Ethyl Nitroacetate in Aza-Henry Addition on Trifluoromethyl Aldimines: A Solvent-Free Procedure To Obtain Chiral Trifluoromethyl α,ß-Diamino Esters.

A self-catalyzed aza-Henry addition of ethyl nitroacetate on N-alkyl trifluoromethyl aldimines was reported to synthesize ß-amino α-nitro trifluoromethyl esters, precursors of α,ß-diamino acid derivatives. In the presence of a resident chiral center on the imine nitrogen, the use of a suitable Lewis acid leads to a good stereofacial control, always resulting from a nucleophilic unlike attack. By starting from optically pure N-protected trifluoromethyl aldimines or directly from N-α-amino ester trifluoromethyl aldimines, small ψ[CH(CF3)NH]-peptidomimetic backbones can be achieved in which a new primary amine function represents a possible center for synthetic extension. Finally, a very interesting, and never observed before, palladium-catalyzed syn ß-elimination occurred, leading to the selective nitro group reduction reaction on the syn-α-amino ester functionalized aza-Henry adducts and obtaining more stable optically pure trifluoromethyl conjugated imines.

New Synthesis of Trifluoromethyl Aldimines Containing L-α-Amino Ester Moieties and Their Use in Mannich-Type Reactions.

L-α-amino esters were considered valuable chiral starting materials in the condensation reaction with trifluoroacetaldehyde (fluoral) ethyl hemiacetal to obtain new functionalized trifluoromethyl aldimines. Starting from these latter compounds, isovaleraldehyde was used in proline-catalyzed Mannich-type addition reactions to give trifluoromethyl syn- or anti-γ-amino alcohols bearing the L-α-amino ester function, simply by changing the reaction temperature.

Trifluoromethyl-modified dipeptides by ZrCl4-promoted aza-Henry reactions.

Chiral (R)-1-phenylethylamine was successfully employed in a tandem aza-Henry addition-reduction reaction to give chiral ß-nitro α-trifluoromethyl amines. A subsequent coupling reaction with N-Boc-protected amino acids leads to obtain optically pure CF3-modified dipeptides carrying two different N-protecting groups. These peptidomimetic units are characterized by the presence of the [CH(CF3)NH] group as mimetic of the natural [CONH] peptidic bond and can be used for the synthesis of more complex CF3-modified peptides after selective deprotection of one of the two amine functions. 2D NMR spectral analyses were employed to determine the absolute configurations of all newly synthesized chiral compounds.

Selective amination reactions of α-nitro aryl and heteroaryl enoates.

Highly functionalized tetrasubstituted alkenes were obtained by an unexpected amination reaction promoted by ethyl nosyloxycarbamate on various α-nitro aryl and heteroaryl enoates. A nitrene is likely the aminating species responsible for the observed insertion reaction leading to (E)-ß-amino α-nitro enoates as the major products, regardless of the substrate configuration. The compounds, bearing two nitrogenous functional groups in different oxidation states, can be regarded as interesting synthons. In contrast, aziridination was observed for α-nitro alkyl enoates or ß-nitro allylic alcohols.

Fluorinated ß-nitro amines by a selective ZrCl4-catalyzed aza-Henry reaction of (E)-trifluoromethyl aldimines.

ZrCl(4) was found to be an ideal catalyst to promote aza-Henry reactions between trifluoromethyl aldimines and some nitro alkanes giving new fluorinated ß-nitro amines. The reaction is strongly influenced by the CF(3) group, the yield by the alkyl chain of the nitro compound, while the stereochemical outcome seems to be unaffected, the anti isomer being always the major product.

Domino reactions for the synthesis of various α-substituted nitro alkenes.

Efficient one-pot methods for the synthesis of variously functionalised conjugated nitro alkenes have been reported. Despite the utility in different fields of these compounds, only a few multi-step syntheses have been reported in the literature, giving the target compounds in low overall yields. α-Nitro acrylates or cinnamates, α-nitro α,ß-unsaturated ketones and, most importantly, aromatic and heteroaromatic (E)- 2-nitro allylic alcohols, compounds characterised by a well-known anticancer activity, were obtained in high yields and high diastereomeric purity by a domino condensation-dehydration process.

Facile and highly stereoselective one-pot synthesis of either (E)- or (Z)-nitro alkenes.

Aliphatic aldehydes were reacted with nitro alkanes in the presence of catalytic amounts of piperidine over 4 A molecular sieves. Simply by changing reaction conditions (solvent and temperature) it is possible to control the stereochemical outcome of the reactions, obtaining pure (E)- and (Z)-nitro alkenes in high to excellent yields. The role of molecular sieves on the stereochemical control seems crucial in addition to that of piperidine, especially for the synthesis of the Z isomer.