Tandem inverse-electron-demand hetero-/retro-Diels–Alder reactions for aromatic nitrogen heterocycle synthesis

Abstract

The merged inverse-electron-demand hetero-Diels-Alder (ihDA)/retro-Diels-Alder (rDA) reaction sequence can be used to rapidly synthesise highly functionalised nitrogen heteroaromatics. The reaction offers many advantages: high atom economy, high levels of regioselectivity, it rarely requires a catalyst and, in some cases, can be performed in the absence of solvent. In this tutorial review we discuss the range of commonly used dienophiles and aza-dienes for this process whilst highlighting the reactivity trends, and illustrating their applications.

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

“…9,21 A lot of applications for tetrazinebased materials, for example, in the field of addressable sensors, displays, high-energy materials (used in propellants, explosives and pyrotechnics), in coordination chemistry, in the synthesis of heterocycles 9 and in total synthesis already exist, however, another new and exciting application of tetrazines is their incorporation as electron-deficient comonomers in alternating donor-acceptor copolymers used for photovoltaics. 22 This has led to synthesis routes for a considerable amount of different asymmetric and symmetric tetrazines with various functionalities.…”

“…1a) Therefore, as a general rule of thumb, electron-withdrawing substituents at 3-and 6-positions of the tetrazine lower the LUMO of the diene and thus accelerate iEDDA while electrondonating substituents have a negative effect on reaction rates. 9 Furthermore, dienophiles with electron-rich substituents (raising the HOMO of the dienophile) are preferred. Concomitantly, steric effects need to be considered.…”

“…6-13, Fig. 1) react in an inverse electron demand hetero-Diels-Alder (ihDA)-retro-Diels-Alder (rDA) reaction cascade 9 to form dihydropyridazines which might be further oxidised to the corresponding pyridazines. The first step in this sequence is a Diels-Alder [4+2] cycloaddition with inverse electron demand resulting in a highly strained bicyclic adduct (2).…”

“…2,3 Among these, the inverse electron demand Diels-Alder addition (iEDDA, Scheme 1) of 1,2,4,5-tetrazines and olefins, occasionally referred to as CarboniLindsey 4 reaction, has increasingly gained importance in the last few years. Other than iEDDA, 5 SPIEDAC 6,7 (strain-promoted inverse electron demand Diels-Alder cycloaddition), DA inv 8 (Diels-Alder with inverse electron demand) or ihDA/rDA 9 (inverse electron demand hetero Diels-Alder-retro-Diels-Alder) are used as abbreviations. Initially applied for the synthesis of pyridazines, 4,9 iEDDA was introduced as a potential click chemistry scheme almost simultaneously by two groups in 2008.…”

“…Other than iEDDA, 5 SPIEDAC 6,7 (strain-promoted inverse electron demand Diels-Alder cycloaddition), DA inv 8 (Diels-Alder with inverse electron demand) or ihDA/rDA 9 (inverse electron demand hetero Diels-Alder-retro-Diels-Alder) are used as abbreviations. Initially applied for the synthesis of pyridazines, 4,9 iEDDA was introduced as a potential click chemistry scheme almost simultaneously by two groups in 2008. 10,11 Since then, it has gathered a remarkable amount of attention, especially in the life sciences, where challenging problems could be solved…”