Generation of Magnesium Pentafluoropropen-2-olate from Hexafluoroisopropanol and Synthesis of 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones

Abstract

2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones are valuable precursors to difluoroenolates, following fragmentation during the release of trifluoroacetate; however, there are few synthetic strategies to prepare this unique class of compound. We have addressed this issue and report a mild, two-step synthesis of 2,2,4,4,4-pentafluoro-3,3-dihydroxyketones from aldehydes. Specifically, aldehydes are treated with pentafluoropropen-2-olate, generated from a new fragmentation of hexafluoroisopropanol with a mixed Mg/Li amide, to give pentafluoroalcohols. A subsequent oxidation with Dess-Martin periodinane provides the targets in good isolated yields.

Graphical Abstract

The incorporation of fluorine into organic molecules is essential in the pharmaceutical, agrochemical, and polymer industries. Major advances in synthetic chemistry have occurred to enable the production of compounds displaying a fluorine atom¹ or a trifluoromethyl group;^2,3 however, methods to assemble difluoromethyl groups are less developed.^4,5 In 2011, we reported an approach to produce difluoroenolates through the release of trifluoroacetate from highly α-fluorinated gem-diols (Scheme 1).⁶ These difluoroenolates participate in aldol reactions and subsequent investigations demonstrated that these intermediates react with activated imines,^7-9 trifluoromethyl ketones,¹⁰ halogenation reagents,¹¹ and dithianes.¹² Moreover, the difluoroenolates generated during the release of trifluoroacetate can also be immediately trapped as difluoromethyl ketones¹³ or deuterodifluoromethyl ketones¹⁴ with H₂O or D₂O, respectively. Additionally, this method is compatible with catalytic, asymmetric reactions¹⁵ and visible-light photoredox catalysis.¹⁶ Despite the utility of this process and rapid adoption of the method,¹⁷ the requisite highly α-fluorinated gem-diols are not common functional groups in fluorine chemistry and are predominately accessed by only one synthetic strategy.⁶

Scheme 1.

Synthetic Reactions of Difluoroenolates Generated by the Release of Trifluoroacetate from Highly α-Fluorinated gem-Diols

Nearly all highly α-fluorinated gem-diols are accessed through methyl ketones by a two-step process of trifluoroacetylation followed by difluorination with Selectfluor (Figure 1A).^6,17 Even though this strategy enables a quick production of substrates for the release of trifluoroacetate, we recently had to develop an alternative method to access a glucose-derived highly α-fluorinated gem-diol from an aldehyde (Figure 1B).¹⁸ Specifically, we exploited an approach from Qian and Nakai, in which the treatment of hexafluoroisopropanol with n-butyllithium creates a lithium-based pentafluoroenolate that adds smoothly into aldehydes.¹⁹ Next, after the addition of the enolate to the aldehyde, the glucose-derived pentafluorinated product was oxidized with Dess-Martin periodinane to give the targeted gem-diol.¹⁸ In this case, the two-step approach from an aldehyde was quite effective, and also, it provided an opportunity to devise an additional method for the synthesis of highly α-fluorinate gem-diols. Herein, we report that hexafluoroisopropanol can be fragmented with mixed Mg/Li amides of type R₂NMgCl·LiCl and added into aldehydes to produce pentafluorinated products that can be oxidized to the starting materials for the trifluoroacetate-release process. Additionally, we have discovered that the difluoroenolates generated from the release of trifluoroacetate can be trapped as difluoroenoxysilanes and concomitantly arylated using palladium catalyst.

Figure 1.

Synthetic Approaches to Highly a-Fluorinated gem-Diols. A. Primary synthetic strategy by trifluoroacetylation and subsequent difluorination. B. Addition of lithium pentafluoropropen-2-olate and oxidation.

The fragmentation of hexafluoroisopropanol requires two equivalents of n-butyllithium: one to form the alkoxide, and the second to abstract the methine proton and displace fluoride.^19,20 Even though the fragmentation was also reported to occur with NaH and KH,¹⁹ the latter process is believed to be promoted by the coordination of lithium to fluorine, which assists in the displacement process. All of the subsequent studies have used n-buyllithium as a base. ^18,20-25 Although n-butyllitium is a common laboratory reagent, it is quite flammable and the potential for hazards are increased when multiple equivalents are required. Another limitation of using organolithium as a base is that very low temperatures are required (i.e., −78 °C). In order to address the typical limitations of organolithium bases, Knochel and co-workers have pioneered the development of mixed Mg/Li amides of type R₂NMgCl·LiCl.²⁶ Accordingly, we aimed to develop a new method to produce magnesium pentafluoropropen-2-olate from hexafluoroisopropanol by using magnesium bases (Table 1). Initial efforts with methyl magnesium bromide were unproductive, but isopropyl Grignard, with or without added lithium chloride, generated the pentafluoropropen-2-olate in modest yields (i.e., 37–40%) as observed by ¹⁹F NMR (entries 1–4). Exchanging the solvent THF with Et₂O or dioxane did not notably increase conversions (entries 5–6); using cesium chloride instead of lithium chloride also did not affect the formation of the pentafluoroenolate (entry 7). Using the mixed Mg/Li amide of type (i-Pr)₂NMgCl·LiCl²⁶ at room temperature proved to be superior and provided the pentafluoropropen-2-olate with 91% conversion (entry 8). The doubling of yield when (i-Pr)₂NMgCl·LiCl was utilized compared to i-PrMgCl·LiCl was a substantial improvement (i.e., 40% to 91%).

Table 1.

Optimization of the Formation of Magnesium Pentafluoropropen-2-olate from Hexafluoroisopropanol

entry	RMgX	solvent	additive	19F NMR yield (%)
1	MeMgBr	THF		0
2	MeMgBr	THF	LiCl	0
3	i-PrMgCl	THF		37
4	i-PrMgCl	THF	LiCl	40
5	i-PrMgCl	Et2O		52
6	i-PrMgCl	dioxane		18
7	i-PrMgCl	THF	CsCl	48
8	(i-Pr)2NMgCl	THF	LiCl	91

The next step was to determine if the fluoroenolate generated from (i-Pr)₂NMgCl·LiCl and hexafluoroisopropanol would add to aldehydes. Even though the lithium pentafluoropropen-2-olate reacts well with aldehydes,^18,19,25 the reactivity of the magnesium-counterpart is not characterized in the literature to our knowledge. Benzaldehydes 1–5, heteroaromatic aldehydes 6–7, α,β-unsaturated aldehyde 8, and aliphatic aldehyde 9 were treated at room temperature with the pentafluoropropen-2-olate generated with (i-Pr)₂NMgCl·LiCl (Table 2). The pentafluoroalcohol 10 was obtained in 59% isolated yield from addition to 4-ethylbenzaldehyde 1. In the case of 4-bromobenzaldehyde 2, the product 11 was isolated in a lower 33% yield most likely due to debromination of the benzene. All of the other substrates provided the pentafluoroalcohols 12-18 in 52–87% isolated yields. Substituted benzene rings, heterocycles, styrene, and alkyl groups are compatible with the magnesium pentafluoropropen-2-olate. Moreover, during the analysis of the ¹⁹F NMR spectra following workup, two products were routinely observed: 1) the desired target and 2) the aminal formed by addition of diisopropylamine to the gem-diol. The latter was readily cleaved during purification by silica gel flash chromatography. Overall, the conversions with the pentafluoropropen-2-olate generated from (i-Pr)₂NMgCl·LiCl were comparable to the intermediate produced with n-butyllithium.

Table 2.

Addition of Magnesium Pentafluoropropen-2-olate to Aldehydes 1–9.

entry	substrate	product	yielda
1			59%
2			33% (45%)b
3			71% (82%)b
4			77%
5			68% (78%)b
6			68%
7			65%
8			52% (67%)b
9			87%

^aIsolated yields

^bYields determined by ¹⁹F NMR

With the fluoroalcohols 10–18 in hand, oxidations to the fluoroketones¹⁸ were conducted using the oxidant, Dess-Martin periodinane (Table 3).²⁷ Only mild oxidants can be considered for this transformation, because the products will easily eliminate trifluoroacetate in the presence of basic conditions.⁶ All of the aromatic, heteroaromatic, alkenyl, and alkyl substrates 10–18 provided the respective fluoroketones 19–27 in good isolated yields of 78–95%. Moreover, some conversions were nearly quantitative as observed by ¹⁹F NMR. In all cases, the by-products from fragmentation of the compounds 19–27 by trifluoroacetate release were not observed. The oxidation of allylic fluoroalcohol 17 to 26 provided a lower isolated yield at 41%. Although allylic alcohols are typically good substrates for Dess-Martin periodinane,²⁷ allylic fluoroalcohols are not oxidized as well with this reagent.²⁸ In general, the two-step addition/oxidation protocol was successful to produce the pentafluoroketones from readily available aldehydes.

Table 3.

Oxidation of Fluoroalcohols 10–18 to 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones 19–27.

entry	substrate	product	yielda
1	10		80%
2	11		78% (99%)b
3	12		79% (90%)b
4	13		88% (100%)b
5	14		84% (95%)b
6	15		80% (97%)b
7	16		79% (88%)b
8	17		41% (54%)b
9	18		95%c

^aIsolated yields

^bYields determined by ¹⁹F NMR

^cReference 18.

With a new route to starting materials for trifluoroacetate release, additional studies were undertaken to expand the role of the pentafluoroketones as precursors to difluoroenolates. Specifically, difluoroenoxysilanes are valuable fluorinated building blocks²⁰ and we aimed to devise a new method to access these key targets. Treatment of the highly α-fluorinated gem-diol 28⁶ with the strong base, lithium hexamethyldisilazane, according to the protocol reported by Wolf,⁸ promotes the release of trifluoroacetate and unleashes the difluoroenolate which we immediately trapped with chlorotrimethylsilane (Figure 2). The difluoroenoxysilane 29 was produced in 70% by ¹⁹F NMR; the isolated yield of 29 was 47%. The next step was to convert the difluoroenoxysilane to a valuable difluoromethyl ketone using the method of Shreeve.²⁹ Indeed, difluoromethyl ketones are excellent structures in medicinal chemistry due to their propensity to form a stable hydrate.^30,31 Accordingly, gem-diol 30¹³ was treated with LiHMDS and trapped with TMSCl to the difluoroenoxysilane, which, in turn, was immediately subjected to palladium-mediated arylation conditions²⁹ in the presence of bromoanisole and the difluoromethyl ketone 31 was obtained in a good 78% isolated yield.

Figure 2.

Conversion of Fluorinated gem-Diols to Difluoroenoxysilanes

In conclusion, this mild, two-step synthesis provides an additional route to 2,2,4,4,4-pentafluoro-3,3-dihydroxyketones from aldehydes. Moreover, this discovery utilizes a mixed Mg/Li amide for the fragmentation of hexafluoroisopropanol and eliminates the requirement of n-butyllithium. These advances have enabled the expansion of the reactivity of difluoroenolates produced from highly α-fluorinated gem-diols through the release of trifluoroacetate so that difluoroenoxysilanes as well as arylated difluoromethyl ketones can be prepared. This advancement will likely enable new reactivity for fluoroenolates to be characterized.

Experimental Section

Representative Reaction Procedure for Preparation of Pentafluorotriols.

Hexafluoroisopropanol (58 μL, 0.55 mmol) was added dropwise at rt to a freshly prepared solution of (i-Pr₂N)₂MgCl•LiCl²⁶ (5 mL, 0.44 M in THF) and the mixture was stirred for 2 h. Then, a solution of 4-ethylbenzaldehyde 1 (113 μL, 0.83 mmol) in THF (1.5 mL) was added over 10 min and the mixture was stirred for 18 h at rt. The resultant mixture was quenched with saturated aqueous NH₄Cl (2 mL), diluted with H₂O (2 mL), and extracted with Et₂O (3 × 2 mL). The organics were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. SiO₂ flash chromatography (5:1–3:1 hexanes/EtOAc with 1% AcOH) afforded the product 10 as a colorless oil (97 mg, 59% yield).

1-(4-Ethylphenyl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 10.

See representative reaction procedure: ¹H NMR (400 MHz, (CD₃)₂CO) δ 7.46 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.21 (s, 1H), 7.00 (s, 1H), 6.41 (s, 1H), 5.53 (d, J = 22.9 Hz, 1H), 2.69 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 145.3, 133.7, 128.9 (2C), 127.9 (2C), 122.7 (q, J_CF = 288 Hz, 1C), 116.8 (dd, J_CF = 261, 254 Hz, 1C), 93.5 (tq, J_CF = 30.5, 27.0 Hz, 1C), 73.0 (dd, J_CF = 33.2, 22.2 Hz), 28.7, 15.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −81.8 (t, J = 11.8 Hz, 3F), −118.0 (dq, J = 264, 12.9 Hz, 1F), −131.4 (ddq, J = 264, 22.1, 10.9 Hz, 1F); IR (film) v_max 3351, 2967, 1616, 1202, 1159, 1067 cm⁻¹; HRMS (EI) m/z calcd for C₁₂H₁₁F₅O₂ (M–H₂O)⁺ 282.0679, found 282.0687.

1-(4-Bromophenyl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 11.

See representative reaction procedure. SiO2 flash chromatography (3:1 hexanes/EtOAc with 0.5% AcOH) afforded the title compound 11 as a colorless solid (64 mg, 33% yield): mp = 96–98 °C; ¹H NMR (400 MHz, (CD₃)₂CO) δ 7.59 (dt, J = 8.7, 2.1 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.90 (br s, 2H), 5.53 (dd, J = 22.1, 2.7 Hz, 1H), 3.12 (br s, 1H);¹³C NMR (100 MHz, (CD₃)₂CO) δ 136.5, 131.9 (2C), 131.3 (2C), 123.2, 123.0 (q, J_CF = 287 Hz, 1C), 117.2 (dd, J_CF = 259, 253 Hz, 1C), 93.8 (tq, J_CF = 30.5, 26.0 Hz, 1C), 72.9 (dd, J_CF = 32.9, 22.2 Hz, 1C) ; ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.7 (dd, J = 13.3, 11.0 Hz, 3F), −117.9 (dqd, J = 264, 13.3, 2.5 Hz, 1F), −130.5 (ddq, J = 264, 22.0, 11.0 Hz, 1F); IR (film) v_max 3423, 3213, 1490, 1404, 1286, 1212, 1151, 1064 cm⁻¹; HRMS (EI) m/z calcd for C₁₀H₆BrF₅O₂ (M–H–H₂O)⁻ 331.9477, found 331.9461.

1-(4-(tert-Butyl)phenyl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 12.

See representative reaction procedure. SiO₂ flash chromatography (4:1 hexanes/EtOAc with 0.5% AcOH) afforded the title compound 12 as a colorless solid (129 mg, 71% yield): mp = 94–96 °C; ¹H NMR (400 MHz, (CD₃)₂CO) δ 7.45 (s, 4H), 7.18 (s, 1H), 6.97 (s, 1H), 6.34 (s, 1H), 5.50 (d, J = 23.3 Hz, 1H), 1.33 (s, 9H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 152.5, 133.9, 129.1 (2C), 125.7 (2C), 123.1 (q, J_CF = 287 Hz, 1C), 117.3 (dd, J_CF = 259, 252 Hz, 1C), 94.0 (tq, J_CF = 31.3, 27.0 Hz, 1C), 73.4 (dd, J_CF = 33.5, 22.2 Hz, 1C), 35.1, 31.6 (3C); ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.6 (dd, J = 13.2, 11.2 Hz, 3F), −117.8 (dqd, J = 263, 13.2, 1.5 Hz, 1F), −131.0 (ddq, J = 263, 22.5, 11.2 Hz, 1F); IR (film) v_max 3349, 2966, 1617, 1513, 1205, 1161, 1070 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₆F₅O₂ (M+H−H₂O)⁺ 311.1065, found 311.1080.

2,2,4,4,4-Pentafluoro-1-(3-fluoro-4-methoxyphenyl)butane-1,3,3-triol 13.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc with 0.5% AcOH) afforded the title compound 13 as a colorless solid (135 mg, 77% yield): mp = 125–126 °C; ¹H NMR (400 MHz, (CD₃)₂CO) δ 7.28 (m, 2H), 7.14 (t, J = 8.4 Hz, 1H), 6.92 (br s, 3H), 5.49 (dd, J = 22.3, 2.6 Hz, 1H), 3.90 (s, 3H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 152.7 (d, J_CF = 243 Hz, 1C), 149.0 (d, J_CF = 10.6 Hz, 1C), 129.7 (d, J_CF = 5.8 Hz, 1C), 125.6 (d, J_CF = 3.2 Hz, 1C), 123.1 (q, J_CF = 287 Hz, 1C), 117.2 (dd, J_CF = 259, 253 Hz, 1C), 116.6 (d, J_CF = 71.4 Hz, 1C), 113.9 (d, J_CF = 1.9 Hz, 1C), 93.9 (tq, J_CF = 33.0, 27.5 Hz, 1C) 72.7 (dd, J_CF = 33.2, 22.0 Hz, 1C), 56.5; ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.6 (d, J = 13.4, 11.0 Hz, 3F), −117.9 (dq, J = 263, 13.3 Hz, 1F), −131.0 (ddq, J = 263, 22.1, 11.1 Hz, 1F), −137.2 (dd, J = 12.4, 8.6 Hz, 1F); IR (film) v_max 3240, 1628, 1519, 1441, 1276, 1203, 1153, 1120, 1107, 1071 cm⁻¹; HRMS (EI) m/z calcd for C₁₁H₈F₆O₃ (M−H−H₂O)⁻ 302.0383, found 302.0356.

1-(Benzo[1,3]dioxol-5-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 14.

See representative reaction procedure. SiO₂ flash chromatography (2:1 hexanes/EtOAc with 0.5% AcOH) afforded the title compound 14 as a brown oil (118 mg, 68% yield): ¹H NMR (400 MHz, (CDCl₃) δ 6.99 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.99 (s, 2H), 5.35 (dd, J = 21.9, 1.8 Hz, 1H), 3.79 (br s, 3H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 149.0, 148.5, 130.6, 123.2, 123.1 (q, J_CF = 287 Hz, 1C), 117.2 (dd, J_CF = 259, 252 Hz, 1C), 109.4, 108.5, 102.2, 93.9 (tq, J_CF = 30.5, 27.0 Hz, 1C), 73.3 (dd, J_CF = 33.3, 22.1 Hz, 1C); ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.7, (dd, J = 13.2, 11.2 Hz, 3F), −117.8 (dqd, J = 263, 13.2, 2.4 Hz, 1F), −131.3 (ddq, J = 263, 22.3, 11.1 Hz, 1F); IR (film) v_max 3394, 2920, 1506, 1493, 1447, 1248, 1205, 1161, 1039 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₈F₅O₄ (M−H₂O)⁺ 299.0343, found 299.0356.

1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 15.

See representative reaction procedure. SiO₂ flash chromatography (5:2 hexanes/EtOAc with 0.5% AcOH) afforded the title compound 15 as a colorless oil (122 mg, 68% yield): ¹H NMR (400 MHz, (CD₃)₂CO) δ 8.09–7.91 (m, 2H), 7.87 (s, 1H), 7.49–7.28 (m, 3H), 7.00 (s, 1H), 6.49 (s, 1H), 6.03 (d, J = 22.9 Hz, 1H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 141.1, 139.0, 132.3, 128.3, 125.4, 125.1, 123.8 (t, J_CF = 2.2 Hz, 1C), 123.5, 123.1 (q, J_CF = 287 Hz, 1C), 117.8 (dd, J_CF = 259, 253 Hz, 1C), 94.0 (tq, J_CF = 30.8, 28.0 Hz, 1C), 69.2 (dd, J_CF = 33.9, 22.5 Hz, 1C); ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.6 (dd, J = 13.1, 11.2 Hz, 3F), −118.0 (dq, J = 262, 13.1 Hz, 1F), −129.1 (ddq, J = 262, 22.5, 11.2 Hz, 1F); IR (film) v_max 3368, 1625, 1428, 1204, 1160, 1070 cm⁻¹; HRMS (ESI) m/z calcd for C₁₂H₉F₅O₃SNa (M+Na)⁺ 351.0090, found 351.0086.

1-(Benzofuran-3-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol 16.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc with 1.0% AcOH) afforded the title compound 16 as a colorless oil (112 mg, 65% yield): ¹H NMR (400 MHz, (CD₃)₂CO) δ 7.67 (ddd, J = 7.7, 1.2, 0.7 Hz, 1H), 7.54, (dd, J = 8.2, 0.8 Hz, 1H), 7.35 (td, J = 7.8, 1.2 Hz, 1H), 7.27 (td, J = 7.4, 0.9 Hz, 1H), 7.06 (s, 1H), 6.84 (br s, 2H), 5.72 (dd, J = 21.2, 2.6 Hz, 1H), 3.26 (s, 1H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 155.9, 153.4, 128.8, 125.7, 123.9, 123.0 (q, J_CF = 287 Hz, 1C), 122.3, 117.4 (dd, J_CF = 260, 255 Hz, 1C), 112.0, 107.8, 93.7 (qdd, J_CF = 31.2, 29.3, 26.8 Hz, 1C), 68.3 (dd, J_CF = 32.7, 22.7 Hz, 1C); ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.7 (dd, J = 12.9, 10.9 Hz, 3F), −119.0 (dqd, J = 261, 13.0, 3.0 Hz, 1F), −128.5 (ddq, J = 261, 21.5, 10.8, 1F); IR (film) v_max 3368, 1619, 1454, 1205, 1161, 1073 cm⁻¹; HRMS (ESI) m/z calcd for C₁₂H₉F₅O₄Na (M+Na)⁺ 335.0319, found 335.0314.

(E)-1,1,1,3,3-Pentafluoro-6-phenylhex-5-ene-2,2,4-triol 17.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc with 1.0% AcOH) afforded the title compound 17 as a colorless oil (86 mg, 52% yield). All spectral and characterization data matched the reported data.²⁵

(5S,6R,7R)-5,6,7-tris(benzyloxy)-7-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1,1,1,3,3-pentafluoroheptane-2,2,4-triol 18.

Hexafluoroisopropanol (8 μL, 0.07 mmol) was added dropwise at rt to a freshly prepared solution of (i-Pr₂N)₂MgCl•LiCl²⁶ (0.63 mL, 0.44 M in THF) and the mixture was stirred for 2 h. Then, a solution of aldehyde 9¹⁸ (85 mg, 0.17 mmol) in THF (1.5 mL) was added over 10 min and the mixture was stirred for 18 h at rt. The resultant mixture was quenched with saturated aqueous NH₄Cl (2 mL), diluted with H₂O (2 mL), and extracted with Et₂O (3 × 2 mL). The organics were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. SiO₂ flash chromatography (5:2 hexanes/EtOAc) afforded the title compound 18 as a colorless oil (d.r = 2:1, 39 mg, 87% yield). All spectral and characterization data matched the reported data.¹⁸

Representative Reaction Procedure for Preparation of Pentafluoro-gem-diols.

Dess-Martin periodinane (141 mg, 0.333 mmol) was added to a solution of 10 (40 mg, 0.13 mmol) in CH₂Cl₂ (3 mL), and the reaction mixture was stirred for 24 h at rt. Next, the reaction mixture was diluted with CH₂Cl₂ (5 mL), filtered through Celite, and concentrated under reduced pressure. SiO₂ flash chromatography (5:1 hexanes/EtOAc with 1% AcOH) afforded the product 19 as a colorless oil (32 mg, 80% yield).

1-(4-Ethylphenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 19.

See representative reaction procedure: ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 3.99 (br s, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 190.9 (t, J_CF = 28.7 Hz, 1C), 153.1, 130.9 (t, J_CF = 3.5 Hz, 2C), 129.5 (t, J_CF = 2.3 Hz, 1C), 128.4 (2C), 121.4 (q, J_CF = 289 Hz, 1C), 111.7 (t, J_CF = 268 Hz, 1C), 92.8 (qt, J_CF = 32.5, 26.9 Hz, 1C), 29.2, 14.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −82.0 (t, J = 11.0 Hz, 3F), – 112.8 (q, J = 10.5 Hz, 2F); IR (film) v_max 3402, 2972, 1685, 1606, 1205, 1066 cm⁻¹; HRMS (EI) m/z calcd for C₁₂H₉F₅O₂ (M–H₂O)⁺ 280.0523, found 280.0547.

1-(4-Bromophenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 20.

See representative reaction procedure. SiO₂ flash chromatography (3: 1 hexanes/EtOAc) afforded the title compound 20 as a colorless oil (29 mg, 78% yield). All spectral and characterization data matched the reported data.¹⁶

1-(4-(tert-Butyl)phenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 21.

See representative reaction procedure. SiO₂ flash chromatography (3: 1 hexanes/EtOAc) afforded the title compound 21 as a colorless solid (54 mg, 79% yield): mp = 59–61 °C; ¹H NMR (400 MHz, (CD₃)₂CO) δ 8.12 (d, J = 8.8 Hz, 2H), 7.60 (dt, J = 8.9, 2.1 Hz, 2H), 7.47 (br s, 1H), 3.16 (br s, 1H), 1.35 (s, 9H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 188.5 (t, J_CF = 26.7 Hz, 1C), 159.0, 131.7, 131.5 (t, J_CF = 3.5 Hz, 2C), 126.3 (2C), 123.0 (q, J_CF = 288 Hz, 1C), 115.8 (t, J_CF = 263 Hz, 1C), 93.3 (qt, J_CF = 31.5, 28.0 Hz, 1C), 35.8, 31.2 (3C); ¹⁹F NMR (376 MHz, CDCl₃) δ −81.9 (t, J = 11.1 Hz, 3F), −113.1 (q, J = 11.0 Hz, 2F); IR (film) v_max 3420, 2969, 1687, 1604, 1205, 1067 cm⁻¹; HRMS (ESI) m/z calcd for C₁₄H₁₅F₅O₃Na (M+Na)⁺ 349.0839, found 349.0834.

2,2,4,4,4-Pentafluoro-1-(3-fluoro-4-methoxyphenyl)-3,3-dihydroxybutan-1-one 22.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc with 1% AcOH) afforded the title compound 22 as a colorless oil (44 mg, 88% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 11.8, 1.9 Hz, 1H), 7.05 (t, J = 8.4 Hz, 1H), 4.89 (br s, 1H), 4.00 (s, 3H), 1.82 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 188.7 (t, J_CF = 29.3 Hz, 1C), 154.3 (d, J_CF = 10.7 Hz, 1C), 151.9 (d, J_CF = 248 Hz, 1C), 129.2 (q, J_CF = 3.9 Hz, 1C), 124.7 (d, J = 5.0 Hz, 1C), 121.1 (q, J_CF = 286 Hz, 1C), 118.2 (dt, J_CF = 20.0, 3.0 Hz, 1C), 112.7, (t, J_CF = 267 Hz, 1C), 92.9 (qt, J_CF = 32.5, 26.9 Hz, 1C), 56.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −81.9 (t, J = 11.0 Hz, 3F), −113.0 (q, J = 11.0 Hz, 2F), −134.6 (dd, J = 11.8, 8.2 Hz, 1F); IR (film) v_max 3429, 2950, 1684, 1608, 1520, 1442, 1288, 1205, 1108 cm⁻¹; HRMS (ESI) m/z calcd for C₁₁H₈F₆O₄Na (M+Na)⁺ 341.0224, found 341.0229.

1-(Benzo[1,3]dioxol-5-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 23.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc with 1% AcOH) afforded the title compound 23 as a colorless oil (42 mg, 84% yield). All spectral and characterization data matched the reported data.⁶

1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 24.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc with 1% AcOH) afforded the title compound 24 as a colorless oil (43 mg, 80% yield). All spectral and characterization data matched the reported data.¹¹

1-(Benzofuran-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 25.

See representative reaction procedure. SiO₂ flash chromatography (5:2 hexanes/EtOAc) afforded the title compound 25 as a yellow solid (43 mg, 79% yield): mp = 72–74 °C; ¹H NMR (400 MHz, (CD₃)₂CO) δ 8.09–8.01 (m, 1H), 7.93 (dd, J = 7.9, 0.6 Hz, 1H), 7.75–7.56 (m, 3H), 7.47–7.36 (m, 1H), 3.21 (br s, 1H); ¹³C NMR (100 MHz, (CD₃)₂CO) δ 177.7 (t, J_CF = 28.6 Hz, 1C), 156.8, 149.9, 130.7, 127.8, 125.4, 125.3, 123.0 (q, J = 288, 1C), 121.2 (t, J_CF = 5.8 Hz, 1C), 115.3 (t, J_CF = 262 Hz, 1C), 113.0, 93.2 (qt, J_CF = 32.0, 27.8 Hz, 1C); ¹⁹F NMR (376 MHz, (CD₃)₂CO) δ −81.6 (t, J = 10.2 Hz, 3F), −116.5 (qd, J = 10.2, 2.0); IR (film) v_max 3406, 1673, 1614, 1546, 1335, 1191, 1127, 1071 cm⁻¹; HRMS (ESI) m/z calcd for C₁₂H₇F₅O₄Na (M+Na)⁺ 333.0162, found 333.0156.

(E)-4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 26.

See representative reaction procedure. SiO₂ flash chromatography (3:1 hexanes/EtOAc) afforded the title compound 26 as a colorless oil (20 mg, 41% yield). All spectral and characterization data matched the reported data.¹¹

((2,2-Difluoro-1-(naphthalen-2-yl)vinyl)oxy)trimethylsilane 29.

A solution of n-BuLi (1 mL, 1.8 M in hexanes) was added dropwise to a −78 °C solution of hexamethyldisilazane (3 mL, 0.6 M in THF) and the mixture was stirred for 30 min at −78 °C. Then, a −78 °C solution of 28⁶ (300 mg, 0.94 mmol) in THF (3.6 mL) was added slowly, followed by the rapid addition of TMSCl (59 μL, 0.47 mmol). The mixture was stirred for 20 min at −78 °C, warmed to rt, and then concentrated under reduced pressure. The residue was dissolved in hexanes (20 mL), filtered through Celite, and concentrated under reduced pressure to provide the title compound 29 as a colorless oil (61 mg, 47% yield): ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 7.87–7.80 (m, 3H), 7.63 (dt, J = 8.7, 1.7 Hz, 1H), 7.53–7.46 (m, 2H), 0.23 (d, J = 0.9 Hz, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 155.1 (dd, J_CF = 286, 284 Hz, 1C), 133.0, 132.7, 130.1 (dd, J_CF = 7.2, 1.5 Hz, 1C), 128.2, 127.9, 127.6, 126.3 (2C), 125.2 (dd, J_CF = 6.4, 5.0 Hz, 1C), 123.5 (dd, J_CF = 7.9, 2.6 Hz, 1C), 114.2 (dd, J_CF = 34.2, 19.4 Hz, 1C), 0.2 (d, J_CF = 1.2 Hz, 3C); ¹⁹F NMR (376 MHz, CDCl₃) δ −99.9 (d, J = 66.7 Hz, 1F), −112.1 (d, J = 66.6 Hz, 1F); IR (film) v_max 3059, 2962, 1719, 1261, 1252, 1151 cm⁻¹; HRMS (ESI) m/z calcd for C₁₅H₁₆F₂OSi (M)⁺ 278.0938, found 278.0931.

2,2-Difluoro-2-(4-methoxyphenyl)-1-phenylethan-1-one 31.

A solution of n-BuLi (3.1 mL, 1.7 M in hexanes) was added dropwise to a −78 °C solution of hexamethyldisilazane (9 mL, 0.6 M in THF) and the mixture was stirred for 30 min at −78 °C. Then, a solution of 30¹³ (715 mg, 2.65 mmol) in THF (9.8 mL) was added slowly, followed by the rapid addition of TMSCl (504 μL, 3.97 mmol). The mixture was stirred for 10 min at −78 °C, warmed to rt, and concentrated under reduced pressure. The residue was dissolved in hexanes (25 mL), filtered through Celite, and concentrated under reduced pressure. The residue was immediately dissolved in toluene (1.2 mL) under an argon atmosphere and 4-bromoanisole (99 μL, 0.79 mmol), Pd(OAc)₂ (9 mg, 0.04 mmol), and Bu₃SnF (736 mg, 2.38 mmol) were added. Next, a solution of t-Bu₃P (79 μL, 1.0 M in toluene) was added dropwise and the reaction mixture was heated to 85 °C. After 13.5 h. the reaction mixture was cooled to rt, diluted with EtOAc (16 mL), and decanted with additional EtOAc (10 mL). The mixture was treated with saturated aqueous KF (5 mL) and stirred for 1 h at rt. Next, the reaction mixture was filtered through Celite and extracted with EtOAc (3 × 5 mL). The organics were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. SiO₂ flash chromatography (10:1 hexanes/EtOAc) afforded the title compound 31 as a colorless oil (163 mg, 78%). All spectral and characterization data matched the reported data.²⁹