Synthesis of α-Halo-α,α-Difluoromethyl Ketones by a Trifluoroacetate Release/Halogenation Protocol

Abstract

Three series of α-halo-α,α-difluoromethyl ketones are prepared from highly α-fluorinated gem-diols by exploiting the facile release of trifluoroacetate, followed by immediate trapping of the liberated α,α-difluoroenolate with an electrophilic chlorine, bromine, or iodine source. The products are typically isolated in good yields, even in the case of sensitive, α-iodo-α,α-difluoromethyl ketones. Also, we demonstrate that an α-iodo-α,α-difluoromethyl ketone will participate in a copper-promoted reaction to forge a new carbon–carbon bond.

Fluorinated organic compounds have attracted considerable attention from the pharmaceutical, chemical, and agrochemical industries.^1,2 Although multiple synthetic methods are available to introduce fluorine or a trifluoromethyl group, fewer methods are available to install a difluoromethylene group.^3–7 Typically, α-halo-α,α-difluoroacetates are used as building blocks to prepare compounds with difluoromethylene groups.^8–11 Unfortunately, there are very few synthetic methods that can be used to assemble α-halo-α,α-difluoroacetates or other α-halo-α,α-difluoro centers adjacent to carbonyl groups, especially α-halo-α,α-difluoromethyl ketones.^8–15 Existing synthetic strategies to assemble α-halo-α,α-difluoromethyl ketones rely heavily on halogenating α,α-difluoroenoxysilanes^13,14 or adding Grignard reagents into α-bromo-α,α-difluoroacetates or α-chloro-α,α-difluoroacetates (Figure 1).^8,9 Typically, α,α-difluoroenoxysilanes arise from the silylation of a metalloenolate formed after carbon–halogen fragmentation on a α-halo-α,α-difluoromethyl group or on a trifluoromethyl group adjacent to a carbonyl group. Our synthetic plan is an alternative method to assemble α-halo-α,α-difluoromethyl ketones by halogenation of the α,α-difluoroenolate generated from by the facile release of trifluoroacetate and does not require α,α-difluoroenoxysilanes, their precursors, or α-halo-α,α-difluoroacetates.

Figure 1.

Three common methods to prepare α-halo-α,α-difluoromethyl ketones.

The strategy to release trifluoroacetate is based on a report in 1968 that hexafluoroacetone hydrate fragments to eliminate trifluoroacetate.¹⁶ We have recently demonstrated that this fragmentation can be used to generate α,α-difluoroenolates from highly α-fluorinated gem-diols under very mild conditions (i.e. LiBr/Et₃N) and subsequently used in aldol reactions.¹⁷ The major benefits of using this approach are that it is mild, versatile, and typically finished after 3 min at room temperature. The release of trifluoroacetate is rarely explored in synthesis, but other difficult transformations can be accomplished.¹⁸ We now aim to extend this method and trap the difluoroenolate with electrophilic halogenation reagents (Figure 2). We hypothesize that this strategy will be compatible with common halogenation reagents and allow isolation of these sensitive, highly halogenated products. Herein, we describe a versatile, high-yielding protocol that can be used to assemble α-halo-α,α-difluoromethyl ketones that is based on the novel halogenation of α,α-difluoroenolates generated by the facile release of trifluoroacetate. Reactions conditions for chlorination, bromination, and iodination are described and the tri-halogenated products are isolated in good yields. Also, we demonstrate that an α-iodo-α,α-difluoromethyl ketone, which is a highly sensitive organic compound, will participate in a copper-promoted reaction to forge a new carbon–carbon bond.

Figure 2.

Trifluoroacetate release/halogenation strategy.

We have previously reported an efficient, two-step synthesis of highly α-fluorinated gem-diols from methyl ketones.¹⁷ This method was based on the fluorination work of Ley and coworkers.¹⁹ Using the α-fluorinated gem-diols, we discovered that trifluoroacetate release provided the desired brominated product after the starting material was treated with LiBr, Et₃N and Br₂. Even though the reagent bromine served to brominate the difluoroenolate generated in situ, a significant excess of base (i.e., Et₃N) was needed to execute the reaction, likely due to the presence of acidic impurities in bromine. Therefore, we surveyed other electrophilic sources of bromine as part of our optimization efforts but found that the common brominating reagent, NBS, did not provide a brominated product after trifluoroacetate release. Ultimately, we identified the protocol of Shreeve using LiBr/Selectfluor to be an ideal source of electrophilic bromine.²⁰ Using gem-diols 1–4, the combination of LiBr/Selectfluor/Et₃N routinely provided high yields of the respective α-bromo-α,α-difluoroketones 5–8 (Table 1). Bromination on the aromatic rings in substrates 1–4 was not observed under these conditions. Indeed, the substrates have very limited exposure to the halogen source, because trifluoroacetate release is complete after 30 min at room temperature. Also, evidence of the exclusive release of trifluoroacetate from these substrates was obtained as trifluoroacetate was observed in the crude reaction mixture by ¹⁹F NMR (data not shown).

Table 1.

Strategy for α-bromo-α,α-difluoromethyl ketones.

entry	substrate	reagent	major product	yielda
1		Selectfluor		87%
2	1	Br2	5	80%
3		Selectfluor		75%
4		Selectfluor		81%
5	3	Br2	7	81%
6		Selectfluor		72%

^aIsolated yields.

Amides with an α,α-difluoro-α-iodomethyl group adjacent to the carbonyl group are synthetically useful due to their propensity to participate in metal-mediated reactions.^21,22 For example in 2010, copper-mediated cross-coupling with difluoroiodoacetamides was demonstrated by Hu and coworkers.²¹ When we attempted trifluoroacetate release/iodination with 1, the combination of LiI/Selectfluor/Et₃N did not provide a high conversion to the α,α-difluoro-α-iodomethyl ketone as expected. Instead, the additional formation of the α,α-difluoromethyl ketone 9 along with the self-aldol condensation product 10 was observed (eq 1). The formation of product 10 demonstrates that the protonation of the difluoroenolate to 9 and subsequent reaction by additional difluoroenolate will commence if an appropriate electrophile is not present. Also, LiI/I₂/Et₃N gave similar results. However, by substituting LiBr for LiI and using I₂ and Et₃N, the gem-diols 1–3 and 11–13 provided the α,α-difluoro-α-iodomethyl ketones 14–19 in good yields (Table 2). The iodinated products were not stable to storage, as expected,²³ but would readily participate in subsequent coupling reactions (see below). During these investigations, additional stability data for highly α-fluorinated gem-diols was gathered, as the α,β-unsaturated substrate 11 was reduced in high yield to the saturated alkyl derivative 12 (eq 2). Although trace amounts of the ethanol-derived hemi-acetal were formed, dilute acid provided the gem-diol 12 (for subsequent iodination to 18).

(1)

$$\mathbf{11}\underset{\underset{87\%(2\text{steps})}{2)0.5\mathrm{M}{\mathrm{H}}_2{\text{SO}}_4,\text{THF}}}{\overset{1){\mathrm{H}}_2,\text{Pd}/\mathrm{C},\text{EtOH}}{\to }}\mathbf{12}$$ (2)

Table 2.

Strategy for α,α-difluoro-α-iodo-methyl ketones.

entry	substrate	major product	yielda
1	1		73%
2	2		65%
3	3		79%
4			67%
5			83%
6			66%

^aIsolated yields. Products are not stable to storage.

^bSynthesized from 11 (see eq 2).

For the preparation of α-chloro-α,α-difluoromethyl ketones, chlorine gas was not investigated due to its hazardous nature. A survey of alternative reagents to promote the trifluoroacetate release/chlorination was conducted, and finally, the combination of LiCl/NCS/Et₃N was found to be optimal (Table 3). This strategy minimized the formation of both the α,α-difluoromethyl ketone and the self-aldol condensation product as previously observed during the iodination studies (see eq 1). The α-chloro-α,α-difluoromethyl ketones 20–23 were isolated in good yields using this process. However, the incorporation of two additional chlorines at the other α-position of the carbonyl group was observed with the alkyl substrate 12. Clearly, these two protons in 12 are highly acidic, therefore enolate formation and subsequent chlorination is also favorable under these reaction conditions. On the other hand, over-iodination was not prevalent when 12 was subjected similar conditions (see Table 2), so perhaps other factors, such as sterics or the nature of the electrophile, may contribute. Indeed, adding a large excess of I₂ along with LiBr and Et₃N to substrate 12 did not promote the formation products from over-iodination (analogous to over-chlorination in 23), instead benzylic iodination was observed.

Table 3.

Strategy for α-chloro-α,α-difluoromethyl ketones.

entry	substrate	major product	yielda
1	1		80%
2	2		83%
3	11		63%
4	12		73%

^aIsolated yields.

With efficient access to α-halo-α,α-difluoromethyl ketones, we next sought to explore new synthetic roles for these compounds. Based on previous literature precedent with α,α-difluoro-α-iodoacetamides^21,22 and α-bromo-α,α-difluoroacetates,²⁴ we examined copper-promoted reactions with α-iodo-α,α-difluoromethyl ketone 14 (Scheme 1). To our knowledge, such reactions with copper have not been applied to α-halo-α,α-difluoromethyl ketones, and only reactions initiated by UV-irradiation and Pd(Ph₃)₄ have been described.^23,25,26 Upon treatment of α-iodo-α,α-difluoromethyl ketone 14 and olefin 24 with Cu in DMSO followed by heating, the difluoroketone 25 was isolated as the major isomer in a 6:1 mixture with the terminal olefin isomer. Although a modest yield of 25 was obtained (i.e. 50%), this yield correlates well with previous work with acetamides²¹ and avoids the isolation of an iodinated product unlike prior work.^23,25,26 Indeed, additional synthetic strategies for difluoroketones are quite valuable due to the diverse biological activities of these fluorinated compounds.²⁷

Scheme 1.

Copper-mediated reaction.

In conclusion, we have successfully demonstrated that synthetically valuable α-halo-α,α-difluoromethyl ketones can be formed under mild reaction conditions with high yields using a trifluoroacetate release/halogenation protocol. These data correlate well with our previous findings that trifluoroacetate release is a quick, powerful, yet mild reaction to generate reactive intermediates¹⁷ and to synthesize sensitive compounds.^17,18 Also, we have demonstrated that an α-iodo-α,α-difluoromethyl ketone will participate in a copper-promoted reaction to forge a new carbon-carbon bond. Additional studies to elucidate the scope of trifluoroacetate release are underway and will be reported in due course.

Experimental Section

Representative Procedure for the Synthesis of α-Bromo-α,α-difluoromethyl ketones

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)-butan-1-one 1¹⁷ (30 mg, 0.094 mmol) in THF (940 µL) was added LiBr (48 mg, 0.56 mmol) followed by Selectfluor (67 mg, 0.19 mmol). The reaction mixture was stirred for 1 min, and then Et₃N (25 µL, 0.19 mmol) was added. After stirring for 30 min at rt, the reaction mixture was quenched with saturated aqueous NH₄Cl (1 mL). The mixture was extracted with EtOAc (1 mL × 2), and the organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash chromatography (5% Et₂O in hexanes) afforded the 2-bromo-2,2-difluoro-1-(naphthalen-2-yl)ethanone 5 as a colorless oil (23 mg) in 87% yield.

2-Bromo-2,2-difluoro-1-(naphthalen-2-yl)ethanone 5

See representative reaction procedure: ¹H NMR (500 MHz, CDCl₃) δ 8.74 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.69 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.61 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 181.4 (t, J_CF = 25.6 Hz, 1C), 136.3, 133.5, 132.1, 130.2, 129.9, 128.9, 127.9, 127.3, 126.3, 124.9, 113.7 (t, J_CF = 318 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –58.2 (s, 2F); IR (film) ν_max 1705.3, 1626.7, 1152.6, 1119.3 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₇BrF₂O (M)⁺ 283.9648, found 283.9651.

1-(Benzo[1,3]dioxol-5-yl)-2-bromo-2,2-difluoroethanone 6

See representative reaction procedure. 1-(Benzo[1,3]dioxol-6-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 2¹⁷ (10 mg, 0.03 mmol), LiBr (16 mg, 0.19 mmol), Selectfluor (22 mg, 0.063 mmol), and Et₃N (9 µL, 0.06 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided the title compound as a colorless oil (6.4 mg) in 75% yield: ¹H NMR (500 MHz, CDCl₃) δ 7.82 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.11 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 179.7 (t, J_CF = 25.5 Hz, 1C), 153.6, 148.4, 128.0, 123.3, 113.6 (t, J_CF = 319 Hz, 1C), 110.0, 108.4, 102.4; ¹⁹F NMR (282 MHz, CDCl₃) δ –57.8 (s, 2F); IR (film) ν_max 2924.0, 1678.7, 1455.3, 1266.4, 1070.6 cm⁻¹; HRMS (EI/CI) m/z calcd for C₉H₅BrF₂O₃ (M)⁺ 277.9390, found 277.9393.

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

To a −78 °C solution of hexamethyldisilazane (165 mg, 1.01 mmol) in THF (1.5 mL) was added a solution of n-BuLi (400 µL, 2.5 M in hexanes). The mixture was stirred for 30 min at −78 °C, and then a solution of 1-(benzothiophen-3-yl)ethanone (150 mg, 0.85 mmol) in THF (1.5 mL) was added dropwise. After an additional 1 h at −78 °C, 2,2,2-trifluoroethyl 2,2,2-trifluoroacetate (250 mg, 1.3 mmol) was added dropwise, and the mixture was stirred for 30 min at the same temperature. Next, the reaction mixture was quenched at − 78 °C with 0.1 M H₂SO₄ (3 mL) and allowed to warm to rt. The mixture was extracted with CH₂Cl₂ (3 mL × 2). The combined organics were dried over Na₂SO₄ and concentrated under reduced pressure to provide the crude product (230 mg). The crude product was dissolved in CH₃CN (6 mL), treated with Selectfluor (750 mg, 2.1 mmol), and stirred at rt for 24 h. The reaction mixture was diluted with EtOAc (6 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The product was dissolved in CH₂Cl₂ (10 mL), washed with H₂O (5 mL × 2) and brine (5 mL), and the concentrated under reduced pressure to provide the 1-(benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 3 as a colorless solid (250 mg) in 90% yield: mp 72–74 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.90 (t, J = 1.6 Hz, 1H), 8.68 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.58 (m, 1H), 7.53–7.49 (m, 1H), 4.74 (br s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 184.9 (t, J_CF = 28.0 Hz, 1C), 144.8 (t, J_CF = 10.1 Hz, 1C), 138.7, 136.7, 128.4, 126.8, 126.3, 125.0, 122.5, 120.9 (q, J_CF = 287 Hz, 1C), 111.0 (t, J_CF = 269 Hz, 1C), 92.8 (qt, J = 27.8, 5.5 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –81.8 (t, J = 11.0 Hz, 3F), –112.6 (q, J = 10.9 Hz, 2F); IR (film) ν_max 3368.3, 1662.9, 1488.3, 1461.0, 1424.5, 1204.7, 1067.2 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₇F₅O₃S (M–H₂O)⁺ 307.9931, found 307.9936.

1-(Benzothiophen-3-yl)-2-bromo-2,2-difluoroethanone 7

See representative reaction procedure. 1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 3 (10 mg, 0.03 mmol), LiBr (16 mg, 0.19 mmol), Selectfluor (22 mg, 0.063 mmol), and Et₃N (9 µL, 0.06 mmol) were used. Purification by 88semi-prep HPLC (99.9:0.1 hexanes/EtOAc) provided title compound as a colorless oil (7.2 mg) in 81% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.75–8.72 (m, 2H), 7.93 (dt, J = 8.0, 1.0 Hz, 1H), 7.58 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.50 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 176.2 (t, J_CF = 26.2 Hz, 1C), 142.2 (t, J_CF = 6.1 Hz, 1C), 139.0, 137.1, 126.6, 126.3, 125.6, 125.3, 122.4, 113.5 (t, J_CF = 319 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –58.1 (s, 2F); IR (film) ν_max 1688.0, 1489.5, 1142.7, 1102.0 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₀H₅BrF₂OS (M)⁺ 289.9213, found 289.9211.

2-Bromo-1-(4-chlorophenyl)-2,2-difluoroethanone 8

See representative reaction procedure. 1-(4-Chlorophenyl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 4¹⁷ (20 mg, 0.07 mmol), LiBr (16 mg, 0.39 mmol), Selectfluor (47 mg, 0.13 mmol), and Et₃N (18 µL, 0.13 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a colorless oil (12.7 mg) in 72% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 180.3 (t, J_CF = 26.2 Hz, 1C), 142.0, 132.0 (2C), 129.4 (2C), 127.4, 113.3 (t, J_CF = 318 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –59.1 (s, 2F); IR (film) ν_max 1713.1, 1589.9, 1489.7, 1276.7, 1159.5 cm⁻¹; HRMS (EI/CI) m/z calcd for C₈H₄BrClF₂O (M)⁺ 267.9102, found 267.9100.

Representative Procedure for the Synthesis of α,α-Difluoro-α-iodomethyl ketones

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalen-3-yl)butan-1-one 1¹⁷ (10 mg, 0.03 mmol) in THF (310 µL) was added LiBr (16 mg, 0.19 mmol) followed by I₂ (16 mg, 0.062 mmol). The reaction mixture was stirred for 1 min, and then Et₃N (9 µL, 0.06 mmol) was added. After stirring for 30 min at rt, the reaction mixture was quenched with saturated aqueous Na₂S₂O₃ (1 mL). The mixture was extracted in EtOAc (1 mL × 2), and the organics were dried over Na₂SO₄ and concentrated under reduced pressure. Purification by semi-prep HPLC (99.9:0.1 hexanes/EtOAc) afforded the 2,2-difluoro-2-iodo-1-(naphthalen-3-yl)ethanone 14 as a pale yellow oil (7.6 mg) in 73% yield.

2,2-Difluoro-2-iodo-1-(naphthalen-2-yl)ethanone 14

See representative reaction procedure: ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.68 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 182.4 (t, J_CF = 23.1 Hz, 1C), 136.2, 133.6, 132.2, 130.2, 129.9, 128.9, 127.9, 127.3, 125.6, 125.2, 95.8 (t, J_CF = 326 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –54.6 (s, 2F); IR (film) ν_max 1697.2, 1468.5, 1280.4, 1143.4, 1116.0 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₇F₂IO (M)⁺ 331.9510, found 331.9512.

1-(Benzo[1,3]dioxol-5-yl)-2,2-difluoro-2-iodoethanone 15

See representative reaction procedure. 1-(Benzo[1,3]dioxol-6-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 2¹⁷ (10 mg, 0.03 mmol), LiBr (16 mg, 0.19 mmol), I₂ (16 mg, 0.063 mmol), and Et₃N (9 µL, 0.06 mmol) were used. Purification by semi-prep HPLC (99.9:0.1 hexanes/EtOAc) afforded the title compound as a pale yellow oil (6.8 mg) in 65% yield: ¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J = 9.3 Hz, 1H), 7.58 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.11 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 180.7 (t, J_CF = 22.9 Hz, 1C), 153.5, 148.3, 128.2, 122.5, 110.1, 108.4, 102.3, 95.5 (t, J_CF = 326 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –54.1 (s, 2F); IR (film) ν_max 2910.2, 1692.6, 1606.2, 1504.9, 1447.9, 1354.6, 1267.6, 1093.9 cm⁻¹; HRMS (EI/CI) m/z calcd for C₉H₅F₂IO₃ (M)⁺ 325.9252, found 325.9259.

1-(Benzothiophen-3-yl)-2,2-difluoro-2-iodoethanone 16

See representative reaction procedure. 1-(Benzothiophen-3-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 3 (10 mg, 0.03 mmol), LiBr (16 mg, 0.19 mmol), I₂ (16 mg, 0.063 mmol), and Et₃N (9 µL, 0.06 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a pale yellow oil (8.1 mg) in 79% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.74–8.71 (m, 2H), 7.92 (dt, J = 8.2, 0.9 Hz, 1H), 7.57 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.49 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 177.5 (t, J_CF = 23.5 Hz, 1C), 142.0 (t, J_CF = 6.8 Hz, 1C), 138.9, 137.2, 126.6, 126.2, 125.4, 124.6, 122.3, 95.6 (t, J_CF = 326 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –54.1 (s, 2F); IR (film) ν_max 3116.1, 1678.3, 1488.8, 1459.3, 1360.7, 1228.5, 1096.8 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₀H₅F₂IOS (M)⁺ 337.9074, found 337.9077.

(E)-4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 11

To a −78 °C solution of hexamethyldisilazane (265 mg, 1.64 mmol) in THF (3 mL) was added a solution of n-BuLi (650 µL, 2.5 M in hexanes). The mixture was stirred for 30 min at −78 °C, and then a solution of (E)-4-phenylbut-3-en-2-one (200 mg, 1.37 mmol) in THF (3 mL) was added dropwise. After an additional 1 h at −78 °C, 2,2,2-trifluoroethyl 2,2,2-trifluoroacetate (400 mg, 2.05 mmol) was added dropwise, and the mixture was stirred for 30 min at the same temperature. Next, the reaction mixture was quenched at − 78 °C with 0.1 M H₂SO₄ (6 mL) and allowed to warm to rt. The mixture was extracted with CH₂Cl₂ (6 mL × 2). The combined organics were dried over Na₂SO₄ and concentrated under reduced pressure to provide the crude product (335 mg). The crude product was dissolved in CH₃CN (5 mL), treated with Selectfluor (1.24 g, 3.50 mmol), and stirred at rt for 24 h. The reaction mixture was diluted with EtOAc (10 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The product was dissolved in CH₂Cl₂ (20 mL), washed with H₂O (10 mL × 2) and brine (10 mL), and the concentrated under reduced pressure to provide the 4,4,6,6,6-pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 11 as a colorless solid (400 mg) in 99% yield: mp 68–70 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J = 15.9 Hz, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.53–7.50 (m, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 15.9 Hz, 1H), 4.61 (br s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 190.4 (t, J_CF = 28.1 Hz, 1C), 150.9, 133.3, 132.6, 129.6 (2C), 129.3 (2C), 120.8 (q, J_CF = 288 Hz, 1C), 116.8, 110.0 (t, J_CF = 266 Hz, 1C), 92.6 (qt, J = 27.0, 5.8 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –82.3 (t, J = 10.3 Hz, 3F), −120.8 (q, J = 10.1 Hz, 2F); IR (film) ν_max 3398.9, 1697.1, 1594.9, 1575.0, 1451.5, 1206.0, 1072.3 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₉F₅O₃ (M–H₂O)⁺ 278.0366, found 278.0363.

(E)-1,1-Difluoro-1-iodo-4-phenylbut-3-en-2-one 17

See representative reaction procedure. (E)-4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 11 (10 mg, 0.03 mmol), LiBr (17.5 mg, 0.20 mmol), I₂ (17 mg, 0.067 mmol), and Et₃N (10 µL, 0.07 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a pale yellow oil (7.0 mg) in 67% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J = 15.8 Hz, 1H), 7.65 (dd, J = 7.7, 1.5 Hz, 2H), 7.51–7.44 (m, 3H), 7.09 (dt, J = 15.8, 1.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 181.9 (t, J_CF = 23.3 Hz, 1C), 149.9, 133.6, 132.1, 129.2 (4C), 114.2, 96.9 (t, J_CF = 326 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –60.2 (s, 2F); IR (film) ν_max 3055.5, 3032.0, 2923.7, 1703.6, 1608.0, 1496.0, 1449.3, 1343.5, 1206.6, 1053.0 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₀H₇F₂IO (M)⁺ 307.9510, found 307.9508.

4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhexan-3-one 12

To a solution of (E)-4,4,6,6,6-pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 11 (100 mg, 0.34 mmol) in EtOH (3.5 mL) was added Pd/C (17 mg, 0.17 mmol). The reaction mixture was stirred under a H₂ atmosphere for 12 h. The reaction mixture was then filtered through a pad of Celite and concentrated under reduced pressure. The residue was dissolved in 1:1 mixture of THF/0.5 M H₂SO₄ (10 mL) and vigorously stirred for 24 h at rt. The reaction mixture was extracted with EtOAc (5 mL × 2), and the organics were dried over Na₂SO₄ and concentrated under reduced pressure to provide the 4,4,6,6,6-pentafluoro-5,5-dihydroxy-1-phenylhexan-3-one 12. as a colorless oil (86.6 mg) in 86% yield: ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.30 (m, 2H), 7.25–7.19 (m, 3H), 4.19 (br s, 2H), 3.18 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 202.6 (t, J_CF = 28.8 Hz, 1C), 139.3, 128.7 (2C), 128.3 (2C), 126.6, 120.6 (q, J_CF = 288 Hz, 1C), 109.5 (t, J_CF = 267 Hz, 1C), 92.3 (qt, J = 27.4, 5.9 Hz, 1C), 39.6, 28.1; ¹⁹F NMR (282 MHz, CDCl₃) δ –82.1 (t, J = 10.2 Hz, 3F), −120.8 (q, J = 10.2 Hz, 2F); IR (film) ν_max 3462.1, 1742.2, 1209.8, 1171.9, 1069.0 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₁₁F₅O₃ (M–H₂O)⁺ 280.0523, found 280.0525.

1,1-Difluoro-1-iodo-4-phenylbutan-2-one 18

See representative reaction procedure. 4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhexan-3-one 12 (10 mg, 0.036 mmol), LiBr (17 mg, 0.20 mmol), I₂ (17 mg, 0.067 mmol), and Et₃N (10 µL, 0.07 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a pale yellow oil (8.6 mg) in 83% yield: ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.21 (m, 5H), 3.16 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 192.3 (t, J_CF = 24.6 Hz, 1C), 139.5, 128.7 (2C), 128.4 (2C), 126.6, 94.7 (t, J_CF = 334 Hz, 1C), 35.2, 29.1; ¹⁹F NMR (282 MHz, CDCl₃) δ –62.1 (s, 2F); IR (film) ν_max 2929.2, 1748.0, 1585.3, 1496.5, 1454.7, 1134.6, 1049.9 cm⁻¹; HRMS (ESI) m/z calcd for C₁₀H₉F₂IO (M+H)⁺ 310.9744, found 310.9739.

1-(Adamantan-1-yl)-2,2-difluoro-2-iodoethanone 19

See representative reaction procedure. 1-Adamantyl-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 13¹⁷ (10 mg, 0.030 mmol), LiBr (16 mg, 0.19 mmol), I₂ (16 mg, 0.063 mmol), and Et₃N (9 µL, 0.06 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a pale yellow oil (7.0 mg) in 66% yield: ¹H NMR (500 MHz, CDCl₃) δ 2.07–2.05 (m, 9H), 1.75 (q, J = 12.2 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 196.3 (t, J_CF = 20.7 Hz, 1C), 97.4 (t, J_CF = 331 Hz, 1C), 45.4, 38.2 (3C), 36.2 (3C), 27.7 (3C); ¹⁹F NMR (282 MHz, CDCl₃) δ –54.5 (s, 2F); IR (film) ν_max 2908.8, 2854.7, 1722.3, 1453.8, 1213.2, 1117.4 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₁₅F₂IO (M+H)⁺ 341.0214, found 341.0210.

Representative Procedure for the Synthesis of α-Chloro-α,α-difluoromethyl ketones

To a solution of 2,2,4,4,4-pentafluoro-3,3-dihydroxy-1-(naphthalen-3-yl)butan-1-one 1¹⁷ (10 mg, 0.031 mmol) in THF (310 µL) was added LiCl (8 mg, 0.2 mmol) followed by NCS (8 mg, 0.06 mmol). The reaction mixture was stirred for 1 min, and then Et₃N (9 µL, 0.06 mmol) was added. After stirring for 30 min at rt, the reaction mixture was quenched with saturated aqueous NH₄Cl (1 mL). The mixture was extracted in EtOAc (1 mL × 2), and the organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash chromatography (5% Et₂O in hexanes) afforded the 2-chloro-2,2-difluoro-1-(naphthalen-2-yl)ethanone 20 as a colorless oil (6.0 mg) in 80% yield.

2-Chloro-2,2-difluoro-1-(naphthalen-2-yl)ethanone 20

See representative reaction procedure: ¹H NMR (500 MHz, CDCl₃) δ 8.70 (s, 1H), 8.11 (dd, J = 8.7, 1.8 Hz, 1H), 8.02 (dd, J = 8.2, 0.6 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.2, 0.5 Hz, 1H), 7.69 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 181.2 (t, J_CF = 28.9 Hz, 1C), 136.3, 133.5, 132.1, 130.2, 130.0, 128.9, 127.9, 127.3, 126.5, 124.8, 120.3 (t, J_CF = 305 Hz, 1C); ¹⁹F NMR (282 MHz, CDCl₃) δ –61.2 (s, 2F); IR (film) ν_max 1709.0, 1155.0, 989.8, 818.7, 752.5 cm⁻¹; HRMS (EI/CI) m/z calcd for C₁₂H₇ClF₂O (M)⁺ 240.0154, found 240.0153.

1-(Benzo[1,3]dioxol-5-yl)-2-chloro-2,2-difluoroethanone 21

See representative reaction procedure. 1-(Benzo[1,3]dioxol-6-yl)-2,2,4,4,4-pentafluoro-3,3-dihydroxybutan-1-one 2¹⁷ (10 mg, 0.03 mmol), LiCl (8 mg, 0.19 mmol), NCS (8.5 mg, 0.065 mmol), and Et₃N (10 µL, 0.07 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a colorless oil (6.2 mg) in 83% yield: ¹H NMR (500 MHz, CDCl₃) δ 7.78 (ddt, J = 8.3, 2.0, 1.1 Hz, 1H), 7.54 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.11 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 179.4 (t, J = 28.7 Hz, 1C), 153.7, 148.4, 127.9, 123.6, 120.2 (t, J = 305 Hz, 1C), 109.8, 108.4, 102.4; ¹⁹F NMR (282 MHz, CDCl₃) δ –61.0 (s, 2F); IR (film) ν_max 1703.8, 1491.1; 1448.6; 1271.4; 1097.7; 1040.9; 995.4; 744.3 cm⁻¹; HRMS (EI/CI) m/z calcd for C₉H₅ClF₂O₃ (M)⁺ 233.9895, found 233.9894.

(E)-1-Chloro-1,1-difluoro-4-phenylbut-3-en-2-one 22

See representative reaction procedure. (E)-4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhex-1-en-3-one 11 (30 mg, 0.1 mmol), LiCl (26 mg, 0.60 mmol), NCS (27 mg, 0.20 mmol), and Et₃N (30 µL, 0.20 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a colorless oil (13.7 mg) in 63% yield: ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 15.9 Hz, 1H), 7.65 (dd, J = 5.2, 3.2 Hz, 2H), 7.51–7.44 (m, 3H), 7.06 (d, J = 15.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 180.6 (t, J_CF = 29.2 Hz, 1C), 150.2, 133.4, 132.2, 129.2 (4C), 120.2 (t, J_CF = 305 Hz, 1C), 115.7; ¹⁹F NMR (282 MHz, CDCl₃) δ –68.5 (s, 2F); IR (film) ν_max 2919.4, 1715.7, 1610.4, 1577.0, 1450.7, 1339.6, 1145.0 cm⁻¹; HRMS (ESI) m/z calcd for C₁₀H₇ClF₂O (M+H)⁺ 217.0232, found 217.0226.

1,3,3-Trichloro-1,1-difluoro-4-phenylbutan-2-one 23

See representative reaction procedure. 4,4,6,6,6-Pentafluoro-5,5-dihydroxy-1-phenylhexan-3-one 12 (10 mg, 0.033 mmol), LiCl (9 mg, 0.20 mmol), NCS (18 mg, 0.13 mmol), and Et₃N (9 µL, 0.07 mmol) were used. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a colorless oil (7.0 mg) in 73% yield: ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.34 (m, 5H), 3.72 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 180.6 (t, J_CF = 29.6 Hz, 1C), 131.8, 131.7 (2C), 128.3 (3C), 118.9 (t, J_CF = 308 Hz, 1C), 82.3, 48.7; ¹⁹F NMR (376 MHz, CDCl₃) δ –60.0 (s, 2F); IR (film) ν_max 2925.3, 2854.6, 1761.7, 1456.0, 1166.9, 1091.7 cm⁻¹; HRMS (ESI) m/z calcd for C₁₀H₇Cl₃F₂O (M+H)⁺ 286.9609, found 286.9603.

2,2-Difluoro-4,5-dimethyl-1-(naphthalen-2-yl)hex-4-en-1-one 25

A suspension of 2,2-difluoro-2-iodo-1-(naphthalen-3-yl)ethanone 14 (26 mg, 0.078 mmol), Cu powder (20 mg, 0.32 mmol), and 2,3-dimethyl-2-butene 24 (100 µL, 0.78 mmol) in DMSO (150 µL) was stirred at 60 °C for 15 h. The reaction mixture was cooled to rt, diluted with H₂O (5 mL), and extracted with EtOAc (2 mL × 2). The organics were dried over Na₂SO₄ and concentrated under reduced pressure. SiO₂ flash chromatography (5% Et₂O in hexanes) provided title compound as a colorless oil (11.2 mg) in 50% yield (6:1): ¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 13.8, 8.5 Hz, 2H), 7.64 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.58 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 3.04 (t, J = 18.7 Hz, 2H), 1.78 (s, 3H), 1.69 (s, 3H), 1.65 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 190.2 (t, J_CF = 30.9 Hz, 1C), 135.9, 132.7, 132.3, 132.0, 130.1, 129.6, 129.3, 128.5, 127.8, 126.9, 124.9, 120.1 (t, J_CF = 256 Hz, 1C), 118.3, 39.0 (t, J_CF = 22.9 Hz, 1C), 21.2, 20.9, 20.3; ¹⁹F NMR (282 MHz, CDCl₃) δ –98.9 (t, J = 18.6 Hz, 2F); IR (film) ν_max 2925.6, 1698.2, 1627.9, 1597.1, 1465.9, 1289.7, 1153.7, 1037.2 cm⁻¹; HRMS (ESI) m/z calcd for C₁₈H₁₈F₂O (M+Na)⁺ 311.1223, found 311.1233.