Copper-Mediated Fluoroalkylation of Aryl Bromides and Chlorides Enabled by Directing Groups

Abstract

This report describes the reactions between N-heterocyclic carbene copper(I) fluoroalkyl complexes and aryl halides bearing ortho-directing groups. Pyridine, pyrazole, oxazoline, imine, and ester directing groups are shown to dramatically enhance the reactivity of aryl bromides and chlorides with (IPr)Cu^I–fluoroalkyl complexes (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; fluoroalkyl = difluoromethyl and pentafluoroethyl) to afford aryl–fluoroalkyl coupling products. This approach is leveraged to achieve the Cu-catalyzed directed fluoroalkylation of a series of aryl bromide substrates.

Graphical Abstract

Copper-catalyzed cross-coupling is widely used for the construction of aryl–fluoroalkyl (aryl–R_F) bonds.^{1a–b,2a–b} The majority of these transformations involve the reaction of a fluoroalkyl nucleophile (MR_F) with an aryl iodide electrophile. In contrast, more abundant and less expensive aryl bromide/chloride electrophiles are rarely effective substrates in these reactions. This limitation is a consequence of the Cu^I/III mechanism that is outlined in Scheme 1A.^3,4 Specifically, oxidative addition of the aryl halide at Cu^I–R_F intermediate I (step ii) is typically prohibitively slow with bromide and chloride substrates.⁵

Scheme 1.

(A) General catalytic cycle for Cu-catalyzed fluoroalkylation of aryl halides. (B) Previous work: difluoromethylation of aryl halides with 1 (limited to aryl iodides). (C) This work: directing groups enable fluoroalkylation of aryl iodide, bromide, and chloride with various R_F groups.

Our group recently reported stoichiometric studies of steps (ii) and (iii) of this cycle using the well-defined Cu organometallic complex (IPr)Cu^I–CF₂H) (1, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).⁶ The reaction of 1 with aryl iodides (ArI) was slow at room temperature but afforded ArCF₂H products in high yields upon heating at 90 °C for 20 h (Scheme 1B). In contrast, the analogous aryl bromide and chloride substrates showed no reaction with 1 under analogous conditions.⁶

We hypothesized that directing groups (DG) could accelerate oxidative addition at 1 and related Cu^I fluoroalkyl complexes, thus expanding the scope of electrophiles for Cu-catalyzed fluoroalkylation. This hypothesis is predicated on literature reports showing that nitrogen-based directing groups and/or macrocyclic scaffolds facilitate Cu^I/III- and Au^I/III-catalyzed fluorination,^7,8 trifluoromethylthiolation,⁹ and other functionalizations¹⁰ of aryl halides. This report describes detailed studies of the reactions of 1 and its pentafluoroethyl analogue with aryl halides containing a variety of different directing groups. We demonstrate large enhancements in both reaction rate and yield for directed fluoroalkylation in these systems, with sp²-nitrogen-based directing groups proving most effective. These stoichiometric organometallic studies are translated to the (IPr)Cu^I–Cl-catalyzed directed fluoroalkylation of various aryl bromides.

Our initial studies focused on the reaction of (IPr)Cu^I–CF₂H with arylpyridine derivatives to afford the difluoromethylated products 3 or 5. In each case, the difluoromethylation yield after 24 h at 120 °C was evaluated by ¹⁹F NMR spectroscopy for the electronically similar ortho- (2) and para-halophenylpyridine (4). This allows us to assess the impact of pyridine proximity/coordination on reactivity. As shown in Scheme 2, significant differences in reactivity were observed under these conditions. The ortho-iodo substrate 2-I reacted to form 3 in quantitative yield, while the para-iodo derivative 4-I afforded 5 in 73% yield. With the bromo and chloro derivatives, the directing group effect was even more dramatic. Trace yield of the difluoromethylated product 5 (≤1%) was formed in reactions of para-isomers 4-Br and 4-Cl. In contrast, 2-Br and 2-Cl reacted to afford 3 in 96% and 16% yield, respectively. The latter result is particularly noteworthy because it is a rare example of aryl chloride fluoroalkylation at Cu.¹¹

Scheme 2.

Reactions of 1 with ortho- and para-halopyridines.

To assess the role of the fluoroalkyl ligand on this reactivity we next evaluated analogous transformations with the pentafluoroethyl complex (IPr)Cu^I–C₂F₅ (6). This complex was synthesized via the sequential reaction of (IPr)Cu^I–Cl with NaO^tBu and then TMSC₂F₅ (see Supporting Information for complete details).^6,12 Complex 6 was isolated in 40% yield and characterized by NMR spectroscopy, elemental analysis, and X-ray crystallography (ORTEP structure in Figure S45). As summarized in Scheme 3, 6 shows similar reactivity to 1 with the aryl pyridine substrates. Reactions with ortho-halopyridines provide high (2-I, 2-Br) or modest (2-Cl) yields of pentafluoroethylated product 7. In contrast, the para-isomers afford 26% (4-I), trace (≤1%, 4-Br) or no detectable (4-Cl) yield of 8.

Scheme 3.

Reactions of 6 with ortho- and para-halopyridines.

We monitored yield as a function of time via ¹⁹F NMR spectroscopy for the reactions of 6 with 2-I, 2-Br, and 4-I. These experiments were conducted at 90 °C (compared to 120 °C in Scheme 3) to facilitate monitoring of the faster reactions. Notably, no diamagnetic Cu–CF₂CF₃ intermediates were detected, consistent with oxidative addition as the slow step of this sequence. Substrate 2-I reacted extremely fast, affording >90% yield after 5 min at 90 °C (Figure 1, red). In marked contrast, 4-I showed essentially no reaction over 4 h at 90 °C (Figure 1, green). 2-Br showed intermediate reactivity, affording approximately 30% yield within 1 h and 70% yield after 4 h. These results clearly demonstrate the dramatic rate acceleration imparted by the directing group for both aryl iodide and aryl bromide substrates.

Figure 1.

Time study of reaction of 6 with 2-I (red), 2-Br (blue), and 4-I (green). Conditions: 6 (0.01 mmol), aryl pyridine (0.008 mmol) in a 3:1 solvent mixture of dioxane/toluene (0.7 mL) at 90 °C. Reactions monitored by ¹⁹F NMR spectroscopy.

We next investigated a series of other directing groups for the reaction of aryl bromide substrates with 1 and 6. As summarized in Scheme 4, both difluoromethylation and pentafluoroethylation proceeded in good to excellent yield with pyridine, oxazoline, pyrazole, and imine-based directing groups. Modest to good yields (25% for difluoromethylation and 73% for pentafluoroethylation) were also obtained with a methyl ester directing group. In contrast, no fluoroalkylated products were detected with the corresponding dimethylamide. In general, reactions of the difluoromethyl complex 1 proceeded in lower yield than those of the pentafluoroethyl analogue 6. This is due to competing decomposition of 1. This Cu^I–CF₂H complex is completely consumed over the course of the reactions and fluorine-containing decomposition products, including CH₂F₂ and cis-C₂H₂F₂, are detected by ¹⁹F NMR spectroscopy (see Figure S1–S17). These byproducts are in line with previously reported decomposition pathways for of [Cu(CF₂H)] species.^{6, 13}

Scheme 4.

Stoichiometric fluoroalkylation of aryl bromides with different directing groups

Finally, we translated the stoichiometric reactions to a (IPr)Cu^I–Cl-catalyzed directed fluoroalkylation of aryl bromides. As shown in Scheme 5, using 20 mol % of (IPr)Cu^I–Cl, 2 equiv of TMSR_F, and 3 equiv of an MF salt at 120 °C for 24 h led to the catalytic fluoroalkylation of the aryl bromides used in the stoichiometric reactions above.¹⁴ Higher yields were generally observed for pentafluoroethylation than difluoromethylation.¹⁵ Consistent with this observation, fewer fluorine-containing side products were observed in the pentafluoroathylation reactions. Overall, this represents the first Cu-catalyzed difluoromethylation and second Cu-catalyzed pentafluoroethylation⁴ of aryl bromide electrophiles.

Scheme 5.

Cu-catalyzed directed fluoroalkylation of aryl bromides.

In conclusion, this report demonstrates that sp²-nitrogen and -oxygen directing groups enable the Cu^I-mediated fluoroalkylation of aryl bromides and chlorides, substrates that are typically inert under analogous conditions in the absence of a directing group. The role of these groups is to accelerate oxidative addition at the Cu^I center. We anticipate that this strategy should prove broadly applicable for achieving challenging Cu-catalyzed cross-coupling reactions of aryl halides.