Isomerizations of allylic esters

Qualitative studies of the effects of allylic substituents, acyl substituents, and reaction conditions on rates of isomerization of allylic esters played a prominent role in the development of mechanistic theories of anionotropic rearrangements . Burton and Ingold observed that a-phenylallyl p-nitrobenzoate isomerizes more rapidly than a-phenylallyl acetate, that electron-releasing a-substituents facilitate isomerization of a-substituted allyl acetates, and that the rate of isomerization of a-phenylallyl p-nitrobenzoate increases as the dielectric constant of the solvent increases. All of these observations support the mechanism, which involves dissociation of the allylic ester into an allylic carbonium carboxylate ion pair, which reassociates to the starting material and its allylic isomer, viz. 

In non-polar solvents recombination of the ion pair exhibits considerable stereospecificity. The carbonyl oxygen of the starting material tends to become the alkyl oxygen of the product (see below), and the carboxylate ion tends to re-bond to the same side of the planar allylic system as that from which it departed . 

Meisenheimer et were the first to study the kinetics of allylic ester isomerizations. They followed the isomerization of a-phenylallyl p-nitroben-zoate and a-phenylallyl 3,4,5-tribromobenzoate to the corresponding cinnamyl benzoates by a tedious analytical procedure involving use of melting point-composition diagrams. They observed that isomerization of the molten esters at 137°C is autocatalytic due to partial slow decomposition of the esters to substituted benzoic acids and unidentified products, and demonstrated that the reaction is catalyzed by added benzoic acids. The rate law for these reactions is 

Braude later pointed out that mechanistic conclusions based on these early studies of allylic ester isomerization are of doubtful validity, since they do not account for the sensitivity of these reactions to adventitious acidic impurities. Braude et ti/, and Pocker studied the kinetics of isomerization of a-phenylallyl esters [(3), R = = YCgH, R == H] in the weakly 

For isomerization of a-phenylallyl p-nitrobenzoate in chlorobenzene at 155°C, A , = 1.16 X 10 -1-6.62 X 10 [02NC6H4C02H] sec The reaction rate is not significantly changed by addition of 3.6 x 10 Af pyridine or 4.5 x 10 Af tetrabutylammonium p-nitrobenzoate to the reaction mixture. a-Phenylallyl benzoate isomerizes more slowly than the p-nitrobenzoate 

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When C2H5 is replaced with the more electron withdrawing CF3, the rate is slower, indicating that reaction does not proceed via allylic carbanions, the path for thermal isomerization of allylic esters. Oxygen-18-labeling experiments and the electronic effects are consistent with an internal ox3q>alladation mechanism ... 

In protic solvents, the allylic carbonium ion formed by acid-catalyzed alkyl carbon-oxygen bond fission can recombine either with the carboxylic acid molecule or with a solvent molecule. The electrostatic attraction between the carbonium and carboxylate ions, which is a major factor in isomerization of allylic esters by ion-pair internal return during solvolysis, is absent in the acid-catalyzed reaction. The more numerous, usually more nucleophilic, solvent molecules in the solvation shell of the carbonium ion should compete effectively with the departed carboxylic acid molecule and solvolysis rather than isomerization should be the predominant reaction. For example, in the presence of 0.05 M perchloric acid, solvolyses of cis- and //- //7.s-5-methyl-2-cyclohexenyl p-nitrobenzoates are not only very much faster than in the absence of the acid, but polarimetric and titrimetric rates of solvolysis of optically-active esters were identical within experimental error. For these esters, the acid-catalyzed solvolysis was not accompanied by a detectable amount of isomerization. Braude reported, on the basis of indirect evidence, that isomerization accompanies acid-catalyzed hydrolysis of a-ethynyl-y-methylallyl acetate in aqueous dioxane. It was shown that, under some experimental conditions, the spectrophotometrically determined rate of appearance of the rearranged 1 -yne-3-ene chromophore exceeds the titrimetrically determined rate of hydrolysis,... 

The dissociation of molecules to ions followed by fast ion recombination in the ion pair results in isomerization if the molecule contains the double bond. In particular, the isomerization of allyl esters accompanied by the migration of the double bond occurs in such manner... 

As has already been detailed for the allyloxycarbonyl (Aloe) moiety, allyl esters also proved to be very versatile and useful carboxy-protecting groups. They can be easily constructed by azeotropic esterification or nucleophilic displacement on allylic halides. For the cleavage of these esters lithium di-methylcuprate can be used. However, a much milder method is found in the Rh -catalyzed isomerization of the allyl moiety to a propenyl ester which immediately hydrolyzes under the reaction conditions (Scheme 67). Even milder is the Pd°-catalyzed allyl transfer to morpholine as an accepting nucleophile. The removal of allyl ester protection has earlier been used in particular in -lactam anti-... 

Allyl-allyl cross-coupling of allyl bromides (Structure 1) and allyl sulfides (2) carrying homoallylic alcohol or ester functions takes place under irradiation with hexamethylditin (see eq. (1)). The reaction cleanly leads to 2,6-dienes (3) and no isomerization of allylic bromides is oberserved [56]. 

Several possible reactions may give rise to impurities in the preparation of phosphonic or phosphinic acid esters by the Michaelis-Arbuzov reaction, and it is possible that, in some cases, such reactions become preponderant. Triethyl phosphite, for instance, has been successfully used as a dehalogenating agent, in particular, for debrominations. Isomerization of allylic groups may occur through S T-type processes (reaction 5) or be induced thermally (reactions 6 and 7) 25,126... 

In contrast to facile Pd(0)-catalyzed reactions of allyl esters with soft carbon nucleophiles via r-allylpalladium intermediate, propargyl esters such as acetate are less reactive toward soft carbon nucleophiles. However, /3-keto esters and malonates react under neutral conditions with propargyl carbonates using DPPE as a ligand [37], Acetoacetate reacts with meAyl propargyl carbonate (119) in THF at room temperature to afford 4-(methoxycarbonyl)-5-methyl-3-methylene-2,3-dihydrofuran (120) in 88 % yield. The furan 121 was obtained by isomerization of the methylenefuran 120 under slightly acidic conditions. 

An isomerization/enantioselective intramolecular Alder-ene cyclization of enynes 467 was reported by Okamoto and co-workers (Scheme 2-54). The reaction was catalyzed by a cationic Rh(I)-(i )-BrNAP complex to afford various bicyclic and trycyclic dihydrobenzofurans and dihydronaphthofurans 469 in good yields and excellent enantioselectivity. Another example of an Alder-ene cyclization is the reaction of allylic ester 470, which yielded a-methylene-y-butyrolactone 471 in 50% yield. It was found that other transition metals, such as Pd, Ru, and Ti, were unable to catalyze this reaction (Scheme 2-55). ... 

The enzyme catalyzed reactions that lead to geraniol and farnesol (as their pyrophosphate esters) are mechanistically related to the acid catalyzed dimerization of alkenes discussed m Section 6 21 The reaction of an allylic pyrophosphate or a carbo cation with a source of rr electrons is a recurring theme m terpene biosynthesis and is invoked to explain the origin of more complicated structural types Consider for exam pie the formation of cyclic monoterpenes Neryl pyrophosphate formed by an enzyme catalyzed isomerization of the E double bond m geranyl pyrophosphate has the proper geometry to form a six membered ring via intramolecular attack of the double bond on the allylic pyrophosphate unit... 

The Noc group, developed for amino acid protection, is introduced with the acid chloride (Et3N, H2O, dioxane, 2 h, 20°, 61-95% yield). It is cleaved with Pd(Ph3P)4 (THF, A, A -dimethyibarbituric acid, 8 h, 20°, 80% yield). It is not isomerized by Wilkinson s catalyst, thus allowing selective removal of the allyl ester group. 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

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