted substrates. Nevertheless, this reactivity much contrasts with slower pyridyl N-directed ortho-C–H halogenation reactions developed with related pyridyl aryl sulfones[11b] and aryl sulfoxides.[11a] The rigid three-dimensional hindered structure of these S-oxidized groups likely makes o-C–H difunctionalization reactions more difficult. We systematically found for pyridyl aryl sulfides that the first bromination reaction is quickly followed by a facile second halogenation (Scheme ). We relate this fast access to dihalides—compared to sulfones reactivity—to a lesser steric pressure at the sulfur atom near the palladium coordination sphere. Thus, aryl sulfide 9para-functionalized at C4 with an electron-donating tert-butyl group was dibrominated to give quantitatively 9d in 1 h in the presence of 3 equiv of NBS. In the presence of the p-chloro electron-withdrawing group on the aryl (10), 50% conversion to 10d was achieved in the same conditions. Quantitative dibromination was also achieved in the absence of functional groups on the aryl sulfide to give 11d. In the presence of functional groups in the C3 meta-position of aryl sulfides, excellent conversion into 12d was achieved in the presence of the electron-donating m-methyl group, while the m-chloro analogue was isolated only in modest 22% yield despite the 17 h reaction time (13d). Dibromination with an unsubstituted pyridyl directing group gave only incomplete conversion of 14d and 15d (58% and 41%, respectively) despite forcing conditions (5 equiv of NBS, 17 h).

Scheme 4

Palladium-Catalyzed C–H Oxidative Dihalogenation of Pyridyl Aryl Sulfides

17 h.

NBS (5 equiv), 17 h.

2 h. Conversion to Xn (isolated yield).

We extended the catalyzed C–H functionalization of pyridyl aryl sulfides to diiodination (9e–13e, Scheme ) with good to excellent conversion (71–99%) and good isolated yields (56–81%). The reactions proceeded in 2 h reaction time, making iodination a suitable alternative to o-C–H bromination of pyridyl aryl sulfides for further functionalization.

Extension to C–O Bond Formation and Electrophilic Aromatic Bromination

Having shown that palladium-catalyzed oxidative conditions are compatible with direct C–H halogenation of pyridyl sulfides—provided that appropriate solvent is used and that strict conditions are maintained—we examined another valuable C–H functionalization in the presence of a stronger acetoxylation oxidant[18] (Scheme ). This could be a priori challenging since for instance NFSI easily leads to sulfone formation. By using phenyliodine diacetate (PIDA) in dry chlorobenzene the acetoxylation of pyridyl aryl sulfides was achieved, pleasingly without oxidation of the heteroatoms. With 1 equiv of PIDA, monoacetoxylation reactions gave compounds 5f or 16f which were isolated in 64% and 34% yield, respectively. Using 3-methylated pyridyl phenyl sulfide, we achieved C–O bond formation to mono- and diacetoxylated compounds 17f and 17g, respectively, by adjusting the amount of oxidant. Here again the second C–H functionalization quickly follows the first acetoxylation, limiting the yield in monoacetoxylation.

Scheme 5

C–H Acetoxylation of Aryl Sulfide C–H and Alternative Bromination

In the course of our investigations focused on the solvent influence on sulfur oxidation, some control experiments revealed that the use of anhydrous 1,4-dioxane, in the absence of palladium, promotes electrophilic aromatic bromination (uncatalyzed) at the pyridyl moiety (Scheme , bottom).

The C–H functionalization takes places in the ortho- and para-position of the sulfur atom, which indicates clearly a complex combination of activating electronic effects from both the sulfur and nitrogen atoms since the more electron-rich phenyl ring remains untouched. We checked that the corresponding pyridyl aryl sulfone does not undergo this reaction, showing here the influence of the nonoxidized sulfide function. This bromination of sulfanyl-functionalized pyridines resembles electrophilic aromatic substitution reactions reported for other heterocycles substituted with methoxy and amido groups.[19] Pyridyl bromination by NBS gives product 18h in 79% conversion and 43% isolated yield. When the pyridyl C3-position is not methylated, we isolated the new dibrominated compound 14i.

Access to Polyaromatic Sulfides

Directly o-halogenated aryl sulfides allow the facile installation of aryl groups by using the polyhalides 9d, 11d, 14d, and 1a to form in a straightforward way valuable,[15,16,20,21] highly congested polyaromatic pyridyl sulfides (Scheme ).

Scheme 6

Suzuki–Miyaura Coupling of Halogenated Pyridyl Aryl Sulfides

The halogenated aryl sulfides undergo cross-coupling reaction with aryl boronic acids to form in one step the tris(phenyl)sulfanylpyridines 19–21 with satisfactory to good isolated yields of 41–75%. Suzuki–Miyaura coupling also efficiently allowed the formation of the new biphenyl sulfides 22–24,[21] in 41–75% isolated yield, which are ready for further functionalization at the carbon-chloride bond.

Conclusion

In summary, palladium oxidative pyridyl-directed selective ortho-C–H functionalization is achieved from S-unprotected aryl pyridyl sulfides, without any sulfur oxidation, in fast reactions (40 min, 85%), which contrast with slower analogous C–H halogenation methods that employed S-oxidized pyridyl sulfoxides and sulfones. This approach allows a direct C–H sulfide functionalization, which avoids any reduction step (or protection/deprotection) of sulfoxides and sulfones, which are challenging reactions owing to the high thermodynamic stability of such groups. Strictly anhydrous conditions in chlorobenzene with controlled amount of halosuccinimide source or PIDA allowed mono and ortho-dihalogenation—previously undescribed—in highly functionalized pyridyl aryl sulfides. Polyhalogenated aryl sulfides are useful building blocks for synthesizing in a single step highly congested polyaromatic or biphenyl pyridyl sulfides.

Experimental Section

The synthesis section is also reported in the archived thesis.[22]

General Conditions

Reagents were purchased from commercial suppliers and used without purification. Unless otherwise stated, the solvents used were anhydrous: specifically, chlorobenzene anhydrous 99.8% (Sigma-Aldrich Sure/Seal, <0.005% water) and 1,4-dioxane extra dry 99.8% (Acros Organics AcroSeal, <0.005% water). Reactions were performed under an argon atmosphere using vacuum-lines and Schlenk techniques. 1H (500 MHz), 13C (126 MHz), 19F (470 MHz) NMR were recorded on Bruker AVANCE III instruments in CDCl3 solutions. Chemical shifts are reported in ppm relative to CDCl3 (1H: 7.26 and 13C: 77.16), and coupling constants J are given in Hz. GC-MS experiments were performed with a Trace GC Ultra equipped with a mass-selective detector, and high-resolution mass spectra (HRMS) were obtained on a Thermo LTQ-Orbitrap XL with ESI source. Flash chromatography was performed on silica gel (230–400 mesh) or with PuriFlash 450 from Interchim. Elemental analysis experiments were performed on Thermo Electron Flash EA 1112 Series.

Catalytic Halogenation and Acetoxylation Reactions

As a typical experiment, thioether, the oxidant NBS (NIS, NCS, or PIDA), and Pd(acac)2 were introduced in a Schlenk tube, equipped with a magnetic stirring bar. Anhydrous chlorobenzene (Sigma-Aldrich 99.8% anhydrous Sure/Seal, <0.005% water) was added, and the Schlenk tube was purged several times with argon. The Schlenk tube was placed in a preheated oil bath at 120 °C, and reactants were allowed to stir for 1, 2, or 17 h. After cooling the mixture to −10 °C, a part of the recrystallized NXS reagent is filtered off and washed with cool chlorobenzene. PhCl solvent was then removed in vacuum, and the crude residue was purified by silica gel column chromatography to afford the halogenated thioethers.

Catalytic Suzuki Reactions

As a typical experiment, halogenated thioether, Pd(dba)2, PhB(OH)2, and K2CO3 were introduced in a Schlenk tube, equipped with a magnetic stirring bar. Dry toluene was added, and the Schlenk tube was purged several times with argon. The Schlenk tube was placed in a preheated oil bath at 110 °C, and reactants were allowed to stir for 17 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and was washed three times with water. The combined organic layers were washed with water and dried over MgSO4. The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography to afford the products.

2-((2-Bromo-6-chloro-phenyl)sulfanyl)-3-methyl-pyridine (1a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 1a in 62% (0.098 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (dd, J = 4.9, 1.6 Hz, 1H), 7.63 (dd, J = 8.0, 1.3 Hz, 1H), 7.49 (dd, J = 8.0, 1.3 Hz, 1H), 7.38 (ddd, J = 7.4, 1.7, 0.9 Hz, 1H), 7.19 (dd, J = 8.0, 8.0 Hz, 1H), 6.94 (dd, J = 7.4, 4.9 Hz, 1H), 2.41 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.5, 147.4, 141.6, 137.2, 132.7, 132.1, 131.1, 131.0, 129.4, 120.4, 19.0. Elemental analysis: Calcd (%) for C12H9BrClNS: C 45.81, H 2.88, N 4.45. Found: C 45.73, H 2.62, N 4.21. HRMS + p ESI (m/z) [M + Na+] calcd for C12H9BrClNSNa: 335.922. Found: m/z = 335.923.

2-((2-Bromo-6-fluoro-phenyl)sulfanyl)-3-methyl-pyridine (2a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (2.5 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 2a in 44% (0.066 g) yield. White solid (dichloromethane/heptane = 5/5). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.12 (dd, J = 4.9, 1.8 Hz, 1H), 7.53 (dt, J = 8.0, 1.3 Hz, 1H), 7.38 (ddd, J = 7.4, 1.8, 0.9 Hz, 1H), 7.31–7.25 (m, 1H), 7.14 (dt, J = 8.0, 1.3 Hz, 1H), 6.94 (dd, J = 7.4, 4.9 Hz, 1H), 2.42 (s, 3H). 19F NMR (470 MHz, Chloroform-d) δ (ppm) = −97.8. 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 163.8 (d, J = 250.8 Hz), 156.0, 147.3, 137.2, 131.7, 131.6 (d, J = 9.2 Hz), 131.0, 129.1 (d, J = 3.6 Hz), 120.8 (d, J = 20.4 Hz), 120.5, 115.2 (d, J = 24.5 Hz), 19.0. Elemental analysis: Calcd (%) for C12H9BrFNS: C 48.34, H 3.04, N 4.70. Found: C 48.76, H 2.78, N 4.35. HRMS + p ESI (m/z) [M + Na+] Calcd for C12H9BrFNSNa: 319.951. Found: m/z = 319.952.

2-((2-Bromo-6-trifluoromethyl-phenyl)sulfanyl)-3-methyl-pyridine (3a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 3a in 64% (0.111 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.07 (dd, J = 5.0, 1.7 Hz, 1H), 7.91 (dd, J = 8.1, 1.3 Hz, 1H), 7.79 (dd, J = 7.5, 1.7 Hz, 1H), 7.43–7.33 (m, 2H), 6.92 (dd, J = 7.5, 5.0 Hz, 1H), 2.42 (s, 3H). 19F NMR (470 MHz, Chloroform-d) δ (ppm) = −60.2. 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.9, 147.3, 137.1, 137.1, 136.9 (q, J = 29.7 Hz), 135.7, 131.5, 130.8, 130.3, 126.3 (q, J = 5.8 Hz), 123.1 (q, J = 274.3 Hz), 120.3, 18.8. Elemental analysis: Calcd (%) for C13H9BrF3NS: C 44.85, H 2.61, N 4.02. Found: C 44.16, H 2.40, N 3.74. HRMS + p ESI (m/z) [M + H+] Calcd for C13H10BrF3NS: 347.966. Found: m/z = 347.967.

2-((2-Bromo-6-methoxy-phenyl)sulfanyl)-3-methyl-pyridine (4a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 4a in 55% (0.086 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.11 (dd, J = 4.9, 1.1 Hz, 1H), 7.36–7.32 (m, 2H), 7.25 (t, J = 8.2 Hz, 1H), 6.93 (dd, J = 7.8, 1.1 Hz, 1H), 6.90 (dd, J = 7.8, 4.9 Hz, 1H), 3.76 (s, 3H), 2.41 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 161.8, 157.2, 147.2, 136.9, 132.3, 131.2, 131.1, 125.8, 121.0, 119.9, 110.7, 56.7, 19.1. Elemental analysis: Calcd (%) for C13H12BrNOS: C 50.33, H 3.90, N 4.52. Found: C 50.08, H 3.55, N 4.18. HRMS + p ESI (m/z) [M + Na+] Calcd for C13H12BrNOSNa: 331.972. Found: m/z = 331.972.

2-((2-Bromo-6-methyl-phenyl)sulfanyl)-3-methyl-pyridine (5a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 5a in 64% (0.094 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.12 (dd, J = 4.9, 1.7 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.5, 1.7 Hz, 1H), 7.29–7.26 (m, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.90 (dd, J = 7.5, 4.9 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.3, 147.4, 146.2, 137.0, 132.3, 131.7, 131.3, 131.0, 130.4, 129.6, 119.9, 23.1, 19.0. Elemental analysis: Calcd (%) for C13H12BrNS: C 53.07, H 4.11, N 4.76. Found: C 52.76, H 3.70, N 4.32. HRMS + p ESI (m/z) [M + Na+] Calcd for C13H12BrNSNa: 315.977. Found: m/z = 315.977.

2-((2-Bromo-6-chloro-phenyl)sulfanyl)pyridine (6a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 6a in 48% (0.072 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.40 (ddd, J = 4.9, 1.7, 0.8 Hz, 1H), 7.67 (dd, J = 8.1, 1.3 Hz, 1H), 7.52 (dd, J = 8.1, 1.3 Hz, 1H), 7.49 (dd, J = 7.8, 1.9 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.02 (dd, J = 7.4, 4.9 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 158.6, 149.9, 141.9, 137.0, 133.1, 132.5, 131.6, 131.6, 129.7, 120.7, 120.3. Elemental analysis: Calcd (%) for C11H7BrClNS: C 43.95, H 2.35, N 4.66. Found: C 44.45, H 2.17, N 4.41. HRMS + p ESI (m/z) [M + H+] Calcd for C11H8BrClNS: 299.924. Found: m/z = 299.925.

2-((2-Bromo-6-trifluoromethyl-phenyl)sulfanyl)pyridine (7a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 7a in 42% (0.070 g) yield. White solid (dichloromethane/heptane = 0.5/9.5). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.37 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.53–7.37 (m, 2H), 7.06–6.98 (m, 1H), 6.80 (d, J = 8.1 Hz, 1H). 19F NMR (470 MHz, Chloroform-d) δ (ppm) = −60.3. 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 159.0, 149.8, 137.5, 137.0 (q, J = 29.9 Hz), 136.9, 135.8, 131.0, 130.8, 126.6 (q, J = 5.7 Hz), 123.0 (q, J = 274.3 Hz), 120.8, 120.3. Elemental analysis: Calcd (%) for C12H7BrF3NS: C 43.13, H 2.11, N 4.19. Found: C 43.09, H 1.91, N 3.84. HRMS + p ESI (m/z) [M + H+] Calcd for C12H8BrF3NS: 333.951. Found: m/z = 333.950.

2-((2-Bromo-6-methoxy-phenyl)sulfanyl)pyridine (8a)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 8a in 20% (0.030 g) yield. Yellow solid (AcOEt/heptane = 3/7). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.39 (d, J = 4.6 Hz, 1H), 7.43 (dd, J = 7.7, 2.3 Hz, 1H), 7.37 (dd, J = 8.2, 1.2 Hz, 1H), 7.29 (dd, J = 8.2 Hz, 1H), 6.99–6.96 (m, 1H), 6.95 (dd, J = 8.5, 0.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 3.79 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 161.8, 159.9, 149.7, 136.6, 132.8, 131.9, 126.0, 120.6, 120.3, 119.7, 110.7, 56.7. Elemental analysis: Calcd (%) for C12H10BrNOS: C 48.66, H 3.40, N 4.73. Found: C 48.64, H 3.44, N 4.80. HRMS + p ESI (m/z) [M + H+] Calcd for C12H11BrNOS: 295.974. Found: m/z = 295.974.

2-((2-Iodo-6-chloro-phenyl)sulfanyl)-3-methyl-pyridine (1b)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 1b in 53% (0.096 g) yield. Brown solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (dd, J = 8.0, 1.3 Hz, 1H), 7.51 (dd, J = 8.0, 1.3 Hz, 1H), 7.38 (ddd, J = 7.4, 1.7, 0.8 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 7.4, 4.9 Hz, 1H), 2.40 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.7, 147.4, 140.0, 138.8, 137.2, 135.8, 131.5, 131.1, 130.4, 120.4, 110.7, 18.9. Elemental analysis: Calcd (%) for C12H9ClINS: C 39.86, H 2.51, N 3.87. Found: C 39.91, H 2.41, N 3.81. HRMS + p ESI (m/z) [M + H+] Calcd for C12H10ClINS: 361.926. Found: m/z = 361.926.

2-((2-Iodo-6-trifluoromethyl-phenyl)sulfanyl)-3-methyl-pyridine (3b)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 3b in 45% (0.090 g) yield. Brown solid (dichloromethane/heptane = 9/1). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.20 (d, J = 7.9 Hz, 1H), 8.08 (dd, J = 4.8, 1.1 Hz, 1H), 7.83 (dd, J = 8.0, 1.1 Hz, 1H), 7.39 (ddd, J = 7.5, 1.9, 0.9 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 7.5, 4.8 Hz, 1H), 2.41 (s, 3H). 19F NMR (470 MHz, Chloroform-d) δ (ppm) = −60.6. 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.0, 147.2, 143.8, 137.3, 136.2 (q, J = 29.4 Hz), 134.9, 131.0, 130.5, 127.3 (q, J = 6.1 Hz), 123.0 (q, J = 274.4 Hz), 120.3, 115.4, 18.9. Elemental analysis: Calcd (%) for C13H9F3INS: C 39.51, H 2.30, N 3.54. Found: C 39.24, H 2.25, N 3.52. HRMS + p ESI (m/z) [M + H+] Calcd for C13H10F3INS: 395.953. Found: m/z = 395.953.

2-((2-Iodo-6-methoxy-phenyl)sulfanyl)pyridine (4b)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 4b in 79% (0.178 g) yield. Brown solid (dichloromethane/heptane = 7/3). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.12 (dd, J = 4.8, 1.8 Hz, 1H), 7.61 (dd, J = 8.1, 1.1 Hz, 1H), 7.35 (ddd, J = 7.4, 1.8, 0.8 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 1.1 Hz, 1H), 6.90 (dd, J = 7.4, 4.8 Hz, 1H), 3.74 (s, 3H), 2.41 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 161.1, 157.3, 147.2, 137.0, 132.3, 131.9, 131.2, 124.8, 119.9, 111.6, 111.0, 56.6, 19.1. Elemental analysis: Calcd (%) for C13H12INOS: C 43.85, H 3.38, N 3.98. Found: C 43.71, H 3.39, N 3.92. HRMS + p ESI (m/z) [M + H+] Calcd for C13H13INOS: 357.975. Found: m/z = 357.975.

2-((2-Iodo-6-methyl-phenyl)sulfanyl)pyridine (5b)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (2 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 5b in 74% (0.126 g) yield. Brown solid (dichloromethane/heptane = 7/3). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (dd, J = 4.8, 1.8 Hz, 1H), 7.84 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 (ddd, J = 7.4, 1.8, 0.8 Hz, 1H), 7.30 (dd, J = 7.9, 1.4 Hz, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.91 (dd, J = 7.4, 4.8 Hz, 1H), 2.46 (s, 3H), 2.40 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.3, 147.4, 145.5, 138.1, 137.0, 135.5, 131.0, 130.8, 130.6, 120.0, 111.3, 24.1, 19.0. Elemental analysis: Calcd (%) for C13H12INS: C 45.76, H 3.55, N 4.11. Found: C 45.72, H 3.58, N 4.02. HRMS + p ESI (m/z) [M + H+] Calcd for C13H13INS: 341.980. Found: m/z = 341.980.

2-((2,6-Dichloro-phenyl)sulfanyl)-3-methyl-pyridine (1c)

The reaction of the corresponding thioether (0.5 mmol), N-chlorosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 1c in 22% (0.030 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.12 (dd, J = 4.8, 1.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (ddd, J = 7.4, 1.7, 0.9 Hz, 1H), 7.30–7.25 (m, 1H), 6.93 (dd, J = 7.4, 4.8 Hz, 1H), 2.42 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.4, 147.4, 141.8, 137.2, 131.1, 130.6, 130.2, 128.7, 120.4, 19.0. Elemental analysis: Calcd (%) for C12H9Cl2NS: C 53.35, H 3.36, N 5.18. Found: C 53.24, H 3.26, N 5.35. HRMS + p ESI (m/z) [M + H+] Calcd for C12H10Cl2NS: 269.990. Found: m/z = 269.990.

2-((2-Chloro-6-trifluoro-phenyl)sulfanyl)-3-methyl-pyridine (3c)

The reaction of the corresponding thioether (0.5 mmol), N-chlorosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 3c in 24% (0.036 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.07 (dd, J = 4.8, 1.4 Hz, 1H), 7.75 (dd, J = 8.0, 1.4 Hz, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.48 (dd, J = 8.0, 1.4 Hz, 1H), 7.37 (ddd, J = 7.4, 1.4, 0.9 Hz, 1H), 6.92 (dd, J = 7.4, 4.8 Hz, 1H), 2.42 (s, 3H). 19F NMR (470 MHz, Chloroform-d) δ (ppm) = −60.1. 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.7, 147.3, 143.6, 137.1, 136.7 (q, J = 29.7 Hz), 133.6, 130.8, 130.2, 129.5, 125.6 (q, J = 6.2 Hz), 123.2 (q, J = 274.1 Hz), 120.3, 18.9. Elemental analysis: Calcd (%) for C13H9ClF3NS: C 51.41, H 2.99, N 4.61. Found: C 51.41, H 2.83, N 4.50. HRMS + p ESI (m/z) [M + H+] Calcd for C13H10ClF3NS: 304.016. Found: m/z = 304.016.

2-((2-Chloro-6-methyl-phenyl)sulfanyl)-3-methyl-pyridine (5c)

The reaction of the corresponding thioether (0.5 mmol), N-chlorosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 5c in 56% (0.070 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.14 (d, J = 4.8 Hz, 1H), 7.42–7.37 (m, 2H), 7.29–7.25 (m, 2H), 6.93 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 2.44 (d, J = 1.1 Hz, 3H), 2.44 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.2, 147.4, 145.9, 140.7, 137.0, 131.0, 130.1, 129.5, 129.0, 127.8, 119.9, 22.6, 19.0. Elemental analysis: Calcd (%) for C13H12ClNS: C 62.52, H 4.84, N 5.61. Found: C 62.62, H 4.91, N 5.56. HRMS + p ESI (m/z) [M + H+] Calcd for C13H13ClNS: 250.045. Found: m/z = 250.044.

2-((2,6-Dibromo-4-tert-butyl-phenyl)sulfanyl)-3-methyl-pyridine (9d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 9d in 74% (0.1458 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.15 (dd, J = 4.8, 1.2 Hz, 1H), 7.67 (s, 2H), 7.37 (ddd, J = 7.4, 1.2, 0.9 Hz, 1H), 6.94 (dd, J = 7.4, 4.8 Hz, 1H), 2.40 (s, 3H), 1.32 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.9, 155.3, 147.4, 137.2, 132.0, 131.1, 130.3, 120.3, 35.1, 31.1, 19.0. Elemental analysis: Calcd (%) for C16H17Br2NS: C 46.29, H 4.13, N 3.37. Found: C 45.75, H 4.16, N 3.08. HRMS + p ESI (m/z) [M + H+] Calcd for C16H18Br2NS: 413.952. Found: m/z = 413.953.

2-((2,6-Dibromo-4-chloro-phenyl)sulfanyl)-3-methyl-pyridine (10d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17h affords 10d in 30% (0.058 g) yield. White solid (EtOAc/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (dd, J = 5.0, 1.8 Hz, 1H), 7.69 (s, 2H), 7.38 (ddd, J = 7.4, 1.8, 0.9 Hz, 1H), 6.95 (dd, J = 7.4, 4.8 Hz, 1H), 2.39 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.2, 147.4, 137.3, 136.2, 132.8, 132.6, 132.5, 131.1, 120.5, 18.8. Elemental analysis: Calcd (%) for C12H8Br2ClNS: C 36.63, H 2.05, N 3.56. Found: C 36.61, H 1.89, N 3.27. HRMS + p ESI (m/z) [M + H+] Calcd for C12H9Br2ClNS: 391.851. Found: m/z = 391.851.

2-((2,6-Dibromo-phenyl)sulfanyl)-3-methyl-pyridine (11d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 11d in 60% (0.108 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (dd, J = 4.8, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.38 (ddd, J = 7.5, 1.6, 0.9 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 7.5, 4.8 Hz, 1H), 2.40 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.6, 147.4, 137.2, 134.0, 132.8, 132.4, 131.3, 131.1, 120.4, 18.9. Elemental analysis: Calcd (%) for C12H9Br2NS: C 40.14, H 2.53, N 3.90. Found: C 40.24, H 2.29, N 3.60. HRMS + p ESI (m/z) [M + H+] Calcd for C12H10Br2NS: 357.890. Found: m/z = 359.888.

2-((2,6-Dibromo-3-methyl-phenyl)sulfanyl)-3-methyl-pyridine (12d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 1 h affords 12d in 65% (0.117 g) yield. White solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (dd, J = 4.8, 1.7 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.38 (ddd, J = 7.4, 1.7, 0.8 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 7.4, 4.8 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.9, 147.4, 139.3, 137.2, 134.7, 133.9, 132.3, 131.9, 131.1, 129.1, 120.2, 25.0, 19.0. Elemental analysis: Calcd (%) for C13H11Br2NS: C 41.85, H 2.97, N 3.75. Found: C 42.01, H 2.78, N 3.70. HRMS + p ESI (m/z) [M + Na+] Calcd for C13H11Br2NSNa: 413.952. Found: m/z = 413.953.

2-((2,6-Dibromo-3-chloro-phenyl)sulfanyl)-3-methyl-pyridine (13d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 13d in 22% (0.043 g) yield. Yellow solid; (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.12 (dd, J = 4.8, 1.5 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.39 (ddd, J = 7.5, 1.5, 0.9 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.96 (dd, J = 7.5, 4.8 Hz, 1H), 2.40 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.3, 147.5, 137.4, 136.4, 135.4, 132.8, 132.7, 131.6, 131.1, 130.2, 120.6, 18.9. Elemental analysis: Calcd (%) for C12H8Br2ClNS: C 36.63, H 2.05, N 3.56. Found: C 36.58, H 1.86, N 3.12. HRMS + p ESI (m/z) [M + Na+] Calcd for C12H8Br2ClNSNa: 413.952. Found: m/z = 413.953.

2-((2,6-Dibromo-phenyl)sulfanyl)pyridine (14d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (5 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 14d in 31% (0.053 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.41 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.50 (ddd, J = 7.4, 1.9 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.03 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 158.7, 149.9, 137.1, 133.4, 133.2, 132.8, 132.0, 120.7, 120.2. Elemental analysis: Calcd (%) for C11H7Br2NS: C 38.29, H 2.04, N 4.06. Found: C 38.69, H 1.98, N 3.89. HRMS + p ESI (m/z) [M + H+] Calcd for C11H8Br2NS: 345.872. Found: m/z = 345.872.

2-((2,6-Dibromo-4-chloro-phenyl)sulfanyl)pyridine (15d)

The reaction of the corresponding thioether (0.5 mmol), N-bromosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 17 h affords 15d in 21% (0.040 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.39 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.73 (s, 2H), 7.51 (ddd, J = 7.4, 1.9 Hz, 1H), 7.04 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 6.89 (dd, J = 8.1, 1.0 Hz, 1H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 158.1, 150.1, 137.0, 136.9, 132.9, 132.8, 132.2, 120.8, 120.4. Elemental analysis: Calcd (%) for C11H6Br2ClNS: C 34.82, H 1.59, N 3.69. Found: C 34.92, H 1.30, N 3.58. HRMS + p ESI (m/z) [M + H+] Calcd for C11H7Br2ClNS: 377.835. Found: m/z = 377.835.

2-((2,6-Diiodo-4-tert-butyl-phenyl)sulfanyl)-3-methyl-pyridine (9e)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 9e in 65% (0.167 g) yield. Yellow solid (dichloromethane/heptane = 3/7). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.18 (dd, J = 4.8, 1.5 Hz, 1H), 7.95 (s, 2H), 7.39 (ddd, J = 7.4, 1.5, 0.9 Hz, 1H), 6.96 (dd, J = 7.4, 4.8 Hz, 1H), 2.38 (s, 3H), 1.30 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.1, 155.5, 147.5, 138.1, 137.6, 137.3, 131.1, 120.3, 107.8, 34.5, 31.1, 19.0. Elemental analysis: Calcd (%) for C16H17I2NS: C 37.74, H 3.37, N 2.75. Found: C 37.75, H 3.45, N 2.87. HRMS + p ESI (m/z) [M + H+] Calcd for C16H18I2NS: 509.924. Found: m/z = 509.924.

2-((2,6-Diiodo-4-chloro-phenyl)sulfanyl)-3-methyl-pyridine (10e)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 10e in 56% (0.137 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.15 (dd, J = 4.7, 1.8 Hz, 1H), 7.97 (s, 2H), 7.40 (ddd, J = 7.4, 1.8, 0.7 Hz, 1H), 6.97 (dd, J = 7.4, 4.7 Hz, 1H), 2.37 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.5, 147.5, 139.9, 139.8, 137.4, 135.8, 131.1, 120.5, 107.3, 18.9. Elemental analysis: Calcd (%) for C12H8ClI2NS: C 29.56, H 1.65, N 2.87. Found: C 29.42, H 1.55, N 2.91. HRMS + p ESI (m/z) [M + H+] Calcd for C12H9ClI2NS: 487.822. Found: m/z = 487.822.

2-((2,6-Diiodo-phenyl)sulfanyl)-3-methyl-pyridine (11e)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 11e in 56% (0.124 g) yield. Yellow solid (dichloromethane/heptane = 3/7). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.16 (dd, J = 4.9, 1.8 Hz, 1H), 7.98 (d, J = 7.9 Hz, 2H), 7.40 (ddd, J = 7.4, 1.8, 0.9 Hz, 1H), 6.96 (dd, J = 7.4, 4.9 Hz, 1H), 6.65 (dd, J = 7.9, 7.9 Hz, 1H), 2.38 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.9, 147.5, 141.0, 140.5, 137.3, 131.8, 131.1, 120.4, 108.1, 18.9. Elemental analysis: Calcd (%) for C12H9I2NS: C 31.81, H 2.00, N 3.09. Found: C 31.65, H 1.83, N 3.22. HRMS + p ESI (m/z) [M + H+] Calcd for C12H10I2NS: 453.862. Found: m/z = 453.862.

2-((2,6-Diiodo-3-methyl-phenyl)sulfanyl)-3-methyl-pyridine (12e)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 12e in 81% (0.190 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.15 (dd, J = 4.8, 1.7 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.39 (ddd, J = 7.4, 1,7, 0.8 Hz, 1H), 6.95 (dd, J = 7.4, 4.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H), 2.38 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.1, 147.5, 144.7, 141.3, 139.5, 137.2, 131.4, 131.1, 120.2, 115.6, 103.9, 31.2, 19.0. Elemental analysis: Calcd (%) for C13H11I2NS: C 33.43, H 2.37, N 3.00. Found: C 34.13, H 2.25, N 3.13. HRMS + p ESI (m/z) [M + H+] Calcd for C13H12I2NS: 467.877. Found: m/z = 467.877.

2-((2,6-Diiodo-3-chloro-phenyl)sulfanyl)-3-methyl-pyridine (13e)

The reaction of the corresponding thioether (0.5 mmol), N-iodosuccinimide (3 equiv), and Pd(acac)2 (20 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 13e in 60% (0.146 g) yield. Yellow solid (dichloromethane/heptane = 6/4). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.14 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.41 (ddd, J = 7.4, 1.7, 0.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 7.4, 4.9 Hz, 1H), 2.38 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 156.6, 147.6, 144.0, 140.8, 140.4, 137.4, 131.1, 130.5, 120.5, 113.5, 105.0, 18.9. Elemental analysis: Calcd (%) for C12H8ClI2NS: C 29.56, H 1.65, N 2.87. Found: C 29.66, H 1.53, N 2.82. HRMS + p ESI (m/z) [M + H+] Calcd for C12H9ClI2NS: 487.823. Found: m/z = 487.823.

2-(2-Diacetoxy-6-methyl-phenylsulfanyl)-3-methyl-pyridine (5f)

The reaction of the corresponding thioether (0.5 mmol), (diacetoxyiodo)benzene (1 equiv), and Pd(acac)2 (10 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 5f in 64% (0.087 g) yield. Yellow solid (AcOEt/heptane = 2/8). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.06 (ddd, J = 4.8, 1.8, 0.7 Hz, 1H), 7.32–7.24 (m, 2H), 7.16 (ddd, J = 7.6, 1.4, 0.7 Hz, 1H), 6.97 (ddd, J = 8.1, 1.4, 0.7 Hz, 1H), 6.83 (dd, J = 7.4, 4.8 Hz, 1H), 2.31 (d, J = 3.1 Hz, 6H), 2.05 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 169.3, 157.1, 152.7, 147.3, 145.1, 136.8, 130.7, 129.9, 128.2, 123.5, 120.4, 119.9, 31.9, 22.7, 21.4, 20.8, 19.0. Elemental analysis: Calcd (%) for C15H15NO2S: C 65.91, H 5.53, N 5.12. Found: C 65.35, H 5.23, N 5.31. HRMS + p ESI (m/z) [M + H+] Calcd for C15H16NO2S: 274.090. Found: m/z = 274.091.

2-(2-Diacetoxy-6-methyl-phenylsulfanyl)-pyridine (16f)

The reaction of the corresponding thioether (0.5 mmol), (diacetoxyiodo)benzene (1 equiv), and Pd(acac)2 (10 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 16f in 34% (0.044 g) yield. Yellow solid (dichloromethane/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.39 (ddd, J = 4.9, 1.6, 0.9 Hz, 1H), 7.44–7.37 (m, 2H), 7.26 (ddd, J = 7.7, 1.6, 0.6 Hz, 1H), 7.07 (dd, J = 7.9, 1.4 Hz, 1H), 6.98 (ddd, J = 7.7, 4.9, 1.1 Hz, 1H), 6.70 (dt, J = 8.2, 1.0 Hz, 1H), 2.42 (s, 3H), 2.19 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 169.6, 160.2, 153.3, 149.6, 145.4, 136.9, 130.8, 128.7, 123.8, 121.0, 120.3, 119.9, 21.4, 20.9. Elemental analysis: Calcd (%) for C14H13NO2S: C 64.84, H 5.05, N 5.40. Found: C 65.23, H 4.93, N 6.01. HRMS + p ESI (m/z) [M + H+] Calcd for C14H14NO2S: 260.074. Found: m/z = 260.074.

2-(2-Acetoxy-phenylsulfanyl)-3-methyl-pyridine (17f)

The reaction of the corresponding thioether (0.5 mmol), (diacetoxyiodo)benzene (1 equiv), and Pd(acac)2 (10 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 17f in 40% (0.051 g) yield. Yellow solid (EtOAc/heptane = 2/8). 7% of 17g was also observed. 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.20 (ddd, J = 4.9, 1.6, 0.7 Hz, 1H), 7.53 (dd, J = 7.7, 1.6 Hz, 1H), 7.43–7.38 (m, 2H), 7.27–7.24 (m, 1H), 7.20 (dd, J = 8.1, 1.3 Hz, 1H), 6.98 (dd, J = 7.7, 4.9 Hz, 1H), 2.36 (s, 3H), 2.10 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 169.0, 156.7, 151.4, 147.5, 137.3, 135.9, 132.0, 129.9, 126.6, 124.8, 123.3, 120.8, 20.8, 19.2. Elemental analysis: Calcd (%) for C14H13NO2S (+0.1 heptane+0.07 acetone): C 65.34, H 5.42, N 5.18. Found: C 65.78, H 5.55, N 5.13. HRMS + p ESI (m/z) [M + H+] Calcd for C14H14NO2S: 230.074. Found: m/z = 230.074.

2-(2-6-Diacetoxy-phenylsulfanyl)-3-methyl-pyridine (17g)

The reaction of the corresponding thioether (0.5 mmol), (diacetoxyiodo)benzene (3 equiv), and Pd(acac)2 (10 mol %) in chlorobenzene (4 mL) at 120 °C during 2 h affords 17g in 54% (0.086 g) yield. Yellow solid (EtOAc/heptane = 4/6). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.14 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.45 (dd, J = 8.2 Hz, 1H), 7.36 (ddd, J = 7.5, 1.7, 0.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.94 (dd, J = 7.5, 4.8 Hz, 1H), 2.36 (s, 3H), 2.08 (s, 6H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 168.7, 156.2, 152.9, 147.5, 137.1, 131.1, 130.1, 120.7, 120.5, 118.4, 20.8, 19.1. Elemental analysis: Calcd (%) for C16H15NO4S: C 60.55, H 4.76, N 4.41. Found: C 60.55, H 5.00, N 4.43. HRMS + p ESI (m/z) [M + H+] Calcd for C16H16NO4S: 318.079. Found: m/z = 318.079.

2-(Phenylsulfanyl)-3-bromo-5-methyl-pyridine (18h)

The reaction of the corresponding thioether (0.5 mmol) and N-bromosuccinimide (3 equiv) in 1,4-dioxane extra dry 99.8% (Acros Organics AcroSeal, <0.005% water, 4 mL) at 120 °C during 17 h affords 18h in 43% (0.050 g) yield. Yellow solid (dichloromethane/heptane = 5/5). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.12 (d, J = 1.3 Hz, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.56–7.53 (m, 2H), 7.43–7.39 (m, 3H), 2.24 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 155.4, 148.5, 140.7, 135.1, 131.4, 130.9, 129.3, 129.0, 118.6, 17.5. Elemental analysis: Calcd (%) for C12H10BrNS: C 51.44, H 3.60, N 5.00. Found: C 51.61, H 3.43, N 4.95. HRMS + p ESI (m/z) [M + Na+] Calcd for C12H10BrNSNa: 301.961. Found: m/z = 301.960.

2-(Phenylsulfanyl)-3,5-dibromo-pyridine (14i)

The reaction of the corresponding thioether (0.5 mmol) and N-bromosuccinimide (3 equiv) in 1,4-dioxane extra dry 99.8% (Acros Organics AcroSeal, <0.005% water, 4 mL) at 120 °C during 17 h affords 14i in 36% (0.066 g) yield. Yellow solid (dichloromethane/heptane = 3:7). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.28 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.56–7.51 (m, 2H), 7.45–7.42 (m, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 158.1, 148.9, 141.6, 135.6, 129.8, 129.5, 129.4, 118.3, 116.0. Elemental analysis: Calcd (%) for C11H7Br2NS: C 38.29, H 2.04, N 4.06. Found: C 38.23, H 1.92, N 4.01. HRMS + p ESI (m/z) [M + H+] Calcd for C11H8Br2NS: 343.874. Found: m/z = 343.873.

2-((2,6-Diphenyl-4-tert-butyl-phenyl)sulfanyl)-3-methyl-pyridine (30)

The reaction of the dibromide thioether 16b (0.12 mmol), Pd(dba)2 (10 mol %), PhB(OH)2 (4 equiv), and K2CO3 (4.2 equiv) in toluene (1.5 mL) at 110 °C during 17 h affords 30 in 65% (0.032 g) yield. White solid (dichloromethane/heptane = 6/4). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.14 (dd, J = 4.9, 1.9 Hz, 1H), 7.38 (s, 2H), 7.36–7.32 (m, 4H), 7.25–7.20 (m, 6H), 6.99 (ddd, J = 7.4, 1.9, 0.9 Hz, 1H), 6.75 (dd, J = 7.4, 4.9 Hz, 1H), 1.86 (s, 3H), 1.37 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 159.6, 151.6, 147.2, 147.0, 142.8, 136.2, 131.7, 129.4, 127.5, 127.4, 126.8, 126.3, 119.7, 35.0, 31.5, 19.1. Elemental analysis: Calcd (%) for C28H27NS: C 82.11, H 6.64, N 3.42. Found: C 81.53, H 6.87, N 3.21. HRMS + p ESI (m/z) [M + H+] Calcd for C28H28NS: 410.193. Found: m/z = 410.193.

2-((2,6-Diphenyl-phenyl)sulfanyl)-3-methyl-pyridine (20)

The reaction of the dibromide thioether 11d (0.06 mmol), Pd(dba)2 (10 mol %), PhB(OH)2 (4 equiv), and K2CO3 (4.2 equiv) in toluene (1.5 mL) at 110 °C during 17 h affords 20 in 71% (0.015 g) yield. White solid (dichloromethane/heptane = 6/4). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.13 (ddd, J = 4.8, 1.9, 0.7 Hz, 1H), 7.48 (dd, J = 8.1, 7.1 Hz, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.34–7.31 (m, 4H), 7.24–7.20 (m, 6H), 6.99 (ddd, J = 7.4, 1.9, 0.9 Hz, 1H), 6.76 (dd, J = 7.4, 4.8 Hz, 1H), 1.85 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 159.4, 147.9, 147.0, 142.2, 136.2, 131.6, 130.1, 129.7, 129.3, 128.7, 127.4, 126.9, 119.7, 19.1. Elemental analysis: Calcd (%) for C24H19NS (+0.3 Heptane +0.7 H2O): C 79.09, H 6.43, N 3.46. Found: C 80.1, H 6.61, N 3.24. HRMS + p ESI (m/z) [M + H+] Calcd for C24H20NS: 354.131. Found: m/z = 354.131.

2-((2,6-Diphenyl-phenyl)sulfanyl)pyridine (21)

The reaction of the dibromide thioether 14d (0.25 mmol), Pd(dba)2 (10 mol %), PhB(OH)2 (4 equiv), and K2CO3 (4.2 equiv) in toluene (3 mL) at 110 °C during 17 h affords 21 in 46% (0.039 g) yield. White solid (EtOAc/heptane = 1/9). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.17 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 7.52 (dd, J = 8.0, 7.1 Hz, 1H), 7.42 (d, J = 7.6 Hz, 2H), 7.35–7.31 (m, 4H), 7.28–7.20 (m, 7H), 6.79 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 6.59 (dd, J = 8.0, 1.0 Hz, 1H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 161.2, 149.3, 148.3, 141.7, 135.8, 130.4, 129.5, 129.3, 128.6, 127.6, 127.2, 121.9, 119.3. Elemental analysis: Calcd (%) for C23H17NS: C 81.38, H 5.05, N 4.13. Found: C 81.07, H 5.19, N 3.96. HRMS + p ESI (m/z) [M + H+] Calcd for C23H18NS: 340.115. Found: m/z = 340.115.

2-((2-Phenyl-6-chloro-phenyl)sulfanyl)-3-methyl-pyridine (22)

The reaction of the halogenated thioether 1a (0.5 mmol), Pd(dba)2 (10 mol %), PhB(OH)2 (2 equiv), and K2CO3 (2 equiv) in toluene (5 mL) at 110 °C during 17 h affords 22 in 66% (0.103 g) yield. White solid (dichloromethane/heptane = 6/4). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.16 (dd, J = 4.8, 1.7 Hz, 1H), 7.53 (dd, J = 7.8, 1.7 Hz, 1H), 7.38 (dd, J = 7.8 Hz, 1H), 7.33–7.28 (m, 3H), 7.28–7.19 (m, 4H), 6.88 (dd, J = 7.4, 4.8 Hz, 1H), 2.20 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 158.1, 149.6, 147.3, 141.6, 141.0, 136.8, 131.3, 129.9, 129.6, 129.3, 129.3, 129.1, 127.7, 127.4, 120.0, 19.0. Elemental analysis: Calcd (%) for C18H14ClNS: C 69.33, H 4.53, N 4.49. Found: C 69.30, H 4.69, N 4.35. HRMS + p ESI (m/z) [M + H+] Calcd for C18H15ClNS: 312.061. Found: m/z = 312.061.

2-(2-(para-Trifluoromethylbenzene)-6-chloro-phenyl)sulfanyl)-3-methyl-pyridine (23)

The reaction of the halogenated thioether 1a (0.5 mmol), Pd(dba)2 (10 mol %), ArB(OH)2 (2 equiv), and K2CO3 (2 equiv) in toluene (5 mL) at 110 °C during 17 h affords 23 in 75% (0.143 g) yield. Brown solid (dichloromethane/heptane = 7/3). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.01 (ddd, J = 4.7, 1.5, 0.7 Hz, 1H), 7.43 (dd, J = 8.3, 1.5 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.31–7.27 (m, 3H), 7.17–7.10 (m, 2H), 6.77 (dd, J = 7.4, 4.7 Hz, 1H), 2.07 (s, 3H). 19F NMR (470 MHz, Chloroform-d) δ (ppm) = −62.5. 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 157.6, 148.1, 147.3, 145.1, 141.2, 137.0, 131.4, 130.1, 130.0, 129.8 (q, J = 32.3 Hz), 129.7, 129.5, 129.0, 124.6 (q, J = 3.7 Hz), 124.3 (q, J = 272.1 Hz), 120.3, 19.0. Elemental analysis: Calcd (%) for C19H13ClF3NS: C 60.08, H 3.45, N 3.69. Found: C 59.92, H 3.37, N 3.65. HRMS + p ESI (m/z) [M + H+] Calcd for C19H14ClF3NS: 380.048. Found: m/z = 380.048.

2-(2-(para-Methoxybenzene)-6-chloro-phenyl)sulfanyl)-3-methyl-pyridine (24)

The reaction of the halogenated thioether 1a (0.25 mmol), Pd(dba)2 (10 mol %), ArB(OH)2 (2 equiv), and K2CO3 (2 equiv) in toluene (3 mL) at 110 °C during 17 h affords 24 in 41% (0.035 g) yield. White solid (EtOAc/heptane = 1/9). 1H NMR (500 MHz, Chloroform-d) δ (ppm) = 8.2 (dd, J = 4.8, 1.7 Hz, 1H), 7.5 (dd, J = 7.7, 1.7 Hz, 1H), 7.4 (dd, J = 7.9 Hz, 1H), 7.3–7.3 (m, 4H), 6.9 (dd, J = 7.7, 4.8 Hz, 1H), 6.8–6.8 (m, 2H), 3.8 (s, 3H), 2.2 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ (ppm) = 159.1, 158.2, 149.3, 147.3, 141.0, 136.8, 134.2, 131.2, 130.3, 129.9, 129.5, 129.4, 129.0, 120.0, 113.1, 55.3, 19.0. Elemental analysis: Calcd (%) for C19H16ClNOS: C 60.08, H 3.45, N 3.69. Found: C 60.21, H 3.81, N 3.65. HRMS + p ESI (m/z) [M + H+] Calcd for C19H17ClNOS: 342.071. Found: m/z = 342.071.