Hydrazones as Singular Reagents in Asymmetric Organocatalysis

This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophile–electrophile, cycloaddition, and cyclization reactions. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N-monoalkyl, N,N-dialkyl, and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analyzed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles.Ministerio de Economía y Competitividad CTQ2013-48164-C2-1-P, CTQ201348164-C2-2-PEuropean FEDER fundsJunta de Andalucía 2012/FQM 107

Synthesis of enantioenriched azo compounds: Organocatalytic Michael addition of formaldehyde N-tert-butyl hydrazone to nitroalkenes

The unprecedented diaza-ene reaction of formaldehyde N-tert-butyl hydrazone with nitroalkenes can be efficiently catalyzed by an axially chiral bis-thiourea to afford the corresponding diazenes in good to excellent yields (60-96%) and moderate enantioselectivities, up to 84 : 16 er; additional transformation of diazenes into their tautomeric hydrazones proved to be operationally simple and high-yielding, affording bifunctional compounds which represent useful intermediates for the synthesis of enantioenriched β-nitro-nitriles and derivatives thereof.Ministerio de Ciencia e Innovación CTQ2010-15297, CTQ2010-14974Junta de Andalucía 2008/ FQM-3833, 2009/FQM-453

Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald-Hartwig Amination

The Pd-catalyzed coupling of racemic heterobiaryl bromides, triflates, or nonaflates with aryl/alkyl primary amines using QUINAP as the ligand provides the corresponding axially chiral heterobiaryl amines with excellent yields and enantioselectivities. Reactivity and structural studies of neutral and cationic oxidative addition intermediates support a dynamic kinetic asymmetric amination mechanism based on the labilization of the stereogenic axis in the latter and suggest that coordination of the amine to the Pd center is the stereodetermining step.Ministerio de Ciencia e Innovación CTQ2013-48164-C2-1-P, CTQ2013-48164-C2-2-P, RYC-2013-12585 for A.R.European FEDER FundsJunta de Andalucía 2012/FQM 1078

Formaldehyde tert-butyl hydrazone as a formyl anion equivalent: asymmetric addition to carbonyl compounds

The asymmetric 1,2-addition of formyl anion equivalents to carbonyl compounds is a powerful synthetic tool that ideally provide access to highly functionalizable a-hydroxy aldehydes in an enantioselective fashion. In this context, the nucleophilic character of formaldehyde hydrazones, together with their remarkable stability as monomeric species, has been exploited for the functionalization of diverse carbonyl compounds, using initially auxiliary-based methodologies and, more recently, catalytic enantioselective versions. This feature article highlights our research progress employing formaldehyde tert-butyl hydrazone as a versatile formyl anion equivalent, in combination with bifunctional H-bonding organocatalysis. The design and optimization of different catalytic systems, focusing on a dual activation of both reagents, is reviewed, as well as the racemization free unmasking of the formyl group and representative product transformations for the construction of valuable, densely functionalyzed chiral building blocks.Ministerio de Economía y Competitividad de España (MINECO).CTQ2016-76908-C2-1-P y CTQ2016-76908-C2-2-PFondos FEDER de la Unión Europea y Junta de Andalucía. P18-FR-3531 y US126286

Dynamic Kinetic Resolution of Hetero biaryl Ketones by Zinc- Catalyzed Asymmetr ic Hydrosil ylation

Adiastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile hetero- biaryl ketones is described. The DKR proceeds by zinc- catalyze dhydrosilylation of the carbonyl group ,thus leading to secondary alcohols bearing axial and central chirality .The strategy relies on the labilization of the stereogenic axis that takes place thanks to aLewis acid–base interaction between anitrogen atom in the heterocycle and the ketone carbonyl group .The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocata- lysts.Ministerio de Ciencia e Innovación (Grants CTQ2016-76908-C2-1-P, CTQ2016-76908-C2-2-P, contract RYC-2013-12585)European FEDER FundsJunta de Andalucía (Grant 2012/FQM 10787)European Union - Marie Skłodowska-Curie (COFUND—Grant Agreement n 8 8 291780

Room Temperature Ionic Liquids in Asymmetric Hetero-Ene Type Reactions: Improving Organocatalyst Performance at Lower Temperatures

Abstract: Room temperature ionic liquids (RTILs) have been widely used as (co)solvents in several catalytic processes modifying, in most of the cases, the catalyst activity and/or the selectivity for the studied reactions. However, there are just a few examples of their use in hydrogen bonding organocatalysis. In this paper, we show the positive effect of a set of imidazole-based ionic liquids ([bmim]BF4 and [hmim]PF6 ) in the enantioselective addition of formaldehyde tert-butylhydrazone to prochiral α-keto esters catalyzed by a sugar-based chiral thiourea. Reactions performed in the presence of low percentages of RTILs led to an increase of the catalyst activity, thereby making possible to work at lower temperatures. Thus, the chiral tert-butyl azomethyl tertiary alcohols could be obtained with moderate to good conversions and higher enantioselectivities for most of the studied substrates when using up to 30 vol% of [hmim]PF6 as a cosolvent in processes performed in toluene.Ministerio de Economia, Industria y Competitividad del gobierno español-CTQ2016- 76908-C2-1-P y CTQ2016- 76908-C2-2-PFondos europeos FEDER y Junta de Andalucía- Beca P18-FR-353

Asymmetric Organocatalytic Synthesis of Fluorinated β-Hydroxy Diazenes

The nucleophilic addition of formaldehyde tert-butyl hydrazone to fluoromethyl ketones provides a valuable tool for the synthesis of highly functionalized β-hydroxy β-tri- and difluoromethyl diazenes. Excellent reactivities and moderate to good enantioselectivities (up to 90 % ee) were achieved by H-bonding activation exerted by tert-Leucine derived H-bonding (squaramide or thiourea) organocatalysts. Subsequent derivatizations in one-pot fashion provide synthetically useful intermediates for target-oriented synthesis: tri- and di-fluoromethylated azoxy compounds, β-amino alcohols, α-hydroxy aldoximes and derivatives thereof.Ministerio de Economía y Competitividad CTQ2016-76908-C2-1-P, CTQ2016-76908-C2-2-PJunta de Andalucía 2012/FQM107

A Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality

A highly diastereo- and enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sulfonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent diastereo- and enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol % in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially chiral heterobiaryl α-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily transformed into N,N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a β-hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction.Ministerio de Ciencia e Innovación (Grants CTQ2016-76908-C2-1-P; CTQ2016-76908-C2-2-P; CTQ2016-78083-P; RYC-2013-12585)European Commission (FEDER Programme)Junta de Andalucía (Grant 2012/FQM 10787)Universidad de Sevilla (Grant No. 1800511201)European Union - Marie Skłodowska-Curie (COFUND—Grant Agreement nº 291780

Chirality and catalysis with aromatic N-fused heterobicyclic carbenes

The benzoannulation of the most common families of aromatic NHCs, imidazol-2-ylidenes and 1,2,4-triazol-3-ylidenes, results in heterobicyclic imidazo[1,5-a]pyridin-3-ylidenes (ImPy's) and [1,2,4]triazolo[4,3-a]pyridin-3-ylidenes (TriPy's), characterized by a bridged N atom. These are versatile platforms that offer multiple possibilities for the modulation of the steric and electronic properties of the carbene ligand and/or organocatalyst, and offer also diverse opportunities for the introduction of several types of chiralities. In this paper the different families of chiral ImPy and TriPy carbenes and their application in asymmetric catalysis will be discussed.España, Ministerio de Economía y Competitividad (CTQ2013-48164-C2-1-P, CTQ2013- 48164-C2-2-P, and predoctoral fellowship to C. I.),España Junta de Andalucía (Grant 2012/FQM 1078