Reactions of Ethers Claisen Rearrangement

Write the mechanism of the acid-catalyzed cleavage of terf-butyl cyclohexyl ether to yield cyclohexanol and 2-methylpropene. 

Why are HI and HBr more effective than HCl in cleaving ethers (See Section 11.3.) 

Unlike the acid-catalyzed ether cleavage reaction discussed in the previous section, which is general to all ethers, the Claisen rearrangement is specific to allyl aryl ethers, Ar—O—Cl l2CH=CH2. Treatment of a phenoxide ion with 3-bromopropene (allyl bromide) results in a Williamson ether synthesis and formation of an allyl aryl ether. Heating the allyl aryl ether to 200 to 250 °C then effects Claisen rearrangement, leading to an o-allylphenol. The net result is alkylation of the phenol in an ortho position. 

Problem 18.10 What product would you expect from Claisen rearrangement of 2-butenyl phenyl ether  

Allyl phenyf Transition state Intermediate o-Allylphenol 

A similar rearrangement takes place with allyl vinyl ethers, leading to a so-called y,S-unsaturated ketone or aldehyde. 

Claisen rearrangements are uncommon in biological pathways, but a well-studied example does occur during biosynthesis of the amino acids phenylalanine and tyrosine. Both phenylalanine and tyrosine arise from a precursor called prephenate, which is itself formed by a biological Claisen rearrangement of the allylic vinyl ether chorismate. 

Unlike the acid-catalyzed ether cleavage reaction discussed in the previou section, which is general to all ethers, the Claisen rearrangement is spe-1 cific to allyl aryl ethers, Ar-0-CH2CH=CH2. Treatment of a phenoxide ion 

The mechanism of the Claisen rearrangement. The bond-density surface for the transition state shows that C-0 bond-breaking and C-C bond-making occur 

Evidence for this mechanism conies from the observation that the rearrangement takes place with an inversion of the allyl group. That is, allyl phenyl ether containing a 0 label on the allyl ether carbon atom yields o-allylphenol in which the label is on the terminal carbon. It would be vei) difficult to explain this result by any mechanism other than a pericyclic one. We ll look at more details in Section 30.9, 

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Two other important sigmatropic reactions are the Claisen rearrangement of an allyl aryl ether discussed in Section 18.4 and the Cope rearrangement of a 1,5-hexadiene. These two, along with the Diels-Alder reaction, are the most useful pericyclic reactions for organic synthesis many thousands of examples of all three are known. Note that the Claisen rearrangement occurs with both allylic aryl ethers and allylic vinylic ethers. 

The basic pattern of the Claisen rearrangement is the conversion of a vinyl allyl ether to a y,8-enone. The reaction is also observed for allyl phenyl ethers, in which case the products are o-allylphenols. 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

The usefulness of the Claisen rearrangement in synthetic work depends on the following facts. The allyl aryl ethers, such as phenyl allyl ether (LX), can be prepared easily in high yields and can be transformed readily in good yields to the 2-allylphenols (LXI). The reaction thus... 

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