The Hexadehydro-Diels–Alder Reaction: A New Chapter in Aryne Chemistry

Arynes continue to stimulate new reactions and theoretical insight in aromatic chemistry. This has been driven in recent years by the exceptional versatility of 2-(trimethylsilyl)phenyl triflate (1) as a precursor to ortho-benzyne. Such compounds react under mild conditions and have enabled a substantial development of aryne chemistry both in terms of classical transformations (nucleophilic addition, pericyclic reactions) and in opening up new areas, such as s-insertion reactions and transition-metal-catalyzed processes. As with all methods for the generation of ortho-benzyne to date, compound 1 requires the removal of two adjacent groups from a pre-existing arene. Recent work from the groups of Hoye and Lee has utilized a completely different approach to ortho-arynes, which proceeds through the intramolecular cycloaddition of triynes 3 (Scheme 1). This transformation, which was termed a hexadehydro-Diels–Alder (HDDA) reaction by Hoye in analogy to other dehydropericyclic reactions, is perhaps surprising at first glance because of the infrequently depicted aryne resonance structure 4, which immediately arises from the [4+2] cycloaddition. The trapping of an ortho-benzyne intermediate generated in this fashion can then be accomplished by a variety of interand intramolecular transformations, affording new approaches to valuable benzenoid compounds. The origin of the HDDA reaction lies in two independent reports from the groups of Johnson and Ueda in 1997. Johnson and co-workers subjected the simple hydrocarbon 1,3,8-nonatriyne (6) to flash vacuum pyrolysis and were able to isolate indane and indene in a combined yield of 95% (Scheme 1c). The most likely mechanism appeared to be a [4+2] cycloaddition to form an aryne, followed by reduction under the pyrolytic conditions. Deuterium labeling studies support this mechanism, ruling out a possible 1,2-shift/Bergman cyclization pathway. DFT calculations for the cycloaddition of acetylene with butadiyne gave the surprising result that the formation of benzyne through an HDDA reaction would be highly exothermic ( 52 kcalmol ) and accompanied by a large free energy of activation (37 kcal mol ). The Ueda group observed that tetraynes such as 9 could cyclize to 5H-fluorenol derivatives at room temperature, with the intermediacy of an ortho-benzyne species being established by intraand intermolecular trapping experiments (to give 10, for example). Ueda and co-workers then continued to investigate the scope of the HDDA reaction and established intramolecular trapping reactions with oxygen, sulfur, and nitrogen nucleophiles. Applications were demonstrated in the areas of helical polyene synthesis and in studies on the DNA-cleaving properties of the ortho-aryne generated in this fashion. The similarities to the Bergman and Myers–Saito cycloaromatization reactions are evident, and cleavage of the DNA strands, analogous to the en–diyne para-benzyne Scheme 1. Generation of ortho-aryne intermediates from the established triflate precursor 1 (a) and through the hexadehydro-Diels–Alder (HDDA) reaction (b–d). OTf= trifluoromethanesulfonate, TMS= trimethylsilyl.