Recent Advances in the Selective Oxidative Dearomatization of Phenols to o-Quinones and o-Quinols with Hypervalent Iodine Reagents

Abstract

ortho-Quinones are valuable molecular frameworks with diverse applications across biology, materials, organic synthesis, catalysis, and coordination chemistry. Despite their broad utility, their synthesis remains challenging, in particular via the direct oxidation of readily accessible phenols, due to the need to affect regioselective ortho oxidation coupled with the sensitivity of the resulting o-quinone products. The perspective looks at the emergence of I(V) hypervalent iodine reagents as an effective class of oxidants for regioselective o-quinone synthesis. The application of these reagents in regioselective phenol oxidation to both o-quinones and o-quinols will be discussed, including a recent report from our laboratory on the first method for the oxidation of electron-deficient phenols using a novel nitrogen-ligated I(V) reagent. Also included are select examples of total syntheses utilizing this methodology as well as recent advancements in chiral I(V) reagent design for asymmetric phenol dearomatization.

Graphical Abstract

1. Introduction

o-Quinones (1) are six-carbon molecular frameworks consisting of two adjacent carbonyl groups and a conjugated diene. This dense functionality translates to diverse chemical reactivity and these motifs play roles in biology,¹ materials,² organic synthesis,³ catalysis,⁴ and coordination chemistry.⁵ Their versatility as synthetic intermediates provides access to a wide variety of polycyclic and heterocyclic architectures as well as functionalized arenes via cycloadditions, nucleophilic additions, redox reactions, and condensations (Figure 1).^3c-e

Figure 1.

The diverse applications and reactivity of o-quinones

Despite their wide utility, the synthesis of these motifs remains a significant synthetic challenge.⁶ o-Quinones are most commonly accessed via the oxidative dearomatization of lower oxidation state phenol (2) or catechol (3) precursors, however, significant limitations still exist (Scheme 1A). The abundance of phenol precursors makes their 4e⁻ oxidation a highly attractive approach to access o-quinones, however, this strategy remains underdeveloped due to several key challenges.⁶ The first oxidation must occur regioselectively at the ortho (3) vs. para (4) position; however, oxidants such as Fremy’s radical^7a (6), dimethyldioxirane^7b (7), benzeneselenic anhydride^7c (8), Ru(IV),^7d and MeRe₃O₃–H₂O₂^7e (9) (Scheme 1B) provide either mixtures of 4 and 5 or favor 5 unless the para position is blocked. Next, typical oxidant systems require the use of electron-rich substrates, with neutral or electron-poor phenols proving unreactive, thereby limiting the scope of o-quinones available for study.⁸ Finally, the high reactivity of the o-quinone products makes them prone to degradation and therefore incompatible with the harsh reaction conditions required of many oxidants.

Scheme 1.

Synthesis of o-quinones: (A) synthetic challenges in the direct dearomatization of phenols; (B) common oxidant systems in phenol dearomatization

Recent advancements in biomimetic aerobic copper catalysis, inspired by the tyrosinase enzyme system have been successful in meeting some of the aforementioned challenges (Scheme 1B).⁹ Leading work from the Lumb group¹⁰ has led to the development of a dinuclear Cu(II)-peroxo complex 10 that effects regioselective oxidation via generation of a Cu(II) semiquinone complex 11. As this work was recently the subject of an excellent review,¹¹ we will not be discussing it here except when providing relevant context.

In this perspective, we will discuss the recent advances in the selective synthesis of o-quinones and related o-quinols via the direct oxidative dearomatization of phenols with I(V) hypervalent iodine reagents. The use of I(V) reagents has emerged as one of the most enabling approaches to effect this challenging transformation, offering high levels of site-selectivity and mild reaction conditions. A recent report from our laboratory expanded the scope of these oxidations to include electron-deficient substrates, addressing a long-standing challenge in the field. Along with o-quinones, we will also discuss the selective synthesis of o-quinols with I(V) compounds as the synthetic challenges are similar and the applications in total synthesis have been highly impactful.

2. I(V): Hypervalent Iodine Reagents

Hypervalent iodine reagents (HVIs) are attractive, green alternatives to traditional heavy-metal oxidants, and have seen wide application in organic synthesis.¹² HVIs in both the I(III) and I(V) oxidation state have been widely applied in phenol dearomatization, however, only I(V) reagents offer highly selective ortho oxidation.¹³ Iodine(V) compounds 12 adopt a square pyramidal geometry with the carbon (aryl) substituent and a lone pair of electrons occupying the axial positions and four X ligands residing equatorially, bound by 3c–4e⁻ hypervalent bonds (Scheme 2). Generally, I(V) reagents act as strong oxidants, capable of extracting a total of 4e⁻ via the sequential reduction of I(V) to I(III) (13 to 14) and further to the most stable I(I) (14 to 15) oxidation state (Scheme 2). The polymeric nature of the simplest I(V) compound iodylbenzene (PhIO₂) makes it insoluble in most organic solvents. The more synthetically useful reagents are cyclic or pseudocyclic, possessing a substituent in the 2-position which binds to the iodine center and generates a more stable, monomeric species. Perhaps the most well-known of the cyclic I(V) compounds is Dess–Martin periodinane (DMP), but while it is a ubiquitous tool for alcohol oxidation, it has seen limited application in phenol dearomatization. Rather, it has been its precursor 2-iodoxybenzoic acid (16, IBX), its stabilized formulation S-IBX (17), and the sulfonate analogue IBS (18) that have seen broad application for the transformation of phenols to o-quinones and o-quinols. IBS has also seen catalytic applications starting from the I(I) pre-IBS (19) in combination with stoichiometric co-oxidants. Finally, a recent report from our laboratory described the first synthetic application of Bi(N)-HVIs (20), I(V) reagents possessing bidentate nitrogen ligands, for the dearomatization of particularly challenging electron-poor phenols. The use of I(V) reagents results in excellent levels of selectivity for ortho vs. para oxidation, a direct result of the mechanism of oxidation.

Scheme 2.

I(V) reagents: structure, general reactivity, and common reagents used in phenol dearomatization to o-quinones

3. I(V)-Mediated Dearomatization to o-Quinones

The first report of an I(V)-mediated phenol dearomatization to o-quinones came from Pettus in 2002 (Scheme 3).¹⁴ At this time, there were no existing synthetic methods for the regioselective conversion of a phenol into an o-quinone, making this a landmark discovery. Using mild conditions of IBX (16) at room temperature, the method gave good to excellent yields of a wide range of nonsymmetrical o-quinones possessing electron-donating substituents (Scheme 1). The resulting o-quinones could also be subjected to one-pot reduction–acylation to yield the corresponding protected nonsymmetrical catechols. The authors noted that electron-poor phenols, and even phenol itself, gave no conversion under the conditions, highlighting a common limitation to oxidative dearomatization strategies, both with I(V) reagents and metal catalysis.

Scheme 3.

Pettus’ first report of IBX-mediated phenol dearomatization

In the following years, this method was utilized in several total syntheses, including aiphanol (21) and brazilin (25) by Ohira¹⁵ and Pettus,¹⁶ respectively (Scheme 4). In Pettus’ synthesis of brazilin, oxidation of nonsymmetrical phenol 22 led to a 4:1 mixture of the desired C6 oxidation to that at C2. The C2 isomer was found to degrade over time, and thus a one-pot oxidation–reduction was employed to allow purification of catechol 24, followed by reoxidation with PhI(OTFA)₂ to cleanly give 23. o-Quinone 23 could then be taken on to brazilin through a tautomerization–Michael addition cascade sequence.

Scheme 4.

Total synthesis applications of IBX-mediated dearomatization en route to aiphanol and brazilin

A general mechanism, first put forth by Pettus¹⁴ and recently further elucidated by DFT,¹⁷ is presented in Scheme 5. This mechanism has been widely adopted and explains both the regioselectivity and substituent effects of I(V)-mediated dearomatization. Initial ligand exchange between the phenol and a less stable isomer of IBX (16), wherein the oxo group is trans to the carboxylate, gives intermediate 26, with the phenolate trans to the vacant site. This ligand exchange also involves a water molecule which facilitates the proton shuffle from the incoming phenol to a dissociating water molecule. The first oxidation proceeds via an associative mechanism, resulting in site-selective ortho delivery of an oxo group and reduction of I(V) to I(III) occur in a single operation via TS-27. Alternative pathways considered included a dissociative mechanism via TS-29 and a single-electron-transfer process to give 31, however, these were found to be disfavored by 3.2 and 5.9 kcal mol⁻¹, respectively, versus TS-27. The associative mechanism is a key point of differentiation between the I(V) dearomatization and that of I(III)-mediated process; the latter involves a dissociated phenoxenium ion, which helps explain the divergence in regioselectivity between the two reagent classes. The second oxidation proceeds from catechol-ligated I(III) complex 28, releasing o-quinone with reduction of I(III) to I(I). DFT calculations also revealed a high degree of phenoxenium ion character in the transition state of the first oxidation (TS-27) which is stabilized by electron-donating groups, particularly those at the para position. This insight explains the consistent requirement of electron-rich phenol rings for efficient oxidation. The same is not true for the second oxidation event, wherein the activation barrier is independent from substituent effects on the phenol.

Scheme 5.

Proposed mechanism and DFT study of I(V) ortho dearomatization

Pettus’ report stimulated a significant interest in the application of I(V) reagents for ortho-selective phenol dearomatizations, both to o-quinones as well as the closely related o-quinols (see Section 5 ). In 2003, the Quideau group reported the use of SIBX, or ‘stabilized IBX’, a nonexplosive commercial formulation of IBX,¹⁸ for the regioselective synthesis of o-quinones and o-quinols. In this first report, oxidation with SIBX was compared to anodic and I(III)-mediated oxidation and found to be superior in both conversion and regioselectivity (Scheme 6).¹⁹

Scheme 6.

SIBX-mediated oxidation of phenols to o-quinones and o-quinols

Oxidation of nonsymmetrical 2-Me-5-t-Bu-phenol (32) with SIBX gave exclusively ortho oxidation, albeit as a 1:1 mixture of o-quinone 33 and dimer 34, resulting from regioisomeric oxidation at C2 to give an o-quinol followed by spontaneous dimerization. In contrast, anodic oxidation and use of the I(III) reagent PhI(OAc)₂ gave either exclusively or majority p-quinone 35 (Scheme 6, inset).

In 2012, Ishihara reported the first catalytic method for I(V)-mediated o-quinone synthesis relying on in situ generated sulfone-based reagent IBS (18). First reported by Zhdankin^20a and subsequently developed in catalytic applications by Ishihara, IBS generally displays superior catalytic activity to IBX in a variety of transformations due to the more ionic character of the I–OSO₂ bond.^20b The use of 5 mol% of pre-5-Me-IBS 36, along with 2 equivalents of powdered Oxone as a co-oxidant in EtOAc, gave good yields in the oxidation of phenols, naphthols, and phenanthrols to the corresponding o-quinones (Scheme 7).²¹ It is worth noting that when aqueous acetonitrile was used in place of EtOAc, almost exclusive p-quinone was obtained, likely due to competitive intermolecular attack of H₂O in the para position. While phenol substrates were again limited to those possessing electron-donating groups (37–39), polycyclic scaffolds could be unsubstituted (40, 43) or even possess halogen substituents such as p-Cl (41) and p-Br (42) naphthoquinones, highlighting both the increased reactivity of IBS as well as the more facile oxidation of polycyclic arenols. A notable exception was the use of 3-OMe-naphthol, which instead gave high yields of the p-quinone 44, but this can likely be attributed to observe high levels of background oxidation by Oxone in this highly activated substrate. This strategy was later applied to nonsymmetrical 2-substituted phenols to selectively give o-quinols (see Section 5).

Scheme 7.

Use of catalytic 5-Me-IBS in the regioselective oxidation of phenols to o-quinones

Polycyclic aromatic o-quinones play central roles in materials and biological chemistry and are generally much more stable than monocyclic o-quinones. As a result of the additional aromatic stabilization, oxidative access to these scaffolds using either IBX or IBS generally occurs smoothly and with high levels of ortho selectivity (Figure 2). While Ishihara had demonstrated select examples of polycyclic phenol oxidation using catalytic IBS²¹ (see Scheme 6), the first comprehensive report of this type came from Harvey in 2010, where a panel of polycyclic aromatic phenols were examined in oxidation with IBX, representative examples of which are shown in Figure 2 (45–49).²² In the cases of 45–47, the same o-quinone products were obtained starting from either the 1- or 2-arenol. Oxidation was also examined with I(III) reagent PhI(O₂CCF₃)₂ and in all cases this gave preferential formation of p-quinone products unless the 4-position was blocked, in which case o-quinones were obtained. In 2015, Suemune synthesized the racemic [5]he-licene o-quinone (50) en route to the synthesis of chiral [5]carbonhelicenes via the oxidation of the 2-[5]-helicenol with IBX.²³ They were able to justify the regioselectivity of the oxidation with DFT calculations, showing a 1.6 kcal mol⁻¹ difference in the transition state favoring oxidation at the 1-position over the 3-position. Finally, Stack leveraged IBX oxidation in an effort to synthesize various metabolites of the bisphenol A (BPA), a widely utilized and potentially toxic compound used in the production of plastics and epoxy resins.²⁴ By carefully controlling the equivalents of IBX, either the mono- (51) or bis- (52) o-quinones could be obtained in good yields from BPA. Prior studies had attempted to use Fremy’s salt to access these metabolites and seen low conversions and complex mixtures of products.

Figure 2.

Regioselective oxidation of polycyclic arenols with IBX or IBS

4. Bisnitrogen-Ligated I(V) Reagents: ortho Dearomatization of Electron-Poor Phenols

While I(V) reagents clearly offer an effective solution to the regioselective synthesis of o-quinones, a key unaddressed challenge in the above reports is the oxidation of electron-neutral and electron-poor phenols. As noted in Pettus’ 2002 report,¹⁴ even simple phenol proved unreactive to oxidation, a trend that held true in future studies, with at least one alkyl group needed to sufficiently activate the ring to oxidation. This was further confirmed by DFT calculations¹⁷ which indicated a high degree of phenoxenium character in the first oxidation transition state which was stabilized by electron-donating groups (see Scheme 5). To overcome this one could envision simply designing more powerful oxidants, however this needs to be balanced with relatively mild reaction conditions to not decompose the sensitive o-quinone products.

One approach to tackling this delicate balance would be to develop novel, tunable I(V) scaffolds. However, IBX and IBS are subject to only limited derivatization, and the analogues designed to date with substitution on the aromatic ring had not unlocked oxidation of electron-poor phenols. In 2002, Zhdankin disclosed the synthesis of an I(V) scaffold possessing a bidentate bipyridyl ligand 55, however, no studies on its reactivity were ever reported (Scheme 8).²⁵ Given the documented effects of Lewis base activation on hypervalent iodine reagent reactivity,²⁶ it seemed likely that these reagents may be poised to be highly reactive analogues of their oxygen-ligated counterparts. As a part of our laboratories ongoing interest in nitrogen-ligated hypervalent iodine reagents,²⁷ we began studies into the reactivity of this reagent class, which we termed Bi(N)-HVIs. In 2019, we reported on the utility of Bi(N)-HVIs in the dearomatization of electron-poor phenols, providing the first general method for the oxidation of these challenging motifs (Scheme 8).²⁸ The Bi(N)-HVIs are accessed via the activation of PhI(O)(OAc)₂ (54), itself just one step from commercial PhIO₂ (53), with TMSOTf in the presence of the bidentate ligand and can be generated and used in situ. Using 4-NO₂-phenol (56) as a model substrate, we screened a small library of in situ generated Bi(N)-HVIs (55–65) with diverse bidentate nitrogen ligands and were pleased to find that several derivatives gave good to excellent yields of the corresponding 4-NO₂-o-quinone 57. As expected, a screen of common I(V) reagents such as DMP, IBX, 53, and 70 gave low or no conversion into 57 (Scheme 8, inset).

Scheme 8.

Development Bi(N)-HVI reagent class and application to dearomatization of electron-poor phenols to o-quinones

While several Bi(N)-HVIs produced good yields of 57, in situ Bi(4-CO₂Et-BiPy)-HVI 58 was selected for further scope studies (Scheme 9). The oxidation is efficient across a range of 4-substituted electron-deficient phenols (57–80), including those possessing multiple electron-withdrawing groups (88–91). The importance of ‘matched’ redox potentials between substrate and reagent in these systems is exemplified in that Bi(N)-HVIs gave inferior yields with the more readily oxidized electron-rich substrates, such as 4-CH₃ (82) or 4-Ph (83). In nonsymmetrical 3-substituted phenols (84–87) oxidation favored the C6 position, with selectivities ranging from 1.5:1 to 6:1. This selectivity likely arises from both sterics of the substituent and destabilization of the developing positive charge on the carbon proximal to the electron-withdrawing group. Several naphthols (92, 42, 40) could also be efficiently oxidized although in the cases of unsubstituted 2-naphthol (42) and 4-Br-naphthol (40) competitive p-quinone formation was also observed.

Scheme 9.

Scope of electron-deficient phenol dearomatization with Bi(N)-HVIs

Further functionalization of the resulting o-quinones were carried out with hydride and heteroatom nucleophiles, either in one pot or stepwise, to give densely functionalized catechols (Scheme 10). Many functionalizations typical of o-quinones failed on these electron-poor substrates, demonstrating the divergent and underexplored reactivity of these analogues. Given these findings, we believe Bi(N)-HVIs represent a powerful new platform for modular, tunable, and highly reactive I(V) reagent development and studies to this effect are ongoing in our laboratory.

Scheme 10.

Subsequent functionalizations of electron-poor o-quinones to densely functionalized catechols.

5. I(V)-Mediated Dearomatization to o-Quinols

o-Quinols (93) arise from regioselective two-electron ortho oxidation of 2-alkyl phenols at the substituted C2-position, in favor of competitive oxidation at C6 or C4 to give the corresponding quinones (Scheme 11). While in o-quinols substitution at the site of oxidation prevents further reaction to the quinone, they are included in this perspective due to the similar selectivity challenges faced in their synthesis from phenols as those of o-quinones and the prominent role of I(V) reagents in their synthesis.

Scheme 11.

Site-selectivity in the oxidation of 2-alkyl phenols to o-quinols

In 2007, Quideau expanded on their prior report on the use of SIBX, examining the oxidation of substituted phenols and naphthols to their corresponding o-quinols or their respective dimers (Scheme 12).²⁹ Moderate to good yields were obtained across the scope of alkyl- and alkoxy-substituted phenols and naphthols, with varying amounts of either o-quinol or dimer obtained. Most significantly, no products arising from para oxidation were observed in any cases.

Scheme 12.

Selective oxidation of 2-alkyl phenols and naphthols with SIBX

Ishihara examined the use of catalytic IBS in the oxidation of phenol substrates with two biased but accessible ortho positions to examine the competitive effects of sterics vs. electronics (Scheme 13).³⁰ Their previous report (see Scheme 7) focused on substrates possessing either no ortho substituents or a sterically hindered ortho t-Bu, therefore avoiding issues of regioselectivity. In this latter report, using pre-IBS with stoichiometric Oxone, high levels of site-selectivity (5:1 or greater) were obtained for o-quinols over o-quinones in nonsymmetrical systems possessing 2,5-disubstitution; this is in contrast to the findings from Quideau when SIBX was used on similar systems (see Scheme 5). Their site-selectivity was rationalized based on the increased electrophilicity of the IBS iodine center relative to IBX, leading to a greater degree of positive charge build up on the ortho positions, which occurred preferentially on the more substituted center. Another notable aspect of the scope is with regards to electronics; even relatively electron-deficient phenols possessing ester or halogen moieties, underwent clean dimerization, providing a rare example of oxidation of these substrates. The regioselectivity of oxidation began to breakdown in the absence of a 5-substituent, with the oxidation of simple o-cresol (100) giving a complex mixture of products. To address this issue, various α-trialkylsilyl-o-cresol derivatives were synthesized to stabilize partial positive charge at the 2-position via the β-silicon effect. Using either α-Me₃Si (101) or α-PhMe₂Si-o-cresol (102) derivatives, clean reaction to give the cyclodimers 103 could be achieved in good yields. Finally, the α-silylated phenol 105 was leveraged to give [2.2.2] bicyclic product 106 via an oxidation–Peterson elimination-cycloaddition cascade in the presence of an electron-deficient olefin such as methyl vinyl ketone (MVK). Overall, this work demonstrates the utility of tuning the reactivity of the I(V) reagent in improving both scope and selectivity in oxidative dearomatization.

Scheme 13.

Use of catalytic IBS in the regioselective synthesis of o-quinol dimers. Introduction of an α-SiR₃ group controls reactivity and enables cascade sequences.

The attention given to the selective synthesis of o-quinols is due to their widespread presence in bioactive natural products, either in their monomeric or dimerized forms. It is widely hypothesized that the biosyntheses of o-quinol-derived compounds follows an analogous oxidation of a parent phenol followed by spontaneous dimerization, which occurs with high endo selectivity. Thus, IBX-mediated o-quinol synthesis has seen wide application in both total synthesis and probing potential biosynthetic pathways. Several representative total syntheses utilizing this approach are shown in Scheme 14.^31-33

Scheme 14.

Representative syntheses of o-quinol-based natural products using I(V)-mediated dearomatization

Finally, as dearomatization to an o-quinol generates a chiral product, there has been extensive effort given to the development of asymmetric oxidative methods for their synthesis. Much of the success in this area has relied on chiral I(III) or I(V) hypervalent iodine reagents,³⁴ however, significant challenges remain. While chiral I(III) reagents have shown excellent yields and ee values in intramolecular oxidative cyclizations, their utility in intermolecular processes is hampered by a competitive nonselective dissociative reaction pathway that proceeds via an achiral phenoxenium intermediate. Highly selective, broadly applicable chiral I(V) scaffolds have proven extremely challenging to design,³⁵ however, there have been some promising reports from the Quideau group demonstrating the potential of this reagent class in intermolecular oxidative dearomatization reactions.

Building on their findings in SIBX-mediated regioselective ortho oxidation²⁹ (see Scheme 12) the Quideau group reported on their efforts to develop an asymmetric variant. Extensive screening led to 2-iodobinaphthyl scaffold 116 as the most promising lead compound (Scheme 15).³⁶ Using stoichiometric loadings of 116, their best result came in the hydroxylation of 2-methylnaphthol, giving o-quinol (S)-96 in high yield and moderate levels of enantioselectivity. Unfortunately, attempts to use catalytic loadings of 116 led to competitive epoxidation of the remaining quinol double bond by m-CPBA. Tracking the reaction progress using ESI-MS provided strong support for the active oxidant being in the I(V) rather than the I(III) oxidation state. A tentative stereochemical model was proposed to explain the enantioinduction, with reactive conformer 117 obtained after initial ligand exchange and a subsequent sterically driven reorganization or ‘hypervalent twist’ placing the ligated naphthol substrate in the apical position. While selectivities are only moderate, this serves as the first report of an I(V)-mediated intermolecular asymmetric phenol dearomatization reaction.

Scheme 15.

Enantioselective oxidative dearomatization of phenols to o-quinols

In 2014, Quideau followed with a set of second-generation scaffolds for asymmetric ortho hydroxylation of phenols (Scheme 15).³⁷ From a library of successfully synthesized I(III) and I(V) binaphthyl scaffolds, partially reduced C₂-symmetric binaphthyl reagent 120 emerged as the most effective. Hydroxylation of 115 was again used as a benchmark, and (S)-96 was produced in reduced yield but improved enantioselectivity (73% ee) at −80 °C. Screening of related I(III) scaffolds also gave 96 in comparable yield, but with a maximum ee of 53%. The use of 120 was then extended to phenol oxidation to give o-quinols which undergo spontaneous dimerization, a transformation central to the total synthesis of these dimeric natural products (see 107 to 108, Scheme 12). In these cases, 120 performed exceptionally well, giving dimers in good yields and up to 94% ee as a factor of the sterics on the phenol ring (121, 122). This method compares favorably with the aerobic copper-sparteine method reported by Porco,³⁸ offering the [4+2] dimers with comparable or higher yields, regio- and enantio-selectivities.

Since these reports, the Quideau lab has continued their efforts in developing novel chiral I(V) scaffolds, including those based on helical chirality (123)³⁹ and C₂-symmetrical Salen-type scaffolds (123, 124),⁴⁰ and a representative example from their use in phenol dearomatization is shown in Figure 3. It was a common observation across each of these studies that while steric bulk around the iodane center had a positive effect on stereoselectivity, it also led to an erosion of C2 vs. C6 site-selectivity and increasing amounts of o-quinone formation, leading to reduced yields. Taken together the efforts from the Quideau lab demonstrate the diversity of scaffolds that can be employed in the development of chiral I(V) scaffolds and provide the community several excellent platforms for further development.

Figure 3.

Chiral I(V) scaffolds and their efficiency in asymmetric phenol dearomatization reactions

6. Conclusion and Outlook

In summary, this perspective has covered the recent developments in the application of I(V) hypervalent iodine reagents in the regioselective synthesis of o-quinones and o-quinols from phenols. Along with biomimetic aerobic copper catalysis, I(V) reagents represent a primary means of affecting this challenging transformation. The high selectivity for ortho oxidation is a result of intramolecular oxygen delivery from a ligated iodane intermediate via an associative mechanism. Commonly employed reagents include IBX, SIBX, and IBS the latter of which has been demonstrated catalytically. In the context of o-quinols, promising results in the use of chiral I(V) scaffolds for asymmetric dearomatization have been reported, however, work remains in the ability to achieve broadly high levels of selectivity as well as in developing catalytic systems. One long-standing limitation to the field of oxidative phenol dearomatization has been the oxidation of electron-neutral and electron-poor phenols, a challenge which was recently addressed in our laboratory. We reported on the development and application of a new class of I(V) reagents, Bi(N)-HVIs, which are able to efficiently oxidize a broad scope of electron-poor phenols to the corresponding o-quinones. Able to be generated in situ and possessing a modular and tunable ligand scaffold, we believe Bi(N)-HVIs open new directions in phenol dearomatization and oxidative reagent development. As the chemistry community continues to place an emphasis on green, metal-free, and cost-effective strategies, it is likely that hypervalent iodine reagents will continue to play a central role in advancing the synthesis of o-quinones and o-quinols.

Biography

Dr. Sarah E. Wengryniuk obtained her BSc from Winthrop University in 2007 with degrees in chemistry and biology. She then went on to doctoral studies at Duke University under the supervision of Professor Don Coltart, where she was supported as an NSF Graduate Fellow. In 2012, she began studies as a Ruth L. Kirchstein Postdoctoral Fellow in the laboratory of Prof. Phil S. Baran at The Scripps Research Institute. In 2015, Dr. Wengryniuk began her independent career at Temple University where her laboratory has focused on the development of novel umpolung transformations using hypervalent iodine chemistry and applications in total synthesis.

Dr. Xiao Xiao received her bachelor’s degree in applied chemistry (2007) from Sichuan University and her PhD in organic chemistry (2012) from the Institute of Chemistry Academy of Sciences (ICCAS) under the supervision of Prof. Yian Shi. After working at Shenyang Pharmaceutical University as a lecture, she began postdoctoral research with Prof. Wengryniuk at Temple University in 2017. Dr. Xiao joined in Shanghai Normal University in December 2020 as an associate professor and her current research focuses on organic biomimetic methodology and total synthesis.