Palladium catalyzed C_sp²–H activation for direct aryl hydroxylation: the unprecedented role of 1,4-dioxane as a source of hydroxyl radicals

Abstract

A novel strategy for direct aryl hydroxylation via Pd-catalysed C_sp²–H activation through an unprecedented hydroxyl radical transfer from 1,4-dioxane, used as a solvent, is reported with bio relevant and sterically hindered heterocycles and various acyclic functionalities as versatile directing groups.

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The wide occurrence of hydroxylated aromatics (phenols) in bioactive compounds¹ makes them highly sought for synthetic targets. Aryl hydroxylation through C–H activation has emerged as a new synthetic route to phenols.² However, this route represents indirect hydroxylation, as the reaction proceeds via the intermediate formation of the acyloxy arenes that are converted to hydroxyaromatics during the workup or on further hydrolytic transformation.³ The issue on direct aryl hydroxylation remains inadequately addressed (Scheme 1).⁴

Scheme 1 Different strategies for direct aryl hydroxylation.

Fujiwara et al.^4a revealed the feasibility of direct aryl hydroxylation but the low yield (∼5%) and turnover ratio (10–15 to Pd), poor selectivity, and harsh reaction conditions (15 atm O₂, 15 atm CO, 180 °C, AcOH) make it less attractive. The strategy of Kim et al.^4b involving the use of the 2-pyridyl moiety as the directing group (DG) for C_sp²–H activation though affords good yields, requires excess oxidants (5 equiv.), is applicable to highly substituted DGs (2-pyridyl), and does not work with aryl moieties bearing o-substitution. The use of carboxylic acid as a DG by Yu et al.^4c requires an excess of base, benzoquinone as an additional oxidant (in addition to O₂ at 1–5 atm), and leads to decarboxylation (e.g. 1-naphthoic acid). The tandem C–S coupling-hydroxylation strategy by Pan et al.^4d requires a special ligand, an excess of base, and aryl bromide/iodide as the reaction partner (additional reagent). The recent report on 2-pyridyl directed C_sp²–H activation by Jiao et al.,^4e though circumvents the limitations of the protocol by Kim et al.,^4b requires N-hydroxyphthalimide (NHPI) and toluene as an additional reagent system (in addition to O₂ at 1 atm) to form the benzyl radical that acts as the effective agent/species for hydroxyl radical generation and leads to the formation of high boiling by-products (benzaldehyde/benzoic acid).

Functionalised 2-(benzoxazol-2-yl)phenols have diverse biological activities.⁵ Thus, it would be attractive to use the 2-benzoxazolyl scaffold as the DG for C_sp²–H activation for direct aryl hydroxylation to further potentiate their biological activity⁶ and as there is no report on direct aryl hydroxylation with the 2-benzoxazolyl moiety as the DG. 2-Phenylbenzoxazole (1a)⁷ was considered as a model substrate for oxidative hydroxylation via aryl C_sp²–H activation under various conditions (Scheme 2).

Scheme 2 Direct hydroxylation of 1a to form 2a.

It appears that the limited reports on direct hydroxylation involve the generation of the oxygen/hydroxyl radical^4b–d that adds on to the metal centre in its higher oxidation state in the cyclometallated intermediate and acts as the effective species for C–O bond formation. 1,4-Dioxane is reported to generate the hydroxyl radical upon pyrolysis.⁸ However, high temperature (1550–2100 K) is required to generate the hydroxyl radical by ring opening (homolytic C–O cleavage), isomerisation, and dissociation of the resulting linear species. We reasoned that the hydroxyl radical generation from 1,4-dioxane may be achieved under milder conditions in the presence of an oxidant that would abstract H from 1,4-dioxane and facilitate its dissociation via ring opening C–O cleavage involving the free radical mechanism. Thus, it was hypothesised that the use of 1,4-dioxane in combination with persulfate would serve the dual purpose of the reaction medium and the oxo/hydroxyl transfer agent without the requirement of any additional oxidant/reactant and base.

Treatment of 1a with different variations of the reaction parameters (ESI: Table S1A–E)† revealed the use of Pd(OAc)₂ (2.5 mol%) and Na₂S₂O₈ (1.25 equiv.) in 1,4-dioxane at 80 °C for 14 h to be the best operative reaction conditions affording 2a in 62% yield which could be further improved to 82% after reusing the unreacted 1a recovered after the first use. The lack of formation of 2a in any other solvent (ESI: Table S1D and E)† suggested 1,4-dioxane to be the hydroxyl transfer agent, as the comparable results using commercial grade as well as dry and degassed 1,4-dioxane under N₂ or O₂ eliminated the possibility of hydroxyl transfer from any dissolved oxygen/moisture. That the reaction forms the hydroxyarene directly was demonstrated by the fact that 2a was obtained in comparable yield (64%) avoiding any aqueous workup. However, the Pd(OAc)₂-catalysed reaction of 1a with Na₂S₂O₈ (1.5 equiv.) in HOAc–Ac₂O (1 : 1) or Ac₂O instead of 1,4-dioxane afforded O-acetylated 2a following a non-aqueous workup in 53 and 55% yields, respectively (ESI: Table S2A).† Thus, the persulfate-dioxane combination constitutes a novel reagent system for Pd-catalysed direct aryl hydroxylation.

Treatment of 1a under the reported conditions for acetoxylation/hydroxylation and minor variation (using 1,4-dioxane as solvent) did not produce a significant amount of 2a (ESI: Table S3A and B)† and established the distinctiveness of the present work.

The direct hydroxylation protocol is applicable to benzoxazoles bearing a substituent in the 2-aryl moiety as well as in the benzenoid ring of the benzoxazole scaffold (Table 1). The applicability of the direct hydroxylation towards various substituted 2-arylbenzothiazoles (Table 1),⁹ another bio relevant and sterically hindered DG, demonstrated the versatility with respect to the DG.¹⁰ The presence of Cl, Br, CF₃, and NO₂ in the 2-aryl moiety appears to be beneficial, as such substrates afforded the corresponding hydroxyarenes in better yields compared to that of the unsubstituted analogue 1a/3a. The effect of these substituents was more pronounced with the 2-benzothiazolyl moiety as the DG. The presence of an electron donating substituent such as the Me group decreased the yield.

Table 1 Substrate scope for direct aryl hydroxylation via C–H activation with bio relevant and sterically hindered DGs

a The figure in the parentheses is the total yield based on recovery and reuse of the unreacted starting material after the first attempt.

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The results summarized in Table 2 demonstrate the further scope with acyclic DGs such as azo, amide, anilide, carbamate, and unsymmetrical urea. The F and Cl substituted azo benzenes produced the corresponding azoxy-benzene in 40 and 24% yields, respectively, along with the desired hydroxylated products. The chemoselective hydroxylation with substrates bearing halogen provides the scope of structural modification through Suzuki coupling¹¹ to broaden the chemical space. Catalyst [Pd(OAc)₂] was recovered and reused for five consecutive reactions affording comparable yields.†

Table 2 Scope of acyclic DGs for direct aryl hydroxylation

a The figure in the parentheses is the total yield based on recovery and reuse of the unreacted starting material after the first attempt.

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A plausible mechanism is depicted in Scheme 3. The Pd-catalyst forms complex I through coordination with the nitrogen centre of the DG and trigers aryl C_sp²–H activation and ligand-assisted intra-molecular aryl proton abstraction in II to form cyclopalladated species III. Oxidative addition of the hydroxyl radical, formed by degradation of 1,4-dioxane with the persulfate anion, (Scheme 4) generates Pd(IV) species IV¹² or Pd^III–Pd^III species V.¹³ The aryl C–O bond forming reductive elimination from IV/V leads to the hydroxyarene (phenol) and brings the Pd(II) compound back to the catalytic cycle to form I through ligand exchange (facilitated by intramolecular hydrogen bond formation between the newly inserted OH and the nitrogen atom of the DG).¹⁴

Scheme 3 Plausible pathway for the direct aryl hydroxylation.

Scheme 4 Generation of the OH radical from 1,4-dioxane and Na₂S₂O₈.

The generation of the hydroxyl radical from Na₂S₂O₈ and 1,4-dioxane is presented in Scheme 4. The sulfate anion radical, generated from the persulfate anion,¹⁵ has the ability to abstract C–H hydrogen^15a and reacts with 1,4-dioxane (A) to form the 1,4-dioxan-2yl radical (B). Homolytic ring C–O cleavage⁸ of B produces radical C which on further homolytic C–O cleavage is converted to the tetrahydrofuran-2-yl radical D. The liberated oxygen diradical is converted to the hydroxyl radical through H-abstraction from another molecule of 1,4-dioxane generating radical B to propagate the radical chain reaction. The relevant intermediates could be identified in the GC-MS spectra of aliquot samples (withdrawn at an interval of 2 h) of the reaction mixture of 1,4-dioxane and Na₂S₂O₈ at 80 °C that showed ion peaks corresponding to B (m/z 87) (ESI: 10.2.3) and D/E (m/z 71) (ESI: 10.2.2) that compared well with the GC-MS and ms² (of the ion at m/z 71) spectra of an authentic sample of THF.† Some of the daughter ions observed in the ms² spectra of the ion at m/z 71 were also observed in the ms² spectra of the ion at m/z 87 (e.g. 70.81 vs. 70.82; 42.93 vs. 42.87) suggesting that the ion at m/z 71 is derived from the ion at m/z 87 through loss of active oxygen species. The GC-MS spectra of aliquots of the reaction mixture during the treatment of 2-phenylbenzoxazole (1a) with Na₂S₂O₈ and 1,4-dioxane at 80 °C revealed the presence of the ion peaks at m/z 87 and 71 corresponding to B and D/E, respectively (ESI: 10.5.3 and 10.5.2).†

The influence of ligand/counter anions on the catalytic potential of the Pd-compounds (ESI: Table S1B)† and the lack of improvement of yield using NH₄OAc, KOAc and (KOAc + 18-C-6) as external base (ESI: Table S5A)† during the Pd-catalysed reactions implicate that the abstraction of the aryl proton during the C–H activation step occurs via an intramolecular process involving II. Thus the strong electron withdrawing CF₃ group reduces the HB acceptor property of TFA in Pd(TFA)₂¹⁶ making it an inferior catalyst compared to Pd(OAc)₂. The HB formation ability of the counter anion plays a key role in the formation of the reaction intermediate (transition state) in various organic reactions.¹⁷ The importance of the HB has also been realised in forming metal centred transition states.¹⁸

The involvement of radical species was corroborated by the fact that a drastic decrease in the product (2a) yield (17%) was observed in performing the Pd(OAc)₂-catalysed reaction of 1a in the presence of a radical scavenger (TEMPO) (ESI: Scheme S5C).† The indispensable role of 1,4-dioxane is reflected in its ability to form radical species in the presence of persulfate¹⁵ or other oxidants.¹⁹

The present work provides a novel strategy for direct aryl hydroxylation via palladium-catalysed aryl C_sp²–H activation with bioactive and sterically hindered heterocyclic moieties and other acyclic functionalities (azo, amide, anilide, carbamate, and urea) as versatile directing groups through unprecedented generation of hydroxyl radicals, as the effective aryl hydroxylation species, from 1,4-dioxane (used as a solvent).

Financial support from DST (SR/S1/OC-33/2008) and CSIR [senior research fellowship to KS], New Delhi, India is acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Spectroscopic data of all compounds and scanned spectra of new compounds. See DOI: 10.1039/c4cc06864e

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