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

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

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

Hydrazones as C-Nucleophiles in Asymmetric Organocatalysis

In this PhD Thesis, novel catalytic processes and methodologies for the asymmetric functionalization of prochiral substrates (neutral or ionic) employing hydrazones as versatile umpolung reagents have been developed. In general, double H-bond donors organocatalysts based on unnatural amino acids provided good reactivities and suitable chiral environments for that purpose, affording valuable building blocks and appealing structures for multiple applications in Organic Synthesis (M. G. Retamosa, E. Matador, D. Monge, J. M. Lassaletta, R. Fernández, Chem. Eur. J. 2016, 22, 13430-13455; E. Matador, M. G. Retamosa, D. Monge, R. Fernández, J. M. Lassaletta, Chem. Commun. 2020, 56, 9256-9267). In this context, the present dissertation is structured as follow: Along Chapter I, the contextualization of the developed work are first shown, starting from the activation modes in Asymmetric Organocatalysis to the state of the art of the different strategies developed which employ hydrazones as C-nucleophiles in that field. In Chapter II and III, the specific objectives and a brief summary of the results accomplished are displayed, respectively. A deep discussion of the results obtained is presented along Chapter IV in four different sections: In Section IV.1, the nucleophilic 1,2-addition of formaldehyde N-tert-butylhydrazone to simple aldehydes is described. This strategy could be performed with both excellent reactivity and enantioselectivity by virtue of the dual H-bonding activation exerted by amide-squaramide derived organocatalysts (up to 96% ee). The resulting hydroxydiazenes were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent high-yielding and racemization-free derivatizations led to valuable β-amino alcohols and derivatives thereof (E. Matador, M. G. Retamosa, D. Monge, J. Iglesias-Sigüenza, R. Fernández, J. M. Lassaletta, Chem. Eur. J. 2018, 24, 6854-6860). Along Section IV.2, the formal diaza-ene reactivity of formaldehyde N-tert-butylhydrazone was extended to the use of more challenging fluorinated ketones for the synthesis of densely functionalized fluorine-containing tertiary alcohols. H-Bonding thiourea/squaramide organocatalysts enabled an enantioselective approach for a variety of di- and tri-fluoromethyl ketones and afforded diazenes (N-oxides) in good-to-excellent yields and moderate-to-good enantioselectivities (up to 90% ee). The synthesis of valuable building blocks was also highlighted by virtue of the marked versatility of the diazenyl group (E. Matador, M. G. Retamosa, A. Jiménez-Sánchez, D. Monge, R. Fernández, J. M. Lassaletta, Eur. J. Org. Chem. 2019, 130-138). Ensuing the high intrinsic reactivity observed for the reactions between formaldehyde N-tert-butylhydrazone and trifluoromethyl ketones, a green key step of a nucleophilic formylation strategy is depicted in Section IV.3. The unprecedented reaction of this hydrazone with trifluoromethyl ketones under solvent-free conditions afforded analytically pure diazenes in short reaction times without the need of any purification process (>99% yield in all cases). Subsequent unmasking of the formyl group in one pot fashion afforded valuable α-hydroxy α-trifluoromethyl aldehydes as key intermediates for the construction of relevant building blocks for target-oriented synthesis (E. Matador, D. Monge, R. Fernández, J. M. Lassaletta, Green Chem. 2016, 18, 4042-4050). In Section IV.4, a highly stereoselective, and scalable thiourea-organocatalyzed dearomatization of isoquinolines with N-tert-butylhydrazones is described. This multicomponent reaction afforded diazenes in excellent enantio- and diastereomeric ratios (up to >99% ee, dr >20/1 in all cases). The proposed activation model relies on a simultaneous binding of the thiourea and the hydrazone nucleophile to the chloride anion with preferential positioning of the isoquinolinium cation, thereby inducing excellent stereocontrol in the formation of two contiguous stereogenic centers. Subsequent simple derivatizations of primary adducts under mild conditions gave enantioenriched valuable building blocks with appealing structures for Organic Synthesis (E. Matador, J. Iglesias-Sigüenza, D. Monge, P. Merino, R. Fernández, J. M. Lassaletta, Angew. Chem. Int. Ed. 2020, early view 10.1002/anie.202012861). Finally, the conclusions of the present PhD Thesis are shown in Chapter V, and the original articles and their corresponding supplementary materials are provided in Appendix II. All the reactivities and strategies developed during this PhD thesis, supported by experimental and computational methods, have contributed to the advance of the previously contextualized field, and provided efficient alternatives to solve problems of great interest in fundamental chemical research

Pyridine-Hydrazone Ligands in Asymmetric Palladium-Catalyzed 1,4- and 1,6-Additions of Arylboronic Acids to Cyclic (Di)enones

Catalysts generated by combinations of Pd(TFA) and enantiomerically pure pyridine-hydrazone ligands have been applied to the 1,4-addition of arylboronic acids to β-substituted cyclic enones, building all-carbon quaternary stereocenters in high yields and enantioselectivities (up to 93% ee). The developed methodology allows the efficient introduction of ortho-substituted aryl groups in β-position of cyclopentanone cores, giving scaffolds present in a broad range of biologically active natural products. These Pd(II)-complexes served also as catalysts in the 1,6-addition of arylboronic acids to cyclic dienones, affording complete regioselectivities, moderate yields and good enantioselectivities (up to 80% ee). (Figure presented.)