SYNTHETIC, STRUCTURAL, REACTIVE AND BIOLOGICAL ASPECTS OF NOVEL TETRAAZABICYCLOOCTANES

The conversion of carbonyl compounds into hydrazones containing an ele ctronegative substituent X in alpha-position and subsequent base induc ed 1,4-elimination of HX furnishes azo-alkenes. This conjugate system undergoes 1,4-addition of nucleophiles affording alpha-substituted hyd razones. The addition of the ambident nucleophile phenylhydrazines giv es rise to alpha-1- or alpha-2-phenylhydrazino phenylhydrazones depend ing on the structure of the azo-alkene. The addition of thiocyanic aci d to phenylazo-alkenes results in the formation of cycloadducts, 2,3-d ihydro-1-phenylamino-1H-imidazole-2-thiones. The same products are for med in the reaction of alpha-thiocyanato carbonyl compounds with pheny lhydrazine involving the corresponding phenylazo-alkenes as intermedia tes. Thiocyanic acid adds to the azo-alkene, and the primary [3 + 2] c ycloadduct, a heterocyclic azomethine imine, is eventually stabilized by [1,4] H-shift and formation of the heteroaromatic product. This mec hanism is supported by the preparation of the heterobicyclic product, hydro-1H-imidazo[3,4-b]1,2,4-triazolo-2,5-dithione when an alpha,alpha -disubstituted alpha-thiocyanato ketone reacts with phenylhydrazine. I n this case, the azomethine imine intermediate cannot rearrange but re acts as a 1,3-dipolar species and adds another molecule of thiocyanic acid. Bicyclic compounds of this type, ,2,4,7-tetraazabicyclo[3.3.0]oc tane-3,8-dithiones, are readily accessible in a very efficient one-pot procedure from suitably substituted alpha-bromocarbonyl compounds and a monosubstituted hydrazine. This tandem [3 + 2] cycloaddition sequen ce is analogous to the long known Criss-Cross'' reaction of azines wit h heterocumulenes. The reactivity of the 1,2,4,7-tetraazabicyclo[3.3.0 ]octane-3,8-dithiones has been investigated: The thione functions can be converted into carbonyl groups. The base induced partial cycloelimi nation of thiocyanic or isothiocyanic acid provides 5-methylene-1-phen ylaminoimidazole derivatives featuring an ene-hydrazine function. Thes e compounds, in turn, exhibit a versatile reactivity: [3 + 2] Cycloadd ition with protic heterocumulenes rebuilds the triazole ring fused to the imidazole ring; the [2 + 2] cycloaddition of dimethyl azodicarboxy late forms a spirobicyclic product; the exocyclic C = C bond reacts bo th with nucleophiles and electrophiles. Both conversion of the thione function into the thiomethyl derivative and acetylation of the 1-pheny lamino group give rise to products exhibiting atropisomerism around th e N-N single bond. Several 1,2,4,7-tetraazabicyclo[3.3.0]octane-3,8-di thiones turned out to be biologically active and are presently under i nvestigation.