Dearomatization reactions oxidative

What follows is a description of the trials and tribulations we experienced during our development of a short synthetic route to sorbicillactone a target that Porco has described as a deceptively simple molecule. To be clear, this work led to the synthesis of racemic material. Our group does have a strong interest in developing aryl iodide catalysts for asymmetric oxidative dearomatization reactions, and we have made some progress in this area. However, this has proved to be a very challenging area of research and still requires a fair amount of development. ... 

There were hints in the literature that certain silylated phenols were more efficient substrates than free phenols in hypervalent iodine-mediated oxidative dearomatization reactions." The mechanistic underpinnings for this observation are still murky. Nevertheless, when phenol 40 was first converted into the corresponding trimethylsilyl ether and then treated with PhI(OAc)2 in acetonitrile-water, the desired quinol (42) was formed with improved yields (77-95%) and on larger scale (>1 g) (Scheme 16B). The conditions used to... 

A final type of oxidative carbon-carbon bond forming dearomatization process involves electrophile-induced dearomatization. The most common variant of this reaction entails activation of an alkyne or alkene moiety with an electrophilic halide source to initiate intramolecular dearomatization accompanied by formal arene oxidation (Scheme 15.26) [72]. Proper positioning of an electron-donating methoxy group is crucial for success of this transformation. Other examples of halocyclization-dearomatization reactions involving appropriately substituted arenes tethered to alkynes and alkenes have been reported, along with an intramolecular Pummerer-type dearomatization initiated by an electrophilic thionium ion [73, 74]. 

Literature reported that phenolic compound would yield substituted ortho-quinone compound after Wessely oxidative dearomatization reaction. The obtained compound could act as a diene to trigger intramolecular or intermolecular Diels—Alder reaction and produce [2.2.2] bicyclic compound. This synthetic methodology has been extensively used in total synthesis [26]. 

Oxidative dearomatization reaction can start from ortho-substimted phenol and quickly construct dienes structure after oxidation. It is often used to design Diels-Alder reaction. 

Prof. Fengpeng Wang from Sichuan University utilized oxidative dearomatization reaction to construct the precursor of intramolecular Diels-Alder reaction in the synthesis of atisine [12]. As shown in Fig. 2.11, after Diels-Alder reaction, the core structure of atisine could be obtained. After several steps of functional group conversion, they obtained the common precursor of the synthesis used by Prof. Pelletier and completed the formal total synthesis. 

Model compound 2.1.1 was designed to test key reactions, which may be applied to the total synthesis, such as intramolecular Diels-Alder reaction, Wessely oxidative dearomatization reaction, and Pinhey arylation. The synthetic strategy of model research is shown in Fig. 2.16 compound 2.1.1 could be constructed from the precursor 2.1.2 after IMDA. Compound 2.1.2 could be prepared from compound 2.1.3 through esterification. Compound 2.1.3 could be obtained from 2.1.4 by reduction. Compound 2.1.4 was designed to be obtained by Pinhey arylation between 1,3-keto ester compounds 2.1.5 and organic lead compound 2.1.6. The advantage of this model system is that it contains three key reactions in total synthesis design, which can effectively supply the synthetic information for the total synthesis. 

Though MOM deprivation product 2.2.21 was accidentally obtained, it was still useful to test two key reactions for total synthesis Wessely oxidative dearomatization reaction and intramolecular Diels-Alder reaction (Fig. 2.20). A pair of diethyl phthalate derivative 2.2.22 with the ratio of 2 1 and 95 % yield could be obtained from phenol 2.2.21 in acetic acid solvent with the presence of lead tetraacetate at room temperature after 5 min. Then, we tried intennolecular Diels-Alder reaction. Unfoitunately, both substrate 2.2.22 and dimethyl acetylene dicarboxylate were not producing Diels-Alder product 2.2.23 under toluene refluxing or sealing mbe heating conditions, only gave the results of raw material recovery. 

Arylation of organolead reagents to 1,3-keto ester, oxidative dearomatization reaction, and intramolecular Diels-Alder reaction were applied as the key reactions to successfully construct the tetracyclic structure of natural product Maoecrystal V and two consecutive quaternary carbons. 

En route to the total synthesis oftashironin (7-114a) and the debenzoylated compound 7-114b, which shows an interesting promotion of neurite growth, Danishefsky and coworkers have developed a domino oxidative dearomatization/trans-annular Diels-Alder reaction [54]. In this line, treatment of 7-115 with phenyl-iodine(III) diacetate (PIDA) led to an intermediate 7-116, which immediately underwent a transannular Diels-Alder reaction to furnish the complex cycloadducts 7-117 in good yields (Scheme 7.31). 

Scheme 7.31. Domino oxidative dearomatization/transannular-Diels-Alder reaction.

Reaction of nucleophiles with the polarized N=C bond of azines proceeds via dearomatization and formation of the corresponding 1,2-adduct. With alkyllithiums, for example, it is possible to isolate the dihydro products by careful neutralization of the reaction mixtures these are, in general, rather unstable, however, and can easily be reoxidized to the fully aromatic compounds (Scheme 4). The dihydro adducts formed in these direct nucleophilic addition reactions can also be utilized for the introduction of substituent groups /3 to the heteroatom. Thus, reaction of (35) with one of a number of electrophiles, followed by oxidation of the intermediate dihydro product, constitutes a simple and, in many cases, effective method for the introduction of substituent groups at both the 2- and 5-positions of the pyridine ring (Scheme 4). Use of LAH in this sequence, of course, results in the formation of 3-substituted pyridines. 

Anodic oxidation can be used to dearomatize 2-substituted arenols. The outcome of such an electrochemical transformation is extremely sensitive to the reaction conditions used,... 

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... 

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. 

Our first specific Wessely oxidation approach is outlined in Scheme 2. Following an aldol-type reaction between an appropriately protected resorcinol fragment and an aldehyde, we expected the Wessely oxidation to selectively dearomatize at the ortho position of both phenols. The intramolecular Diels-Alder cycloaddition reaction was then expected to form the tricyclic core, which could then be converted to the critical tetracyclic cage via a samarium diiodide(II)-type 6-exo-trig ketyl radical cyclization reaction. 

---