Synthesis of 1-azacycl[3.2.2]azine and 1-azabenzo[h]cycl[3.2.2]azine

1-Azacycl[3.2.2]azines were synthesized from 2-methylthioimidazo[1,2-a]pyridines, 2a and 2b , by using [2 + 8] cycloaddition reaction with dimethyl acetylenedicarboxylate as the key step. Synthesis of 1-azabenzo-[h]cycl[3.2.2]azine was also described.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Rearrangement of a mesylate tropane intermediate in nucleophilic substitution reactions. Synthesis of aza-bicyclo[3.2.1]octane and aza-bicyclo[3.2.2]nonane ethers,imides, and amines

Nucleophilic substitution of 2beta-mesyloxymethyl-N-methyl-3beta-p-tolyl-tropane intermediate with alkoxides, metal imides, or amines was found to lead not only to the expected bicyclo[3.2.1]octane (tropane) ether, imide, and amine derivatives but also to unexpected bicyclo[3.2.2]nonane derivatives. When alkoxides were used as nucleophile, only the rearranged bicyclo[3.2.2]nonane structure was obtained, whereas the use of amines or imides as nucleophile afforded a mixture of the two structures. The bicyclo[3.2.2]nonane structure was assigned by NMR analysis.     

Synthesis and nucleophilic displacement reactions of fluoropyrazine and 2-fluoroquinoxaline

An improved method for the preparation of fluoropyrazine (I) by halogen exchange and a synthesis of 2-fluoroquinoxaline (II) by a Balz-Schiemann reaction are presented. Compound I hydrolyzes slowly in 0.01N sodium hydroxide, rapidly in 1.07N sodium hydroxide at 26.00°. Compound II hydrolyzes 240 times faster than I in 0.01N sodium hydroxide at 26.00°. Hydrolysis of I in 6N hydrochloric acid at room temperature is slow. Compound I underwent nucleophilic reactions with formation of hydroxy, amino, methylamino, piperidino, benzylamino and anilinopyrazines. Pyrazinesulfonic acid was obtained from I and sodium sulfite and tetrazolo[1, 5-a]pyrazine (IV), a novel ring system, from I and sodium azide.     

Nature of the 2-bicyclo[3.2.1]octanyl and 2-bicyclo[3.2.2]nonanyl cations.

Density functional and ab initio calculations have been employed to explore the nature of the cations formed in the solvolysis of 2-bicyclo[3.2.1]octanyl tosylate the 2-bicyclo[3.2.2]nonanyl tosylate. In contrast to recent conclusions in the literature, the various proposed classical carbocations postulated to explain the products of the 2-bicyclo[3.2.2]nonanyl tosylate solvolysis were found to have nonclassical structures.     

The Influence of Benzo‐Fusion on the Aromatic Pathways and Ring Currents of Cycl[3.2.2]azine

The effect of benzene ring fusion on the aromaticity of cycl[3.2.2]azine was studied by calculating topological resonance energy (TRE), the percentage topological resonance energy (%TRE), and magnetic resonance energy (MRE). The bond resonance energy (BRE) and circuit resonance energy (CRE) indices were used to estimate the local aromaticity. Our BRE and CRE results show that the central nitrogen atom plays a significant role both in the global and local aromaticity of the compounds in our study, and contrary to what has been reported in the literature, none of these compounds are peripheral π‐electronic systems. In the case of benzene ring‐fused derivatives, benzene ring(s) exhibit relatively larger local aromaticity and reduce the local aromaticity of the central portion of cycl[3.2.2]azine to a level comparable to a corresponding non‐benzene fused parent system. Ring current results predict that a strong diamagnetic current flows around the whole molecular perimeter. The diatropic bond current results, as computed here, are in good agreement with the observed ¹H‐NMR chemical shifts of these compounds.     

Energy disposal in gas-phase nucleophilic displacement reactions

The partitioning of reaction exothermicity into relative translational energy of the products of gas-phase S_N2 (F^? + CH₃Cl) and nucleophilic aromatic substitution (F^? + C₆H₅Cl) reactions has been investigated using kinetic energy release Fourier transform ion cyclotron resonance spectroscopy. The chloride product ion is observed to be highly translationally excited for the S_N2 reaction, indicating a cold internal energy distribution for the products. For the chlorobenzene reaction the products are not generated with large translational energies. The results are compared with a statistical model. Ion-intensity profiles for the CH₃Cl reaction deviate significantly from the statistical model whereas the chlorobenzene results are consistent with this model. The kinetic energy release for the CH₃C1 reaction is compared with energy-disposal results for the photodissociation and dissociative electron-attachment processes of halomethanes. In all three cases a node in the molecular orbital between the carbon atom and the departing halogen results in a repulsive energy release. Ion-retention curves for the nucleophilic aromatic substitution reaction are consistent with the existence of a long-lived ion-dipole complex on the exit channel for this reaction.     

Preparation of cyclohepta and benzo[ef]cycl[3.2.2]azines

Some cyclohepta[ef]cycl[3.2.2]azines were prepared from cyclohepta[hi]indolizines and electron deficient acetylenes in the presence of appropriate oxidants. Also, benzo[ef]cycl[3.2.2]azines were obtained similarly in good yields.     

Some nucleophilic substitution reactions of s-triazolo[1,5-c]pyrimidines

Nucleophilic substitution of 5-methylthio- and 5-cyanomethylthio-7-amino-s-triazolo[1,5-c]pyrimidines has been carried out using sodium hydroxide, ammonia, hydrazine hydrate, and four amines. The cyanomethyl group is particularly reactive under these conditions and 5-cyanomethylthiotriazolopyrimidine can be used to functionalize this heterocycle.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 382–385, March, 1992.     

Acyl derivatives of 5-amino-2-azabicyclo[3.2.2]nonanes

5-Amino-2-azabicyclo[3.2.2]nonanes possess activity against the causative organisms of Human African trypanosomiasis and Malaria tropica. Their newly prepared N-acyl derivatives were inactive against Trypanosoma b. rhodesiense, but some of them showed good antiplasmodial activity against a multiresistant strain of Plasmodium falciparum. The results are compared to the activities of the N-unsubstituted compounds and N-sulfonyl analogues. The diastereomeric character of the formed amides was elucidated by NMR spectroscopy.     

Synthesis of 1-Bicyclo [3.2.2]nonene and 1 (7)-Bicyclo [3.2.2]nonene by Intramolecular Wittig Reaction

The synthesis of 1-bicyclo[3.2.2]nonene (2) and of 1 (7)-bicyclo [3.2.2]nonene (3) , two isomeric bridged (E)-cycloheptenes, by intramolecular Wittig reaction is described. These ‘Bredt olefins’ could not be isolated, but dimerized rapidly. In both cases, the main product was shown to be a head-to-tail dimer with a cyclobutane ring. The ‘Bredt olefins’ were also trapped in situ with furan or 2,5-diphenylbenzo [c]furan.     

Polyesters containing bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane rings

Polyesters containing bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane rings are prepared from 1,4-bis(carboethoxy)bicyclo[2.2.2]octane, 1,4-bis(hydroxymethyl)bicyclo[2.2.2]-octane and the 1,5-disubstituted bicyclo[3.2.2]nonane analogs. These polyesters are compared to the related polymers containing 1,4-phenylene and trans-1,4-cyclohexylene rings in terms of their melting point, thermal stabilities and oxidative stabilities. The lower symmetry of the bicyclo[3.2.2]nonane ring produces lower-melting polymers than the other ring systems. The remaining three rings are approximately equivalent in their effect on the melting point of a polymer provided that no more than one bicyclo[2.2.2]octane ring is present per polymer repeat unit. Two such rings produce a highermelting polymer than any other combination. Both the thermal and oxidative stabilities of the polyesters is improved by the presence of the bicyclo rings. This is attributed to the rings providing an approximation of a ladder polymer.     

Synthesis of the 5-thia-1,3,6-triazacycl[3.2.3]azine and 4-thia-1,3,6-triazacycl[3.2.3]azine systems

The syntheses, structural proofs, and chemical and spectral properties of four members of the 5-thia-1,3,6-triazacycl[3.2.3]azine system and of two members of the 4-thia-1,3,6-triazacycl[3.2.3]azine system are described. Electrophilic substitution is predicted and found to occur in the 8-position in both systems.     

Diazabicycloalkanes with nitrogen atoms in bridgehead positions. 24. Synthesis and reactions of benzo[f]-1,5-diazabicyclo[3.2.2]nonen-3-one

Benzo[f]-1,5-diazabicyclo[3.2.2]nonen-3-one was synthesized by the oxidation of benzo[f]-1,5-diazabicydo[3.2.2]nonen-3-ol by dimethyl sulfoxide in the presence of N,N-dicycohexylcarbodiimide and the reactions of this compound with 2,4-dinitrophenylhydrazine, phenylmagnesium bromide, and condensation with 4-nitro-benzaldehyde were carried out. It was shown that on heating with hydrobromic acid, benzo[f]-1,5-diazabicyclo[3.2.2]nonen-3-one undergoes dealkylation with the formation of 1,2,3,4-tetrahydroquinoxaline.For Communication 23, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1117–1120, August, 1991.     

New 4-Amino-2-azabicyclo[3.2.2]nonane Derivatives and their Antiprotozoal Potencies

Summary. Several 2-substituted 4-amino-2-azabicyclo [3.2.2]nonane derivatives were synthesized. The new compounds were investigated for their activities against the causative organism of East African sleeping sickness, Trypanosoma b. rhodesiense, and a protozoan parasite which causes Malaria tropica, Plasmodium falciparum K₁, a strain which is resistant to chloroquine and pyrimethamine. The results are compared to the activities of 2-unsubstituted 4-amino-2-azabicyclo[3.2.2]nonanes.