Piperazine derivatives, cyclization with

Derivatives of the 2,5-diazabicyclo[2.2.1]heptaine ring system (bridged piperazines) have been prepared from 4-hydroxyprolines. In a multistep transformation from tra j-4-hydroxy-L-proline (the last step was cyclization with benzylamine) a mixture of diastereoisomers 71 was obtained and separated [92H(34)241]. In a similar manner, the methyl and oxo analogs were obtained [67AJC1493 92H(34)679]. The commercially available N-... 

Finally, ortho aminoesters have been used to produce 7-deazaxanthines. For example ethyl 2-amino-5-phenyl-l//-pyrrole-3-carboxylate is first treated with 2-chloroethyl isocyanate in refluxing toluene. The resulting urea derivative is then allowed to react with l-(2-methoxyphenyl)piperazine and cyclized to the expected pyrrolo[2,3-,7 pyrimidin-2,4(177,377)-dione <2006BMCL150>. 

The known capacity of the sulfonamide nitrogen in 1,2-benzothiazines to undergo alkylation4 has been extended 96 with methyl bromoacetate produced ester 97 which was further cyclized to the piperazine derivative 98 by sulfuric acid (Eq. 23).8... 

Treatment of the piperazine ester 72 with phenyl isocyanate, followed by refluxing with hydrochloric acid, gave the perhydrodioxo derivative 73. Other perhydro derivatives (74) have been obtained by cyclization of anilinomethylpiperazines with aldehydes. " ... 

The related 6 Nf-exo-trig cyclization of carbamate (233), catalysed by the AuCl complex with diphosphine (235), has been reported to produce the piperazine derivative (234) in <94% ee ... 

It is well known that derivatives of a-amino acids, especially the esters, can undergo cyclodimerization to form piperazine-2,5-diones. The stereochemistry of such self-condensation of initial stages but increasing amounts of the trans product were formed later. The results have been interpreted as reflecting the difference in the rates of cyclization of the two diastereomeric dipeptide esters. 

A similar 3-(2-bromoethyl) derivative has been utilized to synthesize 1-aminocyclopropane-1 -carboxylic acid by an intramolecular base-catalyzed cyclization. This was possible when position 6 was blocked by the presence of two substituents. Some unexpected stereochemical results also came up in this study (85MI2). The starting material was the piperazine-2,5-dione derived from (/ )-(+ )-2-methyl-3-phenylalanine and glycine. The bislactim ether derived from this, on treatment with butyl lithium in THF at -78°C, gave the lithio derivative. Alkylation of this with 2-haloethyl... 

Troxler and Weber160 found that alkali cleaved the dihydropyrimidine ring in 169 to a diacid that cyclized to the imidazobenzimida-zole 170a with thionyl chloride. Subsequent treatment with methyl-piperazine yielded a stable derivative 170b. 

The synthesis of thieno[3,4-6][ 1,5]benzothiazepin-10(9/7)-ones (60) was carried out by cyclizing mercaptans 59 in the presence of polyphosphoric acid the reaction afforded compounds 60 and benzothiazoles 61 in approximately equal amounts. Lactams 60 were transformed into 10-piperazinyl derivatives 63 directly on treatment in refluxing toluene with piperazines or through the formation of iminochloride intermediates 62, which then reacted with an excess of piperazines under the same experimental... 

Evidence for kinetic control as opposed to thermodynamic control results from the comparison of the mercury-induced cyclization of. V./V-diallyla ni lines and JV-allylcarbamate. When A1, A -dial lylanilines were treated with mercury(II) acetate in tetrahydrofuran (kinetic control), trnns-WV-diary I-2,5-dimethyl piperazines 2 were stereoselectively prepared in good yield. Formation of the less stable Pv2rt.y-2,6-dimcthyl derivative is a result of kinetic control of the cyclization124. 

Other hexahydro derivatives (485) have been obtained by cyclization of anilinomethyl-piperazines (484) with aldehydes (66JMC868, 70JMC77). 

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 ... 

Cyclization may also occur as a result of an intramolecular rearrangement, sometimes unintentionally, as in the cyclization of vitamin Dj in the heated injection port of a gas chromatograph [1], which was evident from the appearance of unexpected extra peaks. Condensation or polymerization reactions may also lead to cyclic derivatives, for example the formation of diketo-piperazines from dipeptide esters or the production of paraldehyde from three molecules of formaldehyde. However, this chapter is mainly concerned with the deliberate formation of a cyclic derivative, most often by a bridging type of reagent ( bidentate ligand ), and the emphasis will be on analysis and quantitation by... 

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