Sequential Functionalization of meta-C–H and ipso-C–O Bonds of Phenols

Abstract

The use of a template as a linchpin motif in directed remote C–H functionalization is a versatile yet relatively underexplored strategy. We have developed a template-directed approach to realizing one-pot sequential palladium-catalyzed meta-selective C–H olefination of phenols, and nickel-catalyzed ipso-C–O activation and arylation. Thus, this bifunctional template converts phenols to synthetically useful 1,3-disubstituted arenes.

Graphical Abstract

Realizing remote selective C–H functionalization is essential for broad application of directed C–H activation reactions in the presence of multiple C–H bonds.¹ Over the past two decades, transition-metal-catalyzed arene ortho-C–H functionalization has been extensively exploited via σ-chelation-assisted directing effect.² More recently, directed remote meta- and para-C–H functionalization of arenes has also been achieved using distance and geometry as the key recognition parameters.^3–5 However, the installation and removal of these templates for remote C–H activation reduces the step economy in synthetic applications. Therefore, a one-pot procedure that can both directly remove the directing group and install additional desired functionality would greatly improve the synthetic efficacy of directed arene C–H activation. In this context, Chatani and others have demonstrated a commendable example with the ortho-selective directing group 2-pyridyloxy (OPy) (Figure 1a).⁶ Herein we report the development of a palladium-catalyzed remote meta-C–H olefination of phenols enabled by a novel bifunctional template, which can also be directly converted into other functional groups, i.e. an aryl group (vide infra), via the catalytic cleavage of the ipso-C–O bonds in the meta-functionalized phenols (Figure 1b). Notably, this template is easily installed in a single step from the commercially available 2,4-dichloro-6-methoxy-1,3,5-triazine (Figure 1c).

Figure 1.

Development of new bifunctional templates for sequential meta-C–H/ipso-C–O functionalization of phenols.

It is well established that the positional selectivity of template-assisted remote C–H activation is highly associated with the template geometry.^3,4 An appropriate template facilitates the assembly of a conformationally favored macrocyclic metallocycle that enables the metal catalyst to activate the remote C–H bond of the arene through an agnostic interaction.⁷ Moreover, a rigid backbone in the template readily forms a large yet less strained macrocyclic pre-transition state, and therefore provides the palladacycle intermediate with higher stability and a longer lifetime.^3f For example, we^3f,8 and others⁹ have found that the use of a relatively rigid template could functionalize remote meta-C–H bonds in long-chain aromatic alcohols. Bearing in mind that the unreactive C–O bonds in phenols may be directly functionalized via transition-metal-catalyzed C–O cleavage of aryl ethers, such as 2-pyridyloxy,^6,10 and 2-triazinyloxy groups¹¹, we strove to develop a bifunctional template that could both direct the meta-C–H functionalization of phenols and be subsequently removed through a transition-metal-catalyzed ipso-C–O cleavage, consisting of a 1,3,5-triazine-derived rigid biaryl scaffold (Figure 1b).

Initially, the biaryl templates T₁–T₃ were synthesized via a Suzuki coupling from the commercially available 2,4-dichloro-6-methoxy-1,3,5-triazine (Figure 1c), and the latter can also be prepared from inexpensive cyanuric chloride in almost quantitative yield (see the SI). The substrate bearing the template T₁ was subjected to the previously established meta-C–H olefination conditions.^3,8 Much to our delight, the C–H olefination occurred exclusively at the meta-position with meta:others > 20:1 regioselectivity. Ortho-C–H functionalization directed by the donor heteroatom of 1,3,5-triazine was not observed under the reaction conditions.¹² Not surprisingly, using templates T₂ and T₃ also afforded the products in >20:1 meta-selectivity. Increasing the electron density of the phenyl rings in the templates T₂ and T₃ did not significantly improve the reactivity, but led to a lower ratio of mono- to di-olefinated products (Scheme 1). With the template T₁, however, the desired meta-C–H olefination product could be obtained in 82% yield after an elongated reaction time (36 h). Thus, T₁ was selected as the optimal template.

Scheme 1. Design of New Template for meta-C-H Olefination of Phenol^a.

^aYield and regioselectivity were determined by 1H NMR with CH₂Br₂ as an internal standard. ^bReaction time: 36 h.

Having identified the optimal template, we further investigated the generality of the template-assisted meta-C–H olefination (Table 1). Both electron-donating and -withdrawing groups are well tolerated with predominant meta-selectivity. Excluding alkyl and alkoxyl groups, a variety of functional groups such as halogen (2e, 2f, 2j, 2n and 2o), ester (2g), and acetyl (2p) groups afforded the meta-olefinated products in isolated yields of 49–89%. Substrates bearing two groups in different substitution patterns are also compatible with the present protocol (2q–s). Compared with meta- and para-substituted phenols, substrates derived from ortho-substituted phenols delivered the meta-C–H olefination products in higher yields (2b–g). The presence of an ortho-substituent significantly improves the mono-selectivity as the di-meta-C–H olefination will be subjected to steric hindrance from the adjacent ortho-substituent. It is noteworthy that, using template T₁, naturally occurring L-tyrosine (2t) and estrone (2u) also yielded the corresponding olefination products in exclusive meta-selectivity. The synthetically valuable meta-olefinated phenols could be readily obtained through removing the template (See SI for details). In addition, the olefin coupling partner scope was examined. Various α,β-unsaturated esters, amide, sulfone, and phosphonate olefins were reactive, affording the meta-olefinated products in good yields (2v₁–2v₆). Under the reaction conditions, α- or β-substituted olefins proved to be compatible substrates (2v₇ and 2v₈). Moreover, C–H olefination with cyclic α,β-unsaturated esters and 2-amidoacrylates also provided the desired meta-products with exclusive Z-selectivity in satisfactory yields (2v₉–2v₁₂). The stereochemistry of the double bond is determined by the two competing transition state energy of the β-hydride elimination, analogous to the Heck Coupling. The transition state with the electron-withdrawing ester group being anti to the phenyl group is generally favored which accounts for the observed Z-selectivity of meta-C–H olefinated products (for stereochemistry assignment, see the SI).

Table 1.

Pd-Catalyzed Template-Directed meta-C–H Olefination of Phenols^a

^aIsolated yield. Regioselectivity was determined to be meta:others > 20:1 by ¹H NMR using CH₂Br₂ as an internal standard.

In template-directed C–H functionalization, an additional step is typically required to remove the template and release the C–H functionalized product.^3–5 We wonder whether the template could serve as a linchpin to enable further elaboration of the product via C–O activation. Undoubtedly, direct functionalization via template-induced ipso-C–O bond cross-coupling will not only reduce the cost of the process, but also improve the synthetic efficacy. Therefore, transition-metal-catalyzed direct ipso-C–O cross-coupling of the meta-C–H olefinated phenol 2a with arylboronic acid was investigated. Reaction parameters such as metal catalysts, ligand, base, solvent, and temperature were examined (see SI for details), showing that Ni(xantphos)Cl₂ (10 mol%), K₃PO₄ (7.0 eq), in toluene at 120 °C comprised the optimal reaction conditions.

Next, the substrate scope and the functional group tolerance of this nickel-catalyzed transformation were also surveyed (Table 2). Using p-methoxyl phenylboronic acid as a coupling partner, Ni-catalyzed C–O cross-coupling with various o-, m-, and p-substituted phenol substrates provided the biaryl products 3 in good to excellent yields under the optimized reaction conditions (3b–k). Various functional groups, such as alkyl, alkoxyl, halogen, trifluoromethyl, and ester groups, are tolerated in this transformation. Moreover, m-, m′-diolefinated phenol substrates successf-ully underwent the reaction in good yield (3l). Using the meta-C–H olefinated product of N-protected L-tyrosine, it was also possible to synthesize an unnatural amino acid (3m). Single crystal X-ray diffraction analyses of compounds 3i (p-OMe) and 3j (p-F) validated the exclusive meta-selectivity of C–H functionalization and ipso-C–O cross-coupling (see SI for details). The scope of organoboron reagents was also evaluated: both m- and p-substituents on arylboronic acids including alkyl, halogen, trifluoromethyl, and ester groups were tolerated (3n–t). Notably, heteroarylboronic acid (3u) afforded the biaryl product in 83% yield. Regrettably, o-substituted arylboronic acids give the target products in poor yields, probably due to the steric congestion.

Table 2.

Ni-Catalyzed C–O Cross-Coupling of meta-Olefinated Phenols^a

^aIsolated yield.

^b110 °C, 36 h.

^c110 °C.

To improve the synthetic utility of this strategy and avoid the tedious separation of C–H olefination products, a one-pot meta-C–H/ipso-C–O functionalization procedure was pursued (Table 3). Following palladium-catalyzed meta-C–H olefination, the unpurified intermediate was subjected to nickel-catalyzed ipso-C–O cross-coupling reaction with an arylboronic acid. Gratifyingly, this one-pot procedure furnished the desired m-substituted biaryls in good overall yields (3a, 4a–e). These results further demonstrated the synthetic applicability of this template-assisted transformation. More importantly, template T₁ can be recovered and regenerated after nickel-catalyzed C–O coupling in excellent yield (Scheme 2), which further enhances the synthetic efficacy and atom-economy of the strategy.

Table 3.

Template-Assisted Tandem meta-C–H/ipso-C–O Functionalization of Phenols^a

^aOverall yield for two steps.

Scheme 2.

Recovery and Regeneration of Template

Finally, this template-directed remote C–H functionalization strategy was tested in the synthesis of key building blocks of natural products. Template-assisted meta-C–H olefination of the substrate derived from guaiacol afforded the olefinated product 6 in 68% yield. While direct C–O coupling of compound 6 with arylboronate 9 under the present conditions gave the biaryl scaffold 10 in low yield (18%), an alternative route featuring quantitative removal of the template T₁, borylation, and palladium-catalyzed Suzuki coupling with bromide 8 efficiently delivered the left-hand moiety 10 of TMC-95 A–D (Scheme 3), a small class of naturally occurring selective proteasome inhibitors with IC₅₀ values of 5–60 nM.¹³ The synthetic strategy allows for facile modification of the biaryl units and the amino acid residue, for such purposes as a structure-activity relationship (SAR) study for this family of natural products.

Scheme 3. Application to Synthesis of the Central Scaffold of Natural Antibiotic TMC-95^a.

^aConditions: (1) T₁ (1 eq), KOH (1 eq), THF, rt, 95%. (2) olefin (3 eq), Pd(OAc)₂ (10 mol%), Ac-Gly-OH (20 mol%), AgOAc (1.5 eq), HFIP (0.2 M), 80 °C, 36 h, 68%. (3) morpholine (1 eq), dioxane, 100 °C, 12 h, 99%. (4) Tf₂O (1.1 eq), Pyridine (2.5 eq), CH₂Cl₂, 0 °C to rt, 3 h, 75%. (5) B₂(pin)₂ (2 eq), Pd(OAc)₂ (10 mol%), DPEphos (20 mol%), TEA (4 eq), dioxane, 80 °C, 16 h, 90 %. (6) ArBr 8 (1.1 eq), Pd(dppf)Cl₂ (20 mol%), K₂CO₃ (4 eq), DME, 80 °C, 14 h, 92%. (7) ArBpin 9 (4 eq), Ni(xantphos)Cl₂ (10 mol%), K₃PO₄ (7 eq), toluene, 120 °C, 24 h, 18%.

In summary, a robust bifunctional template has been developed for the palladium-catalyzed remote meta-C–H olefination of phenols. The template can be synthesized concisely in a two-step sequence from inexpensive cyanuric chloride, and is easily installed and removed. In addition, this bifunctional template is amenable to nickel-catalyzed ipso-C–O cross-coupling. This template-assisted one-pot sequential meta-C–H/ipso-C–O functionalization methodology allows for the expedited synthesis of multiply substituted arenes from simple phenol substrates. Further applications of this template-assisted strategy are under investigation in our laboratory.