Practical Method for the Cu-Mediated Trifluoromethylation of Arylboronic Acids with CF₃ Radicals Derived from NaSO₂CF₃ and tert-Butyl Hydroperoxide (TBHP)

Abstract

A mild and practical protocol for the copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids using NaSO₂CF₃ (Langlois’ reagent) and TBHP is described. The reaction proceeds at room temperature under ambient conditions, and the products can be readily purified by extraction or column chromatography.

Trifluoromethyl-substituted arenes and heteroarenes are increasingly important structural motifs in pharmaceuticals, agrochemicals, and organic materials.¹ As a result, the development of practical protocols to achieve aromatic trifluoromethylation efficiently, selectively, and cost effectively has been the subject of intense research effort.² Over the past 3 years, a variety of Cu-mediated and/or catalyzed methods have been reported for the trifluoromethylation of aryl and heteroaryl boronic acids using “CF₃⁻” or “CF₃⁺” reagents, including TMSCF₃,³ K[CF₃B(OMe)₃],⁴ CF₃H,⁵ S-(trifluoromethyl)diphenylsulfonium triflate,⁶ Togni’s reagent,⁷ and Umemoto’s reagent.^8,9 However, most of these procedures are limited by the requirement for an inert atmosphere and/or dry solvents. Further, the high cost and/or lack of bulk availability of many of these trifluoromethylating reagents limits their usage on a large scale. Finally, these methods commonly lead to competitive formation of protodeboronated by-products, which are challenging to separate from the desired compounds.

We recently reported the Cu-catalyzed trifluoromethylation of aryl boronic acids with CF₃I in the presence of a photocatalyst and visible light (Scheme 1a).¹⁰ A key feature of this transformation is the merger of CF₃• (generated via a photocatalysis cycle)¹¹ with a Cu–aryl intermediate. The high selectivity and mild conditions associated with this process led us to consider more practical potential sources of CF₃• to use in Cu-mediated boronic acid trifluoromethylation. Several reports have shown that the combination of NaSO₂CF₃ (Langlois’ reagent) and TBHP generates trifluoromethyl radicals at room temperature in the presence of ambient air and moisture.^12,13 This in situ generated CF₃• has been shown to react with electron-rich arenes and heterocycles to afford mixtures of isomeric C–H trifluoromethylation products.^12,13 We reasoned that in the presence of a Cu salt, the CF₃• generated from NaSO₂CF₃ and TBHP could instead be harnessed to achieve site selective trifluoromethylation of a boronic acid (Scheme 1b). We report herein the feasibility of this aproach and the development of a general, mild, and practical protocol for Cu-mediated trifluoromethylation of aryl boronic acids with NaSO₂CF₃ and TBHP.

Scheme 1.

Cu-Mediated Trifluoromethylation of Aryl Boronic Acids using in situ generated CF₃ Radical

Our initial studies focused on the CuOAc-mediated reaction of [1,1'-biphenyl]-4-ylboronic acid (1) with NaSO₂CF₃ and TBHP at room temperature in DCM/H₂O. With 0.2 equiv of CuOAc, the desired trifluoromethylated product (1a) was formed in 18% yield.¹⁴ The yield increased to 47% in the presence of 1 equiv of CuOAc. Optimization of the solvent (to a 5:5:4 mixture of MeOH, DCM and H₂O) resulted in a further increase in yield to 71%.¹⁵ Finally, an extensive evaluation of copper salts revealed that CuCl provides 80% yield of 1a on a 0.05 mmol scale.¹⁶ There are several important features of this protocol that highlight its practicality. First, the reactions are all set up on the bench top, without any purification of commercial solvents and reagents. Second, protodeboronation is not observed under these conditions, and the only detectable by-product is 4-hydroxybiphenyl. Third, the reaction scales well, proceeding in 85% isolated yield on 0.5 mmol scale.

While electron-neutral and rich boronic acids underwent trifluoromethylation in excelent yields under the optimal conditions from Table 1 (vide infra), several electron deficient derivatives did not. For example, (4-cyanophenyl)boronic acid (2) reacted to afford 2a in only 36% yield. We reasoned that the lower yield might be due to slower transmetallation of the electron deficient boronic acid. Consistent with this proposal, the addition of 1 equiv of NaHCO₃ (which is expected to accelerate transmetallation) led to an increase in yield to 46%. Further evaluation of different Cu sources showed that the substitution of CuCl with (MeCN)₄CuPF₆ resulted in the best yield of 2a (59%).

Table 1.

Optimization of the Trifluoromethylation of 1^[a][b]

entry	copper salt	solvent	yield
1c,d	CuOAc	DCM/H2O	18%
2d	CuOAc	DCM/H2O	47%
3d	CuOAc	MeOH/H2O	60%
4e	CuOAc	MeOH/DCM/H2O	71%
5e	CuCl	MeOH/DCM/H2O	80%
6e	–	MeOH/DCM/H2O	<1%

^[a]General conditions: substrate 1 (1 equiv, 0.05 mmol), [Cu] (1 equiv), NaSO₂CF₃ (3 equiv), TBHP (5 equiv) at 23 °C for 12 h.

^[b]Yields determined by ¹⁹F NMR analysis.

^[c]0.2 equiv CuOAc.

^[d]Solvent ratio = 5:2.

^[e]Solvent ratio = 5:5:4

With these two sets of conditions in hand, we next explored the full substrate scope of Cu-mediated trifluoromethylation with NaSO₂CF₃ and TBHP. As shown in Scheme 2, arenes bearing electron-donating alkyl, alkoxy, or phenoxy substituents reacted in excellent yield under the CuCl-mediated conditions (conditions a). Trifluoromethylation of electron deficient substrates (eg, cyano, trifluoromethyl, and carbonyl-substituted aryl boronic acids) afforded the desired trifluoromethylated products in good to excellent yield in the presence of (MeCN)₄CuPF₆ and NaHCO₃ (conditions b).¹⁷ Interestingly, the reaction of (4-iodophenyl)boronic acid resulted in exclusive trifluoromethylation of the C–B bond, leaving the C–I linkage intact. Sterically hindered boronic acid derivatives, which are generally challenging substrates for Cu-mediated cross-couplings,¹⁸ afforded good to excellent yields in this transformation (cf, products 6a, 8a, 14a, 20a and 23a). Moreover, the reaction is compatible with diverse functional groups, including enolizable ketones, esters, amides, and phenols. Finally, heteroaryl boronic acids based on pyridine, quinoline, thiophene, and furan afforded moderate to excellent yield. Notably, trifluoromethylation of the C–B bond outcompeted free radical C–H trifluoromethylation in all of these substrates.

Scheme 2.

Substrate Scope of Copper-Mediated Trifluoromethylation of Aryl Boronic Acids[c]

^[a] Reaction conditions: substrate (1 equiv, 0.5 mmol), CuCl (1 equiv), NaSO₂CF₃ (3 equiv), TBHP (5 equiv) in DCM/MeOH/H2O (5:5:4 ratio) at 23 °C for 12 h. ^[b] Reaction conditions: substrate (1 equiv), (MeCN)₄CuPF₆ (1 equiv), NaSO₂CF₃ (3 equiv), NaHCO₃ (1 equiv), TBHP (4 equiv) in MeOH at 23 °C for 12 h. ^[c] Isolated yield. ^[d] Yields determined by ¹⁹F NMR analysis.

As noted above, most previously reported boronic acid trifluoromethylation protocols employ inert atmosphere conditions and dry solvents. Even under these controlled conditions, significant quantities (2–10%) of protodeboronated products are commonly observed and are very challenging to separate and purify from the desired Aryl–CF₃ products. In contrast, all of the trifluoromethylation reactions in Scheme 2 were insenstive to ambient air and moisture and were set up on the benchtop without purification of commercial reagents nor solvents. Despite the presence of water, protodeboronation of the boronic acid was not detected under these conditions. This makes product isolation extremely straightforward, as the major side-product (the corresponding hydroxylated arene) is readily removable by extraction or column chromatography.

In conclusion, this paper describes a practical copper-mediated trifluoromethylation of a variety of aryl and heteroaryl boronic acids using readily available NaSO₂CF₃ and TBHP. These reageants are believed to react in situ to generate CF₃• as the active trifluoromethylating reagent. The reactions are easy to set up under ambient conditions, and product purification is similarly straightforward. As a result, this protocol represents a significant synthetic advance for the selective preparation of trifluoromethylated compounds.

Table 2.

Optimization for Electron Poor Boronic Acids ^[a],^[b]

entry	copper salt	base	yield
1c	CuCl	–	36%
2c	CuCl	NaHCO3	46%
3d	(MeCN)4CuPF6	–	42%
4d,e	(MeCN)4CuPF6	–	38%
5d	(MeCN)4CuPF6	NaHCO3	49%
6d,e	(MeCN)4CuPF6	NaHCO3	59%

^[a]General conditions: substrate 2 (1 equiv, 0.05 mmol), [Cu] (1 equiv), base (1 equiv), NaSO₂CF₃ (3 equiv), TBHP (5 equiv) at 23 °C for 12 h.

^[b]Yields determined by ¹⁹F NMR analysis.

^[c]Solvent = MeOH/DCM/H₂O (5:5:4 ratio).

^[d]Solvent = MeOH.

^[e]4 equiv TBHP.