Oxidative dearomatization of phenols

New data on the chemistry of 4,5-dihydroisoxazole 2-oxides were reported. Oxidative dearomatization of phenol 51 with bis(trifluoroacetoxyiodo)benzene (PIFA) afforded spironitronate 52 in 74% yield. Lastly, spiroisoxazoline 53 was obtained in quantitative yield by reduction of 52 with refluxing trimethylphosphite <07OL3229>. 

Scheme 7 Hypervalent iodine-induced oxidative dearomatization of phenols leading to spirodienones...

A conformationally flexible C2-symmetric organoiodine(in) catalyst (68) has been developed for the oxidative dearomatization of phenols with m ta-chloroperbenzoic acid (wt-CPBA) in CHCI3 to give the corresponding cyclohexadienone in 72% yield with 91 % ee. Catalysis is controlled by intramolecular hydrogen-bonding interactions and addition of achiral alcohols. ... 

Oxidation of a phenol to an acetoxy enone The key step in a recent synthesis of anthracyclinones is the oxidative dearomatization of the A ring of 1 to the enone 2 in 50-55% yield. The product was converted in several steps into the aglycone SM-173B (3). 

An intramolecular Michael reaction (catalyzed by 2C) following the oxidative dearomatization of 4-substituted phenols provides valuable octalones. A method involving two consecutive Michael reactions to form optically active polysubstituted cyclopentanes should be highly rated. 

In principle, cyclohexadienones can be accessed through tautomerization of the corresponding phenol. However, the loss of aromatic stabilization makes this impractical in all but the most specialized of cases. In order to access an isolable cyclohexadienone, the aromaticity of the phenol must be destroyed. One way to do this is through C-alkylation, but this is mostly limited to intramolecular electrophiles. Oxidative dearomatization of the phenol is by far the most conunon method used to prepare both 2,4- and 2,5-cyclohexadienones. A variety of oxidants can be used for this transforma-tiOTi, but iodine(III)- and iodine(V)-based oxidants" have emerged as the reagents of choice in many cases. An attractive feature of these oxidants, especially those based on iodine(III), is that they can be used with a variety of different nucleophiles, thereby providing access to cyclohexadienones with different substitutents. 

Of particular use are the reactions of oxidative dearomatization of 4- or 2-substituted phenols 222 and 225 with -iodanes in the presence of an external or internal nucleophile (Nu) leading to the respective... 

Oxidative dearomatization of 4-substituted phenols 222 with [bis(acyloxy)iodo]arenes in the presence of an external nucleophile provides a convenient approach to various 3,3-disubstituted cyclohexadienones 224 according to Scheme 3.92. Several examples of this reaction are provided below in Schemes 3.93-3.97. 

Synthetic application of the oxidative dearomatization of ort/io-substituted phenolic substrates in the intramolecular mode is exemplified by the preparation of azacarbocyclic spirodienones 274 from phenol derivatives 273 (Scheme 3.114) [322]. 

Hypervalent iodine induced oxidative dearomatization of orf/io-substituted phenolic substrates in the intramolecular mode has been realized as an enantioselective reaction. In particular, Kita and coworkers have developed the enantioselective spirocyclization reaction of the orfho-substituted phenolic substrates 275 using chiral aryliodine(III) diacetate 276 having a rigid spirobiindane backbone (Scheme 3.115) [346]. Similar enantioselective oxidative spirocyclization reactions of the ort/io-substituted phenolic substrates under catalytic conditions in the presence of chiral iodoarenes or chiral quaternary ammonium iodide catalysts are discussed in Sections 4.1.6 and 4.4. 

The oxidative dearomatization of ort/io-substituted phenols 225 leads to 6,6-disubstituted cyclohexa-2,4-dienones 226 (Scheme 3.92), which can be conveniently utilized in situ as dienes in the Diels-Alder cycloaddition reaction. When the oxidation of phenols is performed in the absence of an external dienophile, a dimerization via [4-f2] cycloaddition often occurs spontaneously at ambient temperature to afford the corresponding dimers with an extraordinary level of regio-, site- and stereoselectivity [348-350]. A detailed experimental and theoretical investigation of such hypervalent iodine induced Diels-Alder cyclodimerizations... 

The IBX-mediated oxygenative dearomatization of phenols leading to cyclohexa-2,4- or -2,5-dienone systems is a particularly useful synthetic transformation [292]. Representative examples include the use of IBX in key oxidation steps in the total synthesis of the resveratrol-derived polyphenol natural products... 

The oxidative dearomatization of appropriately substituted phenolic substrates resulting in intramolecular cyclization with the formation of spirocyclic products represents one of the most powerful synthetic tools in modern organic synthesis (Seetion 3.1.11). Kita and coworkers were the first to report a catalytic variant of the oxidative spirocyclization reaction based on the in situ regeneration of a [bis(trifluoroacetoxy)iodo]arene from iodoarene using mCPBA as a terminal oxidant [2]. In a representative example, the oxidation of... 

Recently, an oxidative dearomatization of substituted phenols followed by a desymmetrizing asymmetric intramolecular Michael addition catalyzed by the pro-linol derivative 27 has been described towards the synthesis of highly functionalized polycyclic molecules with excellent enantioselectivities [40]. As shown in Scheme 2.15, the reaction starts with an oxidation of the phenol moiety to the corresponding mera-cyclohexadienones employing PhlCOAc), mild oxidant that does not react with the aldehyde nor with the catalyst. In the presence of different nucleophiles such as, methanol, cyanide, or fluoride, intermediates 26 are formed, which suffer intramolecular Michael addition of the aldehyde moiety to afford the desired chiral products 28 with excellent diastereo- and enantioselectivities. 

Danishefsky s group [13] utilized sequential oxidative dearomatization/IMDA reaction to finish the total synthesis of natural product 11-O-debenzoyltashironin. As shown in Fig. 2.12, after undergoing oxidative dearomatization, the phenol substrate formed ten-membered ring skeleton. Under microwave heating, the core structure of natural product was obtained. This step could also be seen as trans-annular Diels-Alder reaction. After several conversions, Danishefsky s group obtained the natural product 11-O-debenzoyltashironin. 

Liao s group [15] used the masked benzoquinone to trigger intramolecular Diels-Alder reaction and completed a series of total synthesis (Fig. 2.14). In the total synthesis of bilosespenes A and bilosespenes B, they used oxidative dearomatization to construct masked benzoquinone. With the allyl alcohol, they triggered oxidative dearomatization of the phenol substrate using iodosobenzene diacetate. At the same time, they completed the allyl alcohol protection to benzoquinone. And the intramolecular Diels-Alder reaction happened between the double bond of side chain and the diene in bone structure, and [2.2.2] caged scaffold system was constructed. 

In addition. Green and Pettus have reported efficient syntheses of a-cedrene, a-pipitzol, and ec-cedrenol on the basis of a novel domino oxidative dearomatization-intramolecular [5+2] cycloaddition-acetic acid addition reaction [96]. Indeed, the key step of the syntheses began with the oxidative dearomatization of ortAo-(pent-4-enyl)-phenols 92, followed by an intramolecular [5+2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin to afford the corresponding tricyclo-[5.3.1.0 ]-undecanes, which finally added acetic acid to provide the final products 93 in low to good yields, as shown in Scheme 20.40. The benzylic... 

The oxidative activation of arenes is a powerful and versatile synthetic tactic that enables dearomatization to give useful synthons. Central to this chemistry are hydroxylated arenes or arenols, the phenolic functions of which can be exploited to facilitate the dearomatizing process by two-electron oxidation. Suitably substituted arenols can hence be converted, with the help of oxygen- or carbon-based nucleophiles, into ortho-quinone monoketals and ortho-quinols. These 6-oxocyclohexa-2,4-dienones are ideally functionalized for the construction of many complex and polyoxygenated natural product architectures. Today, the inherent and multiple reactivity of arenol-derived ortho-quinone monoketals and ortho-quinols species is finding numerous and, in many cases, biomimetic applications in modern organic synthesis. 

The humulones 23a-d have been known for many years, but they can still be considered as a topical family of natural products (Figure 8). Found in hop resins and brewing hops, these natural ortho-quinols aroused early interest because of their antibiotic and tuberculostatic properties. Oxidative dearomatizing hydroxylation of their phenolic parents 24a-d was used in their synthesis [1]. 

Ytterbium has the oxidation states 4-2 and -t-3. A stereochemical dichotomy exists in their enolate chemistry . Yb(II) enolates react with aldehydes to form the erythro-fi-hydroxyketones while Yb(III) enolates yield the threo stereoisomers. We fail to understand this by either thermodynamic or mechanistic reasoning. Analogous to corresponding reaction chemistry for samarium, preformed ytterbium benzophenone dimer, [Yb(Ph2CO) (HMPA)2]2, reacts " with sterically crowded phenols to form in low yield (5%) the enolate complex 22b by dearomatization of benzophenone. The major product (80%) is the... 

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

Aniline derivatives can be oxidatively dearomatized analogously to the phenol derivatives. In particular, the oxidative //Ji o-tluorination of para-substituted tosylated anilines 286 using hypervalent iodine reagents... 

---