Phenols 2-cyclohexenones

One of the most popular dioxygenated dienes is l-methoxy-3-trimethylsilyloxy-1,3-butadiene (109), the so-called Danishefsky diene (Scheme 30). The elegant application of this and related polyoxygen-ated dienes in synthesis was reviewed in 1981. ° [4 + 2] Cycloadditions of diene (109), wifo typical electron-poor dienophiles, display increased reactivity and legiochemical control owing to die synergism of die two oxygen atoms. Acidic hydrolysis of the initial cycloadducts readily affords cyclohexenones, phenols or cyclohexadienones (c/. Action 4.1.2, Schemes 12, 17,18 and 21). A pertinent example is the... 

An unusual reaction was been observed in the reaction of old yellow enzyme with a,(3-unsat-urated ketones. A dismutation took place under aerobic or anaerobic conditions, with the formation from cyclohex-l-keto-2-ene of the corresponding phenol and cyclohexanone, and an analogous reaction from representative cyclodec-3-keto-4-enes—putatively by hydride-ion transfer (Vaz et al. 1995). Reduction of the double bond in a,p-unsaturated ketones has been observed, and the enone reductases from Saccharomyces cerevisiae have been purified and characterized. They are able to carry out reduction of the C=C bonds in aliphatic aldehydes and ketones, and ring double bonds in cyclohexenones (Wanner and Tressel 1998). Reductions of steroid l,4-diene-3-ones can be mediated by the related old yellow enzyme and pentaerythritol tetranitrate reductase, for example, androsta-A -3,17-dione to androsta-A -3,17-dione (Vaz etal. 1995) and prednisone to pregna-A -17a, 20-diol-3,ll,20-trione (Barna et al. 2001) respectively. 

Protonated phenols and phenol ethers formed in superacids can be trapped by aromatics (benzene, naphthalene, tetrahydroquinoline). The products are either cyclohexenone derivatives301 [Eq. (5.112)] or aryl-substituted phenols. In the reaction of phloroglucinol with benzene, the diphenyl-substituted derivative is the main product [Eq. (5.113)], whereas 1,3,5-trimethoxybenzene gives selectively the monophenyl derivative (80% yield). Protonated dicationic species, such as 76, detected by Olah and Mo302 using NMR, were suggested to be intermediates in these processes. 

Monocyclic phenols and their methyl ethers react with benzene in HF—SbF5 medium to provide 4,4-disubstituted cyclohexenones 237 [Eq. (5.308)].3O1para-Methylanisole gives three products two cyclohexenone derivatives [see Eq. (5.112)] and an interesting tricyclic ketone 238. 

Aromatization of cyclohexenonesf This reaction is possible by selenenylation of (lie lithium enolate of the cyclohexenone, followed by oxidation of the resulting xclcnide. To obtain satisfactory yields of the phenol, an aromatic amine is added in llu oxidation step to react selectively with the benzeneselenenic acid formed. For this pin pose, 3,5-dimethoxyaniline is the most satisfactory amine. 

Cyclization of quinone methides.2 p-Quinone methides, particularly those substituted at the 2- and 6-positions, are stable enough to be characterized by IR and NMR, and can be generated in fairly high yield by oxidation of a phenol with Ag,0 (10 equiv.) in CH2C12. When substituted by a suitable terminator, these quinonemethides can undergo Lewis-acid-catalyzed cyclization. Suitable terminators that can survive the initial oxidation include allylsilanes and 3-keto esters. In the latter case, the initial product undergoes oxidation to afford a cyclohexenone. 

For weak acids, the proton is directly transferred from the acid to the substrate in a reagent-controlled manner and, in order to increase the selectivity, extremely shielded 2 -substituted m-terphenyls have been developed as concave protonating reagents inspired by the geometry of enzymes. Thus, the diastereoselective protonation by a series of substituted phenols of endocyclic keto enolates, obtained by the stereocontrolled 1,4-addition of lithiocuprates onto substituted cyclohexenones, was reported by Krause and coworkers354 355 and applied to the synthesis of racemic methyl dihydroepijasmonate356. 

The aromatization of cyclohexenones is an important process that can be easily accomplished by the use of selenium-based reagents using similar techniques to those previously discussed for other carbonyl species. Thus, enolates derived from a,3-enones readily undergo selenenylation at the a -position and on oxidation and elimination afford the corresponding phenols. ... 

Conjugated ketenes. a-Diazo-y.S-unsaturated P-ketoesters undergo rearrangement to ketenes which enter Diels-Alder reactions as dienes toward electron-rich alkenes. Substituted phenols are acquired. 3-Acyloxy-2-chloro-2-cyclohexenones are formed when 2-diazocyclohexane-l,3-diones are treated with acid chlorides in the presence of Rh COAc),. ... 

PCrWnOjs - Cyclohexene Cyclohexenone, cyclohexenol, cyclohexene oxide Phenol... 

Birch reduction of aromatic ethers is well known to afford alicyclic compounds such as cyclohexadienes and cyclohexenones, from which a number of natural products have been synthesized. Oxidation of phenols also affords alicyclic cyclohexadienones and masked quinones in addition to C—C and/or C—O coupled products. All of them are regarded as promising synthetic intermediates for a variety of bioactive compounds including natural products. However, in contrast to Birch reduction, systematic reviews on phenolic oxidation have not hitherto appeared from the viewpoint of synthetic organic chemistry, particularly natural products synthesis. In the case of phenolic oxidation, difficulties involving radical polymerization should be overcome. This chapter demonstrates that phenolic oxidation is satisfactorily used as a key step for the synthesis of bioactive compounds and their building blocks. 

Arylbismuth 671, 673 Arylboronic acid 671, 673 Arylbutenes, formation of 613 Aryl-2-cyclohexenones 653 Aryl ethers—see also AUyl aryl ethers. Diaryl ethers. Phenyl ethers, Propargyl aryl ethers formation from calixarenes 1387 Aryl haUdes, as phenol precursors 396, 397 Ai-Arylhydroxylamines, isomerization of 801-805 oxidation of 419 3-Arylindoles, synthesis of 1236 Aryl ketones, oxidation of 424, 425 Aryloxylium cations 179 Asatone, synthesis of 1178, 1179 Ash, from incineration of municipal waste, phenoUc compounds in 938 Aspersitin, synthesis of 1327, 1328 Aspirin 10, 11... 

Substrates with electron acceptors are given in Scheme 4. For these rather unreactive n-systems, besides longer reaction times and excess dioxirane, elevated temperature (ca. 25 °C) was essential for complete conversion into their corresponding epoxides. Fortunately, these epoxides, which were all obtained quantitatively, were sufficiently stable for rigorous characterization. The specific substrate types include oc,P-unsaturated acids [20] 21 and esters [20] 22 hydroxychalcones [21] 23 a,P-enones [20] 24 2-cyclohexenones [20] 25 methylene-P-lactones [22] 26 tetracyclone [20] 27 and naphthaquinone [16] 28. The particular advantage of the dioxirane methodology is that labile functional groups, e.g. the phenolic moiety in the chalcones, do not require protection. 

Aromatization. Cyclohexenones substituted with an unsaturated side chain are converted into phenols when heated in ethanol at 100° (sealed tube) with a catalytic amount of this transition metal salt. The double bond can be remote because RhCls catalyzes isomerization of double bonds to give more stable systems (3, 242-243). 

Dehydrogenation of cyclohexanol to phenol can start with the formation of cyclohexanone intermediate (the stable tautomer of cyclohexenone ... 

The enone formation has been applied to a number of natural product syntheses. The enone 524 was prepared from the complex molecule 523 and successfully applied to the total synthesis of pallescensin [212], Even the phenolic OH in 525 was converted to the conjugated ketone. The reaction was utilized as a key step in hypoxyxylerone synthesis [213]. In the total synthesis of galbulimima alkaloid GB 13, Mander converted a cyclohexanone in the complicated molecule 526 to the corresponding cyclohexenone via silyl enol ether in 82% yield [214]. 

The first total syntheses of two skyrins were presented by Nicolaou et al. in 2005 (554). For both, the same route was taken, which is shown in Scheme 12.6. The starting material was the chiral diester 816, which was MOM-protected and then regioselectively mono-hydrolyzed with porcine liver esterase. Oxidation of the remaining alcohol 817 with pyridinium chlorochromate, following elimination with diazabicyclo[5.4.0]undec-7-ene, gave the cyclohexenone 818 in good yield. The phenol 819 was first TBS-protected, and then the amide 820 was obtained from the acid chloride. With ferf-butyllithium and DMF, the corresponding aldehyde was formed, which was converted into the deprotected nitrile by treatment with TMSCN. 

Fig. 13.15), through a commonly applicable methodology (635). The synthesis sequence (Scheme 13.8) involved manipulation of a silyl-protected 4-hydroxycyclohex-2-enone (902) through several steps to the 2-bromo-3-carboxymethyl ester 905, then reaction of this species with the aldehyde 906 to form the intermediate benzophenone 907. This product was first desilylated, then de-allylated, with a second deprotection followed by an in situ cyclization of the phenolic intermediate, to give blennolide C (897) and the diastereomer 908 in an approximately 2 1 diastereomeric ratio, after 11 steps from cyclohexenone 258 (635). 

In 2008, Nicolaou andLi reported a synthesis of diversonol (932) (Scheme 13.14) (635). The synthesis involved the nucleophilic addition of a lithiated cyclohexene species derived from bromide 938 with the allyl-protected aldehyde 939, followed by oxidation, desilylation, deallylation, and spontaneous xanthone-ring closure of the intermediate phenol (not shown). As in the Brdse synthesis, the enol moiety is oxidized and the C-ring ketone reduced with NaBH4 to generate diversonol (932), which was obtained in eight steps from cyclohexenone 937. 

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