Studies of the thermal rearrangements of dispiro-1,2,4-Trioxanes
Abstract
A series of α-alkoxy-3,6-dispiro-1,2,4-trioxanes have been synthesised by acid-catalysed
perhydrolyses of α-alkoxy methylenecyclohexane oxides (provides ring A) to give
selectively the corresponding 1-hydroperoxy-1-(hydroxymethyl)cyclohexanes followed
by acid-catalysed condensation with an appropriate cycloalkanone (provides ring C).
Analogous perhydrolyses catalysed by MoO2(acac)2 afforded mixtures of regioisomeric
β-hydroxy hydroperoxides, albeit in overall increased yields. The resulting 1-
(hydroperoxymethyl)-1-hydroxycyclohexanes allowed entry to the isomeric 3,5-dispiro-
1,2,4-trioxanes. X-ray crystallographic analysis of the isomeric dispiro-1,2,4-trioxanes
revealed that (a) they originate from different diastereoisomers of the epoxide
substrates, and (b) the 1,2,4-trioxane rings of the 3,5-isomers adopt distorted half-chair
rather than chair conformations as a consequence of intramolecular 1,3-diaxial steric
interactions. Modelling studies of the perhydrolysis process are in broad agreement with
the regioselectivity of the acid-catalysed reactions, but suggest that the α-alkoxysubstituted
epoxides can act as bidentate ligands which can adopt different binding
modes to the Mo catalyst and hence provide alternative reaction pathways.
Thermolysis of dilute solutions of the α-alkoxy-3,6-dispiro-1,2,4-trioxanes in decane
afforded a variety of 13-, 14-, 15- and 20-membered fully ring-expanded keto lactones
in high yield via stepwise, β-scission/radical recombination reactions in contrast to the
partially ring-expanded oxalactones obtained previously from other 3,6-dispiro-1,2,4-
trioxane derivatives.
An investigation of substituent effects on the thermal rearrangement mechanisms of 3,6-
dispiro-1,2,4-trioxanes using DFT calculations indicated that, after the initial O-O bond
homolysis to form the corresponding oxy biradical, ring C generally opens significantly
faster than the unsubstituted ring A because of the greater delocalisation of radical
character into ring C. In these cases, the lowest rearrangement energy barrier links
directly to the partially ring-expanded oxalactone product as observed experimentally.
Methyl or methoxy substituents at the α-position of ring A render its ring opening by β-
scission increasingly more competitive to that of ring C due to increased delocalisation
of radical character onto the α-substituent, consistent with the ‘α-effect’. Methoxysubstituents
are also noted to engage in close range interactions with the 1,2,4-trioxane
ring. Since the energy barrier for ring A opening falls below that of ring C in the
methoxy model, formation of the fully ring-expanded keto lactone becomes favoured.