Synthesis of highly substituted enantiopure piperazines and ketopiperazines from vicinal N-sulfinyl diamines

Enantiopure 1-benzyl-2,3-disubstituted piperazines (4) have been synthesized by treatment of N-sulfinyl-N-benzyldiamino alcohols (1) with diethyl oxalate and sodium methoxide followed by reduction with borane. Alternatively, the sulfinamido group was preserved by an N-acylation/cyclization protocol using alpha-chloroacetyl chloride that led to the synthesis of N-sulfinyl ketopiperazines (11). Ensuing elimination of the sulfinyl group with NaH produced imino ketopiperazines (9) that are suitably functionalized for nucleophilic addition to the imino moiety. Stereoselective and high yielding allylation of imino ketopiperazines (9c) was achieved under Barbier conditions using CeCl3.7H2O as the additive.     

Synthesis of monofluorinated 1-(naphthalen-1-yl)piperazines

A series of regioisomerically monofluorinated 1-(naphthalen-1-yl)piperazines is described.     

Synthesis of 2,6-disubstituted piperazines by a diastereoselective palladium-catalyzed hydroamination reaction

A highly diastereoselective intramolecular hydroamination is the key step in a modular synthesis of 2,6-disubstituted piperazines. The requisite hydroamination substrates were prepared in excellent yields by nucleophilic displacement of cyclic sulfamidates derived from amino acids. A variety of alkyl and aryl substituents at the 2-position were tolerated. The stereochemistry of the piperazines was determined to be trans by X-ray crystallography, which also showed the preferred conformation of the 2,6-disubstituted piperazine to be a twist-boat due to A(1,3) strain.     

Synthesis of 2-substituted piperazines via direct α-lithiation

A novel efficient synthetic route towards the pharmaceutically relevant 2-substituted piperazine class is described. The key step involves α-lithiation of N-Boc piperazines, followed by reaction with several electrophiles. To obtain high yields, in some cases transmetallation to copper after the lithiation step is required.     

Synthesis of new polysubstituted piperazines and dihydro-2H-pyrazines by selective reduction of 2-oxo-piperazines

New enantiomerically enriched 1,4,5-piperazines and 1,4,5-dihydro-2H-pyrazines have been prepared by reduction of the corresponding 2-oxo-piperazines. Selective reduction can be achieved by careful control of the reaction conditions using LiAlH₄. Notably the two nitrogen atoms of the final compounds are orthogonally protected.     

Reactions of vinylphosphonates with piperazines

Russian Journal of General Chemistry - Dialkyl [2-(piperazin-1-yl)ethyl]phosphonates were obtained by the reactions of piperazine with dialkyl vinylphosphonates. The addition of...     

Stereoselective synthesis of substituted piperazines

The treatment of allylarylamines with mercury(II) acetate in tetrahydrofuran followed by a double decomposition reaction with potassium bromide leads to trans-2,5-bis(bromomercuriomethyl)-1,4-diarylpiperazines (2). The stereochemistry of the reaction products has been elucidated by an ¹H-nmr spectroscopic study of the trans-2,5-dimethyl-1,4-diarylpiperazines (3) obtained by sodium borohydride reduction of 2 in alkaline media. The course of the reaction strongly depends on the steric demand of the groups attached to either the allylic group or the ortho-position in the aromatic ring of the starting amine (1).     

Synthesis of N,N′-bis(alkyloxymethyl)piperazines and examination of their antimicrobial properties

Russian Journal of Applied Chemistry - Three-component condensation of piperazine with formaldehyde and aliphatic alcohols was employed for elucidating the possibility to synthesize...     

Synthesis of [1,2,4]triazolo[4,3-alpha]piperazines via highly reactive chloromethyloxadiazoles

[reaction: see text] A concise, modular approach for the synthesis of [1,2,4]triazolo[4,3-alpha]piperazines via condensation of highly reactive chloromethyloxadiazoles with ethylenediamines is described. NMR studies of this reaction provide evidence that suggests a novel activation mechanism for electron-deficient chloromethyloxadiazoles.     

Synthesis of Chromeno[3,4-b]piperazines by an Enol-Ugi/Reduction/Cyclization Sequence

Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.     

C-phosphorylated furazano-[3,4-b]piperazines

The reaction of phosphorylated α-chloroacetaldehydes with 3,4-diaminofurazane gives enamines, bisenamines, semiaminals, and O,N-acetals, whose cyclization leads to previously unreported phosphorylated furazano[3,4-b]piperazines. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1220–1229, August, 2006.     

A general, enantioselective synthesis of protected morpholines and piperazines

A short, high yielding protocol has been developed for the enantioselective and general synthesis of C2-functionalized, benzyl protected morpholines and orthogonally N,N'-protected piperazines from a common intermediate.     

Diastereoselective synthesis of piperazines by manganese-mediated reductive cyclization

A simple and effective synthesis of trans aryl-substituted piperazines using a Br?nsted acid and manganese(0) is described. [reaction: see text]     

Iridium catalysed synthesis of piperazines from diols

A green and atom-economical method has been developed for the synthesis of piperazines by cyclocondensation of diols and amines in aqueous media in the presence of a catalytic amount of [Cp*IrCl2]2.     

A facile synthesis of piperazines from primary amines

A general procedure is described for converting primary amines to N-substituted piperazines. Reaction of an amine with an N-substituted iminodiacetic acid anhydride (V) yields an iminodiacetic acid monoamide (VI) which closes to a 2,6-piperazinedione (VII) upon treatment with acetic anhydride. The diones are reduced to piperazines with borane-THF. Fourteen examples of this process, using twelve aliphatic or aromatic amines and three iminodiacetic acids, are presented. Yields of piperazines, based upon starting amine, ranged from 21 to 52%. The procedure is rapid and no purification problems were encountered. Alternate methods for preparing the 2,6-piperazinedione intermediates are discussed.     

A general and convenient synthesis of N-aryl piperazines

A general and convenient synthesis of N-aryl piperazines from bis(2-chloroethyl)amine hydrochloride and a broad range of anilines in diethylene glycol monomethyl ether is described.     

1,2-cyclic sulfamidates as versatile precursors to thiomorpholines and piperazines

[reaction: see text] 1,2-Cyclic sulfamidates undergo regiospecific nucleophilic displacement with either methyl thioglycolate or alpha-amino esters, followed by lactamization (thermal, base-mediated, or cyanide-catalyzed), to give thiomorpholin-3-ones and piperazin-2-ones.