Piperazine halogenation

Preparation of the substituted piperazine required for sul-falene (114) starts with bromination of 2-aminopiperazine to give the dihalide (150). Displacement of halogen by sodium methoxide proceeds regioselectively at the more reactive 3 position to give 151. Hydrogenolysis over palladium on charcoal gives the desired intermediate (152). 

A related and relatively simple quinoline derivative has been reported to exhibit antidepressant activity. Its preparation merely involves displacement of halogen in 12 with piperazine to afford quipazine (13).6... 

Incorporation of a piperazine function on the heterocyclic ring leads to a compound in which bronchodilator activity predominates. Treatment of the amino-amide (73-1) with trimethyl orthoformate provides the additional carbon atom for the formation of the quinazolone ring in (73-2). Reaction with phosphoms oxychloride in effect converts the ring to its aromatic form (73-3) by locking in the former amide as an enol chloride. Displacement of the halogen with the isobutyryl urethane (73-4) from piperazine affords piquizil (73-5) [82]. 

The starting material (48-1) for a pyrrazolopyridazine can be obtained by treating the corresponding enol, which is simply the condensation product of methylmaleic anhydride and hydrazine, with phosphorus oxychloride. Reaction with piperazine leads to the displacement of the sterically more accessible chlorine to afford the alkylation product (48-2). Treatment with hydrazine leads to the replacement of the remaining halogen and the formation of (48-3). The missing carbon is, in this case, supplied by formamide to afford zindotrine (48-4) [51], a compound that shows activity as a bronchodilator. 

Several synthetic routes to benzhydrylpiperazine opioids have been published or presented, including stereoselective routes. The most common route to building the benzhydrylpiperazine core involves displacement of a halogen from the benzhydryl central carbon by a piperazine (Scheme 1). 

The halogen atom of 2-(w-haloalkyl)-l,3,4,6,ll,lla-hexahydro-2//-pyrazino[l,2-fi]isoquinoline-l,3-diones was replaced by 4-substituted piperazines (88EUP2%048 90EUP378468). 

Dick (38, 39) has shown that a number of 1-alkylaziridines are converted into the corresponding 1,4-dialkylpiperazines in yields as high as 95%, when treated with hydrohalic acids in acetone or methyl ethyl ketone. Perchloric acid and p-toluene-sulfonic acid resulted in the formation of poly(l-alkylaziridines) rather than piperazines. The major products formed in a water solvent were the polymers with 1,4-dialkylpiperazines being formed in maximum yields of 27% in the case of hydroiodic acid. The mechanism proposed by Dick is, that the piperazine are formed via a dimer in which the halogen atom of the initiating acid has formed a covalent bond with a... 

Piperazines are introduced by tacking on to a halogen of the main molecule... 

Cyclohepta[4,5)pyrrolo[l,2-fl]imidazoles, 2-aryl-, halogenation. 59, 283 Cyclohepta[4,5)pyrrolo[3,2-e][l,2,4]triazine, 3-chloro- 10-(4-chlorobutyD-5,6,7,8,9,10-hexahydro-, 59, 50 3//-Cyclohept(e]isoxazoles, 3a,4,5,6,7,8-hexahydro-, 60, 311-3 Cyclohex-2-en-l-ones, 2- and 3-bromo-, regioselectivity of nitrile oxide cycloaddition, 60, 304 Cyclols, piperazine-2,5-dione-related, 57, 211-7... 

N-Ary piperazines can be synthesized using this catalyst and unprotected piperazines.IS Key to this protocol is the use of excess piperazine to favor mono-ary lation versus the di-arylated product. Moderate yields of the mono-arylated product can be obtained with a variety of aryl bromides. The major side product is the de-halogenated arene caused by the p-elimination pathway. 

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