2,6-Piperazinediones amines

Preparation of diketopiperazine as part of a bicyclic system was developed by a one-pot Ugi-4-center-3-component reaction (U-4C-3CR) [50]. A 3-keto or aldo acid 155 was used as bifunctional educt for an intramolecular Ugi reaction forming a five-membered ring. The application of C-protected amino acids 156 as amine components enables an intramolecular cyclization forming 2,6-piperazinediones 158 (Scheme 26). 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

Other recent repiorts of the automated synthesis of SP libraries of discretes include those of Wilson et al. (166), who prepared a library of more than 1000 aminohydantoins from a-hydrazino amino acids, amines, and aldehydes Perumattam et al. (167), who reported a 200-member library based on an anhydride template using anhydrides, primary amines, and a-amino acids Smith et al. (168), who described the synthesis of a library of more than 1000 piperazinediones from a-amino acids Crawshaw et al. (169), who presented a >200-member Ubrary of cyclohexanones from maleimides, nitrostyrenes, and aminobutadienes Shao et al. (170), who described a 96-member library of quina-zolinediones from anhydrides and amines Lebl et al. (21), presenting a 30,816-member... 

Piperazinedione, usually called 2,5-diketopiperazine, can be prepared by heating either glycine (e.g., in glycerol) or glycine ethyl ester hydrochloride.41 An equilibrium between A-methylenemethyl-amine (MeN=CH2) and its cyclic trimer (25a) is known to favor the latter... 

The method of piperazinedione synthesis [119] illustrated above (Scheme 22) is an example of scaffold proliferation by branching out from common intermediate structures ( divergent library design ). Resin-bound bromides such as 97 are suitable for bromine displacement with primary amines to obtain acyclic precursors of piperazinediones, but direct treatment with TFA also induces cycliza-tion, providing an efficient route to analogous morpholine derivatives. The intramolecular displacement of bromine by the carboxylate seems to occur in the cleavage solution, once the acyclic intermediate has been released from the solid support. 

In the 1960s, a somewhat stable five-membered cyclic a-adduct could also be formed by an isocyano-alkylcarboxylic and a Schiff base. At > 80 °C this a-adduct can be rearranged into a 2,5-piperazinedione derivative. At lower temperatures, a peptide derivative can be formed from this a-adduct, in addition to a secondary amine [8,102]. 

Next, BrCN reacts with pyridine to yield glutaconic aldehyde. This aldehyde is condensed with an aromatic amine such as p-phenylenediamine [9,10], benzidine [11,12], barbituric acid, 2,4-quinolinediol, 2,5-piperazinedione and hydantoin [9-13] to form a red polymethine dye. The molar absorptivities at An x = 530 nm are 6.0 x 10 and 3.1 x 10 for benzidine and p-phenylenediamine, respectively. The probable mechanism of the reaction with p-phenylenediamine is explained by Botto et al. [10] ... 

The synthesis of 3,5-diaroylpiperidines by the double Michael-addition of an amine to 2,4-bismethylene-l,5-diketones has been described by a Russian group (Scheme 99). The Raney Nickel-catalysed reduction of the tricyclic cyanoester (213) gave the lactam (214) which is a useful diterpene alkaloid intermediate. 4-Substituted-2,6-piperazinediones (215) have been easily prepared by the cycliz-ation of the appropriate dicarboxylic acids with formamide or ammonium carbonate. ... 

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