Copper-Mediated Radical Trifluoromethylation of Unsaturated Potassium Organotrifluoroborates

Abstract

Copper-mediated trifluoromethylation of unsaturated organotrifluoroborates with the Langlois reagent (NaSO₂CF₃) and TBHP allows the introduction of trifluoromethyl groups into a variety of organic substructures. The reactions are easy to set up, the conditions are mild and general, and the process provides access to trifluoromethylated alkynes, alkenes, arenes and heteroarenes in fair to good yields.

The unique properties of the trifluoromethyl group have been appreciated in diverse fields of chemistry.¹ The CF₃ group is notably popular with medicinal chemists as a compact, lipophilic group that slows the metabolic breakdown of aromatics.² This has led to the development of many new reagents and methods for its introduction.^3,4 Among the substrates used for these trifluoromethylations, organoboron compounds have emerged as precursors of choice because of their increasing and pivotal role in synthetic organic chemistry.⁵ Indeed, the past years have witnessed the emergence of new methods involving different classes of borylated starting materials reacting with nucleophilic, electrophilic and radical CF₃ species, all of which can be mediated or catalyzed by copper sources (Scheme 1).

Scheme 1.

Trifluoromethylations of organoboron compounds

Boronic acids were the first class of compounds studied, and in a pioneering study Qing described the oxidative trifluoromethylation of aryl-, heteroaryl-, and alkenylboronic acids by the nucleophilic Ruppert- Prakash reagent (TMSCF₃)⁶ in a process similar to Chan-Lam-Evans coupling.^7,8,9 Shortly thereafter, Buchwald developed a related, but more practical, catalytic version of this reaction,¹⁰ also achieved by Qing one year later.¹¹ Importantly, Grushin developed a protocol using simple fluoroform¹² together with alkylboronic acids that could be used in a strategy similar to that reported by Fu.¹³

The complementary use of electrophilic trifluoromethylation reagents has also been intensively studied in the case of boronic acids. Whereas Liu¹⁴ and Xiao¹⁵ described the use of trifluoromethylsulfonium salts, Shen expanded this reactivity to Togni’s reagent.¹⁶ As protodeborylation of the boronic acid starting material was observed as the main side reaction in all of these examples, the trifluoromethylation of protected boron species was also investigated. Hartwig and Goosen reported the oxidative nucleophilic trifluoromethylation of aryl pinacol boronates, but these required the use of either [(phen)CuCF₃] or K[CF₃B(OMe)₃].^17,18 The use of the electrophilic Togni reagent [3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole] was found to be more general as it could be used for arylboronates,¹⁹ aryltrifluoroborates²⁰ or alkenyltrifluoroborates.²¹

Sanford recently made a very interesting contribution to the field.²² Her group reported the conversion of aryl- and heteroarylboronic acids by trifluoromethyl radicals generated in situ from the inexpensive Langlois reagent (NaSO₂CF₃) and tert-butyl hydroperoxide (THBP).²³ This reagent was already used for the C–H trifluoromethylation of heterocycles ²⁴ and similar copper-mediated conditions were subsequently reported by Beller with an extension to alkenylboronic acids.²⁵ Importantly, Sanford’s protocol is very practical, as the reaction proceeds under ambient conditions, and isolation of the products is straightforward. Owing to their added value compared to their boronic acid and -ester counterparts,^26,27,28 an extension of this method to organotrifluoroborates was envisioned because only two examples had been reported in a study published during the course of our investigation.²⁵ Herein, efforts toward the development of such a general trifluoromethylation method are revealed.

Potassium organotrifluoroborates can be efficiently used in radical reactions,²⁹ even under aqueous conditions.³⁰ Therefore, in a quest for a general protocol, investigations were initiated under the previously reported conditions for boronic acids: NaSO₂CF₃ (3.0 equiv), TBHP (5.0 equiv), CuCl (1.0 equiv) in CH₂Cl₂/MeOH/H₂O (1:1:0.8) at rt for electron-rich substrates and NaSO₂CF₃ (3.0 equiv), TBHP (4.0 equiv), (CH₃CN)CuPF₆ (1.0 equiv), NaHCO₃ (1.0 equiv) in MeOH at rt for electron-poor substrates. Although an excess of the Langlois reagent was required, the overall process remains one of the more cost-effective owing to the lower cost of this reagent compared to other trifluoromethylation reagents. The results obtained with aryl-and heteroaryltrifluoroborates are summarized in Table 1. In all of these examples and similar to the case of boronic acids, isolation of the desired products is very easy, as these materials can be obtained with good purity by a simple aqueous work-up. As expected, electron-rich substrates such as 1a and 1c were efficiently trifluoromethylated, but a decreased yield was observed in the case of ortho-substituted products such as 2c, which may be attributed to steric hindrance. Additionally, the reaction performed with 1b led to a poor yield (21%). The case of unactivated substrates was less straightforward. The simple trifluoromethylbenzene 2d was generated from the corresponding trifluoroborate in 28% yield under the same conditions, and electron-poor arenes such as 1e and 1f required the use of modified conditions B. Under these conditions, 2e and 2f were obtained in yields of 61% and 27%, respectively. We next turned our attention to the case of heteroaryl substrates. Five- and six-membered heteroaryltrifluoroborates afforded the corresponding trifluoromethylated products in 6–67% yields, and the observed trend was the same as that seen for simple arenes. A broad variety of electron-rich substrates such as indole 1g, pyrazole 1h, thiazole 1i and benzofuran 1j afforded the desired products in good yields under generic conditions A. However, the case of electron-poor quinoline was once again problematic, and 2k was obtained in a poor 6% yield. Even though the yields obtained with electron-poor potassium organotrifluoroborates are in general lower than the ones observed with the corresponding boronic acids,²² the increased stability of the trifluoroborate salts as compared to boronic acids makes the use of the former reagents very attractive.

Table 1.

Scope of the Trifluoromethylation of Aryl- and Heteroaryltrifluoroborates^a

Entry	Substrate	Method a	Product	Yield b
1	1a	A	2a	99% (93%)
2	1b	A	2b	21% (14%)
3	1c	A	2c	66% (50%)
4	1d	A	2d	28% (−)
5	1e	B	2e	61% (34%)
6	1f	B	2f	27% (−)
7	1g	A	2g	67% (64%)
8	1h	A	2h	48% (−)
9	1i	A	2i	43% (24%)
10	1j	A	2j	53% (−)
11	1k	B	2k	6% (−)

^aConditions A: NaSO₂CF₃ (3.0 equiv), TBHP (5.0 equiv), CuCl (1.0 equiv), CH₂Cl₂/MeOH/H₂O, 1:1:0.8 ([1] = 0.1 M), open flask, rt, 12 h; conditions B: NaSO₂CF₃ (3.0 equiv), TBHP (4.0 equiv), (CH₃CN)CuPF₆ (1.0 equiv), NaHCO₃ (1.0 equiv), MeOH ([1] = 0.1 M), open flask, rt, 12 h.

^bYields determined by ¹⁹F analysis; isolated yields are reported in brackets.

To investigate the scope of the reaction further, we also evaluated the case of alkynyl- and alkenyltrifluoroborates (Table 2). Owing to the electron-rich nature of these substrates, only conditions A mentioned above were applied. Alkynyltrifluoroborates 3a and 3d afforded the desired products in fair yields, opening a new route to the preparation of trifluoromethyl-substituted alkynes. The case of alkenyltrifluoroborates 4a–d afforded valuable information. Under exactly the same conditions, simple styrene derivatives 6a and 6b were obtained in fair to good yields similar of those reported by other methods,^21,25 and only a small amount (~5%) of isomerization was detected. Moreover, the substitution pattern of the olefin was found to be crucial. When the trifluoroborate group was placed at the β-position of the aryl ring, the trisubstituted olefin 6c was obtained in a similarly good yield of 70%, but in the case where the CF₃ resides in the α-position, the yield in 6d decreased to 12%. Ultimately, no product was observed in the case of cyclic olefins such as 4e, even using specifically designed conditions for alkenyltrifluoroborates.²¹

Table 2.

Scope of the Trifluoromethylation of Alkynyl- and Alkenyltrifluoroborates

Entry	Substrate	Method a	Product	Yield b
1	3a	A	5a	50% (−)
2	3b	A	5b	51% (45%)
3	4a	A	6a	54% (−)c
4	4b	A	6b	77% (77%)c
5	4c	A	6c	70% (59%)
6	4d	A	6d	12% (10%)
7	4e	A	-	-

^aConditions A: NaSO₂CF₃ (3.0 equiv), TBHP (5.0 equiv), CuCl (1.0 equiv), CH₂Cl₂/MeOH/H₂O, 1:1:0.8 ([3 or 4] = 0.1 M), open flask, rt, 12 h.

^bYields determined by ¹⁹F analysis; isolated yields are reported in brackets.

^cWith ~5% of the (Z) product.

In conclusion, the copper-mediated radical trifluoromethylation of unsaturated potassium organotrifluoroborates is described. The conditions previously reported were successfully extended to various trifluoroborato-containing arenes and heteroarenes. Additionally, the trifluoromethylation of alkynyltrifluoroborates as well as mono- and di-substituted alkenyltrifluoroborates was achieved. These results, in conjunction with the simplicity of this protocol, demonstrate the usefulness of the radical trifluoromethylation of boronated substrates toward a generic trifluoromethylation protocol.

Experimental Section

Preparation of starting materials 1, 3 and 4

General procedure C from commercially available boronated derivatives

In air, the boronated starting material (1.0 mmol, 1.0 equiv) was weighed in a round-bottomed flask and solubilized in MeOH (5 mL, [SM] = 0.2 M). Sat. aq. KHF₂ (0.9 mL, 4.5 M, 4.0 equiv) was added. The flask was closed with a septum, and the resulting mixture stirred at rt for 1 h. The reaction mixture was evaporated to dryness, and the resulting salt was extracted with hot acetone using a Soxhlet apparatus overnight. The filtrate was concentrated to ca. 5 mL, and precipitation was achieved by dropwise addition of the filtrate to Et₂O (100 mL) at 0 °C. The product was collected by gravity filtration on a fritted funnel and dried to afford the corresponding potassium organotrifluoroborate.

Potassium 3-Benzyloxyphenyltrifluoroborate 1b

Following general procedure C, the reaction performed with 3-benzyloxyphenylboronic acid (2.0 g, 8.77 mmol) afforded 1b (2.24 g, 88%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₃H₁₁BF₃O (M – K)⁻ 251.0861, found 251.0854. ¹H NMR (400 MHz / DMSO-d₆): δ 7.46 – 7.41 (m, 2H), 7.41 – 7.34 (m, 2H), 7.34 – 7.27 (m, 1H), 7.03 – 6.89 (m, 3H), 6.65 (ddd, J = 8, 3, 1 Hz, 1H), 5.02 (s, 2H). ¹³C NMR (100 MHz / DMSO-d₆): δ 157.2 (C), 138.0 (C), 128.3 (2 CH), 127.5 (CH), 127.4 (2 CH), 127.1 (CH), 124.1 (CH), 117.3 (CH), 111.5 (CH), 68.64 (CH₂). ¹¹B NMR (128 MHz / DMSO-d₆): δ 3.08 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −139.2 (br).

Potassium 2-Benzyloxyphenyltrifluoroborate 1c

Following general procedure C, the reaction performed with 2-benzyloxyphenylboronic acid (0.5 g, 2.19 mmol) afforded 1c (597 mg, 94%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₃H₁₁BF₃O (M – K)⁻ 251.0861, found 251.0856. ¹H NMR (400 MHz / DMSO-d₆): δ 7.54 (d, J = 7 Hz, 2H), 7.40 – 7.29 (m, 3H), 7.29 – 7.22 (m, 1H), 6.98 (td, J = 8, 2 Hz, 1H), 6.75 – 6.65 (m, 2H), 4.99 (s, 2H). ¹³C NMR (100 MHz / DMSO-d₆): δ 161.5 (C), 138.9 (C), 133.4 (CH), 133.4 (CH), 127.9 (2 CH), 126.8 (2 CH), 126.3 (CH), 119.4 (CH), 111.7 (CH), 68.8 (CH₂). ¹¹B NMR (128 MHz / DMSOd₆): δ 3.09 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −136.8 (br).

Potassium 1-Boc-6-(Methoxycarbonyl)indolyl-2-trifluoroborate 1g

Following general procedure C, the reaction performed with 1-Boc-6-(methoxycarbonyl)indole-2-boronic acid (1.0 g, 3.13 mmol) afforded 1g (903 mg, 76%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₅H₁₆BF₃NO₄ (M – K)⁻ 342.1130, found 342.1130. ¹H NMR (400 MHz / DMSO-d₆): δ 8.71 (s, 1H), 7.69 (dd, J = 8, 1 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 6.51 (d, J = 1 Hz, 1H), 3.85 (s, 3H), 1.58 (s, 9H). ¹³C NMR (100 MHz / DMSO-d₆): δ 167.2 (C), 151.1 (C), 136.9 (C), 134.6 (C), 122.6 (C), 122.3 (CH), 119.0 (CH), 115.9 (CH), 111.4 (CH), 82.0 (C), 51.7 (CH₃), 27.5 (3 CH₃). ¹¹B NMR (128 MHz / DMSO-d₆): δ 1.29 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −136.7 (br).

Potassium 4-Methyl-2-phenyl-5-(trifluoroborato)-1,3-thiazole 1i

Following general procedure C, the reaction performed with 4-methyl-2-phenyl-5-boronic-1,3-thiazole acid pinacol ester (0.5 g, 1.66 mmol) afforded 1i (386 mg, 83%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₀H₈BF₃NS (M – K)⁻ 242.0428, found 242.0421. ¹H NMR (400 MHz / DMSO-d₆): δ 7.86 – 7.79 (m, 2H), 7.45 – 7.37 (m, 2H), 7.37 – 7.31 (m, 1H), 2.35 (s, 3H). ¹³C NMR (100 MHz / DMSO-d₆): δ 163.4 (C), 152.5 (C), 134.5 (C), 128.8 (2 CH), 128.5 (CH), 125.5 (2 CH), 16.8 (CH₃). ¹¹B NMR (128 MHz / DMSO-d₆): δ 2.25 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −132.3 (br).

Potassium (E)-4-Phenylstyryltrifluoroborate 4b

Following general procedure C, the reaction performed with (E)-4-phenylstyrylboronic acid (535 mg, 2.39 mmol) afforded 4b (292 mg, 43%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₄H₁₁BF₃ (M – K)⁻ 247.0911, found 247.0904. ¹H NMR (400 MHz / DMSO-d₆): δ 7.67 – 7.62 (m, 2H), 7.56 (d, J = 8 Hz, 2H), 7.48 – 7.37 (m, 4H), 7.36 – 7.29 (m, 1H), 6.52 (d, J = 18 Hz, 1H), 6.30 – 6.20 (m, 1H). ¹³C NMR (100 MHz / DMSO-d₆): δ 140.1 (C), 139.5 (C), 137.5 (C), 132.5 (CH), 128.9 (2 CH), 127.0 (CH), 126.5 (2 CH), 126.3 (2 CH), 125.9 (2 CH). ¹¹B NMR (128 MHz / DMSO-d₆): δ 2.67 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −137.8 (br).

Potassium N-Boc-1,2,5,6-Tetrahydropyridinyl-4-trifluoroborate 4e

Following general procedure C, the reaction performed with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.5 g, 1.62 mmol) afforded 4e (396 mg, 85%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₀H₁₆BF₃NO₂ (M – K)⁻ 250.1232, found 250.1237. ¹H NMR (400 MHz / acetone-d₆): δ 5.56 (br, 1H), 3.72 (br, 2H), 3.33 (t, J = 6 Hz, 2H), 2.07 (br, 2H), 1.42 (s, 9H). ¹³C NMR (100 MHz / acetone-d₆): δ 155.4 (C), 121.3 (CH), 78.7 (C), 44.7 (CH₂), 42.3 (CH₂), 28.8 (3 CH₃), 27.6 (CH₂). ¹¹B NMR (128 MHz / acetone-d₆): δ 2.91 (br). ¹⁹F NMR (376 MHz / acetone-d₆): δ −146.7 (br).

Preparation of 3b

³¹ In air, 4-ethynylbiphenyl (1.0 g, 5.61 mmol, 1.0 equiv) was weighed in a 50 mL round bottom flask equipped with a stir bar. The flask was closed with a septum, evacuated and backfilled with N₂. THF (10 mL, [SM] = 0.5 M) was added and the mixture was cooled to −78 °C. n-BuLi (2.2 mL, 2.5 M in hexanes, 5.61 mmol, 1.0 equiv) was added slowly, and the reaction was stirred 1 h at −78 °C. Triisopropyl borate (1.9 mL, 8.42 mmol, 1.5 equiv) was added, and the reaction was stirred 1 h at −78 °C and then warmed to −20 °C in 1 h. Sat. aq. KHF₂ (7.5 mL, 4.5 M, 6.0 equiv) was added, and the reaction was stirred at rt for 2 h. The reaction mixture was evaporated to dryness, and the resulting salt was extracted with hot acetone using a Soxhlet apparatus overnight. The filtrate was concentrated to ca. 5 mL, and precipitation was achieved by dropwise addition of the filtrate to Et₂O (100 mL) at 0 °C. The resulting product was collected by gravity filtration on a fritted funnel and dried to afford 3b (280 mg, Purity = 95%, 17%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₄H₉BF₃ (M – K)⁻ 245.0755, found 245.0750. ¹H NMR (400 MHz / DMSO-d₆): δ 7.66 (d, J = 7 Hz, 2H), 7.59 (d, J = 8 Hz, 2H), 7.46 (dd, J = 8, 8 Hz, 2H), 7.40 – 7.33 (m, 3H). ¹³C NMR (100 MHz / DMSO-d₆): δ 139.5 (C), 138.2 (C), 131.5 (2 CH), 128.9 (2 CH), 127.4 (CH), 126.4 (2 CH), 126.4 (2 CH), 124.7 (C), 89.0 (C). ¹¹B NMR (128 MHz / DMSO-d₆): δ −1.56 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −131.7 (br).

Preparation of 4c and 4d

4-(Propyn-1-yl)-biphenyl

In air, 4-ethynylbiphenyl (1.0 g, 5.61 mmol, 1.0 equiv) was weighed in a round bottom flask equipped with a stir bar. The flask was closed with a septum, evacuated, and backfilled with N₂. THF (20 mL, [SM] = 0.25 M) was added, and the mixture was cooled to −78 °C. n-BuLi (2.5 mL, 2.5 M in hexanes, 6.17 mmol, 1.1 equiv) was slowly added (by syringe) and the reaction was stirred 15 min at −78 °C. MeI (0.4 mL, 6.17 mmol, 1.1 equiv) was added, and the reaction was allowed to warm to rt over 2 h and then stirred at rt for 4 h. Subsequently, the reaction mixture was poured into sat. aq. NH₄Cl (20 mL), and the resulting solution was extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO₄) and evaporated to afford the crude product. Purification by flash column chromatography (80 g SiO₂, heptane to EtOAc/heptane, 1:9) afforded the title compound (654 mg, 60%) as a white solid, mp = 69–70 ºC. ¹H NMR (400 MHz / CDCl₃): δ 7.63 – 7.58 (m, 2H), 7.57 – 7.53 (m, 2H), 7.51 – 7.43 (m, 4H), 7.40 - 7.340 (m, 1H), 2.10 (s, 3H). Spectral data were consistent with that previously reported.³²

Compound 4c

³³ In air, CuCl (5 mg, 0.05 mmol, 5 mol %), Ph₃P (27 mg, 0.10 mmol, 10 mol %) and NaOt-Bu (20 mg, 0.21 mmol, 20 mol %) were weighed in a 2–5 mL MW vial equipped with a stir bar. The vial was sealed, evacuated, and backfilled with N₂ (x3). THF (0.5 mL) was added and the resulting mixture stirred at rt for 30 min. A solution of bis(pinacolato)diboron (290 mg, 1.14 mmol, 1.1 equiv) in THF (1 mL) was added, and the mixture stirred at rt for 5 min. A solution of 4-(propyn-1-yl)-biphenyl (200 mg, 1.04 mmol, 1.0 equiv) in THF (0.5 mL) and MeOH (84 μL, 2.08 mmol, 2.0 equiv) were successively added, and the reaction stirred at rt for 14 h. Then, the reaction mixture was diluted with Et₂O (10 mL) and filtered through a pad of Celite. The filtrate was evaporated and purified by flash column chromatography (24 g SiO₂, heptane to EtOAc/heptane, 1/4). In air, this boronate was charged in a round-bottomed flask and solubilized in THF (10 mL). Sat. aq. KHF₂ (0.9 mL, 4.5 M, 4.2 mmol, 4.0 equiv) was added. The flask was closed with a septum, and the resulting mixture stirred at rt for 2 h. The reaction mixture was evaporated to dryness, and the resulting salt was extracted with hot acetone using a Soxhlet overnight. The filtrate was concentrated to ca. 5 mL, and precipitation was achieved by dropwise addition of the filtrate to Et₂O (100 mL) at 0 °C. The product was collected by gravity filtration on a fritted funnel and dried to afford 4c (208 mg, 67%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₅H₁₃BF₃ (M – K)⁻ 261.1068, found 261.1065. ¹H NMR (400 MHz / DMSO-d₆): δ 7.65 (d, J = 8 Hz, 2H), 7.57 (d, J = 8 Hz, 2H), 7.44 (dd, J = 8, 8 Hz, 2H), 7.36 – 7.30 (m, 1H), 7.27 (d, J = 8 Hz, 2H), 6.41 (s, 1H), 1.76 (s, 3H). ¹³C NMR (100 MHz / DMSO-d₆): δ 140.2 (C), 139.9 (C), 136.1 (C), 129.0 (2 CH), 128.8 (2 CH), 126.9 (CH), 126.3 (2 CH), 126.0 (2 CH), 125.6 (CH), 16.7 (CH₃). ¹¹B NMR (128 MHz / DMSO-d₆): δ 3.08 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −143.6 (br).

Compound 4d

³⁴ In air, CuCl (4 mg, 0.04 mmol, 5 mol %), xantphos (51 mg, 0.09 mmol, 10 mol %) and NaOt- Bu (17 mg, 0.18 mmol, 20 mol %) were weighed in a 2–5 mL MW vial equipped with a stir bar. The vessel was sealed, evacuated, and backfilled with N₂ (x3). Toluene (1 mL) was added and the mixture stirred at rt for 15 min. Pinacolborane (0.2 mL, 1.33 mol, 1.5 equiv) was added, and the mixture stirred at rt for 5 min. A solution of 4-(propyn-1-yl)-biphenyl (171 mg, 0.89 mmol, 1.0 equiv) in toluene (1 mL) was added and the reaction stirred at rt for 3 d. The reaction mixture was diluted with EtOAc (10 mL) and filtered through a pad of Celite. The filtrate was evaporated to afford the crude boronate intermediate. In air, this boronate was charged in a round-bottomed flask and solubilized in THF (10 mL). Sat. aq. KHF₂ (0.8 mL, 4.5 M, 3.6 mmol, 4.0 equiv) was added. The flask was closed with a septum, and the resulting mixture was stirred at rt for 2 h. The reaction mixture was evaporated to dryness, and the resulting salt was extracted with hot acetone using a Soxhlet apparatus overnight. The filtrate was concentrated to ca. 5 mL, and precipitation was achieved by dropwise addition of the filtrate to Et₂O (100 mL) at 0 °C. The product was collected by gravity filtration on a fritted funnel and dried to afford 4d (69 mg, 26%) as a white solid, mp > 200 °C (dec). HRMS (ESI): m/z calcd. for C₁₅H₁₃BF₃ (M – K)⁻ 261.1068, found 261.1058. ¹H NMR (400 MHz / DMSO-d₆): δ 7.63 (dd, J = 8, 1 Hz, 2H), 7.50 – 7.40 (m, 4H), 7.33 – 7.27 (m, 1H), 7.12 (d, J = 8 Hz, 2H), 5.69 (q, J = 7 Hz, 1H), 1.48 (t, J = 7 Hz, 3H). ¹³C NMR (100 MHz / DMSO-d₆): δ 145.2 (C), 140.8 (C), 135.4 (C), 128.9 (2 CH), 128.7 (2 CH), 126.6 (CH), 126.2 (2 CH), 125.2 (2 CH), 122.6 (CH), 15.0 (CH₃). ¹¹B NMR (128 MHz / DMSO-d₆): δ 2.73 (br). ¹⁹F NMR (376 MHz / DMSO-d₆): δ −139.4 (br).

Radical Trifluoromethylation of Unsaturated Potassium Organotrifluoroborates

General procedure A for the preparation of trifluoromethylated compounds 2, 5 and 6

In air, potassium organotrifluoroborates 1 or 3 or 4 (0.5 mmol, 1.0 equiv), NaSO₂CF₃ (234 mg, 1.5 mmol, 3.0 equiv) and CuCl (50 mg, 0.5 mmol, 1.0 equiv) were weighed in a 2–5 mL MW vial equipped with a stir bar. MeOH (1 mL), CH₂Cl₂ (1 mL) and distilled H₂O (0.8 mL) were successively added, and the tube was sealed with a tap open to air by a needle. This solution was cooled to 0 °C and TBHP (0.35 mL, 70% in H₂O, 2.5 mmol, 5.0 equiv) was slowly added. The reaction was allowed to warm to rt and stirred at rt for 12 h. The reaction mixture was diluted with Et₂O (10 mL) and this solution was washed successively with sat. aq. NaHCO₃ (5 mL) and 5% aq. Na₂S₂O₃ (5 mL). The organic layer was dried (MgSO₄) and 1,3,5-trifluorobenzene (51.7 μL, 0.5 mmol, 1.0 equiv) was added as an internal standard. The solution was analyzed by ¹⁹F NMR and GCMS. Additionally, this solution can be evaporated and purified by flash column chromatography (SiO₂, mixtures of EtOAc and heptane) to afford the pure compound 2 or 5 or 6.

General procedure B for the preparation of trifluoromethylated compounds 2

In air, potassium organotrifluoroborates 1 (0.5 mmol, 1.0 equiv), NaSO₂CF₃ (234 mg, 1.5 mmol, 3.0 equiv) and (MeCN)₄CuPF₆ (157 mg, 0.5 mmol, 1.0 equiv) were weighed in a 2–5 mL MW vial equipped with a stir bar. MeOH (3 mL) was added, and the tube was sealed with a tap open to air by a needle. This solution was cooled to 0 °C and TBHP (0.28 mL, 70% in H₂O, 2.0 mmol, 4.0 equiv) was slowly added. The reaction was allowed to warm to rt and stirred at rt for 12 h. The reaction mixture was diluted with Et₂O (10 mL) and this solution was washed successively with sat. aq. NaHCO₃ (5 mL) and 5% aq. Na₂S₂O₃ (5 mL). The organic layer was dried (MgSO₄) and 1,3,5-trifluorobenzene (51.7 μL, 0.5 mmol, 1.0 equiv) was added as an internal standard. The solution was analyzed by ¹⁹F NMR and GCMS. Additionally, this solution can be evaporated and purified by flash column chromatography (SiO₂, mixtures of EtOAc and heptane) to afford the pure compound 2.

1-(Benzyloxy)-4-(trifluoromethyl)benzene 2a

Following general procedure A, the reaction performed with 1a (145 mg, 0.5 mmol) afforded 2a in ¹⁹F yield = 99% and, after purification, 117 mg (93%) as a white solid, mp = 79–80 ºC. GC-MS: 5.438 min (m/z 252 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −61.4 (s). Spectral data were consistent with that previously reported.¹⁶

1-(Benzyloxy)-3-(trifluoromethyl)benzene 2b

Following general procedure A, the reaction performed with 1b (145 mg, 0.5 mmol) afforded 2b in ¹⁹F yield = 21% and, after purification, 18 mg (14%) as a colorless oil. GC-MS: 5.241 min (m/z 252 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −62.9 (s). Spectral data were consistent with that previously reported.³⁵

1-(Benzyloxy)-2-(trifluoromethyl)benzene 2c

Following general procedure A, the reaction performed with 1c (145 mg, 0.5 mmol) afforded 2c in ¹⁹F yield = 66% and, after purification, 63 mg (50%) as a colorless oil. GC-MS: 5.462 min (m/z 252 (M)⁺). HRMS (ESI): m/z calcd. for C₁₄H₁₁F₃O (M)⁺ 252.0762, found 252.0748. ¹H NMR (400 MHz / CDCl₃): δ 7.64 (dd, J = 8, 1 Hz, 1H), 7.52 – 7.46 (m, 3H), 7.46 – 7.40 (m, 2H), 7.39 - 7.33 (m, 1H), 7.11 – 7.00 (m, 2H), 5.22 (s, 2H). ¹³C NMR (100 MHz / CDCl₃): δ 156.4 (C), 136.3 (C), 133.2 (CH), 128.6 (2 CH), 127.9 (CH), 127.1 (q, J = 5 Hz, CH), 126.8 (2 CH), 123.8 (q, J = 272 Hz, C), 120.2 (CH), 119.2 (q, J = 31 Hz, C), 113.2 (CH), 70.2 (CH₂). ¹⁹F NMR (376 MHz / CDCl₃): δ −62.3 (s).

Trifluoromethylbenzene 2d

Following general procedure A, the reaction performed with 1d (92 mg, 0.5 mmol) afforded 2d in ¹⁹F yield = 28%. GC-MS: 0.624 min (m/z 146 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ − 62.9 (s). Spectral data were consistent with that previously reported.²²

1-Fluoro-2-phenyl-5-trifluoromethylbenzene 2e

Following general procedure B, the reaction performed with 1e (139 mg, 0.5 mmol) afforded 2e in ¹⁹F yield = 61% and, after purification, 41 mg (34%) as a colorless oil. GC-MS: 4.151 min (m/z 240 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −62.8 (s, 3F), 115.7 (s, 1F). Spectral data were consistent with that previously reported.¹⁶

4-Acetyl-trifluoromethylbenzene 2f

Following general procedure B, the reaction performed with 1f (113 mg, 0.5 mmol) afforded 2f in ¹⁹F yield = 27%. GC-MS: 2.437 min (m/z 188 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ−63.2 (s). Spectral data were consistent with that previously reported.²²

1-Boc-2-Trifluoromethyl-6-(methoxycarbonyl)indole 2g

Following general procedure A, the reaction performed with 1g (191 mg, 0.5 mmol) afforded 2g in ¹⁹F yield = 67% and, after purification, 110 mg (64%) as a white solid, mp = 83–84 °C. GC-MS: 7.321 min (m/z 343 (M)⁺). HRMS (ESI): m/z calcd. for C₁₁H₈F₃NO₂ (M-Boc+H)⁺ 243.0507, found 243.0533. ¹H NMR (400 MHz / CDCl₃): δ 8.99 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.66 (d, J = 8 Hz, 1H), 7.16 (s, 1H), 3.97 (s, 3H), 1.70 (s, 9H). ¹³C NMR (100 MHz / CDCl₃): δ 167.1 (C), 148.0 (C), 137.1 (C), 129.9 (C), 129.5 (q, J = 40 Hz, C), 128.6 (C), 124.5 (CH), 121.8 (CH), 120.4 (q, J = 268 Hz, C), 118.1 (CH), 112.8 (q, J = 5 Hz, CH), 86.1 (C), 52.2 (CH₃), 27.8 (3 CH₃). ¹⁹F NMR (376 MHz / CDCl₃): δ −58.4 (s).

1-Methyl-4-trifluoromethyl-1H-pyrazole 2h

Following general procedure A, the reaction performed with 1h (47 mg, 0.25 mmol) afforded 2f in ¹⁹F yield = 48% (in this case, 2.0 equiv of internal standard were used). GCMS: 0.882 min (m/z 150 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −56.4 (s). Spectral data were consistent with that previously reported.³⁶

4-Methyl-2-phenyl-5-trifluoromethyl-1,3-thiazole 2i

Following general procedure A, the reaction performed with 1i (140 mg, 0.5 mmol) afforded 2i in ¹⁹F yield = 43% and, after purification, 37 mg (24%) as a colorless oil (contaminated by 5% of the bis-trifluoromethylated product). GC-MS: 4.642 min (m/z 243 (M)⁺). HRMS (ESI): m/z calcd. for C₁₁H₈F₃NS (M)⁺ 243.0330, found 243.0331. ¹H NMR (400 MHz / CDCl₃): δ 7.95 – 7.89 (m, 2H), 7.50 – 7.43 (m, 3H), 2.62 (q, J = 2 Hz, 3H). ¹³C NMR (100 MHz / CDCl₃): δ 168.4 (C), 155.2 (C), 132.5 (C), 131.0 (CH), 129.1 (2 CH), 126.7 (2 CH), 122.7 (q, J = 269 Hz, C), 119.7 (q, J = 37 Hz, C), 16.1 (CH₃). ¹⁹F NMR (376 MHz / CDCl₃): δ −53.0 (s).

2-Trifluoromethylbenzofuran 2j

Following general procedure A, the reaction performed with 1j (124 mg, 0.5 mmol) afforded 2j in ¹⁹F yield = 53%. GC-MS: 1.902 min (m/z 186 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ − 65.0 (s). Spectral data were consistent with that previously reported.²²

3-Trifluoromethylquinoline 2k

Following general procedure B, the reaction performed with 1k (117 mg, 0.5 mmol) afforded 2k in ¹⁹F yield = 6%. GC-MS: 3.277 min (m/z 197 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −62.0 (s). Spectral data were consistent with that previously reported.¹⁶

1′-Trifluoromethylphenylacetylene 5a

Following general procedure A, the reaction performed with 1j (104 mg, 0.5 mmol) afforded 5a in ¹⁹F yield = 50%. GC-MS: 1.344 min (m/z 170 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −49.9 (s). Spectral data were consistent with that previously reported.³⁷

1′-Trifluoromethyl-1-biphenylacetylene 5b

Following general procedure A, the reaction performed with 3b (149 mg, 0.5 mmol) afforded 5b in ¹⁹F yield = 51% and, after purification, 56 mg (45%) as a white solid, mp = 82–83 ºC. GC-MS: 5.471 min [m/z 246 (M)⁺]. ¹⁹F NMR (376 MHz / CDCl₃): δ −49.9 (s). Spectral data were consistent with that previously reported.³⁷

Compound 6a

Following general procedure A, the reaction performed with 4a (105 mg, 0.5 mmol) afforded 6a in ¹⁹F yield = 54% (contaminated by 5% of the isomerized (Z)-product). GC-MS: 1.806 min (m/z 172 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −63.4 (s). Spectral data were consistent with that previously reported.³⁸

Compound 6b

Following general procedure A, the reaction performed with 4b (143 mg, 0.5 mmol) afforded 6b in ¹⁹F yield = 77% and, after purification, 101 mg (77%) as a white solid (contaminated by 5% of the isomerized (Z)-product). GC-MS: 5.890 min (m/z 248 (M)⁺). ¹⁹F NMR (376 MHz / CDCl₃): δ −63.4 (s). Spectral data were consistent with that previously reported.¹⁶

Compound 6c

Following general procedure A, the reaction performed with 4c (75 mg, 0.25 mmol) afforded 6c in ¹⁹F yield = 70% (in this case, 2.0 equiv of internal standard were used) and, after purification, 39 mg (59%) as a white solid, mp = 82–83 °C. GC-MS: 6.183 min (m/z 262 (M)⁺). HRMS (ESI): m/z calcd. for C₁₆H₁₃F₃ (M)⁺ 262.0969, found 262.0970. ¹H NMR (400 MHz / CDCl₃): δ 7.73 – 7.60 (m, 4H), 7.54 – 7.35 (m, 5H), 7.12 (s, 1H), 2.10 (s, 3H). ¹³C NMR (100 MHz / CDCl₃): δ 141.0 (C), 140.3 (C), 133.5 (C), 130.9 (q, J = 6 Hz, CH), 129.7 (2 CH), 128.9 (2 CH), 127.6 (CH), 127.1 (2 CH), 127.0 (2 CH), 126.2 (q, J = 29 Hz, C), 124.6 (q, J = 272 Hz, C), 12.3 (CH₃). ¹⁹F NMR (376 MHz / CDCl₃): δ −69.5 (s).

Compound 6d

Following general procedure A, the reaction performed with 4d (62 mg, 0.21 mmol) afforded 6d in ¹⁹F yield = 12% (in this case, 2.0 equiv of internal standard were used) and, after purification, 6 mg (10%) as a white solid, mp = 64–65 °C. GC-MS: 5.862 min (m/z 262 (M)⁺). HRMS (ESI): m/z calcd. for C₁₆H₁₃F₃ (M)⁺ 262.0969, found 262.0963. ¹H NMR (400 MHz / CDCl₃): δ 7.68 – 7.57 (m, 5H), 7.54 – 7.42 (m, 2H), 7.42 – 7.30 (m, 2H) 6.58 (m, 1H), 1.74 (m, 3H). ¹³C NMR (100 MHz / CDCl₃): δ 141.2 (C), 140.5 (C), 131.9 (C), 131.6 (q, J = 5 Hz, CH), 131.3 (q, J = 45 Hz, C), 130.1 (2 CH), 128.8 (2 CH), 128.6 (q, J = 275 Hz, C), 127.5 (CH), 127.1 (4 CH), 14.3 (CH₃). ¹⁹F NMR (376 MHz / CDCl₃): δ −65.7 (s).