Piperazin-2-ones

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

Pyrazino[l, 2-a Jpyrimidines can also be prepared from piperazin-2-ones. Catalytic hydrogenation of 4-benzyl-l-(2-cyanoethyl)piperazin-2-one (279) over Raney nickel gives the cyclized product (280) in near quantitative yield. The cyanoethyl piperazine can be prepared from the corresponding piperazine (278) by reaction with acrylonitrile (73BCJ3612). 

The regiospecific nucleophilic displacement of 1,2-cyclic sulfamidates 130 with methyl thioglycolate or a-amino esters 130 can be accompanied by lactamization (thermal, base mediated, or cyanide catalyzed) to give thiomorpho-lin-3-ones and piperazin-2-ones 131 (Scheme 19) <20030L811>. If malonate esters, phosphonate-stabilized esters, or aryl-substituted enolates were used as nucleophiles in this reaction, trisubstituted pyrrolidines were obtained in high yield <2004OL4727>. 

Difenchyl imidazolinium salt 587 when treated with a strong base (to form the putative carbene) followed by the addition of copper(II) triflate, gave the unexpected piperazin-2-one 589 and urea 588 (Scheme 140) <20060L3049>. The formation of 589 was confirmed by X-ray structural analyses and probably results via dimerization following deprotonation of 587. The putative carbene intermediate has not been isolated. 

Ramage and Landquist 1959 1,2-, 2,3-, 2,5-, and 1,4-Dihydropyrazines, tetrahydropyrazines, piperazin-2-ones, piperazine-2,3- and 2,5-diones, piperazinetri- and tetraones, piperazines 37... 

The preparation of piperazin-2-ones by reduction of 2-oxo-l,2-dihydropyrazines has been described in Section V.5A(1) (853). 

Disubstituted piperazin-2-ones (83) were first synthesized by the reaction of a-chloro oximes (81) with esters of amino acids, followed by reductive cyclization... 

Condensations of chloroacetyl chloride (and similar compounds) with substituted ethylenediamines to give 1,4-disubstituted piperazin-2-ones have been described, and a number of 4-alkyl(or aralkyl)- -arylpiperazin-2-ones has been prepared either by catalytic debenzylation or pyrolytic debenzylation (or demethylation) of I,l-dialkyl(or l,l-diaralkyl)-3-oxo-4-arylpiperazinium halides (1609). 3-Ethoxy-carbonylmethylene-6-methylpiperazin-2-one has been synthesized by the reaction of diethyl acetylenedicarboxylate with propylenediamine (1610), and treatment of diethyl fumarate with propylenediamine has been shown to give 3-ethoxycarbonyl-methyl-6-methylpiperazin-2-one, also prepared from the diethyl ester of N- 2 -hydroxyiminopropyl)aspartic acid (84) (1611). 

Piperazin-2-one with benzyl chloride and sodium carbonate gave 4-benzyl-piperazin-2-one, which with acrylonitrile gave 4-benzyl-l-cyanoethylpiperazin-2-one or with butyl bromide and sodium in toluene formed 4-benzyl-1-butylpiperazin-2-one (1615) but (Z)-3-benzylidene-l-methylpiperazine-2,5-dione methylated with methyl iodide and silver carbonate produced (Z)-3-benzylidene-5-methoxy-1 -methyl-2-oxo-l,2,3,6-tetrahydropyrazine (88) and a small amount of (Z)-3-benzylidene-l,4-dimethylpiperazine-2,5-dione (89) (1616). 

Catalytic reduction of 2-hydroxyiminopiperazine over Raney nickel afforded 2-iminopiperazine (90) (1614). This was converted by methanolic hydroxylamine at room temperature to 2-hydroxyiminopiperazine, and by hydrogen sulfide to piperazine-2-thione (1614). Reduction of 4-benzoylpiperazin-2-one with sodium borohydride in pyridine formed 1-benzylpiperazine and 4-benzylpiperazin-2-one, but reduction with sodium borohydride in triethylamine gave only some 1-benzoyl-piperazine (1617). Piperazin-2-one with amyl nitrite in butanol produced 4-nitroso-piperazin-2-one (1614), and 3-(l, l-ethylenedioxy)ethyl-l,4-dimethylpiperazin-2-one (87) with ethanolic hydrogen chloride gave 3-acetyl-1,4-dimethylpiperazin-2-one (91) (1594). 

Piperazine-2,3,5-trione has been prepared from aminoacetamide and diethyl oxalate in methanolic sodium methoxide (365b). Oxanilic acid (PhNHCOCOOH) refluxed with thionyl chloride gave 1,4-diphenylpiperazinetetraone (identical with authentic material obtained by chromic acid oxidation of 1,4-diphenylpiperazine-2,5-dione) (1640). Hydrolysis of 3,3,5,5,6,6-hexachloro-4-cyclohexyl-I-phenyl-piperazin-2-one by heating at 100° with aqueous acetic acid gave l-cyclohexyl-4-phenylpiperazinetetraone (probably) (853). 

A novel route for the synthesis of piperazin-2-ones on a solid support relies on an intramolecular Mitsunobu reaction [111]. First, commercially available amino alcohols are attached to an aldehyde resin by reductive ami-nation. The alcohol function is protected and the secondary amine obtained is acylated with an amino add. Sulfonamide activation of the free amino group allows intramolecular alkylation through a Mitsunobu reaction, and thereby the formation of a derivatized ring. 

Reacting nitrogen-stabilized a-carbenium dithioates 110 and 111 (inner salts) with electrophiles yields the a-carbenium dithioesters 112 and 113, respectively, in high yields, as shown in Scheme 23 [64] and Scheme 24 [65]. Hydrolysis of 112 and 113 gives a-oxo dithioates 114 and 115, respectively. In the case of imidazolidinium dithioate 117, prepared from the inner salt 116, the hydrolysis is followed by intramolecular cyclization to give a 28% yield of 3-thioxo piperazin-2-one 118 (Scheme 25) [64]. The alkylation of p-carbenium dithioate 119 proceeds similarly (Scheme 26) [66]. 

Obtained by hydrolytic cleavage of 2-amino-3-(2-hydroxy-3,4,5,6-tetrafluorobenzoyl)acrylic acid (I) or of 3-(2-hydroxy-3,4,5,6-tetrafluorobenzoylmethylene)-piperazin-2-one (II) in boiling aqueous sodium hydroxide for 20 min (53% and 44% yields, respectively) [1778]. 

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