Visible-light-induced photocatalytic four-component fluoroalkylation–dithiocarbamylation via difunctionalization of styrenes

Patamawadee Silalai; Rungnapha Saeeng

doi:10.1039/D4OB00699B

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DOI: 10.1039/D4OB00699B (Paper) Org. Biomol. Chem., 2024, Advance Article

Visible-light-induced photocatalytic four-component fluoroalkylation–dithiocarbamylation via difunctionalization of styrenes†

Patamawadee Silalai^a and Rungnapha Saeeng*^ab
^aDepartment of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand. E-mail: rungnaph@buu.ac.th
^bThe Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, Thailand

Received 30th April 2024 , Accepted 31st July 2024

First published on 1st August 2024

Abstract

Herein we demonstrate that a visible-light-induced photocatalytic four-component fluoroalkylation–dithiocarbamylation is a unified method for the fluoroalkylation of diverse activated fluoroalkyl halides, including monofluoroalkyl bromides, difluoroalkyl bromides, trifluoromethyl iodide, and perfluoroalkyl iodides. The synthetic value of this method has been demonstrated by the transformations of various substrates containing drug/natural product skeletons, gram scale reactions, and further derivatizations of the fluorodithiocarbamate products. This work features an atom economical protocol that is simple to operate, does not require any additives or strong bases, and can be carried out under mild conditions.

Introduction

Fluorine atoms are prevalent motifs in agrochemicals, pharmaceutical molecules, and materials, and the addition of fluorine atoms to compounds often significantly enhances their biological activity.^1–4 The significance of these structural motifs in drug discovery is further indicated by the wide variety of fluoroalkyl-containing pharmaceutical compounds such as gemcitabine, cedazuridine, eflornithine, gemigliptin and glecaprevir (Fig. 1A).^5,6 Hence, the design of novel fluorinated motifs and the development of synthetic methods are focal points in organic chemistry.^7–10 Moreover, organic dithiocarbamates have become a significant class of sulfur containing compounds with potential biological activities. For example, these compounds have demonstrated efficacy in the treatment of cancer (Fig. 1B).^11–15 Therefore, the preparation of libraries of fluorinated molecules bearing dithiocarbamates is in high demand for drug discovery. In recent years, visible-light-mediated photoredox-catalyzed reactions have been shown to be of significant potential in organic synthesis because these reactions could occur under mild conditions with high efficiency and cleanliness.^16–18 Difunctionalizations of alkenes are commonly of interest to synthetic organic chemists because they allow extensive diversification of original building blocks in fewer steps and with a higher atom economy.^19–21


	Fig. 1 [A] Some bioactive compounds containing fluoroalkyl or [B] dithiocarbamate structures.

In 2021, Kumar's group first used visible-light photoredox catalysis for the synthesis of β-keto by the difunctionalization of styrenes, successfully achieving both C–O and C–S bond formations (Scheme 1A).²² However, studies on the construction of C–S and C–F bonds within the same molecule based on light-induced difunctionalization strategies are still rarely reported.


	Scheme 1 (A) Photocatalytic dithiocarbamylation of alkenes. (B) Copper-catalyzed visible-light induced fluoroalkylthiolation of alkenes. (C) Visible-light induced photocatalytic four-component fluoroalkylthiolation of alkenes.

Considering the significance of incorporating both fluorine and sulfur within the same molecules, only a few methods have been developed for these constructions. In 2021, Zhang and co-workers reported a copper-catalyzed and photocatalytic fluoroalkylphosphorothiolation of alkenes and expanded the scope of F-containing groups under mild conditions.²³ Very recently, Wang's group developed a visible-light induced four-component reaction of styrene with BrCF₂CO₂Et to furnish thiodifluoroesters in moderate to good yields.²⁴ This method has a limited substrate scope and relies on a stoichiometric amount of a base (Scheme 1B).

To overcome this limitation, we report a photocatalyzed four-component reaction of alkenes and easily accessible fluoroalkyl halides including monofluoroalkyl bromides, difluoroalkyl bromides, trifluoromethyl iodide, or perfluoroalkyl iodides which serve as cost effective and readily available starting materials. This approach offers several advantages, including tolerance towards a wide range of substrates, mild reaction conditions, and the the desired product being afforded in good isolated yield without the need for any special additives or strong bases. Our method has exceptional tolerance towards functional groups and can be practically applied to target molecules containing drug and natural product skeletons. Therefore, our work allows the important expansion of the chemical space of this class of compounds (Scheme 1C).

Results and discussion

This four-component fluoroalkylative dithiocarbamylation reaction was commenced using 4-tert-butylstyrene 1a, ethyl bromodifluoroacetate 2a, CS₂ 3 and phenylpiperazine 4a as the model substrates and using [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%) with irradiation by blue LEDs under a N₂ atmosphere (see Table 1).

Table 1 Optimization studies and control reactions^a


Entry	Photocatalyst	Solvents	[M]	Additives (0.5 eq.)	5 Yield^b (%)
a Conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3 (0.4 mmol), 4a (0.4 mmol), PC (1 mol%), room temperature for 24 h, 36 W blue LEDs under a nitrogen atmosphere.b Isolated yields.c 1a (0.2 mmol), 2a (0.3 mmol), 3 (0.3 mmol), 4a (0.3 mmol).d 1a (0.2 mmol), 2a (0.6 mmol), 3 (0.6 mmol), 4a (0.6 mmol).e Without PC.f Without light.g Under air.
1	PC-1	DCM	0.02	—	66
2	PC-1	CHCl₃	0.02	—	60
3	PC-1	CCl₄	0.02	—	33
4	PC-1	PhCl	0.02	—	30
5	PC-1	DMF	0.02	—	31
6	PC-1	DMSO	0.02	—	31
7	PC-1	DCM:DMF	0.02	—	38
8	PC-1	THF	0.02	—	51
9	PC-1	CH₃CN	0.02	—	32
10	PC-1	EtOAc	0.02	—	Trace
11	PC-1	Dioxane	0.02	—	15
12	PC-1	Et₂O	0.02	—	NR
13	PC-1	Acetone	0.02	—	18
14^c	PC-1	DCM	0.02	—	25
15^d	PC-1	DCM	0.02	—	72
16	PC-1	DCM	0.013	—	47
17	PC-1	DCM	0.007	—	NR
18^d	PC-1	DCM	0.04	—	85
19^d	PC-2	DCM	0.04	—	21
20^d	PC-3	DCM	0.04	—	22
21^d	PC-4	DCM	0.04	—	52
22^d	4CzIPN	DCM	0.04	—	NR
23^d	Rose bengal	DCM	0.04	—	NR
24^d	PC-1	DCM	0.04	FeSO₄	Trace
25^d	PC-1	DCM	0.04	Cu(OAc)₂	32
26^d^,^e	PC-1	DCM	0.04	—	NR
27^d^,^f	PC-1	DCM	0.04	—	NR
28^d^,^g	PC-1	DCM	0.04	—	14

To further improve the efficiency, we carefully investigated the effect of solvents and found that halogenated solvents (Table 1, entries 1–4) were effective media for this four-component reaction, and when DCM (c = 0.02 M) was used, 5a was generated in 66% yield (Table 1, entry 1). Polar solvents namely DMF and DMSO were not advantageous to this reaction (Table 1, entries 5 and 6). Next, we screened a range of solvents (c = 0.02 M) including THF, CH₃CN, EtOAc, dioxane, Et₂O, acetone and mixed solvents (Table 1, entries 7–13), and it was found that DCM still explicitly turned out to be the optimal solvent. Further improvement could be obtained by modifying the 2a [thin space (1/6-em)] :3:4a ratio to 0.6 mmol and the target product was obtained in 72% yield (Table 1, entry 15). The effect of changing the concentration of the reactants (0.013, 0.007, and 0.04 M) in DCM at room temperature on the yield of product 5a was examined. Notably, the reaction efficiency was further enhanced in a less diluted solution of 1a in DCM (c = 0.04 M), providing up to 85% isolated yield of 5a. Replacing [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (PC-1) with different photocatalysts, including iridium complexes (PC-2 and PC-3) and [Ru(bpy)₃]²⁺Cl₂·6H₂O (PC-4), reduced the yield of the desired product (Table 1, entries 19–21). The desired product was not observed when organic photocatalysts, such as 4CzIPN and rose bengal, were employed (Table 1, entries 22 and 23). To further study the reaction conditions, additives FeSO₄ and Cu(OAc)₂ (0.5 eq.) were added to coordinate with the thiocarbamate anion but the reaction showed no improvement (Table 1, entries 24 and 25).

Control experiments conducted without a photocatalyst and visible-light irradiation (Table 1, entries 26 and 27) led to no reaction, confirming unequivocally that the synthesis of 5a requires both.

The reaction affords a low yield when this transformation was carried out in air (14% yield). Having optimized the reaction conditions, we studied the scope of the fluoroalkylation–dithiocarbamylation (Scheme 2). We further investigated the scope of the nucleophile by incorporating different substitutions on the benzene ring of phenylpiperazines. It was found that the electronic properties of the substituents on the benzene ring did not affect the efficiency but the substitution position had a pronounced effect on reactivity trends (5a–5d). Furthermore, the steric hindrance of the substituents affected reactivity. For example, a diphenylpiperazine delivered 5e and 5f in a lower yield compared to 5a, 5b and 5d. A diverse range of substituted piperazines could be used in this reaction under the standard conditions, including benzyl (5g and 5h), carbonylbenzodioxane (5i), pyrimidine (5j), Ac (5l), and CH₂CH₂OH (5m), affording the corresponding products in moderate to good yields; we tested the reaction with 4-pyridylpiperazine (5k), but the reaction did not take place due to the complexation of pyridine with the photocatalyst (Ir), which might decrease the reactivity. Additionally, we used secondary amines different from piperazine, including N-methylbenzylamine, morpholine and diethylamine. The reactions proceeded smoothly and furnished the desired products in acceptable to good yields (5n–5q, 36–80%).


	Scheme 2 Scope of the substituent group of amines: (a) reaction conditions: 1a (0.2 or 0.6 mmol), 2a (0.2 or 0.6 mmol), 3 (0.6 mmol), 4 (0.6 mmol), [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%), room temperature for 24 h, 36 W blue LEDs, under a nitrogen atmosphere. (b) Isolated yields. NR = no reaction.

Furthermore, the substrate scope of alkenes and alkylhalides were investigated (Schemes 3 and 4). Various alkenes bearing different substituents on the aromatic ring reacted with 2a, 3 and 4a to yield the corresponding four-component fluoroalkylthiolation products.


	Scheme 3 Scope of the styrenes: (a) reaction conditions: 1 (0.2 or 0.6 mmol), 2a (0.2 or 0.6 mmol), 3 (0.6 mmol), 4a (0.6 mmol), [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%), room temperature for 24 h, 36 W blue LEDs under a nitrogen atmosphere. (b) Isolated yields.


	Scheme 4 Scope of the alkylhalides: (a) reaction conditions: 1a (0.2 or 0.6 mmol), 2 (0.2 or 0.6 mmol), 3 (0.6 mmol), 4a (0.6 mmol), [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%), room temperature for 24 h, 36 W blue LEDs under a nitrogen atmosphere. (b) Isolated yields.

Styrene derivatives bearing electron-donating and electron withdrawing substituents, including methyl (6b and 6c), methoxy (6e and 6f), acetoxy (6g), halogens (6h and 6i), and trifluoromethyl (6l), reacted smoothly to afford the desired products in 44–99% yields. It should be noted that the steric hindrance of α-methylstyrene (6d) notably influenced the formation of the target products. Additionally, when the aromatic ring of styrene, with a fluorine atom at either the para- or meta-position, was employed in the reaction, it resulted in the assembly of the corresponding products 6j and 6k in diminishing yields of 40% and 21%, respectively. Next, the scope of bromo difluoroacetamide compounds were studied (Scheme 4). Using morpholine and piperazine-derived difluoroacetamides yielded products (7a–7d) in good yields (66–81%). Ethyl α-bromoisobutyrate showed smooth reactivity in this transformation, yielding the expected compound 7e in a satisfactory yield of 95%. Regrettably, monofluoroalkyl bromides, such as ethyl 2-bromo-2-fluoroacetate, showed poor reactivity as reaction partners (7f). It is intriguing that diverse perfluoroalkyl iodides, including CF₃I, C₃F₇I, C₄F₉I, C₆F₁₃I, and C₁₂F₂₅I, could participate in the fluoroalkylation–dithiocarbamylation process to give the β-perfluoroalkyl-substituted products (7g–7l) in low to moderate yields.

Finally, the late-stage functionalization of these bioactive or drug molecules further showed the utility of this method.^25,26 More complex substrates, for example, those derived from cholesterol and pregnenolone were also suitable for producing the desired products 8d and 8e. The flexibility of the method was similarly appropriate for the diversification of marketed drugs, including (−)-menthol (8a), borneol (8b), fenchol (8c), ibuprofen (8f), naproxen (8g) and gemfibrozil (8h) (Scheme 5).


	Scheme 5 Late-stage functionalization of natural products and drug molecules: (a) reaction conditions: 1a (0.2 or 0.6 mmol), 2a (0.2 or 0.6 mmol), 3 (0.6 mmol), 4a (0.6 mmol), [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%), room temperature for 24 h, 36 W blue LEDs under a nitrogen atmosphere. (b) Isolated yields.

Moreover, the radical scavenger (2,2,6,6-tetramethyl piperidine-1-yl)oxidanyl (TEMPO) was used under the standard conditions. The reaction was suppressed, and the desired product 5a was not detected. The TEMPO-trapped products 10 and 11 were detected by high-resolution mass spectrometry (HRMS) analysis. These results indicated that a radical pathway was probably involved in this transformation (Scheme 6).


	Scheme 6 TEMPO-trapping experiment.

After the screening of the substrate scope, the developed methodology was applied to large-scale synthesis and further transformations, as shown in Schemes 7 and 8. The reaction of 1 was scaled up to 1.0 mmol scale and the desired product 5d was obtained in a satisfactory yield.


	Scheme 7 Large-scale reaction.


	Scheme 8 Late-stage transformations.

Finally, we have studied the synthetic applications of these protocols. The reduction of the ester group S1 using NaBH₄ resulted in the formation of the alcohol derivative 9 in an impressive yield of 87%. However, employing DIBAL-H for the same reaction led to a slightly diminished yield of product 9 (Scheme 8).

Additionally, a Stern–Volmer quenching study was performed to further investigated the reaction mechanism. As can be seen from Fig. S5 (see the ESI†), bromodifluoroacetate 2a had a pronounced quenching effect on the excited photocatalyst. At the same time, a linear relationship between the fluorescence intensity of F₀/F and the concentration of 2a was observed (for details, see the ESI†). These results indicate that a single electron transfer (SET) process between 2a and the excited photocatalyst should be possible.

A plausible mechanism based on control experiments and literature studies^27,28 is proposed, as shown in Scheme 9. The reaction commences with the initiation of radicals from the alkyl halide under blue light irradiation; Ir^III is excited to Ir^III* and the radical intermediate A is formed. Subsequently, the attack of the alkyl radical on styrene 1a leads to the formation of intermediate B which then participated in the SET process with an excited photocatalyst to generate the cationic intermediate C. Finally, the nucleophile dithiocarbamate (N–C–S⁻) effectively traps intermediate C and undergoes reductive elimination, resulting in the formation of product 5.


	Scheme 9 Proposed mechanism.

Conclusion

In summary, we report a method for the photocatalytic four-component fluoroalkylation–dithiocarbamylation of styrenes. The reaction avoids the use of organometallic reagents, metallic reductants, bases and other additives by employing a photoredox catalyst as an electron shuttle under mild conditions. Importantly, several bioactive compounds were found to be suitable, highlighting the synthetic significance of this new transformation.

Experimental section

General information

Proton NMR spectra were recorded using a BRUKER AVANCE (400 MHz) spectrometer. All spectra were recorded in CDCl₃ solvent and chemical shifts are reported as δ values in parts per million (ppm) relative to tetramethylsilane (δ 0.00), CDCl₃ (δ 7.26) or DMSO-d₆ (δ 2.50) as internal standard. Carbon NMR spectra were recorded on a BRUKER AVANCE (100 MHz) spectrometer. All spectra were recorded in CDCl₃ solvent and chemical shifts are reported as δ values in parts per million (ppm) relative to CDCl₃ (δ 77.0) or DMSO-d₆ (δ 2.50) as the internal standard. High-resolution mass spectra (HRMS) data were recorded at Naresuan university. Light-promoted reactions were performed using blue LEDs, using a homemade photoreactor having blue LED strips with λ 460–463 nm. 36 W blue LEDs were purchased from a commercial source (Budget led). A borosilicate reaction tube was used as the irradiation vessel. The distance between the light source and the reaction tube was approximately 5 cm and no filter was used for the reaction. A fan was used to ensure that the reactions remained at or near room temperature when using the LED.

General procedure for the photocatalytic four-component fluoroalkylation–dithiocarbamylation via difunctionalization of styrenes

An oven-dried 10.0 mL transparent Schlenk tube equipped with a stirring bar was sequentially charged with alkenes 1 (0.2 mmol), R_fX 2 (0.6 mmol), [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%), NHR³R⁴ (0.6 mmol) and DCM (5.0 mL). The mixture was degassed via three freeze–pump–thaw cycles, refilled with N₂ 3 times followed by the addition of CS₂ 3 (0.6 mmol) and then placed in the irradiation apparatus equipped with a 36 W blue light-emitting diode (LED) strip and stirred at room temperature (with a fan to cool down the reaction) for 24 h. Upon completion of the reaction, the reaction mixture was purified by silica gel flash column chromatography using (hexanes [thin space (1/6-em)]

EtOAc) to afford pure products 5–8.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-phenylpiperazine-1-carbonothioyl)thio)butanoate (5a). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-phenylpiperazine (0.6 mmol, 94.0 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 85% yield (75.3 mg) as an orange solid (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.34), m.p. = 98–100 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.33 (q, J = 10.0 Hz, 4H), 7.28 (t, J = 6.8 Hz, 2H), 6.95–6.87 (m, 3H), 5.36 (dd, J = 10.8, 4.0 Hz, 1H), 4.62–4.25 (m, 2H), 4.20–3.90 (m, 4H), 3.37–3.22 (m, 4H), 3.22–3.08 (m, 1H), 3.02–2.85 (m, 1H), 1.30 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 163.6 (t, J = 32.0 Hz), 151.1, 150.2, 134.5, 129.4, 128.2, 125.6, 120.6, 116.5, 114.7 (t, J = 252.0 Hz), 62.8, 50.4–49.5 (m), 49.6, 49.5 (t, J = 4.0 Hz), 40.7 (t, J = 24.0 Hz), 34.6, 31.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.72 (d, J = 280.0 Hz), −104.97 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₂₇H₃₄F₂N₂O₂S₂ [M + Na]⁺: 521.2108, found: 521.2103.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-(2-methoxyphenyl)piperazine-1-carbonothioyl)thio)butanoate (5b). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-(2-methoxyphenyl)piperazine (0.6 mmol, 105.3 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (10 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 91% yield (100.0 mg) as a yellow oil (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.35). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (q, J = 10.0 Hz, 4H), 7.05 (td, J = 7.2, 2.4 Hz, 1H), 6.95–6.85 (m, 3H), 5.36 (dd, J = 11.2, 4.0 Hz, 1H), 4.62–4.32 (m, 2H), 4.11–3.90 (m, 4H), 3.87 (s, 3H), 3.23–3.00 (m, 5H), 3.00–2.83 (m, 1H), 1.29 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 163.6 (t, J = 32.0 Hz), 152.2, 151.1, 139.8, 134.6, 128.2, 125.5, 123.9, 121.1, 118.6, 114.7 (t, J = 252.0 Hz), 111.4, 62.7, 55.4, 50.2, 49.5 (t, J = 4.0 Hz), 40.7 (t, J = 24.0 Hz), 34.5, 31.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.31 (d, J = 280.0 Hz), −104.92 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₂₈H₃₆F₂N₂O₃S₂ [M + H]⁺: 551.2214, found: 551.2214.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-(p-tolyl)piperazine-1-carbonothioyl)thio)butanoate (5c). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-(4-methylphenyl)piperazine (0.6 mmol, 104.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 76% yield (81.1 mg) as a yellow oil (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.34). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (q, J = 8.8 Hz, 4H), 7.08 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 5.36 (dd, J = 10.8, 4.0 Hz, 1H), 4.55–4.30 (m, 2H), 4.10–3.89 (m, 4H), 3.27–3.07 (m, 5H), 3.00–2.83 (m, 1H), 2.28 (s, 3H), 1.30 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 163.6 (t, J = 32.0 Hz), 151.1, 148.1, 134.6, 130.3, 129.9, 129.8, 128.2, 125.6, 117.2, 116.8, 114.7 (t, J = 249.2 Hz), 62.8, 49.5 (t, J = 4.0 Hz), 49.4, 40.7 (t, J = 24.0 Hz), 34.6, 31.2, 20.4, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.26 (d, J = 276.0 Hz), −104.94 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₈H₃₆F₂N₂O₂S₂ [M + H]⁺: 535.2265, found: 535.2265.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-(2-fluorophenyl)piperazine-1-carbonothioyl)thio)butanoate (5d). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (10 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 92% yield (88.5 mg) as a yellow solid (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.36), m.p. = 108–114 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.32 (q, J = 8.8 Hz, 4H), 7.10–6.95 (m, 3H), 6.90 (t, J = 8.4 Hz, 1H), 5.35 (dd, J = 10.8, 4.0 Hz, 1H), 4.69–4.21 (m, 2H), 4.20–3.86 (m, 4H), 3.25–3.10 (m, 5H), 3.00–2.85 (m, 1H), 1.30 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.6, 163.6 (t, J = 32.0 Hz), 155.7 (d, J = 245.0 Hz), 151.2, 138.8 (d, J = 9.0 Hz), 134.6, 128.2, 125.6, 124.6 (d, J = 3.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2, 116.3 (d, J = 21.0 Hz), 114.7 (t, J = 251.0 Hz), 62.8, 50.0, 49.6 (t, J = 4.0 Hz), 40.7 (t, J = 23.0 Hz), 34.6, 31.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.26 (d, J = 276.0 Hz), −104.96 (d, J = 276.0 Hz), 122.92 ppm. HRMS (ESI) calcd for C₂₇H₃₃F₃N₂O₂S₂ [M + H]⁺: 539.2014, found: 539.2001.

Ethyl 4-(4-(tert-butyl)phenyl)-4-((4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-carbonothioyl)thio)-2,2-difluorobutanoate (5e). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-((4-chlorophenyl)(phenyl)methyl)piperazine (0.6 mmol, 172.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (10 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 76% yield as a yellow oil (89.0 mg) (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.32). ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.32 (m, 5H), 7.32–7.29 (m, 2H), 7.29–7.25 (m, 4H), 7.25–7.19 (m, 2H), 5.32 (dd, J = 10.8, 4.0 Hz, 1H), 4.38–4.25 (m, 2H), 4.23 (s, 1H), 3.94 (t, J = 7.2 Hz, 2H), 3.88–3.75 (m, 2H), 3.17–3.02 (m, 1H), 2.96–2.80 (m, 1H), 2.55–2.35 (m, 4H), 1.28 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.2, 163.6 (t, J = 32.0 Hz), 151.1, 141.0, 140.2, 134.6, 133.0, 129.0, 128.9, 128.8, 128.2, 127.7, 125.5, 114.7 (t, J = 252.0 Hz), 74.9, 62.7, 51.2, 49.5 (t, J = 4.0 Hz), 40.7 (t, J = 23.0 Hz), 34.5, 31.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.24 (d, J = 276.0 Hz), −104.93 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₃₄H₃₉ClF₂N₂O₂S₂ [M + H]⁺: 645.2188, found: 645.2189.

Ethyl 4-((4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonothioyl)thio)-4-(4-(tert-butyl)phenyl)-2,2-difluorobutanoate (5f). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-(bis(4-fluorophenyl)methyl)piperazine (0.6 mmol, 173.0 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (10 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 68% yield (80.9 mg) as a colorless oil (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.37). ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.27 (m, 6H), 7.25–7.22 (m, 2H), 6.95 (td, J = 8.4, 2.0 Hz, 4H), 5.30 (dd, J = 10.8, 4.0 Hz, 1H), 4.35–4.23 (m, 2H), 4.21 (s, 1H), 3.96–3.87 (m, 2H), 3.85–3.70 (m, 2H), 3.16–3.00 (m, 1H), 2.95–2.78 (m, 1H), 2.40 (brs, 4H), 1.26 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.2, 163.6 (t, J = 32.0 Hz), 161.9 (t, J = 245.0 Hz), 151.1, 137.2, 134.6, 129.2 (d, J = 8.0 Hz), 128.2, 125.5, 115.6 (d, J = 21.0 Hz), 114.7 (t, J = 249.3 Hz), 74.0, 62.7, 51.1, 49.6 (t, J = 4.0 Hz), 40.7 (t, J = 23.0 Hz), 34.5, 31.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.18 (d, J = 280.0 Hz, 1F), −104.98 (d, J = 280.0 Hz, 1F), −114.89 (s, 2F) ppm. HRMS (ESI) calcd for C₃₄H₃₈F₄N₂O₂S₂ [M + H]⁺: 647.2389, found: 647.2383.

Ethyl 4-(4-(tert-butyl)phenyl)-4-((4-(4-chlorobenzyl)piperazine-1-carbonothioyl)thio)-2,2-difluorobutanoate (5g). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-(4-chlorobenzyl)piperazine (0.6 mmol, 110.9 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (6 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 89% yield (101.6 mg) as a yellow solid (eluent: hexane/EtOAc = 5 [thin space (1/6-em)]

1, R_f = 0.33), m.p. = 88–90 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.22 (m, 8H), 5.31 (dd, J = 11.2, 4.0 Hz, 1H), 4.45–4.23 (m, 2H), 4.02–3.76 (m, 4H), 3.50 (s, 2H), 3.20–3.05 (m, 1H), 2.97–2.80 (m, 1H), 2.50 (brs, 4H), 1.29 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.3, 163.6 (t, J = 32.0 Hz), 151.1, 135.4, 134.6, 133.3, 130.4, 128.6, 128.2, 125.5, 114.7 (t, J = 249.0 Hz), 62.7, 61.6, 52.2, 49.5 (t, J = 4.0 Hz), 40.7 (t, J = 23.0 Hz), 34.5, 31.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.26 (d, J = 276.0 Hz), −104.94 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₈H₃₅ClF₂N₂O₂S₂ [M + H]⁺: 569.1875, found: 569.1876.

Ethyl 4-((4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbonothioyl)thio)-4-(4-(tert-butyl)phenyl)-2,2-difluorobutanoate (5h). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-piperonylpiperazine (0.6 mmol, 132.2 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (5 [thin space (1/6-em)]

1 to 2

1 hexane/EtOAc) gave the product in 82% yield (89.8 mg) as a yellow oil (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.29). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (q, J = 10.8 Hz, 4H), 6.82 (brs, 1H), 6.77–6.68 (m, 2H), 5.94 (s, 2H), 5.32 (dd, J = 10.8, 4.0 Hz, 1H), 4.43–4.20 (m, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.89–3.71 (m, 2H), 3.43 (bs, 2H), 3.20–3.05 (m, 1H), 2.97–2.80 (m, 1H), 2.48 (bs, 4H), 1.29 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.1, 163.6 (t, J = 32.0 Hz), 151.0, 147.7, 146.9, 134.6, 130.9, 128.2, 125.5, 122.2, 114.7 (t, J = 249.0 Hz), 109.3, 107.9, 100.9, 62.7, 62.1, 52.2, 49.5 (t, J = 4.0 Hz), 40.7 (t, J = 24.0 Hz), 34.5, 31.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.27 (d, J = 280.0 Hz), −104.90 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₂₉H₃₆F₂N₂O₄S₂ [M + H]⁺: 579.2163, found: 579.2167.

Ethyl 4-(4-(tert-butyl)phenyl)-4-((4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazine-1-carbonothioyl)thio)-2,2-difluorobutanoate (5i). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-(1,4-benzodioxan-2-ylcarbonyl)piperazine (0.6 mmol, 149.0 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (2 [thin space (1/6-em)]

1 hexane/EtOAc/DCM) gave the product in 74% yield (89.8 mg) as a white solid (eluent: hexane/EtOAc = 5 [thin space (1/6-em)]

1, R_f = 0.20), m.p. = 70–72 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.32 (q, J = 8.4 Hz, 4H), 6.95–6.80 (m, 4H), 5.34 (dd, J = 10.8, 4.0 Hz, 1H), 4.83 (dd, J = 7.6, 2.4 Hz, 1H), 4.49 (dd, J = 12.0, 2.5 Hz, 1H), 4.34 (dd, J = 12.0, 7.8 Hz, 1H), 4.30–4.10 (m, 2H), 4.20–3.84 (m, 6H), 3.68–3.48 (m, 2H), 3.18–3.02 (m, 1H), 3.00–2.84 (m, 1H), 1.30 (bs, 9H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.4, 165.3, 163.5 (t, J = 32.0 Hz), 151.2, 143.2, 142.1, 134.3, 128.1, 125.5, 122.4, 121.6, 117.4, 117.0, 114.6 (t, J = 249.0 Hz), 70.7, 64.8, 62.7, 49.7 (t, J = 5.0 Hz), 44.7, 41.4, 40.6 (t, J = 23.0 Hz), 34.5, 31.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.13 (d, J = 280.0 Hz), −105.12 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₃₀H₃₆F₂N₂O₅S₂ [M + H]⁺: 607.2112, found: 607.2126.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-(pyrimidin-2-yl)piperazine-1-carbonothioyl)thio)butanoate (5j). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 2-piperazin-1-yl-pyrimidine (0.6 mmol, 92.1 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (5 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 43% yield (45.3 mg) as a yellow solid (eluent: hexane/EtOAc = 5 [thin space (1/6-em)]

1, R_f = 0.34), m.p. = 130–136 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 4.8 Hz, 2H), 7.33 (q, J = 7.2 Hz, 4H), 6.56 (t, J = 4.8 Hz, 1H), 5.37 (dd, J = 11.2, 3.2 Hz, 1H), 4.55–4.25 (m, 2H), 4.10–3.80 (m, 8H), 3.22–3.06 (m, 1H), 3.01–2.84 (m, 1H), 1.29 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.7, 163.6 (t, J = 32.0 Hz), 161.2, 157.8, 151.1, 134.5, 128.2, 125.6, 114.7 (t, J = 249.0 Hz), 110.7, 62.7, 49.5 (t, J = 4.0 Hz), 42.9, 40.7 (t, J = 24.0 Hz), 34.5, 31.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.3 (d, J = 280.0 Hz), −104.9 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₂₅H₃₂F₂N₄O₂S₂ [M + H]⁺: 523.2013, found: 523.2014.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-(pyrimidin-2-yl)piperazine-1-carbonothioyl)thio)butanoate (5l). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 hexane/EtOAc/DCM) gave the product in 48% (46.4 mg) yield as a pale yellow oil (eluent: EtOAc/hexane = 2 [thin space (1/6-em)]

1, R_f = 0.47). ¹H NMR (400 MHz, CDCl₃) δ 7.33 (q, J = 8.4 Hz, 4H), 5.32 (dd, J = 11.2, 4.4 Hz, 1H), 4.50–4.10 (m, 2H), 3.90–3.82 (m, 4H), 3.69 (brs, 2H), 3.56 (brs, 2H), 3.18–3.03 (m, 1H), 3.00–2.82 (m, 1H), 2.11 (s, 3H), 1.29 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.2, 169.3, 163.5 (t, J = 32.0 Hz), 151.2, 134.3, 128.1, 125.5, 114.6 (t, J = 249.0 Hz), 62.7, 49.6 (t, J = 4.0 Hz), 45.1, 40.5 (t, J = 24.0 Hz), 34.5, 31.2, 21.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.2 (d, J = 280.0 Hz), −105.2 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₂₃H₃₂F₂N₂O₃S₂ [M + H]⁺: 487.1901, found: 487.1900.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((4-(2-hydroxyethyl)piperazine-1-carbonothioyl)thio)butanoate (5m). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 2-piperazin-1-yl-ethanol (0.6 mmol, 94.0 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 hexane/EtOAc to 1 [thin space (1/6-em)]

1 EA/MeOH) gave the product in 42% yield (40.7 mg) as a yellow oil (eluent: hexane/EtOAc = 1 [thin space (1/6-em)]

1, R_f = 0.27). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (q, J = 8.4 Hz, 4H), 5.32 (dd, J = 11.2, 4.0 Hz, 1H), 4.45–4.15 (m, 2H), 4.20–3.76 (m, 4H), 3.66 (t, J = 5.6 Hz, 2H), 3.20–3.06 (m, 1H), 2.98–2.82 (m, 1H), 2.59 (t, J = 5.2 Hz, 4H), 1.30 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 163.6 (t, J = 32.0 Hz), 151.2, 134.5, 128.2, 125.6, 114.7 (t, J = 252.0 Hz), 62.8, 59.0, 57.8, 52.3, 49.6 (t, J = 5.0 Hz), 40.7 (t, J = 23.0 Hz), 34.6, 31.2, 13.8 ppm. HRMS (ESI) calcd for C₂₃H₃₄F₂N₂O₃S₂ [M + H]⁺: 489.2057, found: 489.2058.

Ethyl 4-((benzyl(methyl)carbamothioyl)thio)-4-(4-(tert-butyl)phenyl)-2,2-difluorobutanoate (5n). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), N-methylbenzylamine (0.6 mmol, 77.4 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 36% yield (35 mg) as a yellow oil (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.36). ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.24 (m, 8H), 7.21–7.10 (m, 1H), 5.41–5.25 (m, 2H), 4.93 (brs, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.42 (brs, 1H), 3.18 (brs, 3H), 3.03–2.80 (m, 1H), 1.30 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 196.2 (195.2), 163.6 (t, J = 32.0 Hz), 161.1, 151.1, 135.4, 134.6, 128.9, 128.8, 128.7, 127.8, 127.0, 125.6, 114.8 (t, J = 249.0 Hz), 62.8, 59.2 (57.5), 50.2, 40.7 (t, J = 24.0 Hz), 38.6, 34.6, 31.2, 13.8 ppm. HRMS (ESI) calcd for C₂₅H₃₁F₂NO₂S₂ [M + H]⁺: 480.1843, found: 480.1843.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-(((4-fluorobenzyl)(methyl)carbamothioyl)thio)butanoate (5o). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 4-fluoro-N-methylbenzylamine (0.6 mmol, 75.4 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 62% yield (62.3 mg) as a white solid (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.36). ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.29 (m, 4H), 7.29–7.23 (m, 1H), 7.18–7.08 (m, 1H), 7.02 (t, J = 8.8 Hz, 2H), 5.40–5.20 (m, 2H), 4.88 (brs, 1H), 4.03–3.90 (m, 2H), 3.40 (brs, 1H), 3.17 (brs, 3H), 3.02–2.85 (m, 1H), 1.30 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 196.3, 163.6 (t, J = 32.0 Hz), 162.4.6 (d, J = 245.0 Hz), 151.1, 134.6, 131.2, 129.6 (d, J = 9.0 Hz), 128.8, 128.2, 125.5, 115.8 (t, J = 21.0 Hz), 114.7 (t, J = 252.0 Hz), 62.7, 58.4 (57.1), 50.2 (t, J = 4.0 Hz), 40.7 (t, J = 24.0 Hz), 38.6, 34.5, 31.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.1 (d, J = 280.0 Hz, 1F), −104.9 (d, J = 280.0 Hz, 1F), −114.0 (d, J = 160.0 Hz, 1F) ppm. HRMS (ESI) calcd for C₂₅H₃₀F₃NO₂S₂ [M + H]⁺: 498.1748, found: 498.1748.

Ethyl 4-(4-(tert-butyl)phenyl)-2,2-difluoro-4-((morpholine-4-carbonothioyl)thio)butanoate (5p). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 75% yield (66.8 mg) as a white solid (eluent: hexane/EtOAc = 8 [thin space (1/6-em)]

1, R_f = 0.17), m.p. = 92–96 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (q, J = 8.4 Hz, 4H), 5.34 (dd, J = 10.8, 4.0 Hz, 1H), 4.45–4.10 (m, 2H), 4.06–3.81 (m, 4H), 3.78 (brs, 4H), 3.20–3.05 (m, 1H), 2.98–2.82 (m, 1H), 1.29 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 163.6 (t, J = 32.0 Hz), 151.2, 134.5, 128.2, 125.5, 114.6 (t, J = 255.0 Hz), 66.2, 62.7, 50.6, 49.4 (t, J = 4.0 Hz), 40.6 (t, J = 24.0 Hz), 34.5, 31.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.2 (d, J = 276.0 Hz), −105.1 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₁H₂₉F₂NO₃S₂ [M + H]⁺: 446.1635, found: 446.1628.

Ethyl 4-(4-(tert-butyl)phenyl)-4-((diethylcarbamothioyl)thio)-2,2-difluorobutanoate (5q). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-butylstyrene (0.6 mmol, 37.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), diethylamine (0.6 mmol, 62.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (20 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 80% yield (68.9 mg) as a yellow oil (eluent: hexane/EtOAc = 20 [thin space (1/6-em)]

1, R_f = 0.35), ¹H NMR (400 MHz, CDCl₃) δ 7.31 (q, J = 7.2 Hz, 4H), 5.30 (dd, J = 10.8, 3.6 Hz, 1H), 4.06–3.88 (m, 4H), 3.65 (q, J = 7.2 Hz, 2H), 3.22–3.06 (m, 1H), 2.98–2.80 (m, 1H), 1.29 (s, 9H), 1.26–1.09 (m, 9H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 193.1, 163.7 (t, J = 32.0 Hz), 150.9, 134.8, 128.3, 125.5, 114.8 (t, J = 249.0 Hz), 62.7, 49.4 (t, J = 4.0 Hz), 49.2, 46.5, 40.8 (t, J = 23.0 Hz), 34.6, 31.2, 13.8, 12.6, 11.5 ppm. HRMS (ESI) calcd for C₂₁H₃₁F₂NO₂S₂ [M + H]⁺: 432.1843, found: 432.1843.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-phenylbutanoate (6a). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-tert-styrene (0.2 mmol, 22.9 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 hexane/EtOAc to 1 [thin space (1/6-em)]

20 MeOH

DCM) gave the product in 68% yield (59.0 mg) as a colorless oil (eluent: EtOAc/hexane = 2 [thin space (1/6-em)]

1, R_f = 0.46).

¹H NMR (400 MHz, CDCl₃) δ 7.40–7.27 (m, 5H), 5.36 (dd, J = 10.4, 4.0 Hz, 1H), 4.33–3.83 (m, 6H), 3.80–3.45 (m, 4H), 3.18–3.02 (m, 1H), 2.98–2.82 (m, 1H), 2.11 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 169.3, 163.5 (t, J = 32.0 Hz), 137.8, 128.6, 128.5, 128.2, 114.6 (t, J = 251.0 Hz), 62.8, 49.9 (t, J = 4.0 Hz), 45.1, 40.6 (t, J = 24.0 Hz), 40.5, 21.2, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.9 (d, J = 276.0 Hz), −104.4 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₁₉H₂₄F₂N₂O₃S₂ [M + H]⁺: 431.1275, found: 431.1275.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(p-tolyl)butanoate (6b). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methylstyrene (0.2 mmol, 26.3 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 hexane/EtOAc to 1 [thin space (1/6-em)]

20 MeOH

DCM) gave the product in 82% yield (88.9 mg) as a white oil (eluent: EtOAc/hexane = 2 [thin space (1/6-em)]

1, R_f = 0.46). ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 5.32 (dd, J = 10.8, 4.0 Hz, 1H), 4.45–4.15 (m, 2H), 4.11–3.85 (m, 4H), 3.70 (brs, 2H), 3.56 (brs, 2H), 3.20–3.03 (m, 1H), 2.98–2.80 (m, 1H), 2.33 (s, 3H), 2.12 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.2, 169.3, 163.5 (t, J = 32.0 Hz), 138.1, 134.6, 129.3, 128.3, 114.6 (t, J = 253.0 Hz), 62.8, 49.7 (t, J = 4.0 Hz), 45.1, 40.5 (t, J = 24.0 Hz), 21.3, 21.1, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.0 (d, J = 276.0 Hz), −104.3 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₀H₂₆F₂N₂O₃S₂ [M + Na]⁺: 467.1251, found: 467.1252.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(2,4,5-trimethylphenyl)butanoate (6c). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 2,4,6-trimethylstyrene (0.2 mmol, 32.3 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 to 3

1 EtOAc/hexane) gave the product in 63% yield (59.6 mg) as a yellow oil (eluent: EtOAc/hexane = 3 [thin space (1/6-em)]

1, R_f = 0.58). ¹H NMR (400 MHz, CDCl₃) δ 6.81 (d, J = 12.4 Hz, 2H), 5.96 (dd, J = 11.6, 4.3 Hz, 1H), 4.40–3.92 (m, 4H), 3.92–3.80 (m, 2H), 3.71(s, 2H), 3.57 (s, 2H), 3.31–3.10 (m, 1H), 3.05–2.88 (m, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 196.1, 169.3, 163.4 (t, J = 32.0 Hz), 137.7, 137.6, 137.5, 131.0, 130.3, 129.5, 114.6 (t, J = 250.0 Hz), 62.7, 49.4 (brs), 45.2 (d, J = 8.0 Hz), 45.0, 40.5, 38.7 (t, J = 23.0 Hz), 21.8, 21.3, 21.2, 20.6, 13.5 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −100.3 (d, J = 280.0 Hz), −106.9 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₂H₃₀F₂N₂O₃S₂ [M + Na]⁺: 495.1564, found: 495.1569.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-phenylpentanoate (6d). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, α-methylstyrene (0.2 mmol, 26.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 to 2

1 EtOAc/hexane) gave the product in 27% yield (23.8 mg) as a yellow oil (eluent: EtOAc/hexane = 2 [thin space (1/6-em)]

1, R_f = 0.40). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.26 (q, J = 14.8 Hz, 1H), 4.19–4.10 (m, 2H), 4.08–3.97 (m, 2H), 3.98–2.84 (m, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.17 (q, J = 15.6 Hz, 1H), 2.34 (s, 3H), 2.11 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.6, 169.4, 163.8 (t, J = 32.0 Hz), 141.5, 128.3, 128.0, 127.5, 115.2 (t, J = 251.5 Hz), 62.8, 57.5 (d, J = 4.0 Hz), 49.0, 48.6, 45.2, 42.8 (t, J = 23.0 Hz), 40.6, 29.7, 23.8, 21.3, 13.7 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −97.4 (d, J = 272.0 Hz), −101.1 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₀H₂₆F₂N₂O₃S₂ [M + Na]⁺: 467.1251, found: 467.1248.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(4-methoxyphenyl)butanoate (6e). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane/DCM to 4 [thin space (1/6-em)]

2 EtOAc/hexane/DCM/MeOH) gave the product in 98% yield (90.8 mg) as a yellow oil (eluent: EtOAc/hexane/DCM = 2 [thin space (1/6-em)]

1, R_f = 0.60). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.30 (dd, J = 10.8, 4.0 Hz, 1H), 4.37–3.90 (m, 6H), 3.79 (s, 3H), 3.74–3.50 (m, 4H), 3.18–3.01 (m, 1H), 2.96–2.80 (m, 1H), 2.12 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.3, 169.3, 163.6 (t, J = 32.0 Hz), 159.5, 129.7, 129.6, 114.7 (t, J = 250.0 Hz), 114.2, 62.9, 55.3, 49.6 (d, J = 4.0 Hz), 45.2, 40.6 (d, J = 8.0 Hz), 21.3, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.9 (d, J = 276.0 Hz), −104.5 (d, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₂₀H₂₆F₂N₂O₄S₂ [M + Na]⁺: 483.1200, found: 483.1194.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(2-methoxyphenyl)butanoate (6f). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 2-methoxystyrene (0.2 mmol, 26.8 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane/DCM to 4 [thin space (1/6-em)]

2 EtOAc/hexane/DCM/MeOH) gave the product in 60% yield (92 mg) as a colorless oil (eluent: EtOAc/hexane/DCM = 2 [thin space (1/6-em)]

1, R_f = 0.60). ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J = 7.6, 1.6 Hz, 1H), 7.27 (td, J = 8.0, 1.6 Hz, 1H), 6.90 (q, J = 8.0 Hz, 2H), 5.73 (dd, J = 10.8, 4.4 Hz, 1H), 4.38–4.12 (m, 2H), 4.12–3.97 (m, 4H), 3.89 (s, 3H), 3.72 (t, J = 4.8 Hz, 2H), 3.57 (t, J = 5.2 Hz, 2H), 3.24–3.07 (m, 1H), 3.05–2.90 (m, 1H), 2.12 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 196.8, 169.4, 163.6 (t, J = 32.0 Hz), 157.5, 130.2, 129.6, 129.4, 128.6, 127.7, 126.1, 120.8, 120.5, 114.9 (t, J = 252.0 Hz), 62.8, 55.6, 49.7, 46.5, 45.2, 39.2 (d, J = 23.0 Hz), 21.3, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.2 (d, J = 280.0 Hz), −104.7 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₀H₂₆F₂N₂O₄S₂ [M + Na]⁺: 483.1200, found: 483.1198.

Ethyl 4-(4-acetoxyphenyl)-4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluorobutanoate (6g). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-acetylstyrene (0.2 mmol, 30.6 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (3 [thin space (1/6-em)]

1 EtOAc/hexane to 1 [thin space (1/6-em)]

30 MeOH

EA) gave the product in 40% yield (39.1 mg) as a yellow oil (eluent: EtOAc/hexane = 3 [thin space (1/6-em)]

1, R_f = 0.43). ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.38 (dd, J = 10.8, 4.8 Hz, 1H), 4.40–4.15 (m, 2H), 4.13–3.82 (m, 4H), 3.80–3.68 (m, 2H), 3.64–3.54 (m, 2H), 3.17–3.00 (m, 1H), 2.97–2.80 (m, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.7, 169.3, 169.2, 163.4 (t, J = 32.0 Hz), 150.4, 135.5, 129.6, 121.7, 115.5, 114.5 (t, J = 253.0 Hz), 63.0, 49.2 (t, J = 4.0 Hz), 45.1, 40.6 (d, J = 24.0 Hz), 40.5, 21.3, 21.1, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −101.7 (d, J = 280.0 Hz), −104.7 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₂₁H₂₆F₂N₂O₅S₂ [M + Na]⁺: 511.1149, found: 511.1143.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-4-(4-chlorophenyl)-2,2-difluorobutanoate (6h). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-chlorostyrene (0.6 mmol, 108.0 μL), ethyl bromodifluoroacetate (0.2 mmol, 26.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane to 3 [thin space (1/6-em)]

1 EtOAc/hexane) gave the product in 44% yield (41.0 mg) as a white oil (eluent: EtOAc/hexane = 3 [thin space (1/6-em)]

1, R_f = 0.57). ¹H NMR (400 MHz, CDCl₃) δ 7.34–7.27 (m, 4H), 5.36 (dd, J = 10.8, 4.4 Hz, 1H), 4.40–4.20 (m, 2H), 4.12 (qd, J = 6.8, 2.0 Hz, 2H), 4.10–3.80 (m, 2H), 3.76–3.65 (m, 2H), 3.62–3.50 (m, 2H), 3.13–2.97 (m, 1H), 2.94–2.75 (m, 1H), 2.11 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 169.3, 163.4 (t, J = 32.0 Hz), 136.7, 134.0, 129.8, 128.8, 114.5 (t, J = 252.0 Hz), 63.0, 49.2 (t, J = 4.0 Hz), 45.1, 40.5, 40.4 (d, J = 24.0 Hz), 21.3, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.5 (d, J = 280.0 Hz), −103.8 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₁₉H₂₃ClF₂N₂O₃S₂ [M + Na]⁺: 487.0704, found: 487.0700.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-4-(4-bromophenyl)-2,2-difluorobutanoate (6i). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-bromostyrene (0.6 mmol, 78.0 μL), ethyl bromodifluoroacetate (0.2 mmol, 26.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane/DCM to 2 [thin space (1/6-em)]

1 EtOAc/hexane/DCM) gave the product in 91% yield (92.5 mg) as a yellow oil (eluent: EtOAc/hexane/DCM = 2 [thin space (1/6-em)]

1, R_f = 0.48). ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.34 (dd, J = 10.8, 4.4 Hz, 1H), 4.50–4.20 (m, 2H), 4.12 (qd, J = 7.2, 2.4 Hz, 2H), 4.08–3.78 (m, 2H), 3.78–3.63 (m, 2H), 3.62–3.50 (m, 2H), 3.13–2.97 (m, 1H), 2.92–2.75 (m, 1H), 2.11 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 169.3, 163.4 (t, J = 32.0 Hz), 137.2, 131.7, 130.2, 122.2, 114.5 (t, J = 252.0 Hz), 63.05, 49.2 (t, J = 4.0 Hz), 45.1, 40.5, 40.4 (d, J = 24.0 Hz), 21.3, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.5 (d, J = 280.0 Hz), −103.8 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₁₉H₂₃BrF₂N₂O₃S₂ [M + Na]⁺: 531.0199, found: 531.0193.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(4-fluorophenyl)butanoate (6j). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-fluorostyrene (0.2 mmol, 23.8 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane to 2 [thin space (1/6-em)]

1 EtOAc/hexane) gave the product in 40% yield (35.9 mg) as a colorless oil (eluent: EtOAc/hexane = 2 [thin space (1/6-em)]

1, R_f = 0.55). ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J = 8.8, 5.2 Hz, 2H), 7.01 (t, J = 8.4 Hz, 2H), 5.36 (dd, J = 10.8, 4.4 Hz, 1H), 4.36–4.17 (m, 2H), 4.11 (qd, J = 7.2, 1.6 Hz, 2H), 4.06–3.85 (m, 2H), 3.78–3.65 (m, 2H), 3.64–3.50 (m, 2H), 3.16–2.99 (m, 1H), 2.96–2.77 (m, 1H), 2.12 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.6, 169.3, 163.4 (t, J = 32.0 Hz), 161.1, 133.8 (d, J = 4.0 Hz), 130.2 (d, J = 9.0 Hz), 115.6 (d, J = 22.0 Hz), 114.5 (t, J = 252.0 Hz), 63.0, 49.1 (t, J = 4.0 Hz), 45.1, 40.6 (d, J = 23.0 Hz), 40.5, 21.3, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.4 (d, J = 284.0 Hz), −104.0 (d, J = 288.0 Hz), −113.2 ppm. HRMS (ESI) calcd for C₁₉H₂₃F₃N₂O₃S₂ [M + Na]⁺: 471.1000, found: 471.1029.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(3-fluorophenyl)butanoate (6k). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 3-fluorostyrene (0.2 mmol, 23.8 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane to 3 [thin space (1/6-em)]

1 EtOAc/hexane) gave the product in 21% yield (18.6 mg) as a yellow oil (eluent: EtOAc/hexane = 3 [thin space (1/6-em)]

1, R_f = 0.54). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (q, J = 8.0 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.09 (dt, J = 9.6, 2.4 Hz, 1H), 6.98 (td, J = 8.4, 2.0 Hz, 1H), 5.39 (dd, J = 10.4, 4.4 Hz, 1H), 4.40–4.18 (m, 2H), 4.13 (q, J = 6.8 Hz, 2H), 4.08–3.85 (m, 2H), 3.77–3.65 (m, 2H), 3.64–3.50 (m, 2H), 3.15–2.95 (m, 1H), 2.94–2.77 (m, 1H), 2.12 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 169.2, 163.8, 163.4 (t, J = 32.0 Hz), 161.4, 140.6 (d, J = 7.0 Hz), 130.1 (d, J = 8.0 Hz), 124.2 (d, J = 2.0 Hz), 115.6, 115.3 (d, J = 7.0 Hz), 115.0, 114.4 (t, J = 252.0 Hz), 63.0, 52.5–49.2 (m), 49.3 (t, J = 4.0 Hz), 45.1, 40.5 (d, J = 23.0 Hz), 40.4, 21.3, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.6 (d, J = 280.0 Hz), −103.8 (d, J = 280.0 Hz), −122.2 ppm. HRMS (ESI) calcd for C₁₉H₂₃F₃N₂O₃S₂ [M + Na]⁺: 471.1000, found: 471.1024.

Ethyl 4-((4-acetylpiperazine-1-carbonothioyl)thio)-2,2-difluoro-4-(4-(trifluoromethyl)phenyl)butanoate (6l). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-(trifluoromethyl)styrene (0.2 mmol, 30.0 μL), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), 1-acetylpiperazine (0.6 mmol, 71.5 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (1 [thin space (1/6-em)]

1 EtOAc/hexane to 3 [thin space (1/6-em)]

1 EtOAc/hexane) gave the product in 71% yield (70.9 mg) as a yellow oil (eluent: EtOAc/hexane = 3 [thin space (1/6-em)]

1, R_f = 0.44). ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 5.47 (dd, J = 10.4, 4.4 Hz, 1H), 4.37–4.17 (m, 2H), 4.12 (qd, J = 7.2, 2.4 Hz, 2H), 4.01–3.80 (m, 2H), 3.78–3.65 (m, 2H), 3.63–3.52 (m, 2H), 3.15–2.99 (m, 1H), 2.98–2.79 (m, 1H), 2.18 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.1, 169.3, 163.3 (t, J = 32.0 Hz), 142.5, 133.5, 130.2 (q, J = 33.0 Hz), 128.9, 125.5 (q, J = 3.0 Hz), 123.8 (d, J = 271.0 Hz), 114.4 (t, J = 251.0 Hz), 63.0, 50.0 (brs), 49.2 (t, J = 4.0 Hz), 45.1, 40.4, 40.3 (d, J = 23.0 Hz), 21.2, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −62.7 (s, 3F), −102.6 (d, J = 276.0 Hz, 1F), −103.6 (d, J = 280.0 Hz, 1F) ppm. HRMS (ESI) calcd for C₂₀H₂₃F₅N₂O₃S₂ [M + Na]⁺: 521.0968, found: 521.0967.

3,3-Difluoro-1-(4-methoxyphenyl)-4-morpholino-4-oxobutyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7a). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (0.6 mmol, 146.4 mg), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (2 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 66% yield (72.6 mg) as a yellow oil (eluent: hexane/EtOAc = 2 [thin space (1/6-em)]

1, R_f = 0.25). ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 7.03–6.89 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.45 (dd, J = 10.4, 4.4 Hz, 1H), 4.70–4.28 (m, 2H), 4.25–3.90 (m, 2H), 3.80 (s, 3H), 3.73–3.66 (m, 4H), 3.66–3.55 (m, 4H), 3.30–3.17 (m, 1H), 3.18–3.07 (m, 4H), 3.06–2.88 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 161.8 (t, J = 32.0 Hz), 159.2, 155.7 (d, J = 244.0 Hz), 138.9 (d, J = 9.0 Hz), 130.9, 129.4, 128.8, 124.6 (d, J = 4.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2 (d, J = 2.0 Hz), 116.3 (d, J = 20.0 Hz), 114.2, 114.0, 66.6 (d, J = 7.0 Hz), 55.2, 50.0, 49.5, 46.5 (t, J = 7.0 Hz), 43.3, 40.4 (t, J = 21.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −96.6 (d, J = 296.0 Hz), −99.7 (d, J = 296.0 Hz), −122.9 ppm. HRMS (ESI) calcd for C₂₆H₃₀F₃N₃O₃S₂ [M + Na]⁺: 576.1578, found: 576.1555.

3,3-Difluoro-4-(4-(2-fluorophenyl)piperazin-1-yl)-1-(4-methoxyphenyl)-4-oxobutyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7b). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 2-bromo-2,2-difluoro-1-(4-(2-fluorophenyl)piperazin-1-yl)ethan-1-one (0.6 mmol, 202.3 mg), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (6 [thin space (1/6-em)]

1 hexane/EtOAc to 5 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 66% yield (84.7 mg) as a yellow solid (eluent: hexane/EtOAc = 6 [thin space (1/6-em)]

1, R_f = 0.31), m.p. = 74–76 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 8.8 Hz, 2H), 7.10–7.03 (m, 3H), 7.03–6.94 (m, 3H), 6.91–6.85 (m, 4H), 5.48 (dd, J = 10.8, 4.0 Hz, 1H), 4.70–4.30 (m, 2H), 4.25–3.92 (m, 2H), 3.88–3.82 (m, 2H), 3.79–3.70 (m, 5H), 3.32–3.18 (m, 1H), 3.17–3.10 (m, 4H), 3.10–3.02 (m, 4H), 3.03–2.90 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 161.8, 159.2, 155.7 (d, J = 247.0 Hz), 139.3 (d, J = 9.0 Hz), 138.9 (d, J = 9.0 Hz), 131.0, 129.4, 124.6 (t, J = 5.0 Hz), 123.3 (dd, J = 17.0, 8.0 Hz), 119.2 (d, J = 2.0 Hz), 116.3 (d, J = 5.0 Hz), 116.2 (d, J = 6.0 Hz), 114.0, 55.2, 50.8, 50.3, 50.0, 49.5, 46.0 (t, J = 4.0 Hz), 43.2, 40.4 (t, J = 21.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −96.4 (d, J = 296.0 Hz, 1F), −99.4 (d, J = 292.0 Hz, 1F), −122.9 (s, 2F) ppm. HRMS (ESI) calcd for C₃₂H₃₄F₄N₄O₂S₂ [M + Na]⁺: 669.1957, found: 669.1953.

4-(4-Benzhydrylpiperazin-1-yl)-3,3-difluoro-1-(4-methoxyphenyl)-4-oxobutyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7c). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 1-(4-benzhydrylpiperazin-1-yl)-2-bromo-2,2-difluoroethan-1-one (0.6 mmol, 245.6 mg), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (6 [thin space (1/6-em)]

1 hexane/EtOAc to 5 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 61% yield (87.6 mg) as a yellow solid (eluent: hexane/EtOAc = 6 [thin space (1/6-em)]

1, R_f = 0.26), m.p. = 88–90 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 7.6 Hz, 4H), 7.31 (q, J = 7.6 Hz, 6H), 7.22 (t, J = 7.2 Hz, 2H), 7.10–7.04 (m, 2H), 7.03–6.95 (m, 1H), 6.94–6.87 (m, 1H), 6.85 (d, J = 8.8 Hz, 2H), 5.43 (dd, J = 10.4, 4.0 Hz, 1H), 4.60–4.35 (m, 2H), 4.31 (s, 1H), 4.20–3.95 (m, 2H), 3.79 (s, 3H), 3.78–3.60 (m, 4H), 3.26–3.05 (m, 5H), 3.04–2.85 (m, 1H), 2.60–2.40 (m, 4H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 161.5, 159.1, 155.7 (d, J = 244.0 Hz), 138.9 (d, J = 9.0 Hz), 131.1, 129.4, 128.8, 127.9, 127.6, 124.6 (d, J = 4.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2 (d, J = 3.0 Hz), 116.2 (d, J = 21.0 Hz), 114.0, 55.2, 52.1, 51.5, 50.0, 49.5, 45.4, 42.7, 40.5 (t, J = 21.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −96.5 (d, J = 292.0 Hz, 1F), −99.3 (d, J = 296.0 Hz, 1F), −122.9 (s, 1F) ppm. HRMS (ESI) calcd for C₃₉H₄₁F₃N₄O₂S₂ [M + H]⁺: 719.2701, found: 719.2704.

3,3-Difluoro-1-(4-methoxyphenyl)-4-oxo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7d). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 2-bromo-2,2-difluoro-1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (0.6 mmol, 192.7 mg), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (3 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 81% yield (102.4 mg) as a yellow oil (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.20). ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 4.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.05 (q, J = 7.2, 2H), 7.02–6.94 (m, 1H), 6.91 (d, J = 8.8, 1H), 6.54 (t, J = 4.8 Hz, 1H), 5.47 (dd, J = 10.8, 4.0 Hz, 1H), 4.62–4.28 (m, 2H), 4.22–3.95 (m, 2H), 3.87–3.80 (m, 4H), 3.78 (s, 3H), 3.76–3.70 (m, 2H), 3.68–3.62 (m, 2H), 3.30–3.20 (m, 1H), 3.18–3.07 (m, 4H), 3.06–2.90 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 162.0 (t, J = 28.0 Hz), 161.3, 159.1, 157.7, 155.6 (d, J = 245.0 Hz), 139.0 (d, J = 9.0 Hz), 131.0, 129.5, 126.8, 124.6 (d, J = 4.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2, 116.2 (d, J = 20.0 Hz), 114.0, 113.9, 110.6, 55.3, 51.0–50.8 (m), 50.0, 49.6, 45.7 (t, J = 7.0 Hz), 43.9, 43.2 (d, J = 20.0 Hz), 40.4 (t, J = 21.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −96.5 (d, J = 292.0 Hz, 1F), −99.5 (d, J = 296.0 Hz, 1F), −122.9 (s, 1F) ppm. HRMS (ESI) calcd for C₃₀H₃₃F₃N₆O₂S₂ [M + Na]⁺: 653.1956, found: 653.1955.

Ethyl 4-((4-(2-fluorophenyl)piperazine-1-carbonothioyl)thio)-4-(4-methoxyphenyl)-2,2-dimethylbutanoate (7e). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), ethyl-α-bromoisobutyrate (0.6 mmol, 84.0 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (10 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 95% yield (89.7 mg) as a yellow oil (eluent: hexane/EtOAc = 15 [thin space (1/6-em)]

1, R_f = 0.17). ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 8.8 Hz, 2H), 7.10–6.95 (m, 3H), 6.89 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 5.26 (dd, J = 10.4, 4.8 Hz, 1H), 4.60–3.90 (m, 4H), 3.77 (s, 3H), 3.74–3.58 (m, 2H), 3.31–3.00 (m, 4H), 2.55–2.37 (m, 2H), 1.27 (s, 3H), 1.18 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.8, 176.9, 158.9, 155.6 (d, J = 244.0 Hz), 138.9 (d, J = 9.0 Hz), 124.5 (d, J = 4.0 Hz), 123.2 (d, J = 7.0 Hz), 119.1 (d, J = 2.0 Hz), 116.2 (d, J = 20.0 Hz), 113.6, 60.2, 55.1, 53.1, 49.9, 46.0, 42.0, 27.1, 24.0, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −122.9 ppm. HRMS (ESI) calcd for C₃₀H₃₃F₃N₆O₂S₂ [M + Na]⁺: 527.1814, found: 527.1814.

Ethyl 2-fluoro-4-((4-(2-fluorophenyl)piperazine-1-carbonothioyl)thio)-4-(4-methoxyphenyl)butanoate (7f, dr = 1.2 [thin space (1/6-em)]

1). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), ethylbromofluoroacetate (0.6 mmol, 70.9 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (8 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 23% yield (23.1 mg) as a yellow oil (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.10). ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 8.4 Hz, 2H), 7.06 (q, J = 7.2 Hz, 2H), 7.02–6.84 (m, 4H), 5.42 (t, J = 8.0 Hz, 0.52H), 5.35 (dd, J = 11.6, 4.8 Hz, 0.43H), 5.02–4.83 (m, 0.54H), 4.73–4.55 (m, 0.62H), 4.55–4.38 (m, 2H), 4.24–4.15 (m, 2H), 4.14–3.95 (m, 2H), 3.79 (d, J = 3.6 Hz, 3H), 3.20–3.09 (m, 4H), 2.94–2.77 (m, 1H), 2.65–2.43 (m, 1H), 2.30 (dt, J = 12.8, 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.1, 194.9, 169.5 (d, J = 11.0 Hz), 169.2 (d, J = 12.0 Hz), 159.3 (d, J = 13.0 Hz), 155.7 (d, J = 245.0 Hz), 138.9 (d, J = 9.0 Hz), 131.3, 130.0, 129.7, 129.4, 124.6 (d, J = 4.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2 (d, J = 2.0 Hz), 116.3 (d, J = 21.0 Hz), 114.2 (d, J = 22.0 Hz), 87.0 (d, J = 186.0 Hz), 86.6 (d, J = 186.0 Hz), 61.7 (d, J = 5.0 Hz), 55.3, 51.3 (d, J = 21.0 Hz), 50.0, 38.8 (t, J = 20.0 Hz), 14.1 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −122.9 (s, 1F), −184.4, −194.0 ppm. HRMS (ESI) calcd for C₂₄H₂₈F₂N₂O₃S₂ [M + Na]⁺: 517.1407, found: 517.1408.

3,3,3-Trifluoro-1-(4-methoxyphenyl)propyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7g). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), trifluoroiodomethane (0.6 mmol, 46.1 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 16% yield (15.2 mg) as a yellow oil (eluent: hexane/EtOAc = 15 [thin space (1/6-em)]

1, R_f = 0.31). ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 8.8 Hz, 2H), 7.11–6.95 (m, 3H), 6.94–6.85 (m, 3H), 5.34 (dd, J = 11.2, 4.0 Hz, 1H), 4.70–4.25 (m, 2H), 4.20–3.90 (m, 2H), 3.80 (s, 3H), 3.32–3.19 (m, 1H), 3.22–3.04 (m, 4H), 2.88–2.73 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 159.5, 157.0, 155.7 (d, J = 245.0 Hz), 138.9 (d, J = 9.0 Hz), 129.4, 124.6 (d, J = 4.0 Hz), 123.5 (d, J = 8.0 Hz), 119.2 (d, J = 2.0 Hz), 116.3 (d, J = 21.0 Hz), 114.2, 55.3, 50.8, 50.1, 49.4 (d, J = 2.0 Hz), 40.0 (q, J = 28.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −63.2 (s, 3F), −122.9 (s, 1F), ppm. HRMS (ESI) calcd for C₂₁H₂₂F₄N₂OS₂ [M + H]⁺: 459.1188, found: 459.1238. HRMS (ESI) calcd for C₂₁H₂₂F₄N₂OS₂ [M + H]⁺: 459.1188, found: 459.1238.

3,3,4,4,5,5,5-Heptafluoro-1-(4-methoxyphenyl)pentyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7h). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), heptafluoro-1-iodopropane (0.6 mmol, 86.4 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 46% yield (52.0 mg) as a yellow oil (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.32). ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.8 Hz, 2H), 7.12–7.04 (m, 2H), 7.03–6.95 (m, 1H), 6.95–6.85 (m, 3H), 5.44 (dd, J = 11.2, 4.0 Hz, 1H), 4.71–4.29 (m, 2H), 4.21–3.93 (m, 2H), 3.81 (s, 3H), 3.37–3.20 (m, 1H), 3.21–3.05 (m, 4H), 2.86–2.69 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.3, 159.4, 155.7 (d, J = 245.0 Hz), 138.7 (d, J = 9.0 Hz), 129.7, 129.2, 124.5 (d, J = 4.0 Hz), 123.3 (d, J = 8.0 Hz), 119.1 (d, J = 3.0 Hz), 116.2 (d, J = 20.0 Hz), 114.1, 55.1, 50.0, 49.9, 48.6 (d, J = 2.4 Hz), 36.3 (t, J = 20.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −80.3 (s, 3F), −110.7 (dm, J = 280.0 Hz, 1F), −115.3 (dm, J = 288.0 Hz, 1F), −122.9 (s, 1F), −127.7 (d, J = 8.0 Hz, 1F), −127.8 (d, J = 8.0 Hz, 1F) ppm. HRMS (ESI) calcd for C₂₃H₂₂F₈N₂OS₂ [M + H]⁺: 559.1124, found: 559.1124.

3,4,4,4-Tetrafluoro-1-(4-methoxyphenyl)-3-(trifluoromethyl)butyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7i). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), heptafluoro-2-iodopropane (0.6 mmol, 85.4 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 19% yield (21.3 mg) as a white solid (eluent: hexane/EtOAc = 15 [thin space (1/6-em)]

1, R_f = 0.34), m.p. = 121–125 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J = 8.8 Hz, 2H), 7.10–7.03 (m, 2H), 7.03–6.95 (m, 1H), 6.94–6.86 (m, 3H), 5.42 (dd, J = 11.6, 4.0 Hz, 1H), 4.68–4.29 (m, 2H), 4.15–3.90 (m, 2H), 3.80 (s, 3H), 3.34–3.19 (m, 1H), 3.19–3.04 (m, 4H), 2.96–2.84 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.3, 159.4, 155.7 (d, J = 245.0 Hz), 138.8 (d, J = 9.0 Hz), 129.5, 129.2, 124.6 (d, J = 4.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2 (d, J = 3.0 Hz), 116.3 (d, J = 20.0 Hz), 114.1, 55.2, 50.7(brs), 50.2, 50.0, 34.0 (d, J = 18.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −74.3 (s, 3F), −77.5 (s, 3F), −122.9 (s, 1F), −184.2 (s, 1F) ppm. HRMS (ESI) calcd for C₂₃H₂₂F₈N₂OS₂ [M + H]⁺: 559.1124, found: 559.1124.

3,3,4,4,5,5,6,6,6-Nonafluoro-1-(4-methoxyphenyl)hexyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7j). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), nonafluoro-1-iodobutane (0.6 mmol, 103.3 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 44% yield (53.0 mg) as a yellow oil (eluent: hexane/EtOAc = 15 [thin space (1/6-em)]

1, R_f = 0.23). ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.8 Hz, 2H), 7.11–7.03 (m, 2H), 7.03–6.95 (m, 1H), 6.95–6.85 (m, 3H), 5.44 (dd, J = 11.2, 3.6 Hz, 1H), 4.71–4.27 (m, 2H), 4.20–3.93 (m, 2H), 3.80 (s, 3H), 3.40–3.20 (m, 1H), 3.21–3.05 (m, 4H), 2.88–2.70 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.3, 159.4, 155.7 (d, J = 245.0 Hz), 138.8 (d, J = 9.0 Hz), 129.7, 129.2, 124.6 (d, J = 3.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2 (d, J = 3.0 Hz), 116.2 (d, J = 20.0 Hz), 114.2, 55.2, 50.2, 50.0, 48.6, 36.5 (t, J = 21.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −81.0 (s, 3F), −110.4 (d, J = 280.0 Hz, 1F), −114.9 (d, J = 288.0 Hz, 1F), −122.9 (s, 1F), −(124.4–124.7) (m, 1F), −(125.8–125.9) (m, 1F) ppm. HRMS (ESI) calcd for C₂₄H₂₂F₁₀N₂OS₂ [M + Na]⁺: 609.1092, found: 609.1088.

3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluoro-1-(4-methoxyphenyl)octyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7k). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 1-iodoperfluorohexane (0.6 mmol, 129.7 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (10 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 51% yield (72.0 mg) as a yellow solid (eluent: hexane/EtOAc = 5 [thin space (1/6-em)]

1, R_f = 0.56). ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.8 Hz, 2H), 7.12–7.02 (m, 2H), 7.03–6.95 (m, 1H), 6.92–6.85 (m, 3H), 5.44 (dd, J = 10.8, 3.6 Hz, 1H), 4.69–4.28 (m, 2H), 4.21–3.90 (m, 2H), 3.80 (s, 3H), 3.38–3.20 (m, 1H), 3.21–3.03 (m, 4H), 2.88–2.70 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 159.4, 155.7 (d, J = 245.0 Hz), 138.8 (d, J = 9.0 Hz), 129.7, 129.3, 124.6 (d, J = 3.0 Hz), 123.4 (d, J = 8.0 Hz), 116.3 (d, J = 20.0 Hz), 114.2, 55.2, 50.2, 50.0, 48.7, 36.7 (t, J = 20.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −80.8 (s, 3F), −109.8 (d, J = 288.0 Hz, 1F), −114.3 (d, J = 288.0 Hz, 1F), −121.8 (s, 2F), −122.8 (s, 2F), −122.8 (s, 1F), −123.5 (s, 2F), −126.1 (s, 2F) ppm. HRMS (ESI) calcd for C₂₆H₂₂F₁₄N₂OS₂ [M + H]⁺: 709.1028, found: 709.1028.

3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluoro-1-(4-methoxyphenyl)octyl 4-(2-fluorophenyl)piperazine-1-carbodithioate (7m). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.6 mmol, 162.0 μL), perfluorododecyl iodide (0.2 mmol, 149.0 μL), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 27% yield (54 mg) as a white solid (eluent: hexane/EtOAc = 15 [thin space (1/6-em)]

1, R_f = 0.14), m.p. = 156–158° C.

¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.8 Hz, 2H), 7.10–7.03 (m, 2H), 7.03–6.95 (m, 1H), 6.94–6.85 (m, 3H), 5.44 (dd, J = 11.2, 4.0 Hz, 1H), 4.74–4.25 (m, 2H), 4.23–3.90 (m, 2H), 3.80 (s, 3H), 3.52–3.00 (m, 5H), 2.90–2.69 (m, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 159.5, 155.7 (d, J = 245.0 Hz), 138.8 (d, J = 9.0 Hz), 129.8, 129.3, 124.6 (d, J = 3.0 Hz), 123.4 (d, J = 7.0 Hz), 119.2 (d, J = 3.0 Hz), 114.2, 55.2, 50.2, 50.0, 48.7, 36.7 (t, J = 20.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −80.7 (s, 3F), −109.8 (d, J = 288.0 Hz, 1F), −114.2 (d, J = 284.0 Hz, 1F), −121.5 (s, 14F), −121.3 (s, 2F), −123.0 (s, 1F), −123.5 (s, 2F), −126.1 (s, 2F) ppm. HRMS (ESI) calcd for C₃₂H₂₂F₂₆N₂OS₂ [M + Na]⁺: 1031.0656, found: 1031.0651.

(1R,2R,5R)-2-Isopropyl-5-methylcyclohexyl 2,2-difluoro-4-((4-(2-fluorophenyl)piperazine-1-carbonothioyl)thio)-4-(4-methoxyphenyl)butanoate (8a). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), (1R,2R,5R)-2-isopropyl-5-methylcyclohexyl-2-bromo-2,2-difluoroacetate (0.6 mmol, 187.9 mg), 1-(2-fluorophenyl)piperazine (0.6 mmol, 108.1 mg) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (15 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 44% yield (54.7 mg) as a yellow oil (eluent: hexane/EtOAc = 10 [thin space (1/6-em)]

1, R_f = 0.18). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 8.4 Hz, 2H), 7.10–7.03 (m, 2H), 7.03–6.95 (m, 1H), 6.94–6.87 (m, 1H), 6.85 (d, J = 8.8 Hz, 2H), 5.39 (td, J = 10.8, 4.4 Hz, 1H), 4.76–4.66 (m, 1H), 4.60–3.90 (m, 4H), 3.79 (s, 3H), 3.52–3.04 (m, 5H), 2.95–2.77 (m, 2H), 1.98–1.77 (m, 2H), 1.73–1.63 (m, 2H), 1.53–1.40 (m, 2H), 1.10–0.95 (m, 2H), 0.90 (dd, J = 12.0, 1.6 Hz, 7H), 0.73 (t, J = 6.8 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.6, 163.4 (td, J = 31.0, 12.0 Hz), 159.3 (d, J = 9.0 Hz), 155.7 (d, J = 245.0 Hz), 138.9 (d, J = 9.0 Hz), 130.6, 130.2, 129.6, 124.6 (d, J = 4.0 Hz), 123.4 (d, J = 8.0 Hz), 119.2 (d, J = 2.0 Hz), 119.3 (d, J = 20.0 Hz), 114.0, 77.8, 55.2, 50.2, 49.6, 49.5 (d, J = 4.0 Hz), 46.7 (d, J = 6.0 Hz), 40.2 (d, J = 7.0 Hz), 34.0, 31.4, 26.0 (d, J = 9.0 Hz), 23.3 (d, J = 6.0 Hz), 21.9, 20.7 (d, J = 7.0 Hz), 16.1 (d, J = 6.0 Hz) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.3 (s, 2F), −122.9 (s, 1F) ppm. HRMS (ESI) calcd for C₃₂H₄₁F₃N₂O₃S₂ [M + Na]⁺: 645.2408, found: 645.2445.

1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 2,2-difluoro-4-(4-methoxyphenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate (8b). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-bromo-2,2-difluoroacetate (0.6 mmol, 186.6 mg), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (5 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 61% yield (64.0 mg) as a yellow oil (eluent: hexane/EtOAc = 6 [thin space (1/6-em)]

1, R_f = 0.23). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (dd, J = 8.8, 2.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.34 (td, J = 10.0, 4.4 Hz, 1H), 4.88–4.80 (m, 1H), 4.40–3.82 (m, 4H), 3.78 (s, 3H), 3.78–3.62 (m, 4H), 3.22–3.05 (m, 1H), 2.98–2.78 (m, 1H), 2.40–2.22 (m, 1H), 1.96–1.87 (m, 1H), 1.80–1.71 (m, 1H), 1.69 (q, J = 4.4 Hz, 1H), 1.35–1.18 (m, 2H), 1.00 (td, J = 14.0, 3.2 Hz, 1H), 0.90–0.88 (m, 3H), 0.87–0.86 (m, 3H), 0.83 (d, J = 14.0 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 164.0 (d, J = 32.0 Hz), 159.3 (d, J = 3.0 Hz), 130.0 (d, J = 22.0 Hz), 129.6 (d, J = 4.0 Hz), 114.6 (d, J = 270.0 Hz), 114.0, 83.2, 66.2, 55.2, 50.5, 49.3 (d, J = 4.0 Hz), 49.1, 48.0, 44.7, 40.4 (d, J = 22.0, 7.0 Hz), 36.2 (d, J = 12.0 Hz), 27.8 (d, J = 5.0 Hz), 26.9, 19.6, 18.8, 13.5 (d, J = 6.0 Hz) ppm. HRMS (ESI) calcd for C₂₆H₃₅F₂NO₄S₂ [M + Na]⁺: 550.1873, found: 550.1874.

1,3,3-Trimethylbicyclo[2.2.1]heptan-2-yl 2,2-difluoro-4-(4-methoxyphenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate (8c). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.2 mmol, 26.8 μL), 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl-2-bromo-2,2-difluoroacetate (0.6 mmol, 186.7 mg), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (6 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 96% yield (101.0 mg) as a yellow oil (eluent: hexane/EtOAc = 6 [thin space (1/6-em)]

1, R_f = 0.26). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.41 (dt, J = 10.4, 4.4 Hz, 1H), 4.39 (d, J = 8.0 Hz, 1H), 4.33–4.10 (m, 4H), 3.78 (s, 3H), 3.76–3.65 (m, 4H), 3.25–3.07 (m, 1H), 2.93–2.75 (m, 1H), 1.69 (d, J = 10.0 Hz, 2H), 1.59 (d, J = 10.0 Hz, 2H), 1.51–1.45 (m, 1H), 1.24 (d, J = 10.4 Hz, 2H), 1.09 (d, J = 5.2 Hz, 3H), 1.06 (d, J = 13.6 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 164.2 (td, J = 32.0, 6.0 Hz), 159.3, 130.5, 129.5, 115.0 (t, J = 253.0 Hz), 114.0, 89.1, 66.2, 55.2, 50.5, 49.2, 48.5 (d, J = 7.0 Hz), 48.3, 41.3, 40.2 (td, J = 22.0, 7.0 Hz), 39.7, 29.6, 25.7, 20.0, 19.5, 19.4 ppm. HRMS (ESI) calcd for C₂₆H₃₅F₂NO₄S₂ [M + Na]⁺: 550.1873, found: 550.1873.

(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2,2-difluoro-4-(4-methoxyphenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate (8d). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.6 mmol, 80.4 μL), (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-bromo-2,2-difluoroacetate (0.2 mmol, 108.7 mg), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (6 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 58% yield (88.2 mg) as a sticky yellow oil (eluent: hexane/EtOAc = 6 [thin space (1/6-em)]

1, R_f = 0.25). ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.42–5.29 (m, 2H), 4.57–4.45 (m, 1H), 4.44–3.80 (m, 4H), 3.78 (s, 3H), 3.80–3.60 (m, 4H), 3.20–3.03 (m, 1H), 2.95–2.77 (m, 1H), 2.40–2.23 (m, 2H), 2.05–1.93 (m, 2H), 1.90–1.75 (m, 2H), 1.70–1.23 (m, 13H), 1.38–1.05 (m, 8H), 1.01 (s, 4H), 0.91 (d, J = 8.0 Hz, 3H), 0.86 (dd, J = 6.8, 2.0 Hz, 6H), 0.67 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.8, 163.0 (d, J = 32.0 Hz), 159.3, 138.9 (d, J = 3.0 Hz), 129.8 (d, J = 6.0 Hz), 129.6, 123.2, 114.0, 66.1, 56.6, 56.0, 55.2, 50.2, 49.9, 49.3, 42.2, 39.6, 39.4, 37.5 (d, J = 4.0 Hz), 36.7, 36.4, 36.1, 35.7, 31.7 (d, J = 8.0 Hz), 28.2, 27.9, 27.2 (d, J = 4.0 Hz), 24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.6, 11.8 ppm. HRMS (ESI) calcd for C₄₃H₆₃F₂NO₄S₂ [M + Na]⁺: 782.4064, found: 782.4068.

Methyl (4R)-4-((3R,8R,9S,10S,13R,14S,17R)-3-((2,2-difluoro-4-(4-methoxyphenyl)-4-((morpholine-4-carbonothioyl)thio)butanoyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (8e). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-methoxystyrene (0.6 mmol, 80.4 μL), methyl (4R)-4-((3R,8R,9S,10S,13R,14S,17R)-3-(2-bromo-2,2-difluoroacetoxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (0.2 mmol, 109.5 mg), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (3 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 43% yield (66.2 mg) as a sticky yellow oil (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.38). ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.34 (dt, J = 9.6, 4.0 Hz, 1H), 4.70–4.58 (m, 1H), 4.45–4.15 (m, 2H), 4.10–3.90 (m, 2H), 3.78 (s, 3H), 3.76–3.67 (m, 4H), 3.66 (s, 3H), 3.18–3.00 (m, 1H), 2.95–2.78 (m, 1H), 2.40–2.30 (m, 1H), 2.28–2.15 (m, 1H), 1.96 (d, J = 11.6 Hz, 1H), 1.91–1.75 (m, 6H), 1.50–1.30 (m, 12H), 1.16–1.00 (m, 7H), 0.92 (s, 6H), 0.64 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 174.8, 163.1 (t, J = 32.0 Hz), 159.4, 129.8 (d, J = 38.0 Hz), 129.7, 114.7 (t, J = 252.0 Hz), 113.9, 77.8, 66.2, 56.4, 56.0, 55.3, 51.5, 50.7, 49.4, 42.7, 41.9, 40.4, 40.1, 35.8, 35.4, 34.9, 34.6, 31.7 (d, J = 4.0 Hz), 31.1 (d, J = 6.0 Hz), 28.2, 27.0, 26.3, 26.2 (d, J = 5.0 Hz), 24.2, 23.3, 20.9, 18.3, 12.0 ppm. HRMS (ESI) calcd for C₄₁H₅₉F₂NO₆S₂ [M + Na]⁺: 786.3650, found: 786.3653.

Ethyl 2,2-difluoro-4-(4-(((2-(4-isobutylphenyl)propanoyl)oxy)methyl)phenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate (8f). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-vinylbenzyl 2-(4-isobutylphenyl)propanoate (0.2 mmol, 64.5 mg), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL), purification by silica gel column chromatography (6 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 67% yield (82.0 mg) as a yellow solid (eluent: hexane/EtOAc = 6 [thin space (1/6-em)]

1, R_f = 0.20), m.p. = 75–83 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 8.0, 1.6 Hz, 4H), 7.09 (d, J = 8.0 Hz, 2H), 5.37 (dd, J = 10.8, 4.4 Hz, 1H), 5.07 (d, J = 2.8 Hz, 2H), 4.36–4.15 (m, 2H), 4.36–4.15 (m, 2H), 4.10–4.00 (m, 2H), 3.99–3.80 (m, 2H), 3.80–3.65 (m, 5H), 3.17–3.01 (m, 1H), 2.95–2.78 (m, 1H), 2.45 (d, J = 7.2 Hz, 2H), 1.92–1.79 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.91 (s, 3H), 0.90 (s, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 174.4, 163.5 (t, J = 32.0 Hz), 140.6, 137.8, 137.5, 136.1, 129.3, 128.6, 127.9, 127.1, 114.6 (t, J = 251.0 Hz), 66.1, 65.7, 62.9, 50.5, 49.3 (t, J = 5.0 Hz), 45.0 (d, J = 10.0 Hz), 40.5 (t, J = 23.0 Hz), 30.1, 22.3, 18.4, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.3 (dm, J = 278.0 Hz), −104.0 (dm, J = 278.0 Hz) ppm. HRMS (ESI) calcd for C₃₁H₃₉F₂NO₅S₂ [M + Na]⁺: 630.2135, found: 630.2134.

Ethyl 2,2-difluoro-4-(4-((((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)oxy)methyl)phenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate (8g). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 4-vinylbenzyl (S)-2-(6-methoxynaphthalen-2-yl)propanoate (0.2 mmol, 69.3 mg), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (4 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 68% yield (85.6 mg) as a yellow solid (eluent: hexane/EtOAc = 3 [thin space (1/6-em)]

1, R_f = 0.07), m.p. = 67–83 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (t, J = 8.0 Hz, 2H), 7.64 (brs, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.37 (dd, J = 10.8, 4.4 Hz, 1H), 5.08 (q, J = 8.0 Hz, 2H), 4.35–4.20 (m, 2H), 4.07–3.99 (m, 4H), 3.91 (s, 3H), 3.79 (t, J = 4.8 Hz, 1H), 3.76–3.59 (m, 4H), 3.17–3.00 (m, 1H), 2.95–2.79 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 174.3, 163.4 (t, J = 31.0 Hz), 157.6, 137.8, 136.0, 135.4, 133.6, 129.2, 128.8, 128.6, 128.0, 127.1, 126.1, 125.9, 118.9, 114.5 (t, J = 252.0 Hz), 105.5, 66.3, 65.8, 62.8, 55.2, 50.6, 49.2 (t, J = 4.0 Hz), 45.3, 18.4, 13.7. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.2 (dm, J = 280.0 Hz), −103.8 (dm, J = 280.0 Hz) ppm. HRMS (ESI) calcd for C₃₂H₃₅F₂NO₆S₂ [M + H]⁺: 632.1952, found: 632.1952.

3-(4-Ethoxy-3,3-difluoro-1-((morpholine-4-carbonothioyl)thio)-4-oxobutyl)benzyl 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoate (8h). Following the general procedure, using 1 mol% [Ir(ppy)₂(4,4′-dtb-bpy)]PF₆, 3-vinylbenzyl 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoate (0.2 mmol, 73.3 mg), ethyl bromodifluoroacetate (0.6 mmol, 78.0 μL), morpholine (0.6 mmol, 51.7 μL) and CS₂ (0.6 mmol, 36.0 μL) in DCM (5.0 mL) and purification by silica gel column chromatography (5 [thin space (1/6-em)]

1 hexane/EtOAc) gave the product in 67% yield (87.7 mg) as a yellow oil (eluent: hexane/EtOAc = 5 [thin space (1/6-em)]

1, R_f = 0.18). ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 5.40 (dd, J = 10.8, 4.0 Hz, 1H), 5.08 (s, 2H), 4.40–4.15 (m, 2H), 4.13–4.03 (m, 2H), 3.89 (t, J = 5.6 Hz, 4H), 3.80–3.60 (m, 4H), 3.18–3.00 (m, 1H), 2.97–2.79 (m, 1H), 2.30 (s, 3H), 2.16 (s, 3H), 1.78 (s, 4H), 1.27 (t, J = 7.2 Hz, 3H), 1.24 (s, 6H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 177.5, 163.5 (t, J = 32.0 Hz), 156.9, 137.9, 136.4 (d, J = 8.0 Hz), 130.3, 128.7, 128.0, 123.5, 120.7, 114.3 (t, J = 251.0 Hz), 111.9, 67.8, 66.2, 65.6, 62.9, 50.5, 49.4 (t, J = 5.0 Hz), 42.2, 40.6 (t, J = 23.0 Hz), 37.1, 25.1, 21.4, 15.8, 13.8 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.4 (dm, J = 272.0 Hz), −103.8 (dm, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₃₃H₄₃F₂NO₆S₂ [M + H]⁺: 652.2578, found: 652.2572.

Large-scale reaction

[Ir(ppy)₂(4,4′-dtb-bpy)]PF₆ (1 mol%, 9.0 mg), ethyl bromodifluoroacetate (3 mmol, 234.0 μL), 1-(2-fluorophenyl)piperazine (3 mmol, 540.0 μL) and 4-tert-butylstyrene (1 mmol, 185.0 μL) in DCM (25 mL) were placed in a dry Schlenk tube. The reaction vessel was evacuated and filled with N₂ three times. CS₂ (3 mmol, 180.0 μL) was then added and the mixture was stirred under irradiation with a 36 W blue light-emitting diode (LED) strip at room temperature (with a fan to cool down the reaction) for 24 h. Upon completion of the reaction, the resulting mixture was extracted with CH₂Cl₂ and dried over anhydrous Na₂SO₄. After the solvent was removed by evaporation under reduced pressure, the residue was purified by silica gel flash column chromatography using 10 [thin space (1/6-em)]

1 hexane/EtOAc as the eluent to give the corresponding product 5d (0.3712 g, 69%).

Transformation reaction

Reduction using NaBH₄. To an oven-dried 10 mL Schlenk tube equipped with a magnetic stir bar under nitrogen was added ethyl-2,2-difluoro-4-(4-methoxyphenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate S1 (0.2387 mmol, 1.0 equiv.) in THF (2 mL). Then NaBH₄ (2.3866 mmol, 10.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 0.5 h. Upon completion of the reaction, the organic phase was washed with saturated aqueous NH₄Cl (15 mL) and extracted with EtOAc followed by water and brine. After filtration over Na₂SO₄, the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography using 2 [thin space (1/6-em)]

1 hexane/EtOAc as the eluent to give the corresponding product 9 as a yellow oil (78.6 mg, 87%).

Reduction using DIBAL-H. To an oven-dried 10 mL Schlenk tube equipped with a magnetic stir bar under nitrogen was added ethyl 2,2-difluoro-4-(4-methoxyphenyl)-4-((morpholine-4-carbonothioyl)thio)butanoate S1 (0.2387 mmol, 1.0 equiv.) in dry DCM (2 mL). Then DIBAL-H (2.3866 mmol, 10.0 equiv.) was added at −78 °C, and the reaction mixture was stirred for 1.5 h. Upon completion of the reaction, the reaction mixture was cooled to 0 °C and slowly quenched with MeOH to remove excess DIBAL-H, followed by quenching with 1 M HCl and stirred for 0.5 h. The organic phase was washed with 1 M HCl (15 mL) and extracted with DCM followed by water and brine. After filtration over Na₂SO₄, the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography using 2 [thin space (1/6-em)]

1 hexane/EtOAc as the eluent to give the corresponding product 9 as a yellow oil (67.4 mg, 75%).

3,3-Difluoro-4-hydroxy-1-(4-methoxyphenyl)butyl morpholine-4-carbodithioate (9). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.33 (dd, J = 11.2, 3.6 Hz, 1H), 4.50–4.15 (m, 2H), 3.95–3.55 (m, 11H), 3.05–2.88 (m, 1H), 2.82–2.67 (m, 1H), 2.40 (t, J = 7.2 Hz, 1H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 195.5, 159.3, 130.4, 129.3, 121.9 (t, J = 244.0 Hz), 114.1, 66.8–65.4 (m), 63.6 (t, J = 33.0 Hz), 55.2, 51.4–50.0 (m), 49.9 (dd, J = 24.0, 3.0 Hz), 39.5 (t, J = 24.0 Hz), 29.6 ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −102.0 (d, J = 276.0 Hz), −105.7 (d, J = 276.0 Hz) ppm. HRMS (ESI) calcd for C₁₆H₂₁F₂NO₃S₂ [M + Na]⁺: 400.0829, found: 400.0829.

Data availability

Data for this article, are available at: https://doi.org/10.1039/D4OB00699B. The link within the Data Availability statement refers to by accessing this link, readers will be able to view and download our research's data in the article “Visible-light-induced photocatalytic four-component fluoroalkylation–dithiocarbamylation via difunctionalization of styrenes”.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Research Council of Thailand (NRCT) NRCT5-RSA63012-02, the Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND) and the Center of Excellence for Innovation in Chemistry (PERCH-CIC). R. S. and P. S. are grateful for support through the Postdoctoral Fellowship Award from Burapha University and the student training program at Lanzhou University. The authors would like to thank Prof. Chun-An Fan and Dr Ye-Xing Cao, College of Chemistry and Chemical Engineering, Lanzhou University for helpful discussions on photoredox catalyzed reactions.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ob00699b