An unusually rapid Claisen rearrangement involving ring expansion

Abstract

A Claisen rearrangement of a partially-fluorinated system involving ring expansion occurred at an unusually low temperature, 100 °C lower than a comparable system from the literature.Paquette and co-workers showed how the Claisen rearrangement could be used to transform readily available vinylic lactones into medium-ring carbocycles during a series of landmark natural product syntheses. 1 The Tebbe reaction 2 fulfils a critical role in providing the vinyl ether component of the allyl vinyl rearrangement precursor; Scheme 1 summarises the sequence.The rearrangement step requires the use of high temperatures and some special experimental precautions; 3 after the Tebbe reaction, the allyl vinyl ether is sealed in base washed tubes to minimise decomposition through enol ether protiolysis and Paquette notes that following minimal enol ether purification, traces of the Tebbe reagent by-products may be present in the rearrangement medium. Given that aluminium reagents are indeed known to cause dramatic accelerations of [3,3]-Claisen rearrangements, 4 some assistance to the rearrangement would not be surprising, though the nature of the active Lewis acid is not clear nor is the effect large given the reaction conditions (23 h at 175 °C in Scheme 1). Double bond migration can also compete with rearrangement forming non-productive allyl vinyl ethers.We were interested to see if halogenation of the allylic fragment would accelerate the ring expansion and lower the reaction temperature. The literature suggests that g,g-difluorination accelerates [3,3]-Claisen rearrangements in some cases; 5 though the idea has not been tested fully and definitive theoretical work does not exist, a general concensus exists that the rehybridisation of an sp 2 CF 2 centre to sp 3 is favoured as geminal CF 2 -substitution destabilises the alkene. Unambiguous accelerative effects exerted in g,g-difluorinated systems have also been reported in other rearrangement systems including [2,3]-Wittigs, 6 heteroatomic [2,3]-rearrangements 7 and oxyCope 8 reactions.Stork enamine chemistry allowed the syntheses of ketoesters 2a and 2b and the addition of 1-chloro-2,2-difluoroethenyllithium 9 generated from 1-chloro-2,2,2-trifluoroethane afforded good yields of alcohol products 3a as a mixture of diastereoisomers (Scheme 2); we assume that the major product has a trans-relationship between the sidechains. 3 No lactone products were detected; what we expected was the collapse of the initial alkoxide onto the ester in at least one of the diastereoisomers. After isolating the hydroxyester, we tried to lactonise it under acidic and basic conditions but failed. Instead of hydrolysing the acid, we synthesised tert-butyl ester 3c as a mixture of diastereoisomers; a single lactone, to which we assigned structure 4a, was isolated in moderate yield after treatment of these hydroxyesters with trifluoroacetic acid in dichloromethane. Presumably, alkyl-O cleavage and carboxy protonation allows closure to the lactone; it seems less likely that the acid intercepts an ally...

Titanium reagents for the alkylidenation of carboxylic acid and carbonic acid derivatives

“…24 There is one report of methylenation of α,β-unsaturated esters giving higher yields than with the Petasis reagent discussed below. 25 Vinyl and aryl halides including vinyl fluorides, 26 vinyl chlorides, 26 aryl bromides, 27 and aryl iodides, 28 are tolerated by the reagent. Ethers including benzyl, 29 and trityl ethers 30 are stable to the reaction conditions.…”

“…Thus, Tebbe methylenation of lactone 329 gives enol ether 330, which undergoes Claisen rearrangement and elimination of hydrogen fluoride to give conjugated ketone 331 (Scheme 140). 26 The favourable rehybridisation of the sp Claisen rearrangement to give medium-ring ketone 334. Organometallic impurities had to be removed before Claisen rearrangement as they led to isomerisation of the exocyclic double bond to give the corresponding endocyclic enol ether.…”

Recent progress in the use of fluoroorganic compounds in pericyclic reactions

“…142 An instance where difluorination on the allylic terminus results in a more facile Claisen rearrangement was documented by Percy and Dimartino. 143 The difluorinated substrate 96b rearranges smoothly with concomitant HF elimination at 85 C within 4 h, whereas the nonfluorinated substrate 96a is much less reactive and requires a temperature 90 C higher and a longer reaction time (Scheme 53).…”

A direct and rapid route to α,α-difluoroacylsilanes from trifluoroethanol

“…Fluorination in the allyl part of the Claisen system also results in relatively facile rearrangement in acyclic [4] and cyclic [5] systems, though the effects are generally smaller. All these effects are attributed qualitatively to the destabilising effect of the CF 2 centre upon the alkene p-bond.…”