Selective Oxidative Phenol Coupling by Iron ... - ACS Publications

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Selective Oxidative Phenol Coupling by Iron Catalysis Hadas Shalit, Alina Dyadyuk, and Doron Pappo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03084 • Publication Date (Web): 18 Jan 2019 Downloaded from http://pubs.acs.org on January 18, 2019

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The Journal of Organic Chemistry

Selective Oxidative Phenol Coupling by Iron Catalysis Hadas Shalit,† Alina Dyadyuk,† Doron Pappo* Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel E-mail: [email protected] This work is dedicated to Prof. Yoel Kashman on the occasion of his 80th birthday

TOC

Abstract The iron-catalyzed oxidative coupling of phenols has emerged as a powerful method for preparing complex phenolic frameworks from simple and readily available compounds. This synopsis describes the selectivity challenges inherent in oxidative coupling reactions, while at the same time presents our mechanistic-driven strategy employed to confront them.

Oxidative cross-coupling reactions between phenols and C-H nucleophiles is a powerful synthetic method for preparing complex phenolic architectures with minimum synthetic steps.1 Such transformations are mediated by redox catalysts that promote the transfer of two electrons and two protons from strong C-H bonds to an oxidant while forging a new C-C bond. As a cheap, readily accessible, and environmentally benign metal, iron is considered an attractive candidate for serving as a catalyst in these reactions.2 Recent synthetic advancements together with an improved mechanistic 1 ACS Paragon Plus Environment

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understanding have led to the development of efficient catalytic systems with significant selectivity and efficiency. This essay describes the contribution of our group as well as others to the progress of iron-catalyzed oxidative phenol coupling reactions. The most reliable method for preparing biaryl bonds (Ar-Ar’) relies on transitionmetal-catalyzed cross-coupling reactions between two activated arene units that are fixed with inverted electronic nature (Ar-X and Ar’-M).3 This chemistry offers sufficient synthetic versatility to construct almost any biaryl bond not only with precise selectivity but also high chemical yield.4 Nevertheless, one of this method’s limitations is concealed in the fact that both the chemoselectivity and the regioselectivity are established prior to the coupling step. Consequently, the entire synthesis becomes inefficient in terms of atom- and step economy as it involves a number of activation and protection/deprotection steps, sequences that produce large quantities of toxic waste. Alternatively, oxidative coupling reactions offer a single-step approach for preparing biaryl bonds by merging two unfunctionalized arenes.5 Oxidative phenol coupling reaction is a fundamental transformation, frequently used in the plant kingdom during the biosynthesis of phenolic metabolites, vital to the growth and protection of plants. In general, the basic principles that facilitate oxidative phenol coupling by iron and copper complexes in oxidases are similar to those in the laboratory, thereby supplying a wealth of ideas and inspiration. The selectivity in the oxidative phenol coupling reaction is catalyst-controlled, as it is determined during the formation of a new bond. Thus, in order to control the regio- (ortho, meta and para), chemo- (homocoupling vs. cross-coupling, C-C vs. C-O) and stereo-selectivity (axial chirality and point chirality) of an oxidative phenol coupling reaction, it is necessary to develop a set of bioinspired catalytic systems that follow distinct mechanisms. For many years phenolic residues within a given sample have been identified by the ferric chloride test, which indicates the existence of phenols by color change (Scheme 1A).6 The aforementioned change results from the existence of iron-phenolate complexes, and can be attributed to electron density transfer from the ligated phenolate to the metal (Ia ↔ Ib, Scheme 1A). This reversible transition, also known as the ‘push effect,’7 reduces the oxidation state of the metal while generating a metal-ligated phenoxyl radical. The latter electrophilic species is prone to reactions with other radical species 2 ACS Paragon Plus Environment

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such as oxygen species, anions, or p-nucleophiles, leading to the formation of dehydrogenation or coupling products and a reduced iron complex. In the presence of an oxidant, such as dioxygen or peroxides, the initial oxidation state of the metal is restored and a catalytic cycle is generated (Scheme 1A). In the laboratory setting, this reactivity provides an opportunity to synthesize complex phenolic compounds. Naturally, in an ongoing effort, our group and others have utilized this fundamental reactivity for the coupling of iron-bound phenols with various nucleophiles (Scheme 1B), such as bketoesters,8 a-substituted-b-ketoesters,9 conjugated alkenes,10 arenes, polyaromatic hydrocarbons (PAHs),11 and anilines,12 in addition to a second phenolic coupling partner.13

Scheme 1. (A) General mechanistic scheme for iron-catalyzed oxidative phenol coupling reactions supported by Ferric chloride test and (B) Oxidative coupling of phenols with various nucleophiles.

This synopsis draws attention to the challenges inherent in oxidative coupling reactions between two phenols and such reactions between phenols and arene nucleophiles. The essay also reviews recent progress made in the synthesis of biaryl 3 ACS Paragon Plus Environment


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bonds with respect to the four types of selectivity, namely chemoselectivity, regioselectivity and stereoselectivity, both on a relative (diastereoselectivity) and absolute basis (enantioselectivity). Chemoselectivity (cross-coupling vs. homocoupling) The main challenge in oxidative coupling reactions is to promote a selective cross-coupling between two electron-rich phenolic coupling partners with relatively low oxidation potentials. This reaction has rarely been developed because most early studies evaded this problem by offering efficient oxidation conditions for homocoupling of phenols. In the early 1990s Hovorka and Zavada alongside Kočovský14 conducted the first meaningful study that investigated the cross-coupling of two different 2-naphtholic units. Their studies showed that 3-carbomethoxy-2-naphthol and 2-naphthol derivatives afford unsymmetrical BINOLs in moderate chemoselectivity when mixed with a stoichiometric amount of copper amine oxidant. Recently, Kozlowski’s group studied the catalytic activity of several M[sale(a)n] complexes (M = Fe, V, Cr and Mn) under aerobic conditions and identified Cr[salen] as a suitable catalyst for the oxidative cross-coupling of phenols.15 Other oxidation conditions based on hypervalent iodine chemistry (Kita),16 electrochemical techniques (Waldvogel),17 and inorganic peroxides (Jeganmohan)18 were found to be selective toward the cross-coupling of certain phenols. However, the basic principles guiding cross-coupling selectivity in these oxidation systems remained unclear. The only attempt to rationalize the observed cross-coupling selectivity was made by Kočovský, who hypothesized that phenolic coupling partners will favor cross-coupling if they have sufficient difference in redox potentials (i.e., if ∆Eox > 0.25 V).14a,

19

Nonetheless, the

predictive extent of this simple model is limited since it does not take into consideration catalyst properties, solvent effect and, most importantly, the nature of the mechanism. For example, the ∆Eox value of 2,6-dimethoxyphenol (1a) and 6-bromo-2-naphthol (1b) in 1,2-dichloroethane (DCE) is 0.25 V (Scheme 2A) therefore, according to Kočovský’s model, the cross-coupling pathway should be preferred. Yet, the oxidative coupling by FeCl3 (10 mol %, t-BuOOt-Bu, 70 oC) in DCE produces BINOL 3 as a single product in a 96% yield.11c On the other hand, in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), despite the fact that the ∆Eox [HFIP] value is only 0.17 V, the two phenols 1a and 1b follows a highly 4 ACS Paragon Plus Environment

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selective cross-coupling by the same catalyst, affording unsymmetrical biphenol 4 with an excellent 82% yield.11c Intrigued by the high level of chemoselectivity observed when coupling is carried out by the FeCl3/t-BuOOt-Bu/HFIP catalytic system (Scheme 2A), we initiated a research study that aimed to elucidate the coupling mechanism. Kinetic studies carried out for the FeCl3/t-BuOOt-Bu/HFIP catalytic system revealed a zero rate dependence for both phenols and oxidant, suggesting an innersphere coupling.13c In addition, oxidative homocoupling of 2,6-dimethoxyphenol (1a) was found to be a powerful mechanistic probe in distinguishing between different coupling mechanisms (Scheme 2B).13a, 13c While the homocoupling of 1a by the FeCl3/t-BuOOtBu/HFIP catalytic system afforded the unsymmetrical biphenol 2 as a sole coupling product, the catalytic reaction in DCE (FeCl3/t-BuOOt-Bu) at 70 oC yielded simply the symmetrical biphenol 5 (Scheme 2B). Indeed, due to mechanistic constraints it is unlikely that a meta-phenoxyl radical can exist, therefore the formation of unsymmetrical biphenol 2 could result only from the coupling of a para-phenoxyl radical and the meta position (i.e., the most nucleophilic site) of phenolate 1a via a radical-anion coupling mechanism. Conversely, oxidative coupling between two para-phenoxyl radicals of 1a will afford biphenol 5 via a radical-radical coupling mechanism.

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Scheme 2. (A) Solvent effect on coupling selectivity between phenols 1a and 1b and (B) Oxidative homocoupling of 2,6-dimethoxyphenol as a probe for mechanistic determination. Notes: aEox[V] vs. Ag/AgNO3; bThe yield refers to the oxidized form of 5 (diphenoquinone).

Initial mechanistic studies showed that HFIP plays an important role during the catalytic cycle of oxidative phenol coupling reactions. Indeed, the role of fluorinated alcohols as solvent-assisted selectivity in oxidation processes has been studied by Eberson,20 Berkessel21 and others.22 HFIP is a polar protic solvent with a low boiling point, a high dielectric constant, and high ionization power that makes radical cation intermediates significantly more persistent.21a, 23 Eberson observed that the lifetime of 1,36 ACS Paragon Plus Environment

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benzodioxoIe radical cation in HFIP (2.5 h) is 150 times longer than that in 2,2,2trifluoroacetic acid (TFA).20,

22c

HFIP is a strong hydrogen-bond donor (HBD) that

interacts with hydrogen-bond acceptor (HBA) groups such as ethers, peroxides,21a, 23c-f sulfoxides, alcohols, and carbonyl compounds.21a,

24

As such, it interferes with the

catalytic cycle of polar reactions, positively affecting kinetic profile as well as selectivity.25 The ability of HFIP to form stabilizing H-bond donor–acceptor adducts with phenoxyl radicals has been observed spectroscopically by EPR.26 In addition, cyclic voltammetry measurements have disclosed that, compared to other polar solvents, HFIP lowers the oxidation potential of phenols.11c Keeping in mind the notion that chemoselectivity in oxidative cross-coupling reactions is controlled by the catalytic system, we turned our attention to developing a predictive model that would anticipate the feasibility of cross-coupling for a given pair of phenols. Our model accommodates oxidation potential and the relative nucleophilicity of the two coupling partners while also considering coupling mechanism of the reaction. According to our model (Figure 1A), oxidative cross-coupling between two phenols (A and B) would be favorable under an oxidative radical-anion coupling mechanism so long as: (1)

the oxidation of phenol A to a phenoxyl A• radical in the presence of phenol B (EoxA < EoxB) is selective and,

(2)

phenol B is a stronger nucleophilic species than phenol A (NB > NA, with N = theoretical global nucleophilicity).27

A reactivity map that offers the Eox (measured in HFIP using cyclic voltammetry) and the N values (determined by DFT methods) was plotted, thus enabling us to predict the feasibility of two phenols to react in a cross-coupling fashion (Figure 2).13c Our presumption that reaction selectivity is highly dependent on the difference in nucleophilicity between phenols A and B was proven by the good correlation we observed between the DN values (DN = NB - NA) and chemoselectivity.13c



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Figure 1. (A) Model for predicting cross-coupling selectivity in oxidative phenol-phenol coupling following a radical-anion coupling mechanism; Eox = Oxidation potential, N = Global Nucleophilicity and (B) Selected examples of unsymmetrical biphenols prepared by FeCl3-catalyzed oxidative cross-coupling between two phenolic units; DN = NB-NA.


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3,4,5-triOMe

4.2

Global nucleophilicity N [eV]

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4.0 3.8

3,4-diOMe 2,4-diOMe

2,6-diOMe

2,5-diOMe

2-t-Bu,4-OMe

2-OMe,4-Me

4-OMe

3.6

3,4-diOMe,2-Me 3,5-diOMe,4-Me 2-OMe,5-Me 2,3,4-triOMe

2-OMe 2,4-diMe

3.4

2-OMe,6-Me

3,4-diMe 2,5-diMe 2,6-diMe

3.2

3,5-diOMe

5-OH,2-Me 2,3-diMe 4-Me

3-OMe 4-t-Bu

2-Me

2-t-Bu 3-Me

3,5-diMe 2-Cl

H

3.0

4-Br 2-Br

0.35

0.40

0.45

0.50

0.55

0.60

0.65

4-Cl

0.70

Eox [V] in HFIP

Figure 2. A reactivity map for substituted phenols (N vs Eox).13c The colors refer to the capability of each phenol to coordinate to Fe[TPP][OCH2(CF3)2] in the presence of the competitive HFIP ligand, as determined by 1H-NMR; red circles represent phenols that do not form detectable Fe[TPP][phenolate] complexes and blue diamonds attributed to phenols that do form detectable Fe[TPP][phenolate] complexes.13a

The oxidative coupling of phenols by the multi-coordinated FeCl3 catalyst involves an oxidative radical-anion coupling mechanism, therefore selectivity depends on the relative nucleophilicity of the two phenols (Figure 1B). Consequently, this method has proven efficient for phenolic pairs with positive DN values. To address this mechanistic constraint and to execute coupling of less activated phenols with large negative DN values, we envisioned that the iron[tetraphenylporphyrin] chloride (Fe[TPP]Cl) complex (Scheme 3A), which possess a single available coordination site for phenol binding, might mediate the reaction via a different mechanism. To our delight, an alternative catalytic system based on Fe[TPP]Cl (1 mol %) and t-BuOOH as the oxidant in HFIP [Fe[TPP]Cl/tBuOOH/HFIP] facilitated the cross-coupling between phenolic pairs with a noncomplementary relationship (DN < 0 and even DN

Selective Oxidative Phenol Coupling by Iron ... - ACS Publications

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