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Communication

Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives

by
Kotaro Kikushima
*,
Haruka Koyama
,
Kazuki Kodama
and
Toshifumi Dohi
*
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525–8577, Japan
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(5), 1365; https://doi.org/10.3390/molecules26051365
Submission received: 16 February 2021 / Revised: 24 February 2021 / Accepted: 25 February 2021 / Published: 4 March 2021
(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)
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Abstract

:
Nucleophilic aromatic substitution (SNAr) reactions can provide metal-free access to synthesize monosubstituted aromatic compounds. We developed efficient SNAr conditions for p-selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10-phenylphenothiazine (PTH) derivatives. The resulting polyfluoroarene-bearing PTH derivatives were subjected to a second SNAr reaction to generate highly functionalized PTH derivatives with potential applicability as photocatalysts for the reduction of carbon–halogen bonds.

1. Introduction

Owing to the high electronegativity of fluorine atoms, polyfluoroarenes can undergo nucleophilic aromatic substitution (SNAr) [1], wherein nucleophiles attack the low-electron-density arene core, and the fluoride anion is eliminated as a fluoride salt. Although transition-metal-catalyzed C-F and C-H bond functionalization of polyfluoroarenes have advanced considerably in recent years [2,3,4,5,6], SNAr of polyfluoroarenes offers a transition-metal-free approach to substituted polyfluoroarenes. Polyfluoroarenes react with organometallic compounds, such as organolithium or organomagnesium reagents, to convert aromatic C-F bonds into C-C bonds without the use of transition metal catalysts [7,8]. The combination of a fluoride salt and organosilane compounds as nucleophiles has also been successful in the SNAr of polyfluoroarenes, wherein the reaction proceeds with a catalytic amount of a fluoride anion [9,10,11,12,13]. The use of alcohols or amines as nucleophiles enables C-O and C-N bond formation to produce the corresponding aryl ether and aniline derivatives [8,14,15].
Functionalized arenes, such as arylamine derivatives, can be synthesized via transition-metal-catalyzed cross-coupling reactions [16,17,18,19,20,21]. However, the high cost of organometallic catalysts and contamination of the resulting products with metal traces represent major drawbacks of such methods. Alternative methods for transition-metal-free synthesis of arylamine derivatives have been achieved using hypervalent iodine reagents [22,23,24,25,26,27], sulfonium reagents [28], nitorarenes [29,30,31,32,33], or electrochemical conditions [34]. The SNAr reaction also offers an alternative method without the use of transition metals, which is therefore potentially applicable in the facile synthesis of organic functional materials containing substituted arenes. For instance, 1,2,3,5-tetrakis(carbazolyl)-4,6-dicyanobenzene (4CzIPN), an organic photocatalyst, has been produced by multiple SNAr reactions using carbazole and 1,3-dicyano-2,4,5,6-terafluorobenzene with NaH as the base [35]. In this context, we focused on the application of a sequential and controllable SNAr reaction for the synthesis of 10-phenylphenothiazine (PTH) derivatives, which serve as organic photocatalysts that induce dehalogenative bond formation via processes such as atom transfer radical polymerization [36,37,38,39,40,41,42,43,44,45,46].
PTH derivatives are generally prepared via palladium- or copper-catalyzed coupling reactions of phenothiazine with aryl halides or arylboronic acids (Scheme 1a) [36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. Transition-metal-free methods for the synthesis of PTH derivatives include oxidative C-H amination in the presence of oxidants [53,54,55,56,57] or under electrolytic conditions [58,59], although starting materials are limited to phenols and anilines (Scheme 1b). In addition, SNAr of triphenylsulfonium salts, nitroarenes, and fluoroarenes with phenothiazine have been demonstrated for the preparation of PTH derivatives (Scheme 1c) [28,60,61,62,63,64,65,66,67].
We envisioned that a reaction between phenothiazine and polyfluoroarenes would afford the corresponding polyfluoroarene-bearing PTH derivatives, which would then undergo a second SNAr reaction for the introduction of other nucleophiles to afford highly functionalized PTH derivatives (Scheme 2). In addition to the synthetic utility of polyfluoroarenes, their introduction provides unique functionalities crucial in materials science, such as improvement of oxidation resistance, lowering of both HOMO and LUMO energy levels, and favorable stacking interactions with electron-rich aromatic rings [68,69,70]. However, SNAr of polyfluoroarenes often suffers from uncontrollable substitution, resulting in a mixture of regioisomers and/or multisubstituted products. Therefore, it is necessary to establish appropriate conditions that suppress unselective substitution events and over-reactions, while being applicable to a wide range of polyfluoroarenes. Herein, we demonstrate SNAr of various polyfluoroarenes resulting in mono-phenothiazination in the presence of an appropriate base to afford PTH derivatives bearing polyfluoroarenes, and further transformation of the resulting PTH derivatives to highly functionalized PTH derivatives via a second SNAr reaction.

2. Results and Discussion

The reaction of phenothiazine with octafluorotoluene in the presence of K2CO3 in N,N-dimethylformamide (DMF) at 60 °C afforded the corresponding PTH derivative 3aa as the sole product in 96% yield (Scheme 3). The fluorine atom at the p-position of the trifluoromethyl group of octafluorotoluene was substituted by phenothiazine, without the formation of regioisomers or multisubstituted products. The observed regioselectivity was in agreement with previously reported outcomes of octafluorotoluene SNAr [11,13], and it is governed by the electron density at the reactive carbons (ortho- and para-positions) on the aromatic ring and the steric repulsion between the trifluoromethyl group and bulky phenothiazine. The K2CO3/DMF system was found to be an efficient combination for mono SNAr between various phenothiazines and octafluorotoluene (Scheme 3). For example, phenothiazine derivatives bearing electron-deficient and electron-donating groups (1b–1e) were employed in the present reaction to give the corresponding PTH derivatives (3ba–3ea). Moreover, phenoxazine derivative 3fa was synthesized under similar conditions. Next, we examined various polyfluoroarenes for the SNAr reaction with phenothiazine.
In contrast to octafluorotoluene, several other polyfluoroarenes exhibited decreased selectivities with the combination of K2CO3 and DMF, due to their inherently high reactivities, and the reaction of pentafluorobenzonitrile yielded complex mixtures including p- and o-substituted products, 3ab and 3ab’, respectively (Scheme 4). Pentafluoronitrobenzene provided similar results, undergoing uncontrollable SNAr.
Thus, optimization of the reaction conditions was performed for pentafluorobenzonitrile (2b) to suppress multiple substitution (Table 1). Using Li2CO3 or Na2CO3 instead of K2CO3 afforded the desired product 3ab in low yield along with unreacted 2b (entries 1 and 2). On the other hand, the use of Cs2CO3 led to high reactivity, and multiple substitutions occurred to give a complex mixture, containing 3ab in 13% (entry 3). Inorganic phosphate salts, such as Li3PO4 and Na3PO4, exhibited comparable results to those of carbonate salts (entries 4 and 5). On the other hand, the use of K3PO4 improved the reaction yield of 3ab to 48% (entry 6). The use of Na3PO4 or K3PO4 at an elevated reaction temperature of 80 °C resulted in lower yields compared to those attained under the conditions in entry 6 (entries 7 and 8). Next, we surveyed reaction solvents. In the case of acetonitrile (MeCN) at 60 °C, the reaction yield improved to 76% (entry 9). N,N-Dimethylacetoamide (DMA) and dimethyl sulfoxide (DMSO) were also suitable, albeit providing slightly decreased yields (entries 10 and 11). Chloroform, tetrahydrofuran (THF), and 1,4-dioxane were found to be inappropriate solvents (entries 12–14).
Next, various polyfluoroarenes were subjected to SNAr with phenothiazine under the optimum conditions of K3PO4 in MeCN at 60 °C, as summarized in Scheme 5. Under these conditions, octafluorotoluene (2a) produced 3aa in 67% yield, which was lower than that obtained with the use of K2CO3 and DMF. Pentafluoronitrobenzene (2c) also underwent SNAr with high selectivity to afford p-substituted product 3ac in 78% yield. Ester-bearing PTH derivative 3ad was synthesized from methyl pentafluorobenzoate (2d) in 69% yield. Thus, the combination of K3PO4 and MeCN proved effective for achieving p-selective mono-substitution of a wide range of highly reactive polyfluoroarenes. Chloropentafluorobenzene (2e) underwent SNAr using K2CO3 in DMSO at 85 °C to afford the corresponding product 3ae, while the K3PO4/MeCN system resulted in low yield. The use of DMSO improved the reactivity of substitution presumably due to the higher solubility of the base. It should be noted that selective C–F bond functionalization occurred and the chlorine atom remained intact under these SNAr conditions, allowing for further product transformation via transition-metal-catalyzed cross-coupling reactions. In contrast to results obtained with electron-deficient groups, methyl-substituted pentafluorobenzene did not furnish the desired product even under K2CO3/DMSO conditions. When pentafluoropyridine (2f) was employed as the substrate, the SNAr reaction proceeded smoothly under K3PO4/MeCN conditions to produce fluorinated pyridylphenothiazine 3af in 92% yield. Simple polyfluoroarenes lacking other functional groups were also tested in the present SNAr protocol. The reaction of decafluorobiphenyl (2g) afforded the corresponding mono-substituted product 3ag in 51% yield, along with a trace amount of the disubstituted compound (4aga). On the other hand, octafluoronaphthalene (2h) underwent double substitution to give 4aha in 22% yield, even with 2 equivalents of 2h. Hexafluorobenzene (2i) exhibited low reactivity under the K3PO4/MeCN system, as was the case with 2e. The combination of K2CO3 and DMSO at 85 °C led to double substitution of 2i affording 4aia in 64% yield. In this case, 2i exists in the vapor phase as a result of its low boiling point (bp: ca. 80 °C); therefore, once the first SNAr reaction occurs, the second is favored due to the monosubstituted product being in solution while the bulk of 2i remains in the vapor phase.
Next, further transformations of obtained PTH derivatives 3 were performed (Scheme 6). Thus, SNAr of 3ab with p-methoxyphenol proceeded in the presence of K2CO3 to afford PTH derivative 4abb, bearing both cyano and phenoxy groups. Phthalimide, commonly used as a protecting group and photosensitizer, was also introduced onto 3ac via further SNAr to obtain multifunctionalized 4acc. Transition-metal-free carbon–carbon bond formation was also examined using a combination of organosilanes and a catalytic amount of Bu4NSiF2Ph3 (TBAT). Thiophene moieties, ubiquitous in functional organic materials owing to their high electron density, can be introduced onto 3af via the reaction with thienyl silane and TBAT to afford diheteroaromatic 4afd. Similarly, ethynylsilane participated in the carbon–carbon bond forming reaction with 3ag to produce linear analog 4age. Hence, PTH derivatives bearing various functional groups, connected through C–O, C–N, and C–C bonds, were synthesized via sequential SNAr of polyfluoroarenes under transition-metal-free conditions.

3. Materials and Methods

3.1. General Information

1H, 13C, and 19F nuclear magnetic resonance (NMR) spectra were recorded on a JEOL JMN-400 spectrometer at 25 °C unless otherwise noted. The data are reported as follows: chemical shift in part per million (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet), integration, and coupling constant (Hz). The chemical shifts in the 1H NMR spectra were recorded relative to the residual solvent peaks (CDCl3: δ 7.26). The chemical shifts in the 13C NMR spectrum were also recorded relative to the residual solvent peaks (CDCl3: δ 77.0). The chemical shifts in the 19F NMR spectrum were recorded relative to that of the internal standard (4-fluorotoluene: δ −121.0). High-resolution mass spectra (HRMS) were obtained using a Thermo Scientific Exactive Plus Orbitrap (Thermo Fisher Scientific, Inc., Waltham, MA, USA). All commercially available reagents were used as received unless otherwise noted.

3.2. SNAr Reaction of Phenothiazines with Polyfluoroarenes

3.2.1. General Procedure A for the Reaction of Phenothiazines with Polyfluoroarenes

Phenothiazine derivatives (1.0 mmol) and base (4.0 mmol, 4.0 eq) were placed in a screw-capped test tube and dried under vacuum for 1 h. After backfilling with N2, solvent (10 mL) and polyfluoroarenes (2.1 mmol, 2.1 eq) were added in this order. The reaction mixture was stirred at 60 °C for 24 h. The reaction was quenched with water (50 mL), and the mixture was transferred to a separatory funnel containing diethyl ether (50 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, and all volatiles were removed under vacuum. The residue was purified by flash column chromatography (SiO2) to yield the corresponding 10-phenylphenothiazine (PTH) derivatives.

3.2.2. 10-(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)-10H-phenothiazine (3aa)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 200 mg, 1.0 mmol), octafluorotoluene (2a, 300 μL, 2.1 mmol, 2.1 eq), and K2CO3 (554 mg, 4.0 mmol, 4.0 eq) in DMF (10 mL). 3aa was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/100) in 96% yield (398 mg, 0.958 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.12 (dd, J = 7.3, 2.0 Hz, 2H), 6.93–7.02 (m, 4H), 6.26 (dd, J = 7.8, 1.5 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −58.5 (t, J = 22.0 Hz, 3F), −140.5–(−140.6) (m, 2F), −142.0–(−142.1) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C19H9F7NS 416.0338; Found 416.0342.

3.2.3. 2-Chloro-10-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-10H-phenothiazine (3ba)

The title compound was prepared according to General Procedure A with 2-chloro-10H-phenothiazine (1b, 66.9 mg, 0.50 mmol), octafluorotoluene (2a, 150 μL, 1.05 mmol, 2.1 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMF (5 mL). 3ba was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/200) in 67% yield (150 mg, 0.334 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.11 (dd, J = 7.3, 2.0 Hz, 1H), 7.04–6.93 (m, 4H), 6.27–6.23 (m, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −58.5 (t, J = 22.0 Hz, 3F), −140.4–(−140.6) (m, 2F), −142.1–(−142.2) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C19H8ClF7NS+ 449.9949; Found 449.9946.

3.2.4. 10-(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)- 10H-phenothiazine (3ca)

The title compound was prepared according to General Procedure A with 2-(trifluoromethyl)-10H-phenothiazine (1c, 133.6 mg, 0.50 mmol), octafluorotoluene (2a, 150 μL, 1.05 mmol, 2.1 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMF (5 mL). 3ca was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/200) in 91% yield (220 mg, 0.455 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.21 (s, 2H), 7.13–7.10 (m, 1H), 7.06–6.98 (m, 2H), 6.43 (s, 1H), 6.27 (d, J = 7.3 Hz, 1H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −58.5 (t, J = 22.0 Hz, 3F), −65.1 (s, 3F), −139.3–(−139.7) (m, 2F), −142.1–(−142.2) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C20H8F10NS+ 484.0212; Found 484.0210.

3.2.5. 2-Methoxy-10-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-10H-phenothiazine (3da)

The title compound was prepared according to General Procedure A with 2-methoxy-10H-phenothiazine (1d, 114.6 mg, 0.50 mmol), octafluorotoluene (2a, 150 μL, 1.05 mmol, 2.1 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMF (5 mL). 3da was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/150) in 89% yield (200 mg, 0.449 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.05 (dd, J = 7.8, 2.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.93–6.87 (m, 2H), 6.46 (d, J = 7.3 Hz, 1H), 6.20–6.17 (m, 1H), 5.79–5.77 (m, 1H), 3.64 (s, 3H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −58.5 (t, J = 22.0 Hz, 3F), −139.7–(−140.0) (m, 2F), −142.1–(−142.2) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C20H11F7NS+ 446.0444; Found 446.0447.

3.2.6. 2-(Ethylthio)-10-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-10H-phenothiazine (3ea)

The title compound was prepared according to General Procedure A with 2-ethylthio-10H-phenothiazine (1e, 129.7 mg, 0.50 mmol), octafluorotoluene (2a, 150 μL, 1.05 mmol, 2.1 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMF (5 mL). 3ea was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/100) in 55% yield (130 mg, 0.273 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.10–7.08 (m, 1H), 7.03–6.91 (m, 4H), 6.25–6.21 (m, 2H), 2.81 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −58.5 (t, J = 19.5 Hz, 3F), −140.2–(−140.4) (m, 2F), −142.1–(−142.2) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C21H13F7NS2+ 476.0372; Found 476.0371.

3.2.7. 10-(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)-10H-phenoxazine (3fa)

The title compound was prepared according to General Procedure A with 10H-phenoxazine (1f, 91.6 mg, 0.50 mmol), octafluorotoluene (2a, 150 μL, 1.05 mmol, 2.1 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMF (5 mL). 3fa was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/100) in 80% yield (160 mg, 0.400 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 6.82–6.78 (m, 4H), 6.75–6.69 (m, 2H), 6.00 (dd, J = 7.3, 1.5 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −58.5 (t, J = 22.0 Hz, 3F), −140.3–(−140.5) (m, 2F), −142.0–(−142.1) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C19H9F7ON+ 400.0567; Found 400.0565.

3.2.8. 2,3,5,6-Tetrafluoro-4-(10H-phenothiazin-10-yl)benzonitrile (3ab)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 399 mg, 2.0 mmol), pentafluorobenzonitrile (2b, 512 μL, 4.0 mmol, 2.0 eq), and K3PO4 (1.70 g, 8.0 mmol, 4.0 eq) in MeCN (20 mL). 3ab was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/40) in 76% yield (568 mg, 1.53 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.13 (dd, J = 7.3, 2.0 Hz, 2H), 7.08–6.95 (m, 4H), 6.27 (dd, J = 7.8, 1.5 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −132.4–(−132.5) (m, 2F), −140.6–(−140.7) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C19H9F4N2S 373.0417; Found 373.0415.

3.2.9. 10-(2,3,5,6-Tetrafluoro-4-nitrophenyl)-10H-phenothiazine (3ac)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 399 mg, 2.0 mmol), pentafluoronitrobenzene (2c, 496 μL, 4.0 mmol, 2.0 eq), and K3PO4 (1.70 g, 8.0 mmol, 4.0 eq) in MeCN (20 mL). 3ac was isolated by flash column chromatography (SiO2, hexane) in 78% yield (613 mg, 1.56 mmol) as an orange solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.11 (dd, J = 7.3, 1.5 Hz, 2H), 7.02–6.94 (m, 4H), 6.26 (dd, J = 7.3, 1.5 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −140.1–(−140.1) (m, 2F), −146.9–(−146.9) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C18H9F4N2O2S+ 393.0315; Found 393.0317.

3.2.10. Methyl 2,3,5,6-tetrafluoro-4-(10H-phenothiazin-10-yl)benzoate (3ad)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 100 mg, 0.50 mmol), methyl pentafluorobenzoate (2d, 146 μL, 1.0 mmol, 2.0 eq), and K3PO4 (424.5 mg, 2.0 mmol, 4.0 eq) in MeCN (5 mL). 3ad was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/200) in 69% yield (140 mg, 0.345 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.10 (dd, J = 7.3, 1.5 Hz, 2H), 7.00–6.91 (m, 4H), 6.25 (dd, J = 7.8, 1.0 Hz, 2H), 4.05 (s, 3H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −143.2–(−143.3) (m, 2F), −139.7–(−139.8) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C20H12F4NO2S+ 406.0519; Found 406.0520.

3.2.11. 10-(4-Chloro-2,3,5,6-tetrafluorophenyl)-10H-phenothiazine (3ae)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 100 mg, 0.50 mmol), chloropentafluorobenzene (2e, 129 μL, 1.0 mmol, 2.0 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMSO (5 mL) at 80 °C. 3ae was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/200) in 62% yield (118 mg, 0.309 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.09 (dd, J = 7.3, 1.5 Hz, 2H), 7.00–6.91 (m, 4H), 6.26 (dd, J = 7.8, 1.5 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −141.0–(−141.0) (m, 2F), −143.8–(−143.8) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C18H9ClF4NS+ 382.0075; Found 382.0075.

3.2.12. 10-(Perfluoropyridin-4-yl)-10H-phenothiazine (3af)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 399 mg, 2.0 mmol), pentafluoropyridine (2f, 430 μL, 4.0 mmol, 2.0 eq), and K3PO4 (1.70 g, 8.0 mmol, 4.0 eq) in MeCN (20 mL). 3af was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/50) in 92% yield (640 mg, 1.84 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.06 (dd, J = 6.8, 1.5 Hz, 2H), 7.04–6.94 (m, 4H), 6.34 (d, J = 7.8 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −88.9–(−89.0) (m, 2F), −144.5–(−144.7) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C17H9F4N2S+ 349.0417; Found 349.0420.

3.2.13. 10-(Perfluoro-[1,1’-biphenyl]-4-yl)-10H-phenothiazine (3ag)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 100 mg, 0.50 mmol), decafluorobiphenyl (2g, 334 mg, 1.0 mmol, 2.0 eq), and K3PO4 (424.5 mg, 2.0 mmol, 4.0 eq) in MeCN (5 mL). 3ag was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/100) in 51% yield (130 mg, 0.253 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.10 (dd, J = 7.8, 1.5 Hz, 2H), 7.03–6.92 (m, 4H), 6.33 (d, J = 7.8 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −138.4–(−138.4) (m, 2F), −139.1–(−139.2) (m, 2F), −143.4–(−143.5) (m, 1F), −151.4–(−151.6) (m, 2F), −162.2–(−162.3) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C24H9F9NS+ 514.0307; Found 514.0303.

3.2.14. 10,10’-(Perfluoronaphthalene-2,6-diyl)bis(10H-phenothiazine) (4aha)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 100 mg, 0.50 mmol), octafluoronaphthalene (2h, 270 mg, 1.0 mmol, 2.0 eq), and K3PO4 (424.5 mg, 2.0 mmol, 4.0 eq) in MeCN (5 mL). 4aha was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/10) in 22% yield (70 mg, 0.111 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.12 (dd, J = 7.8, 1.5 Hz, 2H), 6.99–6.96 (m, 4H), 6.32 (d, J = 7.8 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −123.5–(−123.8) (m, 2F), −140.9–(−140.9) (m, 2F), −144.5–(−144.8) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C34H17F6N2S2+ 631.0732; Found 631.0733.

3.2.15. 10,10’-(Perfluoro-1,4-phenylene)bis(10H-phenothiazine) (4aia)

The title compound was prepared according to General Procedure A with phenothiazine (1a, 100 mg, 0.50 mmol), hexafluorobenzene (2i, 177 μL, 1.0 mmol, 2.0 eq), and K2CO3 (277 mg, 2.0 mmol, 4.0 eq) in DMSO (5 mL) at 80 °C. 4aia was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/50) in 64% yield (174 mg, 0.320 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.14 (dd, J = 7.3, 1.5 Hz, 2H), 7.06–6.98 (m, 4H), 6.39 (d, J = 8.3 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −143.0 (s, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C30H17F4N2S2+ 545.0764; Found 545.0766.

3.3. Sequential SNAr Reaction with 3ab, 3ac, 3af, and 3ag

3.3.1. 3,5-Difluoro-2,6-bis(4-methoxyphenoxy)-4-(10H-phenothiazin-10-yl)benzonitrile (4abb)

Phenothiazine derivative 3ab (0.10 mmol), 4-methoxyphenol (0.40 mmol, 4.0 eq), and K2CO3 (0.80 mmol, 8.0 eq) were placed in a screw-capped test tube and dried under vacuum for 1 h. After backfilling with N2, DMF (1.5 mL) was added to the test tube. The reaction mixture was stored at room temperature for 24 h. The reaction was quenched with water (20 mL) and the mixture was transferred to a separatory funnel containing diethyl ether (20 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, and all volatiles were removed under vacuum. 4abb was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/10) in 86% yield (50 mg, 0.0862 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.06–7.03 (m, 2H), 6.99–6.83 (m, 12H), 6.20 (d, J = 6.8 Hz, 2H), 3.77 (s, 6H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −132.2 (s, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C33H23F2N2S+ 581.1341; Found 581.1342.

3.3.2. 2-(2,4,5-Trifluoro-6-nitro-3-(10H-phenothiazin-10-yl)phenyl)isoindoline-1,3-dione (4acc)

In a well-dried screw-capped test tube, 3ac (78.5 mg, 0.20 mmol) was dissolved in DMF. Phthalimide (40.7 mg, 0.22 mmol, 1.1 eq) was added to the mixture and the test tube was sealed with a cap, and the reaction mixture was stirred at 60 °C for 20 h. The reaction was quenched with water (20 mL) and the mixture was then transferred to a separatory funnel with diethyl ether (20 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2 × 10 mL). The combined organic fractions were washed with brine (20 mL) and then dried over Na2SO4, and all the volatiles were removed under vacuum. 4acc was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/10) in 69% yield (72.3 mg, 0.139 mmol) as a white solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 8.00 (dd, J = 5.4, 2.9 Hz, 2H), 7.87 (dd, 5.9, 2.9 Hz, 2H), 7.12 (dd, J = 7.3, 1.5 Hz, 2H). 7.06 (dt, J = 7.8, 1.5 Hz, 2H), 6.98 (t, J = 7.6 Hz, 2H), 6.39 (d, J = 7.3 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −120.6–(−120.7) (m, 1F), −131.0–(−131.1) (m, 1F), −144.8–(−144.9) (m, 1F). HRMS (DART) m/z: ([M + H]+) Calcd for C26H13F3O4N3S+ 520.0573; Found 520.0572.

3.3.3. 10-(2-(Benzo[b]thiophen-2-yl)-3,5,6-trifluoropyridin-4-yl)-10H-phenothiazine (4afd)

In a well-dried screw-capped test tube, tetrabutylammonium difluorotriphenylsilicate (TBAT, 5.4 mg, 0.01 mmol, 10 mol%) and 3af (34.8 mg, 0.10 mmol) were added and dried under vacuum for 1 h. After backfilling with N2, THF (1.0 mL) and benzo[b]thiophen-2-yltrimethylsilane (24.8 mg, 0.12 mmol, 1.2 eq) were added to the mixture in this order. The test tube was sealed with a cap, and the reaction mixture was stirred at 60 °C for 20 h. The reaction was quenched with water (20 mL) and the mixture was then transferred to a separatory funnel with AcOEt (20 mL). The organic layer was separated, and the aqueous layer was extracted with AcOEt (2 × 10 mL). The combined organic fractions were washed with brine (20 mL) and then dried over Na2SO4, and all the volatiles were removed under vacuum. 4afd was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/30) in 65% yield (30.0 mg, 0.0649 mmol) as a white solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 8.07 (s, 1H), 7.95–7.82 (m, 2H), 7.43–7.37 (m, 2H),7.14 (dd, J = 7.3, 1.5 Hz, 2H), 7.03–6.95 (m, 4H), 6.39 (d, J = 7.8 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −85.5–(−85.6) (m, 1F), −126.9–(−126.9) (m, 1F), −141.8–(−141.9) (m, 1F). HRMS (DART) m/z: ([M + H]+) Calcd for C25H14F3N2S2+ 463.0545; Found 463.0544.

3.3.4. 10-(2,2’,3,3’,5,5’,6,6’-octafluoro-4’-(phenylethynyl)-[1,1’-biphenyl]-4-yl)-10H-phenothiazine (4age)

In a well-dried screw-capped test tube, tetrabutylammonium difluorotriphenylsilicate (TBAT, 10.8 mg, 0.02 mmol, 20 mol%) and 3ag (51.3 mg, 0.10 mmol) were added and dried under vacuum for 1 h. After backfilling with N2, THF (1.0 mL) and 1-phenyl-2-(trimethylsilyl)acetylene (24 μL, 0.12 mmol, 1.2 eq) were added to the mixture in this order. The test tube was sealed with a cap, and the reaction mixture was stirred at 60 °C for 20 h. The reaction was quenched with water (20 mL) and the mixture was then transferred to a separatory funnel with AcOEt (20 mL). The organic layer was separated, and the aqueous layer was extracted with AcOEt (2 × 10 mL). The combined organic fractions were washed with brine (20 mL) and then dried over Na2SO4, and all the volatiles were removed under vacuum. 4age was isolated by flash column chromatography (SiO2, AcOEt/hexane = 1/19) in 73% yield (43.3 mg, 0.0727 mmol) as a white solid. 1H NMR (400 MHz, CDCl3, rt, δ/ppm): 7.64 (dd, J = 8.0, 1.7 Hz, 2H), 7.47–7.42 (m, 3H), 7.12 (dd, J = 7.3, 1.5 Hz, 2H). 7.04 (dt, J = 7.8, 1.4 Hz, 2H), 6.96 (dt, J = 7.3, 1.5 Hz, 2H), 6.35 (d, J = 7.8 Hz, 2H). 19F NMR (376 MHz, CDCl3, rt, δ/ppm): −137.7–(−137.8) (m, 2F), −138.0–(−138.1) (m, 2F), −140.4–(−140.5) (m, 2F), −143.6–(−143.7) (m, 2F). HRMS (DART) m/z: ([M + H]+) Calcd for C32H14F8NS+ 596.0714; Found 596.0715.

4. Conclusions

In conclusion, we demonstrated a controllable SNAr reaction of polyfluoroaenes with phenothiazine for the transition-metal-free synthesis of PTH derivatives. The combination of K3PO4 as the base and MeCN as the solvent was found to be widely applicable for the regioselective monosubstitution of highly reactive polyfluoroarenes, whereas the combination of K2CO3 and DMF resulted in multisubstitution. Various functional groups, including cyano, nitro, ester, and chlorine atoms, tolerated to the present conditions, thus enabling further transformations of the SNAr products. The obtained fluorine-containing PTH derivatives were employed in a sequential SNAr reaction to afford highly functionalized PTH derivatives. Further investigation of the optical characteristics of these compounds and their photocatalytic capabilities is currently underway.

Author Contributions

K.K. (Kotaro Kikushima) and T.D. conceived and designed the experiments and directed the project; K.K. (Kotaro Kikushima), H.K., and K.K. (Kazuki Kodama) performed the experiments; K.K. (Kotaro Kikushima), H.K. and T.D. analyzed the data and checked the experimental details; K.K. (Kotaro Kikushima) and T.D. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially supported by JSPS KAKENHI Grant Number 18H02014 (KoKi), and 19K05466 (T.D.). T.D. also acknowledges support from the Ritsumeikan Global Innovation Research Organization (R-GIRO) project.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in Materials and Methods.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 26 01365 sch001 550
Scheme 1. Access to PTH derivatives under various conditions.
Scheme 1. Access to PTH derivatives under various conditions.
Molecules 26 01365 sch001
Molecules 26 01365 sch002 550
Scheme 2. Synthesis of highly functionalized PTH derivatives via sequential SNAr reactions.
Scheme 2. Synthesis of highly functionalized PTH derivatives via sequential SNAr reactions.
Molecules 26 01365 sch002
Molecules 26 01365 sch003 550
Scheme 3. SNAr reaction of octafluorotoluene with phenothiazine derivatives or phenoxazine.
Scheme 3. SNAr reaction of octafluorotoluene with phenothiazine derivatives or phenoxazine.
Molecules 26 01365 sch003
Molecules 26 01365 sch004 550
Scheme 4. Reaction of pentafluorobenzonitrile with phenothiazine using the K2CO3/DMF system.
Scheme 4. Reaction of pentafluorobenzonitrile with phenothiazine using the K2CO3/DMF system.
Molecules 26 01365 sch004
Molecules 26 01365 sch005 550
Scheme 5. SNAr reaction of phenothiazine with various polyfluoroarenes.
Scheme 5. SNAr reaction of phenothiazine with various polyfluoroarenes.
Molecules 26 01365 sch005
Molecules 26 01365 sch006 550
Scheme 6. Synthesis of highly functionalized PTH derivatives via SNAr.
Scheme 6. Synthesis of highly functionalized PTH derivatives via SNAr.
Molecules 26 01365 sch006
Table
Table 1. Optimization of reaction conditions using pentafluorobenzonitrile a.
Table 1. Optimization of reaction conditions using pentafluorobenzonitrile a.
Molecules 26 01365 i001
EntryBaseSolventTemperature3ab Yield
1Li2CO3DMF60 °C0% b
2Na2CO3DMF60 °C7% b
3Cs2CO3DMF60 °C13% b,c
4Li3PO4DMF60 °C1% b
5Na3PO4DMF60 °C13% b
6K3PO4DMF60 °C48% d
7Na3PO4DMF80 °C32% d
8K3PO4DMF80 °C38% d
9K3PO4MeCN60 °C76% d
10K3PO4DMA60 °C43% d
11K3PO4DMSO60 °C38% d
12K3PO4CHCl360 °C0%
13K3PO4THF60 °C0%
14K3PO41,4-dioxane60 °C0%
a Reaction conditions: Phenothiazine 1a (0.50 mmol), pentafluorobenzonitrile 2b (1.0 mmol), and base (2.0 mmol) in solvent (5.0 mL, 0.1 M). b Determined by 19F-NMR using 4-fluorotoluene as an internal standard. c With multi-substitution products d Isolated yield.
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Kikushima, K.; Koyama, H.; Kodama, K.; Dohi, T. Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives. Molecules 2021, 26, 1365. https://doi.org/10.3390/molecules26051365

AMA Style

Kikushima K, Koyama H, Kodama K, Dohi T. Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives. Molecules. 2021; 26(5):1365. https://doi.org/10.3390/molecules26051365

Chicago/Turabian Style

Kikushima, Kotaro, Haruka Koyama, Kazuki Kodama, and Toshifumi Dohi. 2021. "Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives" Molecules 26, no. 5: 1365. https://doi.org/10.3390/molecules26051365

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