Experimental and Computational Investigations into the Benzyl-Claisen Rearrangement

Abstract

Being a prime example of a [3,3]-sigmatropic process, the Claisen rearrangement is an essential reaction at the core of modern organic chemistry. Its undisputed value is derived not only from its reliable and predictable application to the synthesis of complex molecules but, also, in being a reaction of longstanding interest in the field of computational organic chemistry, contributing to our theoretical understanding of pericyclic reactions. A long-standing shortcoming of the Claisen rearrangement is that while allyl-vinyl and allyl-phenyl ethers are viable substrates for the reaction, applications to benzyl-vinyl ethers have rarely been reported. To date, a very limited number of benzylic substrates have been investigated, with the few successful reactions typically requiring harsh conditions. Herein, we report the optimisation of a procedure for Claisen rearrangements of benzylvinyl ethers (referred to here as the "Benzyl-Claisen" rearrangement) based on a previous literature procedure and, for the first time, investigate the scope of such a process. Benzyl ketene acetals were generated in a short two-step procedure by bromoacetalisation of the requisite benzyl alcohol followed by elimination of HBr. Heating the ketene acetals in refluxing DMF smoothly converted the substrates to the product tolylacetates, which were saponified and isolated as their carboxylic acid derivatives. In the course of the reaction optimisation, a pronounced solvent effect was observed: DMF led to the [3,3]-rearranged product, whereas conducting the reaction in xylene led to a mixture of radical dissociation-recombination products. Electron-donating and electron-neutral substituents (-Me, -Ph, -Cl, -Br, -OMe and -SMe) gave the highest yields in the Benzyl-Claisen rearrangement (24-50%) whereas substrates derived from electron-poor aromatic systems (-NO 2 , -CN, -COOBn, -SO 2 Me or -CF 3 ) tended to decompose under the reaction conditions. Claisen rearrangements conducted on meta-substituted systems were observed, unexpectedly, to preferentially generate products via rearrangement "towards" the meta substituent, leading to sterically crowded 1,2,3-trisubstituted tolylacetates. iii The mechanism of the Benzyl-Claisen rearrangement was investigated using computational methods. The activation free energy for rearrangement of benzyl vinyl ether calculated with the high-accuracy CBS-QB3 method was 40.1 kcal/mol, which is 10.2 kcal/mol higher than that of the aliphatic Claisen rearrangement of allyl vinyl ether at the same level of theory. The C-2 alkoxy substituent on the ketene acetal was shown to be essential in making the process both thermodynamically and kinetically favourable, lowering the barrier by 10.2 kcal/mol and stabilising the intermediate isotoluene by 18.0 kcal/mol. As a general rule, substitution of the aromatic systems with an electron-donor group was calculated to lower the barrier for the reaction whilst electronwithdrawing substituents were calculated to raise it. The para-OMe substituent was calculated to lower...

Claisen Rearrangements of Benzyl Vinyl Ethers and Heterobenzyl Vinyl Ethers

“…Further evidence for the operation of a concerted [3,3]sigmatropic pathway has also been provided by our group with the Benzyl-Claisen rearrangement of the mesityl-derived ketene acetal 115 (Scheme 22). 28 One-pot elimination/Claisen rearrangement of bromacetaldehyde ethyl mesityl acetal (114) in the usual manner yielded, after basic…”