Tandem [4+2]/[3+2] Cycloadditions of 1,3,4-Oxadiazoles with Alkenes

Abstract

A review on the tandem [4+2]/[3+2] cycloaddition reactions of 1,3,4-oxadiazoles with alkenes is presented. This reaction presents a powerful synthetic tool in the construction of complex polycyclic molecules in a one-pot reaction. Special attention is paid to synthesis of [n]polynorbornane and oxanorbornyl systems. In continuation, a review on the 1,3,4-oxadiazole reactions used in stereoselective total synthesis of alkaloids is given. Both intermolecular and intramolecular tandem [4+2]/[3+2] reactions are discussed. Stereospecificities and mechanistic rationale of various reactions are supported by quantum-chemical calculations (RHF/6-31G*). TANDEM [4+2]/[3+2] CYCLOADDITION REACTIONS OF OXADIAZOLES WITH ACYCLIC ALKENESVasil'ev reported that a series of polyfluorinated 1,3,4oxadiazoles 1-4 undergo a tandem [4+2]/[3+2] cycloadditions with acyclic alkenes, representative examples are given in Scheme 3.[15] Ethylene reacts in a sealed vessel at 200-220 o C with OD producing 1,4-bis(trifluoromethyl)-7-oxabicyclo[2.2.1]heptane 5 in 41% yield. Stereochemical or regiochemical factors come into play when the alkene bears substituents. Both regio-isomers (2,5-, 2,6-) and stereo-isomers (exo-, endo-) are then possible. The regiochemical outcome depends on the size of the substituent rather than its electronic properties. Thus, the reaction of propylene, ethyl vinyl ether, ethyl acrylate, methyl metacrylate, and isoprene give mixtures of the 2,5-and the 2,6-isomers 9-13 in each case, whereas reaction with styrene regiospecifically gave product 14. TANDEM [4+2]/[3+2] CYCLOADDITION REACTIONS OF OXADIAZOLES WITH CYCLIC ALKENESA range of cycloalkenes have been found to react with OD to form highly symmetrical coupled products 15 (n=1,2,3,5), in which the rings were exo-fused to the 7-oxanorbornane subframe (Scheme 4) [18].Reaction with cyclopentadiene proceeds in relatively mild conditions, while cyclopentene, cyclohexene and 1,4-cyclohexadiene require more drastic conditions, heating at 140-200 o C (Scheme 5) N N

High-Pressure Cycloaddition Reactions in the Synthesis of Biologically Relevant Heterocycles

“…1,3,4-Oxadiazole is an alternative reagent to furan for the synthesis of the 7-oxabicyclo[2.2.1] skeleton [47]. High pressure triggers tandem [4 + 2]/[3 + 2] cycloadditions of 2,5-bis-trifluoromethyl-1,3,4-oxadiazole 118 with norbornene dienophiles 97a and 119.…”

Conformationally preorganised hosts for anions using norbornane and fused [n]polynorbornane frameworks

“…39,41,43 Several cycloaddition strategies have been developed to access these fused polynorbornane structures [44][45][46][47][48][49][50][51][52][53][54][55] and inventive descriptions such as LEGO 48 are used to describe their construction. Other monikers including 'molecular glue' have been used to describe oxadiazole coupling 54 and also BLOCK as an acronym for 'bonzer little organic construction kit'. 55 All such terminology hints at the modular nature of the various approaches to the ready assembly of these large molecular architectures.…”

Tandem Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications

“…25,26 Although a limited number of reports had described the cycloadditions of electron-deficient 1,3,4-oxadiazoles, they typically employed symmetrical oxadiazoles bearing two strong electron-withdrawing substituents (CF 3 , SO 2 Et, CO 2 Me) and all had been examined only in intermolecular reactions (Figure 1). 27–47 Reactions of olefinic dienophiles were found to proceed through an initial [4 + 2] cycloadduct that loses N 2 to provide a carbonyl ylide that subsequently reacted again with the same olefin in a 1,3-dipolar cycloaddition reaction to provide only 2:1 cycloadducts, limiting their synthetic utility.…”