The facile dearomatization of nitroaromatic compounds using lithium enolates of unsaturated ketones in conjugate additions and (4+2) formal cycloadditions

Karine Pasturaud (1) , Batoul Rkein (1) , Morgane Sanselme (2) , Muriel Sebban , Sami Lakhdar , Muriel Durandetti (1) , Julien Legros (1) , Isabelle Chataigner (1, 3)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 SMS - Sciences et Méthodes Séparatives
3 LCT - Laboratoire de chimie théorique

Dearomatization of conventional nitroarenes by lithiated enolates derived from methyl vinyl ketones easily takes place, following a formal (4+2) cycloaddition process. While nitroindoles react readily with in situ generated conjugated enolates, the deaggregation of these latter species by HMPA extends the reaction scope to the more aromatic nitronaphthalenes and pyridines. For a long time, drug design has been oriented towards « flat molecules », involving mostly aromatic structures. The last decade has been marked with a strategic turnaround , pharmaceutical industry orienting now its quest for new bioactive molecules through the development of novel 3D scaffolds such as to generate a larger number of differentiated products. 1 At first glance, a straightforward approach to such targets relies on commercially available alicyclic building blocks. A cost-effective alternative consists in dearomatizing arenes. 2 Cycloadditions or annulations reactions are attractive transformations in this context, generating polycyclic 3D scaffolds in one operation. Because of the electron-richness of most arenes, (4+2) dearomatizing processes rely mainly on their involvement as dienes in normal electron demand (NED) transformations. 3 The dienophilic behavior of electron-depleted aromatics is more scarcely described. Nevertheless, provided that the arene is sufficiently electron-poor, substituted C=C aromatic double bonds have been shown to react with electron-rich 1,3-dienes in (4+2) Diels-Alder cycloadditions. 4 Nitroarenes such as in nitro-indoles,-pyrroles or-naphthalenes have been successfully reacted in this way. 5 However, efficient transformations are generally observed under drastic reaction conditions, including extended heating at high temperatures. 4,5 Such harsh procedures lead to the rearomatization of the cycloadducts most of the time and thus loss of functional groups. Electrophilic activation of the dienophilic partner by acid catalysis (Lewis or Brønsted) usually allows to decrease the reaction temperature by lowering its LUMO energy. 6 However, the acid sensitivity of the functionalized (silyl)oxydienes, such as Danishefsky diene for instance, prevents their use in many cases. 7 High pressure activation has been shown to overcome this difficulty, allowing to perform the reactions in a range of temperatures compatible with most substrates/cycloadducts. 4,5,8 But hyperbaric equipment being seldom available in organic laboratories, a more general alternative method is highly desirable. In this context, the less intuitive activation of the dienic partner, by raising its HOMO energy, appears as an attractive option. This has been considered through (poly)enamine catalysis, an elegant but somewhat limited strategy, notably for aromatic substrates. 5e-f,9 Scheme 1. Reaction between activated lithium enolate 2a and tetrasubstituted cumbersome dienophiles to afford formal (4+2) cycloadducts. In 1988, Baker et al. showed that a nucleophilic activation of Danishefsky diene 1 could overcome the lack of reactivity of inert tetrasubstituted dienophilic substrates, by transforming 1 into lithium enolate 2a in the presence of methyllithium in dimethoxyethane (DME) at-50 °C (Scheme 1). 10 Reaction with the dienophile 4a occurred at-90°C in THF to afford the Michael adduct, which was further cyclized under acidic conditions to provide the corresponding formal cycloadduct. Danishefsky et al. reported a related transformation, involving 4b, in the context of the total synthesis of (±)-aplikurodinone. 11 Recently, Snyder et al. performed a similar nucleophilic activation to access Hajos-Parrish ketone isomers

Domaines: Chimie

Karine Pasturaud, Batoul Rkein, Morgane Sanselme, Muriel Sebban, Sami Lakhdar, et al.. The facile dearomatization of nitroaromatic compounds using lithium enolates of unsaturated ketones in conjugate additions and (4+2) formal cycloadditions. Chemical Communications, 2019, 55 (52), pp.7494-7497. ⟨10.1039/C9CC02924A⟩. ⟨hal-03003225⟩