Keto piperazine

Abstract Piperazines and its congeners, (di)keto piperazines are valuable tools in drug discovery, providing a natural path for the process peptide > peptidomimetic > small molecule also called depeptisation. Moreover, they can provide molecular probes to understand molecular pathways for diseases of unmet medical need. However, in order to better understand the design of such value added compounds, the detailed understanding of scope and limitation of their synthesis as well as their 3D structures and associated physicochemical properties is indispensables. Isocyanide multicomponent reaction (MCR) chemistry provides a prime tool for entering the chemical space of (di)(keto)piperazines since not less then 20 different ways exist to access a diversity of related scaffolds. 

Keywords Multicomponent reaction Isocyanide Ugi van Leusen Medicinal chemistry Molecular probes Piperazine Keto-piperazine Diketo-piperazine... 

The initiating nucleophile in the vast majority of these studies is the hydroxide anion. However, in principle, any nucleophile can add to the keto or formyl group to give rise to an anionic intermediate, which then could act as an intramolecular nucleophile and effect hydrolysis of the ester. Their relative effectiveness will depend on two factors the relative extent of formation and the nucleophilicity of the adduct. The nucleophiles that have been investigated are hydroxide, cyanide, morpholine and piperazine. The only quantitative comparison available is that of hydroxide, morpholine and piperazine, which are effective in the order of ca. 102 10-3 1 (Bender et al., 1965 Dahlgren and Schell, 1967). For morpholine and piperazine this is as expected on the basis of their relative basicities. However, the expected order of increasing formation of the adducts would be cyanide > nitrogen bases > hydroxide (Hine, 1971). At this time, these results cannot be analysed further, but more work on the systems could enable the structural dependence and reactivity to be elucidated. 

Rhodium and palladium catalysts that contain 4 display high enantioselectivities for the asymmetric hydrogenation of enamides, itaconates, P-keto esters, asymmetric hydroboration, and asymmetric allylic alkylation,80 82 but this ligand system distinguishes itself from other chiral bisphos-phines in the asymmetric reduction of tetrahydropyrazines and tetrasubstituted olefins (see also Chapter 15). The reduction of tetrahydropyrazines produces the piperazine-2-carboxylate core,... 

KGK120 CAS 58013-13-1 HR 3 1-(2-KETO-2-(3 -PYRIDYL)ETHYL)-4-(2 -CHLOROPHENYL)PIPERAZINE... 

In many of these cases, both the enolate anion and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters. The (E) enolates gave the syn pair of enantiomers (p. 166), while (Z) enolates gave the anti pair. Nitro compounds add to conjugated ketones in the presence of a dipeptide and a piperazine. ° Malonate derivatives also add to conjugated ketones, and keto esters add to conjugated esters.Addition of chiral additives to the reaction, such as metal-salen complexes,proline derivatives, or (—)-sparteine, ... 

It is remarkable that the intermediates in the conversion of hydroxyanthranilic acid to nicotinic acid are still not known with certainty. Intermediates A and B of diagram 21 are plausible suggestions, but no synthesis of either has been reported. Both are extremely unlikely to be stable in the free state, but should be obtainable as simple derivatives. In the free state Intermediate A, for example, might be expected to tautomerize to the imino acid, and hence give keto acid and ammonia, or it could cyclize to a piperazine or to quinolinic acid. Tautomerism through the imino acid would eliminate the necessity for a fumaric —> maleic isomerization. It is quite possible that spontaneous cyclization explains the prominent part quinolinic acid plays in work on hydroxyanthranilic-nicotinic conversion. If the latter occurred in the following.way ... 

Thus a support-bound benzylpiperazine (282) was allowed to undergo a Man-nich reaction with formaldehyde and a-keto-aldehyde hydrazones. Upon addition of 1,2-dibromo-ethane (388) the support-bound piperazine tether is N, N -dialky-lated to give a quinuclidinium species (389). Subsequent Hoffmann elimination released a diazaalkadiene (390) from the polymeric support, allowing it to react with isonitriles to give pyrazoles (395). With electron-rich dienophiles, HDA reactions were also reported to have been performed to yield compound (393) (Scheme 80). 

Later, Shaw and co-workers further employed sugar derived aldehydes 312 as electrophiles in the chalcogeno-MBH reaction (Scheme 2.170). The resulting allyl chlorides 313 can be easily transformed into allylamines 314 via treatment with various amine (Et2NH, pyrrolidine, piperidine and piperazine derivatives) (Scheme 2.170). They also evaluated these allyl chlorides and allylamines for their biological activity and found that (Z)-keto allyl chlorides possess antimycobacterial activity. ... 

Fifty years of established views of the Ugi reaction have been challenged by results of a theoretical study which suggests, for example, that the intermediate imine is not in equilibrium with its isocyanide adduct." An asymmetric three-component Ugi reaction has applied chiral cyclic imines in synthesis of morpholino- or piperazine-keto-carboxamide derivatives." ... 

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