Total synthesis of insect sex pheromones: recent improvements based on iron-mediated cross-coupling chemistry.

In the current ecological context, use of insect sex pheromones as an alternative to conventional pesticides is in constant growth. In this report, we discuss the recent contributions brought by our groups in the field of iron-catalyzed cross-couplings applied to the synthesis of insect pheromones. The pivotal question of the development of sustainable synthetic procedures involving cheap, non-toxic and efficient additives is also discussed, as well as the mechanistic features guiding the reactivity of such catalytic systems.

The molecular-level effect of alkoxide additives in iron-catalyzed Kumada cross-coupling with simple ferric salts.

The molecular-level role of alkoxide salts, used as alternative additive to N-methylpyrrolidone in iron-catalyzed alkyl-alkenyl/aryl cross-coupling reactions, is investigated. Detailed spectroscopic studies reveal that alkoxides promote the formation of homoleptic organoferrates such as [FeMe3]-, providing an alternative to toxic NMP to access these reactive intermediates.

Mechanistic Facets of the Competition between Cross-Coupling and Homocoupling in Supporting Ligand-Free Iron-Mediated Aryl-Aryl Bond Formations.

In the context of cross-coupling chemistry, the competition between the cross-coupling path itself and the oxidative homocoupling of the nucleophile is a classic issue. In that case, the electrophilic partner acts as a sacrificial oxidant. We investigate in this report the factors governing the cross- versus homocoupling distribution using aryl nucleophiles ArMgBr and (hetero)aryl electrophiles Ar'Cl in the presence of an iron catalyst. When electron-deficient electrophiles are used, a key transient heteroleptic [Ar2Ar'FeII]- complex is formed. DFT calculations show that an asynchronous two-electron reductive elimination follows, which governs the selective evolution of the system toward either a cross- or homocoupling product. Proficiency of the cross-coupling reductive elimination strongly depends on both π-accepting and σ-donating effects of the FeII-ligated Ar' ring. The reactivity trends discussed in this article rely on two-electron elementary steps, which are in contrast with the usually described tendencies in iron-mediated oxidative homocouplings which involve single-electron transfers. The results are probed by paramagnetic 1H NMR spectroscopy, experimental kinetics data, and DFT calculations.

Gram-Scale, Cheap, and Eco-Friendly Iron-Catalyzed Cross-Coupling between Alkyl Grignard Reagents and Alkenyl or Aryl Halides.

A new robust methodology for gram-scale iron-catalyzed cross-coupling between alkyl Grignard reagents and alkenyl or aryl halides is developed. This method does not require toxic additives such as NMP or expensive ligands. Its efficiency relies on the use of simple alkoxide magnesium salts as additives. On the basis of these results, a new procedure for one-pot synthesis of substituted benzamides from chloroesters is also proposed.

Axial preferences in allylation reactions via the Zimmerman-Traxler transition state.

The reaction of a substituted allylmetal with a prostereogenic carbonyl compound can give rise to up to two racemic diastereomers (syn and anti). Classically, in such reactions, when pure E-isomers have afforded anti-selectivity and the Z-isomers exhibit syn-selectivity, researchers have used the empirical Zimmerman-Traxler model. In this model, chair-like transition states dominate over boat-like arrangements. The incoming aldehyde alkyl (aryl) residue occupies a pseudoequatorial rather than a pseudoaxial position to avoid potential 1,3-diaxial steric interactions. However, the reaction of γ,γ-disubstituted allylzinc species with carbonyl compounds generates two gauche interactions, which may result in a completely different stereochemical outcome. With these two gauche interactions, would a transition state in which the aldehyde substituent occupies a pseudoequatorial position or a pseudoaxial position be preferred? In this Account, we show that reaction of γ,γ-disubstituted allylzinc species with carbonyl compounds proceeds through a chair-like transition state and the substituent of the incoming aldehyde residue prefers to occupy a pseudoaxial position to avoid these two gauche interactions. Theoretical calculations on model systems support our experimental results. We have extended this new stereochemical outcome to describe the formation of α-alkoxyallylation of aldehydes through the formation of the rather uncommon (E)-γ,γ-disubstituted alkoxyallylzinc species. We also used this method to transform aromatic ketones and α-alkoxyaldehydes and ketones into functionalized adducts. In a one-pot reaction and using simple alkynes, three new carbon-carbon bonds and two to three stereogenic centers, including an all-carbon quaternary stereocenter could be created in acyclic systems. Because 1,3-diaxial interactions are now produced with the axial substituent, an increase in the substituent size on the zinc atom decreases the diastereoselectivity.

Tandem reactions involving 1-silyl-3-boryl-2-alkenes. New access to (Z)-1-fluoro-1-alkenes, allyl fluorides, and diversely α-substituted allylboronates.

The reactions of 1-silyl-3-boryl-2-alkenes with various electrophilic reagents (Selectfluor, N-halosuccinimides, benzhydryl, and propargylic alcohols in the presence of a Lewis acid, N-alkoxycarbonyliminium ion) have been investigated as new routes to α-substituted allylboronates. Further functional transformations, including allylboration, Suzuki coupling, protodeboronation, and cycloisomerization, have been carried out to illustrate the synthetic potential of these γ-borylallylsilanes.

Stereoselective and catalytic access to ß-enaminones: an entry to pyrimidines.

We describe herein a highly stereoselective access to Cbz-protected ß-enaminones 2 based on the NaOH catalyzed rearrangement of propargylic hydroxylamines 1. The synthetic potential of these ß-enaminones is illustrated in an original synthesis of pyrimidines.

Transition-metal-catalyzed uninterrupted four-step sequence to access trisubstituted isoxazoles.

We describe herein a novel uninterrupted four-step sequence to access trisubstituted isoxazoles from readily available propargylic alcohols using sequentially iron and palladium catalytic systems. The advantages of such a strategy are illustrated by the high overall yields and the time-saving procedure that are reported.

Gold-catalyzed propargylic substitutions: Scope and synthetic developments.

This personal account summarizes our recent developments in gold-catalyzed direct substitutions on propargylic (allylic, benzylic) alcohols, with various nucleophiles (and bi-nucleophiles) based on the σ- and/or π-acidity of gold(III) complexes. Synthetic developments are also briefly described.

A versatile iron-catalyzed protocol for the one-pot synthesis of isoxazoles or isoxazolines from the same propargylic alcohols.

The use N-sulfonyl-protected hydroxylamines as bi-nucleophiles in iron-catalyzed propargylic substitutions allows the selective one-pot synthesis of four classes of substituted isoxazoles or isoxazolines from the same propargylic alcohols (21 examples) by simply tuning the nature of the base. By using an iron(III) catalyst and a base such as triethylamine (3 equiv), isoxazoles 3 are obtained in good isolated yields (56-95%), whereas N-sulfonyl-protected isoxazolines 6 are selectively obtained (77-93% yield) by using iron and gold catalysts in the presence of a catalytic amount of pyridine (10 mol%).

Highly diastereoselective Baldwin rearrangement of isoxazolines into cis-acylaziridines.

An atom-economical and practical synthesis of cis-N-benzenesulfonamide acylaziridines through the Baldwin rearrangement of various N-benzenesulfonamide isoxazolines has been reported. A detailed experimental study revealed the beneficial effect of microwaves and pointed out the crucial role of the temperature in the reaction course. Moderate to good yields and excellent cis stereoselectivities were achieved for 13 examples.