Synthesis of Fluorinated Benzophenones, Xanthones, Acridones, and Thioxanthones by Iterative Nucleophilic Aromatic Substitution

Abstract

Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic properties. To facilitate access to fluorinated fluorophores, bis(2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential nucleophilic aromatic substitution reactions, first at one or both of the more reactive 4, 4′ fluorines, and second by cyclization through substitution of the less reactive 2, 2′ fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones, and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach should allow access to a wide variety of novel fluorinated fluorophores and related compounds.

INTRODUCTION

Substitution of hydrogen with fluorine is extensively employed in medicinal chemistry to alter the binding of small molecules to biological targets and modulate metabolic reactivity.^1,2 Fluorination can also alter the photophysical properties of compounds.^3,4 Fluorination of fluorescein (1, Figure 1) at the 2′- and 7′-positions yields Oregon Green (2),⁵ a bright fluorophore with decreased phenol pKa (4.8 for 2 versus 6.3–6.8⁶ for 1), improving fluorescence in acidic aqueous environments, and enhancing photostability. Although a limited number of fluorinated fluorophores have been reported, modification of other dyes^7,8 including Tokyo Green⁹ (3) to yield Pennsylvania Green (4),^10,11 and tetramethylrhodamine (5) to yield fluorinated rhodamines (e.g. 6)¹² can confer beneficial photophysical properties. However, the synthesis and isolation of single isomers of fluorinated fluorophores such as 5-carboxy-Oregon Green⁵ is challenging and costly using existing methods.

Figure 1.

Structures of fluorinated fluorophores and related compounds.

To facilitate access to fluorinated fluorophores, we sought to develop a practical method to synthesize diverse fluorinated xanthone (7), acridone (8), and thioxanthone (9) precursors. Many of these compounds are biologically active,^13–25 some are highly fluorescent,²⁶ and the addition of Grignard reagents to protected xanthones has been used to prepare 4-carboxy-Tokyo Green,⁹ a fluorescent reporter of kinase activity,²⁷ 4-carboxy-Penn Green,¹⁰ Tokyo Magenta,²⁸ and other rhodamine and fluorescein analogues.^29–32 Methods for synthesis of derivatives of 7–9 have advanced over the past decade,^13,33–41 but only a few reports^27,42–44 describe derivatives with fluorine at the 2 and 7 positions and nitrogen or oxygen at carbons 3 and 6. Because existing syntheses of fluorinated xanthones and similar compounds are lengthy and low yielding, relatively little is known about their cognate photophysical and biological properties.

RESULTS AND DISCUSSION

As shown in Scheme 1, we postulated that repeated S_NAr reactions of the novel benzophenone 10 might allow access to other fluorinated benzophenones (11–12), as well as xanthones, acridones, and thioxanthones (13), as precursors to more highly conjugated fluorophores (14).⁴⁵ The high selectivity observed for the sequential addition of multiple nucleophiles to cyanuric chloride⁴⁶ and pentafluoropyridine⁴⁷ through a similar mechanism offers precedent for this strategy. To evaluate this hypothesis, we synthesized 10 in a two-pot process involving magnesium-halogen exchange of inexpensive 1-bromo-2,4,5-trifluorobenzene (15) followed by addition to 2,4,5-trifluorobenzaldehyde (16) to generate the alcohol (17) in nearly quantitative yield (Scheme 2). Oxidation with TEMPO free radical and sodium hypochlorite⁴⁸ produced benzophenone 10 in excellent overall yield. These reactions were scalable, and multiple grams of 10 could be produced in a single run.

Scheme 1.

A general synthesis of fluorinated benzophenones, xanthones, acridones, thioxanthones, and derivatives involving iterative addition of nucleophiles (Nu:) to bis(2,4,5-trifluorophenyl)methanone (10).

Scheme 2.

Synthesis of bis(2,4,5-trifluorophenyl)methanone (10).

Using the strategy outlined in Scheme 1, novel fluorinated benzophenone derivatives (18–29, shown in Figure 2) were prepared from 10 with a variety of oxygen and nitrogen-derived nucleophiles in good to excellent yields. As summarized in Table 1, heating of 10 in aqueous KOH/DMSO at 80 °C efficiently substituted both fluorines at the 4, 4′-positions with hydroxyl groups to afford 18 (Table 1, entry 1). Sodium methoxide added to 10 at room temperature in nearly quantitative yield to produce 19 (entry 2).

Figure 2.

Structures of fluorinated benzophenones and xanthones derived from 10.

Table 1.

Reagents and conditions for synthesis of benzophenones 18–29 and xanthones 30–39.

Entry	Nucleophile	Solvent	Temp (°C)	Time (h)	Yield (%)	Product (reactant)
1	KOH	DMSO/H2O	80	12	92	18 (10)
2	NaOMe	MeOH	26	12	99	19 (10)
3	NH4OH	DMSO/H2O	110c	12	93	20 (10)
4	NH4OH	DMSO/H2O	35	12	75	21 (10)
5	DMF/KOHa	H2O	60	12	78	22 (10)
6	HNEt2	—b	90c	12	85	23 (10)
7	HNEt2	—b	26	12	70	24 (10)
8	H2NiPr	—b	60c	3	93	25 (10)
9	H2NtBu	—b	46	12	82	26 (10)
10	Piperidine	THF	26	12	91	27 (10)
11	Piperidine	THF	26	3	76	28 (10)
12	Morpholine	THF	26	12	81	29 (10)
13	KOH	H2O	200c	3	99	30 (10)
14	KOH	H2O	110	48	99	30 (10)
15	KOH	DMSO/H2O	150c	12	80	31 (21)
16	KOH	DMSO/H2O	150c	12	85	32 (22)
17	KOH	DMSO/H2O	170c	12	85	33 (23)
18	KOH	DMSO/H2O	150c	12	95	34 (24)
19	KOH	DMSO/H2O	150c	16	92	35 (25)
20	KOH	DMSO/H2O	150c	12	90	36 (26)
21	KOH	DMSO/H2O	170c	12	92	37 (27)
22	KOH	DMSO/H2O	150c	12	95	38 (28)
23	KOH	DMSO/H2O	170c	12	83	39 (29)

^aDimethylamine derives from decomposition of DMF.

^bReaction was performed neat.

^cReaction performed in a sealed tube.

A wide variety of primary and secondary amines generated similar S_NAr adducts in good to excellent yields (Table 1, entries 3 – 12). Piperidine and morpholine exhibited particularly high reactivity towards 10, and dilution was necessary to prevent formation of tri- and tetrasubstituted products. As listed in Table 1, either monosubstituted or disubstituted fluorinated benzophenones derived from ammonia, diethylamine and piperidine (Table 1, entries 3, 4, 6, 7–10, 11) were obtained in >70% yield by adjusting reaction concentrations and temperatures, offering additional opportunities for structural diversification.

Symmetrical and asymmetrical xanthones (30–39) were readily accessed by addition of hydroxide to fluorinated benzophenones using the conditions listed in Table 1. Although previous routes^10,27 to 30, a valuable precursor for preparation of fluorophores such as Pennsylvania Green, required five to eight steps and achieved only modest overall yields, heating benzophenone 10 with aqueous NaOH either in a sealed tube at 200 °C for 3 h or at reflux for 48 h provided 30 in nearly quantitative yield (Table 1, entries 13 and 14). This latter method was scalable, and multiple grams of 30 could be prepared. Aminobenzophenones (20–29) were cleanly converted to symmetric and asymetric xanthones via hydroxide-mediated S_NAr reactions with DMSO as a cosolvent (Table 1, entries 15–23).

Cyclization with amine nucleophiles converted fluorinated benzophenones to fluorinated acridones (40–48, Figure 3). The conditions for synthesis of 40–48 are summarized in Table 2. Heating of 10 in DMF containing KOH provided N, N-dimethylacridone 41 in 93% yield (Table 2, entry 2). Decomposition of DMF was responsible for generation of the dimethylamine nucleophile. Using the same reaction conditions, acridones 42–45 were synthesized from benzophenones 25, 21, 27, and 28 in > 90% yield. Dimethoxyacridones 46, 47, and 48, produced by heating 19 with the corresponding amines, required subsequent treatment with NaH, or heating in higher-boiling dimethylacetamide, for completion. Attempts to demethylate 46–48 to generate 49–51 with NaSEt or Na₂S cleaved only one of the two methyl groups at 130 °C. Further heating (170 °C) also cleaved the N-linked alkyl group of 46 and 47. However, reflux with BBr₃ in 1,2-dichloroethane provided 49–51 in high yield (Table 2).

Figure 3.

Structures of fluorinated acridone and thioxanthone products.

Table 2.

Reagents and conditions for synthesis of acridones 40–51 and thioxanthones 52–59.

Entry	Nucleophile	Solvent	Temp (°C)	Time (h)	Yield (%)	Product (reactant)
1	H2NiPr	—b	100c	12	45	40 (10)
2	DMF/KOHa	DMF/H2O	150c	6	93	41 (10)
3	DMF/KOHa	DMF/H2O	80	12	95	42 (25)
4	DMF/KOHa	DMF/H2O	150c	12	93	43 (21)
5	DMF/KOHa	DMF/H2O	150c	4	96	44 (27)
6	DMF/KOHa	DMF/H2O	150c	12	91	45 (28)
7	H2NiPr	—b	100c	12	83	46 (19)
8	H2NBn	—b	100	12	86	47 (19)
9	H2NPh	—b	130	12	72	48 (19)
10	—e	Cl(CH2)2Cl	reflux	12	83	49 (46)
11	—e	Cl(CH2)2Cl	reflux	12	91	50 (47)
12	—e	Cl(CH2)2Cl	reflux	12	79	51 (48)
13	Na2S	DMA	26	12	92	52 (19)
14	Na2S	DMA	90	12	74	53 (19)
15	Na2S	DMA	70	12	91	54 (22)
16	Na2S	DMA	70	12	90	55 (23)
17	Na2S	DMA	70	12	85	56 (25)
18	Na2S	DMA	70	12	89	57 (26)
19	Na2S	DMA	70	12	85	58 (27)
20	Na2S	DMA	70	12	94	59 (29)

^aDimethylamine derives from decomposition of DMF.

^bReaction was performed neat.

^cReaction performed in a sealed tube.

^eBBr₃ was employed for demethylation.

To the best of our knowledge, 2,7-difluorinated thioxanthones have not been previously reported. To access these compounds, Na₂S was employed to synthesize 52–59 (Figure 3) as summarized in Table 2. By controlling the temperature and concentration of Na₂S, dimethoxybenzophenone 19 was converted into either 52 or 53 (Table 2, entries 13 and 14). Additionally, diaminobenzophenones 22, 23, 25, 26, 27, and 29 reacted with Na₂S at 70 °C in greater than 85% yield (Table 2, entries 15–20).

Absorbance (18–59) and fluorescence emission spectra (30–59) were acquired on selected compounds. Values for λ_max, molar extinction coefficient (Σ), determined for compounds with quantum yield (Φ) > 0.2, and Φ relative to diphenylanthracene (Φ = 0.95 in EtOH) and anthracene (Φ = 0.27 in EtOH) are listed in Table 3. Absorbance and emission spectra of 30–59 are provided in the Supporting Information. Among these compounds, substituents modulated absorbance by up to 77 nm and emission by up to 71 nm, with Stokes shifts of >100 nm in some cases. The ability to readily access multigram quantities of these precursors via iterative S_NAr should have broad utility for the synthesis of diverse fluorinated fluorophores and related molecular probes.

Table 3.

Spectral properties of compounds in ethanol (18–51 and 53–59) or DMSO (52). Values not determined are indicated by –.

Compd	Abs. λmax (nm)	ε (M−1 cm−1)	Fluor. λmax(nm)	Φ
18	306	–	–	–
19	301	–	–	–
20	340	–	–	–
21	335	–	–	–
22	358	–	–	–
23	369	–	–	–
24	361	–	–	–
25	357	–	–	–
26	348	–	–	–
27	354	–	–	–
28	350	–	–	–
29	342	–	–	–
30	369	13300 @ 369 nm	439	0.26
31	366	39200 @ 366 nm	425	0.44
32	378	–	446	< 0.1
33	389	–	452	< 0.1
34	379	–	438	< 0.1
35	370	36200 @ 370 nm	422	0.41
36	368	48600 @ 368 nm	418	0.31
37	369	–	457	< 0.1
38	373	15300 @ 373 nm	445	0.23
39	344	–	448	< 0.1
40	376	36800 @ 376 nm	423	0.32
41	384	–	441	< 0.1
42	377	56700 @ 377 nm	421	0.31
43	369	–	432	< 0.1
44	368	–	455	< 0.1
45	364	–	443	< 0.1
46	383	–	425	< 0.1
47	381	–	416	< 0.1
48	378	–	424	< 0.1
49	379	–	438	< 0.1
50	381	–	431	< 0.1
51	377	–	454	< 0.1
52	316	–	416	< 0.1
53	377	–	465	< 0.1
54	382	–	477	< 0.1
55	393	–	475	< 0.1
56	377	–	446	< 0.1
57	373	–	432	< 0.1
58	377	–	487	< 0.1
59	361	–	481	< 0.1

EXPERIMENTAL SECTION

Optical spectroscopy

Quantum yields (Φ) of the highly emissive compounds 30, 31, 35, 36, 38, 40, 42 in ethanol were quantified by the method of Williams.⁴⁹ Quantum yields for other compounds were determined to be < 0.1 by comparison. Diphenylanthracene (Φ = 0.95 in ethanol⁵⁰) and anthracene (Φ = 0.27 in ethanol⁵¹) were used as standards, and data from these measurements is provided in the Supporting Information. Molar extinction coefficients (ε) of 30, 31, 35, 36, 38, 40, 42 in ethanol were determined by linear least squares fitting of Beer’s Law plots of absorbance versus concentration, and data from these measurements is provided in the Supporting Information.

Synthesis

In addition to specific methods described below, general procedures A–F were used to access structurally related compounds.

General Procedure A

A mixture of bis(2,4,5-trifluorophenyl)methanone (10, 2.00 g, 6.9 mmol) and the corresponding amine (73.3 mmol) was heated in a sealed tube. The reaction mixture was cooled and volatiles were removed in vacuo. If impurities were evident, compounds were purified by column chromatography (5% EtOAc in hexanes) to provide viscous oils that typically crystallized when washed with hexanes.

General Procedure B

A mixture of bis(2,4,5-trifluorophenyl)methanone (10, 1.00 g, 3.45 mmol), the corresponding amine (10.1 mmol), and THF (10.0 mL) were stirred for 12 h at 26 °C. The reaction mixture was concentrated in vacuo. If impurities were evident, compounds were purified by column chromatography (5% EtOAc in hexanes) to give viscous oils that typically crystallized upon standing.

General Procedure C

A mixture of the corresponding diaminoxanthone (21 – 29, 1.0 mmol), aqueous KOH (10 M, 1.5 mL, 15.0 mmol), and DMSO (1.5 mL) were heated in a sealed tube. After the time indicated, the reaction mixtures were cooled and transferred to ice water (150 mL). The resulting precipitate was collected by vacuum filtration and washed with water (3 × 100 mL). If impurities were evident, products were purified by washing with an organic solvent or by column chromatography.

General Procedure D

The corresponding benzophenone (10, 21, 25, 27, or 28, 1.0 mmol) was dissolved in a solution of DMF (2.0 mL, 25.9 mmol) and aqueous KOH (10 M, 2.0 mL, 20.0 mmol). This mixture was heated in a sealed tube and at 150 °C for the time indicated, cooled, and transferred to ice water (100 mL). The resulting precipitate was filtered, washed with water (3 × 50 mL) and washed with either diethyl ether or acetone to afford the product.

General Procedure E

The corresponding dimethoxyacridone (46 – 48, 0.10 mmol) was dissolved in 1,2-dichloroethane (4.0 mL) and treated with BBr₃ in CH₂Cl₂ (0.57 mL of a 0.7 M solution, 0.40 mmol). The reaction mixture was heated to reflux for 12 h, cooled to room temperature, and quenched with methanol (1.00 mL). The product was concentrated and purified by column chromatography (0% to 3 % MeOH in CH₂Cl₂).

General Procedure F

A solution of diaminoxanthone (19, 22, 23, 25 – 27, 29, 1.0 mmol) in DMA (5.0 mL), was vigorously purged with Ar for 30 min followed by treatment with finely ground Na₂S (0.375 g, 5.0 mmol). The resulting yellow-orange slurry was heated to 70 °C for 12 h with stirring. The hot reaction mixture was poured into ice-cold water (150 mL), and the precipitate was collected by vacuum filtration. The crude yellow solid was air dried and further purified by column chromatography or by washing with an organic solvent to give the corresponding thioxanthone.

Bis(2,4,5-trifluorophenyl)methanone (10)

To a solution of 17 (400 mg, 1.37 mmol) in CH₂Cl₂ (12 mL) was added KBr (33.2 mg, 0.28 mmol), TEMPO (11.0 mg, 0.07 mmol, 5 mol%), and saturated aqueous NaHCO₃. The biphasic mixture was vigorously stirred and aqueous NaOCl (6.0 mL, 0.7 M) was added. The resulting bright orange mixture was stirred for 3 h, and the orange color dissipated. The colorless biphasic layers were separated, the aqueous layer was extracted with CH₂Cl₂ (2 × 12 mL), and the combined organic fractions were dried over anhydrous Na₂SO₄ and concentrated to give a crude yellow solid. The solid was purified elution through a plug of silica gel (10% EtOAc in hexanes). The filtrate was concentrated to yield 10 as a colorless solid (370 mg, 92%). mp 80–81 °C; ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (qd, J = 8.8, 6.4 Hz, 2H), 6.95 (qd, J = 9.2, 6.4 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 184.7 (s), 156.8 (dd, J = 254.7, 9.8 Hz), 153.3 (ddd, J = 260.0, 14.5, 12.2 Hz), 147.1 (ddd, J = 248.1, 12.7, 3.1 Hz), 123.2 (d, J = 14.9 Hz), 118.8 (d, J = 20.1 Hz), 111.6 – 98.1 (m); IR (thin film) 3073, 1667, 1623, 1509, 1437, 1420, 1333, 1293, 1208, 1138, 889 cm⁻¹; HRMS (ESI) m/z 291.0263 (M+H⁺, C₁₃H₅F₆O requires 291.0245).

Bis(2,4,5-trifluoro-phenyl)methanol (17)

To a solution of 1-bromo-2,4,5-trifluorobenzene (2.34 mL, 20.0 mmol) in THF (30 mL) at −78 °C was added i-PrMgCl (1.3 M in Et₂O, 16.1 mL, 21.0 mmol), dropwise. The resulting pale yellow solution was stirred at −78 °C for 10 min, was warmed to 4 °C, and was maintained at 4 °C for 1 h. This solution was cooled again to −78 °C and treated with 2,4,5-trifluorobenzaldehyde (2.55 mL, 22.0 mmol). This mixture was allowed to slowly warm to ambient temperature (23 °C). After stirring at room temperature for 3 h, the reaction mixture was slowly quenched with saturated aqueous NH₄Cl solution (20 mL). The resulting phases were separated, the aqueous fraction was extracted with Et₂O (2 × 30 mL), the combined organic phases were dried over anhydrous Na₂SO₄, and the solution was concentrated to give a crude oil that was purified by flash chromatography (5% EtOAc in hexanes) to provide pure 17 (5.74 g, 99%). mp 81 – 83 °C ¹H NMR (CDCl₃, 400 MHz) δ 7.27 (qd, J = 10.0, 6.4 Hz, 2H), 6.95 (qd, J = 9.2, 6.4 Hz, 2H), 6.29 (d, J = 3.2 Hz, 1H), 2.46 (d, J = 3.2Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 154.6 (ddd, J = 246.9, 9.3, 2.8 Hz), 151.5 – 148.5 (m), 148.4 – 145.2 (m), 125.4 (d, J = 15.7 Hz), 116.5 – 114.1 (m), 105.8 (dd, J = 27.4, 21.1 Hz), 62.8 (s); IR (thin film) 3364, 1631, 1513, 1430, 1337, 1200, 1147, 1096 cm⁻¹; HRMS (ESI) m/z 291.0263 (M-H, C₁₃H₅F₆O requires 291.0245).

Bis(2,5-difluoro-4-hydroxyphenyl)methanone (18)

A mixture of 10 (3.0 g, 10.3 mmol), aqueous KOH (10 M, 10 mL, 100 mmol), and DMSO (10 mL) was heated to 80 °C for 12 h. This solution was transferred to a mixture of concentrated aqueous HCl (15 mL) and ice (200 g) to generate a fine precipitate that was collected by vacuum filtration. This colorless precipitate was washed with cold water (3 × 100 mL) and dried overnight (16 h) under high vacuum to provide pure 18 (2.71 g, 92%). mp 170–171 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (brs, 2H), 7.45 (dd, J = 10.8, 7.0 Hz, 2H), 6.83 (dd, J = 11.6, 7.0 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 184.7 (s), 157.1 (d, J = 249.8 Hz), 150.6 (t, J = 13.5 Hz), 147.4 (d, J = 239.6 Hz), 117.4 (dd, J = 15.1, 4.9 Hz), 117.2 (dd, J = 21.5, 3.9 Hz), 104.9 (dd, J = 27.3, 3.0 Hz); IR (film) 3162, 3071, 2964, 1621, 1514, 1303, 1199, 1143, 789 cm⁻¹; HRMS (ESI) m/z 285.0161 (M-H, C₁₃H₅F₄O₃ requires 285.0175).

Bis(2,5-difluoro-4-methoxyphenyl)methanone (19)

A mixture of 10 (2.00 g, 6.8 mmol) and methanol (28 mL) was treated with NaOMe in methanol (5.4 M, 5.50 mL, 29.6 mmol), dropwise. This mixture was stirred for 12 h, and water (300 mL) was added. A colorless precipitate was collected by vacuum filtration, washed with water (2 × 150 mL), and dried under high vacuum to provide of pure 19 (2.11 g, 99%). mp 158–160 °C; ¹H NMR (400 MHz, 10% CD₃OD in CDCl₃) δ 7.47 (dd, J = 10.8, 7.0 Hz, 2H), 6.70 (dd, J = 11.2, 7.0 Hz, 2H); ¹³C NMR (126 MHz, 10% CD₃OD in CDCl₃) δ 185.5 (s), 157.9 (d, J = 252.5 Hz), 152.3 (dd, J = 12.8, 10.6 Hz), 148.4 (dd, J = 244.5, 2.2 Hz), 120.4 – 118.0 (m), 117.1 (dd, J = 21.4, 3.7 Hz), 103.6 – 99.7 (m), 56.6 (s); IR (film) 3066, 2951, 1663, 1621, 1513, 1346, 1145, 794 cm⁻¹; HRMS (ESI) m/z 337.0474 (M+Na⁺, C₁₅H₁₀F₄O₃Na requires 337.0464).

Bis(4-amino-2,5-difluorophenyl)methanone (20)

Bis(2,4,5-trifluorophenyl)methanone (10, 3.00 g, 10.3 mmol) was dissolved in DMSO (10.0 mL) and treated with concentrated aqueous NH₄OH (10.0 mL, 145 mmol). This mixture was stirred at 110 °C for 12 h (sealed tube), followed by addition to ice water (400 mL). A yellow precipitate was collected by vacuum filtration, washed with water (3 × 150 mL), and dried under high vacuum for 12 h to provide pure 20 (2.73 g 93%). mp 180–182 °C; ¹H NMR (400 MHz, 10% CD₃OD in CDCl₃) δ 7.22 (dd, J = 11.2, 7.0 Hz, 2H), 6.37 (dd, J = 11.2, 7.0 Hz, 2H); ¹³C NMR (10% CD₃OD in CDCl₃) δ 187.7 (s), 160.1 (d, J = 250.1 Hz), 148.2 (d, J = 236.3 Hz), 142.6 (dd, J = 15.2, 12.7 Hz), 118.0 (dd, J = 21.0, 3.7 Hz), 117.2 (d, J = 13.7 Hz), 104.9 – 101.4 (m); IR (film) 3343, 3087, 1627, 1599, 1523, 1459, 1362, 1314, 1371, 750 cm⁻¹; HRMS (ESI) m/z 307.0450 (M+Na⁺, C₁₃H₈F₄N₂ONa requires 307.0470).

(4-amino-2,5-difluorophenyl)-(2,4,5-trifluorophenyl)methanone (21)

Bis(2,4,5-trifluorophenyl)methanone (10, 1.00 g, 3.43 mmol) in DMSO (2.50 mL) was treated with concentrated aqueous NH₄OH (2.50 mL, 36.3 mmol). This mixture was stirred at 35 °C for 12 h, diluted with ice-cold water (100 mL), and extracted with EtOAc (3 × 50 mL). The combined organic fractions were dried over anhydrous Na₂SO₄ and concentrated in vacuo to give a crude yellow oil that was purified by column chromatography (10% to 20% EtOAc in hexanes) to provide pure 21 (0.738 g, 75%). mp 134–136 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.60 (m, 2H), 7.00 (ddd, J = 15.6, 6.0, 3.6 Hz, 1H), 6.43 (dd, J = 11.6, 6.8 Hz, 2H), 4.45 (s, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 184.9 (s), 159.4 (d, J = 252.3 Hz), 155.9 (ddt, J = 252.5, 9.9, 2.5 Hz), 152.2 (ddd, J = 257.0, 14.5, 12.2 Hz), 147.0 (d, J = 239.1 Hz), 148.1 – 145.5 (m), 141.7 (dd, J = 15.2, 12.9 Hz), 127.4 – 123.0 (m), 119.7 – 117.0 (m), 116.8 (dd, J = 21.5, 4.0 Hz), 115.1 (dd, J = 13.4, 5.5 Hz), 106.1 (dd, J = 28.3, 21.1 Hz), 102.2 (dd, J = 28.8, 3.5 Hz); IR (film) 3489, 3343, 3218, 1661, 1593, 1511, 1456, 1425, 1331, 1249, 1144, 900, 787 cm⁻¹; HRMS (ESI) m/z 286.0276 (M-H, C₁₃H₅F₅NO requires 286.0291).

Bis(4-(dimethylamino)-2,5-difluorophenyl)methanone (22)

Bis(2,4,5-trifluorophenyl)methanone (10, 291 mg, 1.00 mmol) was dissolved in DMF (2.00 mL, 25.9 mmol), treated with aqueous KOH (10 M, 2.00 mL, 20.0 mmol), and stirred at 60 °C for 12 h. This mixture was cooled to room temperature (23 °C), transferred to ice water (50 mL), extracted with EtOAc (3 × 20 mL), and the combined organic fractions were washed with water (2 × 30 mL). The organic layer was dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified by flash chromatography (5% to 10% EtOAc in hexanes) to provide pure 22 (265 mg, 78%) as a yellow solid. mp 120–121 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J = 14.1, 7.0 Hz, 2H), 6.39 (dd, J = 12.8, 7.0 Hz, 2H), 3.01 (s, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 185.2 (s), 158.2 (d, J = 249.8 Hz), 148.9 (d, J = 240.7 Hz), 144.7 (s), 120.4 – 116.9 (m), 117.1 – 115.6 (m), 106.9 – 99.3 (m), 42.1 (d, J = 6.1 Hz); IR (film) 2954, 2807, 1619, 1526, 1446, 1359, 1121, 782 cm⁻¹; HRMS (ESI) m/z 341.1259 (M+H⁺, C₁₇H₁₇F₄N₂O requires 341.1277).

Bis(4-(diethylamino)-2,5-difluorophenyl)methanone (23)

Using General Procedure A at 90 °C for 12 h, bis(2,4,5-trifluorophenyl)methanone 10 (1.00 g, 3.45 mmol), and diethylamine (7.0 mL, 71.0 mmol) afforded 23 (1.07 g, 85%). mp 60–62 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J = 12.4, 5.6 Hz, 2H), 6.54 (dd, J = 12.8, 5.6 Hz, 2H), 4.50 (d, J = 3.6 Hz, 2H), 1.46 (s, 18H); ¹³C NMR (126 MHz, CDCl₃) δ 184.9 (s), 158.4 (d, J = 249.6 Hz), 148.3 (d, J = 239.2 Hz), 142.5 (s), 118.22 (dd, J = 25.9, 5.2 Hz), 116.4 – 115.5 (m), 102.7 (d, J = 28.7 Hz), 46.0 (d, J = 5.7 Hz), 13.6 – 12.5 (m); IR (film) 2976, 2934, 1618, 1523, 1443, 1394, 1356, 1279, 1234, 1192, 1077, 779 cm⁻¹; HRMS (ESI) m/z 397.1877 (M+H⁺, C₂₁H₂₅F₄N₂O requires 397.1903).

(4-(diethylamino)-2,5-difluorophenyl)-(2,4,5-trifluorophenyl)methanone (24)

Using General Procedure A at 26 °C for 12 h, bis(2,4,5-trifluorophenyl)methanone (10, 2.60 g, 6.90 mmol), and diethylamine (1.02 mL, 10.3 mmol), afforded 24 (1.65 g, 70%) after column chromatography (5% to 10% EtOAc in hexanes). mp 74–78 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.50 (m, 2H), 6.96 (ddd, J = 15.7, 6.2, 3.4 Hz, 1H), 6.32 (dd, J = 14.1, 7.2 Hz, 2H), 3.41 (q, J = 6.2 Hz, 2H), 1.23 (t, J = 6.2 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 184.3 (s), 162.6 – 156.0 (m), 155.6 (ddt, J = 252.5, 9.9, 2.5 Hz), 149.4 – 146.1 (m), 147.9 – 145.2 (m),146.6 (d, J = 239.1 Hz), 141.4 (dd, J = 15.2, 12.9 Hz), 127.2 – 122.7 (m), 118.4 (d, J = 4.5 Hz), 116.4 (dd, J = 21.5, 4.0 Hz), 114.9 (dd, J = 13.4, 5.5 Hz), 105.9 (dd, J = 28.4, 21.1 Hz), 103.0 – 99.5 (m), 46.3 (d, J = 6.3 Hz), 13.1 (d, J = 1.8 Hz); IR (film) 3067, 2980, 2938, 1650, 1607, 1528, 1511, 1424, 1392, 1329, 1280, 1131, 1076, 887, 791 cm⁻¹; HRMS (ESI) m/z 366.0889 (M+Na⁺, C₁₇H₁₄F₅NONa requires 366.0893).

Bis(2,5-difluoro-4-(isopropylamino)phenyl)methanone (25)

Using General Procedure A, 10 (2.0 g), isopropylamine (6.00 mL, 73.3 mmol), and heating in a sealed tube at 60 °C for 3 h, provided pure 25 (2.32 g, 92%). mp 91– 92 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J = 12.0, 5.2 Hz, 2H), 6.30 (dd, J = 12.4, 5.6 Hz, 2H), 4.32 (d, J = 5.2 Hz, 2H), 3.66 (hept, J = 6.8 Hz, 2H), 1.30 (s, J = 6.4 Hz, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 185.4 (s), 159.2 (d, J = 249.5 Hz), 146.7 (d, J = 235.7 Hz), 140.9 (dd, J = 14.0, 12.2 Hz), 115.7 (dd, J = 21.7, 4.8 Hz), 114.8 – 113.2 (m), 98.4 – 96.9 (m), 44.2 (s), 22.6 (s); IR (film) 3433, 3366, 2972, 2934, 1625, 1607, 1534, 1456, 1368, 1280, 1156, 907, 727 cm⁻¹; HRMS (ESI) m/z 391.1402 (M+Na⁺, C₁₉H₂₀F₄N₂ONa requires 391.1409).

Bis(4-(tert-butylamino)-2,5-difluorophenyl)methanone (26)

Using General Procedure A, 10 (500 mg, 1.72 mmol), t-butylamine (7.00 mL, 71.0 mmol), and heating at 46 °C for 12 h, afforded 26 (560 mg, 82%). mp 135–137 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J = 12.4, 5.6 Hz, 2H), 6.54 (dd, J = 12.8, 5.6 Hz, 2H), 4.50 (d, J = 3.6 Hz, 2H), 1.46 (s, 18H); ¹³C NMR (126 MHz, CDCl₃) δ 184.3 (s), 157.5 (d, J = 249.0 Hz), 146.2 (d, J = 235.6 Hz), 139.2 (s), 114.2 (d, J = 4.5 Hz), 113.4 – 112.4 (m), 99.5 – 97.6 (m), 50.3 (s), 28.3 (s); IR (film) 3436, 2979, 1626, 1534, 1462, 1371, 1288, 1211, 796 cm⁻¹; HRMS (ESI) m/z 397.1877 (M+H⁺, C₂₁H₂₅F₄N₂O requires 397.1903).

Bis(2,5-difluoro-4-(piperidin-1-yl)phenyl)methanone (27)

Using General Procedure B, 10 (1.00 g, 3.45 mmol), piperidine (1.0 mL, 10.1 mmol), and THF (6.00 mL), and a reaction time of 12 h, afforded 27 (1.28 g, 91%). mp 141–143 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (dd, J = 13.3, 6.4 Hz, 2H), 6.53 (dd, J = 12.4, 5.5 Hz, 2H), 3.17 (t, J = 5.2 Hz, 8H), 1.72 (p, J = 5.7 Hz, 8H), 1.61 (p, J = 5.4 Hz, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 185.6 (s), 158.0 (d, J = 251.1 Hz), 150.4 (dd, J = 242.6, 1.6 Hz), 145.7 (s), 119.5 – 117.9 (m), 118.3 – 116.5 (m), 105.1 (s), 51.0 (d, J = 5.0 Hz), 25.8 (s), 24.1 (s); IR (film) 2937, 2854, 2821, 1614, 1508, 1437, 1385, 1255, 1164, 1123, 782 cm⁻¹; HRMS (ESI) m/z 421.1877 (M+H⁺, C₂₃H₂₅F₄N₂O requires 421.1903).

(2,5-difluoro-4-(piperidin-1-yl)phenyl)(2,4,5-trifluorophenyl)methanone (28)

Using General Procedure B, 10 (640 mg, 2.20 mmol), piperidine (0.24 mL, 2.40 mmol), THF (10 mL), and a reaction time of 3 h, afforded 28 (600 mg, 76%). mp 71–73 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.52 (m, 2H), 6.96 (ddd, J = 15.7, 6.1, 3.5 Hz, 1H), 6.50 (dd, J = 13.1, 7.0 Hz, 1H), 3.24 (t, J = 5.2 Hz, 4H), 1.71 (p, J = 5.4 Hz, 8H), 1.65 (p, J = 5.2 Hz, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 184.8 (s), 159.0 (d, J = 315.0 Hz), 154.2 (dd, J = 163.8, 12.5 Hz), 150.3 (dd, J = 312.5, 12.3 Hz), 149.5 (d, J = 225.3 Hz), 146.9 (dd, J = 325.3, 9.8 Hz), 146.5 – 146.8 (m), 122.2 – 122.7 (m), 118.3 (d, J = 23.7 Hz), 117.4 (dd, J = 31.6, 5.1 Hz), 116.0 – 116.5 (m), 106.1 (dd, J = 35.5, 26.4 Hz), 104.9 (dd, J = 35.3, 5.0 Hz), 50.8 (s), 25.7 (s), 24.1 (s); IR (film) 3070, 2940, 2856, 1665, 1614, 1509, 1438, 1256, 1126, 878, 758 cm⁻¹; HRMS (ESI) m/z 356.1067 (M+H⁺, C₁₈H₁₅F₅NO requires 356.1074).

Bis(2,5-difluoro-4-morpholinophenyl)methanone (29)

Using General Procedure B, 10 (1.00 g, 3.45 mmol), morpholine (0.75 mL, 8.62 mmol), THF (8 mL), and a reaction time of 12 h, afforded 29 (1.18 g, 81%). mp 189–191 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J = 6.7, 5.6 Hz, 2H), 6.54 (dd, J = 12.0, 5.2 Hz, 2H), 3.86 (t, J = 4.6 Hz, 8H), 3.21 (t, J = 4.6 Hz, 8H); ¹³C NMR (125 MHz, CDCl3) δ 185.3 (s), 158.0 (d, J = 314.7 Hz), 150.5 (d, J = 305.0 Hz), 144.7 (d, J = 12.1 Hz), 119.2 – 119.8 (m), 117.7 (d, J = 30.6 Hz), 105.1 (d, J = 34.4 Hz), 66.6 (s), 49.9 (s); IR (film) 2960, 2916, 2861, 1620, 1509, 1267, 1170, 1115, 782 cm⁻¹; HRMS (ESI) m/z 447.1300 (M+Na⁺, C₂₁H₂₀F₄N₂O₃Na requires 447.1308).

2,7-Difluoro-3,6-dihydroxy-xanthen-9-one (30)

A mixture of 10 (4.46 g, 15.4 mmol) and aqueous KOH (10 M, 30 mL, 0.300 mol) was heated to reflux for 48 h. During this time, 10 slowly dissolved to give a bright yellow-orange solution. This hot solution was poured onto acidic ice (20 mL of 12 M HCl and 200 g of ice) and was allowed to stand for 3 h. The resulting colorless slurry was filtered via vacuum and the filtrate was washed with cool water (3 × 100 mL), ethanol (2 × 50 mL), and dried under high vacuum to yield pure colorless difluoroxanthone 30 (3.91 g, 96%). Xanthone 30 had spectral properties identical to those previously reported.²⁷

3-amino-2,7-difluoro-6-hydroxy-9H-xanthen-9-one (31)

Using General Procedure C, 21 (1.17 g, 4.07 mmol) and heating at 150 °C for 12 h, afforded 31 (726 mg, 80%). mp 247–250 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (d, J = 10.9 Hz, 1H), 7.56 (d, J = 11.3 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.55 (s, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.7 (s), 154.0 (s), 152.8 (s), 151.3 (d, J = 14.8 Hz), 149.2 (d, J = 85.9 Hz), 147.2 (d, J = 83.7 Hz), 144.1 (d, J = 15.9 Hz), 112.8 (d, J = 5.5 Hz), 110.9 (d, J = 19.9 Hz), 109.7 (d, J = 19.8 Hz), 109.0 – 108.2 (m), 104.7 (d, J = 2.5 Hz), 100.1 (d, J = 4.5 Hz); IR (film) 3369, 3221, 2986, 1614, 1481, 1288, 773 cm⁻¹; HRMS (ESI) m/z 262.0291 (M-H, C₁₃H₆F₂NO₃ requires 262.0316).

3,6-bis(dimethylamino)-2,7-difluoro-9H-xanthen-9-one (32)

Using General Procedure C, 22 (2.00 g, 5.05 mmol), and heating to 150 °C for 12 h, afforded 32 (1.61 g, 85%). mp 211–213 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J = 14.0 Hz, 2H), 6.76 (d, J = 7.6 Hz, 2H), 3.03 (s, 12H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.4 (s), 153.2 (s), 150.7 (s), 149.5 – 144.7 (m), 111.4 (d, J = 6.7 Hz), 110.8 (d, J = 23.7 Hz), 103.1 (d, J = 4.1 Hz), 41.8 (d, J = 6.0 Hz); IR (film) 3450, 2922, 2850, 2798, 1615, 15221, 1447, 1371, 1332, 1257, 1132, 777 cm⁻¹; HRMS (ESI) m/z 341.1087 (M+Na⁺, C₁₇H₁₆F₂N₂O₂Na requires 341.1078).

3,6-bis(diethylamino)-2,7-difluoro-9H-xanthen-9-one (33)

Using General Procedure C, 23 (1.50 g, 3.78 mmol), and heating at 170 °C for 12 h, afforded 33 (1.20 g, 85%). mp 108–109 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 14.4 Hz, 2H), 6.31 (d, J = 7.3 Hz, 2H), 3.42 (q, J = 7.0 Hz, 8H), 1.23 (t, J = 7.0 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 173.0 (s), 152.9 (s), 148.9 (d, J = 219.2 Hz), 142.5 (d, J = 10.5 Hz), 111.1(d, J = 24.9 Hz), 110.8 (d, J = 7.1 Hz), 101.5 (s), 45.1 (d, J = 5.9 Hz), 11.9 (d, J = 1.5 Hz); IR (film) 2976, 2934, 1615, 1519, 1457, 1274, 1246, 1071, 773 cm⁻¹; HRMS (ESI) m/z 375.1857 (M+H⁺, C₂₁H₂₅F₂N₂O₂ requires 375.1884).

3-(diethylamino)-2,7-difluoro-6-hydroxy-9H-xanthen-9-one (34)

Using General Procedure C, 24 (1.00 g, 2.92 mmol), and heating at 150 °C for 12 h, afforded 34 (884 mg, 95%). mp 299–300 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (brs, 1 H), 7.71 (d, J = 10.8 Hz, 1H), 7.59 (d, J = 12.8 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 3.43 (q, J = 6.5 Hz, 4H), 1.17 (t, J = 6.5 Hz, 6H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.6 (s), 153.6 (s), 152.9 (s), 151.6 (s), 151.5 (s), 149.9 (d, J = 84.3 Hz), 148.0 (d, J = 84.6 Hz), 143.3 (d, J = 10.1 Hz), 112.8 (d, J = 5.4 Hz), 111.8 – 110.31 (m), 110.3 (s), 104.6 (d, J = 2.6 Hz), 102.4 (s), 45.7 (d, J = 5.9 Hz), 12.8 (s); IR (film) 3069, 2975, 2733, 1618, 1578, 1475, 1398, 1275, 1213, 1080, 775 cm⁻¹; HRMS (ESI) m/z 318.0916 (M-H, C₁₇H₁₄F₂NO₃ requires 318.0942).

2,7-difluoro-3,6-bis(isopropylamino)-9H-xanthen-9-one (35)

Using General Procedure C, 25 (2.50 g, 6.79 mmol), and heating at 150 °C for 16 h, afforded 35 (2.15 g, 92%). mp 238–239 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J = 12.0 Hz, 2H), 6.64 (d, J = 7.2 Hz, 2H), 6.45 (dd, J = 2, 8.0 Hz, 2H), 3.76 (hept, J = 6.4 Hz, 2H), 1.22 (d, J = 6.4 Hz, 12H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.3 (s), 154.2 (s), 147.7 (d, J = 129.2 Hz), 142.0 (s), 141.8 (s), 110.8 – 106.0 (m), 96.9 (d, J = 3.8 Hz), 43.5 (s), 21.7 (s); IR (film) 3435, 2392, 3968, 2837, 1645, 1610, 1531, 1461, 1296, 1016 cm⁻¹; HRMS (ESI) m/z 347.1592 (M+H⁺, C₁₉H₂₁F₂N₂O₂ requires 347.1571).

3,6-bis(tert-butylamino)-2,7-difluoro-9H-xanthen-9-one (36)

Using General Procedure C, 26 (1.00 g, 2.52 mmol), and heating at 150 °C for 12 h, afforded 36 (848 mg, 90%). mp 289–291 °C; ¹H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 12.0 Hz, 2H), 6.75 (d, J = 6.7 Hz, 2H), 4.60 (d, J = 4.9 Hz, 2H), 1.48 (s, 18H); ¹³C NMR (126 MHz, CDCl₃) δ 174.3 (s), 154.1 (s), 148.8 (d, J = 239.0 Hz), 140.8 (d, J = 13.0 Hz), 110.1 (d, J = 6.7 Hz), 109.4 (d, J = 21.7 Hz), 99.1 (d, J = 2.2 Hz), 51.4 (s), 29.2 (s); IR (film) 3451, 2972, 1623, 1527, 1491, 1294, 1217, 887, 821 cm⁻¹; HRMS (ESI) m/z 375.1897 (M+H⁺, C₂₁H₂₅F₂N₂O₂ requires 375.1884).

2,7-difluoro-3,6-di(piperidin-1-yl)-9H-xanthen-9-one (37)

Using General Procedure C, 27 (840 mg, 2.00 mmol), and heating to 170 °C for 12 h, afforded 37 (733 mg, 92%). mp 200–201 °C; ¹H NMR (400 MHz, 10% CD₃OD in CDCl₃) δ 7.45 (d, J = 13.2 Hz, 2H), 6.58 (d, J = 6.8 Hz, 2H), 2.99 (t, J = 4.8 Hz, 8H), 1.49 (p, J = 4.8 Hz, 8H), 1.41 (hept, J = 4.8 Hz, 4H); ¹³C NMR (125 MHz, 10% CD₃OD in CDCl3) δ 175.2 (s), 153.9 (s), 151.9 (d, J = 252.0 Hz), 147.3 (d, J =10.1 Hz), 113.5 (d, J = 6.3 Hz), 111.0 (d, J = 23.9 Hz), 105.4 (d, J = 3.8 Hz), 51.1 (d, J = 5.0 Hz), 25.6 (s), 24.0 (s); IR (film) 2931, 1619, 1461, 1234, 1130, 776 cm⁻¹; HRMS (ESI) m/z 421.1714 (M+Na⁺, C₂₃H₂₄F₂N₂O₂Na requires 421.1704).

2,7-difluoro-3-hydroxy-6-(piperidin-1-yl)-9H-xanthen-9-one (38)

Using General Procedure C, 28 (710 mg, 2.01 mmol), and heating at 150 °C for 12 h, afforded 38 (630 mg, 95%). mp 230–231 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 2H), 7.73 (d, J = 10.8 Hz, 1H), 7.64 (d, J = 13.3 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 7.01 (d, J = 6.9 Hz, 1H), 3.21 (t, J = 5.4 Hz, 1H), 1.65 (p, J = 5.2 Hz, 1H), 1.58 (p, J = 5.4 Hz, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.9 (s), 152.6 (d, J = 161.3 Hz), 155.0 (d, J = 155.0 Hz), 152.1 (s), 150.1 (s), 149.7 (s), 147.7 (s), 146.5 (d, J = 10.1 Hz), 113.1 – 112.5 (m), 111.0 (d, J = 20.2 Hz), 110.7 (d, J = 23.5 Hz), 105.9 (s), 104.6 (s), 50.5 (d, J = 5.0 Hz), 25.3 (s), 23.6 (s); IR (film) 3126, 2936, 1625, 1587, 1484, 1296, 1090, 832, 778 cm⁻¹; HRMS (ESI) m/z 330.0925 (M-H, C₁₈H₁₄F₂NO₃ requires 330.0942).

2,7-difluoro-3,6-dimorpholino-9H-xanthen-9-one (39)

Using General Procedure C, 29 (1.00 g, 2.36 mmol), and heating at 170 °C for 12 h, afforded 39 (787 mg, 83%). mp 236–237 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 13.0 Hz, 2H), 6.80 (d, J = 6.8 Hz, 2H), 3.90 (t, J = 5.0 Hz, 8H), 3.26 (t, J = 5.0 Hz, 8H); ¹³C NMR (125 MHz, CDCl3) δ ¹³C NMR (126 MHz, CDCl₃) δ 174.4 (s), 153.6 (s), 151.9 (d, J = 245.9 Hz), 146.1 (d, J = 10.6 Hz), 114.9 (d, J = 7.2 Hz), 112.0 (d, J = 23.5 Hz), 105.5 (d, J = 3.0 Hz), 66.6 (s), 50.1 (d, J = 4.8 Hz); IR (film) 2921, 2863, 1619, 1473, 1259, 1198, 1123, 1030, 900, 777 cm⁻¹; HRMS (ESI) m/z 403.1490 (M+H⁺, C₂₁H₂₁F₂N₂O₄ requires 403.1469).

2,7-difluoro-10-isopropyl-3,6-bis(isopropylamino)acridin-9(10H)-one (40)

Bis(2,4,5-trifluorophenyl)methanone 10 (291 mg, 1.00 mmol) was dissolved in isopropylamine (3.00 mL, 36.7 mmol) and transferred to a sealed tube. The reaction was stirred at 100 °C for 12 h, and all volatiles were removed under reduced pressure. The residual oil was purified by flash chromatography to yield 40 (170 mg, 45%) as a white solid. mp 160–162 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 12.0 Hz, 2H), 6.56 (d, J = 8.0 Hz, 2H), 5.01 (hept, J = 7.0 Hz, 1H), 4.34 (brs, 2H), 3.75 (hept, J = 5.92 Hz, 2H), 1.75 (d, J = 7.0 Hz, 6H), 1.33 (d, J = 7.0 Hz, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 173.9 (s), 146.5 (d, J = 238.3 Hz), 140.1 (s), 138.9 (d, J = 13.7 Hz), 112.4 (d, J = 5.8 Hz), 109.7 (d, J = 19.5 Hz), 95.4 (s), 50.8 (s), 43.0 (s), 21.6 (s), 20.5 (s); IR (film) 3437, 3304, 2970, 2934, 1622, 1599, 1498, 1281 cm⁻¹; HRMS (ESI) m/z 388.2204 (M+H⁺, C₂₂H₂₈F₂N₃O requires 388.2200).

3,6-bis(dimethylamino)-2,7-difluoro-10-methylacridin-9(10H)-one (41)

Using General Procedure D, 10 (291 mg, 1.00 mmol), a reaction time of 6 h, purification by washing with acetone, and removal of solvent in vacuo, afforded 41 (307 mg, 93%). mp 200–203 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 14.2 Hz, 2H), 6.51 (d, J = 6.5 Hz, 2H), 3.73 (s, 3H), 3.06 (s, 12H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.8 (s), 149.3 (d, J = 241.6 Hz), 144.9 (d, J = 10.3 Hz), 140.4 (s), 113.5 (s), 111.3 (d, J = 22.3 Hz), 102.2 (d, J = 3.3 Hz), 42.0 (d, J = 5.5 Hz), 34.2 (s); IR (film) 2916, 1602, 1329, 1267, 750 cm⁻¹; HRMS (ESI) m/z 332.1548 (M+H⁺, C₁₈H₂₀F₂N₃O requires 332.1574).

2,7-difluoro-3,6-bis(isopropylamino)-10-methylacridin-9(10H)-one (42)

Using General Procedure D, 25 (1.70 g, 4.62 mmol), heating to 80 °C for 12 h, and purification by washing with ether and removal of solvent in vacuo, afforded 42 (1.58 g, 95%) mp 232–233 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, J = 12.2 Hz, 2H), 6.33 (d, J = 6.8 Hz, 2H), 4.33 (d, J = 4.0 Hz, 2H), 3.73 (hept, J = 6.6 Hz, 2H), 3.69 (s, 3H), 1.31 (d, J = 6.3 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 172.5 (s), 146.9 (d, J = 244.4 Hz), 141.3 (s), 140.8 (d, J = 13.9 Hz), 110.4 (d, J = 5.1 Hz), 109.3 (d, J = 18.9 Hz), 94.9 (d, J = 3.1 Hz), 43.1 (s), 34.3 (s), 21.9 (s); IR (film) 3405, 3302, 2970, 1623, 1596, 1505, 1284, 1034, 800 cm⁻¹; HRMS (ESI) m/z 360.1866 (M+H⁺, C₂₀H₂₄F₂N₃O requires 360.1887).

3-amino-6-(dimethylamino)-2,7-difluoro-10-methylacridin-9(10H)-one (43)

Using General Procedure D, 21 (300 mg, 1.05 mmol), a reaction time of 12 h, and purification by washing with ether and removal of solvent in vacuo, afforded 43 (295 mg, 93%). mp 263–264 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J = 14.3 Hz, 1H), 7.71 (d, J = 11.7 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.24 (s, 2H), 3.75 (s, 3H), 3.03 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆) δ 173.3 (s), 149.8 (d, J = 200.6 Hz), 147.4 (d, J = 250.7 Hz), 145.1 (d, J = 10.3 Hz), 143.3 (s), 143.1 (s), 141.5 (s), 140.5 (s), 113.9 (d, J = 6.3 Hz), 111.8 (d, J = 22.3 Hz), 110.6 (d, J = 18.6 Hz), 102.5 (d, J = 3.3 Hz), 99.0 (d, J = 3.9 Hz), 42.5 (s), 34.4 (s); IR (film) 3322, 3176, 1619, 1493, 1309, 1256, 1026, 902, 777 cm⁻¹; HRMS (ESI) m/z 304.1260 (M+H⁺, C₁₆H₁₆F₂N₃O requires 304.1261).

2,7-difluoro-10-methyl-3,6-di(piperidin-1-yl)acridin-9(10H)-one (44)

Using General Procedure D, 27 (1.50 g, 3.58 mmol), a reaction time of 4 h, and purification by washing the product with ether and removal of solvent in vacuo, afforded 44 (1.37 g, 93%). mp 243–244 °C; ¹H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 12.1 Hz, 2H), 6.69 (d, J = 6.9 Hz, 2H), 3.74 (s, 3H), 3.21 (t, J = 5.2 Hz, 8H), 1.79 (p, J = 5.2 Hz, 8H), 1.64 (hept, J = 5.2 Hz, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 174.9 (s), 151.1 (d, J = 245.7 Hz), 146.5 (d, J = 10.4 Hz), 140.3 (s), 115.9 (d, J = 6.7 Hz), 112.6 (d, J = 22.5 Hz), 102.9 (d, J = 2.7 Hz), 51.5 (d, J = 4.5 Hz), 34.2 (s), 26.0 (s), 24.2 (s); IR (film) 2938, 2846, 1624, 1597, 1494, 1274, 1225, 1145, 783 cm⁻¹; HRMS (ESI) m/z 412.2196 (M+H⁺, C₂₄H₂₈F₂N₃O requires 412.2200).

3-(dimethylamino)-2,7-difluoro-10-methyl-6-(piperidin-1-yl)acridin-9(10H)-one (45)

Using General Procedure D, 28 (355 mg, 1.00 mmol), a reaction time of 12 h, and purification by washing with ether and removal of solvent in vacuo, afforded 45 (338 mg, 91%). mp 227–229 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 12.6 Hz, 1H), 7.96 (d, J = 14.2 Hz, 1H), 6.65 (d, J = 6.9 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 3.67 (s, 3H), 3.19 (t, J = 5.2 Hz, 4H), 3.05 (s, 6H), 1.78 (p, J = 5.4 Hz, 4H), 1.65 (p, J = 5.4 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 173.6 (s), 151.3 (d, J = 138.6 Hz), 149.5 (d, J = 127.8 Hz), 146.1 (d, J = 10.4 Hz), 145.5 (d, J = 10.0 Hz), 141.1 (s), 141.0 (s), 115.5 (s), 114.2 (s), 111.9 (d, J = 22.5 Hz), 111.7 (d, J = 22.6 Hz), 104.7 (d, J = 2.6 Hz), 102.4 (d, J = 3.4 Hz), 51.5 (d, J = 4.7 Hz), 42.5 (d, J = 5.8 Hz), 34.7 (s), 26.0 (s), 24.2 (s); IR (film) 2836, 1626, 1601, 1503, 1280, 1011, 895 cm⁻¹; HRMS (ESI) m/z 372.1889 (M+H⁺, C₂₁H₂₄F₂N₃O requires 372.1887).

2,7-difluoro-10-isopropyl-3,6-dimethoxyacridin-9(10H)-one (46)

A solution of 19 (100 mg, 0.32 mmol) in isopropylamine (3.00 mL, 36.6 mmol) was heated to 100 °C in a sealed tube for 12 h. This mixture was cooled and residual isopropylamine removed in vacuo. The resulting crude yellow oil was dissolved in THF (7.00 mL), treated with NaH (60%, 77.0 mg, 1.92 mmol), and heated to 60 °C for 12 h. The reaction mixture was cooled in an ice bath and carefully neutralized with saturated aqueous NaHCO₃ (20 mL). Extraction with THF (3 × 20 mL), drying of the combined organic fractions over anhydrous Na₂SO₄, and removal of solvent in vacuo provided a crude yellow oil that was purified by column chromatography (CH₂Cl₂) to provide dimethoxyacridone 46 (88.4 mg, 83%). mp 158–159 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 11.2 Hz, 2H), 7.04 (d, J = 6.8 Hz, 2H), 5.09 (p, J = 7.2 Hz, 1H), 4.06 (s, 6H), 1.83 (d, J = 7.2 Hz, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 175.3 (s), 152.1 (d, J = 12.9 Hz), 148.5 (d, J = 245.9 Hz), 140.2 (s), 117.0 (d, J = 5.4 Hz), 112.8 (d, J = 18.9 Hz), 100.1 (s), 56.4 (s), 52.4 (s), 21.4 (s); IR (film) 2924, 2851, 1736, 1626, 1603, 1488, 1263, 1091, 796 cm⁻¹; HRMS (ESI) m/z 334.1255 (M+H⁺, C₁₈H₁₈F₂NO₃ requires 334.1255).

10-benzyl-2,7-difluoro-3,6-dimethoxyacridin-9(10H)-one (47)

A solution of 19 (1.50 g, 4.78 mmol) in benzylamine (8.00 mL, 73.3 mmol) was heated to 100 °C for 12 h. This mixture was cooled and residual benzylamine removed by vacuum distillation (36 °C, 1 mm Hg). The resulting crude yellow oil was dissolved in THF (30 mL), treated with NaH (60%, 574 mg, 14.4 mmol), and heated to 60 °C for 12 h. The reaction mixture was cooled in an ice bath and carefully neutralized with saturated aqueous NaHCO₃ (20 mL). The resulting biphasic mixture was extracted with THF (3 × 20 mL) and the combined organic fractions were dried over anhydrous Na₂SO₄ and concentrated to give a crude yellow oil that was purified by column chromatography (CH₂Cl₂) to provide dimethoxyacridone 47 (1.56 g, 86%). mp 205–206 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 11.2 Hz, 2H), 7.45-7.30 (m, 3H), 7.22 (d, J = 6.8 Hz, 2H), 6.93 (d, J = 6.8 Hz, 2H), 5.70 (s, 2H), 4.82 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 174.9 (s), 153.0 (d, J = 13.0 Hz), 148.7 (d, J = 246.0 Hz), 140.1 (s), 135.1 (s), 129.5 (s), 128.22 (s), 125.6 (s), 115.6 (d, J = 5.4 Hz), 112.5 (d, J = 19.1 Hz), 98.5 (s), 56.21 (s), 51.6 (s); IR (film) 2989, 2938, 1607, 1498, 1273, 1042 cm⁻¹; HRMS (ESI) m/z 382.1278 (M+H⁺, C₂₂H₁₈F₂NO₃ requires 382.1255).

2,7-difluoro-3,6-dimethoxy-10-phenylacridin-9(10H)-one (48)

A solution of 19 (100 mg, 0.320 mmol) in aniline (2.00 mL, 21.9 mmol) was heated to 130 °C for 12 h in a sealed tube. The reaction mixture was cooled and the residual aniline was removed by vacuum distillation (40 °C, 1 mm Hg). The resulting crude yellow oil was dissolved in DMA (3.5 mL) and heated at 170 °C for 12 h. The reaction mixture was cooled, diluted with water (30 mL), and extracted with THF (3 × 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄ and concentrated to give a crude yellow oil that was purified by column chromatography (CH₂Cl₂) to provide dimethoxyacridone 48 (84.5 mg, 72%). mp 256–257 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J = 11.6 Hz, 2H), 7.74–7.87 (m, 3H), 7.59 (d, J = 7.2 Hz, 2H), 6.17 (d, J = 7.2 Hz, 2H)), 3.62 (s, 6H); ¹³C NMR (126 MHz, DMSO-d₆) δ 173.5 (s), 151.8 (d, J = 13.1 Hz), 148.0 (d, J = 244.2 Hz), 140.7 (s), 138.0 (s), 131.4 (s), 130.3 (s), 129.6 (s), 113.9 (d, J = 5.1 Hz), 111.0 (d, J = 18.7 Hz), 100.1 (s), 55.8 (s); IR (film) 3057, 2939, 1612, 1580, 1479, 1306, 1256, 1084, 823, 701 cm⁻¹; HRMS (ESI) m/z 368.1098 (M+H⁺, C₂₁H₁₆F₂NO₃ requires 368.1098).

2,7-difluoro-3,6-dihydroxy-10-isopropylacridin-9(10H)-one (49)

Using General Procedure E, 46 (20.0 mg, 0.0601 mmol) afforded dihydroxylacridone 49 (15.2 mg, 83%). mp 172–173 °C; ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J = 11.6 Hz, 2H), 7.29 (d, J = 7.2 Hz, 2H), 5.18 (p, J = 7.2 Hz, 2H), 1.75 (d, J = 7.2 Hz, 2H); ¹³C NMR (126 MHz, CD₃OD) δ 177.2 (s), 152.4 (d, J = 15.4 Hz), 149.6 (d, J = 242.1 Hz), 142.1 (s), 116.7 (d, J = 5.1 Hz), 112.8 (d, J = 19.2 Hz), 105.2 (s), 53.6 (s), 20.9 (s); IR (film) 3357, 3075, 2977, 1701, 1627, 1542, 1490, 1448, 1406, 1277, 1199, 889, 770 cm⁻¹; HRMS (ESI) m/z 304.0765 (M-H, C₁₆H₁₂F₂NO₃ requires 304.0785).

10-benzyl-2,7-difluoro-3,6-dihydroxyacridin-9(10H)-one (50)

Using General Procedure E, 47 (20.0 mg, 0.0526 mmol) afforded dihydroxyacridone 50 (17.0 mg, 91%). mp 247–249 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (d, J = 11.2 Hz, 2H), 7.25–7.45 (m, 3H), 7.18 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 5.53 (s, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ 173.6 (s), 151.2 (s), 147.8 (d, J = 241.4 Hz), 140.3 (s), 135.6 (s), 129.0 (s), 127.4 (s), 125.7 (s), 113.8 (s), 111.6 (d, J = 18.9 Hz), 102.8 (s), 50.3 (s); IR (film) 3369, 3050, 3007, 1629, 1574, 1490, 1276, 750 cm⁻¹; HRMS (ESI) m/z 352.0776 (M-H, C₂₀H₁₂F₂NO₃ requires 352.0785).

2,7-difluoro-3,6-dihydroxy-10-phenylacridin-9(10H)-one (51)

Using General Procedure E, 48 (20.0 mg, 0.0545 mmol) afforded dihydroxylacridone 51 (14.6 mg, 79%). mp 257–259 °C; ¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J = 11.2 Hz, 2H), 7.75–7.90 (m, 3H), 7.49 (d, J = 6.8 Hz, 2H), 6.36 (d, J = 7.2 Hz, 2H); ¹³C NMR (126 MHz, CD₃OD) δ 174.4 (s), 154.1 (d, J = 15.5 Hz), 150.7 (d, J = 245.7 Hz), 143.3 (s), 140.1 (s), 132.6 (s), 131.6 (s), 130.6 (s), 113.6 (d, J = 6.2 Hz), 112.0 (d, J = 20.4 Hz), 104.8 (d, J = 2.4 Hz); IR (film) 3369, 3064, 2924, 1727, 1624, 1547, 1489, 1395, 1268, 1193, 893 cm⁻¹; HRMS (ESI) m/z 338.0609 (M-H, C₁₉H₁₀F₂NO₃ requires 338.0629).

2,7-difluoro-3,6-dimethoxy-9H-thioxanthen-9-one (52)

Using General Procedure F, 19 (3.15 g, 10.0 mmol), 26 °C, and purification by washing with water (3 × 100 mL), methanol (3 × 50 mL), acetone (3 × 50 mL), and removal of solvent in vacuo, afforded 52 (2.74 g, 92%). mp >300 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J = 12.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 4.032 (s, 2H); IR (film) 3047, 2967, 1603, 1419, 1346, 1263, 1046, 894, 771 cm⁻¹; HRMS (ESI) m/z 309.0407 (M+H⁺, C₁₅H₁₁F₂O₃S requires 309.0397).

2,7-difluoro-3,6-dihydroxy-9H-thioxanthen-9-one (53)

Using General Procedure F, 19 (1.58 g, 5.00 mmol), heating to 90 °C, and purification by column chromatography (1% to 3% MeOH in CH₂Cl₂), afforded 53 (1.04 g, 74%). mp >300 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J = 12.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 3.42 (brs, 2H); ¹³C NMR (126 MHz, DMSO) δ 175.7 (s), 150.5 (d, J = 243.2 Hz), 150.2 (d, J = 14.1 Hz), 133.4 (d, J = 1.9 Hz), 120.1 (d, J = 5.0 Hz), 115.3 (d, J = 19.5 Hz), 112.7 (d, J = 2.7 Hz); IR (film) 3393, 3064, 1617, 1553, 1502, 1413, 1391, 1303, 1287, 1182, 1114, 903 cm⁻¹; HRMS (ESI) m/z 278.9924 (M-H, C₁₃H₅F₂O₃S requires 278.9927).

3,6-bis(dimethylamino)-2,7-difluoro-9H-thioxanthen-9-one (54)

Using General Procedure F, 22 (150 mg, 0.440 mmol), and purification by column chromatography (10% to 20% EtOAc in hexanes), afforded 54 (134 mg, 91%). mp 218–220 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J = 15.1 Hz, 2H), 6.63 (d, J = 8.0 Hz, 2H), 3.02 (s, 12H); ¹³C NMR (126 MHz, CDCl₃) δ 175.8 (s), 151.4 (d, J = 246.1 Hz), 142.7 (d, J = 10.0 Hz), 132.9 (s), 119.5 (d, J = 6.3 Hz), 114.8 (d, J = 23.5 Hz), 110.0 (d, J = 3.7 Hz), 41.1 (d, J = 6.0 Hz); IR (film) 2907, 2898, 2853, 1682, 1601, 1583, 1354, 1256, 1116, 722 cm⁻¹; HRMS (ESI) m/z 335.1042 (M+H⁺, C₁₇H₁₇F₂N₂OS requires 335.1030).

3,6-bis(diethylamino)-2,7-difluoro-9H-thioxanthen-9-one (55)

Using General Procedure F, 23 (1.10 g, 2.77 mmol), and purification by column chromatography (10% to 20% EtOAc in hexanes), afforded 55 (973 mg, 90%). mp 145–147 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 15.6 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 3.40 (q, J = 7.0 Hz, 8H), 1.21 (t, J = 7.0 Hz, 12H); ¹³C NMR (101 MHz, CDCl₃) δ 176.7 (s), 152.1 (d, J = 312.5 Hz), 141.8 (d, J = 9.9 Hz), 134.0 (d, J = 1.5 Hz), 119.7 (s), 116.3 (d, J = 24.3 Hz), 110.6 (s), 46.0 (d, J = 5.8 Hz), 13.0 (d, J = 1.5 Hz); IR (film) 2972, 2931, 2872, 1590, 1504, 1426, 1352, 1264, 1238, 1071, 901, 790 cm⁻¹; HRMS (ESI) m/z 391.1662 (M+H⁺, C₂₁H₂₅F₂N₂OS requires 391.1656).

2,7-difluoro-3,6-bis(isopropylamino)-9H-thioxanthen-9-one (56)

Using General Procedure F, 25 (1.00 g, 2.71 mmol), and purification by column chromatography (CH₂Cl), afforded 56 (834 mg, 85%). mp 164–165 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 12.8 Hz, 2H), 6.59 (d, J = 7.6 Hz, 2H), 4.41 (brs, 2H), 3.74 (hept, J = 6.4 Hz, 2H), 1.33 (d, J = 6.4 Hz, 12H); ¹³C NMR (126 MHz, CDCl₃) 176.9 (s), 150.4 (d, J = 225.5 Hz), 139.3 (d, J = 41.6 Hz), 134.8 (s), 118.2 (s), 113.8 (d, J = 18.9 Hz), 104.9 (s), 44.0 (s), 22.6 (s); IR (film) 3435, 3322, 2969, 1610, 1592, 1515, 1426, 1287, 1326, 1026, 774 cm⁻¹; HRMS (ESI) m/z 363.1338 (M+H⁺, C₁₉H₂₁F₂N₂OS requires 363.1343).

3,6-bis(tert-butylamino)-2,7-difluoro-9H-thioxanthen-9-one (57)

Using General Procedure F, 26 (300 mg, 0.762 mmol), and purification by column chromatography (10% to 20% EtOAc in hexanes), afforded 57 (263 mg, 89%). mp 199–201 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 13.2 Hz, 2H), 6.33 (d, J = 7.8 Hz, 2H), 4.57 (d, J = 4.6 Hz, 2H), 1.47 (s, 18H), 1.31 (d, J = 6.3 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 176.9 (s), 150.9 (d, J = 241.0 Hz), 139.2 (d, J = 12.2 Hz), 135.6 – 132.8 (m), 118.0 (d, J = 6.1 Hz), 113.6 (d, J = 21.3 Hz), 106.6 (s), 51.4 (s), 29.3 (s); IR (film) 3437, 2978, 1598, 1514, 1420, 1364, 1202 cm⁻¹; HRMS (ESI) m/z 391.1649 (M+H⁺, C₂₁H₂₅F₂N₂OS requires 391.1656).

2,7-difluoro-3,6-di(piperidin-1-yl)-9H-thioxanthen-9-one (58)

Using General Procedure F, 27 (400 mg, 1.00 mmol), and purification by column chromatography (10% to 20% EtOAc in hexanes), afforded 58 (352 mg, 85%). mp 205–206 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 14.3 Hz, 2H), 6.87 (d, J = 7.7 Hz, 2H), 3.23 (t, J = 5.2 Hz, 8H), 1.75 (p, J = 5.2 Hz, 8H), 1.63 (hept, J = 5.2 Hz, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 177.1 (s), 153.9 (d, J = 238.1 Hz), 145.1 (d, J = 10.0 Hz), 133.9 (s), 122.0 (d, J = 6.5 Hz), 115.8 (d, J = 23.2 Hz), 113.3 (d, J = 3.0 Hz), 51.2 (d, J = 4.8 Hz), 25.8 (s), 24.2 (s); IR (film) ν_max 2936, 2852, 1624, 1597, 1497, 1420, 1350, 1269, 1252, 1240, 1115, 750 cm⁻¹; HRMS (ESI) m/z 415.1650 (M+H⁺, C₂₃H₂₅F₂N₂OS requires 415.1656).

2,7-difluoro-3,6-dimorpholino-9H-thioxanthen-9-one (59)

Using General Procedure F, 29 (213 mg, 0.500 mmol), and purification by column chromatography (15% to 30% EtOAc in hexanes), afforded 59 (195 mg, 94%). mp 275–276 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 14.2 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 3.90 (t, J = 4.7 Hz, 8H), 3.26 (t, J = 4.7 Hz, 8H); ¹³C NMR (126 MHz, CDCl₃) δ 176.0 (s), 152.9 (d, J = 258.3 Hz), 143.1 (d, J = 9.9 Hz), 132.8 (d, J = 2.0 Hz), 122.0 (d, J = 6.7 Hz), 115.1 (d, J = 23.1 Hz), 112.1 (d, J = 2.8 Hz), 65.6 (s), 49.1 (d, J = 4.7 Hz); IR (film) 2990, 2923, 2887, 1602, 1499, 1426, 1271, 1122, 1006 cm⁻¹; HRMS (ESI) m/z 441.1056 (M+Na⁺, C₂₁H₂₀F₂N₂O₃SNa requires 441.1060).