Classical Claisen Rearrangement

The preparation involves an oxymercuration (Section 3.5.3) of the C=C double bond of the ethyl vinyl ether. The Hg(OAc) ion is the electrophile as expected, but it forms an open-chain cation A as an intermediate rather than a cyclic mercurinium ion. The open-chain cation A is more stable than the mercurinium ion because it can be stabilized by way of oxocarbe-nium ion resonance. Next, cation A reacts with the allyl alcohol, and a protonated mixed acetal B is formed. Compound B eliminates EtOH and Hg(OAc) in an El process, and the desired enol ether D results. The enol ether D is in equilibrium with the substrate alcohol and ethyl vinyl ether. The equilibrium constant is about 1. However, the use of a large excess of the ethyl vinyl ether shifts the equilibrium to the side of the enol ether D so that the latter can be isolated in high yield. 

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The C-H functionalization protocol is not limited to the development of surrogate chemistry to enolate transformations. The C-H activation at allylic C-H bonds readily generates 7,6-unsaturated esters, the products of the classic Claisen rearrangement (Figure 6). 

The classical Claisen rearrangement is the first and slow step of the isomerization of allyl aryl ethers to orlho-a ly lated phenols (Figure 14.46). A cyclohexadienone A is formed in the actual rearrangement step, which is a [3,3]-sigmatropic rearrangement. Three valence electron pairs are shifted simultaneously in this step. Cyclohexadienone A, a nonaromatic compound, cannot be isolated and tautomerizes immediately to the aromatic and consequently more stable phenol B. 

Ireland-Claisen rearrangements obviously occur under much milder conditions than the classical Claisen rearrangements of Figures 14.46 and 14.47. Among other things, this is due to product development control. The rearranged product of a Claisen-Ireland rearrangement is an a-allylated silyl ester, and its C=0 bond is stabilized by ester resonance (=14 kcal/mol... 

Rearrangements, especially those only involving heat or a small amount of catalyst to activate the reaction, display total atom economy. A classic example of this is the Claisen rearrangement, which involves the rearrangement of aromatic allyl ethers as shown in Scheme 1.2. Although... 

Asymmetric allylic C-H activation of more complex substrates reveals some intrinsic features of the Rh2(S-DOSP)4 donor/acceptor carbenoids [135, 136]. Cyclopropanation of trans-disubstituted or highly substituted alkenes is rarely observed, due to the steric demands of these carbenoids [16]. Therefore, the C-H activation pathway is inherently enhanced at substituted allylic sites and the bulky rhodium carbenoid discriminates between accessible secondary sites for diastereoselective C-H insertion. As a result, the asymmetric allylic C-H activation provides alternative methods for the preparation of chiral molecules traditionally derived from classic C-C bond-forming reactions such as the Michael reaction and the Claisen rearrangement [135, 136]. 

The Claisen rearrangement of allyl vinyl ethers is a classic method for the stereoselective synthesis of y,J-unsaturated esters. The allylic C-H activation is an alternative way of generating the same products [135]. Reactions with silyl-substituted cyclohexenes 197 demonstrate how the diastereoselectivity in the formation of 198 improves (40% to 88% de) for the C-H insertion reactions as the size of the silyl group increases (TMS to TBDPS) (Tab. 14.14). Indeed, in cases where there is good size differentiation between the two substituents at a methylene site, high diastereo- and enantioselectivity is possible in the C-H activation. 

Classical organic reactions that have been carried out in water include, among others, the Diels-Alder reaction, the Claisen rearrangement, aldol condensations, Michael additions, and nucleophilic substitutions. In the Diels-Alder reaction, for example, water has been found to increase the reaction rate and to enhance the endoselectivity 120). Two reviews summarize the results for organic reactions in water 121). 

Before we embark on our journey into the world of six-membered transition states, I would like to speak briefly about one reaction, to illustrate how a transition state is drawn throughout the book. The enzyme-catalyzed transformation of chorsimate (2) to prephenate (3) is a classic example of a [3,3]-sigmatropic Claisen rearrangement6 (Scheme IV). As an old bond is being broken and at the same time a new bond is formed in the transition state, the transition state for the Claisen rearrangement of chorismate to prephenate would look more like transistion state A than like B. Still, for the convenience of following the bond connection event clearly, I prefer to draw the transition state like B. 

One classic example that confirms the preference of Claisen rearrangement for a chairlike transition state was provided by Hansen and others. In 1968, they investigated the Claisen rearrangement of the crotyl propenyl ethers 5a and 5b to examine the stereochemistry of the rearrangement in the gas phase at 160° C10 (Scheme l.V). Both the E,E- and Z,Z-isomers rearrange to afford a syn-isomer as the major product. The stereochemical outcome of the reaction can be explained... 

Another series of publications from Ken s group compared kinetic isotope effects, computed for different possible transition structures for a variety of reactions, with the experimental values, either obtained from the literature or measured by Singleton s group at Texas A M. These comparisons established the most important features of the transition states for several classic organic reactions — Diels-Alder cycloadditions, Cope and Claisen rearrangements, peracid epoxidations, carbene and triazolinedione cycloadditions and, most recently, osmium tetroxide bis-hydroxylations. Due to Ken s research, the three-dimensional structures of many transition states have become nearly as well-understood as the structures of stable molecules. 

Mandai, Saito and cowoikers recently described a new synthesis of isocaibacyclin, which features a crucial one-pot, three-step transformation tandem tertiary allyl vinyl ether formation, Claisen rearrangement, and ene cyclization led from alcohol (57) directly to bicyclo[3.3.0]octane (59 heme 10). Clearly, due to improvements in the preparation of Ae allyl vinyl ether moiety, there is a trend even in the classical Qaisen rearrangement to taclde more complex structural challenges successfully. 

The arylsulfonyl carbanion accelerated Claisen rearrangement is completely regioselective and has also been found to be highly diastereoselective (Scheme 2). The stereochemical course of the reaction conforms to the familiar chair-like transition state model usually invoked for the classic thermal process. Recently, high degrees of asymmetric induction have been observed in tlie rearrangements of chiral cyclic phosphoramidate stabilized carbanion derivatives. ... 

This is a classic Claisen [3,3]-sigmatropic rearrangement sequence starting with an allylic alcohol This product was used in a ind forming a vinyl ether by acetal (or in this case, orf/ioester) exchange. The reaction is very trans- synthesis of chrysanthemic acid by... 

To exploit the whole capacity of the Claisen rearrangement, appropriate methods for the preparation of the allyl vinyl ethers starting from allyl alcohols are necessary. The classical approach involves vinyl-ation with simple vinyl ethers or acetals. Unfortunately these methods fail with more complex systems and do not allow, except in the case of cyclic enol ethers, control of the stereochemistry of the substituted enol ether double bond. Until recently it was only possible to generate such substituted systems with appreciable stereocontrol via ketene N.O-acetals. Their preparation by addition of lyl alcohols to substituted ynamines can lead to adducts of either ( )- or (Z)-geometry, depending upon the conditions used (Scheme 60). 

Johnson, Faulkner, et al.B have developed another approach to synthesis of polyisoprenoids which also utilizes the Claisen rearrangement to establish trans-trisubstituted double bonds. In a model experiment, the allylic alcohol (5) was heated with 7 equivalents of triethyl orthoacetate and 0.06 equivalent of propionic acid at 138° for 1 hour with provision for distillative removal of ethanol the diene ester (6) was obtained in 92% yield. Analysis by vpc indicated that (6) is the trans isomer to the extent of > 98% with less than 2% of the cis isomer. If the classical... 

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