Piperazine, catalytic reaction

The direct conversimi of esters into amides is a synthetically useful transformation. However, most of the methodologies developed till now usually require harsh reaction conditions, are poorly compatible with sensitive substrates, and present a low atom economy [136, and references cited therein]. Very recently, MUstein and co-workers demonstrated that esters can be selectively converted into amides generating molecular hydrogen as the only by-product (Scheme 31) [137]. The catalytic reactions were carried out with 2 equiv. of amine per ester in toluene or benzene at reflux in the presence of 0.1 mol% of the dearomatized PNN-pincer ruthenium complex [RuH(CO)(PNN)] (28) (see Scheme 21). Strikingly, both the acyl and the aUcoxo units of the starting ester are involved in the amide production. Hence, to avoid mixtures of products, the process was only applied to symmetrical esters. The catalytic protocol was effective for both primary and secondary cyclic amines. In addition, the coupling of piperazine and butylbutyrate provided compound 46, which results from the bis-acylation of the diamine (Scheme 31). 

A number of reductive procedures have found general applicability. a-Azidoketones may be reduced catalytically to the dihydropyrazines (80OPP265) and a direct conversion of a-azidoketones to pyrazines by treatment with triphenylphosphine in benzene (Scheme 55) has been reported to proceed in moderate to good yields (69LA(727)23l). Similarly, a-nitroketones may be reduced to the a-aminoketones which dimerize spontaneously (69USP3453279). The products from this reaction are pyrazines and piperazines and an intermolecular redox reaction between the initially formed dihydropyrazines may explain their formation. Normally, if the reaction is carried out in aqueous acetic acid the pyrazine predominates, but in less polar solvents over-reduction results in extensive piperazine formation. 

Alteration of the structural pattern produces a pair of adrenergic a-blocking agents which serve as anti hypertensives. These structures are reminiscent of prazoci n. Reaction of piperazine with 2-furoy1 chloride followed by catalytic reduction of the furan ring leads to synthon 69. This, when heated... 

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). 

Rossen et al. [71a] has reported a synthesis of piperazine 113, a key intermediate in the synthesis of the HIV protease inhibitor Crixivan . The reaction between a preformed imine 110, f-butyl isocyanide, and formic acid afforded the Ugi product 111, which was dehydrohalogenated with triethylamine and cyclized with KO Bu to the tetrahydropyrazine 112. Catalytic hydrogenation in the presence of Rh-BINAP (97% ee) and deformylation with aqueous hydrazine gave the target piperazine 113 (Scheme 2.40). 

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). 

Reaction of N-(2-pyridinyl)piperazines with CO and ethylene in the presence of a catalytic amount of Rh4(CO)12 in toluene at 160°C results in a complicated carbonylation reaction, which involves dehydrogenation and carbonylation at a C-H bond (Eq. 29) [43]. In this reaction, the carbonylation proceeds at the C-H bond a to the nitrogen atom substituted by pyridine. It is found that the reaction involves two discrete reactions (a) dehydrogenation of the piperazine ring and (b) carbonylation at a C-H bond in the resulting olefin. An amide functionality can also serve as the directing group for carbonylation at the a C-H bond (Eq. 30) [44]. 

Catalytic synthesis of l-ethyl>6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-quinoline-3-carboxylic acid ethyl ester (Norfloxacin ethyl ester) (15a). To a dry 15 mL recovery flask equipped with a reflux condenser was added 13 (150 mg, 0.5 mmole), (R)-binap (10 mg, 0.017 mmole), cesium carbonate (360 mg, 0.950 mmole), piperazine (215 mg, 2.5 mmole), Pd2(dba)3 (10 mg, 0.010 mmole), and 1.5 mL of DMF. The reaction vessel was purged with nitrogen and heated to reflux. After three hours, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography on a 500 micron silica gel preparative plate with an elution mixture of chloroform methanol water ammonia (80 20 2 0.2) to give 101 mg of 15a as an off-white solid in 58% yield and, separately, 29 mg of 17 as a light brown solid in 22% yield. Using this procedure, the yield of 15a... 

Catalytic asymmetric synthesis of piperazines (102) can be achieved by palladium-catalysed tandem allylic substitution reactions [93JOC(S8)6826]. 

Treatment of dithiol (135), prepared by the reaction of p-methylacetophenone with carbon disulfide in the presence of sodium t-butoxide, with piperidine, piperazine or morpholine and excess formaldehyde in the presence of a catalytic amount of hydrochloric acid resulted in a Mannich-type reaction to give the 1,3,5-dithiazepines (136) in high yields (Equation (6)) <88Mi 916-01 >. 

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