Displacement nitramine

A rather simple derivative of imidazoimidazoline has been described as an antidepressant agent. Preparation of this compound starts with the displacement of the nitramine grouping in imidazoline derivative by phenyl ethanol amine The product of this reaction is then treated with thio-nyl chloride. The probable chloro intermediate ( ) cyclizes under the reaction conditions to afford imafen (5. ... 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

Diazophenol formation is most competitive when a nitramine substrate contains an electron-withdrawing nitro group ortho to the nitro group being displaced and hence meta to the nitramine functionality, assumedly because that site is then activated towards nucleophilic aromatic substitution. Heating nitramines in inert chlorinated solvents also favours diazophenol formation but this is suppressed by using urea or sulfamic acid as additives. 

Displacements with azido anion are tolerant of many pre-existing explosophoric groups but the nitrate ester group readily undergoes displacement as seen for the synthesis of bis(2-azidoethyl)nitramine (13) from Ai-nitrodiethanolamine dinitrate (12) (DINA). " ... 

A related scheme starts with the conversion of the exocyclic amino group in 2-methylaminoimidazohne to a good leaving group by conversion to its nitramine derivative (5-2). Reaction of that intermediate with phenylethanolamine (5-1) leads to the displacement of the nitramine by the primary amine on the reagent and the formation of the substitution product (5-3). This is then cyclized with concentrated sulfuric acid to give an imidazoimidazole, probably via the benzylic carbocation. There is thus obtained imafen (5-4) [5], a compound described as an antidepressant. 

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