Copper-Catalyzed Trifluoromethylation of Alkyl Bromides

Abstract

Copper oxidative addition into organo-halides is a challenging two-electron process. In contrast, formal oxidative addition of copper to C_sp² carbon−bromine bonds can be accomplished by employing latent silyl radicals under photoredox conditions. This novel paradigm for copper oxidative addition has now been applied to a Cu-catalyzed cross-coupling of C_sp³-bromides. Specifically, a copper/photoredox dual catalytic system for the coupling of alkyl bromides with trifluoromethyl groups is presented. This operationally simple and robust protocol successfully converts a variety of alkyl, allyl, benzyl, and heterobenzyl bromides into the corresponding alkyl trifluoromethanes.

Over the past four decades, a range of novel ligand classes in combination with palladium and nickel salts have enabled the efficient catalytic conversion of C−X bonds into carbon−carbon, −nitrogen, −sulfur, and −oxygen bonds across a vast array of reaction manifolds.¹ In contrast, copper has achieved limited success in analogous transformations, a notable deficiency given its salient potential for economical and operational benefit.² Copper’s diminished utility arises from an intrinsically high barrier to oxidative addition with both haloarenes and aliphatic halides. This feature necessitates the use of activated aryl bromides and iodides along with elevated temperatures in the former case, while haloalkanes remain effectively inert to almost all forms of catalytic copper insertion.³ This deficiency is further underscored by the fact that high-valent Cu(III) complexes undergo reductive elimination with electronegative coupling partners (e.g., CF₃, CN, F moieties) at rates that are often superior to Ni and Pd salts.⁴

Recently, we became interested in overcoming the copper oxidative addition problem via the conversion of aryl and alkyl bromides to their aryl- and alkyl-Cu(III) analogs using a halogen-atom abstraction/metal-radical capture mechanism. More specifically, silicon-centered radicals have long been established as potent abstractors of bromine atoms that can rapidly convert organobromides into carbon-centered radicals under mild conditions (Figure 1).⁵ In contrast to their limited capacity for oxidative addition, copper salts can efficiently trap carbon-centered radicals at rates approaching diffusion control, thereby allowing copper C−X insertion to be readily accomplished via an alternative open-shell mechanism.⁶ Recently, this previously unknown approach has enabled aryl bromides to undergo copper-catalyzed trifluoromethylation at room temperature,⁷ a transformation that was generally considered to be challenging given the kinetically high barrier to reductive elimination of aryl−CF₃ products using either nickel or palladium salts.⁸ In this disclosure, we elevate this radical capture/copper oxidative addition platform to the implementation of aliphatic bromides, a structural format that has previously been outside the scope of most copper-catalyzed cross-coupling protocols.

Figure 1.

Catalytic trifluoromethylation of alkyl bromides

Within medicinal chemistry, the introduction of trifluoromethyl groups onto C_sp³-rich scaffolds can often enhance the pharmacokinetic properties of lead candidates in drug discovery, generally via improvements in surface hydrophobicity and/or decreased rates of enzymatic metabolism and clearance.⁹ However, the catalytic trifluoromethylation of alkyl halides has historically been challenging, and at the present time substrate tolerance is limited to allylic or benzylic halides.¹⁰ The production of C_sp³−CF₃ bonds has been accomplished using stoichiometric Cu(III)-based reagents; however, only recently have catalytic variants been investigated.¹¹ Given the success of our copper/aryl halide insertion−trifluoromethylation studies, we questioned whether this open shell cross-coupling mechanism might be translated to all classes of aliphatic bromides, thereby delivering a catalytic CF₃-installation protocol of significant utility to medicinal and process chemists. Herein we disclose the successful execution of these ideals and present a mild, broadly applicable, one-step protocol for the conversion of alkyl bromides into alkyl trifluoromethanes.

We envisioned that a dual copper/photoredox trifluoromethylation mechanism might be initiated by photoexcitation of Ir^III photocatalyst 1 with blue LEDs to generate a long-lived Ir^III excited state (2) (Figure 2). Given the relative oxidation potentials of the excited-state Ir^III catalyst (2, E_1/2^red [*Ir^III/Ir^II] = +1.60 V vs SCE in MeCN) and tris(trimethylsilyl)silanol (4, E_p^red [(TMS)₃ SiOH⁺•/(TMS)₃SiOH] = +1.54 V vs SCE in MeCN),⁷ we assumed that a rapid SET event would generate silicon-centered radical 5 after a deprotonation and radical Brook rearrangement sequence.¹² At this stage, silyl radical 5 was expected to abstract a bromine atom from alkyl bromide 6 at a rate on the order of 10⁷ M⁻¹ s⁻¹ to generate corresponding alkyl radical 7.^5b At the same time, single electron transfer between the Ir^II reductant (3, E_1/2red [Ir^III/Ir^II] = −0.81 V vs SCE in MeCN) and electrophilic trifluoromethylation reagent 8 (E_p^red = −0.52 V in MeCN)^7,10g would regenerate photocatalyst 1 while inducing the production of the trifluoromethyl radical (9).¹³ Rapid capture of 9 by Cu^I species 10 would produce Cu^II−CF₃ adduct 11. Subsequent combination of this Cu^II−CF₃ adduct with alkyl radical 7, a step that is considered to happen with kinetics approaching diffusion rates, would afford critical alkyl-Cu^III−CF₃ species 12, which upon reductive elimination would afford the desired product 13 and regenerate the Cu^I catalyst.¹⁴

Figure 2.

Proposed mechanism for the copper-catalyzed trifluoromethylation of alkyl bromides via metallophotoredox.

Initial experiments on a representative alkyl bromide, 15, revealed that the combination of silanol 4, trifluoromethylsulfonium salt 8, photocatalyst 1, and CuCl₂ was highly effective, affording the desired CF₃-bearing product 16 in 94% yield (Table 1, entry 1). In agreement with our previous studies, silanol 4 proved to be superior to tris(trimethylsilyl)-silane, presumably due to the feature that supersilane has a weak Si−H bond (BDE = 84 kcal/mol)¹⁵ and can participate in competitive hydrogen-atom transfer to produce proto-dehalogenated material (entry 2). Notably, the Adachi-Zhang organic photocatalyst, 4CzIPN (17), was also highly effective for this transformation (entry 3).¹⁶ While control reactions revealed that the copper catalyst, silanol, blue light, and photocatalyst were all individually necessary (entries 4−7, 0% yield), the omission of base resulted in decreased but measurable product formation (entry 8). Moreover, the use of ligated copper salts led to decreased yields. Lastly, an examination of alternate metal chlorides including Ni, Fe, Co, and Pd salts showed no activity, further highlighting the unique effectiveness of Cu.¹⁷

Table 1.

Control Reactions of Optimized Conditions^a,b

entry	deviation	yield
1	none	94%
2	TMS3SiH instead of 4	50%
3	4CzIPN (17) instead of 1	94%
4	no CuCl2	0%
5	no TMS3SiOH	0%
6	no light	0%
7	no photocatalyst	0%
8	no base	26%

^aPerformed with 15 (0.05 mmol), CuCl₂ (20 mol %), 1 or 17 (1 or 5 mol %, respectively), 8 (2 equiv), (TMS)₃SiOH (2 equiv), and Na₂CO₃ (4 equiv) in DMSO (0.025 M) for 4 h at 30 °C.

^bYields are reported on the basis of ¹⁹F NMR analysis using PhCF₃ as an internal standard.

With these conditions in hand, we next turned our attention to evaluating the scope of this new alkyl trifluoromethylation reaction. First, with a diverse set of primary alkyl bromides, we determined that excellent functional group compatibility was possible with substrates containing alcohols, esters, amides, and protected amines (Table 2, 18−22, 61−83% yield). Next, secondary cyclic alkyl bromides were converted to their trifluoromethyl congeners in good to excellent yield (23−25, 52−95% yield), presaging the utility of this transformation for rapid access to analogs of drug-like molecules. The observed lack of diastereoselectivity for cyclobutane adduct 24 is consistent with a carbon-centered, radical-based mechanism. Saturated heterocycles such as tetrahydropyrans and piperidines, prevalent moieties in medicinal agents, could also be readily employed (13, 26−28, 61−91% yield). Notably, homobenzylic bromides, which are prone to E2 elimination in base-mediated cross-coupling reactions, were well-tolerated using this mild protocol (30, 63% yield).¹⁸ Similarly, rigid frameworks such as 2-bromoadamantane and 5-bromo-2-adamantanone readily afforded CF₃-bearing analogs 31 and 32 (74% and 43% yield, respectively).

Table 2.

Scope of the Copper-Catalyzed Trifluoromethylation Reaction of Alkyl Bromides via Metallophotoredox^a,b

`

^aPerformed with CuCl₂ (20 mol %), 8 (2 equiv), 4 (2 equiv), Na₂CO₃ (4 equiv), and with either 1 (1 mol %) or 17 (5 mol %) in MeCN or DMSO, respectively (see Supporting Information for full experimental details).

^bDue to the volatility of a number of products, yields are reported on the basis of ¹⁹F NMR analysis using PhCF₃ as an internal standard. Isolated yields are in parentheses.

^cPerformed with 17 in DMSO for 1 h.

^dPerformed with 1 in MeCN for 4 h.

^ePerformed with 17 in DMSO for 30 min.

We next examined activated allylic and benzylic bromides substrates, given the prevalence of benzylic CF₃ substituents in medicinal chemistry. A series of diversely substituted benzyl bromides could be readily functionalized in good yield (34− 41, 39−87% yield). Notably, an alkyl bromide was engaged faster than an aryl bromide (39, 39% yield), enabling the possibility of sequential cross-coupling functionalization. We were delighted to find that other activated substrates such as allylic and secondary benzylic bromides were also tolerated (42−45, 38−81% yield).¹⁹

Heteroarenes, among the most widely used core structures in pharmaceutical synthesis, were also evaluated as trifluoromethylation substrates.²⁰ (Bromomethyl)pyridines afforded the corresponding CF₃-adducts in good yield (46 and 47, 72% and 59% yield, respectively). Surprisingly, anilines, substrates that can be easily oxidized in photocatalytic SET processes, were competent substrates for trifluoromethyl incorporation (48, 67% yield). Heterocycles that are often susceptible to N−O and N−N bond cleavage,²¹ such as isoxazoles, oxadiazoles, and pyrazoles, were all accommodated in this new copper-mediated transformation, yielding the corresponding trifluoromethylated adducts (51−54, 42−89% yield). Moreover, imidazoles such as 55, which are often problematic in metal-catalyzed protocols, provided a level of effciency suitable for medicinal chemistry purposes.

We next sought to establish the intermediacy of alkyl radicals by testing the functionalization of cyclopropyl-bearing substrates 56 and 57 (Figure 3). Cross-coupling of halomethyl cyclopropanes under reducing Grignard conditions is known to proceed without cyclopropane opening. As such, functionalization of these radical clock substrates would enable us to distinguish the mechanistic basis for the current protocol from direct oxidative addition by either low-valent or nano-particulate copper in solution.²² Upon exposure of 56 to our standard protocol, we observed the production of 58 in 14% yield. Similarly, cross-coupling of 57 also afforded ring-opened product 59 in 17% yield. These results directly support the presence of discrete alkyl radical intermediates in the reaction, consistent with our proposed mechanism.

Figure 3.

Studies into the proposed open-shell mechanism.

To demonstrate the utility of this transformation in late-stage functionalization of drug analogs, we next undertook the rapid synthesis of trifluoromethylated celecoxib and ticagrelor derivatives 60 and 61 in 61% and 55% yield, respectively, from the corresponding alkyl bromides (Figure 4). These relatively complex medicinal agents underwent trifluoromethylation using the standard conditions outlined in Table 1, further demonstrating the general utility of this new protocol. Moreover, the trifluoromethyl moiety has also been recognized as an isopropyl group isostere in medicinal chemistry based on their similarities in molecular volume and hydrophobicity.²³ With this goal in mind, we successfully synthesized a trifluoromethyl isostere of pregabalin 62 (92% yield, dehydrated, cyclic form) from the commercial precursor bromide. The application of this new trifluoromethylation protocol to a diverse range of medicinally relevant structural classes serves to emphasize the real-world utility and versatility of this new copper-mediated protocol for both early- and late-stage applications.

Figure 4.

Late-stage trifluoromethylation of medicinal agents.