Rubén Manzano

Novel Bifunctional Chiral Urea and Thiourea Derivatives as Organocatalysts: Enantioselective Nitro-Michael Reaction of Malonates and Diketones

The ability of chiral hydrogen-bond donors to catalyze useful enantioselective transformations constitutes an increasing area of interest, and diverse types of structures have been described to this end. An important class of species are urea and thiourea compounds which have frequently been used in several transformations, such as Henry or aza-Henry, Mannich, Strecker, and Friedel–Crafts reactions or Michael and nitro-Michael additions. The modular design of these types of catalysts requires the possibility to introduce different urea and thiourea moieties and the modification of the structure with the chiral information. Most of the described catalysts until now are aryl or diaryl ureas or thioureas with electron withdrawing groups, although some relatively electron rich derivatives have proved to catalyze a variety of enantioselective transformations. The chiral information in the catalyst has been placed at both the nitrogen terminus in the urea or thiourea or in the central chiral core. In this respect, a few structures are used in the preparation of the catalysts, namely chiral diamines, both enantiomers of trans cyclohexane-1,2-diamine, binaphthylamines, diamines derived from cinchona alkaloids, amino alcohols, and very recently, sugars. In our opinion, the development of novel chiral scaffolds to be incorporated into urea and thiourea derivatives, capable to act as bifunctional organocatalyts, is necessary. Because, in general, 1,2-diamines are the structures that lead to the best results, we planned to prepare these compounds taking into account three facts: i) The starting material would have be commercially available and cheap; ii) both enantiomers of the amine must be accessible; and iii) the synthesis should be able to provide the ability to fine-tune the substituents at the nitrogen atoms. We envisioned that natural a-amino acids would be the starting material of choice and we describe here the synthesis of chiral diamines derived from them and their use as organocatalysts in nitro-Michael additions of stabilized carbanions. The generality of the synthesis was demonstrated in the preparation of catalysts 4a–i in three steps from commercially available N-Boc protected a-amino acids. The nature of the substituent at the stereocenter is dictated by the election of the starting amino acid, the substituents at the nitrogen atom can be varied in the formation of the aamino amide, and the structure of the urea–thiourea component is selected depending on the isocyanate–isothiocyanate used in the last step. In this way, N-Boc protected l-valine, l-isoleucine, l-phenylalanine, and l-tert-leucine were converted into 1a–h by reaction with the corresponding amines, which were transformed into 2a–h by deprotection with TFA in methylene chloride. Lithium aluminum hydride reduction to 3a–g and condensation with the corresponding isocyanate or isothiocyanate yielded the final urea or thiourea derivatives 4a–h in good yields. The same protocol allowed the preparation of ent-4a starting from d-valine, and 4 i, regioisomer of 4a, was obtained from l-valinamide hydrochloride by dimethylation, lithium aluminum hydride reduction and reaction with 3,5-bis(trifluoromethyl)phenyl isothiocyanate (Scheme 1). The catalytic activity of 4a–i was first evaluated in the reaction of trans b-nitrostyrene 5a with diethyl malonate 6a in the presence of 10 mol% of catalyst at room temperature, and the results are collected in Table 1. A set of five different solvents was tested as reaction media (entries 1–5 in Table 1) showing that the reactions occurred in good yields and moderate to good ee. Only in the case of methanol (entry 1) the enantioselectivity decreased to 40% ee, probably because the competitive establishment of hydrogen activation of the solvent with the catalyst, and the enantioselectivity increased when less polar solvents were used (compare entries 1–5), or if the reaction was carried out without [a] Dr. J. M. Andr>s, R. Manzano, Prof. Dr. R. Pedrosa Centro de InnovaciAn en QuCmica y Materiales Avanzados ACHTUNGTRENNUNG(CINQUIMA) and Departamento de QuCmica OrgEnica Facultad de Ciencias, Universidad de Valladolid Dr. Mergelina s/n, 47011 Valladolid (Spain) Fax: (+34)983423211 pedrosa@qo.uva.es Supporting information for this article is available on the WWW under http://www.chemistry.org or from the author.

Enantioselective Conjugate Addition of Nitro Compounds to α,β‐Unsaturated Ketones: An Experimental and Computational Study

A series of chiral thioureas derived from easily available diamines, prepared from α-amino acids, have been tested as catalysts in the enantioselective Michael additions of nitroalkanes to α,β-unsaturated ketones. The best results are obtained with the bifunctional catalyst prepared from L-valine. This thiourea promotes the reaction with high enantioselectivities and chemical yields for aryl/vinyl ketones, but the enantiomeric ratio for alkyl/vinyl derivatives is very modest. The addition of substituted nitromethanes led to the corresponding adducts with excellent enantioselectivity but very poor diastereoselectivity. Evidence for the isomerization of the addition products has been obtained from the reaction of chalcone with [D(3)]nitromethane, which shows that the final addition products epimerize under the reaction conditions. The epimerization explains the low diastereoselectivity observed in the formation of adducts with two adjacent tertiary stereocenters. Density functional studies of the transition structures corresponding to two alternative activation modes of the nitroalkanes and α,β-unsaturated ketones by the bifunctional organocatalyst have been carried out at the B3LYP/3-21G* level. The computations are consistent with a reaction model involving the Michael addition of the thiourea-activated nitronate to the ketone activated by the protonated amine of the organocatalyst. The enantioselectivities predicted by the computations are consistent with the experimental values obtained for aryl- and alkyl-substituted α,β-unsaturated ketones.

Room-Temperature Hydrohydrazination of Terminal Alkynes Catalyzed by Saturated Abnormal N-Heterocyclic Carbene–Gold(I) Complexes

A number of saturated abnormal N-heterocyclic carbene (NHC) complexes of gold, in combination with KBAr(F) 4 as activator, were successfully applied in the chemoselective addition of hydrazine to alkynes. The reaction proceeds even at room temperature, which was not possible to date with gold catalysts. The reaction can be applied to a number of substituted arylalkynes. With alkylalkynes the yields are low. The saturated abnormal NHC ligands are resistant to isomerization to the saturated normal NHC coordination mode under basic reaction conditions. Under acidic conditions, a simple protonation at the nitrogen atom not neighboring the carbene center was observed and unambiguously characterized by an X-ray crystal-structure analysis. Computational studies confirm that such an isomerization would be highly exothermic, the observed kinetic stability probably results from the need to shift two protons in such a process.

Synthesis of both Enantiomers of Hemiesters by Enantioselective Methanolysis of Meso Cyclic Anhydrides Catalyzed by α-Amino Acid-Derived Chiral Thioureas†

Both ureas and thioureas derived from L- or D-valine act as bifunctional organocatalysts able to induce the enantioselective alcoholysis of mono-, bi-, and tricyclic meso anhydrides. The desymmetrization occurs in near quantitative yields and excellent enantiomeric ratios (up to >99:<1) under low catalyst loading. Both enantiomers of the hemiesters can be directly obtained by changing the configuration of the catalyst.