Ligand Design Enables Cu-Catalyzed Etherification of Aryl Bromides Using Mild Bases

Abstract

We report a Cu-catalyzed method for the efficient coupling of base-sensitive aryl bromides and alcohols utilizing a newly developed N ¹,N ²-diarylbenzene-1,2-diamine ligand, L15. This ligand was developed to increase the Lewis acidity of the Cu center, thereby permitting the use of a substantially milder base (NaOTMS or NaOPh) relative to those required in a previous iteration of this methodology (NaOMe or NaOt-Bu). Under the optimized reaction conditions, several classes of previously incompatible aryl bromides were efficiently transformed, including base-sensitive heterocycles and those containing acidic functional groups. Kinetic analyses support that C–O coupling proceeds via a mechanism involving binding/deprotonation of alcohol nucleophiles, that the pK _a of the base influences the overall rate law, and that substoichiometric quantities of strong base can be utilized to accelerate ligand activation and thereby increase the overall rate of the transformation.

Owing to the prevalence of aryl–alkyl ethers in small-molecule therapeutics, C–O bond-forming reactions have become some of the most commonly employed transformations in the pharmaceutical industry (Figure A). − In recent years, transition-metal-catalyzed approaches have emerged as useful alternatives to classical substitution methods due to their broader applicability and functional group tolerance. ,, In particular, protocols involving base metal catalysts are of interest due to their diminished cost and toxicity relative to precious metal analogues. − Recently, we have developed a new class of anionic Cu ligands based on the N ¹,N ²-diarylbenzene-1,2-diamine scaffold. − Guided by density functional theory (DFT) calculations, these ligands were designed to increase the electron density on Cu while stabilizing the anionic catalyst through a Cu−π interaction. We previously disclosed a method for the construction of aryl–alkyl ethers utilizing the catalyst derived from L8 (Figure B). In this study, we demonstrated that the mechanism of C–O bond formation proceeded via transmetalation of an in situ-generated alkoxide ion, which necessitated the use of a strong alkoxide base (NaOMe or NaOt-Bu). The use of such strong bases was found to compromise functional group tolerance, especially with base-sensitive functional groups and heterocycles that are ubiquitous in functional molecules. With this in mind, we hypothesized that the design of a new ligand could promote a mechanism of nucleophile transfer involving binding and deprotonation of the alcohol at the active Cu center. This binding event would significantly increase the acidity of the O–H bond, thereby enabling the use of a comparatively milder base (Figure C).

1.

(A) Examples of pharmaceuticals containing aryl–alkyl ethers. (B) Previously reported C–O coupling using the catalyst derived from L8 and NaOt-Bu. (C) This work, in which L15 was designed to promote a reaction mechanism involving alcohol binding and deprotonation, thereby enabling the use of milder bases.

A central challenge that we identified was that the activation of this class of ligands is reliant on deprotonation of the central N–H bonds. With this in mind, we surmised that the use of a ligand featuring more acidic N–H bonds would be crucial, as it was in the mechanistically similar amination of base-sensitive aryl bromides. However, lowering of the amine pK _a also has a negative impact on the ability of the ligand to donate electron density to the Cu center, which is required to facilitate oxidative addition with a relatively low energy barrier. To overcome these challenges, we surmised that a design strategy would be needed to fine-tune the Lewis acidity of the Cu^III oxidative addition complex without inhibiting productive catalysis. We hypothesized that by increasing the Lewis acidity of this intermediate, we could promote efficient binding of the alcohol coupling partner, thereby enabling the use of a milder base.

We began by examining the coupling of 4-bromoanisole (1a) and n-butanol (2a) to yield aryl–alkyl ether 3a (Table ). Our recent finding that the mild base NaOTMS was useful in the amination of base-sensitive aryl halides using the catalyst derived from L8 prompted us to explore this reagent combination in the analogous C–O coupling reaction. However, as with our previous report, no observable product was formed. This observation is likely due to the simultaneous and reinforcing effects of NaOTMS not being strong enough to deprotonate alcohol nucleophiles and the catalyst derived from L8 not being Lewis acidic enough to promote alcohol binding. In order to achieve alcohol binding prior to deprotonation, we introduced electron-withdrawing trifluoromethyl groups onto the pendant arms of the ligand scaffold. We reasoned that these groups would be (1) stable under the reaction conditions and (2) remote enough to fine-tune the electronic properties of the oxidative addition complex without inhibiting catalysis. The use of L12, which was developed for the amination of base-sensitive aryl chlorides, led to the formation of 3a in good yield, albeit with a substantial amount of the protodehalogenated byproduct. Returning to the symmetric bis­(naphthyl) backbone present in L8, the use of the Cu catalyst derived from L15 suppressed these protodehalogenated byproducts and enabled quantitative formation of 3a at room temperature. The presence of additional electron-withdrawing substituents, such as in L17, led to a substantial decrease in reaction performance. In addition to NaOTMS, NaOPh also enabled quantitative formation of the desired product, while weaker organic (Et₃N) and inorganic (K₃PO₄ or K₂CO₃) bases resulted in 0% conversion of 1a, presumably due to their inability to activate L15 through deprotonation. Finally, omitting either CuI or L15 from the reaction mixture resulted in 0% conversion, an observation that is consistent with the need to form the Cu catalyst derived from these ligands.

1. Optimization of Cu-Catalyzed C–O Coupling .

^aStandard reaction conditions: 1a (0.10 mmol, 1.0 equiv), 2a (0.12 mmol, 1.2 equiv), NaOTMS (0.15 mmol, 1.5 equiv), CuI (5 mol %), ligand (10 mol %), DMSO (0.1 mL), 24 °C, 16 h. Yields were determined by ¹H NMR spectroscopy of the crude reaction mixtures using 1,1,2,2-tetrachloroethane as an internal standard.

Upon optimizing the reaction conditions, we set out to assess the scope of aryl bromides and alcohols, with a particular emphasis on substrate combinations incompatible with our previously developed method (Scheme ). Specifically, the catalyst derived from L15 was able to functionalize many base-sensitive and/or coordinating heterocycles such as thiazole (1a), pyrazole (1b), triazole (1c), pyrimidine (1d and 1o), 3-pyridyl (1f, 1m, and 1o), indazole (1g), quinoline (1p), and oxadiazole (1r). In addition, the method tolerated several acidic or coordinating functional groups, including an amide (1j), an enolizable ketone (1k), a nitro group (1n), a Boc-protected primary amine (1p), and a sulfone (1q) that interfered with productive catalysis in our previous report. Collectively, the ability to prepare a variety of structurally diverse aryl–alkyl ethers in good-to-excellent yields highlights the utility of this protocol.

1. Substrate Scope of the Cu-Catalyzed Etherification of Base-Sensitive Aryl Bromides .

^a All reported yields are averages of two isolated yields. Standard reaction conditions: aryl bromide (0.50 mmol), alcohol (0.60 mmol), NaOTMS (0.750 mmol), CuI (5 mol %), L15 (10 mol %), DMSO (0.5 mL), 24 °C, 16 h.

^b Previous method standard reaction conditions: aryl bromide (0.10 mmol, 1.0 equiv), alcohol (0.12 mmol, 1.2 equiv), NaOt-Bu (0.20 mmol, 2.0 equiv), CuI (5 mol %), L8 (10 mol %), DMSO (0.2 mL), 24 °C, 16 h. Yields were determined by ¹H NMR spectroscopy of the crude reaction mixtures using 1,1,2,2-tetrachloroethane as an internal standard.

^c Base = NaOPh.

^d Reaction temperature = 50 °C.

^e Reaction temperature = 70 °C.

In order to investigate whether the C–O coupling proceeded via a mechanism involving alcohol binding and subsequent deprotonation, we performed kinetic analyses of C–O coupling reactions using the catalyst derived from L15. Empirical rate laws for the coupling of 4-bromoanisole (1a) and n-butanol (2a) utilizing either NaOTMS or NaOAr [Ar = 3,5-(Me₂)­C₆H₃] were determined using initial rate measurements. NaOAr was used in place of NaOPh to ensure complete solubility of the base when used at relatively high concentrations and is expected to display a comparable basicity to NaOPh. For the model reaction using NaOTMS as the base, a positive first-order dependence on the concentration of aryl bromide, saturation kinetics with respect to the alcohol concentration, and a zeroth-order dependence on the concentration of base were observed (Figure A–C). In contrast to the observations made for the reactions utilizing NaOTMS, the reaction rate for the coupling of 1a and 2a utilizing NaOAr as the base was found to be independent of the concentration of 4-bromoanisole (Figure A). However, the reaction now exhibited a positive first-order dependence on the concentration of NaOAr (Figure C). Similarly, saturation kinetics were observed when the concentration of n-butanol was varied. In both systems, the observation of saturation kinetics when varying the initial concentration of n-butanol is consistent with a mechanism involving binding of the alcohol nucleophile to the intermediate oxidative addition complex. This validates our initial hypothesis and establishes design criteria to fine-tune the Lewis acidity of the Cu-catalyst, thereby changing the mechanism of C–O bond formation. Reactions utilizing NaOTMS feature a rate equation that is dependent on the concentration of aryl bromide and therefore implicates a rate-determining span at least partially involving oxidative addition. In contrast, reactions employing NaOAr exhibit no kinetic dependence on the concentration of aryl bromide, suggesting a change in the overall rate law. However, the initially collected data present ambiguity as to the identity of the rate-determining step at early time points in the reaction when the concentration of n-butanol is comparatively high. With this in mind, we set out to design an experiment to probe whether alcohol deprotonation or catalyst activation was rate-determining at these time points when NaOAr was utilized as the base.

2.

Mechanistic analyses of C–O coupling reactions utilizing the catalyst derived from L15 and either NaOTMS or NaOAr. (A) Initial rate kinetics in utilizing NaOTMS (red) or NaOAr (blue) in the presence of varying equivalents of 4-bromoanisole. (B) Initial rate kinetics in utilizing NaOTMS (red) or NaOAr (blue) in the presence of varying equivalents of n-butanol. (C) Initial rate kinetics in utilizing NaOTMS (red) or NaOAr (blue) in the presence of varying equivalents of base. (D) Rates of C–O bond formation using the catalyst derived from L15 and NaOt-Bu (red), NaOTMS (purple), or NaOAr (blue). (E) Rates of C–O bond formation using the catalyst derived from L15 and NaOt-Bu (red), NaOTMS (purple), or a combination of NaOTMS (1.3 equiv) and NaOt-Bu (0.2 equiv) (green). (F) Rates of C–O bond formation using the catalyst derived from L15 and NaOt-Bu (red), NaOAr (blue), or a combination of NaOAr (1.3 equiv) and NaOt-Bu (0.2 equiv) (green). (G) Proposed mechanism of C–O bond formation in reactions utilizing NaOTMS. (H) Proposed mechanism of C–O bond formation in reactions utilizing NaOAr.

We began by determining the relative rates of C–O bond formation using the catalyst derived from L15 employing either NaOt-Bu, NaOTMS, or NaOAr as the base. All of these coupling reactions enable quantitative formation of the desired aryl–alkyl ether after 16 h of reaction time. Reactions conducted with bases of increasing strength exhibited higher rates of C–O bond formation, with NaOt-Bu exhibiting the fastest kinetics of the sampled bases (Figure D). We attribute this change to the more efficient generation of the active catalyst compared with the weaker bases. In order to compare kinetic measurements of these reactions under conditions in which equimolar amounts of catalyst had been generated, we determined the relative rates of C–O bond formation when substoichiometric NaOt-Bu (0.2 equiv) was first utilized to deprotonate L15 (10 mol %) in the presence of CuI (5 mol %), after which either NaOTMS (1.3 equiv) or NaOAr (1.3 equiv) was added along with the coupling partners. In the case of NaOTMS, no change in the relative rate of C–O bond formation (k _rel = 0.046, relative to the rate employing only NaOt-Bu) was observed compared to the reaction in the absence of NaOt-Bu, suggesting that the absolute rate of these reactions is not dependent on catalyst activation (Figure E). This observation is consistent with initial rate kinetic data as described in Figure A–C. In the case of NaOAr, a substantial rate increase was observed when substoichiometric NaOt-Bu (k _rel = 0.126, relative to the rate employing only NaOt-Bu) was used to deprotonate L15 relative to reactions employing only NaOAr (k _rel = 0.020) (Figure F). Based on this finding, we propose that at high concentrations of alcohol, catalyst activation is likely the rate-determining step when NaOAr is used as the base in the reaction (Figure H). Moreover, this finding is particularly interesting, as it may enable the development of dual-base methodologies in which a relatively strong base is used for catalyst activation while a weaker, more functional-group-tolerant base is used to facilitate the desired chemistry.

In summary, we have developed a general method for the C–O coupling of base-sensitive aryl bromides and alcohols using the catalyst derived from L15 and either NaOTMS or NaOPh. The catalyst system was found to enable the coupling of substrates that yielded little to no C–O coupled products using the previously reported L8/NaOt-Bu system. Kinetic experiments validated that the design of L15 enabled a mechanism of C–O coupling that proceeded via alcohol binding to the oxidative addition complex, followed by deprotonation by the mild base. Finally, we demonstrated that in the case of NaOPh, substoichiometric quantities of NaOt-Bu could be used to accelerate the coupling reaction by promoting efficient activation of L15 to its active, bisanonic state.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c05127.

• Experimental procedures, spectral data, details regarding kinetic analyses, and copies of NMR spectra (PDF)

‡.

M.J.S. and M.E.G. contributed equally.

The authors declare no competing financial interest.